CARDIOMYOPATHY A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2004 by ICON Group International, Inc. Copyright ©2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1 Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Cardiomyopathy: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84366-X 1. Cardiomyopathy-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on cardiomyopathy. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.
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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.
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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health
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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON CARDIOMYOPATHY .................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Cardiomyopathy............................................................................ 4 E-Journals: PubMed Central ....................................................................................................... 65 The National Library of Medicine: PubMed ................................................................................ 70 CHAPTER 2. NUTRITION AND CARDIOMYOPATHY....................................................................... 119 Overview.................................................................................................................................... 119 Finding Nutrition Studies on Cardiomyopathy......................................................................... 119 Federal Resources on Nutrition ................................................................................................. 126 Additional Web Resources ......................................................................................................... 126 CHAPTER 3. ALTERNATIVE MEDICINE AND CARDIOMYOPATHY ................................................ 129 Overview.................................................................................................................................... 129 National Center for Complementary and Alternative Medicine................................................ 129 Additional Web Resources ......................................................................................................... 135 General References ..................................................................................................................... 138 CHAPTER 4. DISSERTATIONS ON CARDIOMYOPATHY .................................................................. 139 Overview.................................................................................................................................... 139 Dissertations on Cardiomyopathy.............................................................................................. 139 Keeping Current ........................................................................................................................ 140 CHAPTER 5. CLINICAL TRIALS AND CARDIOMYOPATHY ............................................................. 141 Overview.................................................................................................................................... 141 Recent Trials on Cardiomyopathy.............................................................................................. 141 Keeping Current on Clinical Trials ........................................................................................... 156 CHAPTER 6. PATENTS ON CARDIOMYOPATHY ............................................................................. 159 Overview.................................................................................................................................... 159 Patents on Cardiomyopathy....................................................................................................... 159 Patent Applications on Cardiomyopathy ................................................................................... 182 Keeping Current ........................................................................................................................ 212 CHAPTER 7. BOOKS ON CARDIOMYOPATHY................................................................................. 213 Overview.................................................................................................................................... 213 Book Summaries: Federal Agencies............................................................................................ 213 Book Summaries: Online Booksellers......................................................................................... 214 Chapters on Cardiomyopathy..................................................................................................... 217 CHAPTER 8. PERIODICALS AND NEWS ON CARDIOMYOPATHY ................................................... 223 Overview.................................................................................................................................... 223 News Services and Press Releases.............................................................................................. 223 Academic Periodicals covering Cardiomyopathy ....................................................................... 228 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 229 Overview.................................................................................................................................... 229 U.S. Pharmacopeia..................................................................................................................... 229 Commercial Databases ............................................................................................................... 230 Researching Orphan Drugs ....................................................................................................... 231 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 235 Overview.................................................................................................................................... 235 NIH Guidelines.......................................................................................................................... 235 NIH Databases........................................................................................................................... 237 Other Commercial Databases..................................................................................................... 239 The Genome Project and Cardiomyopathy................................................................................. 239 APPENDIX B. PATIENT RESOURCES ............................................................................................... 245
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Overview.................................................................................................................................... 245 Patient Guideline Sources.......................................................................................................... 245 Associations and Cardiomyopathy............................................................................................. 249 Finding Associations.................................................................................................................. 251 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 253 Overview.................................................................................................................................... 253 Preparation................................................................................................................................. 253 Finding a Local Medical Library................................................................................................ 253 Medical Libraries in the U.S. and Canada ................................................................................. 253 ONLINE GLOSSARIES................................................................................................................ 259 Online Dictionary Directories ................................................................................................... 262 CARDIOMYOPATHY DICTIONARY ...................................................................................... 265 INDEX .............................................................................................................................................. 355
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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with cardiomyopathy is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about cardiomyopathy, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to cardiomyopathy, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on cardiomyopathy. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to cardiomyopathy, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on cardiomyopathy. The Editors
1
From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON CARDIOMYOPATHY Overview In this chapter, we will show you how to locate peer-reviewed references and studies on cardiomyopathy.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and cardiomyopathy, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “cardiomyopathy” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •
Uremic Cardiomyopathy: Reducing the Cardiac Burden in End-Stage Renal Disease Source: Journal of Critical Illness. 13(10): 613-615, 619-623. October 1998. Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Greenwich, CT 06831-0010. (203) 661-0600. Summary: Left ventricular (LV) hypertrophy and dilatation and systolic dysfunction are common in patients receiving hemodialysis and are associated with significantly decreased survival and increased morbidity. In this article, the authors discuss abnormalities of LV structure and function. They cover the diagnosis of uremic cardiomyopathy, review data on the prevalence and outcomes of LV dysfunction, and explore interventions relevant to the management of these patients. Echocardiography is the standard diagnostic tool for cardiomyopathy in patients with end-stage renal
4
Cardiomyopathy
disease (ESRD). The use of echocardiography to differentiate diastolic from systolic dysfunction can help guide patient management. With few controlled clinical trials specifically examining cardiomyopathy in uremic patients, management generally follows guidelines from studies in the general population. Aims of therapy are to improve quality of life by controlling symptoms of heart failure, ischemic heart disease, cardiac arrhythmias, and dialysis-associated hypotension; and to correct modifiable risk factors, such as hypertension, anemia, uremia, malnutrition, and aortic stenosis. Drug therapy requires great caution in this patient population, and should be begun only after careful consideration of risk and benefit. 1 figure. 6 tables. 38 references. (AA-M). •
Diabetic Cardiomyopathy: A Unique Entity or a Complication of Coronary Artery Disease? Source: Diabetes Care. 18(5): 708-714. May 1995. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This review article explores diabetic cardiomyopathy. The author notes that the three major factors in diabetic heart disease are coronary artery disease, autonomic neuropathy causing cardiac denervation, and diabetic cardiomyopathy. The article covers autopsy studies, animal studies, clinical studies, noninvasive and invasive human cardiac studies, the etiology of diabetic cardiomyopathy, and treatment issues. The author concludes that increased mortality from cardiac disease in the diabetic population is not entirely attributable to ischemic heart disease and may well be caused by diabetic cardiomyopathy. Treatment of diabetic cardiomyopathy should include glycemic control, use of appropriate antihypertensive therapy, and early detection and correction of myocardial ischemia. 79 references.
Federally Funded Research on Cardiomyopathy The U.S. Government supports a variety of research studies relating to cardiomyopathy. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to cardiomyopathy. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore cardiomyopathy. The following is typical of the type of information found when searching the CRISP database for cardiomyopathy:
2 Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
Studies
•
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Project Title: 4-DIMENSIONAL LV TISSUE TRACKING IN CAD FROM TAGGED MRI Principal Investigator & Institution: Amini, Amir A.; Assistant Professor; Barnes-Jewish Hospital Ms 90-94-212 St. Louis, Mo 63110 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2003 Summary: (Adapted from Applicant's Abstract): The applicants propose to develop and validate new image analysis methods aimed at a more accurate, reproducible, and automated approach to assessment of regional left ventricular (LV) function and visualization of 3D cardiac motion from tagged MRI data of patients with coronary artery disease (CAD). The applicants have developed a number of methods for analysis of tagged MRI data which have been validated in phantoms and animal models of myocardial infarction (MI). They propose to continue development of these techniques which utilize all of the available stripe information, including tag intersections and linear tag lines, in automatically taking LV deformations and reconstructing dense displacements at all myocardial points, with the goal of routinely applying these techniques to patient data. The advantage of the developed methods is that since displacement vectors will be available at all myocardial points, indices of LV function will also be available everywhere in the myocardium. These indices can be summed over local myocardial regions resulting in segmental function scores. In human studies, the developed methods will be applied to images acquired from normal volunteers, patients with pharmacologic stress-induced myocardial ischemia, patients with old, healed MI, and patients with ischemic dilated cardiomyopathy. In each case, segmental wall motion as assessed by the algorithms will be compared and correlated with validated clinical techniques such as 2D echocardiography, cine-MRI, and Gadolinium (Gd) contrast MRI. Thus, the specific aims are: (a) To measure statistical distribution (mean and standard deviation) of segmental function scores from 3D + t (short-axis and long-axis) tagged MRI at rest and under pharmacologic (dobutamine) stress in normal controls. (b) To measure the function scores as determined from 2D + t (short-axis) tagged MRI during pharmacologic stress and classified into normal, hypokinetic, or akinetic classes in patients with stress-induced ischemia. These labels will then be statistically correlated to labels assigned to the same segments by 2D echocardiography and cine-NIRI. (c) To measure segmental function scores as determined from 3D + t (short-axis and long-axis) tagged NIRI at rest and classified into normal, hypokinetic, akinetic, or dyskinetic classes in patients with an old, healed MI. The labels will be statistically compared to non-nal or akinetic labels assigned to the same segment from 2D echocardiography and cine-MRI, and with Gd contrast MRI. (d) To measure the segmental function scores from 3D + t (short-axis and long-axis) tagged MRI at rest and classified into normal, hypokinetic, akinetic, or dyskinetic classes in patients with ischemic, dilated cardiomyopathy. The labels will be statistically compared to labels assigned to the same segment from 2D echocardiography and cine-MRI. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: AGING, CARDIOMYOPATHY
INSULIN
RESISTANCE,
AND
DILATED
Principal Investigator & Institution: Shannon, Richard P.; Professor of Medicine; Allegheny-Singer Research Institute 320 E North Ave Pittsburgh, Pa 15212 Timing: Fiscal Year 2004; Project Start 15-JAN-2004; Project End 31-DEC-2008 Summary: (provided by applicant): Congestive heart failure is a leading cause of morbidity and mortality in the elderly, although the mechanisms to explain the
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Cardiomyopathy
enhanced proclivity are poorly understood. It remains debatable as to whether the ageassociated propensity to cardiovascular dysfunction is attributable to aging per se or the accumulation of cardiovascular risk factors that accrue over time. In particular, aging has been closely associated with the development of increased visceral adiposity that has been implicated in the pathogenesis of age associated insulin resistance. Whether age associated insulin resistance contributes to the progression of cardiac dysfunction following myocardial injury has not been explored systematically. The altered cellular actions of insulin that underlie physiological insulin resistance may have significant consequences to the failing heart. The injured myocardium develops an evolving dependence on glucose as its preferred metabolic substrate. The preference is dependent upon the efficiencies of oxidation of glucose in the generation of high-energy phosphates. This preference becomes a requirement as the ability to oxidized fat acids is limited through a series of molecular switches in key regulatory components of fatty acid transport and oxidation. We have determined that advanced, decompensated stages of dilated cardiomyopathy are associated with the development of myocardial insulin resistance, which limits myocardial glucose uptake and oxidation. These physiological features are associated with cellular insulin signaling abnormalities in the myocardium that are distinct from those observed in skeletal muscle and adipose tissue in other insulin resistant states. Together, aging and heart failure share the common pathophysiological features of insulin resistance. Whether the effects are additive or synergistic in explaining the increased incidence and severity of heart failure in the elderly remains to be determined. We will determine if aging is associated with accelerated progression of heart failure in conscious dogs with pacing induced dilated cardiomyopathy. We will define the physiological and cellular effects of insulin resistance in the senescent myocardium during the evolution of dilated cardiomyopathy. Finally, we will determine if overcoming myocardial insulin resistance in the aging and failing heart will prevent the progression of dilated cardiomyopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AKT CARDIOMYOPATHY
ACTIVATION
AS
TREATMENT
FOR
DILATED
Principal Investigator & Institution: Sussman, Mark A.; Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: (the applicant's description verbatim): Primary degenerative changes in the failing heart include remodeling associated with loss of structural organization and cardiomyocyte apoptosis. Optimal treatment strategies must approach the long term goal of a molecular approach that promotes myocardial integrity and inhibits apoptosis to prevent ventricular dilation. Myocardial pathogenesis is inhibited by activation of Akt kinase, although the potential therapeutic effect of Akt activation has never been examined in the context of dilated cardiomyopathy. Recent results have demonstrated nuclear translocation of activated Akt correlates with prevention of dilation in mouse transgenic models of cardiomyopathy. The hypothesis of this proposal is that nuclear translocation of activated Akt inhibits the initiation and progression of dilation and heart failure. Insulin-like growth factor-1 (IGF-1) or the cellular oncogene Tcl-1 initiate nuclear translocation of Akt. In addition, we have discovered similar Akt activation by genistein, a phytoestrogen compound found in soy-based dietary products that exhibits estrogen agonist properties. Innovative approaches to be used involve mice that are genetically engineered or pharmacologically treated to activate Akt, with concurrent experiments to demonstrate beneficial effects of Akt activation in rescuing a transgenic
Studies
7
mouse model of dilated cardiomyopathy. The specific aims are: 1) to reproducibly and precisely induce Akt activation by IGF-1, genistein treatment, and Tcl-l expression; 2) to prevent pathologic and degenerative changes by activation of Akt; 3) to show that beneficial effects of Akt activation are dependent upon induction of phosphoinositide 3kinase. Biochemical, molecular, and confocal microscopic approaches used in combination will demonstrate the efficacy of Akt activation by the various inductive stimuli as well as the impact of the different treatments upon the pathogenesis of dilation. The significance of the study is the identification and characterization of a therapeutic pathway for treatment of heart failure, along with new approaches for the activation of Akt in the heart. This study will demonstrate the relationship between Akt activation and inhibition of cardiomyopathy, providing novel directions for therapeutic treatment to induce Akt translocation and mitigate heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ALCOHOL MODULATION OF CARDIAC CALCIUM CHANNELS Principal Investigator & Institution: Aistrup, Gary L.; Mol Pharm & Biol Chemistry; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: Alcohol exerts a variety of actions on the cardiovascular system, the nervous system, and other organs. Clinical studies, have linked alcohol consumption with a number of asymptomatic and overt cardiovascular abnormalities, including cardiomyopathy, hypertension, arrhythmias, heart failure, and stroke. The mechanisms responsible for these various problems are not well understood. In the nervous system, voltage activated calcium channels and certain ligand-gated channels arc particularly sensitive targets of alcohol. These channels are suspected of being instrumental in acute intoxication and withdrawal. In cardiac tissues, calcium channels play a key role in rhythmicity, conduction, and excitation-contraction coupling. These channels are a major site of control by endogenous hormones and transmitters, and by therapeutic drugs. Calcium channels have been directly linked to a number of the actions of ethanol on the heart. Ethanol interferes with contractility in a variety of models, and it reduces electrically-stimulated calcium transients in ventricular myocytes. Our preliminary data with rat myocytes, and results from other laboratories, have confirmed that ethanol blocks L-type calcium channels in isolated cardiac cells. Defining how alcohol affects the physiology and regulation of these channels is essential in explaining immediate consequences of alcohol ingestion, as well as events that occur during prolonged periods of alcohol ethanol abuse. The overall objective of the proposed studies is to use whole-cell patch clamp techniques to analyze ethanol modulation of cardiac calcium channels. Ventricular myocytes will be dissociated from cardiac tissues of adult rats, and subjected to acute alcohol exposure. Biophysical and pharmacological experiments will evaluate calcium channel function under these conditions, and impossible mechanisms of channel modulation. Certain second messenger systems are known to exert regulatory control over calcium channel function in heart cells. Among these, the betaadrenergic/cAMP/PKA pathway is a critical mechanism for enhancing L-type calcium channels and stimulating cardiac contractility. We will therefore test the hypothesis that ethanol alters regulation of channels through this signal transduction system. Our preliminary data have shown that ethanol not only blocks currents stimulated via the beta-adrenergic system, but it also inhibits desensitization of the coupling process. We have also just completed exciting new preliminary studies demonstrating that ethanol is capable of reversing or occluding nifedipine-induced channel block. This novel action may have major implications, given the widespread clinical use of dihydropyridines
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Cardiomyopathy
and other calcium channel antagonists. Drug interactions of this type will be an important focus of the project. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANIMAL MODELS OF HYPERTROPHIC CARDIOMYOPATHY Principal Investigator & Institution: Robbins, Jeffrey; Professor and Director; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JUL-2003 Summary: (Adapted from the Investigator's Abstract) Familial hypertrophic cardiomyopathy, a major cause of sudden death, is caused by mutations in the genes encoding various components of the cardiac contractile apparatus. The applicant proposes to use a combination of molecular, genetic and functional approaches to understand the pathological processes that occur in the heart as a result of the expression of the mutant proteins in patients with FHC. Using the technique of cardiac specific transgenic overexpression, specific contractile protein isoforms in the cardiac compartment can be replaced in transgenic animals and thereby the functional consequences of the mutations over the lifetime of the animal can be established. Specifically, four constructs will be used, each of which contains a mutation in the sequence known to be associated with FHC:. ELC (essential light chain) (MET 149 VAL), MLC regulatory light chain (GLU 22 LYS), the ILE79ASN mutation in cardiac troponin T, and the truncation mutation in MHC binding protein C (delta 845-1189). The dosedependent consequences of the expression of these mutant proteins will be studied by analyzing multiple transgenic lines. A rabbit model of FHC will be generated using the two light chain constructs, since rabbit heart is more representative of the human organ. The data to be obtained from the rabbit lines when compared with the ongoing mouse studies will allow an assessment of the murine models applicability to the large animal heart and together these models should prove to be invaluable in increasing our understanding of how the primary genetic etiology contributes to the developing hypertrophic response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: ANNEXIN II EXPRESSION DURING CARDIOVASCULAR CELL INJURY Principal Investigator & Institution: Hajjar, Katherine A.; Professor & Chairman; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: Vascular cells within the heart and blood vessels are subject to an array of signals which induces adaptive responses for the maintenance of homeostasis. Because cardiomyocytes are incapable of self-renewal, the heart possesses limited means of responding to biochemical, inflammatory, oxidative, or ischemic stresses. Annexin II is a calcium- regulated, phospholipid-binding endothelial cell surface protein that serves as a co-receptor for endothelial cell derived tissue plasminogen activator and its circulating substrate, plasminogen. Purified annexin II stimulates the catalytic efficiency of plasmin generation by approximately 60-fold. We have developed an annexin II-deficient mouse and observed that these animals develop a degenerative cardiomyopathy with impaired myocardial function. We have further observed that, in endothelial cells propagated in vitro, annexin II is exported to the cell surface via a non- classical secretion pathway in response to stress. The overall goal of this project is to understand the role of annexin II in cardiac function both at baseline and during states of cellular stress. We hypothesize
Studies
9
that annexin II may play a critical cardioprotective role by maintaining the integrity of the myocardial microvascular circulation. Aim I will to determine the cardiovascular consequences of annexin II deficiency in mice. Using our recently developed annexin II knockout mouse, we will study the mechanism by which annexin II deficiency may lead to reduced myocardial contractility, abnormal ventricular architecture and cardiac arrthymia. Aim II will be able to determine the mechanism by which annexin II participates in the endothelial cell stress response. Preliminary data indicate that heat shock and other endothelial stresses lead to protein synthesis-independent, rapid release of annexin II to the cell surface with a concomitant increase in cell surface fibrinolytic activity. This export process does not require an intact endoplasmic reticulum-Golgi axis, and is inhibited by PD98059, an agent that blocks activation of the Erk1/Erk2 MAP kinase signaling cascade. We plan to elucidate this export mechanism and to determine its effect on endothelial cell function. Aim III, finally, will e to determine whether annexin II is cardioprotective during cardiovascular stress states in vivo. Annexin II has been found to be up-regulated in the hearts of humans and animals with cardiac dysfunction. Using models of acute, subacute and chronic stress induced by adrenergic stimuli, exercise, heat stress, biome3chanical compromise, or oxidant agents, we will determine whether annexin II protects against cardiovascular compromise. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: APOPTOSIS CARDIOMYOPATHY
AND
CONTRACTILITY
IN
ISCHEMIC
Principal Investigator & Institution: Canty, John M.; Professor; Medicine; State University of New York at Buffalo Suite 211 Ub Commons Amherst, Ny 14228 Timing: Fiscal Year 2002; Project Start 10-JAN-2000; Project End 31-DEC-2003 Summary: Ischemic cardiomyopathy is the most common etiological cause of heart failure but the factors responsible for initiating decompensated LV dysfunction are unknown. Although considerable work has focused on irreversible injury following infarction, many patients have symptoms of heart failure in association with viable dysfunctional or "hibernating" myocardium. Pathological studies support the notion that the degree of dysfunction frequently exceeds the amount of structural fibrosis identified at postmortem exam. Preliminary studies by the applicant have reproduced the physiological features of hibernating myocardium in pigs with a chronic LAD stenosis. While this occurs with normal LV function and without infarction, there is increased regional myocyte apoptosis, a 30 percent loss of myocytes and compensatory myocyte hypertrophy after a period of 3 months. At the molecular level, there is a regional downregulation of SR calcium uptake proteins. These changes, arising from reversible ischemia (i.e. angina pectoris) and with normal global LV function, are identical to the abnormalities found in end-stage heart failure. Thus, the overall hypothesis of this application is that myocyte apoptosis and SR dysfunction arise in areas with chronically reduced coronary flow reserve and are early rather than late events in the pathogenesis of ischemic cardiomyopathy. Aim 1 will define the role of apoptosis mediated myocyte loss and LV remodeling from reversible ischemia in hibernating myocardium. A 2-vessel stenosis model that progresses to global LV dysfunction with LV dilatation and increased LV filling pressure will be used to determine how diastolic stretch and the size of the dysfunctional region modulates apoptosis and LV remodeling. Aim 2 will identify the temporal progression of apoptosis in ischemic and normal regions in relation to the expression of the pro- and antiapoptotic proteins Bax and Bcl-2 which will be quantified in vivo on a regional basis. Aim 3 will define the extent that apoptosis mediated myocyte loss and altered SR
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Cardiomyopathy
protein expression affects the reversibility of function in hibernating myocardium after surgical revascularization and after stimulating angiogenesis with basic fibroblast growth factor (FGF-5). Aim 4 will determine whether apoptosis and altered SR protein expression can be prevented pharmacologically with beta blockade, by stimulating angiogenesis prior to the development of myocyte loss and by overexpressing Bcl-2 in vivo. This integrative approach should provide a better understanding of the events that lead to the progression of ischemic LV dysfunction at a time when therapeutic interventions such as revascularization and in vivo gene transfer can be used to interrupt the progressive myocyte loss, contractile dysfunction and irreversible structural fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BETA-ADRENERGIC HYPERTROPHY/FAILURE
RESPONSE
IN
CARDIAC
Principal Investigator & Institution: Bond, Meredith; Professor and Chair; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 01-JAN-1997; Project End 31-MAY-2005 Summary: (provided by applicant): Alterations in the signal transduction pathways which regulate Ca2+ dependent force in the heart contribute to the impaired contractile function in heart failure. These functional changes are likely to be mediated by altered phosphorylation of cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) substrates. One of the major PKA/PKC substrates in the cardiac muscle cell is the thin filament regulatory protein, troponin I (TnI). As a result of conformational changes in the TnI molecular upon phosphorylation of the different PKA and PKC sites TnI, interactions between TnI with other proteins of the thin filament - and thus contractile function - are altered. In other words, TnI and its phosphorylation fingerprint represent a critical control point in the pathway regulating contractile state as a function of the incominb Ca2+ signal. We have shown that PKA phosphorylation of TnI is decreased by 25% in human heart failure. This results in increased Ca2+ affinity of troponin C (TnC), and may contribute to enhanced myofilament Ca2+ sensitivity, and prolonged relaxation of failing hearts. In contrast, PKC is reportedly increased in failing hearts; increased PKC phosphorylation of one or more sites on TnI decreases maximal actomyosin (AM) ATPase activity and thus could also contribute to impaired contraction in heart failure. However, reports on the effect of elevated PKC activity on TnI phosphorylation and cardiac function are conflicting. Finally, activity of protein phosphatases - protein phosphatase 1 (PP1) and/or PP2A - will also determine the phosphorylation state of TnI. In Specific Aim 1, we will identify the complete phosphorylation profile of TnI in failing human hearts with dilated cardiomopathy (DCM) and compare this with non-failing hearts. Electrospray ionization mass spectrometry (ESI/MS) will be used to quantify stoichiometry of the phosphorylated residues in tryptic digests of TnI obtained from failing and non-failing hearts, by a rapid one-step isolation to trop the in vivo phosphorylation state. In Specific Aim 2, we will (a) examine conformational changes that result from the combined changes of PKC and PKA phosphorylation of TnI in failing vs non-failing hearts. This will be achieved by measurement of fluorescence quenching tryptophan residues in cTnI, with selected serines and threonine mutated to aspartates or alanines, then reconstituted with human cardiac TnT and TnC. (b) The functional consequences of altered TnI phosphorylation will be assessed by measurement of Ca2+ dependent force in skinned cardiac trabeculae from failing and non-failing hearts. Specific Aim 3 will test the hypothesis that activity of TnI targeted phosphatases is altered in failing hearts. These studies should provide
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new information on the complete complement of changes in PKA and PKC-dependent TnI phosphorylation in human heart failure. Structural and functional outcomes of these changes plus identification of the altered phosphatase activity will shed light on mechanisms responsible for the functional decline in heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOMEDICAL STRESS PATHWAYS AND CARDIOMYOPATHY Principal Investigator & Institution: Chien, Kenneth R.; Professor; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 25-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): The interaction between biomechanical stimuli, such as pressure and volume overload, with discrete hypertrophy, survival, and cell death pathways, plays an important role in the initiation of cardiomyopathy and heart failure. Project 1, ?Biomechanical Stress Pathways and Cardiomyopathy? (K.R. Chien), focuses on molecular pathways that mediate biomechanical stress-induced cardiac responses, based on new genetic pathways for cardiac hypertrophy and cardiomyopathy. The project utilizes unique genetically engineered animal models and novel physiological technology to dissect complex phenotypes in living animals, cardiac papillary muscle preparations, and single cardiac myocytes. Continuing our longstanding interest in pg130 pathways for cardiac hypertrophy and myocyte survival, we have recently identified a downstream component (SOCS3) in the gp130 pathway as being rapidly and markedly induced following in vivo pressure overload. SOCS3 is part of a stressinducible negative feedback loop that prevents the hyper-stimulation of the gp130 pathway. These studies will examine the role of SOCS3 inhibition as a new therapeutic strategy to promote myocyte survival and to prevent the onset of diverse forms of cardiomyopathy. In continuation of our previous studies on the role of mutations in the Z disc protein MLP in dilated cardiomyopathy, we have recently identified MLP as part of the endogenous titin-telethonin complex. This MLP-telethonin interaction is critical for the maintenance of the stretch induced hypertrophy response. We have recently uncovered a mutation in MLP that is associated with human dilated cardiomyopathy in patients with idiopathic forms of the disease. The point mutation results in a severe charge change in a highly conserved residue in the telethonin interacting domain of MLP located in the aminoterminus and interrupts the ability of MLP to interact with telethonin, a known genetic cause of human cardiomyopathy. Similarly, we have identified patients with a deletion in the MLP interacting domain of telethonin. Accordingly, the specific aims are: 1) to identify the effects of the SOCS3 negative feedback loop on cardiac hypertrophy, myocyte survival, and cardiomyopathy in multiple model systems via studies of cardiac restricted SOCS3 KO mice; 2) to directly examine the effects of human mutations in MLP on biomechanical stretch responses and specific features of dilated cardiomyopathy; and 3) to examine the effects of mutations in specific domains of telethonin and telethonin phosphorylation on MLP binding, stretch activation responses, and dilated cardiomyopathy in genetically engineered mouse model systems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CALCIUM CYCLING AND REGULATION OF THE CARDIAC AP Principal Investigator & Institution: Winslow, Raimond L.; Professor; Biomedical Engineering; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-MAY-1998; Project End 31-MAR-2006
12
Cardiomyopathy
Summary: Dilated cardiomyopathy (DCM) is the most common form of primary cardiac muscle disease, with prevalence estimated at 36.5 cases per 100,000. DCM is characterized by ventricular dilation, decreased myocardial contractility and cardiac output, and increased risk of sudden cardiac death. Ventricular myocytes isolated from failing hearts exhibit changes in expression levels of proteins involved in repolarization of the action potential (AP) and intracellular calcium (Ca2+) cycling. These changes are accompanied by reduction of junctional sarcoplasmic reticulum (JSR) Ca2+ concentration, peak intracellular Ca2+ transient amplitude, slowed diastolic Ca2+ extrusion and prolongation of AP duration. We have previously formulated a "minimal" computational model of the failing canine ventricular myocyte that incorporates experimental data on down-regulation of potassium (K+) currents and the SR Ca2+ATPase, and up-regulation of the Na+-Ca2+ exchanger. This model is able to qualitatively reconstruct changes in AP and Ca2+ transient morphology observed in failing myocytes. Model simulations predict that down- regulation of the SR Ca2+ATPase by itself produces significant prolongation of AP duration by reducing JSR Ca2+ level, JSR Ca2+ release and the magnitude of Ca2+-dependent inactivation of L-type Ca2+ current (ICa,L). This decreased Ca2+-dependent inactivation increases ICa,L during the plateau phase, thereby increasing AP duration. These model predictions are supported by results of preliminary experiments. This has led us to hypothesize that JSR Ca2+ level through effects on JSR Ca2+ release and Ca2+-dependent inactivation of ICa.L, modulates AP duration, and that this modulation is important under a range of conditions producing changes in JSR Ca2+ level, including heart failure. The general goal of the proposed research is to test this hypothesis by means of experiments coupled with computational modeling. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CALMODULIN CARDIOMYOPATHY
KINASE
AND
ARRHYTHMIAS
IN
Principal Investigator & Institution: Anderson, Mark E.; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Arrhythmias cause 50% of deaths in patients with cardiomyopathy and heart failure. Recent findings have highlighted the importance of Ca2+-activated kinases and phosphatases in activating gene programs driving morphological and functional changes in cardiomyopathy. One focus of our previous studies has been the arrhythmogenic potential of Ca2+/calmodulin-activated protein kinase (CaMK) II in normal cardiomyocytes with drug-induced action potential prolongation. More recently, we have developed evidence for an arrhythmogenic phenotype in cardiomyopathy that consists of increased CaMKII expression and activity, action potential and QT interval prolongation, disordered intracellular Ca2+ homeostasis, and arrhythmias or sudden death. The goal of this Project is to test the hypothesis that CaMKII is a molecular link between functional and morphological phenotypes, and thus a contributor to arrhythmia susceptibility in cardiomyopathy. To accomplish this goal, two distinct and well-characterized mouse models with cardiomyopathy, increased CaMKII activity, and arrhythmias will be interbred with mice that we have developed with cardiac-specific expression of a CaMKII inhibitory protein, or an inactive control. Using these tools, we will determine the effect of chronic CaMKII inhibition on the arrhythmogenic and the morphological and functional phenotypes in cardiomyopathy. To further understand the mechanisms underlying the salutary effects of CaMKII inhibition, we will determine the effect of chronic, cardiac-
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targeted CaMKII inhibition on potential downstream signaling pathways. These experiments will target an arrhythmogenic molecular mechanism and build from single molecule assays to biochemical, histological, and functional studies in the whole heart. Delineation of the role of CaMKII in arrhythmogenesis will be an important step in developing new antiarrhythmic therapies in patients with heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CARDIAC DISEASE IN COOLEYS ANEMIA--MOLE AND CLIN STUDIES Principal Investigator & Institution: Brittenham, Gary M.; Professor of Medicine; Anatomy and Cell Biology; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 30-SEP-1998; Project End 31-JUL-2004 Summary: The proposed research project is designed to characterize the molecular pathophysiology and clinical consequences of iron-induced cardiac disease using a coordinated series of studies of cardiac myocytes in culture, of the first animal model of the cardiomyopathy of iron overload, and of patients with thalassemia major. Ironinduced myocardial disease is the most frequent cause of death in thalassemia major and is a major life-limiting complication of other transfusion- dependent refractory anemias hereditary hemochromatosis and other forms of iron overload. We hypothesize that (i) the body iron burden is a principal determinant of the magnitude of cardiac iron deposition in patients with thalassemia major, (ii) the nonuniform pattern of iron deposition in the heart results in variability in iron concentrations within cardiac myocytes, and (iii) the increased intracellular iron selectively affects specific ion channels in cardiac myocytes, producing abnormalities in sodium and potassium currents that result in aberrant ventricular repolarization and contribute to arrhythmogenesis. The proposed research has three specific aims: (1) to determine the pathophysiologic mechanisms responsible for iron-induced abnormalities of Na+ and K+ currents in cultured neonatal rat cardiac myocytes and the effects of iron chelators, antiarrhythmic drugs and other agents; (2) to examine the effects of excess iron, iron chelators, antiarrhythmic drugs and other agents on cardiac electrophysiology and function in a gerbil model of iron overload both in the intact animal and in isolated heart preparations; and (3) to determine the relationship in patients with thalassemia major between body iron burden, as measured by non- invasive magnetic susceptometry, and abnormalities of cardiac rhythm and function, as assessed as assessed by the signalaveraged electrocardiogram, T wave alternans, dynamic measures of the QT interval and echocardiography. This research will result in new fundamental information about the molecular basis for the effects of iron on cardiac ion channels, will provide the first electrophysiolgical and functional studies in a new animal model of iron overload, and will develop new non-invasive means of identifying those patients at the highest risk for iron-induced cardiac disease to permit intensive iron chelation therapy and other preventive interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CARDIAC REGULATION
HYPERTROPHY
INDUCED
METABOLIC
GENE
Principal Investigator & Institution: Barger, Philip M.; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 08-APR-1998; Project End 31-MAR-2003
14
Cardiomyopathy
Summary: Cardiac hypertrophy and congestive heart failure are significant causes of morbidity and mortality in the United States. The human heart undergoes hypertrophic growth in response to pathophysiologic stimuli such as chronic hypertension and valvular disease. The transition from normal to hypertrophied ventricle is marked by characteristic molecular phenotypic changes, including a switch in the energy metabolic gene regulatory program from predominantly fatty acid beta-oxidation (FAO) to the more oxygen-efficient glycolysis, a reactivation of fetal metabolism. Little is known about the hypertrophy signaling pathway linked extracellular stimulus to transcriptional regulation. The broad goals of this proposal are to delineate the molecular regulatory signals which ultimately contribute to down-regulation of FAO during hypertrophy. This proposal is specifically designed to i) characterize alterations in fatty acid beta-oxidation gene transcription in cultured rat neonatal cardiocytes undergoing hypertrophy and to delineate the specific cis-acting elements mediating that response utilizing Northern and Western blot analysis, RNase protection, and transient gene transfer studies with FAO enzyme gene promoters; ii) identify the specific transcriptional regulators that bind to the responsive elements in the promoters of betaoxidation genes during cardiocyte hypertrophy utilizing electrophoretic mobility shift assay, cotransfection, Northern and Western blot analysis, RNase protection, and immunofluorescence; iii) determine whether the activity of the regulators are increased during hypertrophy by phosphorylation events utilizing in vitro and in vivo phosphorylation studies, inhibitors of known signal transduction cascades, and phosphorylation site mutations with emphasis on the mitogen-activated protein kinase pathway. The longterm goals will be to determine whether reactivation of this fetal metabolic gene program and/or downregulation of fatty acid beta-oxidation leads to a maladaptive hypertrophied phenotype and thus promotes the transition to heart failure. If so, the studies outlined above will have identified potential targets for therapeutic interventions aimed at delaying or even preventing progression to end-stage cardiomyopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CARDIAC KATP CHANNELS IN HEALTH AND DISEASE Principal Investigator & Institution: Terzic, Andre; Professor of Medicine and Pharmacology; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2004; Project Start 01-APR-2000; Project End 31-MAR-2008 Summary: (provided by applicant): Cardiac ATP-sensitive K (KATP) channels, formed by the pore-forming Kir6.2 and regulatory SUR2A subunits, are characterized by nucleotide-dependent regulation that allows the channel complex to adjust membrane excitability in response to changes in the cellular energetic state. However, it is unknown how cardiac KATP channels translate nucleotide signals into pore gating, what is the full impact of channel activity on cardiac homeostasis, and ultimately whether channel defects contribute to heart disease. In the previous funding period of this proposal we identified an ATPase activity intrinsic to the SUR2A subunit, demonstrated that deficient KATP channel function reduces cardiac tolerance to adrenergic challenge, and discovered KATe channel mutations in initial screening of patients with heart failure. Based on these findings, we here put forward the novel concept that cardiac KATP channels operate as a bi-functional channel/enzyme molecular combination serving a vital role under diverse stressors. Aim #1 will define the molecular mechanisms governing the SUR2A catalysis-based nucleotide gating of the Kir6.2 pore. Aim #2 will establish the impact of KATP channels on prevention of maladaptive structural remodeling, and preservation of energetic and electrical stability
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in the physiologically and pathologically stressed myocardium. Aim #3 will determine the spectrum of cardiac KATP channel mutations in patients with idiopathic dilated cardiomyopathy, and define the consequences of these mutations on the KATP channel/enzyme phenotype, metabolic sensing and cell adaptation to stress. To this end, we will employ murine knockout and disease models, along with genomic specimens from an existing cohort of patients with cardiomyopathy. The complementary technologies of enzymology, electrophysiology, physiological genomics, high-throughput DNA screening and functional proteomic analysis will be applied to study the cardiac KATP channel at the organism, organ, cellular and molecular levels. Thus, this proposal will provide an integrated understanding of cardiac KATP channels in metabolic signal decoding, stress adaptation, and their impact for clinical medicine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CARDIOMYOPATHY IN DIABETES Principal Investigator & Institution: Lewinter, Martin M.; Professor of Medicine and Molecular Phys; Medicine; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: Patients with diabetes mellitus (DM) are subject to a high incidence of death and morbidity due to heart failure, especially following myocardial infarction (MI). These observations suggested and subsequent studies confirmed the presence of a diabetic cardiomyopathy (DBCM), indepenent of macrovascular CAD. In experimental DBCM, multiple mechanial abnormalities and potential mechanisms have been documented. However, the manifestations and mechanisms of DBCM in patients are not well understood. Using strips of myocardium obtained from patients with CAD and DM (CAD/DM) undergoing coronary bypass grafting, we have recently shown depression of the force-frequency relationship (FFR despite the fact that basal ventricular function was normal. This myocardial abnormality in CAD/DM is similar but less severe than that observed in dilated cardiomyopathy and mitral regurgitation and is reversible by forskolin, indicating that its proximate mechanism is likely a defect(s) in excitation-contraction coupling (ECC). This proposal has three aims, to be undertaken in CAD/DM patients and CAD controls: 1) delineate whether there is an in vivo counterpart of in vitro FFR depression in CAD/DM, 2) systematically study the processes involved in ECC in CAD/DM and determine if identified defects cause FFR depression, and 3) test for correlations between abnormal FFR/ECC and markers of both the metabolic effects of DM and associated vasculopathy in order to begin to characterize upstream mechanisms of DBCM. Patients will be recruited at both the University of Vermont and the New York Hospital-Cornell Medical Center. We will employ an integrated, collaborative approach including in vivo and in vitro determination of the FFR, in vitro quantification of ECC, and assessment of defects in glycolysis and vasculopathy in DM myocardium. A major strength of our experimental strategy is correlation, on an individual patient basis, of in vitro FFR depression with other variables of interest. Our long- term plan is to define the steps linkin abnormal carbohydrate metabolism and/or vasculopathy in DM to DBCM and ultimately design rational treatments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Cardiomyopathy
Project Title: CARDIOMYOPATHY:PRO-OXIDANT ROLE OF AZT & MGDEFICIENCY Principal Investigator & Institution: Weglicki, William B.; Professor and Chair; Medicine; George Washington University 2121 I St Nw Washington, Dc 20052 Timing: Fiscal Year 2002; Project Start 01-MAY-2000; Project End 31-MAR-2004 Summary: (Abstract): The pathogenesis of HIV-related cardiomyopathy remains unclear and most likely may have multifactorial causes. Clinical data have revealed that both the virus and myocarditis are present, but often in separate areas, suggesting that HIV may play an indirect cytotoxic role. Both the HIV infection and drug therapy (AZT, pentamidine) may contribute to oxidative stress and Mg wasting. Clinical studies have indicated that HIV/AIDS patients may be deficient in Mg. In our studies, we have documented that Mg-deficiency triggers oxidative cardiomyopathic inflammation. We hypothesize that the drug therapy with AZT may synergize with pentamidine and Mgdeficiency to initiate neurogenic inflammatory events leading to oxidative stress and eventual cardiomyopathy. To test this hypothesis, we propose to use a rat model and cultured cardiovascular cells to determine the prooxidant effects of AZT (Aim 1) or with co-existing Mg-deficiency to induce cardiomyopathy, and cardiac dysfunction with imposed ischemia/reperfusion (I/R) stress (Aim 2). We will assess the therapeutic interventions by NMDA and NK-1 receptor blockade and by vitamin E (Aim 3). In collaboration with Dr. A. Basile of NIH, we will also employ the murine AIDS (MAIDS) model to assess the synergistic contributions of the virus and Mg-deficiency to the oxidative pathogenesis and possible interventional therapy (Aim 4). We will employ sensitive immunochemical techniques to quantify neuropeptides and cytokines, and in collaboration with Dr. Haudenschild of the American Red Cross Holland Laboratory, to characterize histopathological progression in cardiac and skeletal muscles. Oxidative stress will be determined by measuring tissue glutathione and thiol status, accumulation of lipid peroxidation and nitric oxide products, and by free radical production and injury to isolated perfused I/R hearts. We anticipate that the information from these in vivo animal, tissue, and cellular studies may lead to potential diagnostic criteria and therapy for patients at risk of developing cardiomyopathy due to HIV disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CHARACTERIZING RGS MUTATIONS IN CARDIOMYOPATHY Principal Investigator & Institution: Kurrasch-Orbaugh, Deborah M.; Pharmacology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-OCT-2003 Summary: (provided by applicant): The hypothesis of this proposal is that the RGS 16 protein is an integral component of the G-alpha-q/11 signaling complex, serving as a feedback inhibitor of G-alpha-q/11 signaling in stressed cardiomyocytes, thus helping to maintain cardiac homeostasis. We propose that a point mutation in the RGS box of RGS16 (D179Y) found in patients with dilated cardiomyopathy alters the conformation of the interaction surface with G-alpha-q/11 and/or other proteins in the signaling complex, rendering RGS16 D179Y to function as a dominant negative protein, ultimately contributing to dilated cardiomyopathy. To test this hypothesis, we shall explore the following specific aims: Aim 1. We shall examine the GAP and potential dominant negative activity of D179Y and wild type RGS16 proteins in several in vitro assays, including single-turnover assays, transition-state analog binding assays, and G-alpha-q Coupled steady state assays, and G-alpha-q -coupled MAPK activation; Aim 2. We will overexpress D179Y and RGS 16 proteins specifically in cardiomyocytes by employing
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the alpha-MHC promoter in transgenic mice and then characterize the onset of cardiomyocytes hypertrophy; Aim 3. We will create Rgs 16 D179Y knock-in mice and characterize the onset of dilated cardiomyopathy; Aim 4. We will continue to screen cardiac patients and healthy individuals to identify additional Rgs mutation. The primary objective of this proposal is to evaluate the causative role of the D179Y allele of RGS16 in the progression of dilated cardiomyopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CLINICAL EVALUATION OF NOVEL MARKERS OF MI Principal Investigator & Institution: Gerszten, Robert E.; Assistant Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 25-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Presently available serum markers of cardiac injury, such as the troponins, were developed as extensions of studies of these candidate proteins in basic cardiac physiology. In this proposal, we will test the following hypotheses: 1) That analysis of serum proteins from patients undergoing "planned myocardial infarction (PMI)," using unbiased proteomics technologies, will lead to the discovery of both novel markers of cardiac injury and novel serum response proteins which shed insight onto disease pathogenesis; 2) That novel markers and response proteins discovered in the setting of PMI will be valid in a heterogeneous population of myocardial infarction (MI) patients; and 3) That levels of novel markers and response proteins discovered in PMI will predict clinical outcomes in the heterogeneous MI population. Towards the goal of developing new cardiac markers, we first characterized serum from patients undergoing an alcohol septal ablation for hypertrophic cardiomyopathy, an in vivo model of human MI. In this population, we have identified peptide spectra and specific proteins that appear in the serum after myocardial injury. However, findings from this controlled patient subset must be validated in a heterogeneous patient cohort. Therefore, we will apply our preliminary data from the PMI group to the CLARITY-TIMI 28 trial, a large, double-blind, randomized clinical trial studying patients with acute ST elevation myocardial infarction (STEMI). In Specific Aim 1, we will characterize the recently identified peptide markers in the entire cohort of PMI patients. In Specific Aim 2, we will validate the novel markers in a diverse patient population of "normal myocardial infarction" in the TIMI trial. In Specific Aim 3, we will correlate elevations in novel protein markers and response proteins with outcomes in patients with acute MI in the TIMI trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CONTRAST MRI AND CHRONIC MYOCARDIAL INJURY IN HUMANS Principal Investigator & Institution: Kim, Raymond J.; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 15-FEB-2001; Project End 31-DEC-2005 Summary: (Verbatim from the Applicant's Abstract): Two important changes regarding contrast enhanced MRI (ceMRI) of the heart have recently occurred. First, it is now recognized that segmented k-space inversion-recovery imaging pulse sequences result in image intensities in "hyperenhanced" regions which are typically 500 percent higher than in "non hyperenhanced" regions, greatly reducing observer subjectivity. Second, recent data suggest that healed myocardial infarcts hyperenhance. In preliminary studies, the applicants found that ceMRI detects both acute and chronic infarcts with a
18
Cardiomyopathy
sensitivity approaching that of serum assays for cardiac enzymes. Unlike cardiac enzymes which are cleared from the blood in a few days, however, ceMRI provides a permanent record of infarction, localizes the infarct to a specific coronary artery territory, and can be combined with cine MRI to document the effect of the infarct on wall motion with perfect registration. In addition, preliminary results suggest that hyperenhancement may be specific for ischemic injury. The applicant studied patients with non-ischemic cardiomyopathy determined by coronary angiography. Despite profound ventricular dysfunction, hyperenhancement was not observed in these patients. Detailed analysis of the data from patients with ischemic and non-ischemic cardiomyopathy strongly suggested that, for patients with ischemic disease, the presence or absence of irreversible injury. To investigate this further, the applicants examined wall motion in patients before and after revascularization by CABG or PTCA. For the 804 segments with a baseline wall motion abnormality, the likelihood of recovery of wall motion after revascularization was strongly predicted by the presence or absence of hyperenhancement. These preliminary data underscore that ceMRI in combination with cine MRI can provide detailed diagnostic information. The applicants propose to establish the sensitivity of ceMRI to detect chronic infarction in patients (Aim 1), to test the hypothesis that recovery of wall motion following revascularization is predicted by ceMRI (Aim 2), and determine if ceMRI can distinguish between patients with ischemic and non-ischemic cardiomyopathy (Aim3). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--CHEMISTRY Principal Investigator & Institution: Han, Xianlin; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Numerous animal studies have demonstrated that the diabetic states induces a fatty acid-based metabolic dysfunction which has complex effects on multiple endorgan systems. Both accelerated atherosclerosis and diabetic cardiomyopathy are the major etiologic agents in the excessive cardiovascular mortality and morbidity present in diabetic patients. A central theme in diabetic cardiovascular disease is the dysfunctional accumulation of lipids in multiple critical cell types. The proposed research in the component projects focuses on the role of alterations in peroxisomal regulatory proteins (e.g., peroxisomal phospholipases) and proliferative elements (e.g., PPARalpha and PPARgamma) which accelerate atherosclerosis and predispose critical cells in the cardiovascular system to maladaptive metabolic alterations. Core A of the program project embodies five major technical advances either made in our early research or developed in the current chemistry Core. Provision of lipid-analytical, synthetic, and proteomic services to the component projects will facilitate the costeffective accrual of vital scientific information for the elucidation of the molecular mechanisms underlying altered lipid metabolism in the diabetic state. The Core will offer a wide variety of state-of-the-art analytic (mass spectrometry, evaporative light scattering detection (ELSD), fluorescence spectrometry, quantitative PCR) and synthetic (chiral BEL, fluorescence probe for real-time PLA2 assays) expertise. Specifically Core A will perform: 1) analysis of polar and neutral lipid individual molecular species including free fatty acids, triacylglycerides, cholesterol, acylcarnitines, and all types of phospholipids from biological sources using state-of-the-art ESI/MS and ELSD with sensitivity at the subpicomole to picomole range; 2) proteins sequencing and protein post- translational modification determinations utilizing LC/MC (proteomics); 3) the synthesis of the iPA2 suicide inhibitor (i.e., BEL) and its resoled enantiomers which
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selectively inhibit iPA2beta dn iPLA2gamma; 4) real-time PLA2 activity assays utilizing novel fluorescence substrates we have developed; and 5) quantitative PCR utilizing Taqman methodology. As it has done during the current grant interval, the Core will continue to provide methodologic advances to facilitate the study of lipid and protein alterations in the diabetic state (see Progress Report). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CYTOKINES CARDIOMYOPATHY
AND
LV
RECOVERY
IN
RECENT
ONSET
Principal Investigator & Institution: Mcnamara, Dennis M.; Director, Heart Failure Research Program; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 31-MAR-2007 Summary: (provided by applicant): For patients presenting with the recent onset of primary dilated cardiomyopathy, the presence of myocardial inflammation may suggest a potentially self limited and reversible process, and patients with acute "myocarditis" may actually have a better probability of left ventricular recovery than those with more chronic disease. The poor sensitivity of endomyocardial biopsy has limited its clinical utility, and circulating plasma cytokines are potentially more sensitive indicators of a reversible myocardial inflammatory process. This proposal will investigate the hypothesis that the assessment of plasma cytokines in recent onset dilated cardiomyopathy, can help to prospectively delineate patients with greater likelihood of myocardial recovery. Specific Aim 1 will assess the correlation of baseline plasma cytokine levels (TNFa, TNF receptors, and IL-6) with echocardiographic measures of left ventricular systolic and diastolic function. The study will enroll 120 patients with recent onset idiopathic dilated cardiomyopathy or myocarditis with an LVEF less than or equal to 0.40. This will evaluate the hypothesis that plasma cytokines in recent onset cardiomyopathy are markers of cardiac inflammation and will correlate with more profound perturbations of myocardial function. Specific Aim 2 will evaluate the hypothesis that patients with more active myocardial inflammation (higher plasma TNFa) upon presentation, are more likely to have significant recovery of left ventricular systolic function at 12 month follow up. Echocardiographic assessment will be repeated at 6 and 12 months after entry. In addition we will evaluate the hypothesis that patients with higher plasma IL-6 levels will have a poorer event free survival during subsequent follow up. Specific Aim 3 will explore the hypothesis that polymorphisms of cytokine genes, in particular those in the TNFa and IL-6 promoters, will effect levels of their respective mediators, and will subsequently influence clinical outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CYTOSKELETAL INTERACTIONS OF DYSTROPHIN Principal Investigator & Institution: Ervasti, James M.; Professor; Physiology; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 15-JUL-1994; Project End 31-MAR-2005 Summary: (Verbatim from the Applicant's Abstract): The objective of this project is to determine the cytoskeletal interactions of the dystrophin-glycoprotein complex in the skeletal muscle to understand how its absence or abnormality leads to Duchenne (DMD) and Becker (BMD) muscular dystrophies and some forms of cardiomyopathy. Rather than just simply serving to anchor its associated glycoprotein complex to the cortical actin, our previous studies lead us to hypothesize that dystrophin also plays an
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important role in stabilizing the cortical cytoskeleton through an extended lateral association with actin filaments. We further hypothesize that the dystrophin homologue utrophin is missing an actin binding suite important for F-actin stabilization. These hypotheses will be tested, both in vitro and in vivo, through the pursuit of 3 complementary specific aims. The F-actin binding properties of full-length and truncated forms of recombinant dystrophin and utrophin will be measured by established biochemical and spectroscopic procedures (Aim 1). Completion of this aim will yield the first direct structure/function comparison for dystrophin and utrophin up-regulation to effectively compensate for dystrophin deficiency. Recombinant dystrophin/utrophin will be visualized alone and in complex with actin filaments using electron microscopy combined with three-dimensional reconstruction techniques (Aim 2). These studies will yield important new information about the shape, dimensions and flexibility of dystrophin and utrophin and will independently determine how much (and which sub-domains) of dystrophin lie in close apposition with F-actin. Analysis by three-dimensional reconstruction will also identify changes in actin monomer and filament structure that may lead to more stable association of other costameric proteins with F-actin. Finally, we will relate the in vitro features of the dystrophin/F-actin interaction with its role in stabilizing costomeric actin in vivo (Aim 3). Sarcolemmal membranes will be mechanically isolated from muscles of transgenic mdx mice expressing dystrophin constructs deleted in different domains and the status of costameric actin determined by confocal microscopy. We will also determine whether the absence of dystrophin results in an unstable sarcolemmal association of other costameric actin binding proteins. Completion of these aims will result in a highly detailed and integrated understanding of dystrophin's role in stabilizing the muscle membrane cytoskeleton through its interaction with cortical actin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DEVELOPMENT AND MAINTENANCE OF LENS TRANSPARENCY Principal Investigator & Institution: Clark, John I.; Professor and Acting Chairman; Biological Structure; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2003; Project Start 01-JUN-1982; Project End 31-JUL-2008 Summary: (provided by applicant): Human alphaBeta crystallin is the archetype for small heat shock proteins, sHSP, that are involved in protein aggregation and filament assembly diseases including cataracts, neurodegeneration, cardiomyopathy and desmin related myopathy. Interactions between alphaBeta crystallin are necessary for normal filament assembly and organization of crystallins in lens cells. In aim 1, characterization of the interactive sites for subunit assembly, for cytoskeletal proteins and for target peptides on human alphaBeta crystallin, the peptide sequences of the interactive domains on human alphaBeta crystallin will be identified using a protein multipin arrays. The affinities between the interactive domains will be quantified using surface plasmon resonance (SPR) and characterized functionally using in vitro and in vivo assays for chaperone activity. The results are expected to provide new information on the structural basis for the assembly of sHSP subunits to functional complexes and for their interaction with chaperone target proteins and with cellular filaments and cytoskeletal elements. In aim 2, in vivo evaluation of retina - lens relationships that may influence development and maintenance of lens transparency in transgenic mice, the historical hypothesis that a lens - retina relationship is important for normal development of lens cell transparency will be studied. Electroretinograms (ERG) and digital slit lamp recordings of opacity in selected animal models will quantify
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transparency with retinal function during the development of the lens and during loss of transparency in models for cataract formation. Lastly, the hypothesis that lens cytoskeleton provides a scaffold for development and maintenance of transparent lens fiber structure will be investigated in aim 3, observe the cellular organization of major structural proteins in differentiating lens fibers during development of lens transparency and during loss of transparency in the selenite rat and in selected transgenic mouse models using confocal microscopy and electron microscopy (EM). The patterns and distribution of the cytoskeleton and crystallins during differentiation of transparent lens fibers will be investigated using electron microscopy and confocal immunocytochemistry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DEVELOPMENT OF DIABETIC CARDIOMYOPATHY IN GLUT4 +/MICE Principal Investigator & Institution: Charron, Maureen J.; Professor of Biochemistry; Biochemistry; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-APR-1997; Project End 31-MAR-2005 Summary: (Scanned from the applicant's abstract) Mice with a single knockout allele of GLUT4(+/-) on a low fat diet develop type II diabetes including hyperinsulinemia, hyperglycemia, hyperleptinemia, mild hypertension, cardiomyopathy and liver steatosis with age. These pathologies occur independent of obesity, dyslipidemia, pancreatic failure and hepatic insulin resistance. We propose to conduct the first in vivo longitudinal study which examines critical molecular/metabolic/energetic alterations leading to diabetic cardiomyopathy. This addresses the important interplay between whole body metabolism and circulating factors that regulate cellular processes which result in end organ pathology. The central hypothesis is global reduction of GLUT4 expression and/or function leads to alterations in cardiac insulin action, glucose metabolism and energetics mediated by reductions in the activity of PPARgamma and Akt/PKB which result in altered contractile function and diabetic cardiomyopathy. Altered substrate use with increased reliance upon fatty acid metabolism is associated with increased oxidative stress and mitochondrial uncoupling that result in diminished energy reserves. Insulin sensitizer treatment with BRL49653, a thiazolidinedione (TZD) that activates PPARg, will improve whole body glucose homeostasis and cardiac function through alterations in AktJPKB activity, substrate usage and expression of uncoupling protein (UCP) and glucose transporter (GLUT) genes/proteins. These studies will provide unique insight into molecular, metabolic, and morphologic alterations in GLUT4+/- hearts as mice progress to diabetes that should facilitate development of therapeutics to prevent and/or minimize diabetic cardiomyopathy in humans. To accomplish these goals we have four specific aims. Each aim will identify alterations in insulin action through Akt/PKB, GLUT4- and GLUTx1 translocation, substrate partitioning/trafficking, and GLUT and UCP2/3 gene/protein expression in hearts of GLUT4+/- and control mice. Molecular and cellular analyses will be correlated with morphologic and hemodynamic changes in heart and alterations in whole body glucose homeostasis and circulating serum factors (e.g. leptin, insulin, T3/T4, glucose, free fatty acids) as mice progress from normal (N/N) to prediabetic (N/H) to overt diabetic (H/H) phenotypes. Effects of short term treatment with the TZD BRL49653 (PPARg agonist) on these parameters will be defined before significant alterations in body weight or adiposity can be measured. The latter studies will determine the mechanism of action of TZDs in the heart and may reveal novel therapeutic targets and applications.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DIABETIC ALTERATIONS OF CARDIAC METABOLISM AND FUNCTION Principal Investigator & Institution: Chatham, John C.; Associate Professor of Medicine; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-JAN-1995; Project End 31-JUL-2004 Summary: (Adapted from the Investigator's Abstract): Diabetes is associated with an increased risk of heart failure, independently of other risk factors. There is also increased evidence of diabetic cardiomyopathy as an independent entity. The pi and his collaborators have shown a direct link between cardiac dysfunction and metabolic impairments in myocardial metabolism. Evidence from the investigator's laboratory strongly suggests that the provision of substrates for energy production is impaired at the level of the mitochondrion. Based on these observations, the PI has elaborated the hypothesis that this is indeed the case. Specifically, the investigator proposes that this is manifested in alterations at multiple sites such as lactate uptake and oxidation, fatty acid entry and oxidation, pyruvate oxidation and anaplerosis and citrate cataplerosis. These changes then lead to clinical problems under conditions of increased demand when energy provision cannot match utilization. The tools the PI proposes to use include: 1) The spontaneously diabetic BB/Wor rat and the diabetes-resistant controls. 2) The perfused working heart model with measurement of contractile efficiency, which has now been implemented in the laboratory. 3) Perfusion with buffer containing RBC's to increase oxygen carrying capacity and decrease perfusion rate so that a-v differences can be measured. Simultaneous use of C13 labeled substrates, and in situ and high resolution NMR spectroscopy and GCMS in perfusate and extracted myocardial samples to determine metabolite flux rates using isotopomer analyses. Complementary measurements of enzyme activities, transporters (lactate, fatty acid) and their expression in the myocardial tissue extracts. Finally, linkage of all of the above data using metabolic control analysis to establish the principal control points. It is underlined that the understanding of the relationship between cardiac function and metabolism is essential in instituting appropriate treatment so that therapeutic interventions to improve contractile function do not exacerbate the metabolic problems, ultimately increasing tissue injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DIABETIC CARDIOMYOPATHY: TGFBETA ACTIVATION AND FIBROSIS Principal Investigator & Institution: Murphy-Ullrich, Joanne E.; Professor; Pathology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2006 Summary: (provided by applicant): Diabetic cardiomyopathy, characterized by myocyte hypertrophy and interstitial fibrosis, is a potentially life-threatening complication resulting from lack of glycemic control. Hypertension associated with diabetes increases disease severity. TGF-beta is the primary effector of fibrosis in response to hyperglycemia. Bioactivation of latent TGF-beta is a major regulatory step in controlling TGF-beta and a logical point for therapeutic intervention. Yet, regulation of TGF-beta bioactivity in these diseases is not well understood. The platelet/matrix protein, thrombospondin l (TSP 1), is a physiologic regulator of latent TGF-beta activation. TSP 1 regulates glucose-stimulated increases in TGF-beta bioactivity and matrix protein
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synthesis in mesangial cells. TSP-dependent TGF-beta activation is also important for the diabetic myocardium, since high glucose stimulates TSP1 and TGF-beta bioactivity in rat cardiac fibroblasts and increases in TGF-beta bioactivity are blocked with TSP antagonist peptides. Similarly, data show that angiotensin II (Ang 11)-stimulates increased TSP 1 expression and TGF-beta bioactivity that can be blocked by addition of the antagonist peptides. Both glucose and Ang II up-regulate TSP 1 expression, potentially through modulation of PKC and nitric oxide (NO). These data support the hypothesis that glucose-mediated modulation of PKC, NO, ROS, and Ang II are involved in the regulation of TSP1 expression, leading to latent TGF-beta activation, matrix protein synthesis, and myocardial fibrosis. In this proposal, we will use a cultured cardiac fibroblast system to determine 1) the interrelationships between glucose, PKC activity, and oxidative balance in regulation of TSP 1 expression, TGF-beta bioactivity, and matrix protein synthesis and; 2) the role of Ang II in regulation of TSP 1dependent TGF-beta activation and its relation to glucose stimulation. In addition, rats with diabetes (streptozotocin) and hypertensive diabetes will be used to determine 3) whether peptide antagonists of TSP-mediated TGF-beta activation ameliorate diabetic myocardial fibrosis under normo- and hypertensive conditions. These studies will further our understanding of how TGF-beta is regulated in diabetes and hypertension, and will potentially identify new strategies for therapeutically attenuating myocardial fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ETHANOL EFFECTS OF SR CA2+ RELEASE IN CARDIAC MYOCYTES Principal Investigator & Institution: Wasserstrom, J A.; Medicine; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): One of the most serious secondary effects of alcohol abuse is the development of specific alcohol-induced cardiomyopathies which often lead to congestive heart failure. Previous findings suggest that one of the mechanisms underlying reduced cardiac function by ethanol (EtOH) may involve the direct suppression of cardiac excitation-contraction (E-C) coupling. Interestingly, this direct effect does not appear to involve alterations in the trigger for cardiac contraction (via Ltype Ca 2+ current) raising the possibility that the primary negative inotropic effects of EtOH might reside in an altered response to that trigger. The goal of this project is to investigate how EtOH affects Ca2+ release from internal stores in the sarcoplasmic reticulum (SR) during the cardiac cycle. This will be accomplished through measurement of Ca 2+ sparks, which are thought to represent the fundamental Ca 2+ release units responsible for contraction. The Specific Aims of this project are: 1) to determine if the cardiodepressant effects of EtOH occur as the result of a direct suppression of SR Ca 2+ release; and 2) to investigate whether or not these changes in SR Ca 2+ release contribute to the depression in cardiac function that occurs in a chronic model of alcohol-induced cardiomyopathy. Ca 2+ sparks will be measured in rat ventricular myocytes with the Ca2+-sensitive fluorescent indicator fluo-4 using laser scanning confocal microscopy in combination with whole cell voltage clamp techniques. Some experiments will be performed in saponin-permeabilized myocytes exposed to different cytosolic Ca2+ concentrations in order to assess Ca 2+ sensitivity of Ca 2+ sparks activated purely by Ca 2+ in the absence of functional sarcolemmal Ca 2+ current. These methodological approaches will allow the investigation of how EtOH affects SR Ca 2+ release that occurs both as a result of its normal trigger (L-type Ca 2+
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channels) and in response to the final common pathway for E-C coupling, direct activation by Ca 2+. In addition to the study of direct effects of EtOH on the physiological and biophysical processes responsible for SR Ca 2+ release, we will also correlate these changes in SR Ca 2+ signaling with the development of alcohol-induced cardiomyopathy in order to determine if the reduction of cardiac output at the whole organ level occurs as the result of a suppression of E-C coupling at the level of the SR. The results of this study will contribute to our understanding of the mechanisms by which EtOH interferes with SR Ca 2+ release and whether or not this mechanism involves the trigger for E-C coupling or the response to that trigger. More importantly, such information can then be applied to understanding how a reduction in SR function by EtOH might contribute to chronic suppression of overall cardiac function, leading to the development of cardiomyopathies and heart failure associated with long-term alcohol abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FAMILIAL HYPERTROPHIC CARDIOMYOPATHY--SARCOMERIC DISEASE Principal Investigator & Institution: Warshaw, David M.; Professor and Chariman; Molecular Physiol & Biophysics; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2002; Project Start 18-FEB-1999; Project End 31-JAN-2004 Summary: Familial hypertrophic cardiomyopathy (FHC), an inherited disease with a high incidence of premature death due to cardiac failure, has its genetic loci in the contractile proteins in the heart. Thus, FHC may be a disease of the sarcomere, muscle's most basic contractile unit. In the sarcomere, myosin, a molecular motor, interacts with actin to generate the power of the heart. This Program Project (3 projects and 3 cores) focuses on mutations to myosin and the actin regulatory proteins, troponinT, and tropomyosin. Using state-of-the-art techniques, we will characterize FHC from the mechanics of the whole heart down the molecular mechanics of a single contractile protein, to assess how structural alterations to these proteins affect the mechanical properties of the sarcomere, the muscle fiber, and the whole heart. Project #1 will study the mechanical properties of the whole heart and papillary muscles obtained from transgenic mice with mutations in either myosin, troponinT, or alpha- tropomyosin. Project #2 will genetically engineer FHC mutations into myosin using an in vitro protein expression system. Project #2 will biochemically characterize these proteins, while project #3 will use the laser optical trap to assess the force and motion generating capacity of these mutants at the single molecule level. All projects use the Analytical and Modeling Core (Unit B) for expertise in data collection, analysis, and modeling. In addition, the Mouse Production and Ventricular Function Core (Unit C) will generate mice with FHC mutant hearts that will be studied at all anatomical levels by the various projects. In addition, this Core will also characterize the in vivo ventricular performance of the hearts within the transgenic mice. The long-term goals are: 1) to utilize FHCrelated point mutations as a means of identifying key structural domains within the mutant sarcomeric proteins and to determine how these domains relate to the protein's molecular function; 2) to understand how point mutations in contractile proteins compromise sarcomere function, and how these mutations, in turn, may trigger cardiac hypertrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FRIEDRIECHS ATAXIA, MITOCHONDRIA AND CELL DEATH Principal Investigator & Institution: Cortopassi, Gino A.; Associate Professor; Vet Molecular Biosciences; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2002; Project Start 15-APR-1999; Project End 31-MAR-2004 Summary: (adapted from Investigator's abstract) The human disease Friedreich's ataxia (FA) causes progressive age-related neurodegeneration and cardiomyopathy associated with increased mitochondrial oxidative stress and damage. This human cellular model allows intensive experimental testing of cause and effect relationships between increased mitochondrial reactive oxygen species (ROS), and downstream molecular damage, pathophysiology and cell death. Specific aims of this study are: (1) to characterize the type of increased ROS that occurs in FA, (2) to quantify the contribution of increased ROS to damage of mitochondrial lipids, mtDNA, and proteins, (3) to quantify the effects of this damage on the major possible mitochondrial physiological endpoints, and (4) to rescue phenotypes by inhibitors specific for each step in the hypothetical chain, and test its validity at the biochemical and cellular level and in knockout organisms constructed in Aim 5. These molecular targets of mitochondrial and oxidative damage in human cells, once identified and validated as pathophysiologically relevant will serve as targets for further analysis in the more complex situation of aging in humans and animals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FUNCTIONAL MR IN ISCHEMIC CARDIOMYOPATHY Principal Investigator & Institution: Grayburn, Paul A.; Professor; Baylor Research Institute 3434 Live Oak St, Ste 125 Dallas, Tx 75204 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Functional mitral regurgitation (MR) is a common complication of ischemic heart disease. Two large clinical trials confirmed an adverse effect of functional MR on survival after a heart attack. However, studies in heart failure are small and mainly limited to patients with nonischemic cardiomyopathy. Recent animal studies have challenged the traditional concept that functional MR is a consequence of mitral annular dilation, instead suggesting that functional MR is due to leaflet tethering by outward expansion of the left ventricular wall (i.e. LV remodeling). This has critical implications regarding the correct surgical approach to correcting functional MR. TO date, no large prospective studies have examined the mechanism(s) of functional MR in ischemic cardiomyopathy, nor has the interaction between mechanism and prognosis been explored. This is a crucial knowledge gap because 1) 70% of heart failure cases are caused by ischemic heart disease, and 2) functional MR occurs in around 60% of patients with ischemic cardiomyopathy. This proposal aims to fill these gaps by defining the mechanism(s) of functional MR by transesophageal echocardiography in a large clinical trial of patients with ischemic cardiomyopathy. The following specific aims will be addressed: Aim 1: To define the mechanism(s) of functional MR in ischemic cardiomyopathyAim 2: To define the effect of therapy on mechanism and severity of functional MRAim 3: To evaluate the effect of functional MR on prognosis is ischemic cardiomyopathyAim 4: To evaluate the effect of myocardial viability on functional MR and its response to treatment We propose to accomplish these aims as a ancillary study to the Surgical Treatment of Ischemic Heart Failure (STICH) Trial. The STICH Trial will compare surgical revascularization versus medical therapy for treatment of heart failure in 2800 patients with ischemic cardiomyopathy,
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and therefore affords a unique opportunity to investigate the mechanism(s) of functional MR. Despite its known clinical utility of assessing the mechanism and severity of MR, TEE is not currently included in STICH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: G PROTEIN COUPLING OF LIPID METABOLISM IN DIABETIC HEART Principal Investigator & Institution: Muslin, Anthony J.; Professor of Internal Medicine, Cell Bio; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Both Type I and Type II diabetes are accompanied by a profound switch in myocardial substrate utilization form one which utilizes nearly equal amounts of glucose and fatty acid to a state which predominantly employs FA for substrate. Gproteins in he heart have important effects in mediated the electrical and contractile proteins for myocardium which depend, in part, on an appropriate membrane microenvironment to carry out their specific functions. In the diabetic state profound changes in lipid synthesis occur including alterations in phosphatidylinositol (to which Gq is coupled through phospholipase C leading to IP3 generation) and in the content of plasmalogen which have dramatic effects on membrane fluidity and dynamics. During the last fie years substantial evidence has been accrued demonstrating the altered activity and function of the G-protein axis in diabetic myocardium. These include decreases in beta adrenergic receptor number, increases in Gq-protein mass, altered Gprotein receptor-effector coupling, increases in PKCepsilon activity and changes in intracellular calcium ion homeostasis. Thus, it seems likely that altered G signaling contributes to, or underlies the propagation of the pathophysiology manifest in the diabetic heart. The primary hypothesis of Project 4 is that diabetic cardiomyopathy develops as a result of abnormal stimulation of Gq and Gi protein- mediated signaling pathways that leads to alterations in intracellular phospholipases, peroxisomal lipid metabolism and lipid second messenger generation. In order to test this model of diabetic cardiomyopathy we will evaluate the functional and biochemical sequelae of increased or decreased G protein-mediated signal transduction in diabetic murine myocardium. In particular, we will determine whether reduced Gq and Gi signaling in the heart inhibits the development of cardiomyopathy in diabetic mice. G protein signaling will be attenuated by use of RGS4, a GTPase activating protein for Gq and Gi family members. The identify of the specific G protein involved will be determined by targeted disruption of individual Galpha subunit genes. In addition, we will evaluate whether increased Gq signaling potentiates the development of diabetic cardiomyopathy. Furthermore, we will determine whether Gq or Gi signal transduction in heart promotes PLA2 activation and changes in lipid metabolism. Finally, we will examine the transduction in heart promotes PLA2 activation and changes in lipid metabolism. Finally, we will examine the physiological role of the sarcolemmal phospholipase cPLA2gamma, in the pathogenesis of diabetic cardiomyopathy and we will determine whether G protein-mediated signaling regulates activation of this phospholipase. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENE CAUSING PAGET & LIMB-GIRDLE MUSCULAR DYSTROPHY Principal Investigator & Institution: Kimonis, Virginia E.; Children's Hospital (Boston) Boston, Ma 021155737
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Timing: Fiscal Year 2002; Project Start 15-FEB-2001; Project End 31-JAN-2004 Summary: (Taken from the application): Limb-Girdle Muscular Dystrophy (LGMD) encompasses a clinically diverse group of disorders characterized by proximal muscle weakness first affecting the hip and shoulder girdle elevated creatinine kinase values, and non-specific changes in the muscle biopsy. In addition to clinical heterogeneity within the LGMD category, genetic heterogeneity is indicated by the existence of dominant and recessive forms. We have identified a large family with autosomal dominant LGMD and early onset Paget disease of bone (PDB). These individuals have bone pain in the hips, shoulders and back from the Paget disease. Individuals eventually become bed bound and die prematurely from progressive muscle weakness +/cardiomyopathy in their forties to sixties. Laboratory investigation indicates elevated alkaline phosphatase levels in affected individuals. CPK is normal to mildly elevated. Muscle biopsy of the oldest affected male revealed non-specific changes and vacuolated fibers. Preliminary molecular analysis excluded linkage to the known loci for the autosomal dominant and recessive forms as well as 2 loci for autosomal dominant PDB and 6 loci for cardiomyopathy. Exclusion of the candidate loci prompted a genomewide scan of 39 family members (9 affected, 24 unaffected, 6 spouses} with 402 polymorphic microsatellite markers (Marshfield Genotyping Services). The disease locus was linked to chromosome 9p21-q21 with marker D9S301 (max LOD=3.64), thus supporting our hypothesis that this family displays a genetically distinct form of LimbGirdle-Muscular-Dystrophy associated with Paget disease of bone and cardiomyopathy. Subsequent haplotype analysis with a high density of microsatellite markers flanking D9S301 refined the disease locus to a 3.76 cM region on chromosome 9p21-13.2. This region excludes the IBM2 locus for autosomal recessive vacuolar myopathy. Two candidate genes mapped to the critical region, NDUFB6 and IL-11RA, are being examined for disease-associated mutations. NDUFB6 encodes a subunit of Complex I of the mitochondrial respiratory chain and the IL11RA gene product influences proliferation and differentiation of skeletogenic progenitor cells. Identification of the genes involved in the LGMDs has led to the elucidation of an entire family of proteins that function in the dystrophin-glycoprotein complex. and a basis for understanding the pathophysiology of this complex. Delineation of the genetic component responsible for the LGMD/PDB phenotype should promise similar insight and facilitate in the design of novel treatment protocols for the two disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENE THERAPY FOR CHRONIC HEART FAILURE Principal Investigator & Institution: Soltesz, Edward G.; Surgery; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 23-DEC-2002; Project End 31-JUL-2003 Summary: (provided by applicant): Congestive heart failure (CHF) is a growing clinical problem nationwide. Despite advances in traditional approaches to its treatment, CHF remains a leading cause of morbidity and mortality. A key abnormality at the cellular level in failing hearts is a defect in sarcoplasmic reticulum (SR) function which is associated with abnormal intracellular calcium handing. Failing hearts from humans and animal models have demonstrated a decrease in the expression and activity of the SR Ca2+ATPase (SERCA2a). Recently, we have shown that restoring depressed levels of SERCA2a restores contractility and normalizes intracellular calcium cycling in a rodent model of CHF. We are now extending our experiments to a porcine model of ischemic cardiomyopathy with clinical-grade vectors and delivery systems. Specifically, we will investigate whether (1) overexpression of SERCA2a can improve hemodynamic function
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in a porcine model of ischemic cardiomyopathy, and (2) long-term overexpression of SERCA2a will induce ventricular and metabolic remodeling without adversely effecting enerqetics in a porcine model of ischemic cardiomyopathy. To answer these questions, we will utilize a porcine model of heart failure where there is depressed LV function and SERCA2a protein levels to examine the response to overexpressing levels of SERCA2a through gene therapy. We will measure hemodynamic function in these animals before and after the delivery of the gene as well as assess the level of SERCA2a expression. We expect to show that gene transfer of SERCA2a to failing porcine hearts will rescue contractility and lead to ventricular and metabolic remodeling. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENES TRANSGENICS
THAT
CONTROL
CARDIAC
CELL
NUMBER--EIA
Principal Investigator & Institution: Field, Loren J.; Professor; Medicine; Indiana UnivPurdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: Clinical recovery from myocardial infarction is thwarted, in part, by inability of surviving ventricular myocytes to reconstitute functional cardiac mass through a corresponding, compensatory increase in cell number. This highlights the limited capacity to restore cardiac mass by hypertrophy alone, and deleterious effects associated with hypertrophy that further impair survival. On-going myocyte loss also appears likely as an eventual contributor to end-stage heart failure. Conventional therapies for heart failure are aimed at rescuing jeopardized myocardium, optimizing mechanical load, or augmenting the mechanical performance of surviving myocytes. In principle, strategies to increase the number of functional ventricular myocytes have potential for a clinical benefit. (This theme is among the highest priorities expressed by the NHLBI Special Emphasis Panel on Heart Failure Research and the present RFA.) Three complementary, gene-based approaches have been brought to bear on the problem of cardiac cell number in this Collaborative RO1-transdifferentiation, manipulation of cell cycle constraints, and interference with pathways for programmed cell death (apoptosis). Viral delivery of cardiogenic transcription factors and upstream cardiogenic signals will be explored by Dr. Robert Schwartz. Drs. Michael Schneider and Loren Field will use gain-and loss-of- function mutations to dissect the "post-mitotic" phenotype in vivo, and will use co-precipitation or interaction cloning to isolate the endogenous cardiac proteins affecting cell cycle exit. Dr. Konstantin Galaktionov, an expert on Cdc25, will study molecular regulators of the G2/M transition, a second checkpoint that must be overcome for cell number to be increased. Mechanisms and countermeasures for cardiac apoptosis will be tested by Dr. Doug Mann, with emphasis on dilated cardiomyopathy triggered by overexpression of tumor necrosis factor alpha, and on investigations of human myocardium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC ANALYSIS OF DILATED CARDIOMYOPATHY Principal Investigator & Institution: Jha, Sanjay; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2002; Project Start 09-JUL-2001; Project End 31-MAY-2007 Summary: (provided by applicant) Dilated cardiornyopathy (DCN4) is a disease characterized by cardiac chamber dilation and deterioration of systolic function. it accounts for 10,000 deaths annually In the United States, and is an etiologically
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heterogeneous disorder with a strong genetic component. The central goals of this project are to identify genes involved in the pathogenesis of DCM, and to obtain the necessary training in cardiovascular genetics over a proposed five year period, to prepare for a career as an independent investigator. Research will focus on four specific alms critical for identification of genes involved in DCM pathogenesis. 1) Ascertainment and phenotypic characterization of individuals and families with DCM. Families and sporadic cases suitable for genetic analyses will be identified from congestive heart failure and transplant clinics at1he University of Utah and University of Pennsylvania system hospitals. 2) Identification of new DCM loci using genetic linkage analysis in large kindreds. Genome-wide linkage scans using highly polymorphic markers will be performed on large DCM families that do not link to known loci. 3) Positional cloning of a DCM gene on chromosome 3p. The critical genetic interval for a DCM locus previously identified by this laboratory will be cloned. Candidate genes identified in the region will be screened for mutations that co-segregate with the disease phenotype in the family where linkage was established. 4) Identification and mutation screening of candidate genes in familial and sporadic DCM populations. We will identify genes, which on the basis of physiologic rationale, may play central roles in DCM pathogenesis. The candidate genes will be screened for mutations in our patient population. The principle investigator has completed training in clinical cardiology. This application now proposes to build on his research background in Drosophila developmental genetics obtained in the laboratory of Dr. David Hogness. Over a five year period, an expertise in genetic approaches to understanding the molecular pathogenesis of dilated cardlomyopathy will be developed. The candidate's sponsor, Dr. Mark Keating, is a recognized leader in the field of cardiovascular genetics. An advisory committee consisting of two other senior scientists, Dr. Mark Leppert and Dr. Michael Parmacek, will provide additional scientific and career guidance. The Department of Human Genetics at the University of Utah is a center for the study of genetic diseases and provides an outstanding environment for the candidate to develop into an independent investigator. (End of Abstract) Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETICS STUDIES OF FAMILIAL DILATED CARDIOMYOPATHY Principal Investigator & Institution: Mcnally, Elizabeth M.; Associate Professor; Medicine; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: Many etiologies lead to the development of dilated cardiomyopathy. Idiopathic dilated cardiomyopathy arises from intrinsic muscle disease in the presence of normal coronary arteries and the absence of a clear toxic or immunologic insult. Approximately 30 percent of idiopathic dilated cardiomyopathy patients have first degree relatives that also show evidence of cardiac dilatation with or without symptoms of congestive heart failure. Supporting this, genetic loci have been significantly associated with familial dilated cardiomyopathy (FDC). Positional cloning efforts are underway to increase our understanding of the molecular mechanisms that underlie familial dilated cardiomyopathy. Through genetic linkage analysis, we have identified a region of chromosome 6q23 that is associated with dilated cardiomyopathy, conduction system disease that produces progressive atrio-ventricular block and a mild, adult onset, slowly progressive muscular dystrophy. We have constructed a physical map of this region of chromosome 6 and evaluation of candidate genes is underway. We have also discovered a second region, chromosome 2q22, that is associated with dilated cardiomyopathy and ventricular arrhythmias. We propose to refine the genetic interval,
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identify candidate genes and, through mutation analysis, identify the gene responsible for chromosome 2-associated FDC. The FDC-gene product will be studied for expression patterns in both normal and diseased tissue. The murine homolog of the FDC-gene will be determined. We will also establish a clinical and DNA database of dilated cardiomyopathy patients. This database will be used to determine the role of certain mutations in the development of the cardiomyopathic process. While genetic heterogeneity is present in FDC, the study of genes responsible for this disorder will reveal whether multiple cellular mechanism lead to cardiomyopathy. Additionally, in families with dilated cardiomyopathy, we find a prodrome of arrhythmias prior to the onset of cardiac dilatation and congestive heart failure. By developing genetic markers, we will identify those at risk for arrhythmia and most like to benefit from pacemaker and/or implantable defibrillator treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENOMICS OF CARDIOVASCULAR DEVELOPMENT, ADAPTION Principal Investigator & Institution: Izumo, Seigo; Director of Cardiovascular Research; Medicine; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: The goal of this PGA is to begin linking genes to function, dysfunction and structural abnormalities of the cardiovascular system caused by clinically relevant, genetic and environmental stimuli. The principal biological theme to be pursued is how the transcriptional network of the cardiovascular system responds to genetic and environmental stresses to maintain normal function and structure, and how this network is altered in disease. In Specific Aim 1, the investigators will take a multidisciplinary approach combining well-defined mouse models of cardiomyopathy and vasculopathy with an integrated analysis of physiology, pathology, and RNA expression profiling to search for prototypical patterns of gene expression in response to various genetic and non-genetic perturbations. In Specific Aim 2, the investigators will perform transcriptional profiling using human myocardium and vascular tissues obtained at the time of cardiac transplant or biopsy, and compare the transcriptional profile data with those of various mouse models. In Specific Aim 3, the investigators will screen for mutations that cause cardiovascular malformations with particular emphasis on hypertrophic cardiomyopathy, dilated cardiomyopathy, and selected sets of patients with congenital heart disease. In Specific Aim 4, the investigators will examine 200 candidate genes, identified by the mouse and human expression studies, in 2093 individuals drawn from the Framingham Heart Study. In these studies, a single nucleotide DNA polymorphism analysis (SNP) will be correlated with echocardiographic evidence of left ventricle mass, ventricular function, cardiac chamber size and aortic root size. The data generated by all of the above studies will be analyzed by state-of-the-art informatics to search for logics for common as well as disease specific pathways. The data will be extensively annotated and made freely available to the scientific community through the interactive website. In summary, this PGA will generate a high quality, comprehensive data set for the functional genomics of structural and functional adaptation of the cardiovascular system by integrating expression data from animal models and human tissue samples, mutation screening of candidate genes in patients, and DNA polymorphisms in a well characterized general population. Such a data set will serve as a benchmark for future basic, clinical and pharmacogenomic studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GI CARDIOPROTECTION
SIGNALING
IN
CARDIOMYOPATHY
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Principal Investigator & Institution: Baker, Anthony J.; Associate Professor; Northern California Institute Res & Educ 4150 Clement Street (151-Nc) San Francisco, Ca 941211545 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): In humans, chronically increased signaling through Gi-coupled receptors is associated with congestive heart failure (CHF) caused by idiopathic dilated cardiomyopathy or ischemic cardiomyopathy following myocardial infarction. However, the mechanisms responsible are unclear. Our working hypothesis is that chronically increased Gi signaling causes impaired excitation-contraction (ec) coupling. To test this hypothesis we will combine physiological measurements of cardiac muscle function with a novel transgenic mouse model in which a modified Gicoupled receptor (Ro1) is targeted to the heart. Expression of Ro1 is regulated by a tetracycline-controlled expression system (tet-system). We have recently shown that chronic Ro1 expression causes CHF and major abnormalities of Ca2+ transients and contraction. In contrast, acute Ro1 expression causes significant protection against ischemia/reperfusion injury, suggesting a dual role for increased Gi signaling in cardioprotection and disease. For this proposal we will determine the ec-coupling mechanisms and Gi signaling mechanisms involved in CHF and cardioprotection. Using single myocytes, cardiac trabeculae, and Langendorff perfused mouse hearts, we will determine the effect of Ro1 expression on Ca2+ transients and determine the mechanisms responsible by localizing abnormalities to specific Ca2+ handling processes. We will determine the effect of Ro1 expression on Ca2+-responsiveness and determine the mechanisms responsible by localizing abnormalities to specific contractile and regulatory proteins. Using the tet-system to turn off Ro1 expression after induction of CHF, we will determine the extent to which ec-coupling abnormalities are reversible. To elucidate signaling mechanisms, we will determine which of the major Gi pathways in the heart (Gi2 and Gi3) are involved; and whether signaling via the G protein alpha subunit and/or the betagamma dimer is involved. Using 3 model systems we will investigate Gi signaling effects (both deleterious and beneficial) and the ec-couplingand signaling mechanisms involved in: Aim 1. CHF caused by Ro1 expression; and recovery after terminating Ro1 expression. Aim 2. Acute Cardioprotection caused by Ro1 expression. Aim 3. CHF caused by ischemic cardiomyopathy. This research will provide new information on the dual role of Gi signaling in both heart failure and cardioprotection which may help identify new strategies to treat heart disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HEMOCHROMATOSIS--EPIDEMIOLOGY MECHANISMS
AND
MOLECULAR
Principal Investigator & Institution: Beutler, Ernest N.; Chairman; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 28-APR-1998; Project End 31-MAR-2003 Summary: Hereditary hemochromatosis, a disease characterized by excess iron absorption leading to diabetes, cardiomyopathy, cirrhosis, and arthropathies, is arguably the most common clinically important genetic disorder of Europeans. Recently an HLA Class 1 gene, HLA-H was implicated in the etiology of this disease. Over 80 percent of hemochromatosis patients are homozygous for a C282Y mutation. Compound heterozygotes for C282Y and H62D appear to have an increased incidence of
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the disease. Sixty-thousand adults undergoing health care screening in the KaiserPermanente system will be screened, determining serum iron, iron binding capacity, ferritin, and mutations in HLA-H. Patients classified as having hemochromatosis will be phlebotomized to remove excess iron and to measure iron stores. This will establish the relationship between genotype, age, sex and clinical state, and size of iron stores, and provide data that can be used to guide programs screening for hemochromatosis. The hypotheses that heterozygotes are more susceptible to cardiovascular disease and other disorders and that they are benefited by being less susceptible to iron deficiency anemia will be tested using the extensive Kaiser-Permanente database. Hemochromatosis mutations, other than those known, will be sought. The HLA-H gene product may function like other HLA class 1 genes, binding peptides and associating with proteins such as beta2 microglobulin, calreticulin, transporter associated with antigen processing (TAP) and tapascin. Alternatively, it may function as a signaling molecule, like the Fc receptor. Determining how the HLA-H gene product functions should provide insight into its role in maintaining iron homeostasis. This will be done by using immunoprecipitating HLA-H containing complexes, determining HLA-H Fc receptor signaling properties and measuring the binding of peptides and other small molecules by HLA-H. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IGF-1 AND DIABETIC HEART Principal Investigator & Institution: Kajstura, Jan; Associate Professor; Medicine; New York Medical College Valhalla, Ny 10595 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: (Verbatim from the application): The long-term objective of this application is to demonstrate that diabetic cardiomyopathy is characterized by myocyte death in which the local renin-angiotensin system (RAS) plays a primary critical role. Hyperglycemia induced by streptozotocin administration is anticipated to activate the transcription factor p53, respectively, by glycosylation and phosphorylation of the Cterminal of this protein. Enhanced p53 function may upregulate p53-dependent genes, such as bax, angiotensinogen and AT1 receptor, leading to the synthesis and secretion of Ang II and the sustained phosphorylation of the tumor suppressor. This vicious cycle may promote the chronic generation of Aug II and an increased susceptibility of cells to die. The induction of bax and the downregulation of bcl-2 by p53 may potentiate not only apoptosis, but also myocyte necrosis, resulting in restructuring of the ventricular wall, chamber dilation and impaired cardiac hemodynainics. Importantly, Aug Ilmediated responses may involve the formation of reactive oxygen species (ROS). ROS may constitute the ultimate signal in the activation of the cell death pathways. Insulinlike growth factor-i (IGF-1) opposes the consequences of p53 by phosphorylating its Nterminal and by stimulating transcription of mdm2 that may lead to the interaction of Mdzn2 and p53 proteins. Mdm2-p53 complexes attenuate p53 function, Ang II concentration, ROS generation, increase in Bax, decrease in Bcl-2 and, ultimately, cell death and ventricular remodeling. These hypotheses will be tested by performing studies in normal mice and transgenic mice overexpressing IGF-1 following the imposition of diabetes. In vivo studies will be complemented with in vitro experiments utilizing myocyte cultures infected with adenoviral vectors overexpressing human mutated p53 or human wild-type p53. These cells will be exposed to high concentration of glucose to establish a cause and effect relationship between triggers of cell death, i.e., glucose and Aug II, and factors preventing, i.e., mutated p53, and promoting, i.e., wild type p53, cell death mechanisms. These multiple analyses should allow to establish
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whether the myocyte RAS is fundamentally implicated in the development and progression of diabetic cardiomyopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INSULIN SIGNALING AND THE HEART IN DIABETES Principal Investigator & Institution: Abel, Evan D.; Assistant Professor; Internal Medicine; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-DEC-2007 Summary: (provided by applicant): The pathogenesis of cardiac dysfunction in diabetes is partially understood. Our goal is to determine the mechanisms by which reduced insulin signaling in cardiomyocytes and vascular endothelium contributes to the pathogenesis of diabetic cardiomyopathy. Our overall hypotheses are: (1) In diabetes, deficient or reduced insulin signaling in cardiomyocytes leads to an initial defect in glucose/pyruvate oxidation, and a secondary increase in fatty acid oxidation that leads to increased production of reactive oxygen species (ROS) that ultimately causes progressive mitochondrial injury. Increased fatty acid delivery to insulin resistant cardiomyocytes during diabetes will accelerate mitochondrial dysfunction. (2) In the heart the (acute and chronic) regulation of cardiac muscle substrate metabolism by insulin involves paracrine interactions between cardiomyocytes and other cells in the heart such as endothelial cells. Thus, impaired insulin signaling in these cells and in cardiomyocytes both contribute to altered cardiac metabolism and function. The consequences of these defects will be exaggerated when cardiac energy requirements are increased such as during left ventricular hypertrophy. Aim 1: will determine the mechanisms by which chronic deficiency of insulin signaling in cardiomyocytes impairs mitochondrial oxidative capacity and predisposes the heart to lipotoxic injury. Studies will be performed in mice with constitutive and inducible deletion of insulin signaling in cardiomyocytes. We will determine the mechanisms for changes in PDH activity, the mechanisms that lead to increased fatty acid utilization in these models and the role of increased ROS generation in precipitating mitochondrial dysfunction and lipotoxic cardiomyopathy. Aim 2: will determine the mechanisms by which non-myocyte cells in the heart modulate cardiomyocyte metabolism. We will determine if loss of insulin signaling in these compartments will accelerate or exacerbate the metabolic and functional impairment in hearts that lack insulin signaling in cardiomyocytes by studying hearts deprived of insulin signaling in endothelial cells and cardiomyocytes under basal conditions and following pressure overload hypertrophy. The role of nitric oxide in the paracrine regulation of myocardial metabolism by insulin will be determined. These studies will shed important insight into the regulation of cardiac function and metabolism by insulin and the role of impaired insulin signaling in the pathogenesis of diabetic cardiomyopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: INTRINSIC PROBES OF SMOOTH MUSCLE MYOSIN DYMAMICS Principal Investigator & Institution: Berger, Christopher L.; Associate Professor; Molecular Physiol & Biophysics; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2005 Summary: The ultimate goal of this proposal is to examine conformation changes at specific locations within smooth muscle myosin using intrinsic tryptophan fluorescence. Smooth muscle myosin constructs will be genetically engineered to contain a single
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tryptophan at the desired site of interest, which will provide a unique intrinsic fluorescence signal reporting local conformational and structural changes in response to nucleotide binding, ATP hydrolysis, and actin-binding. These experiments are complementary to the ongoing structural studies in the field, allowing us to explicitly test predictions about domain movements and structural arrangements during critical steps in the contractile cycle smooth muscle myosin. Thus we will be able to correlate structural changes in myosin with functional consequences, which relates directly to certain cardiovascular disease. For example, FHC (familial hypertrophic cardiomyopathy) is an inherited, often lethal disease caused by point mutations at key structures within myosin critical to its proper functioning as a molecular motor. We will be examining structural changes in myosin in regions of the molecule directly impacted by mutations that underlie FHC. This will lead to a better understanding of the disease, and thus to better treatment options as well. Therefore, this proposal offers a unique opportunity to critically test fundamental questions about the molecular mechanism of muscle contraction that have not been previously accessible by other spectroscopic probe studies, and the results will have important implications for serious disease states such as FHC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MAGNETIC RESONANCE OF CARDIAC C13 FLUX & METABOLIC RATE Principal Investigator & Institution: Lewandowski, E Douglas.; Professor; Physiology and Biophysics; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 01-AUG-1993; Project End 31-JUL-2008 Summary: (provided by applicant): This proposal exploits the opportunity for a comprehensive 13C NMR evaluation of fatty acid handling within the intact, functioning heart. The overall goal is to further develop and apply our kinetic 13C NMR methods to study the reciprocal relationship between the activity of the key regulator of fatty acid oxidation, carnitine palmitoyl transferase I (CPTI) and turnover of the myocardial triglyceride pool in normal and diabetic animal models. New and exciting findings from the previously funded period enable 13C NMR to distinguish between oxidative rates in the mitochondria and the rate of long chain fatty acid transport, via CPT1, as well as detect the incorporation rate of 13C-enriched palmitate into the myocardial triglyceride pool, all in the intact, beating heart. Therefore, this study explores the hypotheses that: 1) changes in the regulation of long chain fatty acid oxidation, via CPT1 activity, mediate the turnover rate of myocardial triglycerides and can be evaluated in whole hearts by a comprehensive examination of 13C enrichment kinetics; 2) Alterations in triglyceride content and turnover in the diabetic myocardium occur due to a combination of hyperlipidemia and changes in the expression of genes encoding enzymes for fatty acid uptake and oxidation pathways and that these can be distinguished via 13C NMR as independent mediators in the pathogenesis of diabetic cardiomyopathy. This hypothesis will be tested in both in both rat and mouse models of normal, diabetic, and genetically altered cardiac phenotypes. Specific aims are: 1) Determine reciprocal effects of fatty acid oxidation rates on triglyceride turnover via cardiac 13C NMR during partial inhibition of CPT1; 2) Examine long chain fatty acid oxidation rates, CPT1 activity, and triglyceride pool turnover in the hearts of rats with type-I (insulin deficient) diabetes and test for a potential link between triglyceride accumulation and turnover and the activation of protein kinase C; 3) Investigate effects of triglyceride pool size on the reciprocal nature of CPT1 activity and triglyceride turnover in a transgenic mouse model, overexpressing peroxisome proliferator-
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activated receptor alpha (PPAR-alpha), that mimics the diabetic phenotype for fatty acid and glucose metabolism and allows for dietary control of myocardial triglyceride pool size; 4) Examine long chain fatty acid oxidation rates, CPT1 activity, and triglyceride turnover in a more clinically relevant animal model of type II (insulin resistant) diabetes, the db/db mouse model, versus non-diabetic, wild-type mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANICAL REGULATION OF DILATED CARDIOMYOPATHY Principal Investigator & Institution: Omens, Jeffrey H.; Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2005 Summary: Dilated cardiomyopathy is a disease of the heart that in most cases leads to decreased cardiac function and eventually to congestive heart failure. Mechanical factors such as stress and strain have been implicated as regulatory factors in diseases such as cardiac hypertrophy. The overall hypothesis of this proposal is that mechanical factors play a significant role in the tissue remodeling associated with dilated cardiomyopathy and cardiac failure. Sophisticated computational models in conjunction with experimental studies in rodents with different etiologies of heart failure (both genetic and surgically-induced) will help elucidate the role of mechanical factors in the progression of cardiac dilation and failure. The following hypotheses will be tested: (1) Dilated cardiomyopathy and eventual heart failure are mediated by mechanical loads on the heart, and the transition from a compensated hypertrophic state to cardiac failure is dependent on a critical level of stress or strain. Studies of cardiac function before and after this transitory phase can determine which mechanical factors are important. (2) A change in residual stress has important consequences for regional function in the heart, and may be a mechanism of dysfunction in heart failure. We will investigate this possibility by quantifying geometry and tissue structure in the stress-free state of the ventricle during the transition from dilation to failure, and use mathematical models to predict subsequent abnormal changes in diastolic and systolic wall stresses. (3) We expect that changes in. regional myocyte orientation, both at the cellular and global levels, are mechanisms of cardiac dilatation and failure. To test this hypothesis, local myocyte disarray and regional variations in laminar sheet orientation will be measured during the transition to failure. We will incorporate these measures into computational models of the heart, and then independently alter the myocyte orientation in the model, and compare the functional results with those obtained experimentally. We propose that these regional structural changes accompanies dilatory heart failure, and are mechanisms behind the reduction in fiber shortening and the ability of the wall to thicken during systole. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISM OF ARRHYTHMIAS IN THE SETTING OF HEART FAILURE Principal Investigator & Institution: Pogwizd, Steven M.; Associate Professor; Medicine; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 09-AUG-1991; Project End 31-JUL-2003 Summary: The goal of the proposed studies is to define the electrophysiologic and subcellular mechanisms underlying nonreentrant initation of ventricular tachycardia (VT) in the failing heart and its modulation by adrenergic stimulation. In the preceding grant interval, we have performed 3- dimensional mapping studies in arrhythmogenic
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Cardiomyopathy
experimental models of cardiomyopathy and in the failing human heart and demonstrated that VT initiates by a nonreentrant mechanism that is enhanced by catecholamines. The applicant has isolated myocytes from failing hearts and found alterations in Na/Ca exchange activity and intracellular calcium handling that could underlie the development of an arrhythmogenic transient inward current (Iti). Studies will be performed both in an arrhythmogenic rabbit model of nonischemic cardiomyopathy and in the failing human heart. The contribution of Alpha1-, Beta1and Beta2-adrenergic receptor stimulation to arrhythmogenesis in the failing heart will be determined by in vivo 3-dimensional mapping and in vitro electrophysiologic studies. Measurement of Alpha1-, Beta1-, and Beta2- adrenergic receptor density with microscopic resolution using autoradiographic techniques will determine whether the density of adrenergic subtype receptors parallel the arrhythmogenic effects of adrenergic subtype stimulation. To delineate how alterations in sarcoplasmic reticulum (SR) calcium flux, Na/Ca exchange activity and a calcium-activated chloride current lead to activation of a Iti in the failing heart, and to determine how the activation of Iti is enhanced by adrenergic stimulation, whole cell voltage clamping and measurement of intracellular calcium and SR calcium content will be performed in myocytes isolated from myopathic hearts. Lastly, to determine whether nonreentrant activation is due to triggered activity arising from delayed afterdepolarizations (as opposed to early afterdepolarizations or abnormal automaticity), studies will be performed in a novel isolated heart preparation in which transmural mapping in vitro will be combined with recording of monophasic and transmembrane action potentials. The results of these studies will provide new insights into the nature of nonreentrant activation in the failing heart and of the subcellular alterations that underlie adrenergic enhancement of arrhythmogenesis. The results will also provide the foundation for novel therapeutic approaches directed at nonreentrant activation that would be useful in the prevention of sudden death in patients with cardiomyopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM OF DIABETIC CARDIOMYOPATHY Principal Investigator & Institution: Buttrick, Peter M.; Professor of Medicine and Physiology; Medicine; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2005 Summary: This project will investigate cellular events that lead to the development of left ventricular dysfunction in experimental animals and patients with diabetes mellitus. Diabetes mellitus is associated with a cardiomyopathy characterized in part by impaired diastolic relaxation. In previous animal studies, we have defined biochemical features of this myopathy that suggest that chronic protein kinase C activation and subsequent phosphorylation of the thin filament protein, troponin I, is central to the maladaptation and also that this process can be abrogated by treatment with an AT1 receptor antagonist. The present application will extend these observations. Two parallel lines of investigation are proposed: 1. Studies in diabetic rats and mice will be performed to establish the effects of transcriptional and post-translation modification of thin myofilament proteins on the relaxation properties and contraction kinetics of isolated fibers. These will include troponin I exchange experiments in skinned fibers to establish the functional of significance of TnI phosphorylation and also studies in transgenic mice expressing TnI protein with a mutated PKC site. 2. Studies will be performed on cardiocytes isolated from the myocardium of patients with diabetes in order to establish whether the same biochemical and mechanical abnormalities are
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present in human heart disease. It is hoped that this pronged approach will allow the extension of a fundamental experimental observation to clinical practice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MEMBRANE-MEDIATED ALTERATIONS IN DIABETES Principal Investigator & Institution: Gross, Richard W.; Professor; Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 30-SEP-1996; Project End 31-MAR-2007 Summary: A central theme in diabetic cardiovascular disease is the dysfunctional accumulation of lipids in critical cell-types (e.g., cardiac myocytes and macrophages) which underlie the intrinsic cardiomyopathy and accelerated atherosclerosis present in the diabetic patient. The unifying hypothesis of the program project grant is that lipid alterations in these cell types are due to fundamental changes in peroxisomal lipid flux mediated by alterations in intracellular phospholipases, PPAR mediated transcriptional regulation of critical regulatory proteins and altered lipid second messenger generation which collectively predispose candidate target cells to lipid accumulation and maladaptive pathophysiologic responses. In Project 1, we will examine the role of a novel peroxisomal calcium-independent phospholipase A2, iPLA2gamma, as a regulator of peroxisomal lipid synthesis and fatty acid beta oxidation in the cardiac myocyte. Additionally, Project 1 will examine the role of iPA2beta as a potential mediator of altered lipid metabolism and electrophysiologic dysfunction in diabetic myocardium. Dr. Kelly's Project, the role of PPARalpha as a primary determinant of the cardiac metabolic and functional phenotype present in the diabetic state will be examined utilizing mice over-expressing PPARalpha in cardiac myocyte specific fashion and a mice null for PPARalpha. Physiologic and biochemical alterations resulting from PPARalpha over-expression and the ventricular hemodynamic and metabolic abnormalities in diabetic myocardium will be compared. In Project 3, the role of altered peroxisomal lipid metabolism and intracellular phospholipase A2, activities in contributing to monocyte migration, lipid second messenger generation and lipid accumulation will be examined. The contribution of these factors in mediating the accelerated vascular response to mechanical to mechanical injury in diabetic rats will be examined. The contribution of these factors in mediating the accelerated vascular response to mechanical injury in diabetic rats will be examined. Dr. Muslig's Project the hypothesis that diabetic cardiomyopathy develops as a result of abnormal stimulation of Gq and Gi mediated signaling pathways leading to alterations in intracellular phospholipase activity, peroxisomal lipid metabolism and lipid second messenger generation will be studied. The contributions of cardiac myocyte phospholipases to Gprotein signaling will be examined. Collectively, these studies represent a synergistic, targeted, multi-disciplinary investigation aimed at elucidating the role of altered lipid metabolism and second messenger generation in critical cardiovascular cell types as the primary determinants of the excessive cardiovascular mortality and morbidity in diabetic patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MLC2V AND 2A IN CARDIAC DEVELOPMENT AND DISEASE Principal Investigator & Institution: Chen, Ju; Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 05-SEP-2000; Project End 31-JUL-2004
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Summary: (the applicant's description verbatim): Utilizing a combination of genetic engineering in mouse model systems and miniaturized physiological technology, the proposed studies will test two principal hypotheses concerning MLC2v function: 1) MLC2a cannot functionally substitute for MLC2v in ventricular cardiac muscle; 2) Phosphorylation of MLC2v plays an important role in ventricular papillary muscle and cardiac function, and impairment of MLC2v phosphorylation will result in FHC. The overall goals of the proposal are to understand the functional differences between two cardiac MLC2 isoforms, MLC2v and MLC2a and the functional role of MLC2v phosphorylation. We hope to gain insight into mechanisms by which mutations in MLC2v cause cardiomyopathy and the roles of environment, physical state, and genetic background in the incomplete penetrance and variable phenotype of this disease. We will achieve these goals by creating several gene targeted mouse lines through knock-in, and site-specific mutagenesis followed by comprehensive histological, biochemical, and physiological analysis of the resulting cardiac phenotypes. Accordingly, the Specific Aims are: 1. To investigate the functional equivalence of MLC2a and MLC2v by examining the ability of MLC2a to rescue the C2v null mutant phenotype. This will be performed by knocking the MLC2a cDNA into the MLC2v endogenous locus thereby deleting MLC2v and leaving MILC2a under the control of the endogenous MLC2v promoter. 2. To understand the functional significance of MLC2v phosphorylation and to determine whether elimination of MLC2v phosphorylation is sufficient to induce a form of hypertrophic cardiomyopathy. Mouse lines will be generated in which the phosphorylation site(s) (Ser 15 or Ser 15 plus Ser 14) of the endogenous MLC2v gene have been mutated to Ala. 3. To understand the mechanism by which MLC2v mutations cause familial hypertrophic cardiomyopathy (FHC) with middle left ventricular chamber thickening. A mouse model will be created by introducing a Glu22Lys mutation into the ALC2v gene (A Glu22Lys mutation in human MLC2v causes familial hypertrophic cardiomyopathy). For each mouse model proposed in Specific Aims 1-3, comprehensive physiological assessment of cardiac function, and detailed biochemical and biophysical analyses of resulting cardiac muscle phenotypes will be performed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR EPIDEMIOLOGY OF DILATED CARDIOMYOPATH Principal Investigator & Institution: Mestroni, Luisa; Director and Associate Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2005 Summary: This proposal addresses the molecular epidemiology of dilated cardiomyopathy by determining the frequency of disease gene mutations, and the genotype/phenotype correlations in the patient population, and their clinical relevance. Idiopathic dilated cardiomyopathy (DCM) is a disease affecting the cardiac muscle and is a primary cause of heart failure leading to heart transplant. The etiology of DCM is mainly unknown, but the disease is frequently inherited and genetically heterogeneous. Linkage studies have identified 17 FDC disease loci including a locus mapped by the P.I.'s laboratory on chromosome 9 in a large kindred with autosomal dominant FDC. Thus far, 8 disease genes have been identified: the P.I.'s laboratory has contributed to the discovery of mutations in dystrophin gene leading to X-linked FDC, and more recently, has discovered lamin A/C gene mutations in patients with FDC and variable skeletal muscle involvement. Other investigators have reported mutations in cardiac actin, deltasarcoglycan, desmin, tafazzin, beta-myosin heavy chain and troponin T leading to FDC. However, the prevalence, type and clinical relevance of cytoskeletal gene mutations in
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FDC, and in the overall DCM population are unknown. This application proposes a series of experiments designed to test the following hypotheses: 1) gene mutations are a frequent cause of FDC, 2) different gene mutations may have different frequency, different prognostic value, and different clinical relevance, 3) several FDC genes are still unidentified, and they are likely to encode cytoskeletal proteins. The Specific Aims of this proposal are: 1) to investigate of a cohort of patients with FDC and to evaluate their relatives to determine the inheritance pattern, the phenotype, the natural history, and recruit for molecular genetics studies; 2) to identify and characterize novel genes causing FDC using a candidate gene approach and a positional candidate cloning approach; 3) to analyze the molecular epidemiology of known and novel disease genes by studying the prevalence, type, and genotype/phenotype correlation of the FDC gene mutations in a large patient population with or without a familial trait. Clinical data, DNA and, in the case of FDC, lymphoblastoid cell lines have already been collected from 478 subjects, and we anticipate the enrollment of 20 to 30 new families/year. The experimental methods include mutation screening of known and novel candidate genes, positional cloning of the FDC gene on chromosome 9 by linkage and association studies, analysis of the frequency and genotype/phenotype correlations using a large database designed for these studies. The identification of the genes and mutations responsible for DCM will greatly increase the understanding of the molecular basis of this disease and will allow for the development of new molecular- based diagnostic and therapeutic strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR MECHANISM OF A MAMMALIAN CLASS I MYOSIN MOTOR Principal Investigator & Institution: Coluccio, Lynne M.; Boston Biomedical Research Institute 64 Grove St Watertown, Ma 02472 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2008 Summary: (provided by applicant): The association of some forms of cardiomyopathy, deafness, and blindness with defects in myosins, underscores the importance of studying these actin-associated, molecular motors. An understanding of the molecular mechanism of these enzymes can ultimately provide information crucial to the design of rational therapies to avert these diseases. Class I myosins are small, monomeric, mechanoenzymes with a motor domain, which binds actin and nucleotide; a regulatory region to which light chains attach; and a carboxy terminal tail. Class I myosins are widely expressed in mammalian cells and are predicted to mediate important actindependent processes such as cell migration and transport of cargo among intracellular compartments. The broad, long-term objective is to understand the enzymatic mechanism of the mammalian myosin-I, MYR 1, and how it relates to cell function. Key observations made in this laboratory have demonstrated the unique mechanochemical properties of MYR 1. MYR 1-actin exhibits a slow, biphasic transient interaction with nucleotide and a two-step powerstroke observed with single-molecule methods. These properties, not seen before for other myosins, presumably reflect the specialized adaptation of MYR 1 for particular cellular functions. The proposed experiments focus on detailing how MYR 1 interacts with actin and nucleotide. The specific aims are: (i) To investigate the contribution of two specific subdomains to MYR 1's unique mechanochemical properties using mutant proteins. The ability of mutant MYR 1 to interact with actin and nucleotide will be determined with steady and transient state kinetic analyses, in vitro motility assays and single molecule methods. (ii) To determine if MYR 1 undergoes nucleotide-dependent conformational changes using 3D
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reconstructions from cryo-electron micrographs of MYR 1-actin. These studies will allow for visualization of structural changes in MYR 1 during the myosin powerstroke. (iii) To determine if MYR 1 associates with specific subpopulations of actin filaments and whether specific structural elements in the motor domain modulate its binding to microfilaments. The ability of mutant MYR 1 to associate with actin filaments in complex with other actin-binding proteins will be determined in vitro with actin cosedimentation assays and in cells using expressed MYR 1. These studies will provide insight into how motors are targeted to particular sites in the cell, an important question in cell biology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR MECHANISMS IN T. CRUZI CARDIOMYOPATHY IN AIDS Principal Investigator & Institution: Tanowitz, Herbert B.; Professor; Pathology; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2008 Summary: (provided by applicant): Chagas' disease is caused by the protozoan parasite T. cruzi and is now recognized as an emerging HIV/AIDS-related, opportunistic infection. Subsequent to immunosuppression there is reactivation of dormant organisms leading to myocarditis and necrotizing encephalitis. Since HIV-infected patients receiving HAART live for many years there is the likelihood that there will be repeated episodes of reactivation as their immune status waxes and wanes. Hence, progressive myocarditis and cardiovascular remodeling and chronic cardiomyopathy will likely develop in a more rapid fashion. In this application we have defined ventricular remodeling as changes in structure and function following myocardial damage together with characteristic molecular changes. These changes are the result of inflammation and/or necrosis. T. cruzi infection of the myocardium results in a dilated cardiomyopathy. Our overall objective is to examine some of the important signaling pathways involved in cardiac remodeling as a consequence of the T. cruzi infection. We plan to examine the consequences of T. cruzi-infection on cyclins in vitro, Our investigations clearly indicate that T. cruzi-induced ERK activation modulates the expression and/or activity of cyclins, which function as mediators of cellular proliferation and differentiation. Cyclins are responsible for remodeling in the cardiovascular system. Therefore, the kinetics of the expression of cyclins in infected cultured cells and co-culture systems. Since we have demonstrated that T. cruzi induces expression of cyclin D1, we will determine the molecular mechanisms involved in regulation of cyclin D 1 promoter activation in cardiac fibroblasts employing transient transfection/promoter assays. We plan to determine the consequence of T. cruzi infection on cyclins in mouse models of chagasic heart disease on. During acute T. cruzi infection there is activation of ERK, transcription factors AP-1 and NF-kB and increased expression of cyclin D 1 in the myocardium. Therefore, in the mouse model of Chagas' disease the kinetics of expression of cell cycle regulatory proteins in the cells of the myocardium of T. cruzi-infected mice will be determined and correlated with progression of cardiomyopathy. The mechanisms underlying the alterations in these proteins in the myocardium will be investigated by a variety of techniques including immune complex assays and cell proliferation experiments. The contribution of cyclin D 1 in cardiovascular remodeling will be investigated utilizing mouse models including cyclin D1 null mice and mice in which NF-r.d3 and ET-1 have been selectively deleted from cardiac myocytes. These studies will lead to a better understanding of cardiac
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remodeling in chagasic cardiomyopathy, an emerging opportunistic infection in AIDS. In addition, it will provide potential targets of adjunctive therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR MECHANISMS OF MATRIX GLA PROTEIN Principal Investigator & Institution: Bostrom, Kristina I.; Assistant Professor of Medicine; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: Calcification of vessels and cardiac valves causes a multitude of clinical problems including congestive heart failure, cardiomyopathy, angina, and complications during interventional and surgical procedures. Currently, there are no medical therapies able to prevent or reverse calcification. An understanding of the underlying mechanisms would identify new targets for developments of such therapies. Mice deficient in Matrix GLA Protein (MGP) develop extensive vascular calcification with replacement of the vascular wall by typical cartilage cells. This suggests that MGP plays a role in vascular cell differentiation. We hypothesize that the function of MGP is to act as an inhibitor of bone morphogenetic protein 2 (BMP-2), a potent inducer of calcified tissues. In absence of MGP, vascular cells may be induced by BMP-2, and differentiate into cartilage and bone cells instead of vascular smooth muscle cells. We hypothesize that this effect of MGP occurs early in vessel formation. The proposal has four aims. The first is to study the effect of increased levels of MGP on cell differentiation induced by BMP-2 in tissue culture, and then use this system to identify key sequences in MGP by altering the MGP protein. The second aim is to characterize the putative binding between MGP and BMP-2 by using cross-linking and binding studies. The third aim is to identify when in the development of MGP deficient mice, vascular cells lose their normal characteristics and differentiate into cartilage cells, using specific markers for smooth muscle and cartilage cells. Finally, we will generate transgenic mice deficient in normal MGP but expressing selected key sequences of MGP identified in previous aims to affect cell differentiation, and to study the effect of these sequences on in vascular calcification in vivo. Understanding the molecular mechanisms of MGP will provide information that is widely applicable to the development of vascular disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MOLECULAR PATHOGENESIS OF CARDIAC DYSFUNCTION Principal Investigator & Institution: Giroir, Brett P.; Associate Professor; Pediatrics; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: The goal of this proposal is to determine the molecular mechanisms of cardiac dysfunction that occurs during septic shock and following thermal trauma. Previous work has demonstrated that cardiac dysfunction is mediated by the cytokine tumor necrosis factor-alpha (TNF), which is produced locally in the myocardium by cardiac myocytes. This proposal utilizes novel molecular and genetic strategies to investigate the mechanisms of TNF's detrimental effects and to develop therapeutic approaches for TNF-related cardiac contributions. First, we will study transgenic mice in which TNF is constitutively expressed only by cardiac myocytes. These mice develop profound cardiac dysfunction, cardiomyopathy, myocarditis, and cardiac failure which mimics cardiac contractile dysfunction in humans. By breeding these transgenic animals
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to mice which have undergone targeted disruption of iNOS (inducible nitric oxide synthase), IRAK (IL-1 receptor associated kinase), and ICAM-1 / P-selectin, as well as by pharmacological inhibition of specific pathways, we will quantitatively determine the involvement of iNOS, IL-1, and transmigrated leukocytes in the pathogenesis of myocardial failure. Cardiac phenotype will be characterized primarily by in vitro Langendorff perfusion of isolated mouse hearts; confirmatory longitudinal analysis of function will be accomplished in vivo by ECG-gated MRI imaging. Physiologic findings will be correlated with survival, post-mortem histology, and the pattern of cardiac gene expression. Next, we will optimize the transgenic animal model by developing a binary transgene system which is cardiac specific, and regulatable by dietary tetracycline. Through this system, we will determine if the effects of TNF are related to dose and duration of expression. We will describe the cascade of secondary cytokines induced by TNF. We will also determine whether low-level, transient expression of TNF may be evolutionary adaptive, and serve a protective role against subsequent cardiac insults. By understanding the molecular mechanisms by which TNF impedes myocardial performance, it will be possible to develop specific, targeted therapeutic strategies for the treatment of sepsis, burn trauma, and other TNF-related cardiac conditions such as cardiomyopathy, myocarditis, and ischemic heart disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR PATHOGENESIS OF MYOTONIC DYSTROPHY Principal Investigator & Institution: Cooper, Thomas; Associate Professor; Pathology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 08-FEB-1999; Project End 31-JAN-2004 Summary: The goal of this project is to determine the molecular basis for myotonic dystrophy (DM), a dominantly inherited disease caused by an expanded CTG trinucleotide repeat in the 3' untranslated region of the DMPK. DM is a multi-systemic disorder characterized by progressive skeletal muscle weakness, cardiomyopathy and arrhythmias, cataracts, and abnormalities in brain and endocrine function. Despite identification of the genetic defect six years ago, the molecular basis of the disease is unknown. DMPK transcripts containing the expanded repeat accumulate in nuclear foci. One hypothesis is that the expanded repeat creates a grain-of-function in the DMPK RNA which has a trans-dominant effect on the expression of other genes. A proposed mediator of the nucleus of DM cells. Our preliminary results establish the previously hypothesized link between the nuclear accumulation of expanded-CUG transcripts, nuclear accumulation of CUG-BP, and alteration of tissue-specific RNA processing in DM cells. We demonstrate that CUG-BP positively regulates splicing of the cardiac troponin T (cTNT) alternative exon 5 by binding to a previously characterize musclespecific splicing element. cTNT exon 5 is aberrantly included in DM striated muscle, consistent with nuclear accumulation of a positive splicing regulator. The transdominant effect on cTNT splicing was reproduced in normal muscle cells by cotransfection of cTNT minigenes with expanded DMPK minigenes containing up to 1440 CTG repeats. Wild-type cTNT minigenes but not minigenes with a mutated CUG-BP binding site expressed enhanced levels of exon 5 inclusion demonstrating the role of CUG-BP in the trans-dominant effect. The goals of this proposal are to: (i) characterize expression of a novel protein closely related to CUG-BP (etr-3) recently identified in an EST library (ii) determine the mechanism of etr-3 and CUG-BP nuclear accumulation in DM cells; (iii) identify genes that are regulated post-transcriptionally by etr-3 and CUGBP which are likely to directly mediate DM pathogenesis; (iv) establish stable fibroblast and muscle cell lines that inducible express expanded-CUG RNA; (v) establish lines of
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transgenic mice that express expanded-CUG RNA. This proposal will directly test the hypothesis that the expanded trinucleotide creates a gain-of-function mutation in the RNA. It will also establish experimental systems to investigate the basis of a novel pathogenic mechanism and ultimately, test means of therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR PHYSIOLOGY OF MYOCARDIAL TROPONIN I VARIANTS Principal Investigator & Institution: Murphy, Anne M.; Pediatrics; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 13-SEP-1999; Project End 31-MAR-2004 Summary: (the applicant's description verbatim): Contraction of the heart occurs through regulated interactions of the myofilament proteins in response to increasing intercellular calcium concentrations. Contractile dysfunction associated with myocardial disease is linked to an altered response of contractile proteins to calcium. The inhibitory subunit of troponin, troponin I, is a key regulatory protein which modulates contractility based on its phosphorylation status. Recently, modifications and mutants of troponin I have been associated with ischemic injury, heart failure and cardiomyopathy. The goal of this proposal is to understand how disease related alterations to troponin I modify its function and play a central role in myocardial disease states. A comprehensive approach is proposed to delineate the both the pathophysiology and molecular mechanisms of alteration of function produced by troponin I variants in the heart. Specific variants which will be characterized are a) truncated variant (I - 193), a loss of 16 amino acid residues from the carboxy-terminus, which recapitulates the truncated form produced by calcium dependent proteolysis in stunned myocardium, and b) troponin I variants with site-directed mutations in protein kinase A and protein kinase C phosphorylation sites to determine the role of these sites in intrinsic contractility, preconditioning, ischemia/reperfusion and heart failure and finally c) a troponin I variant with a single amino acid mutation in the inhibitory region reproducing a recently described mutant found in a familial hypertrophic cardiomyopathy. Methods include measurements of ventricular mechanics in transgenic mice using a miniaturized conductance-micromanometer catheter, studies of steady state force-calcium relationships in fura-2 loaded intact trabeculae from these mice and in vitro experiments with recombinant protein and synthesized peptides to dissect the altered biochemical properties of these troponin I variants. This work will determine a molecular mechanism of myocardial stunning, the role of troponin I phosphorylation in vivo and the pathophysiology of one form of hypertrophic cardiomyopathy. It is also anticipated that the information gained will ultimately provide a rational basis for the development of novel therapies for cardiac dysfunction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MYOCARDIAL PPAR ALPHA IN DIABETIC CARDIOMYOPATHY Principal Investigator & Institution: Kelly, Daniel P.; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Cardiac dysfunction is a common and important manifestation of diabetes mellitus. It is well recognized that cardiomyopathy occurs frequently in diabetic patients in the absence of known cardiac risk factors. Although little is known about the pathogenesis of diabetic cardiomyopathy, evidence is emerging that cardiac dysfunction
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in the diabetic heart is related to perturbations in myocardial metabolism caused primarily or secondarily by insulin deficiency or resistance. In uncontrolled diabetes, the myocardial extraction and utilization of fat is markedly increased such that the diabetic heart relies almost exclusively on mitochondrial fatty acid oxidation (FAO) for its ATP requirements. Recent studies have defined an important role for the lipid-activated transcription factor, the peroxisome proliferator-activated receptor alpha (PPARalpha), in the control of cardiac fatty acid utilization pathways. Our preliminary data indicates that the activation of cardiac fatty acid utilization in the diabetic heart is mediated by the PPARalpha gene regulatory pathway. Our preliminary data indicates that the activation of cardiac fatty acid utilization in the diabetic heart is mediated by the PPARalpha gene regulatory pathway. This proposal is designed to test the hypothesis that lipid metabolic alterations secondary to increased activity of PPARalpha lead to pathologic remodeling in the diabetic heart. Such pathologic remodeling could occur due top increased oxygen consumption or through toxic lipid intermediates generated by peroxisomal or mitochondrial pathways. This hypothesis will be tested by the phenotypic characterization of mice with cardiac-specific over- expression of PPARalpha (MHCPPAR mice). First, the lipid metabolic and cardiac functional phenotypic of multiple independent lines of MHC-PPARalpha transgenic mice will be evaluated and compared with that of mice rendered diabetic via administration of streptozotocin. Second, the role of PPARalpha in the expression and severity of diabetic cardiomyopathy will be determined by altering its activity via genetically engineered loss-of-function (PPARalpha null mice) and gain- of-function (MHC-PPAR mice) in the context of three different murine models of diabetes. Lastly, the role of altered peroxisomal function in MHC-PPAR mice compared to diabetic mice. The long term goal of this project is to delineate the precise molecular and metabolic bases for diabetic cardiomyopathy including identification of specific lipid mediators of cardiac dysfunction. This work should lead to the development of novel therapeutic strategies aimed at modulating cardiac lipid metabolism to reduced the cardiovascular morbidity and morality in diabetic patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MYOCARDIAL PROTEIN SYNTHESIS AFTER THERMAL INJURY Principal Investigator & Institution: Lang, Charles H.; Professor and Vice-Chairman; Cellular/Molecular Physiology; Pennsylvania State Univ Hershey Med Ctr 500 University Dr Hershey, Pa 17033 Timing: Fiscal Year 2002; Project Start 10-JUL-2001; Project End 31-MAY-2006 Summary: (provided by applicant): Myocardial dysfunction remains a major cause of morbidity and mortality in patients after thermal injury. Our preliminary data provide evidence that the burn-induced decrease in intrinsic mechanical function is associated with an impairment in myocardial protein synthesis and translational efficiency. The working hypothesis to be tested is that the burn-induced decrease in myocardial protein synthesis is mediated by defects in translational efficiency resulting from an impairment in both peptide-chain initiation and elongation, and that these changes are mediated by the overproduction of tumor necrosis factor (TNF)a which alters the responsiveness of the heart to insulin-like growth (IGF)-l and growth hormone (GH), To address the questions implicit in this hypothesis, the proposed research has the following specific aims: (1) to determine the temporal progression of burn-induced changes in protein synthesis, indices of peptide-chain initiation and myocardial function, and to determine whether these changes are mediated by TNFa; (2) to determine the mechanism by which thermal injury decreases activity of eIF2B in heart, by assessing the phosphorylation of
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elF2Be, content of p67, and the importance of alterations in kinase and phosphatase activities directed towards eIF2a and eIF2Be; (3) to determine the mechanism by which burn alters elF4E availability, by assessing the phosphorylation status of the various 4Ebinding proteins and p7OS6 kinase, and quantitating the degradation of eIF4G; (4) to determine the mechanism by which burn impairs peptide-chain elongation in heart, by quantitating the rate of elongation under in vivo conditions and by determining the myocardial content and phosphorylation state of elongation factors EFI and EF2; and (5) to determine the signaling mechanisms by which burn injury impairs GH and IGF-I action in heart. Our data suggest that the bum-induced changes in cardiac protein synthesis and translation initiation are relatively unique, and do not occur in skeletal muscle in response to burn or in heart in response to other traumatic conditions. Overall, the research will elucidate the mechanisms by which myocardial protein synthesis is reduced after thermal injury, leading to the better understanding and treatment of the resulting cardiomyopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MYOCYTE CELL DEATH IN THE INFARCTED HEART Principal Investigator & Institution: Anversa, Piero; Professor and Director; Medicine; New York Medical College Valhalla, Ny 10595 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2003 Summary: The objective of this proposal is to demonstrate that postinfarction cardiomyopathy is dependent upon the changes in size, shape, and number of the surviving myocytes, whereas the alterations in the infarcted myocardium play a minimal role in the long-term evolution of ventricular remodeling and chamber dilation. work during this funding period has documented that the cellular events which characterize the reactive hypertrophy of the spared myocardium, acutely and at the completion of healing, fail to normalize ventricular pump function, leading to a persistent elevation in diastolic wall stress. This mechanical stimulus is postulated by be responsible for continuous myocyte lengthening and the in series addition of newly formed cells through the mechanism of myocyte cellular hyperplasia. Extreme degrees of ventricular dilation may be generated by these cellular growth processes and intractable ventricular dysfunction and failure may supervene. Such an unfavorable outcome lies in the inability of myocytes to increase in diameter and/or be added in parallel within the wall to expand mural thickness and counteract the elevation in diastolic wall stress dictated by the larger cavitary volume. In a similar fashion, hypertensive hypertrophy, with its attendant changes in myocyte diameter and cross section area, may have exhausted one of the most important compensatory reactions of myocytes, which would tend to attenuate the consequences of ventricular dilation after infarction. Thus, the detrimental impact of hypertension induced concentric hypertrophy, prior to coronary artery occlusion, may reflect this phenomenon. Therefore, the recognition of control mechanisms implicated in the transmission of mechanical signals to myocytes and the initiation of the molecular events leading to increases in myocyte diameter, myocyte length and myocyte number may have important clinical implications in the prevention and treatment of the cardiomyopathy generated by myocardial infarction alone or in combination with hypertension. Accordingly, the hypotheses have been made that activation of alpha1b adrenergic receptors and AII receptors, and transmission of signals by these receptors induce myocyte hypertrophy and selectively mediate the increases in myocyte cell length and diameter, respectively. On the other hand, cellular hyperplasia is believed to be triggered by the expression of growth factor receptors on myocytes. In summary,
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myocyte hypertrophy and hyperplasia are assumed to both contribute to accommodate the sudden increase in work load associated with myocardial infarction. When the acute phase has subsided, myocyte hypertrophy, characterized by lengthening of the cells, becomes the predominant factor responsible for ventricular dilation. However, longterm restructuring of the ventricle after infarction may occur exclusively by the addition in a series of newly formed myocytes which may lead to extreme degrees of ventricular dilation. Hypertension may accelerate this sequence of events worsening the myocardial response to infarction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MYOCYTE FUNCTION IN CARDIOMYOPATHIC CREB A133 MICE Principal Investigator & Institution: Moss, Richard L.; Robert Turell Professor and Chair of Phy; Physiology; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 30-SEP-1998; Project End 31-JUL-2003 Summary: Dilated cardiomyopathy (DC) represents an important cause of cardiovascular morbidity and mortality and consumes a disproportionate share of medical resources in this country. Despite recent advances in the treatment of DC, this disorder has a poor prognosis with 5 year mortality rates of 20-50 percent. Progress in understanding the pathophysiology of DC and in devising new therapies for this disorder has been limited by our relative lack of understanding of the molecular pathophysiology of the disease and by the lack of a small animal model which closely resembles the anatomical, physiological, and clinical features of the human disease. The investigators have recently shown that transgenic mice expressing a dominant-negative form of the CREB transcription factor (CREBA133) under the control of the cardiacspecific alpha-MHC promoter reproducibly develop DC that resembles many of the anatomical, physiological and clinical features of human DC. In the studies described in these 3 collaborative R0I applications, the investigators propose to use this new mouse model to better understand the molecular pathways by which CREB regulates cardiac myocyte homeostasis and how perturbations in these pathways produce DC. Specifically, they will 1) elucidate the CREB-dependent signaling pathways that are required to maintain cardiac myocyte homeostasis and determine how these pathways are perturbed in the CREBA133 mice with DC, 2) determine the role of apoptosis in the CREBA133 DC and test the hypothesis that the cardiomyopathic phenotype can be ameliorated by expression of anti-apoptotic genes in the heart, 3) study excitationcontraction coupling, contractility, and calcium homeostasis in the CREBA133 cardiac myocytes, 4) understand the myofibrillar and SR defects underlying cardiac myocyte dysfunction in the CREBA133 mice, 5) study ventricular remodeling and LV-arterial coupling during the development of DC in the CREBA133 mice, and 6) determine the effects of exercise conditioning, gender, and different modes of inhibiting the renin angiotensin system on progression of DC in the CREBA133 mice. These studies represent the continuation of an established collaboration between molecular biologists (Leiden), cell physiologists (Moss) mouse and human physiologists (Lang, Spencer) and clinical cardiologists (Leiden, Lang, Spencer) from the Universities of Chicago and Wisconsin. Taken together the results of this work should provide us with important new insights into the molecular mechanisms underlying human DC and CHF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NITRIC OXIDE METABOLIC CONTROL IN PREGNANCY Principal Investigator & Institution: Hintze, Thomas H.; Professor; Physiology; New York Medical College Valhalla, Ny 10595 Timing: Fiscal Year 2003; Project Start 15-DEC-1993; Project End 31-DEC-2006 Summary: (provided by applicant): The cardiovascular adjustments that occur during pregnancy include chronic increases in cardiac output, falls in total peripheral vascular resistance and tachycardia. There is an upregulation of endothelial nitric oxide synthase in almost all vascular beds studied in the gravid female including skeletal muscle, kidney and utems or placenta. The upregulation of eNOS directly contributes to the fall in TPR which is not confined to the placenta. Many studies have investigated the role of NO in the control of vascular resistance or how NO may buffer vasoconstriction and that a defect in NO production may be involved in pre-eclampsia. Despite increasing evidence that NO also modulates mitochondrial metabolism and substrate uptake by the heart, i.e. prevents glucose uptake and facilitates fatty acid uptake, there are literally no studies that have investigated the role of increased eNOS in the control of substrate uptake and organ oxygen consumption at all. We have previously shown that NO by interacting with cytochrome oxidase in heart, kidney and skeletal muscle serves to maximize the ratio of oxygen consumed to external work performed ie. increases efficiency. We have also shown that when eNOS produces NO in the heart and elsewhere, glucose uptake is prevented. It is important to re-emphasize that pregnancy is characterized by increased eNOS gene expression and increased NO production in every vascular bed of the mother. Furthermore, glucose uptake by the mother is low even insulin insensitive and this is thought to increase the amount of glucose available for uptake through the placenta to support fetal metabolism, since the placenta does not take up fatty acids. In addition a small but significant number of mothers go on to have a post-partum cardiomyopathy often leading to heart transplantation, perhaps when adjustments that occur during pregnancy do not regress after parturition. Thus the focus of this competitive renewal application will be the role of NO in the control of oxygen and substrate use during pregnancy with particular reference to the heart and coronary circulation. In the first specific aim, we will examine the role of NO in the control or metabolism in aged eNOS KO mice. The second aim will focus on the role of NO in the pregnant eNOS KO mouse whereas the third specific aim will focus on the role of NO in cardiac glucose and oxygen uptake in the rat heart during pregnancy. Finally aim 4 will use chronically instrumented conscious pregnant dogs to address the role of NO in the control of cardiac function, substrate use and oxygen consumption during pregnancy and after parturition. For the first time we wilt perform a systematic mechanistic investigation into the role of NO in the control of cardiac oxygen and substrate use during pregnancy. These studies have direct application to the physiology of pregnancy and to the potential mechanisms resulting in post partum cardiac dysfunction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NO AND OXIDATIVE STRESS IN HUMAN MYOCARDIAL FAILURE Principal Investigator & Institution: Givertz, Michael M.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 15-AUG-1999; Project End 31-JUL-2004 Summary: The overall goal of this project is to determine the functional significance of myocardial nitric oxide (NO) and oxidative stress in humans with heart failure (CHF). Recent evidence suggests that NO is increased in failing human myocardium and may contribute to the pathophysiology of CHF. In addition, increased myocardial oxidative
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stress has been demonstrated in heart failure. In vitro studies indicate that reactive oxygen species (ROS) can exert direct toxic effects on the myocardium associated with impaired contractility, fetal gene expression and cell death. Moreover, antioxidants have been shown to attenuate the negative inotropic effects of ROS and prevent the development of heart failure in animal models. In left ventricular (LV) failure, the heart rate- mediated increase in contractility (force-frequency relationship) is attenuated, flat or even inverted. While the failure to increase contractility with tachycardia likely contributes to the reduced cardiac output response and exercise intolerance observed in patients with CHF, the underlying mechanisms are poorly understood. In Specific Aim 1, we will test the hypothesis that increased myocardial NO synthase (NOS) activity attenuates the force- frequency relationship in humans with LV failure by measuring the changes in the peak rate of rise of LV pressure (+dP/dt) that occur with increasing heart rates before and during intracoronary infusion of NG-monomethyl-L-arginine, an inhibitor of NOS. In Specific Aim 2, we will test the hypothesis that increased myocardial oxidative stress attenuates the force-frequency relationship in humans with LV failure by determining the force- frequency relationship before and during intracoronary infusion of the antioxidant ascorbic acid. Aims 1 and 2 are invasive protocols that will assess the acute functional significance of myocardial NO and oxidative stress in heart failure. In Specific Aim 3, we will test the ability of a novel, noninvasive system to detect acute changes in contractile state by measuring LV endsystolic elastance during atrial pacing tachycardia and intracoronary dobutamine infusion in patients with dilated cardiomyopathy. If we show that this new technology is able to measure changes in contractility in the catheterization laboratory, we will assess its ability to detect chronic changes in LV performance by measuring end-systolic elastance before and after therapy with antioxidants and/or anti- inflammatory agents in patients with systolic heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NRTI-INDUCED MITOCHONDRIAL CARDIOMYOPATHY Principal Investigator & Institution: Wallace, Kendall B.; Professor; Biochem/Mole Biol/Biophysics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Cardiovascular disease is a growing complication of HIV. Although there is an increased incidence associated with the infection itself, it is further complicated by the antiviral therapy prescribed to treat the disease. The cornerstone of the HAART drug regimen for treating HIV are nucleoside analog reverse transcriptase inhibitors (NRTIs), which inhibit viral RNA-dependent DNA polymerases. However, these drugs are also recognized by host cell DNA polymerases including Polg, which is responsible for replicating the mitochondrial genome. As a result, the NRTIs inhibit mtDNA replication and biogenesis leading to mitochondrial depletion, which is manifested as a dose-limiting lactic acidosis and life-threatening cardiomyopathy. Although there is considerable evidence implicating mitochondrial depletion in the pathogenesis of NRTI toxicity, little is known regarding the bioenergetic characteristics responsible for the mitochondrial phenotype. The purpose of this investigation is identify which NRTIs induce mitochondrial cardiomyopathy in animal models at relevant doses and to fully characterize the mitochondrial bioenergetic deficits that underlie the metabolic disorder. We propose that the loss of coordinated expression of the nuclear and mitochondrial genomes leads to the assembly of poorly coupled electron transport chains, resulting in a loss of efficiency of oxidative phosphorylation
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accompanied by the catalytic liberation of highly reactive oxygen free radicals. Mitochondrial cardiomyopathy likely reflects both bioenergetic failure and increased oxidative damage owing to this interference with mitochondrial biogenesis. The results of this investigation will provide valuable insight into distinguishing which NRTIs are cardiotoxic and identifying the underlying mechanisms in the pathogenesis of cardiac injury. This information will be essential to predicting possible interactions between components of the HAART drug regimen and for developing reliable biomarkers and/or new treatment strategies designed to minimize the cardiomyopathy and thus improve the clinical success of HIV pharmacotherapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OXIDATIVE RESTRICTION
STESS
AND
HEART
FAILURE
BY
COPPER
Principal Investigator & Institution: Kang, Y James.; Professor; Medicine; University of Louisville University of Louisville Louisville, Ky 40292 Timing: Fiscal Year 2002; Project Start 15-JUN-2001; Project End 31-MAY-2005 Summary: Dietary copper restriction causes cardiac hypertrophy, ultimately leading to heart failure. A proposed mechanism for this cardiomyopathy is the accumulation of reactive oxygen species. Using a cardiac-specific metallothionein (MT)- overexpressing transgenic mouse model, we have observed that elevation of this potent antioxidant in the heart suppresses the progression of heart hypertrophy and likely results in the retarded development of heart failure induced by dietary copper restriction. This observation suggests that oxidative stress may play a crucial role in the pathogenesis of heart failure. We therefore propose to test the hypothesis that oxidative stress triggers the transition from heart hypertrophy to failure induced by copper deficiency. We will use the cardiac-specific MT- overexpressing transgenic mouse model to carry out the following specific aims: (1) To define the role of oxidative stress in the transition from heart hypertrophy to failure, a detailed time- course study of the development of heart failure by dietary copper restriction will be performed. In particular, this study will focus on defining the cause-and-effect relationship between oxidative stress and dynamic changes in cardiomyopathy, cardiac dysfunction and heart failure. (2) To determine cellular events involved in the transition from heart hypertrophy to failure, the significance of cell death in the pathogenesis will be defined by immuno-gold TUNEL and electron microscopy in combination with a novel procedure using cardiac alpha-sarcomeric actin antibody to label necrotic cells. The relative contributions of apoptosis and necrosis to the total cell loss will be analyzed. (3) To investigate signaling pathways leading to myocardial cell death during the transition from heart hypertrophy to failure, oxidative stress-induced mitochondrial cytochrome c release and activation of caspase-9 and -3 will be examined by immunohistochemical method, enzymatic assay and Western blot analysis. The consequence of caspase inhibition will be analyzed in order to dissect major pathways leading to cell death. (4) To examine the role of atrial natriuretic peptide (ANP) and tumor necrosis factor-alpha (TNF-alpha) in the late phase transition from heart hypertrophy to failure, dynamic changes in ANP and TNF-alpha production will be studied. Molecular mechanisms of up-regulation of these cytokines will be analyzed through examining the activation of transcription factors NF-kappaB and AP-1. (5) To explore possible mechanisms by which MT inhibits oxidative stressmediated myocardial cell death induced by dietary copper deficiency, the effect of MT on oxidative stress- mediated mitochondrial membrane changes that lead to cytochrome c release will be examined. The overall goal of this study is to define the role of oxidative stress in copper deficiency-induced pathogenesis of heart failure. This study will give
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critical insights into the signaling pathways and molecular mechanisms of failure induced by copper deficiency. Importantly, the data obtained will provide valuable information for novel experimental as well as clinical approaches for possible interventions of the transition from heart hypertrophy to heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PATHOGENESIS OF CHAGAS HEART DISEASE Principal Investigator & Institution: Engman, David M.; Associate Professor; Pathology; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2007 Summary: (provided by the applicant): The protozoan parasite Trypanosoma cruzi is the etiologic agent of Chagas' disease, an illness that causes severe morbidity and death among millions of Latin Americans. The most common, and most serious, adverse effect of chronic infection with this parasite is Chagas heart disease (CHD), a dilated cardiomyopathy of uncertain etiology. A number of mechanisms have been proposed for the pathogenesis of CHD, two of which are the subject of considerable controversy. Because parasites are scarce in or absent from the heart tissues of Chagas' patients who succumb to heart failure, autoimmunity has been proposed to be responsible for disease pathogenesis. More sensitive techniques, such as in situ PCR and immunohistochemistry, have been used to analyze these hearts and, indeed, parasite DNA and antigen are present. These findings support the hypothesis that parasiteinduced damage plus host immunity to parasite antiqens is the inflammatory stimulus. Another confounding factor is that different combinations of parasite and animal strains give different outcomes, which, in actuality, is reflective of the human disease. To test the autoimmunity hypothesis for CHD pathogenesis, while simultaneously considering the parasite immunity hypothesis, we developed a mouse model of CHD (T. cruzi Brazil strain infection of male A/J mice) in which strong cardiac autoimmunity and parasitespecific immunity rapidly develop upon infection. Our research during the past several years indicates that (i) cardiac autoimmunity develops upon infection that is of similar magnitude and quality as that induced by immunization with cardiac proteins in adjuvant (purely autoimmune), (ii) autoimmunity involving a number of cardiac antigens develops in infected animals, (iii) autoimmunity to cardiac myosin may develop via the mechanisms of molecular mimicry and bystander activation, and (iv) selective suppression of myosin autoimmunity does not eliminate tissue inflammation in infected animals, suggesting that other autoimmune responses may be significant and/or that parasite-specific immunity hypothesis is sufficient to give tissue inflammation. The Specific Aims of our research are (i) to investigate the molecular mimicry mechanism of myosin autoimmunity in CHD, (ii) to identify additional cardiac auto-antigens and determine their roles in CHD pathogenesis and (iii) to test the autoimmune and parasite immune hypotheses for CHD pathogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: AMYLOIDOSIS
PATHOGENESIS
OF
HEREDITARY
TRANSTHYRETIN
Principal Investigator & Institution: Benson, Merrill D.; Professor; Medical and Molecular Genetics; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 01-AUG-1990; Project End 31-MAR-2004
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Summary: (from abstract): The overall objective of this proposal is to define the pathophysiology of the autosomal dominant transthyretin amyloidoses. These diseases, while considered rare, are actually being recognized in increased numbers of kindreds throughout the world and especially in the United States. Transthyretin amyloidosis is usually associated with peripheral neuropathy, nephropathy, and cardiomyopathy which present as late-onset (adult) disease with high degrees of morbidity and mortality. To date at least 72 variants of transthyretin (TTR) have been found to be associated with systemic amyloidosis which is inherited as an autosomal dominant disease. Of particular concern is the fact that: 1) it has recently been shown that there are elderly individuals who develop transthyretin amyloid cardiomyopathy (senile cardiac amyloldosis) in the absence of any detectible mutation in transthyretin; and, 2) there is a high prevalence of one particular transthyretin mutation (isoleucine 122) in the American Black population and this is manifest as amyloid cardiomyopathy. These two findings suggest that, as the population ages, amyloid heart disease will become of greater significance to the American population. Previous studies have centered on determining structural changes of transthyretin which are related to amyloid formation. Structures of amyloid forming variants methionine 30, serine 84, alanine 60, arginine 10, tyrosine 77 have been compared to structures of non amyloid forming threonine 109, serine 6, methionine 119 and normal transthyretin. No common structural change has been found to explain initiation of the fibril forming process but preliminary data suggest that solvent accessability to variant transthyretin dimers may allow a proteolysis event which could lead to the initiation of fibril formation. Metabolic studies using radiolabelled variant and normal transthyretins have suggested increased plasma clearance of variant proteins. The Specific Aims will test the hypothesis that single amino acid substitutions in transthyretin result in changes in tertiary structure of the transthyretin molecule which allow alterations in metabolism of the variant molecule and its associated normal monomers to lead to amyloid formation. Transthyretin proteins isolated from tissues of patients with amyloidosis will be studied to characterize proteolytic peptides and determine if partial proteolysis with generation of carboxyl terminal peptides is a factor in amyloid fibril formation. Fibril forming potential of these fragments will be tested by producing recombinant protein of residues 49 - 127 and testing fibril formation with and without full-length transthyretin in vitro. A new Specific Aim will test the hypothesis that the ratio of the various tetrameric forms of transthyretin affects the propensity to form amyloid fibrils. To accomplish this aim a dual expression system in baculovirus coexpressing normal TTR and variant TIR has been developed. These studies are directed at developing methods to prevent amyloid formation from variant TTR proteins and, thereby providing therapeutic options for a disease which at the present time has no specific therapy other than liver transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: POST DPP FOLLOW-UP STUDY Principal Investigator & Institution: Goldberg, Ronald B.; Chief, Division of Diabetes and Metaboli; Medicine; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2003; Project Start 20-AUG-1994; Project End 31-JAN-2008 Summary: (provided by applicant): The Diabetes Prevention Program is a multicenter controlled clinical trial examining the efficacy of an intensive life-style intervention or metformin to prevent or delay the development of diabetes in a population selected to be at high risk due to the presence of impaired glucose tolerance (IGT). Development of diabetes, defined by 1997 ADA criteria, is the primary outcome while cardiovascular
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disease and its risk factors are important secondary outcomes. The DPP began recruitment in mid-1996. At the time of this application, total study exposure is a mean of approximately 3 years (range 2 to 5) with a total of approximately 10,000 patient years in the 3,234 volunteers in the 3-arm study. On the basis of a statistically significant and clinically compelling decrease in the development of diabetes in the life-style intervention and metformin-treated groups (58% and 31% reductions, respectively) compared with the placebo treated group, the DPP Data Monitoring Board and NIDDK ended the masked treatment phase of the study in May, 2001, one year earlier than originally planned. This application is designed to take further advantage of the scientifically and clinically valuable cohort of DPP volunteers and the large volume of data collected during the study. The highly compliant DPP cohort, including 45% minorities, is the largest IGT population ever studied. Moreover, the subcohort that has developed diabetes (n approximately 700) has been followed from near the exact time of diabetes onset. Clinically important research questions remain in the wake of the DPP. The carefully collected, centrally measured and graded data in this cohort should help to answer, definitively, a number of important questions regarding the clinical course of IGT and early onset type 2 diabetes. Specific aims include: 1. Examine the long-term effects and durability of prior DPP intervention on the major DPP outcomes including diabetes, clinical cardiovascular disease, atherosclerosis, CVD risk factors, quality of life and cost-benefit; 2. Determine the clinical course of new onset type 2 diabetes and IGT, in particular regarding microvascular and neurologic complications; 3. Determine the incidence of cardiovascular disease (CVD), CVD risk factors and atherosclerosis in new onset type 2 diabetes and IGT; and 4. Examine topics 1-3 in minority populations, men vs. women, and in older subjects in the DPP. The current application is for 5 years of funding, although the some of the goals of the projects described will require a 10-year study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PREDICTION OF CARDIOMYOPATHY IN TYPE I DIABETES BY MRS Principal Investigator & Institution: Pohost, Gerald M.; Director; Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2007 Description (provided by applicant): Congestive heart failure is a leading cause of morbidity and mortality in the United States and diabetes has been recognized as a major risk factor for the development of this disease. However, there is a lack of consensus regarding the existence of a diabetes-specific cardiomyopathy as well as the importance of vascular and non-vascular alterations in the development of diabetesrelated cardiac disease. We recently demonstrated a transient decrease in cardiac phosphocreatine (PCr)/ATP with handgrip stress, indicative of ischemia, in women with chest pain but no artery disease. The most likely explanation for these results was the presence of microvascular disease. Thus, given the sensitivity of changes in bioenergetics to ischemia and the lack of any direct, non-invasive measurements of microvascular disease, we will use 31P-NMR spectroscopy to evaluate the effects of diabetes on cardiac metabolism. Specifically, we will test the hypothesis that patients with diabetes will exhibit reversible, exercise-induced decreases in PCr/ATP and PCr/inorganic phosphate consistent with an imbalance in energy supply and demand. Furthermore, we propose that these changes will be present only in those diabetic patients with evidence of systematic microvascular disease and will be accompanied by evidence of contractile dysfunction as assessed by cine MRI. Finally we anticipate that
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the observation of metabolic functional abnormalities will be predictive of short- and long-term outcomes. We will test these hypotheses by determining the effects of handgrip exercise on cardiac bioenergetics and cardiac function in diabetic patients with and without evidence of systematic microvascular disease. We will also evaluate the utility of abnormal cardiac bioenergetics and function as predictors for the development of overt cardiac disease in patients with diabetes. Cardiac bioenergetics will be assessed using 31P-NMR spectroscopy at 4.1T and cardiac function will be measured using cine MRI at 1.5T. Type 1 diabetic patients aged 40 and under with a duration of diabetes greater than 10 years will be studied and grouped based on the presence or absence of systemic microangiopathy. These studies will enable us to assess whether the presence of microvessel disease is a prerequisite for the development of cardiac dysfunction in diabetic patients. This investigation will provide an unprecedented insight into the impact of diabetes on cardiac function and bioenergetics in humans. This will provide valuable information for the development of novel therapeutic interventions and improved management of diabetic patients with cardiac disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INSTABILITY
PROPERTIES
AND
DETERMINANTS
OF
GAA
REPEAT
Principal Investigator & Institution: Bidichandani, Sanjay I.; Biochem and Molecular Biology; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2007 Summary: (provided by applicant): Friedreich ataxia is an autosomal recessive disease, characterized clinically by ataxia (incoordination), cardiomyopathy and diabetes. The most common mutation, seen in >95% of patients is an abnormal expansion of a GAA triplet-repeat sequence in intron 1 of the FRDA (frataxin) gene. Normal and mutant alleles contain 6 - 100 and 100 - 1700 triplets, respectively. Expanded (mutant) alleles exhibit marked instability in somatic cells and during intergenerational transmission. Disease-causing expansions arise when premutation alleles (30 - 100 triplets) undergo hyperexpansion during intergenerational transmission. The mechanism of hyperexpansion of premutation alleles and the subsequent somatic and germline instability of expanded alleles remains poorly understood. The overall goal of this project is to investigate the mutagenic mechanisms underlying the genetic instability of the GAA triplet-repeat sequence. We will perform "small-pool PCR" (SP-PCR) analysis to test the pattern of genetic instability of normal, premutation, and expanded chromosomes, in a wide variety of somatic tissues and germ cells derived from patients and asymptomatic carriers of various alleles. We will investigate the effect of DNA replication on GAA triplet-repeat instability using a defined eukaryotic replication model system. We will also investigate the role of cis-acting and epigenetic modifiers in determining instability of the GAA triplet-repeat sequence. It is hoped that these studies will lead to the development of novel strategies to prevent or reverse the process of GAA triplet-repeat expansion as a possible future therapy for Friedreich ataxia. Our data could potentially lead to the discovery of general properties of triplet-repeat instability, which will have implications for other diseases caused by this mutational mechanism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATION OF NA,K ATPASE BY THE AH RECEPTOR Principal Investigator & Institution: Walker, Mary K.; Associate Professor of Pharmacology And; None; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131 Timing: Fiscal Year 2002; Project Start 05-AUG-2000; Project End 31-JUL-2004 Summary: Human exposure during pregnancy to persistent environmental pollutants, like 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related chemicals, results in decreased birth weights, neurological deficits, thyroid hormone alterations, lung auscultation, and hyperpigmentation. The mechanism by which TCDD mediates developmental toxicity has not been elucidated. The basic helix-loop-helix-PAS transcription factor, aryl hydrocarbon receptor (AhR), is required for TCDD-induced teratogenicity in mice and likely mediates teratogenicity in other species. TCDD toxicity may result from alterations in gene transcription by the AhR. One potential AhR gene target that could account for some of TCDD's teratogenic effects is the Na+/K+ ATPase alpha1. Putative dioxin response elements are conserved in the 5' enhancer region of the mammalian and avian Na+/K+ ATPase alpha1 gene. In the chick embryo, TCDD reduces myocardial Na+/K+ ATPase alpha1 protein expression, induces a dilated cardiomyopathy, and alters ECGs, all consistent with reduced Na+/K+ ATPase activity. In mice lacking the AhR, embryos develop a hypertrophic cardiomyopathy and cardiac fibrosis which worsens with age, consistent with the potential overexpression of Na+/K+ ATPase alpha1 and development of hypertension. I will use the chick embryo and AhR null mice to test the hypothesis that the AhR regulates myocardial expression of the Na+/K+ ATPase alpha1 gene, altering cardiovascular development. The aims of this proposal are to (1) elucidate the regulation of myocardial Na+/K+ ATPase alpha1 gene in AhR null mice and in the developing chick embryo by TCDD using RT-PCR, and in vitro by promoter analysis of the avian gene; (2) determine the tissue significance of this regulation by quantitating myocardial ouabain binding sites and Na+/K+ ATPase enzyme activity in AhR null mice and TCDD-exposed chick embryos; (3) determine the functional significance by measuring blood pressure in AhR null mice and myocardial sensitivity to ouabain in TCDD-exposed chick embryos by ECG; and (4) analyze the expression of murine and avian homologues of candidates genes, whose expression is altered by TCDD in the rat embryo heart and lung as identified by Dr. Selmin, University of Arizona, by PCR-selected subtractive hybridization method and screening of gene microarrays. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ROLE OF BETA-RECEPTOR SIGNALING IN CARDIOMYOPATHY Principal Investigator & Institution: Bernstein, Daniel; Professor of Pediatrics; Pediatrics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2005 Summary: The cardiac responses to stress and cardiomyopathy share a common feature: altered signaling through G protein-coupled receptor (GPCR) pathways that regulate the homeostatic balance of signaling in the heart. This altered signaling can result from changes in the expression or function of receptors, G proteins, as well as down-stream effectors. Restoration of normal homeostasis in cardiomyopathy via GPCR signaling is the basis for medical therapies that target GPCRs, such as the beta-adrenergic receptor (AR). The goal of this proposal is to study the specific roles of beta1 and beta2-ARs in the pathophysiology of cardiomyopathy. Alterations in beta-AR signaling are a central manifestation of chronic sympathetic activation. However, there is controversy as to
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whether beta-AR downregulation is responsible for the decrease in heart function or is a mechanism to protect the heart from chronic sympathetic stimulation. Recent evidence has linked beta-AR signaling not only to alterations in cardiac function, but to mitogenic pathways which could play a role in cardiac remodeling. We have developed an ideal model to examine the role of beta-ARs in cardiomyopathy: mice with targeted disruptions of beta1 and beta2-ARs. We have preliminary evidence suggesting that absence of the beta1-AR may attenuate the development of cardiomyopathy. Further evidence suggests that absence of the beta2-AR may exacerbate the cardiotoxicity of chronically administered catecholamines. We will utilize our knockout models: 1) To determine the role of beta-ARs in the pathogenesis of cardiomyopathy and whether total absence of beta1 and/or beta2-ARs will attenuate or accelerate cardiac dysfunction in models of cardiomyopathy; 2) To determine whether differences between beta1 and beta2-AR subtypes, both in their role in normal physiology and in their contribution to the cardiomyopathic phenotype, are related to differences in regulated expression or to differences in primary structure. For this purpose, we will utilize a gene exchange model, in which the murine beta1-AR is replaced with a murine beta2-AR under control of the native beta1-AR promoter; 3) To determine the role of beta-AR-mediated interactions between cardiac myocytes and fibroblasts in the pathogenesis of cardiomyopathy; 4) To identify signaling events, mediated by both classical (GS) and alternative (non-GS) pathways, that are altered in cardiomyopathy, and to determine the role of beta-ARs in regulating these pathways. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SPECIALIZED CENTER OF RESEARCH IN HEART FAILURE Principal Investigator & Institution: Mann, Douglas; Professor; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 17-FEB-1995; Project End 31-JAN-2005 Summary: The overall objective of the current SCOR and the Proposed Renewal is to elucidate the molecular basis for the long-term adaptive response of the heart to injury, both inherited and acquired, where manifested by hypertrophy or dilitation. This proposal encompasses 5 collaborative investigations, supported by integrated core facilities to address issues fundamental to the etiology, pathogenesis and treatment of cardiac failure. Novel genes will be identified responsible for inherited cardiac disorders, familial dilated cardiomyopathy (FDCM) manifested in the left ventricle and arryhthmogenic right ventricular dysplasia in the right ventricle, as paradigms of dilated cardiomyopathy, the most common form of acquired heart failure. To date, two genes (cytoskeletal) have been identified that cause DCM, actin and desmin. Thus, cytoskeletal proteins may provide a unifying causality for DCM analogous to that of sarcomeric proteins for HCM. Accordingly, insight gained from expression of the mutant desmin in the transgenic mouse should have pathogenetic implications for DCM due to other defective cytoskeletal proteins, whether familial or acquired. While assembly and organization of the cytoskeletal components are an integral part of the cardiac growth response, their role as heretofore been ignored until the identification of the integrin signaling pathway (RhoA, Focal Adhesion Kinase, and Integrin Linked Kinase). In Dr. Schwartz' project, dominant negative mutants of these molecules will be used in cardiac myocytes and Gene-Switch transgenics to determine whether one or all of these are necessary for cytoskeletal assembly and hypertrophy. FHCM, due to over 100 mutations in seven genes, develops the secondary phenotype of increased fibrosis and hypertrophy, providing the opportunity for prevention. Renin-angiotensin system (RAS) inhibitors will be assessed in transgenics harboring the human cTNT mutation
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and, in preparation for future gene therapy, Gene-Switch will be used to determine if the phenotype is reversible. Growth factor(s) responsible for the secondary phenotype will be sought through subtraction hybridization. A novel pathway (TNFalpha) shown in the current SCOR to play a pivotal role in the growth response (hypertrophy) and heart failure (apoptosis), will be pursued to identify molecular interaction with RAS, both in genetic models and in patients with heart failure and to develop novel specific therapies. Strategies to achieve the aims, will utilize "state of the art" techniques: automated genetic analyzers for genotyping and DNA sequencing, BACs, YACs, and DNA microchip arrays to identify genes, the RU-486 Gene Switch to regulate expression of transgenes, PCR-generated dominant negative mutants, "gutless" tetracycline dependent adenoviral vectors, selective elimination of genes (knock-out mice), and Ta178 radionuclide angiography to assess mouse cardiac function. These studies elucidate further the molecular foundations of cardiac hypertrophy and failure and should provide a rational basis for more effective therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SPECIALIZED CENTER OF RESEARCH IN HEART FAILURE Principal Investigator & Institution: Seidman, Christine W.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 15-JAN-1995; Project End 31-JAN-2005 Summary: Heart failure is a leading cause of disability and death in the U.S. affecting at least 4.7 million individuals, with an estimated 400,000 new cases each year. Progress in the prevention and treatment of heart failure has been limited in magnitude due in some part to an incomplete understanding of basic biologic phenomena and mechanisms that underlie the clinical syndrome. This Heart Failure SCOR proposal attacks the problem across a spectrum of basic to clinical studies. The theme unifying these studies is that heart failure is a continuum of molecular phenomena and cellular mechanisms. These direct the progression from an underlying cause, such as a single nucleotide substitution in the DNA of an individual with familial dilated cardiomyopathy-to the multiple disturbances of cell and organ function and regulation that comprise the clinical syndrome of heart failure, irrespective of the initial inciting cause. The participating Project Leaders have an extensive record of produce collaboration and have focused their efforts on five interactive projects with substantial efforts of interface. Dr. C. Seidman's project seeks to identify genetic causes of inherited dilated cardiomyopathy with the expectation that during the next granting period a common theme will emerge that explains the significant genetic heterogeneity of this condition. Dr. (Michel) Project seeks to define the role of the interactions between caveolae and myocyte signaling proteins that evolve during the development and progression of heart failure. Project 3 (Ingwall) combines biophysical, biochemical and molecular biologic tools to test the hypothesis that decreased energy reserve via the creatine kinase system impairs contractile mutated G/a0 subunits that develop dilated cardiomyopathy with compensatory hypertrophy. These die of heart failure within two months. Pathways that link transgene expression to heart failure in these mice will be defined. Dr. Seidman's project has developed two genetically engineered lines of mice that are models of familial hypertrophic cardiomyopathy; these mice will be studied to determine those factors that worsen cardiac hypertrophy and in some, cause dilated cardiomyopathy and heart failure. All projects will interact closely with Core B (Mende and Lee), which has the technology to prepare and characterize contractile function of individual myocytes as well as to obtain non-invasive imaging of murine and human hearts to evaluate cardiac function. Cardiac histology, immunohistochemistry and in situ
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hybridization will be provided by CORE c (Schoen) to evaluate gene expression in the myocardium. In all of these interactive projects, the collaborating fundamental biological phenomena and mechanisms that bear on improved prevention and treatment of patients at risk. The aggregate productivity of coordinated project efforts has already exceeded the expectations of the individual components and we anticipate that these benefits will expand even further during the next granting period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEROL BIOSYNTHESIS IN TRYPANOSOMATID PARASITES Principal Investigator & Institution: Buckner, Frederick S.; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: The long-term objective of this project is to discover new therapeutics for leishmaniasis and Chagas disease. These infectious diseases are caused by parasitic protozoa of the family, Trypanoisomatidae. Leishmaniasis affects 12 million people in 88 countries with an annual incidence of about 2 million people. Visceral leishmaniasis is fatal if untreated and cutaneous leishmaniasis causes serious morbidity, Chagas disease is caused by Trypanosoma cruzi and is endemic in over 20 countries in Latin America. An estimated 16-18 million persons are chronically infected and at risk for developing life threatening cardiomyopathy or megasyndromes of the gastrointestinal tract. The treatments for leishmania infections are inadequate because of the toxicity of currently available drugs and because of the need to administer the drugs by injection. Treatments for Chagas diseases are highly toxic and do not cure most patients with chronic phase disease. Leishmania species and Trypanosoma cruzi synthesize membrane sterols similar to those of fungi. It has been shown that a number of anti-fungal drugs that act on sterol biosynthesis or directly on ergosterol have anti- lishmanial and antitrypanosomal effects. Our hypothesis is that a characterization of the sterol biosynthesis pathway in Trypanosomatids will lead to novel drug treatments. The specific aims of the research are: 1) Clone Trypanosomatid homologs of selected sterol biosynthesis genes. We will concentrate on five enzymes that are potentially enzymes that are potentially excellent drug targets: squalene synthetase, squalene epoxidase, C14 demethylase, delta 14-reductase, and C8 isomerase. Genes will be cloned with the use of sequences in the parasite genome databases that have high homology scores to sterol biosynthesis genes of other organisms. 2) Characterize the Trypanosomatid homologs of sterol biosynthesis genes. The enzymatic function of the cloned parasite genes will be investigated by heterologous complementation of yeast mutants. We will be prepared for the possibility that Trypanosomatids make sterols by a route that differs from the yeast pathway. 3) Interrupt the sterol biosynthesis genes in Leishmania mexicana and Trypanosoma cruzi. Targeted knockout of sterol biosynthesis genes will be done using selectable drug markers. The enzymes that are shown to be essential for parasite viability will be prioritized for subsequent drug studies. 4) Screen sterol biosynthesis inhibitors for anti-Trypanosomatid activity. Test compounds will be obtained from collaborating investigators and pharmaceutical companies. Drugs will be screened in high throughput in vitro systems. The best compounds will be tested in murine models of Chagas disease and leishmaniasis. The drugs discovered in this research program will hopefully provide better future treatment for patients with these devastating diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STRUCTURAL GENOMICS OF NOREPINEPHRINE TRANSPORTERS Principal Investigator & Institution: Blakely, Randy D.; Associate Professor; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): The antidepressant-sensitive norepinephrine (NE) transporters (NETs) constitute the major mode of synaptic inactivation of NE. Recent clinical genetic studies by our groups identified a coding mutation, A457P, in one NET allele of a proband with Orthostatic Intolerance (OI) presenting with reduced NE clearance, increased spillover and reduced intraneuronal NE metabolism. The A457P mutation was found to track with measures of postural tachycardia in the proband?s family and to correlate with altered synaptic NE metabolism. In Specific Aim 1, we propose to ascertain the functional impact of the A457P and other identified NET coding mutations in terms of transport and efflux, transporter trafficking and surface expression using heterologous expression systems. Evidence will be sought to support a dominant-negative interaction between mutant and wildtype subunits and whether homomultimeric complexes support NET function. In Specific Aim 2, we propose to extend our genetic evaluation of NET deficiency to evaluate additional subjects with OI and cardiomyopathy (CM) using high-throughput gene scanning techniques. These studies will focus on the NET coding exons and splice junctions and also include a recently identified intronic region that plays a critical role in NET gene expression. Methods will be implemented to allow for an evaluation of altered NET protein in biopsies tissue. Finally, attention and mood are dependent on proper noradrenergic signaling in the CNS and symptoms are present in our A457P probands indicating attention deficit, anxiety and hyperarousal. Thus, we propose in Specific Aim 3 to examine NET alleles with primary diagnoses of attention-deficit hyperactivity disorder (ADHD), attentional deficit (ADD) subtype and Major Depression, melancholic subtype, which is characterized by hyperarousal and anxiety. We will select subjects for analysis in both cases on the basis of comorbid tachycardia. Together these studies offer an opportunity for a better understanding of the molecular and behavioral manifestations of genetic NET variation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TARGETED ALTERATION OF ACTIN IN THE HEART Principal Investigator & Institution: Lessard, James L.; Professor and Associate Director; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2003; Project Start 01-JAN-1997; Project End 31-MAR-2006 Summary: (provided by applicant): The overarching goal of this research proposal is to understand how the heart responds to alterations in actin, the principal component of thin filaments involved in generating contractile force by the heart. Our previous work strongly supports the hypothesis that the conserved structural differences between cardiac actin and enteric actin are related to unique functional differences between these two proteins. Here, we hypothesize that differences between cardiac actin and enteric actin at position 1 (D->-) and/or position 360 (Q->P) will account for the functional alterations. Thus, the effect of these amino acid alterations in cardiac actin will be assessed in terms of structural, molecular, and physiological changes in the myocardium. We also have transgenically introduced two mutant cardiac actins (R312H and E361G) into the mouse heart that are associated with idiopathic dilated cardiomyopathies in humans and another (A295S) which is associated with hypertrophic cardiomyopathy. This approach will permit us to define the progression of
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the aberrant phenotype, if any, and provide insights into the pathogenesis associated with these mutations. We will also determine whether increased expression of skeletal or vascular actin is required for survival of cardiac actin-deficient mice. The hypothesized requirement for skeletal and vascular actin for survival of cardiac actin null animals to birth and beyond will be tested using mice that are cardiac actin null and skeletal actin null or vascular actin null. The impact of a deficiency in skeletal actin or vascular actin on the survival of cardiac actin heterozygotes will also be of interest. Finally, we plan to seek out modifier loci that affect the survival of cardiac actin heterozygotes. We have recently obtained evidence suggesting that there is a marked strain-specific variation in survival of mice that are heterozygous for the null cardiac actin allele. A reciprocal back-cross strategy will be applied and genes that modify the survival phenotype will be sought using a genome-wide scan for linkage. These approaches will provide new insights into the pathogenesis of heart failure in this model and, in future studies, hopefully permit the identification of candidate genes that affect survival in human populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE CYTOSKELETON IN HAART-INDUCED CARDIOMYOPATHY Principal Investigator & Institution: Bowles, Neil E.; Instructor; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): One of the consequences of the development of improved therapies for the treatment of HIV infection and the acquired immunodeficiency syndrome, and the associated longer survival of infected patients, has been the emergence of diseases such as myocarditis and/or dilated cardiomyopathy (DCM). A number of etiological agents have been proposed to be responsible for the initiation of the pathologic processes leading to the development of myocarditis and DCM in HIV-infected patients. These have included infection of myocytes with HIV or cardiotropic viruses, or cardiotoxicity resulting from drugs commonly used by AIDS patients, such as AZT. Monotherapy with AZT is uncommon today because highly active antiretroviral therapy (HAART) is a formidable clinical combination. However, AZT has been reported to cause a mitochondrial skeletal myopathy, similar to inherited skeletal myopathies, as well as myopathies secondary to inherited cardiomyopathies. Dystrophin was identified as the gene responsible for cardiomyopathy in patients with X-linked cardiomyopathy (XLCM). Dystrophin is thought to provide structural support for the myocyte and cardiomyocyte membrane. Mutations in dystrophin or dystrophin associated protein subcomplexes result in a wide spectrum of skeletal myopathy and/or cardiomyopathy in humans and animal models such as the mouse or hamster. We have recently shown in patients with DCM or ischemic cardiomyopathy that dystrophin remodeling is a useful indicator of left ventricular function. It has been reported that the 2A protease of Coxsackievirus B3, a major etiologic agent of acquired DCM, is capable of cleaving dystrophin, resulting in sarcolemmal disruption in infected mouse hearts. Further, in murine models of DCM defects in the integrity of dystrophin and/or other components of the cytoskeleton may be important in disease pathogenesis in these models. In order to further delineate the role of cytoskeletal disruption in models of acquired DCM we are proposing the following specific aims: Specific Aim 1: Delineation of the events leading to disruption of the cytoskeleton in transgenic mice. Specific Aim 2: Characterization of the cytoskeleton in HAART-treated transgenic mice. Specific Aim 3: Role of extrinsic stimuli in the development of HAART-induced cardiomyopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Cardiomyopathy
Project Title: THE EXERCISE PRESSOR REFLEX IN CARDIOMYOPATHY Principal Investigator & Institution: Garry, Mary G.; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2003; Project Start 13-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Diminished exercise capacity with increased shortness of breath and fatigue are major causes of morbidity in cardiomyopathic patients. Studies suggest that the exaggerated cardiovascular responses to exercise in heart failure patients are mediated, in part, by an over active exercise presser reflex (EPR). The EPR is a mechanism where blood pressure and heart rate increase in response to contraction-induced activation of primary afferent neurons and reflexive changes in autonomic outflow. The existence of an over active EPR in heart failure is also supported by the cardioprotective effects of sympathetic blockade in cardiomyopathic disease. In spite of these compelling clinical findings, however, the lack of an animal model in which the EPR and heart failure can be studied simultaneously has limited our understanding of the mechanisms involved in the evolution of reduced exercise capacity and abnormal circulatory control in heart failure. We have described a novel rat model in which significant increases in blood pressure and heart rate are reliably observed in response to static muscle contraction and passive stretch. Additionally, the EPR is exaggerated in rats with cardiomyopathy following coronary artery ligation. Finally, we demonstrate a molecular dysregulation of skeletal muscle afferent neurons during cardiomyopathy in the rat. The specific aims of this proposal are: Specific Aim #1: Compare the effect of activation of skeletal muscle primary afferent neurons on the EPR in normal animals and in ligated animals at defined intervals during cardiomyopathy. Specific Aim #2: To determine the differential contribution of metabolically vs. mechanically-sensitive skeletal muscle afferent neurons to the EPR in the normal and cardiomyopathic states. Specific Aim #3: Evaluate the spinal pharmacology and molecular dysregulation of the exaggerated EPR. With this model, we will evaluate the contribution of the EPR to circulatory control during cardiomyopathy and provide a multidisciplinary evaluation of circulatory regulation during exercise in cardiovascular disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THE ROLE OF NUCLEAR LAMINS IN MUSCLE DISEASE Principal Investigator & Institution: Burke, Brian; Professor; Anatomy and Cell Biology; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAR-2007 Summary: (provided by applicant): A-type and B-type nuclear lamins form a family of nuclear envelope proteins that have an essential function in the maintenance of nuclear structure. Mutations in the human lamin A gene have been linked to several diseases which include Emery-Dreifuss muscular dystrophy (EDMD) and cardiomyopathy. Since the A-type lamins are found in majority of adult cell types it is extremely puzzling that defects in these proteins should be associated primarily with muscle specific disorders. The goal of this proposal is to elucidate the roles that individual lam in family members play in the organization of the cell nucleus and how in particular this relates to the maintenance of muscle integrity. The proposal will take advantage of mouse strains harboring targeted mutations in lamin genes, including a strain in which the lamin A gene has been deleted and which develops a disorder that closely resembles human EDMD. Inactivation of B-type lamin genes as well as the introduction of specific human disease-linked point mutations into the mouse lamin A gene will provide novel insight
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into the role of individual lamin proteins in nuclear organization and how this relates to disease processes in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROTEINS
THIN
FILAMENTS
WITH
CARDIOMYOPATHIC
MUTANT
Principal Investigator & Institution: Tobacman, Larry S.; Professor; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 15-JAN-2000; Project End 31-DEC-2003 Summary: (adapted from the applicant's description): Familial Hypertrophic Cardiomyopathy (FHC) is an autosomal dominant disorder caused by mutations in any of several genes encoding the proteins of the cardiac contractile apparatus. This project will characterize the effects of FHC-causing mutations on the in vitro function of the various thin filament proteins so far implicated in this disorder: troponin T, troponin 1, and alpha-tropomyosin. By comparing normal and mutant proteins, the project will provide some of the insight required to understand the pathophysiology of cardiac disease in these patients. Also, the applicant will use the mutations to test the mechanism by which cardiac contraction is regulated by troponin and tropomyosin. A multi-faceted study of the mutant proteins is planned, with examination of several protein-protein affinities (including thin filament binding of troponin, of troponintropomyosin, and of myosin Sl; troponin binary subunit interactions; effects of calcium and of myosin on these various processes), calcium affinity, myosin MgATPase regulation, folding stability, in vitro motility, in vitro force, and structural effects on the regulatory conformational switching of the thin filament as determined by 3-D reconstructions of electron micrographs. A smaller number of mutations, identified in the cardiac actin gene, have been found causative in a subset of patients with another genetic disorder: dilated cardiomyopathy. Mutant forms of actin will be similarly examined for alterations in interactions with tropomyosin and troponin. (1) FHC mutations occurring in two regions of troponin T will be investigated. Troponin T mutants R92Q, R92W, Al 04V, and Fl 01 I occur in or near a region of troponin T that the applicant recently identified as forming a critical portion of the troponin tail. In a different region, the effects of FHC-linked COOH-terminal truncation of 28 residues will be studied. (2) Six troponin I mutations that occur in FHC will be similarly investigated, all located in the region of troponin I that interacts with the regulatory domain of troponin C. (3) Five FHC-linked tropomyosin mutants will be created and similarly studied, as will an actin mutation that causes inherited dilated cardiomyopathy and that is hypothesized to interact abnormally with tropomyosin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TISSUE RENIN ANGIOTENSIN/CHYMASE SYSTEM IN HEART FAILURE Principal Investigator & Institution: Dell'italia, Louis J.; Professor; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-AUG-1995; Project End 31-JAN-2006 Summary: (the applicant's description verbatim): The PI has studied the role of the cardiac renin angiotensin system (RAS)/chymase system in mechanisms of angiotensin II (ANG II) formation in the heart in response to volume overload heart failure. These studies demonstrated increased expression of RAS and chymase in the dog heart associated with LV dilatation (decreased wall thickness/diameter ratio), increased
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Cardiomyopathy
matrix metalloproteinase (MMP) activity, and dissolution of the fine collagen weave. Neither suppression of tissue ANG II with ACE inhibitor, nor blockade of the AT1 receptor modulated this remodeling process. Further, heterozygote ACE knockout mice (1/0), having 40 percent of tissue ACE activity compared to wild type, had a significantly lower w/t diameter ratio than wild type mice in response to volume overload. There was a failure to downregulate LV MMP activity in the 1/0 mice vs. 1/1 mice and in dogs with chronic MR. In both animal models, chymase activity was upregulated and not effected by blockade of the RAS. There is recent compelling evidence that remodeling of the extracellular matrix (ECM) is regulated by MMPs in dilated cardiomyopathy. Inhibition of tissue ACE, by its effect of decreasing ANG II and increasing bradykinin (BK), can promote MMP synthesis and activation. In addition, chymase can also directly cleave and activate MMPs. Thus, the hypothesis of the current proposal is that tissue concentrations of ACE and chymase mediate the LV remodeling pattern in response to volume overload by their influence on myocardial MMP activational state. The PI will measure interstitial fluid (ISF) ANG II, BK, and MMP activational state in the conscious rat (low chymase/ACE activity ratio) and hamster (high chymase/ACE activity ratio) in response to volume overload stress. This approach combined with targeted transgenic models of variable ACE expression and increased chymase expression will relate in-vivo LV function and collagen weave by scanning EM to MMP activation. Viral vectors for chymase antisense will be utilized in the heart failure models in the rat, hamster, and mouse. In the absence of an orally effective chymase inhibitor, this approach will answer important questions regarding the physiological importance of the relative concentrations of ACE and chymase in LV remodeling in heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSCRIPTIONAL DEVELOPMENT
REGULATION
OF
CARDIOMYOCYTE
Principal Investigator & Institution: Huggins, Gordon S.; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2002; Project Start 25-SEP-1995; Project End 31-JUL-2004 Summary: (the applicant's description verbatim): The normal development of the cardiovascular system is regulated by a complex set of molecular pathways that interpret environmental and developmental signals into changes in cardiovascular gene expression. Perturbations of these signaling pathways have been implicated in a number of prevalent human cardiovascular diseases including congenital cardiac malformations, pathologic cardiac hypertrophy, and dilated cardiomyopathy. During the last ten years we have studied the nuclear transcription factors that regulate the development and function of the mammalian cardiovascular system. In an initial series of experiments we identified a cardiac-specific transcriptional promoter/enhancer in the 5' flanking region of the cardiac troponin C (cTnC) gene. We used this promoter to identify a set of nuclear transcription factors that appear to play important roles in regulating early cardiomyocyte development and cardiac morphogenesis. Among these was the GATA4 zinc finger protein that binds to and trans-activates a wide variety of cardiac specific transcriptional regulatory elements. Using a gene targeting approach we showed that GATA4 is necessary for the formation of the primitive ventral heart tube during early murine embryogenesis. More recently, we identified a second zinc finger protein called cardiac friend of GATA (CFOG) that is expressed in the developing heart and that binds specifically to the N-terminal zinc finger of GATA4. Similarly, Olson and coworkers recently demonstrated that GATA4 also interacts with the rel-related protein NFAT3
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and that these two proteins appear to be important regulators of cardiac myocyte hypertrophy. The long term goal of the studies described in this continuing RO1 proposal is to understand the molecular mechanisms by which GATA proteins, in conjunction with other transcriptionfactors and coactivator/ repressor proteins regulate cardiogenesis and cardiac hypertrophy. Specifically we will (1) map the regions of GATA4 that are required for its central role in the heart tube formation. (2) genetically and biochemically characterize the interaction between GATA4 and CFOG and understand the effects of this interaction on the transcriptional activity of GATA4, (3) Use gene targeting to determine the roles of NFAT3 and CFOG in cardiac development and function in the mouse. Together, the results of these studies should provide novel basic insights into the molecular pathways that regulate normal cardiac development and function. They should also be relevant to understanding the molecular pathophysiology of a number of clinically important inherited and acquired cardiovascular diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRIGLYCERIDE SYNTHESIS AND LIPOTOXICITY Principal Investigator & Institution: Farese, Robert V.; Associate Investigator; J. David Gladstone Institutes 365 Vermont St San Francisco, Ca 94103 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): The obesity epidemic is threatening world health, largely because of its associated diseases, type 2 diabetes mellitus and atherosclerosis. Although the mechanisms underlying obesity-associated diseases are unclear, the lipotoxicity hypothesis has emerged as a plausible explanation. This hypothesis states that the deposition of excess lipids in tissues other than white adipose tissue over time leads to tissue dysfunction. For example, lipid deposition in skeletal muscle is associated with insulin resistance, in pancreatic beta cells with defective insulin secretion, and in heart muscle with cardiomyopathy. Despite these strong associations from studies in animals and humans, the lipotoxicity hypothesis remains unproven, and its underlying mechanisms remain unclear. Whether triglycerides themselves or precursors of triglyceride synthesis (e.g., diacylglycerol and fatty acyl CoAs) are toxic to nonadipose cells is unclear. We propose to test the lipotoxicity hypothesis by directly modulating triglyceride synthesis in specific tissues of mice. Triglyceride synthesis is catalyzed by acyl CoA:diacylglycerol (DGAT) enzymes. Aim 1 describes the generation and analysis of mice that overexpress DGAT1 in skeletal muscle, pancreatic beta cells, and cardiac muscle. Aim 2 describes the generation and analysis of mice that lack DGAT1 in skeletal muscle, beta cells, and white adipose tissue. We will use these mouse models to determine whether modulating triglyceride synthesis influences tissue lipotoxicity and to explore the mechanisms, including alterations in tissue lipids, gene expression, and signaling pathways, that contribute to lipotoxicity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TROPOMYOSIN CONTRACTION
AND
THE
REGULATION
OF
MUSCLE
Principal Investigator & Institution: Lehrer, Sherwin S.; Senior Scientist; Boston Biomedical Research Institute 64 Grove St Watertown, Ma 02472 Timing: Fiscal Year 2002; Project Start 01-APR-1978; Project End 31-JAN-2005 Summary: (Verbatim from the applicant's abstract) The broad, long-term objective is to elucidate the molecular basis of the regulation of muscle contraction by defining the role
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of each muscle component: actin, tropomyosin (Tm), the troponin components, TnI, TnT, TnC, and myosin. Health Relatedness: This information will help in the understanding of muscle diseases e.g., hypertrophic cardiomyopathy resulting from mutations in Tm, TnT, TnI and myosin and stunned myocardium resulting from coronary artery disease. Tm, in its interaction with actin, plays a key role in determining the equilibria between the 3 states of the muscle thin filament, Blocked/Closed/Open (contraction takes place in the Open state). By interacting with actinTm, the troponin complex and myosin heads change the equilibrium between the states, thereby turning contraction on and off. The specific aims are to test the hypotheses that: (a) Ca2+ and myosin induce changes in position and conformation of Tm on actin which results in a shift of the equilibrium toward the Open biochemical state, thereby allowing contraction; (b) in the absence of Ca2+, TnI, interacts with Tm in addition to actin, to stabilize the thin filament in the Blocked-state; (c) TnT: (i) inhibits actinTm-S1 ATPase by altering Tm conformation, (ii) increases the cooperativity between actinTm units, (iii) interacts differently with Tm in each of the 3 biochemical states; (d) Tm movement to the thin filament On-activity state (Open-state) occurs during myosin binding after Ca2+induced TnI dissociation from actin; (e) the two heads of HMM act cooperatively to shift actinTm from the Closed to the Open-state; (f) mutants of Tm found in patients with FHC alter the equilibria between the 3 biochemical states of the thin filament thereby affecting contraction. Methods: In addition to characterization of the 3 states in solution with ATPase, myosin titrations and stopped-flow techniques, extensive use will be made of high resolution distance measurements between components with timeresolved fluorescence energy transfer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: XANTHINE OXIDASE, MYOCARDIAL GENOMICS AND HEART FAILURE Principal Investigator & Institution: Cappola, Thomas P.; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: (provided by the applicant):Cardiac hypertrophy is a central pathologic feature of congestive heart failure. Prior investigations suggest that oxidative stress induces the expression of hypertrophy genes in vitro, and may be an important cause of cardiac hypertrophy in humans. The applicant proposes to merge his interest in clinical investigation with state-of-the-art genomic approaches to determine how oxidative stress promotes cardiac hypertrophy in humans. Based on preliminary data, he will focus on xanthine oxidase as a source of myocardial oxidative stress. The central thesis of this proposal is that increased myocardial XO contributes to heart failure by stimulating the transcription of hypertrophy genes. In Aim 1, the applicant will use Affymetrix microarrays to determine genes associated with hypertrophy in failing explanted human myocardium. Multiple analytic approaches will be used, including a hypothesis-based analysis of pre-selected candidate genes, exploratory analyses, and global analyses of patterns in gene expression. In Aim 2, the applicant will demonstrate that myocardial XO activity correlates with expression of these hypertrophy genes in humans. In Aim 3, the applicant will test the hypothesis that XO inhibition with allopurinol attenuates the expression of hypertrophy genes in serial endomyocardial biopsies, and prevents an increase in cardiac mass in patients with dilated cardiomyopathy. These experiments will determine the transcriptional targets of XO in human myocardium, thereby clarifying the role of oxidative stress in heart failure. Moreover. they are the first steps in determining whether XO inhibition is a novel
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treatment strategy for heart failure. This research will be performed at the Johns Hopkins Medical Institutions under the mentorship of Dr. Joshua Hare, an expert in the field of oxidative stress in heart failure. Genomic analyses will be performed in collaboration with the HopGene PGAmApplied Genomics in Cardiopulmonary Disease. The applicant's interdisciplinary training, strong mentorship, career development program, supportive environment, and novel research plan will give him the experience and tools he needs to develop into a highly successful, independent clinical investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “cardiomyopathy” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for cardiomyopathy in the PubMed Central database: •
A critical role for PPAR[alpha]-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: Modulation by dietary fat content. by Finck BN, Han X, Courtois M, Aimond F, Nerbonne JM, Kovacs A, Gross RW, Kelly DP.; 2003 Feb 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=298755
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A Familial Hypertrophic Cardiomyopathy Locus Maps to Chromosome 15q2. by Thierfelder L, MacRae C, Watkins H, Tomfohrde J, Williams M, McKenna W, Bohm K, Noeske G, Schlepper M, Bowcock A, Vosberg H, Seidman JG, Seidman C.; 1993 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46910
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Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy. by Yamamoto S, Yang G, Zablocki D, Liu J, Hong C, Kim SJ, Soler S, Odashima M, Thaisz J, Yehia G, Molina CA, Yatani A, Vatner DE, Vatner SF, Sadoshima J.; 2003 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155047
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Apoptosis in heart failure: Release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. by Narula J, Pandey P, Arbustini E, Haider N, Narula N, Kolodgie FD, Dal Bello B, Semigran MJ, Bielsa-Masdeu A, Dec GW, Israels S, Ballester M, Virmani R, Saxena S, Kharbanda S.; 1999 Jul 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22202
3 4
Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.
With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.
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Both hypertrophic and dilated cardiomyopathies are caused by mutation of the same gene, [delta]-sarcoglycan, in hamster: An animal model of disrupted dystrophinassociated glycoprotein complex. by Sakamoto A, Ono K, Abe M, Jasmin G, Eki T, Murakami Y, Masaki T, Toyo-oka T, Hanaoka F.; 1997 Dec 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28400
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Ca2 +-desensitizing effect of a deletion mutation [Delta]K210 in cardiac troponin T that causes familial dilated cardiomyopathy. by Morimoto S, Lu QW, Harada K, Takahashi-Yanaga F, Minakami R, Ohta M, Sasaguri T, Ohtsuki I.; 2002 Jan 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117405
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Cardiac troponin T and familial hypertrophic cardiomyopathy: an energetic affair. by Schwartz K, Mercadier JJ.; 2003 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=182216
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Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways. by Twu C, Liu NQ, Popik W, Bukrinsky M, Sayre J, Roberts J, Rania S, Bramhandam V, Roos KP, MacLellan WR, Fiala M.; 2002 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137893
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Cardiomyopathy in Irx4-Deficient Mice Is Preceded by Abnormal Ventricular Gene Expression. by Bruneau BG, Bao ZZ, Fatkin D, Xavier-Neto J, Georgakopoulos D, Maguire CT, Berul CI, Kass DA, Kuroski-de Bold ML, de Bold AJ, Conner DA, Rosenthal N, Cepko CL, Seidman CE, Seidman JG.; 2001 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86719
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Conditional expression of a Gi-coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy. by Redfern CH, Degtyarev MY, Kwa AT, Salomonis N, Cotte N, Nanevicz T, Fidelman N, Desai K, Vranizan K, Lee EK, Coward P, Shah N, Warrington JA, Fishman GI, Bernstein D, Baker AJ, Conklin BR.; 2000 Apr 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18317
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Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. by Ozcelik C, Erdmann B, Pilz B, Wettschureck N, Britsch S, Hubner N, Chien KR, Birchmeier C, Garratt AN.; 2002 Jun 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124392
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Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. by Arad M, Benson DW, Perez-Atayde AR, McKenna WJ, Sparks EA, Kanter RJ, McGarry K, Seidman JG, Seidman CE.; 2002 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150860
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Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice. by Zhao YY, Liu Y, Stan RV, Fan L, Gu Y, Dalton N, Chu PH, Peterson K, Ross J Jr, Chien KR.; 2002 Aug 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123264
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Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C --deficient mice. by Nikolova V, Leimena C, McMahon AC, Tan JC, Chandar S, Jogia D, Kesteven SH, Michalicek J, Otway R, Verheyen F, Rainer S, Stewart CL, Martin D, Feneley MP, Fatkin D.; 2004 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=324538
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Development of murine ischemic cardiomyopathy is associated with a transient inflammatory reaction and depends on reactive oxygen species. by Dewald O,
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Frangogiannis NG, Zoerlein M, Duerr GD, Klemm C, Knuefermann P, Taffet G, Michael LH, Crapo JD, Welz A, Entman ML.; 2003 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151404 •
Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L. by Stypmann J, Glaser K, Roth W, Tobin DJ, Petermann I, Matthias R, Monnig G, Haverkamp W, Breithardt G, Schmahl W, Peters C, Reinheckel T.; 2002 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122932
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Disruption of the gene encoding the latent transforming growth factor-[beta] binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer. by Sterner-Kock A, Thorey IS, Koli K, Wempe F, Otte J, Bangsow T, Kuhlmeier K, Kirchner T, Jin S, Keski-Oja J, von Melchner H.; 2002 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=186672
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Elaboration by mammalian mesenchymal cells infected with Trypanosoma cruzi of a fibroblast-stimulating factor that may contribute to chagasic cardiomyopathy. by Wyler DJ, Libby P, Prakash S, Prioli RP, Pereira ME.; 1987 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=260047
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Evidence that Development of Severe Cardiomyopathy in Human Chagas' Disease Is Due to a Th1-Specific Immune Response. by Gomes JA, Bahia-Oliveira LM, Rocha MO, Martins-Filho OA, Gazzinelli G, Correa-Oliveira R.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=148818
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Experimental Assessment of the Role of Acetaldehyde in Alcoholic Cardiomyopathy. by Aberle II NS, Ren J.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150386
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Functional analyses of troponin T mutations that cause hypertrophic cardiomyopathy: Insights into disease pathogenesis and troponin function. by Sweeney HL, Feng HS, Yang Z, Watkins H.; 1998 Nov 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24386
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Functional Analysis of Myosin Missense Mutations in Familial Hypertrophic Cardiomyopathy. by Straceski AJ, Geisterfer-Lowrance A, Seidman CE, Seidman JG, Leinwand LA.; 1994 Jan 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42994
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Genetic counselling for hypertrophic cardiomyopathy: are we ready for it? by Vosberg HP.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59597
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Genetic modification of survival in tissue-specific knockout mice with mitochondrial cardiomyopathy. by Li H, Wang J, Wilhelmsson H, Hansson A, Thoren P, Duffy J, Rustin P, Larsson NG.; 2000 Mar 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16263
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Genotype, phenotype: upstairs, downstairs in the family of cardiomyopathies. by Chien KR.; 2003 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151886
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Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. by Haghighi K, Kolokathis F, Pater L,
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Lynch RA, Asahi M, Gramolini AO, Fan GC, Tsiapras D, Hahn HS, Adamopoulos S, Liggett SB, Dorn GW II, MacLennan DH, Kremastinos DT, Kranias EG.; 2003 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153772 •
Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. by Mogensen J, Kubo T, Duque M, Uribe W, Shaw A, Murphy R, Gimeno JR, Elliott P, McKenna WJ.; 2003 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151864
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Lamin A/C truncation in dilated cardiomyopathy with conduction disease. by MacLeod HM, Culley MR, Huber JM, McNally EM.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=169171
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Left ventricular decompression through a patent foramen ovale in a patient with hypertrophic cardiomyopathy: a case report. by Ando' G, Tomai F, Gioffre' PA.; 2004; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=324415
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Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. by Yagyu H, Chen G, Yokoyama M, Hirata K, Augustus A, Kako Y, Seo T, Hu Y, Lutz EP, Merkel M, Bensadoun A, Homma S, Goldberg IJ.; 2003 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151861
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Magnetic Resonance Imaging of Myocardial Fibrosis in Hypertrophic Cardiomyopathy. by Wilson JM, Villareal RP, Hariharan R, Massumi A, Muthupillai R, Flamm SD.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124756
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Medical therapy versus interventional therapy in hypertropic obstructive cardiomyopathy. by Seggewiss H.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59612
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Missense Mutations in the [beta]-Myosin Heavy-Chain Gene Cause Central Core Disease in Hypertrophic Cardiomyopathy. by Fananapazir L, Dalakas MC, Cyran F, Cohn G, Epstein ND.; 1993 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46432
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Molecular Basis of Human Mitochondrial Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency Causing Cardiomyopathy and Sudden Death in Childhood. by Strauss AW, Powell CK, Hale DE, Anderson MM, Ahuja A, Brackett JC, Sims HF.; 1995 Nov 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40638
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Nephropathic cystinosis associated with cardiomyopathy: A 27-year clinical followup. by Dixit MP, Greifer I.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137602
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Nontransplant Cardiac Surgery as a Bridge to Heart Transplantation in Pediatric Dilated Cardiomyopathy. by Hsu RB, Chien CY, Wang SS, Chu SH.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124763
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Rescue of hereditary form of dilated cardiomyopathy by rAAV-mediated somatic gene therapy: Amelioration of morphological findings, sarcolemmal permeability, cardiac performances, and the prognosis of TO-2 hamsters. by Kawada T, Nakazawa M, Nakauchi S, Yamazaki K, Shimamoto R, Urabe M, Nakata J, Hemmi C, Masui F, Nakajima T, Suzuki JI, Monahan J, Sato H, Masaki T, Ozawa K, Toyo-oka T.; 2002 Jan 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117403
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Reversible Alterations in Myocardial Gene Expression in a Young Man with Dilated Cardiomyopathy and Hypothyroidism. by Ladenson PW, Sherman SI, Baughman KL, Ray PE, Feldman AM.; 1992 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49269
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Severe cardiomyopathy in mice lacking dystrophin and MyoD. by Megeney LA, Kablar B, Perry RL, Ying C, May L, Rudnicki MA.; 1999 Jan 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15120
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Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy. by Kunisada K, Negoro S, Tone E, Funamoto M, Osugi T, Yamada S, Okabe M, Kishimoto T, Yamauchi-Takihara K.; 2000 Jan 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26660
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Smooth muscle cell --extrinsic vascular spasm arises from cardiomyocyte degeneration in sarcoglycan-deficient cardiomyopathy. by Wheeler MT, Allikian MJ, Heydemann A, Hadhazy M, Zarnegar S, McNally EM.; 2004 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=351323
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Structural Interpretation of the Mutations in the [beta]-Cardiac Myosin that have been Implicated in Familial Hypertrophic Cardiomyopathy. by Rayment I, Holden HM, Sellers JR, Fananapazir L, Epstein ND.; 1995 Apr 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42062
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Systolic Compression of Epicardial Coronary and Intramural Arteries in Children with Hypertrophic Cardiomyopathy. by Mohiddin SA, Fananapazir L.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140291
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Targeted Disruption of the Murine Bin1/Amphiphysin II Gene Does Not Disable Endocytosis but Results in Embryonic Cardiomyopathy with Aberrant Myofibril Formation. by Muller AJ, Baker JF, DuHadaway JB, Ge K, Farmer G, Donover PS, Meade R, Reid C, Grzanna R, Roach AH, Shah N, Soler AP, Prendergast GC.; 2003 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156129
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Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. by Braz JC, Bueno OF, Liang Q, Wilkins BJ, Dai YS, Parsons S, Braunwart J, Glascock BJ, Klevitsky R, Kimball TF, Hewett TE, Molkentin JD.; 2003 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155046
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Targeted overexpression of protein kinase C [beta]2 isoform in myocardium causes cardiomyopathy. by Wakasaki H, Koya D, Schoen FJ, Jirousek MR, Ways DK, Hoit BD, Walsh RA, King GL.; 1997 Aug 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23178
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The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy. by Liao P, Georgakopoulos D, Kovacs A, Zheng M, Lerner D, Pu H, Saffitz J, Chien K, Xiao RP, Kass DA, Wang Y.; 2001 Oct 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59806
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The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model. by Semsarian C, Ahmad I, Giewat M, Georgakopoulos D, Schmitt JP, McConnell BK, Reiken S, Mende U, Marks AR, Kass DA, Seidman CE, Seidman JG.; 2002 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150949
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The V122I cardiomyopathy variant of transthyretin increases the velocity of ratelimiting tetramer dissociation, resulting in accelerated amyloidosis. by Jiang X, Buxbaum JN, Kelly JW.; 2001 Dec 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64963
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Transient cardiac expression of constitutively active G[alpha]q leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways. by Mende U, Kagen A, Cohen A, Aramburu J, Schoen FJ, Neer EJ.; 1998 Nov 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24952
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Treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an anaplerotic odd-chain triglyceride. by Roe CR, Sweetman L, Roe DS, David F, Brunengraber H.; 2002 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151060
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Unusual Association of Hypertrophic Cardiomyopathy with Complete Atrioventricular Canal Defect and Down Syndrome. by Eidem BW, Jones C, Cetta F.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101082
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Ventricular septal defect and cardiomyopathy in mice lacking the transcription factor CHF1 /Hey2. by Sakata Y, Kamei CN, Nakagami H, Bronson R, Liao JK, Chin MT.; 2002 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138588
The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with cardiomyopathy, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “cardiomyopathy” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for cardiomyopathy (hyperlinks lead to article summaries): 6 PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
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A case of dilated cardiomyopathy due to nutritional vitamin D deficiency rickets. Author(s): Olgun H, Ceviz N, Ozkan B. Source: Turk J Pediatr. 2003 April-June; 45(2): 152-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921304&dopt=Abstract
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A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy. Author(s): Taylor RW, Giordano C, Davidson MM, d'Amati G, Bain H, Hayes CM, Leonard H, Barron MJ, Casali C, Santorelli FM, Hirano M, Lightowlers RN, DiMauro S, Turnbull DM. Source: Journal of the American College of Cardiology. 2003 May 21; 41(10): 1786-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767666&dopt=Abstract
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A new method using pulmonary gas-exchange kinetics to evaluate efficacy of betablocking agents in patients with dilated cardiomyopathy. Author(s): Taniguchi Y, Ueshima K, Chiba I, Segawa I, Kobayashi N, Saito M, Hiramori K. Source: Chest. 2003 September; 124(3): 954-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970023&dopt=Abstract
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A noninvasive means of detecting preclinical cardiomyopathy in Duchenne muscular dystrophy? Author(s): Towbin JA. Source: Journal of the American College of Cardiology. 2003 July 16; 42(2): 317-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875770&dopt=Abstract
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A reversible form of cardiomyopathy. Author(s): Kini SM, Pednekar SJ, Nabar ST, Varthakavi P. Source: Journal of Postgraduate Medicine. 2003 January-March; 49(1): 85-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865580&dopt=Abstract
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Absolute quantitation of myocardial blood flow after nitroglycerin and ischemic cardiomyopathy with a low ejection fraction. Author(s): Bianco JA. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2003 November; 44(11): 1872; Author Reply 1872-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14602873&dopt=Abstract
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Accuracy of European diagnostic criteria for familial hypertrophic cardiomyopathy in a genotyped population. Author(s): Charron P, Forissier JF, Amara ME, Dubourg O, Desnos M, Bouhour JB, Isnard R, Hagege A, Benaiche A, Richard P, Schwartz K, Komajda M. Source: International Journal of Cardiology. 2003 July; 90(1): 33-8; Discussion 38-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821216&dopt=Abstract
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Acromegaly with multiple cardiovascular complications--cardiomyopathy, chordae rupture of mitral valve, myocardial infarction and sick sinus syndrome. Author(s): Yamamoto T, Nakamura H, Ogawa T, Saga T, Ishikawa K. Source: Intern Med. 2003 August; 42(8): 700-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12924495&dopt=Abstract
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Adverse prognosis of patients with hypertrophic cardiomyopathy who have epicardial coronary artery disease. Author(s): Sorajja P, Ommen SR, Nishimura RA, Gersh BJ, Berger PB, Tajik AJ. Source: Circulation. 2003 November 11; 108(19): 2342-8. Epub 2003 October 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14581405&dopt=Abstract
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American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. Author(s): Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman CE, Shah PM, Spencer WH 3rd, Spirito P, Ten Cate FJ, Wigle ED, Vogel RA, Abrams J, Bates ER, Brodie BR, Danias PG, Gregoratos G, Hlatky MA, Hochman JS, Kaul S, Lichtenberg RC, Lindner JR, O'rourke RA, Pohost GM, Schofield RS, Tracy CM, Winters WL Jr, Klein WW, Priori SG, Alonso-Garcia A, Blomstrom-Lundqvist C, De Backer G, Deckers J, Flather M, Hradec J, Oto A, Parkhomenko A, Silber S, Torbicki A; Task Force on Clinical Expert Consensus Documents. American College of Cardiology; Committee for Practice Guidelines. European Society of Cardiology. Source: Journal of the American College of Cardiology. 2003 November 5; 42(9): 1687713. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14607462&dopt=Abstract
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Amiodarone versus implantable cardioverter-defibrillator:randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia--AMIOVIRT. Author(s): Strickberger SA, Hummel JD, Bartlett TG, Frumin HI, Schuger CD, Beau SL, Bitar C, Morady F; AMIOVIRT Investigators. Source: Journal of the American College of Cardiology. 2003 May 21; 41(10): 1707-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767651&dopt=Abstract
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An autopsy study of hypertrophic cardiomyopathy. Author(s): Ahmad M, Afzal S, Malik IA, Mushtaq S, Mubarik A. Source: J Pak Med Assoc. 2003 October; 53(10): 459-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14696885&dopt=Abstract
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Antiphospholipid syndrome presenting as dilated cardiomyopathy in an 11-year-old boy. Author(s): Al-Kiyumi WA, Venugopalan P. Source: Acta Cardiol. 2003 August; 58(4): 359-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12948043&dopt=Abstract
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Apical hypertrophic cardiomyopathy: diagnosis with contrast-enhanced echocardiography--a case report. Author(s): Acarturk E, Bozkurt A, Donmez Y. Source: Angiology. 2003 May-June; 54(3): 373-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12785033&dopt=Abstract
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Are anti-Chlamydia pneumoniae antibodies prognosis indicators for peripartum cardiomyopathy? Author(s): Cenac A, Djibo A, Chaigneau C, Velmans N, Orfila J. Source: Journal of Cardiovascular Risk. 2003 June; 10(3): 195-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12775952&dopt=Abstract
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Are imidazolic drugs effective in the treatment of chronic Chagas cardiomyopathy? Author(s): Vallejo M, Reyes PA. Source: Salud Publica De Mexico. 2003 July-August; 45(4): 243-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12974040&dopt=Abstract
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Area ablation of ventricular tachycardia in a patient with arrhythmogenic right ventricular cardiomyopathy. Author(s): de Groot NM, Schalij MJ, van der Wall EE. Source: Heart (British Cardiac Society). 2003 July; 89(7): 703. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807832&dopt=Abstract
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Arrhythmogenic right ventricular cardiomyopathy: time for a new look. Author(s): Ferrari VA, Scott CH. Source: Journal of Cardiovascular Electrophysiology. 2003 May; 14(5): 483-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12776864&dopt=Abstract
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Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C): a multidisciplinary study: design and protocol. Author(s): Marcus F, Towbin JA, Zareba W, Moss A, Calkins H, Brown M, Gear K; ARVD/C Investigators. Source: Circulation. 2003 June 17; 107(23): 2975-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814984&dopt=Abstract
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Ascertainment strategies and genotype:phenotype correlations in hypertrophic cardiomyopathy. Author(s): Blair E, Redwood C, Watkins H. Source: Circulation. 2003 July 29; 108(4): E24-5; Author Reply E24-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12885737&dopt=Abstract
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Assessing risk in hypertrophic cardiomyopathy. Author(s): Cannon RO 3rd. Source: The New England Journal of Medicine. 2003 September 11; 349(11): 1016-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12968084&dopt=Abstract
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Assessment of regional systolic and diastolic dysfunction in familial hypertrophic cardiomyopathy using MR tagging. Author(s): Ennis DB, Epstein FH, Kellman P, Fananapazir L, McVeigh ER, Arai AE. Source: Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 2003 September; 50(3): 638-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939774&dopt=Abstract
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Assessment of Takotsubo (ampulla) cardiomyopathy using 99mTc-tetrofosmin myocardial SPECT--comparison with acute coronary syndrome. Author(s): Ito K, Sugihara H, Katoh S, Azuma A, Nakagawa M. Source: Ann Nucl Med. 2003 April; 17(2): 115-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12790360&dopt=Abstract
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Association of cardiomyopathy caused by autonomic nervous system impairment with the Miller Fisher syndrome. Author(s): Oomura M, Yamawaki T, Oe H, Moriwaki H, Miyashita K, Naritomi H, Yasumura Y. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 May; 74(5): 689-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700327&dopt=Abstract
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Association of lipoproteins with cytokines and cytokine receptors in heart failure patients. Differences between ischaemic versus idiopathic cardiomyopathy. Author(s): Conraads VM, Bosmans JM, Schuerwegh AJ, De Clerck LS, Bridts CH, Wuyts FL, Stevens WJ, Vrints CJ. Source: European Heart Journal. 2003 December; 24(24): 2221-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14659774&dopt=Abstract
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Atrophic degeneration and loss of myocytes of residual left ventricular myocardium after Dor operation for ischemic cardiomyopathy associated with left ventricular remodeling. Author(s): Kokaji K, Okamoto M, Hotoda K. Source: Jpn J Thorac Cardiovasc Surg. 2003 November; 51(11): 634-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14650598&dopt=Abstract
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Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Author(s): Okazaki T, Tanaka Y, Nishio R, Mitsuiye T, Mizoguchi A, Wang J, Ishida M, Hiai H, Matsumori A, Minato N, Honjo T. Source: Nature Medicine. 2003 December; 9(12): 1477-83. Epub 2003 November 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14595408&dopt=Abstract
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Autopsy findings in siblings with hypertrophic cardiomyopathy caused by Arg92Trp mutation in the cardiac troponin T gene showing dilated cardiomyopathy-like features. Author(s): Shimizu M, Ino H, Yamaguchi M, Terai H, Uchiyama K, Inoue M, Ikeda M, Kawashima A, Mabuchi H. Source: Clin Cardiol. 2003 November; 26(11): 536-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14640471&dopt=Abstract
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Batista operation with aortic valve replacement for valvular cardiomyopathy. Author(s): Harada H, Honma Y, Hachiro Y, Baba T, Abe T. Source: Ann Thorac Cardiovasc Surg. 2003 April; 9(2): 138-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12732094&dopt=Abstract
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Biomolecular interactions between human recombinant beta-MyHC and cMyBP-Cs implicated in familial hypertrophic cardiomyopathy. Author(s): Flavigny J, Robert P, Camelin JC, Schwartz K, Carrier L, Berrebi-Bertrand I. Source: Cardiovascular Research. 2003 November 1; 60(2): 388-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14613868&dopt=Abstract
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Blunted increase in plasma adenosine levels following dipyridamole stress in dilated cardiomyopathy patients. Author(s): Laghi-Pasini F, Guideri F, Petersen C, Lazzerini PE, Sicari R, Capecchi PL, Picano E. Source: Journal of Internal Medicine. 2003 December; 254(6): 591-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14641800&dopt=Abstract
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Brain natriuretic peptide as a predictor of cardiomyopathy in Chagas' disease. Author(s): Walther T, Heringer-Walther S, Wessel N, Schultheiss HP, Moreira Mda C. Source: Lancet. 2003 May 3; 361(9368): 1567. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12737906&dopt=Abstract
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Cardiology patient page. Hypertrophic cardiomyopathy: a patient perspective. Author(s): Nishimura RA, Ommen SR, Tajik AJ. Source: Circulation. 2003 November 11; 108(19): E133-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14609998&dopt=Abstract
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Cardiomyocyte apoptosis in hypertensive cardiomyopathy. Author(s): Gonzalez A, Fortuno MA, Querejeta R, Ravassa S, Lopez B, Lopez N, Diez J. Source: Cardiovascular Research. 2003 September 1; 59(3): 549-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14499856&dopt=Abstract
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Cardiomyopathy in a murine model of AIDS: evidence of reactive nitrogen species and corroboration in human HIV/AIDS cardiac tissues. Author(s): Chaves AA, Mihm MJ, Schanbacher BL, Basuray A, Liu C, Ayers LW, Bauer JA. Source: Cardiovascular Research. 2003 October 15; 60(1): 108-18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14522412&dopt=Abstract
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Cardiomyopathy in muscular dystrophies. Author(s): Muntoni F. Source: Current Opinion in Neurology. 2003 October; 16(5): 577-83. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14501841&dopt=Abstract
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Changes in cardiac sympathetic nerve innervation and activity in pathophysiologic transition from typical to end-stage hypertrophic cardiomyopathy. Author(s): Terai H, Shimizu M, Ino H, Yamaguchi M, Uchiyama K, Oe K, Nakajima K, Taki J, Kawano M, Mabuchi H. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2003 October; 44(10): 1612-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14530475&dopt=Abstract
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Circumstances of death and gross and microscopic observations in a series of 200 cases of sudden death associated with arrhythmogenic right ventricular cardiomyopathy and/or dysplasia. Author(s): Tabib A, Loire R, Chalabreysse L, Meyronnet D, Miras A, Malicier D, Thivolet F, Chevalier P, Bouvagnet P. Source: Circulation. 2003 December 16; 108(24): 3000-5. Epub 2003 Dec 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14662701&dopt=Abstract
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Cirrhotic cardiomyopathy: does it contribute to chronic fatigue and decreased healthrelated quality of life in cirrhosis? Author(s): Girgrah N, Reid G, MacKenzie S, Wong F. Source: Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. 2003 September; 17(9): 545-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14532928&dopt=Abstract
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Clinical and genetic characteristics of alpha cardiac actin gene mutations in hypertrophic cardiomyopathy. Author(s): Mogensen J, Perrot A, Andersen PS, Havndrup O, Klausen IC, Christiansen M, Bross P, Egeblad H, Bundgaard H, Osterziel KJ, Haltern G, Lapp H, Reinecke P, Gregersen N, Borglum AD. Source: Journal of Medical Genetics. 2004 January; 41(1): E10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14729850&dopt=Abstract
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Clinical characteristics of and long-term outcome in Chinese patients with hypertrophic cardiomyopathy. Author(s): Ho HH, Lee KL, Lau CP, Tse HF. Source: The American Journal of Medicine. 2004 January 1; 116(1): 19-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14706661&dopt=Abstract
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Clinical characterization of left ventricular noncompaction in children: a relatively common form of cardiomyopathy. Author(s): Pignatelli RH, McMahon CJ, Dreyer WJ, Denfield SW, Price J, Belmont JW, Craigen WJ, Wu J, El Said H, Bezold LI, Clunie S, Fernbach S, Bowles NE, Towbin JA. Source: Circulation. 2003 November 25; 108(21): 2672-8. Epub 2003 Nov 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14623814&dopt=Abstract
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Coexistence of familial hypertrophic cardiomyopathy and vasospastic angina pectoris in two brothers. Author(s): Suzuki N, Seto S, Koide Y, Sato O, Hirano H, Kawano H, Yano K. Source: Japanese Heart Journal. 2003 September; 44(5): 775-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14587659&dopt=Abstract
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Combined cox maze procedure, septal myectomy, and mitral valve replacement for severe hypertrophic obstructive cardiomyopathy complicated by chronic atrial fibrillation. Author(s): Matsui Y, Fukada Y, Imai T, Naito Y, Sasaki S. Source: Ann Thorac Cardiovasc Surg. 2003 October; 9(5): 323-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14672530&dopt=Abstract
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Comparison of effectiveness of implantable cardioverter defibrillator in patients with idiopathic dilated cardiomyopathy versus those with proved coronary heart disease. Author(s): Cuesta A, Mont L, Rogel U, Valentino M, Matas M, Brugada J. Source: The American Journal of Cardiology. 2003 November 15; 92(10): 1227-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14609607&dopt=Abstract
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Comparison of prevalence of apical hypertrophic cardiomyopathy in Japan and the United States. Author(s): Kitaoka H, Doi Y, Casey SA, Hitomi N, Furuno T, Maron BJ. Source: The American Journal of Cardiology. 2003 November 15; 92(10): 1183-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14609593&dopt=Abstract
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Conditional cardiac overexpression of endothelin-1 induces inflammation and dilated cardiomyopathy in mice. Author(s): Yang LL, Gros R, Kabir MG, Sadi A, Gotlieb AI, Husain M, Stewart DJ. Source: Circulation. 2004 January 20; 109(2): 255-61. Epub 2004 Jan 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14718401&dopt=Abstract
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Conduction system abnormalities in patients with obstructive hypertrophic cardiomyopathy following septal reduction interventions. Author(s): Qin JX, Shiota T, Lever HM, Asher CR, Popovic ZB, Greenberg NL, Agler DA, Drinko JK, Smedira NG, Tuzcu EM, Lytle BW, Thomas JD. Source: The American Journal of Cardiology. 2004 January 15; 93(2): 171-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14715342&dopt=Abstract
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Contrast echocardiography in segmental analysis and intraventricular gradient quantification in hypertrophic cardiomyopathy. Author(s): Candido A, Coucelo J, Galvao J, Azevedo V, Soares L, Anao AO, Bruno MJ, Arroja I, Fernandes J, Azevedo J, Joao I, Nunes JS, Aleixo A. Source: Rev Port Cardiol. 2003 June; 22(6): 789-98. English, Portuguese. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14526696&dopt=Abstract
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Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. Author(s): Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici PG. Source: The New England Journal of Medicine. 2003 September 11; 349(11): 1027-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12968086&dopt=Abstract
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Covered stent septal ablation for hypertrophic obstruction cardiomyopathy. Author(s): Anzuini A, Uretsky BF. Source: Circulation. 2004 January 20; 109(2): E6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14734509&dopt=Abstract
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Crystal methamphetamine-associated cardiomyopathy: tip of the iceberg? Author(s): Wijetunga M, Seto T, Lindsay J, Schatz I. Source: Journal of Toxicology. Clinical Toxicology. 2003; 41(7): 981-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14705845&dopt=Abstract
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Delayed dilated cardiomyopathy for major burn injuries. Author(s): Chen TJ, Shen BH, Yeh FL, Lin JT, Ma H, Huang CH, Fang RH. Source: Burns : Journal of the International Society for Burn Injuries. 2003 June; 29(4): 343-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12781611&dopt=Abstract
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Detection of patients with hypertrophic cardiomyopathy at risk for paroxysmal atrial fibrillation during sinus rhythm by P-wave dispersion. Author(s): Kose S, Aytemir K, Sade E, Can I, Ozer N, Amasyali B, Aksoyek S, Ovunc K, Ozmen F, Atalar E, Isik E, Kes S, Demirtas E, Oto A. Source: Clin Cardiol. 2003 September; 26(9): 431-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14524601&dopt=Abstract
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Diabetic cardiomyopathy. the importance of being earliest. Author(s): Picano E. Source: Journal of the American College of Cardiology. 2003 August 6; 42(3): 454-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12906971&dopt=Abstract
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Diagnostic usefulness of carotid pulse tracing in patients with hypertrophic obstructive cardiomyopathy due to midventricular obstruction: a comparison with idiopathic hypertrophic subaortic stenosis. Author(s): Hamada M, Shigematsu Y, Ohshima K, Suzuki J, Ogimoto A, Ohtsuka T, Hara Y. Source: Chest. 2003 October; 124(4): 1275-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14555556&dopt=Abstract
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Diastolic paradoxic jet flow in patients with hypertrophic cardiomyopathy: report of two patients with different morphologic aspects. Author(s): Mangano S, Carerj S, Pugliatti P, Cavallaro L, La Rosa A, Grassi R. Source: Echocardiography (Mount Kisco, N.Y.). 2003 April; 20(3): 279-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12848666&dopt=Abstract
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Diastolic ventricular dysfunction as a marker for hypertrophic cardiomyopathy in a family with a novel alpha-tropomyosin mutation. Author(s): Earing MG, Ackerman MJ, O'Leary PW. Source: Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. 2003 June; 16(6): 698-702. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12778034&dopt=Abstract
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Different functional properties of troponin T mutants that cause dilated cardiomyopathy. Author(s): Venkatraman G, Harada K, Gomes AV, Kerrick WG, Potter JD. Source: The Journal of Biological Chemistry. 2003 October 24; 278(43): 41670-6. Epub 2003 August 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12923187&dopt=Abstract
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Different presentation of hypertrophic cardiomyopathy in monozygotic twins. Author(s): Palka P, Lange A, Burstow DJ. Source: Heart (British Cardiac Society). 2003 July; 89(7): 751. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807848&dopt=Abstract
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Differentiation of ischemic from nonischemic cardiomyopathy during dobutamine stress by left ventricular long-axis function: additional effect of left bundle-branch block. Author(s): Duncan AM, Francis DP, Gibson DG, Henein MY. Source: Circulation. 2003 September 9; 108(10): 1214-20. Epub 2003 August 25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939221&dopt=Abstract
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Difficult cases in heart failure. Percutaneous transluminal septal myocardial ablation in the management of hypertrophic obstructive cardiomyopathy. Author(s): Feghali G, Alaeddini J, Ramee S, Ventura HO. Source: Congestive Heart Failure (Greenwich, Conn.). 2003 November-December; 9(6): 343-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14688508&dopt=Abstract
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Dilated cardiomyopathy after electrical injury: report of two cases. Author(s): Buono LM, DePace NL, Elbaum DM. Source: J Am Osteopath Assoc. 2003 May; 103(5): 247-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12776766&dopt=Abstract
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Dilated cardiomyopathy due to endocrine dysfunction. Author(s): Brito D, Pedro M, Bordalo A, Orgando AL, Aguiar A, Gouveia R, Martins AP, Vagueiro MC, Madeira H. Source: Rev Port Cardiol. 2003 March; 22(3): 377-87. English, Portuguese. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12847879&dopt=Abstract
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Dilated cardiomyopathy in an adult human immunodeficiency virus type 1-positive patient treated with a zidovudine-containing antiretroviral regimen. Author(s): Tanuma J, Ishizaki A, Gatanaga H, Kikuchi Y, Kimura S, Hiroe M, Oka S. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 October 1; 37(7): E109-11. Epub 2003 September 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13130421&dopt=Abstract
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Dilated cardiomyopathy in Indian children. Author(s): Kothari SS, Dhopeshwarkar RA, Saxena A, Juneja R. Source: Indian Heart J. 2003 March-April; 55(2): 147-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921329&dopt=Abstract
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Dilated cardiomyopathy: a disease of the intercalated disc? Author(s): Perriard JC, Hirschy A, Ehler E. Source: Trends in Cardiovascular Medicine. 2003 January; 13(1): 30-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12554098&dopt=Abstract
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Dilated cardiomyopathy: learning to live with yourself. Author(s): MacLellan WR, Lusis AJ. Source: Nature Medicine. 2003 December; 9(12): 1455-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14647516&dopt=Abstract
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Do some genetic mutations predict the development of dilated cardiomyopathy in patients with Becker's muscular dystrophy? Author(s): Ozdemir O, Arda K, Soylu M, Kutuk E. Source: Angiology. 2003 May-June; 54(3): 383-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12785035&dopt=Abstract
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Doppler estimation of filling pressures in a patient with hypertrophic cardiomyopathy. Author(s): Paelinck BP, Vrints CJ, Gillebert TC. Source: Echocardiography (Mount Kisco, N.Y.). 2003 February; 20(2): 163-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12848681&dopt=Abstract
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Dual-chamber pacing in hypertrophic obstructive cardiomyopathy with biventricular outflow tract obstruction and severe drug-refractory symptoms in a 9-year-old girl. Author(s): Ohtani K, Satoh A, Eto S, Satoh T, Ichinose K, Satoh S, Takahashi T, Koda M, Kinjo M, Yonesaka S. Source: Pediatrics International : Official Journal of the Japan Pediatric Society. 2003 December; 45(6): 743-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14651555&dopt=Abstract
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Dysregulation of endogenous carbon monoxide and nitric oxide production in patients with advanced ischemic or nonischemic cardiomyopathy. Author(s): Seshadri N, Dweik RA, Laskowski D, Pothier C, Rodriguez L, Young JB, Migrino RQ. Source: The American Journal of Cardiology. 2003 October 1; 92(7): 820-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14516883&dopt=Abstract
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Early versus delayed revascularization in patients with ischemic cardiomyopathy and substantial viability: impact on outcome. Author(s): Bax JJ, Schinkel AF, Boersma E, Rizzello V, Elhendy A, Maat A, Roelandt JR, van der Wall EE, Poldermans D. Source: Circulation. 2003 September 9; 108 Suppl 1: Ii39-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970206&dopt=Abstract
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Effect of nicorandil on left ventricular end-diastolic pressure during exercise in patients with hypertrophic cardiomyopathy. Author(s): Izawa H, Iwase M, Takeichi Y, Somura F, Nagata K, Nishizawa T, Noda A, Murohara T, Yokota M. Source: European Heart Journal. 2003 July; 24(14): 1340-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871691&dopt=Abstract
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Effect of thoracic epidural blockade on plasma fibrinogen levels in patients with dilated cardiomyopathy. Author(s): Li Z, Liu F, Fu S, Qu R, Liu Z, Wu S. Source: Chinese Medical Journal. 2003 August; 116(8): 1191-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12935409&dopt=Abstract
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Effects of growth hormone on circulating cytokine network, and left ventricular contractile performance and geometry in patients with idiopathic dilated cardiomyopathy. Author(s): Adamopoulos S, Parissis JT, Paraskevaidis I, Karatzas D, Livanis E, Georgiadis M, Karavolias G, Mitropoulos D, Degiannis D, Kremastinos DT. Source: European Heart Journal. 2003 December; 24(24): 2186-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14659770&dopt=Abstract
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Efficacy and safety of berberine for congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Author(s): Zeng XH, Zeng XJ, Li YY. Source: The American Journal of Cardiology. 2003 July 15; 92(2): 173-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860219&dopt=Abstract
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Efficacy of carvedilol treatment on cardiac function and cardiac sympathetic nerve activity in patients with dilated cardiomyopathy: comparison with metoprolol therapy. Author(s): Toyama T, Hoshizaki H, Seki R, Isobe N, Adachi H, Naito S, Oshima S, Taniguchi K. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2003 October; 44(10): 1604-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14530474&dopt=Abstract
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Efficacy of endoventricular circular patch plasty: will this procedure improve the prognosis of patients with ischemic cardiomyopathy? Author(s): Kokaji K, Okamoto M, Hotoda K, Maehara T, Kumamaru H, Koizumi K. Source: Jpn J Thorac Cardiovasc Surg. 2004 January; 52(1): 1-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14760984&dopt=Abstract
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Efficacy of implantable cardioverter defibrillator therapy for primary and secondary prevention of sudden cardiac death in hypertrophic cardiomyopathy. Author(s): Begley DA, Mohiddin SA, Tripodi D, Winkler JB, Fananapazir L. Source: Pacing and Clinical Electrophysiology : Pace. 2003 September; 26(9): 1887-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12930505&dopt=Abstract
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Efficacy of modified endoventricular circular patch plasty in ischemic cardiomyopathy--innovative delimitation technique using integrated myocardial management. Author(s): Nakamura M, Okamoto F, Hatta E, Nakanishi K, Matano J, Sakai K. Source: Journal of Cardiac Surgery. 2003 July-August; 18 Suppl 2: S87-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12930275&dopt=Abstract
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Elevated plasma amylase levels in advanced chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy: correlation with circulating interleukin-6 activity. Author(s): Parissis JT, Adamopoulos SN, Venetsanou KF, Karas SM, Kremastinos DT. Source: Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research. 2003 June; 23(6): 329-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12859859&dopt=Abstract
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Emerging insights into peripartum cardiomyopathy. Author(s): Fett JD, Carraway RD, Perry H, Dowell DL. Source: J Health Popul Nutr. 2003 March; 21(1): 1-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12751668&dopt=Abstract
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End-stage cardiomyopathy and secondary mitral insufficiency surgical alternative with prosthesis implant and left ventricular remodeling. Author(s): Buffolo E, de Paula IM, Aguiar LF, Branco JN. Source: Journal of Cardiac Surgery. 2003 May-June; 18(3): 201-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12809393&dopt=Abstract
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Enhanced washout of 99mTc-tetrofosmin in hypertrophic cardiomyopathy: quantitative comparisons with regional 123I-BMIPP uptake and wall thickness determined by MRI. Author(s): Thet-Thet-Lwin, Takeda T, Wu J, Fumikura Y, Iida K, Kawano S, Yamaguchi I, Itai Y. Source: European Journal of Nuclear Medicine and Molecular Imaging. 2003 July; 30(7): 966-73. Epub 2003 May 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12756503&dopt=Abstract
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Evaluation of myocardial blood flow reserve in patients with chronic congestive heart failure due to idiopathic dilated cardiomyopathy. Author(s): Canetti M, Akhter MW, Lerman A, Karaalp IS, Zell JA, Singh H, Mehra A, Elkayam U. Source: The American Journal of Cardiology. 2003 November 15; 92(10): 1246-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14609613&dopt=Abstract
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Evaluation of myocardial viability in chronic ischemic cardiomyopathy. Author(s): Bax JJ, van der Wall EE. Source: The International Journal of Cardiovascular Imaging. 2003 April; 19(2): 137-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12749394&dopt=Abstract
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Evaluation of the arrhythmogenecity of stress-induced “Takotsubo cardiomyopathy” from the time course of the 12-lead surface electrocardiogram. Author(s): Matsuoka K, Okubo S, Fujii E, Uchida F, Kasai A, Aoki T, Makino K, Omichi C, Fujimoto N, Ohta S, Sawai T, Nakano T. Source: The American Journal of Cardiology. 2003 July 15; 92(2): 230-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860233&dopt=Abstract
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Evidence for anti-ischemic effect of dual-chamber pacing in patients with the obstructive form of hypertrophic cardiomyopathy. Author(s): Mohri M, Ichiki T, Kuga T, Takeshita A. Source: Japanese Heart Journal. 2003 July; 44(4): 587-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12906041&dopt=Abstract
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Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations. Author(s): Sebillon P, Bouchier C, Bidot LD, Bonne G, Ahamed K, Charron P, DrouinGarraud V, Millaire A, Desrumeaux G, Benaiche A, Charniot JC, Schwartz K, Villard E, Komajda M. Source: Journal of Medical Genetics. 2003 August; 40(8): 560-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12920062&dopt=Abstract
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Expression profiling of human idiopathic dilated cardiomyopathy. Author(s): Grzeskowiak R, Witt H, Drungowski M, Thermann R, Hennig S, Perrot A, Osterziel KJ, Klingbiel D, Scheid S, Spang R, Lehrach H, Ruiz P. Source: Cardiovascular Research. 2003 August 1; 59(2): 400-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12909323&dopt=Abstract
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Extreme hypertrophic cardiomyopathy. Author(s): Maron BJ, Casey SA, Almquist AK. Source: Heart (British Cardiac Society). 2004 January; 90(1): 24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14676234&dopt=Abstract
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Fabry disease: a mimic for obstructive hypertrophic cardiomyopathy? Author(s): Ommen SR, Nishimura RA, Edwards WD. Source: Heart (British Cardiac Society). 2003 August; 89(8): 929-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860876&dopt=Abstract
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Failure to raise blood pressure during exercise is a poor prognostic sign in patients with hypertrophic non-obstructive cardiomyopathy. Author(s): Isobe N, Toyama T, Taniguchi K, Oshima S, Kubota S, Suzuki T, Nagaoka H, Adachi H, Naito S, Hoshizaki H. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2003 March; 67(3): 191-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604864&dopt=Abstract
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Familial dilated cardiomyopathy. Author(s): Martins E, Cardoso JS, Abreu-Lima C. Source: Rev Port Cardiol. 2002 December; 21(12): 1487-503. Review. English, Portuguese. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12621922&dopt=Abstract
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Familial dilated cardiomyopathy: evidence for clinical and immunogenetic heterogeneity. Author(s): Bilinska ZT, Michalak E, Piatosa B, Grzybowski J, Skwarek M, Deptuch TW, Kusmierczyk-Droszcz B, Piotrowski W, Ruzyllo W. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 May; 9(5): Cr167-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12761452&dopt=Abstract
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Familial hypertrophic cardiomyopathy-linked mutant troponin T causes stressinduced ventricular tachycardia and Ca2+-dependent action potential remodeling. Author(s): Knollmann BC, Kirchhof P, Sirenko SG, Degen H, Greene AE, Schober T, Mackow JC, Fabritz L, Potter JD, Morad M. Source: Circulation Research. 2003 March 7; 92(4): 428-36. Epub 2003 February 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12600890&dopt=Abstract
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Familial restrictive cardiomyopathy with skeletal abnormalities. Author(s): Schwartz ML, Colan SD. Source: The American Journal of Cardiology. 2003 September 1; 92(5): 636-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12943897&dopt=Abstract
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Fibromuscular dysplasia of coronary arteries resulting in myocardial infarction associated with hypertrophic cardiomyopathy in Noonan's syndrome. Author(s): Ishikawa Y, Sekiguchi K, Akasaka Y, Ito K, Akishima Y, Zhang L, Itoh M, Ishihara M, Ishii T. Source: Human Pathology. 2003 March; 34(3): 282-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12673564&dopt=Abstract
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First-pass MR imaging in the assessment of perfusion impairment in patients with hypertrophic cardiomyopathy and the Asp175Asn mutation of the alpha-tropomyosin gene. Author(s): Sipola P, Lauerma K, Husso-Saastamoinen M, Kuikka JT, Vanninen E, Laitinen T, Manninen H, Niemi P, Peuhkurinen K, Jaaskelainen P, Laakso M, Kuusisto J, Aronen HJ. Source: Radiology. 2003 January; 226(1): 129-37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12511681&dopt=Abstract
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Focal hypertrophic cardiomyopathy simulating a mass. Author(s): Gonzalez-Juanatey C, Testa-Fernandez A, Vidan J. Source: Clin Cardiol. 2003 November; 26(11): 539. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14640472&dopt=Abstract
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Frequency of development of idiopathic dilated cardiomyopathy among relatives of patients with idiopathic dilated cardiomyopathy. Author(s): Michels VV, Olson TM, Miller FA, Ballman KV, Rosales AG, Driscoll DJ. Source: The American Journal of Cardiology. 2003 June 1; 91(11): 1389-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767445&dopt=Abstract
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From malignant mutations to malignant domains: the continuing search for prognostic significance in the mutant genes causing hypertrophic cardiomyopathy. Author(s): Van Driest SL, Maron BJ, Ackerman MJ. Source: Heart (British Cardiac Society). 2004 January; 90(1): 7-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14676227&dopt=Abstract
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From sarcomeric mutations to heart disease: understanding familial hypertrophic cardiomyopathy. Author(s): Maass A, Konhilas JP, Stauffer BL, Leinwand LA. Source: Cold Spring Harb Symp Quant Biol. 2002; 67: 409-15. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858566&dopt=Abstract
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Functional consequences of mutations in the myosin heavy chain at sites implicated in familial hypertrophic cardiomyopathy. Author(s): Lowey S. Source: Trends in Cardiovascular Medicine. 2002 November; 12(8): 348-54. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12536121&dopt=Abstract
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Gadolinium-enhanced magnetic resonance imaging in hypertrophic cardiomyopathy: in vivo imaging of the pathologic substrate for premature cardiac death? Author(s): Kim RJ, Judd RM. Source: Journal of the American College of Cardiology. 2003 May 7; 41(9): 1568-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12742299&dopt=Abstract
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Ganglioneuroblastoma presenting as dilated cardiomyopathy. Author(s): Lee YH, Lee HD, Lee YA, Lee YS, Jung JA, Hwang GG, Jung GW, Kim DW, Roh MS. Source: Archives of Disease in Childhood. 2003 February; 88(2): 162-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12538326&dopt=Abstract
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Genetics of arrhythmogenic right ventricular cardiomyopathy--status quo and future perspectives. Author(s): Paul M, Schulze-Bahr E, Breithardt G, Wichter T. Source: Zeitschrift Fur Kardiologie. 2003 February; 92(2): 128-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12596074&dopt=Abstract
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Geometric differences of the mitral apparatus between ischemic and dilated cardiomyopathy with significant mitral regurgitation: real-time three-dimensional echocardiography study. Author(s): Kwan J, Shiota T, Agler DA, Popovic ZB, Qin JX, Gillinov MA, Stewart WJ, Cosgrove DM, McCarthy PM, Thomas JD; Real-time three-dimensional echocardiography study. Source: Circulation. 2003 March 4; 107(8): 1135-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615791&dopt=Abstract
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Heart rate turbulence and clinical prognosis in hypertrophic cardiomyopathy and myocardial infarction. Author(s): Kawasaki T, Azuma A, Asada S, Hadase M, Kamitani T, Kawasaki S, Kuribayashi T, Sugihara H. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2003 July; 67(7): 601-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12845183&dopt=Abstract
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Heart transplantation in chemotherapeutic dilated cardiomyopathy. Author(s): Grande AM, Rinaldi M, Sinelli S, D'Armini AM, Vigano M. Source: Transplantation Proceedings. 2003 June; 35(4): 1516-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12826209&dopt=Abstract
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Hemodynamic improvement and removal of autoantibodies against beta1-adrenergic receptor by immunoadsorption therapy in dilated cardiomyopathy. Author(s): Mobini R, Staudt A, Felix SB, Baumann G, Wallukat G, Deinum J, Svensson H, Hjalmarson A, Fu M. Source: Journal of Autoimmunity. 2003 June; 20(4): 345-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791320&dopt=Abstract
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Hemodynamics during chronic amiodarone administration in Japanese patients with idiopathic dilated cardiomyopathy and ventricular arrhythmia: a retrospective study. Author(s): Suzuki T, Shiga T, Wakaumi M, Matsuda N, Ishizuka N, Kasanuki H. Source: J Cardiol. 2003 April; 41(4): 169-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12728537&dopt=Abstract
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HLA-DRB1 gene polymorphism in patients with dilated cardiomyopathy. Author(s): Wang Q, Liao Y, Gong F, Mao H, Zhang J. Source: J Tongji Med Univ. 2000; 20(2): 141-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12845730&dopt=Abstract
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Hypertension and heart failure sine heart failure. The ACC/AHA guidelines: a misadventure in the lexicography of cardiomyopathy and heart failure, particularly for the hypertensive. Author(s): Giles TD. Source: Journal of Clinical Hypertension (Greenwich, Conn.). 2003 July-August; 5(4): 280-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939569&dopt=Abstract
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Hypertrophic cardiomyopathy and diastolic dysfunction. Author(s): Shah PM. Source: Journal of the American College of Cardiology. 2003 July 16; 42(2): 286-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875765&dopt=Abstract
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Hypertrophic cardiomyopathy and outflow tract obstruction. Author(s): Spevack DM. Source: The New England Journal of Medicine. 2003 May 1; 348(18): 1815-6; Author Reply 1815-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12728916&dopt=Abstract
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Hypertrophic cardiomyopathy and outflow tract obstruction. Author(s): Iqbal K, Tramboo NA, Mohi-Ud-Din K. Source: The New England Journal of Medicine. 2003 May 1; 348(18): 1815-6; Author Reply 1815-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12728915&dopt=Abstract
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Hypertrophic cardiomyopathy and outflow tract obstruction. Author(s): Monserrat L, Penas-Lado M, Castro-Beiras A. Source: The New England Journal of Medicine. 2003 May 1; 348(18): 1815-6; Author Reply 1815-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12724493&dopt=Abstract
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Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. Author(s): Crilley JG, Boehm EA, Blair E, Rajagopalan B, Blamire AM, Styles P, McKenna WJ, Ostman-Smith I, Clarke K, Watkins H. Source: Journal of the American College of Cardiology. 2003 May 21; 41(10): 1776-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767664&dopt=Abstract
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Hypertrophic cardiomyopathy: an important global disease. Author(s): Maron BJ. Source: The American Journal of Medicine. 2004 January 1; 116(1): 63-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14706671&dopt=Abstract
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Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Author(s): Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M; EUROGENE Heart Failure Project. Source: Circulation. 2003 May 6; 107(17): 2227-32. Epub 2003 April 21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12707239&dopt=Abstract
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Hypertrophic cardiomyopathy: low frequency of mutations in the beta-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) genes among Spanish patients. Author(s): Garcia-Castro M, Reguero JR, Batalla A, Diaz-Molina B, Gonzalez P, Alvarez V, Cortina A, Cubero GI, Coto E. Source: Clinical Chemistry. 2003 August; 49(8): 1279-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12881443&dopt=Abstract
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Hypertrophic cardiomyopathy: two homozygous cases with “typical” hypertrophic cardiomyopathy and three new mutations in cases with progression to dilated cardiomyopathy. Author(s): Nanni L, Pieroni M, Chimenti C, Simionati B, Zimbello R, Maseri A, Frustaci A, Lanfranchi G. Source: Biochemical and Biophysical Research Communications. 2003 September 19; 309(2): 391-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12951062&dopt=Abstract
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Hypertrophic cardiomyopathy: who plays and who sits. Author(s): Rizvi AA, Thompson PD. Source: Curr Sports Med Rep. 2002 April; 1(2): 93-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12831717&dopt=Abstract
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Hypertrophic cardiomyopathy:a paradigm for myocardial energy depletion. Author(s): Ashrafian H, Redwood C, Blair E, Watkins H. Source: Trends in Genetics : Tig. 2003 May; 19(5): 263-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12711218&dopt=Abstract
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Hypertrophic obstructive cardiomyopathy and septal ablation. Author(s): Steinbis S. Source: Critical Care Nurse. 2003 June; 23(3): 47-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12830780&dopt=Abstract
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Hypertrophic obstructive cardiomyopathy: mechanism of obstruction and response to therapy. Author(s): Yoerger DM, Weyman AE. Source: Reviews in Cardiovascular Medicine. 2003 Fall; 4(4): 199-215. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14668688&dopt=Abstract
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Hypocalcemic rickets: an unusual cause of dilated cardiomyopathy. Author(s): Price DI, Stanford LC Jr, Braden DS, Ebeid MR, Smith JC. Source: Pediatric Cardiology. 2003 September-October; 24(5): 510-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14627327&dopt=Abstract
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Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy. Author(s): Hayashi T, Arimura T, Ueda K, Shibata H, Hohda S, Takahashi M, Hori H, Koga Y, Oka N, Imaizumi T, Yasunami M, Kimura A. Source: Biochemical and Biophysical Research Communications. 2004 January 2; 313(1): 178-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14672715&dopt=Abstract
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Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden. Author(s): Morner S, Richard P, Kazzam E, Hellman U, Hainque B, Schwartz K, Waldenstrom A. Source: Journal of Molecular and Cellular Cardiology. 2003 July; 35(7): 841-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12818575&dopt=Abstract
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Idiopathic cardiomyopathy and recurrent wide QRS tachycardia. Author(s): Delacretaz E, Fuhrer J, Mohacsi P. Source: Pacing and Clinical Electrophysiology : Pace. 2003 June; 26(6): 1407-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12822757&dopt=Abstract
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Images in cardiovascular medicine. Covered stent septal ablation for hypertrophic obstructive cardiomyopathy: initial success but ultimate failure resulting from collateral formation. Author(s): Fifer MA, Yoerger DM, Picard MH, Vlahakes GJ, Palacios IF. Source: Circulation. 2003 July 1; 107(25): 3248-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12835408&dopt=Abstract
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Images in cardiovascular medicine. Epicardial real-time 3-dimensional echocardiography during septal myectomy for obstructive hypertrophic cardiomyopathy. Author(s): Nash PJ, Agler DA, Shin JH, Qin J, Smedira NG, Lever HM, Shiota T, Thomas JD. Source: Circulation. 2003 August 26; 108(8): E54-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939245&dopt=Abstract
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Images in cardiovascular medicine. Rapid progression of extreme septal hypertrophic cardiomyopathy. Author(s): Jefferies JL, Moreira W, Massumi A, Stainback RF. Source: Circulation. 2003 November 11; 108(19): E136. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14609999&dopt=Abstract
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Impaired VE-cadherin/beta-catenin expression mediates endothelial cell degeneration in dilated cardiomyopathy. Author(s): Schafer R, Abraham D, Paulus P, Blumer R, Grimm M, Wojta J, Aharinejad S. Source: Circulation. 2003 September 30; 108(13): 1585-91. Epub 2003 Sep 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12963640&dopt=Abstract
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Implantable cardioverter-defibrillator therapy for prevention of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Author(s): Corrado D, Leoni L, Link MS, Della Bella P, Gaita F, Curnis A, Salerno JU, Igidbashian D, Raviele A, Disertori M, Zanotto G, Verlato R, Vergara G, Delise P, Turrini P, Basso C, Naccarella F, Maddalena F, Estes NA 3rd, Buja G, Thiene G. Source: Circulation. 2003 December 23; 108(25): 3084-91. Epub 2003 November 24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14638546&dopt=Abstract
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Importance of mitral valve repair associated with left ventricular reconstruction for patients with ischemic cardiomyopathy: a real-time three-dimensional echocardiographic study. Author(s): Qin JX, Shiota T, McCarthy PM, Asher CR, Hail M, Agler DA, Popovic ZB, Greenberg NL, Smedira NG, Starling RC, Young JB, Thomas JD. Source: Circulation. 2003 September 9; 108 Suppl 1: Ii241-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970240&dopt=Abstract
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Improved early outcome for end-stage dilated cardiomyopathy in children. Author(s): McMahon AM, van Doorn C, Burch M, Whitmore P, Neligan S, Rees P, Radley-Smith R, Goldman A, Brown K, Cohen G, Tsang V, Elliott M. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 December; 126(6): 1781-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14688687&dopt=Abstract
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Improvement in hypertrophic cardiomyopathy after significant weight loss: case report. Author(s): Uwaifo GI, Fallon EM, Calis KA, Drinkard B, McDuffie JR, Yanovski JA. Source: Southern Medical Journal. 2003 June; 96(6): 626-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12938797&dopt=Abstract
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Improvement of peripheral endothelial dysfunction by acute vitamin C application: different effects in patients with coronary artery disease, ischemic, and dilated cardiomyopathy. Author(s): Erbs S, Gielen S, Linke A, Mobius-Winkler S, Adams V, Baither Y, Schuler G, Hambrecht R. Source: American Heart Journal. 2003 August; 146(2): 280-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12891196&dopt=Abstract
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Improvement of ventricular arrhythmia by octreotide treatment in acromegalic cardiomyopathy. Author(s): Tachibana H, Yamaguchi H, Abe S, Sato T, Inoue S, Abe S, Yamaki M, Kubota I. Source: Japanese Heart Journal. 2003 November; 44(6): 1027-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14711197&dopt=Abstract
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Increased plasma levels of tumor necrosis factor-alpha in asymptomatic/”indeterminate” and Chagas disease cardiomyopathy patients. Author(s): Ferreira RC, Ianni BM, Abel LC, Buck P, Mady C, Kalil J, Cunha-Neto E. Source: Memorias Do Instituto Oswaldo Cruz. 2003 April; 98(3): 407-11. Epub 2003 July 18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12886425&dopt=Abstract
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Individual prediction of functional recovery after coronary revascularization in patients with ischemic cardiomyopathy: the scar-to-biphasic model. Author(s): Rizzello V, Schinkel AF, Bax JJ, Boersma E, Bountioukos M, Vourvouri EC, Krenning B, Agricola E, Roelandt JR, Poldermans D. Source: The American Journal of Cardiology. 2003 June 15; 91(12): 1406-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804724&dopt=Abstract
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Insulin resistance in dilated cardiomyopathy. Author(s): Shah A, Shannon RP. Source: Reviews in Cardiovascular Medicine. 2003; 4 Suppl 6: S50-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14668703&dopt=Abstract
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Is peripartum cardiomyopathy an organ-specific autoimmune disease? Author(s): Sundstrom JB, Fett JD, Carraway RD, Ansari AA. Source: Autoimmunity Reviews. 2002 February; 1(1-2): 73-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849062&dopt=Abstract
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Ischemia due to peripartum cardiomyopathy threatening loss of a leg. Author(s): Gagne PJ, Newman JB, Muhs BE. Source: Cardiology in the Young. 2003 April; 13(2): 209-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12887083&dopt=Abstract
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Ischemic cardiomyopathy: value of different MRI techniques for prediction of functional recovery after revascularization. Author(s): Van Hoe L, Vanderheyden M. Source: Ajr. American Journal of Roentgenology. 2004 January; 182(1): 95-100. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14684520&dopt=Abstract
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Isolated left ventricular non-compaction: cardiomyopathy with homogeneous transmural and heterogeneous segmental perfusion. Author(s): Borges AC, Kivelitz D, Baumann G. Source: Heart (British Cardiac Society). 2003 August; 89(8): E21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860887&dopt=Abstract
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Late improvement in ventricular performance following internal cardioversion for persistent atrial fibrillation: an argument in support of concealed cardiomyopathy. Author(s): Boriani G, Biffi M, Rapezzi C, Ferlito M, Bronzetti G, Bacchi L, Zannoli R, Branzi A. Source: Pacing and Clinical Electrophysiology : Pace. 2003 May; 26(5): 1218-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12765450&dopt=Abstract
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Late-Onset visceral presentation with cardiomyopathy and without neurological symptoms of adult Sanfilippo A syndrome. Author(s): Van Hove JL, Wevers RA, Van Cleemput J, Moerman P, Sciot R, Matthijs G, Schollen E, de Jong JG, Carey WF, Muller V, Nicholls C, Perkins K, Hopwood JJ. Source: American Journal of Medical Genetics. 2003 May 1; 118A(4): 382-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12687673&dopt=Abstract
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Left ventricular enlargement is common in relatives of patients with dilated cardiomyopathy. Author(s): Bilinska ZT, Michalak E, Kusmierczyk-Droszcz B, Rydlewska-Sadowska W, Grzybowski J, Kupsc W, Ruzyllo W. Source: Journal of Cardiac Failure. 1995 December; 1(5): 347-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12836709&dopt=Abstract
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Left ventricular restoration for ischemic cardiomyopathy--comparison of presence and absence of mitral valve procedure. Author(s): Isomura T, Suma H, Yamaguchi A, Kobashi T, Yuda A. Source: European Journal of Cardio-Thoracic Surgery : Official Journal of the European Association for Cardio-Thoracic Surgery. 2003 April; 23(4): 614-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12694786&dopt=Abstract
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Left ventricular systolic dysfunction and ischemic cardiomyopathy. Author(s): Henry LB. Source: Critical Care Nursing Quarterly. 2003 January-March; 26(1): 16-21. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669942&dopt=Abstract
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Left ventricular systolic dysfunction and nonischemic cardiomyopathy. Author(s): Tarolli KA. Source: Critical Care Nursing Quarterly. 2003 January-March; 26(1): 3-15. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669941&dopt=Abstract
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Left ventricular wall stress as a direct correlate of cardiomyocyte apoptosis in patients with severe dilated cardiomyopathy. Author(s): Di Napoli P, Taccardi AA, Grilli A, Felaco M, Balbone A, Angelucci D, Gallina S, Calafiore AM, De Caterina R, Barsotti A. Source: American Heart Journal. 2003 December; 146(6): 1105-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14661007&dopt=Abstract
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Left ventriculoplasty for nonischemic dilated cardiomyopathy. Author(s): Horii T, Isomura T, Komeda M, Suma H. Source: Journal of Cardiac Surgery. 2003 March-April; 18(2): 121-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757338&dopt=Abstract
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LGMD2E patients risk developing dilated cardiomyopathy. Author(s): Fanin M, Melacini P, Boito C, Pegoraro E, Angelini C. Source: Neuromuscular Disorders : Nmd. 2003 May; 13(4): 303-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12868499&dopt=Abstract
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Limitation of cardiac output by total isovolumic time during pharmacologic stress in patients with dilated cardiomyopathy: activation-mediated effects of left bundle branch block and coronary artery disease. Author(s): Duncan AM, Francis DP, Henein MY, Gibson DG. Source: Journal of the American College of Cardiology. 2003 January 1; 41(1): 121-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12570954&dopt=Abstract
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Linkage analysis of five Chinese families with arrhythmogenic right ventricular cardiomyopathy using microsatellite genetic markers. Author(s): Huang J, Yang C, Ma L, Shan Q, Xu D, Hua Z, Cao K. Source: Chinese Medical Journal. 2003 November; 116(11): 1701-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14642141&dopt=Abstract
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Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. Author(s): Yagyu H, Chen G, Yokoyama M, Hirata K, Augustus A, Kako Y, Seo T, Hu Y, Lutz EP, Merkel M, Bensadoun A, Homma S, Goldberg IJ. Source: The Journal of Clinical Investigation. 2003 February; 111(3): 419-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12569168&dopt=Abstract
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Long-term glucose insulin potassium infusion improves systolic and diastolic function in patients with chronic ischemic cardiomyopathy. Author(s): Alan S, Ulgen MS, Dedeoglu I, Kaya H, Toprak N. Source: Swiss Medical Weekly : Official Journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology. 2003 July 26; 133(29-30): 419-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14562192&dopt=Abstract
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Long-term improvements in quality of life by biventricular pacing in patients with chronic heart failure: results from the Multisite Stimulation in Cardiomyopathy study (MUSTIC). Author(s): Linde C, Braunschweig F, Gadler F, Bailleul C, Daubert JC. Source: The American Journal of Cardiology. 2003 May 1; 91(9): 1090-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12714152&dopt=Abstract
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Loss of lamin A/C expression revealed by immuno-electron microscopy in dilated cardiomyopathy with atrioventricular block caused by LMNA gene defects. Author(s): Verga L, Concardi M, Pilotto A, Bellini O, Pasotti M, Repetto A, Tavazzi L, Arbustini E. Source: Virchows Archiv : an International Journal of Pathology. 2003 November; 443(5): 664-71. Epub 2003 July 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12898247&dopt=Abstract
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Mechanisms of the pathogenesis of troponin T-based familial hypertrophic cardiomyopathy. Author(s): Maass AH, Leinwand LA. Source: Trends in Cardiovascular Medicine. 2003 August; 13(6): 232-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12922019&dopt=Abstract
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Microcephaly-cardiomyopathy syndrome: expansion of the phenotype. Author(s): Becker K, Yates R. Source: Journal of Medical Genetics. 2003 June; 40(6): E78. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807977&dopt=Abstract
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Midaortic syndrome in the fetus and premature newborn: a new etiology of nonimmune hydrops fetalis and reversible fetal cardiomyopathy. Author(s): Zeltser I, Parness IA, Ko H, Holzman IR, Kamenir SA. Source: Pediatrics. 2003 June; 111(6 Pt 1): 1437-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12777568&dopt=Abstract
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Mid-ventricular paradoxical dynamic obstruction in a right-sided secondary hypertrophic cardiomyopathy. Author(s): de Gregorio C, Micari A, Triboto F, Arrigo F, Coglitore S. Source: Ital Heart J. 2003 July; 4(7): 492-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14558303&dopt=Abstract
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Mitral valve in ischemic versus idiopathic dilated cardiomyopathy. Author(s): Grossi EA, Sharony R, Colvin SB. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 September; 126(3): 922. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14502200&dopt=Abstract
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Mitral valve repair in uremic congestive cardiomyopathy. Author(s): Chang JP, Kao CL. Source: The Annals of Thoracic Surgery. 2003 September; 76(3): 694-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12963180&dopt=Abstract
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Modified septal myectomy and repair of mitral valve apparatus for the treatment of hypertrophic cardiomyopathy. Author(s): Paruchuru PK, Patel RL. Source: J Heart Valve Dis. 2003 July; 12(4): 527-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12918858&dopt=Abstract
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Multiple coronary artery-left ventricular microfistulae in a patient with apical hypertrophic cardiomyopathy: a demonstration by transthoracic color Doppler echocardiography. Author(s): Hong GR, Choi SH, Kang SM, Lee MH, Rim SJ, Jang YS, Chung NS. Source: Yonsei Medical Journal. 2003 August 30; 44(4): 710-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12950129&dopt=Abstract
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Muscular dystrophies, dilated cardiomyopathy, lipodystrophy and neuropathy: the nuclear connection. Author(s): Maidment SL, Ellis JA. Source: Expert Reviews in Molecular Medicine [electronic Resource]. 2002 July 30; 2002: 1-21. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14585157&dopt=Abstract
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Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction. Author(s): Vatta M, Mohapatra B, Jimenez S, Sanchez X, Faulkner G, Perles Z, Sinagra G, Lin JH, Vu TM, Zhou Q, Bowles KR, Di Lenarda A, Schimmenti L, Fox M, Chrisco MA, Murphy RT, McKenna W, Elliott P, Bowles NE, Chen J, Valle G, Towbin JA. Source: Journal of the American College of Cardiology. 2003 December 3; 42(11): 201427. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14662268&dopt=Abstract
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Mutations of the beta myosin heavy chain gene in hypertrophic cardiomyopathy: critical functional sites determine prognosis. Author(s): Woo A, Rakowski H, Liew JC, Zhao MS, Liew CC, Parker TG, Zeller M, Wigle ED, Sole MJ. Source: Heart (British Cardiac Society). 2003 October; 89(10): 1179-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12975413&dopt=Abstract
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Myocardial bridging in adult patients with hypertrophic cardiomyopathy. Author(s): Sorajja P, Ommen SR, Nishimura RA, Gersh BJ, Tajik AJ, Holmes DR. Source: Journal of the American College of Cardiology. 2003 September 3; 42(5): 889-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957438&dopt=Abstract
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Myocardial collagen turnover in hypertrophic cardiomyopathy. Author(s): Lombardi R, Betocchi S, Losi MA, Tocchetti CG, Aversa M, Miranda M, D'Alessandro G, Cacace A, Ciampi Q, Chiariello M. Source: Circulation. 2003 September 23; 108(12): 1455-60. Epub 2003 Sep 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12952838&dopt=Abstract
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Myocardial infarction after percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy: evaluation by contrast-enhanced magnetic resonance imaging. Author(s): van Dockum WG, ten Cate FJ, ten Berg JM, Beek AM, Twisk JW, Vos J, Hofman MB, Visser CA, van Rossum AC. Source: Journal of the American College of Cardiology. 2004 January 7; 43(1): 27-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14715178&dopt=Abstract
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Myocardial perfusion reserve and peripheral endothelial function in patients with idiopathic dilated cardiomyopathy. Author(s): Stolen KQ, Kemppainen J, Kalliokoski KK, Karanko H, Toikka J, Janatuinen T, Raitakari OT, Airaksinen KE, Nuutila P, Knuuti J. Source: The American Journal of Cardiology. 2004 January 1; 93(1): 64-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14697468&dopt=Abstract
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Myocardial ultrasound tissue characterization in patients with hypertrophic cardiomyopathy: noninvasive evidence of electrical and textural substrate for ventricular arrhythmias. Author(s): Limongelli G, Pacileo G, Cerrato F, Verrengia M, Di Simone A, Severino S, Sarubbi B, Calabro R. Source: Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. 2003 August; 16(8): 803-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12878988&dopt=Abstract
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Myocardial velocity gradient as a noninvasively determined index of left ventricular diastolic dysfunction in patients with hypertrophic cardiomyopathy. Author(s): Kato T, Noda A, Izawa H, Nishizawa T, Somura F, Yamada A, Nagata K, Iwase M, Nakao A, Yokota M. Source: Journal of the American College of Cardiology. 2003 July 16; 42(2): 278-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875764&dopt=Abstract
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Myocarditis and dilated cardiomyopathy: an inflammatory link. Author(s): Mason JW. Source: Cardiovascular Research. 2003 October 15; 60(1): 5-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14522402&dopt=Abstract
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Myocarditis and inflammatory cardiomyopathy: microbiological and molecular biological aspects. Author(s): Calabrese F, Thiene G. Source: Cardiovascular Research. 2003 October 15; 60(1): 11-25. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14522403&dopt=Abstract
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Myopathy with tubular aggregates and hypertrophic cardiomyopathy in a patient with type IIA von Willebrand disease. Author(s): Mares M, Sartori MT, Casonato A, Melacini P, Angelini C, Girolami A. Source: Haematologia. 1996; 27(4): 201-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14651221&dopt=Abstract
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Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. Author(s): Taylor MR, Fain PR, Sinagra G, Robinson ML, Robertson AD, Carniel E, Di Lenarda A, Bohlmeyer TJ, Ferguson DA, Brodsky GL, Boucek MM, Lascor J, Moss AC, Li WL, Stetler GL, Muntoni F, Bristow MR, Mestroni L; Familial Dilated Cardiomyopathy Registry Research Group. Source: Journal of the American College of Cardiology. 2003 March 5; 41(5): 771-80. Erratum In: J Am Coll Cardiol. 2003 August 6; 42(3): 590. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628721&dopt=Abstract
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NCAM(CD56) and RUNX1(AML1) are up-regulated in human ischemic cardiomyopathy and a rat model of chronic cardiac ischemia. Author(s): Gattenlohner S, Waller C, Ertl G, Bultmann BD, Muller-Hermelink HK, Marx A. Source: American Journal of Pathology. 2003 September; 163(3): 1081-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12937148&dopt=Abstract
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Neurohormones and oxidative stress in nonischemic cardiomyopathy: relationship to survival and the effect of treatment with amlodipine. Author(s): Wijeysundera HC, Hansen MS, Stanton E, Cropp AS, Hall C, Dhalla NS, Ghali J, Rouleau JL; PRAISE II Investigators. Source: American Heart Journal. 2003 August; 146(2): 291-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12891198&dopt=Abstract
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New phenotype of familial dilated cardiomyopathy and conduction disorders. Author(s): Oropeza ES, Cadena CN. Source: American Heart Journal. 2003 February; 145(2): 317-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12595850&dopt=Abstract
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Noninvasive arrhythmia risk stratification in idiopathic dilated cardiomyopathy: results of the Marburg Cardiomyopathy Study. Author(s): Grimm W, Christ M, Bach J, Muller HH, Maisch B. Source: Circulation. 2003 December 9; 108(23): 2883-91. Epub 2003 November 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14623812&dopt=Abstract
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Noninvasive identification of myocardial sympathetic and metabolic abnormalities in a patient with restrictive cardiomyopathy--in comparison with perfusion imaging. Author(s): Matsuo S, Nakae I, Takada M, Murata K, Nakamura Y. Source: Ann Nucl Med. 2002 December; 16(8): 569-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12593423&dopt=Abstract
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Nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy: short-term results in 50 consecutive procedures. Author(s): Nielsen CD, Killip D, Spencer WH 3rd. Source: Clin Cardiol. 2003 June; 26(6): 275-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839045&dopt=Abstract
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Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients. Author(s): Monserrat L, Elliott PM, Gimeno JR, Sharma S, Penas-Lado M, McKenna WJ. Source: Journal of the American College of Cardiology. 2003 September 3; 42(5): 873-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957435&dopt=Abstract
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Non-transplant cardiac surgery for end-stage dilated cardiomyopathy in small children. Author(s): Hsu RB, Chen RJ, Wu MH, Wang JK, Wang SS, Chu SH. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 January; 22(1): 94-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12531419&dopt=Abstract
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Normalization of left ventricular parameters following combined pimobendan and carvedilol treatment in a case of unclassified cardiomyopathy with longstanding refractory status. Author(s): Takeda N, Ohtaki E, Misu K, Asano R, Tobaru T, Nagayama M, Kitahara K, Umemura J, Sumiyoshi T, Hosoda S. Source: Intern Med. 2002 December; 41(12): 1147-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12521204&dopt=Abstract
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Nuclear speckle localisation of the small heat shock protein alpha B-crystallin and its inhibition by the R120G cardiomyopathy-linked mutation. Author(s): van den IJssel P, Wheelock R, Prescott A, Russell P, Quinlan RA. Source: Experimental Cell Research. 2003 July 15; 287(2): 249-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12837281&dopt=Abstract
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Obstructive hypertrophic cardiomyopathy: echocardiography, pathophysiology, and the continuing evolution of surgery for obstruction. Author(s): Sherrid MV, Chaudhry FA, Swistel DG. Source: The Annals of Thoracic Surgery. 2003 February; 75(2): 620-32. Review. Erratum In: Ann Thorac Surg. 2003 May; 75(5): 1684. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12607696&dopt=Abstract
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On predictors of sudden cardiac death in hypertrophic cardiomyopathy. Author(s): Marian AJ. Source: Journal of the American College of Cardiology. 2003 March 19; 41(6): 994-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12651047&dopt=Abstract
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Original report. Late myocardial enhancement in hypertrophic cardiomyopathy with contrast-enhanced MR imaging. Author(s): Bogaert J, Goldstein M, Tannouri F, Golzarian J, Dymarkowski S. Source: Ajr. American Journal of Roentgenology. 2003 April; 180(4): 981-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12646440&dopt=Abstract
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Outcome of clinical versus genetic family screening in hypertrophic cardiomyopathy with focus on cardiac beta-myosin gene mutations. Author(s): Havndrup O, Bundgaard H, Andersen PS, Allan Larsen L, Vuust J, Kjeldsen K, Christiansen M. Source: Cardiovascular Research. 2003 February; 57(2): 347-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12566107&dopt=Abstract
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Outcome of clinical versus genetic family screening in hypertrophic cardiomyopathy with focus on cardiac beta-myosin gene mutations: prediction of clinical status--is molecular genetics a new tool for the management of hypertrophic cardiomyopathy in clinical practice? Author(s): Hengstenberg C, Erdmann J, Charron P. Source: Cardiovascular Research. 2003 February; 57(2): 298-301. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12566102&dopt=Abstract
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Partial reversion of left ventricle remodeling in cardiomyopathy patients by means of transthoracic microelectrostimulation. Author(s): Kharchenko EP, Khubulava GG, Pyr'ev VB, Klimenko MN. Source: Doklady Biological Sciences : Proceedings of the Academy of Sciences of the Ussr, Biological Sciences Sections / Translated from Russian. 2001 September-October; 380: 438-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12918398&dopt=Abstract
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Percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy. Author(s): Senaratne V, Sathanandan S, Ekanayake RA. Source: Ceylon Med J. 2003 September; 48(3): 92-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14735809&dopt=Abstract
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Perioperative management of lobectomy in a patient with hypertrophic obstructive cardiomyopathy treated with dual-chamber pacing. Author(s): Amagasa S, Oda S, Abe S, Shinozaki K, Miura Y, Takaoka S, Horikawa H. Source: Journal of Anesthesia. 2003; 17(1): 49-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12908688&dopt=Abstract
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Peripartum cardiomyopathy. Author(s): Rao S, Shenoy JV, Giles RW, Clark JD. Source: Journal of Obstetrics and Gynaecology : the Journal of the Institute of Obstetrics and Gynaecology. 2003 September; 23(5): 567-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12963526&dopt=Abstract
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Peripartum cardiomyopathy: a spoiled birthday party. Author(s): de Ceuninck M, Vermeulen J, Vrints C. Source: Acta Cardiol. 2003 August; 58(4): 367-70. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12948045&dopt=Abstract
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Permanent form of junctional reciprocating tachycardia and tachycardia-induced cardiomyopathy treated by catheter ablation: a case report. Author(s): Semizel E, Ayabakan C, Ceviz N, Celiker A. Source: Turk J Pediatr. 2003 October-December; 45(4): 338-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14768801&dopt=Abstract
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Persistent abnormal left ventricular systolic torsion in dilated cardiomyopathy after partial left ventriculectomy. Author(s): Setser RM, Kasper JM, Lieber ML, Starling RC, McCarthy PM, White RD. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 July; 126(1): 48-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12878938&dopt=Abstract
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Phaeochromocytoma presenting as dilated cardiomyopathy. Author(s): Attar MN, Moulik PK, Salem GD, Rose EL, Khaleeli AA. Source: Int J Clin Pract. 2003 July-August; 57(6): 547-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12918898&dopt=Abstract
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Preclinical diabetic cardiomyopathy: relation of left ventricular diastolic dysfunction to cardiac autonomic neuropathy in men with uncomplicated well-controlled type 2 diabetes. Author(s): Poirier P, Bogaty P, Philippon F, Garneau C, Fortin C, Dumesnil JG. Source: Metabolism: Clinical and Experimental. 2003 August; 52(8): 1056-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12898473&dopt=Abstract
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Pregnancy related complications in women with hypertrophic cardiomyopathy. Author(s): Thaman R, Varnava A, Hamid MS, Firoozi S, Sachdev B, Condon M, Gimeno JR, Murphy R, Elliott PM, McKenna WJ. Source: Heart (British Cardiac Society). 2003 July; 89(7): 752-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807849&dopt=Abstract
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Pregnancy-related mortality due to cardiomyopathy: United States, 1991-1997. Author(s): Whitehead SJ, Berg CJ, Chang J. Source: Obstetrics and Gynecology. 2003 December; 102(6): 1326-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14662222&dopt=Abstract
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Prevalence and clinical profile of troponin T mutations among patients with hypertrophic cardiomyopathy in tuscany. Author(s): Torricelli F, Girolami F, Olivotto I, Passerini I, Frusconi S, Vargiu D, Richard P, Cecchi F. Source: The American Journal of Cardiology. 2003 December 1; 92(11): 1358-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14636924&dopt=Abstract
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Prevalence of hepatitis C virus infection among patients with hypertrophic cardiomyopathy. Author(s): Teragaki M, Nishiguchi S, Takeuchi K, Yoshiyama M, Akioka K, Yoshikawa J. Source: Heart and Vessels. 2003 September; 18(4): 167-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14520482&dopt=Abstract
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Prevalence of idiopathic hypertrophic cardiomyopathy in China: a population-based echocardiographic analysis of 8080 adults. Author(s): Zou Y, Song L, Wang Z, Ma A, Liu T, Gu H, Lu S, Wu P, Zhang dagger Y, Shen dagger L, Cai Y, Zhen double dagger Y, Liu Y, Hui R. Source: The American Journal of Medicine. 2004 January 1; 116(1): 14-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14706660&dopt=Abstract
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Prognostic significance of heart rate turbulence following ventricular premature beats in patients with idiopathic dilated cardiomyopathy. Author(s): Grimm W, Schmidt G, Maisch B, Sharkova J, Muller HH, Christ M. Source: Journal of Cardiovascular Electrophysiology. 2003 August; 14(8): 819-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12890042&dopt=Abstract
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Prognostic significance of morphometric endomyocardial biopsy analysis in patients with idiopathic dilated cardiomyopathy. Author(s): Grimm W, Rudolph S, Christ M, Pankuweit S, Maisch B. Source: American Heart Journal. 2003 August; 146(2): 372-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12891210&dopt=Abstract
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Prognostic significance of post-exercise blood pressure response in patients with dilated cardiomyopathy. Author(s): Kitaoka H, Hitomi N, Okawa M, Furuno T, Doi Y. Source: J Cardiol. 2003 October; 42(4): 165-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14598718&dopt=Abstract
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Prognostic usefulness of echocardiographic dobutamine in younger (14 to 25 years) and older (40 to 55 years) patients with idiopathic dilated cardiomyopathy. Author(s): Paraskevaidis IA, Adamopoulos S, Tsiapras D, Karatzas D, Kremastinos DT. Source: The American Journal of Cardiology. 2004 January 15; 93(2): 251-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14715363&dopt=Abstract
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Progression of familial and non-familial dilated cardiomyopathy: long term follow up. Author(s): Michels VV, Driscoll DJ, Miller FA, Olson TM, Atkinson EJ, Olswold CL, Schaid DJ. Source: Heart (British Cardiac Society). 2003 July; 89(7): 757-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807850&dopt=Abstract
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Proton magnetic resonance spectroscopy can detect creatine depletion associated with the progression of heart failure in cardiomyopathy. Author(s): Nakae I, Mitsunami K, Omura T, Yabe T, Tsutamoto T, Matsuo S, Takahashi M, Morikawa S, Inubushi T, Nakamura Y, Kinoshita M, Horie M. Source: Journal of the American College of Cardiology. 2003 November 5; 42(9): 1587-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14607443&dopt=Abstract
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QT dispersion and left ventricular morphology in patients with hypertrophic cardiomyopathy. Author(s): Sakata K, Shimizu M, Ino H, Yamaguchi M, Terai H, Hayashi K, Kiyama M, Hayashi T, Inoue M, Mabuchi H. Source: Heart (British Cardiac Society). 2003 August; 89(8): 882-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860864&dopt=Abstract
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Quantification of regional left ventricular function in Q wave and non-Q wave dysfunctional regions by tissue Doppler imaging in patients with ischaemic cardiomyopathy. Author(s): Bountioukos M, Schinkel AF, Bax JJ, Rizzello V, Rambaldi R, Vourvouri EC, Roelandt JR, Poldermans D. Source: Heart (British Cardiac Society). 2003 November; 89(11): 1322-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14594890&dopt=Abstract
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Quantitative analysis of cytokine mRNA expression in hearts from patients with nonischemic dilated cardiomyopathy (DCM). Author(s): Ukimura A, Terasaki F, Fujioka S, Deguchi H, Kitaura Y, Isomura T, Suma H. Source: Journal of Cardiac Surgery. 2003 July-August; 18 Suppl 2: S101-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12930277&dopt=Abstract
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Radionuclide viability testing: should it affect treatment strategy in patients with cardiomyopathy and significant coronary artery disease? Author(s): Bourque JM, Velazquez EJ, Borges-Neto S, Shaw LK, Whellan DJ, O'Connor CM. Source: American Heart Journal. 2003 May; 145(5): 758-67. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12766731&dopt=Abstract
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Relation between microvolt-level T-wave alternans and cardiac sympathetic nervous system abnormality using iodine-123 metaiodobenzylguanidine imaging in patients with idiopathic dilated cardiomyopathy. Author(s): Harada M, Shimizu A, Murata M, Ono K, Kubo M, Mitani R, Dairaku Y, Matsumoto T, Yamagata T, Seki K, Matsuzaki M. Source: The American Journal of Cardiology. 2003 October 15; 92(8): 998-1001. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14556884&dopt=Abstract
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Relation between oxidative stress, catecholamines, and impaired chronotropic response to exercise in patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Author(s): Castro PF, Greig D, Perez O, Moraga F, Chiong M, Diaz-Araya G, Padilla I, Nazzal C, Jalil JE, Vukasovic JL, Moreno M, Corbalan R, Lavandero S. Source: The American Journal of Cardiology. 2003 July 15; 92(2): 215-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860229&dopt=Abstract
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Relation between QT dispersion and myocardial viability in ischemic cardiomyopathy. Author(s): Schinkel AF, Bountioukos M, Poldermans D, Elhendy A, Valkema R, Vourvouri EC, Biagini E, Rizzello V, Kertai MD, Krenning B, Krenning EP, Roelandt JR, Bax JJ. Source: The American Journal of Cardiology. 2003 September 15; 92(6): 712-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12972115&dopt=Abstract
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Relation of cardiac sympathetic innervation to proinflammatory cytokine levels in patients with heart failure secondary to idiopathic dilated cardiomyopathy. Author(s): Parthenakis FI, Patrianakos A, Prassopoulos V, Papadimitriou E, Nikitovic D, Karkavitsas NS, Vardas PE. Source: The American Journal of Cardiology. 2003 May 15; 91(10): 1190-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12745101&dopt=Abstract
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Relation of left ventricular thickness to age and gender in hypertrophic cardiomyopathy. Author(s): Maron BJ, Casey SA, Hurrell DG, Aeppli DM. Source: The American Journal of Cardiology. 2003 May 15; 91(10): 1195-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12745102&dopt=Abstract
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Relations among heart failure severity, left ventricular loading conditions, and repolarization length in advanced heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Author(s): Boccalandro F, Velasco A, Thomas C, Richards B, Radovancevic B. Source: The American Journal of Cardiology. 2003 September 1; 92(5): 544-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12943874&dopt=Abstract
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Relationship between exercise-induced myocardial ischemia and reduced left ventricular distensibility in patients with nonobstructive hypertrophic cardiomyopathy. Author(s): Isobe S, Izawa H, Takeichi Y, Nonokawa M, Nanasato M, Ando A, Kato K, Ikeda M, Murohara T, Yokota M. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2003 November; 44(11): 1717-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14602851&dopt=Abstract
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Relationship of race to sudden cardiac death in competitive athletes with hypertrophic cardiomyopathy. Author(s): Maron BJ, Carney KP, Lever HM, Lewis JF, Barac I, Casey SA, Sherrid MV. Source: Journal of the American College of Cardiology. 2003 March 19; 41(6): 974-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12651044&dopt=Abstract
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Reliability of QRS duration and morphology on surface electrocardiogram to identify ventricular dyssynchrony in patients with idiopathic dilated cardiomyopathy. Author(s): Fauchier L, Marie O, Casset-Senon D, Babuty D, Cosnay P, Fauchier JP. Source: The American Journal of Cardiology. 2003 August 1; 92(3): 341-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12888151&dopt=Abstract
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Restrictive cardiomyopathy in familial amyloidosis TTR-Arg-50. Author(s): Boltwood CM Jr. Source: Circulation. 2003 September 9; 108(10): E71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12966927&dopt=Abstract
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Restrictive cardiomyopathy in familial amyloidosis TTR-Arg-50. Author(s): Conraads V. Source: Circulation. 2003 September 9; 108(10): E71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12963686&dopt=Abstract
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Restrictive cardiomyopathy in systemic amyloidosis. Author(s): Wald DS, Gray HH. Source: Qjm : Monthly Journal of the Association of Physicians. 2003 May; 96(5): 380-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12702790&dopt=Abstract
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Reversal of atrial mechanical dysfunction after cardioversion of atrial fibrillation: implications for the mechanisms of tachycardia-mediated atrial cardiomyopathy. Author(s): Sanders P, Morton JB, Kistler PM, Vohra JK, Kalman JM, Sparks PB. Source: Circulation. 2003 October 21; 108(16): 1976-84. Epub 2003 Oct 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557372&dopt=Abstract
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Reverse redistribution of Tc-99m tetrofosmin in a patient with “takotsubo” cardiomyopathy. Author(s): Hadase M, Kawasaki T, Asada S, Kamitani T, Kawasaki S, Sugihara H. Source: Clinical Nuclear Medicine. 2003 September; 28(9): 757-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12972999&dopt=Abstract
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Reversible ventricular dysfunction (takotsubo cardiomyopathy) following polymorphic ventricular tachycardia. Author(s): Akashi YJ, Nakazawa K, Kida K, Ryu S, Takagi A, Kishi R, Kunishima T, Sakakibara M, Miyake F. Source: The Canadian Journal of Cardiology. 2003 March 31; 19(4): 449-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12704494&dopt=Abstract
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Right ventricular exclusion surgery for arrhythmogenic right ventricular dysplasia with cardiomyopathy. Author(s): Motta P, Mossad E, Savage R. Source: Anesthesia and Analgesia. 2003 June; 96(6): 1598-602, Table of Contents. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12760981&dopt=Abstract
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Right ventricular tachycardia-arrhythmogenic right ventricular cardiomyopathy or idiopathic? Author(s): Kottkamp H, Hindricks G. Source: European Heart Journal. 2003 May; 24(9): 787-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12727145&dopt=Abstract
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Risk progression to chronic Chagas cardiomyopathy: influence of male sex and of parasitaemia detected by polymerase chain reaction. Author(s): Basquiera AL, Sembaj A, Aguerri AM, Omelianiuk M, Guzman S, Moreno Barral J, Caeiro TF, Madoery RJ, Salomone OA. Source: Heart (British Cardiac Society). 2003 October; 89(10): 1186-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12975414&dopt=Abstract
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Risk stratification in hypertrophic cardiomyopathy: fact or fiction? Author(s): Hess OM. Source: Journal of the American College of Cardiology. 2003 September 3; 42(5): 880-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957436&dopt=Abstract
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Say no to primary prophylaxis with implantable cardioverter-defibrillators in asymptomatic nonischemic dilated cardiomyopathy? Author(s): Jayachandran JV, Zipes DP. Source: Journal of the American College of Cardiology. 2003 May 21; 41(10): 1713-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767652&dopt=Abstract
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Septal ethanol ablation for hypertrophic obstructive cardiomyopathy: early and intermediate results of a Canadian referral centre. Author(s): Bhagwandeen R, Woo A, Ross J, Wigle ED, Rakowski H, Kwinter J, Eriksson MJ, Schwartz L. Source: The Canadian Journal of Cardiology. 2003 July; 19(8): 912-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12876612&dopt=Abstract
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Severe pulmonary hypertension in a patient with hypertrophic cardiomyopathy: response to alcohol septal ablation. Author(s): Brilakis ES, Nishimura RA. Source: Heart (British Cardiac Society). 2003 July; 89(7): 790. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807862&dopt=Abstract
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Severe reversible cardiomyopathy in four unrelated infants associated with mitochondrial DNA D-loop heteroplasmy. Author(s): Boles RG, Luna C, Ito M. Source: Pediatric Cardiology. 2003 September-October; 24(5): 484-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14627319&dopt=Abstract
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Severe reversible dilated cardiomyopathy and hyperthyroidism: case report and review of the literature. Author(s): Boccalandro C, Boccalandro F, Orlander P, Wei CF. Source: Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2003 March-April; 9(2): 1406. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917077&dopt=Abstract
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Short- and long-term beneficial effects of trimetazidine in patients with diabetes and ischemic cardiomyopathy. Author(s): Fragasso G, Piatti Md PM, Monti L, Palloshi A, Setola E, Puccetti P, Calori G, Lopaschuk GD, Margonato A. Source: American Heart Journal. 2003 November; 146(5): E18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14597947&dopt=Abstract
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Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Author(s): Node K, Fujita M, Kitakaze M, Hori M, Liao JK. Source: Circulation. 2003 August 19; 108(7): 839-43. Epub 2003 July 28. Erratum In: Circulation. 2003 October 28; 108(17): 2170. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12885745&dopt=Abstract
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Significant inducible perfusion abnormality in an asymptomatic patient with hypertrophic cardiomyopathy demonstrated by radionuclide myocardial perfusion imaging. Author(s): Loong CY, Reyes E, Underwood SR. Source: Heart (British Cardiac Society). 2003 September; 89(9): 989. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12923005&dopt=Abstract
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Simultaneous vs. sequential biventricular pacing in dilated cardiomyopathy: an acute hemodynamic study. Author(s): Perego GB, Chianca R, Facchini M, Frattola A, Balla E, Zucchi S, Cavaglia S, Vicini I, Negretto M, Osculati G. Source: European Journal of Heart Failure : Journal of the Working Group on Heart Failure of the European Society of Cardiology. 2003 June; 5(3): 305-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12798828&dopt=Abstract
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Slowly developing heart failure associated with hormonal disorder. Late-stage acromegalic cardiomyopathy. Author(s): Harada T, Nakajima T, Kobayakawa N, Sugiura S, Nagai R. Source: J Cardiol. 2003 August; 42(2): 95-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12964520&dopt=Abstract
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Specific cardiomyopathy caused by multisystemic lipid storage in Jordans' anomaly. Author(s): Nagai H, Oshima Y, Hirota H, Izumi M, Sugiyama S, Nakaoka Y, Terai K, Hasegawa S, Tateyama H, Kikui M, Yamauchi-Takihara K, Kawase I. Source: Intern Med. 2003 July; 42(7): 587-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12879951&dopt=Abstract
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Stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Author(s): Franz WM, Zaruba M, Theiss H, David R. Source: Lancet. 2003 August 30; 362(9385): 675-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957085&dopt=Abstract
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Structure, stability and dynamics of the central domain of cardiac myosin binding protein C (MyBP-C): implications for multidomain assembly and causes for cardiomyopathy. Author(s): Idowu SM, Gautel M, Perkins SJ, Pfuhl M. Source: Journal of Molecular Biology. 2003 June 13; 329(4): 745-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12787675&dopt=Abstract
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Subclinical skeletal muscle abnormalities in patients with hypertrophic cardiomyopathy and their relation to clinical characteristics. Author(s): Anastasakis A, Karandreas N, Stathis P, Rigopoulos A, Theopistou A, Sepp R, Elliott PM, Panagiotakos DB, Stefanadis C, Toutouzas P. Source: International Journal of Cardiology. 2003 June; 89(2-3): 249-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767549&dopt=Abstract
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Successful heart transplantation in patients with inherited myopathies associated with end-stage cardiomyopathy. Author(s): Ruiz-Cano MJ, Delgado JF, Jimenez C, Jimenez S, Cea-Calvo L, Sanchez V, Escribano P, Gomez MA, Gil-Fraguas L, Saenz de la Calzada C. Source: Transplantation Proceedings. 2003 June; 35(4): 1513-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12826208&dopt=Abstract
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Sudden death of a case of hypertrophic obstructive cardiomyopathy 19 months after successful percutaneous transluminal septal myocardial ablation. Author(s): Hirata K, Wake M, Asato H, Kyushima M, Serizawa Y. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2003 June; 67(6): 559-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12808279&dopt=Abstract
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Surgical pathology of subaortic septal myectomy associated with hypertrophic cardiomyopathy. A study of 204 cases (1996-2000). Author(s): Lamke GT, Allen RD, Edwards WD, Tazelaar HD, Danielson GK. Source: Cardiovascular Pathology : the Official Journal of the Society for Cardiovascular Pathology. 2003 May-June; 12(3): 149-58. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12763554&dopt=Abstract
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Survival after myocardial revascularization for ischemic cardiomyopathy: a prospective ten-year follow-up study. Author(s): Shah PJ, Hare DL, Raman JS, Gordon I, Chan RK, Horowitz JD, Rosalion A, Buxton BF. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 November; 126(5): 1320-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14666002&dopt=Abstract
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Sustained cavity obliteration and apical aneurysm formation in apical hypertrophic cardiomyopathy. Author(s): Matsubara K, Nakamura T, Kuribayashi T, Azuma A, Nakagawa M. Source: Journal of the American College of Cardiology. 2003 July 16; 42(2): 288-95. Erratum In: J Am Coll Cardiol. 2003 October 1; 42(7): 1338. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875766&dopt=Abstract
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Sustained improvement after combined anterior mitral leaflet extension and myectomy in hypertrophic obstructive cardiomyopathy. Author(s): van der Lee C, Kofflard MJ, van Herwerden LA, Vletter WB, ten Cate FJ. Source: Circulation. 2003 October 28; 108(17): 2088-92. Epub 2003 September 29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14517170&dopt=Abstract
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Tachycardiomyopathy: a diagnosis not to be missed. Author(s): Walker NL, Cobbe SM, Birnie DH. Source: Heart (British Cardiac Society). 2004 February; 90(2): E7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14729812&dopt=Abstract
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Tetralogy of Fallot with hypertrophic cardiomyopathy. Author(s): Krishnamoorthy KM, Patle A, Rao S. Source: Cardiology. 2003; 100(1): 50-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12975548&dopt=Abstract
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The clinical features of takotsubo cardiomyopathy. Author(s): Akashi YJ, Nakazawa K, Sakakibara M, Miyake F, Koike H, Sasaka K. Source: Qjm : Monthly Journal of the Association of Physicians. 2003 August; 96(8): 56373. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12897341&dopt=Abstract
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The correlation between expression of apoptosis-related proteins and myocardial functional reserve evaluated by dobutamine stress echocardiography in patients with dilated cardiomyopathy. Author(s): Ho YL, Chen CL, Hsu RB, Lin LC, Huang PJ. Source: Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. 2003 September; 16(9): 931-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12931104&dopt=Abstract
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The epidemiology of childhood cardiomyopathy in Australia. Author(s): Nugent AW, Daubeney PE, Chondros P, Carlin JB, Cheung M, Wilkinson LC, Davis AM, Kahler SG, Chow CW, Wilkinson JL, Weintraub RG; National Australian Childhood Cardiomyopathy Study. Source: The New England Journal of Medicine. 2003 April 24; 348(17): 1639-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12711738&dopt=Abstract
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The incidence of pediatric cardiomyopathy in two regions of the United States. Author(s): Lipshultz SE, Sleeper LA, Towbin JA, Lowe AM, Orav EJ, Cox GF, Lurie PR, McCoy KL, McDonald MA, Messere JE, Colan SD. Source: The New England Journal of Medicine. 2003 April 24; 348(17): 1647-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12711739&dopt=Abstract
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The influence of age on gender-specific differences in the left ventricular cavity size and contractility in patients with hypertrophic cardiomyopathy. Author(s): Dimitrow PP, Czarnecka D, Kawecka-Jaszcz K, Dubiel JS. Source: International Journal of Cardiology. 2003 March; 88(1): 11-6; Discussion 16-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12659978&dopt=Abstract
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The MLP family of cytoskeletal Z disc proteins and dilated cardiomyopathy: a stress pathway model for heart failure progression. Author(s): Hoshijima M, Pashmforoush M, Knoll R, Chien KR. Source: Cold Spring Harb Symp Quant Biol. 2002; 67: 399-408. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858565&dopt=Abstract
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The non-invasive assessment of hibernating myocardium in ischaemic cardiomyopathy--a myriad of techniques. Author(s): Galasko GI, Lahiri A. Source: European Journal of Heart Failure : Journal of the Working Group on Heart Failure of the European Society of Cardiology. 2003 June; 5(3): 217-27. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12798818&dopt=Abstract
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The role of coronary revascularization in the treatment of ischemic cardiomyopathy. Author(s): Lytle BW. Source: The Annals of Thoracic Surgery. 2003 June; 75(6 Suppl): S2-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820728&dopt=Abstract
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Thinned myocardial fibrosis with thrombus in the dilated form of hypertrophic cardiomyopathy demonstrated by multislice computed tomography. Author(s): Funabashi N, Yoshida K, Komuro I. Source: Heart (British Cardiac Society). 2003 August; 89(8): 858. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860857&dopt=Abstract
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Tissue Doppler imaging predicts the development of hypertrophic cardiomyopathy in subjects with subclinical disease. Author(s): Nagueh SF, McFalls J, Meyer D, Hill R, Zoghbi WA, Tam JW, Quinones MA, Roberts R, Marian AJ. Source: Circulation. 2003 July 29; 108(4): 395-8. Epub 2003 Jul 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860897&dopt=Abstract
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Tl-201 myocardial SPECT in differentiation of ischemic from nonischemic dilated cardiomyopathy in patients with left ventricular dysfunction. Author(s): Wu YW, Yen RF, Chieng PU, Huang PJ. Source: Journal of Nuclear Cardiology : Official Publication of the American Society of Nuclear Cardiology. 2003 July-August; 10(4): 369-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12900741&dopt=Abstract
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Toward clinical risk assessment in hypertrophic cardiomyopathy with gadolinium cardiovascular magnetic resonance. Author(s): Moon JC, McKenna WJ, McCrohon JA, Elliott PM, Smith GC, Pennell DJ. Source: Journal of the American College of Cardiology. 2003 May 7; 41(9): 1561-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12742298&dopt=Abstract
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Transgenic mice overexpressing mutant PRKAG2 define the cause of WolffParkinson-White syndrome in glycogen storage cardiomyopathy. Author(s): Arad M, Moskowitz IP, Patel VV, Ahmad F, Perez-Atayde AR, Sawyer DB, Walter M, Li GH, Burgon PG, Maguire CT, Stapleton D, Schmitt JP, Guo XX, Pizard A, Kupershmidt S, Roden DM, Berul CI, Seidman CE, Seidman JG. Source: Circulation. 2003 June 10; 107(22): 2850-6. Epub 2003 Jun 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12782567&dopt=Abstract
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Transient hyperinsulinism associated with macrosomia, hypertrophic obstructive cardiomyopathy, hepatomegaly, and nephromegaly. Author(s): Mehta A, Hussain K. Source: Archives of Disease in Childhood. 2003 September; 88(9): 822-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12937110&dopt=Abstract
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Transient ischemic attack with apical hypertrophic cardiomyopathy. Author(s): Ceyhan C, Tekten T, Onbasili OA, Ercan E. Source: Japanese Heart Journal. 2003 March; 44(2): 285-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12718490&dopt=Abstract
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Treatment of hypertrophic cardiomyopathy. Author(s): Penas-Lado M, Barriales-Villa R, Monserrat L. Source: Circulation. 2003 April 29; 107(16): E110; Auhor Reply E110. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12719296&dopt=Abstract
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Tumor necrosis factor-alpha polymorphism in Turkish patients with dilated cardiomyopathy. Author(s): Alikasifoglu M, Tokgozoglu L, Acil T, Atalar E, Ali Oto M, Sirri Kes S, Tuncbilek E. Source: European Journal of Heart Failure : Journal of the Working Group on Heart Failure of the European Society of Cardiology. 2003 March; 5(2): 161-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12644006&dopt=Abstract
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T-Wave alternans for arrhythmia risk stratification in patients with idiopathic dilated cardiomyopathy. Author(s): Verrier RL, Tolat AV, Josephson ME. Source: Journal of the American College of Cardiology. 2003 June 18; 41(12): 2225-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821252&dopt=Abstract
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Unusual morphologic changes in apical hypertrophic cardiomyopathy. Author(s): Fujii H, Kitakaze M, Yamagishi M. Source: Heart (British Cardiac Society). 2003 November; 89(11): 1290. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14594880&dopt=Abstract
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Use of strain imaging in detecting segmental dysfunction in patients with hypertrophic cardiomyopathy. Author(s): Yang H, Sun JP, Lever HM, Popovic ZB, Drinko JK, Greenberg NL, Shiota T, Thomas JD, Garcia MJ. Source: Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. 2003 March; 16(3): 233-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12618731&dopt=Abstract
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Usefulness of 1H MR spectroscopy in the evaluation of myocardial metabolism in patients with dilated idiopathic cardiomyopathy: pilot study. Author(s): Walecki J, Michalak MJ, Michalak E, Bilinska ZT, Ruzyllo W. Source: Academic Radiology. 2003 October; 10(10): 1187-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14587640&dopt=Abstract
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Usefulness of microvolt T-wave alternans for prediction of ventricular tachyarrhythmic events in patients with dilated cardiomyopathy: results from a prospective observational study. Author(s): Hohnloser SH, Klingenheben T, Bloomfield D, Dabbous O, Cohen RJ. Source: Journal of the American College of Cardiology. 2003 June 18; 41(12): 2220-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821251&dopt=Abstract
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Usefulness of myocardial tissue Doppler echocardiography to evaluate left ventricular dyssynchrony before and after biventricular pacing in patients with idiopathic dilated cardiomyopathy. Author(s): Bax JJ, Molhoek SG, van Erven L, Voogd PJ, Somer S, Boersma E, Steendijk P, Schalij MJ, Van der Wall EE. Source: The American Journal of Cardiology. 2003 January 1; 91(1): 94-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12505583&dopt=Abstract
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Utility of genetic screening in hypertrophic cardiomyopathy: prevalence and significance of novel and double (homozygous and heterozygous) beta-myosin mutations. Author(s): Mohiddin SA, Begley DA, McLam E, Cardoso JP, Winkler JB, Sellers JR, Fananapazir L. Source: Genetic Testing. 2003 Spring; 7(1): 21-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820698&dopt=Abstract
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Value of heart rate variability to predict ventricular arrhythmias in recipients of prophylactic defibrillators with idiopathic dilated cardiomyopathy. Author(s): Grimm W, Herzum I, Muller HH, Christ M. Source: Pacing and Clinical Electrophysiology : Pace. 2003 January; 26(1 Pt 2): 411-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12687856&dopt=Abstract
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Variable clinical manifestation of a novel missense mutation in the alphatropomyosin (TPM1) gene in familial hypertrophic cardiomyopathy. Author(s): Jongbloed RJ, Marcelis CL, Doevendans PA, Schmeitz-Mulkens JM, Van Dockum WG, Geraedts JP, Smeets HJ. Source: Journal of the American College of Cardiology. 2003 March 19; 41(6): 981-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12651045&dopt=Abstract
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Varieties of right ventricular diastolic function in patients with non-obstructive hypertrophic cardiomyopathy. Author(s): Komaki K, Sakuma M, Ishigaki H, Hozawa H, Yamamoto Y, Takahashi T, Kumasaka N, Kagaya Y, Ikeda J, Watanabe J, Shirato K. Source: The Tohoku Journal of Experimental Medicine. 2003 January; 199(1): 49-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12688560&dopt=Abstract
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Ventricular dyssynchrony and risk markers of ventricular arrhythmias in nonischemic dilated cardiomyopathy: a study with phase analysis of angioscintigraphy. Author(s): Fauchier L, Marie O, Casset-Senon D, Babuty D, Cosnay P, Fauchier JP. Source: Pacing and Clinical Electrophysiology : Pace. 2003 January; 26(1 Pt 2): 352-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12687844&dopt=Abstract
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Ventricular expression of atrial natriuretic peptide in chronic chagasic cardiomyopathy is not induced by myocarditis. Author(s): Benvenuti LA, Aiello VD, Palomino SA, Higuchi Mde L. Source: International Journal of Cardiology. 2003 March; 88(1): 57-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12659985&dopt=Abstract
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Ventricular long axis function is predictive of outcome in patients with chronic heart failure secondary to non-ischemic dilated cardiomyopathy. Author(s): Faris R, Henein MY, Coats AJ. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 November; 9(11): Cr456-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14586270&dopt=Abstract
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Ventricular reconstruction for ischemic cardiomyopathy. Author(s): Mickleborough LL, Merchant N, Provost Y, Carson S, Ivanov J. Source: The Annals of Thoracic Surgery. 2003 June; 75(6 Suppl): S6-12. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820729&dopt=Abstract
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Viability and differentiation of autologous skeletal myoblast grafts in ischaemic cardiomyopathy. Author(s): Hagege AA, Carrion C, Menasche P, Vilquin JT, Duboc D, Marolleau JP, Desnos M, Bruneval P. Source: Lancet. 2003 February 8; 361(9356): 491-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12583951&dopt=Abstract
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Visualization of myocardial perfusion after percutaneous myocardial septal ablation for hypertrophic cardiomyopathy using superharmonic imaging. Author(s): Ten Cate FJ, Bouakaz A, Krenning B, Vletter W, de Jong N. Source: Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. 2003 April; 16(4): 370-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12712021&dopt=Abstract
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What is the mechanism of abnormal blood pressure response on exercise in hypertrophic cardiomyopathy? Author(s): Campbell R, Manyari DE, McKenna WJ, Frenneaux M. Source: Journal of the American College of Cardiology. 2003 June 4; 41(11): 2102; Author Reply 2102-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12798589&dopt=Abstract
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Who and how to treat with non-surgical myocardial reduction therapy in hypertrophic cardiomyopathy: long-term outcomes. Author(s): Martin WA, Sigwart U. Source: Heart Fail Monit. 2002; 3(1): 15-27. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12634884&dopt=Abstract
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CHAPTER 2. NUTRITION AND CARDIOMYOPATHY Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and cardiomyopathy.
Finding Nutrition Studies on Cardiomyopathy The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail:
[email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “cardiomyopathy” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.
7 Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.
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The following information is typical of that found when using the “Full IBIDS Database” to search for “cardiomyopathy” (or a synonym): •
A case of polymyositis with dilated cardiomyopathy associated with interferon alpha treatment for hepatitis B. Author(s): The Hospital for Rheumatic Diseases, Hanyang University, 17 Haengdongdong, Seongdong-gu, Seoul 133-792, Korea. Source: Lee, Seung Won Kim, Ki Chan Oh, Dong Ho Jung, Sung Soo Yoo, Dae Hyun Kim, Seong Yoon Choe, Gheeyoung Kim, Tae Hwan J-Korean-Med-Sci. 2002 February; 17(1): 141-3 1011-8934
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A rat model of dilated cardiomyopathy to investigate partial left ventriculectomy. Author(s): Department of Cardiovascular Surgery, Matsue Red-Cross Hospital, Shimane, Japan. Source: Yuasa, S Nishina, T Nishimura, K Miwa, S Ikeda, T Hanyu, M Fujioka, Y Kihara, Y Sasayama, S Komeda, M J-Card-Surg. 2001 Jan-February; 16(1): 40-7 0886-0440
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A rat model of ischaemic or dilated cardiomyopathy for investigating left ventricular repair surgery. Author(s): Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Source: Nishina, T Miwa, S Yuasa, S Nishimura, K Komeda, M Clin-Exp-PharmacolPhysiol. 2002 August; 29(8): 728-30 0305-1870
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Activity of GH/IGF-I axis in patients with dilated cardiomyopathy. Author(s): Department of Internal Medicine, University of Turin, Italy. Source: Benso, A Broglio, F Gottero, C Di Vito, L Arvat, E Bobbio, M Ghigo, E JEndocrinol-Invest. 1999; 22(10 Suppl): 63 0391-4097
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Advances in the treatment of dilated cardiomyopathy. Source: Purcell, J A AACN-Clin-Issues-Crit-Care-Nurs. 1990 May; 1(1): 31-45 1046-7467
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Age-associated cardiomyopathy in heterozygous carrier mice of a pathological mutation of carnitine transporter gene, OCTN2. Author(s): Department of Hygiene, Akita University School of Medicine, Japan. Source: Xiaofei, E Wada, Yasuhiko Dakeishi, Miwako Hirasawa, Fujiko Murata, Katsuyuki Masuda, Hirotake Sugiyama, Toshihiro Nikaido, Hiroko Koizumi, Akio JGerontol-A-Biol-Sci-Med-Sci. 2002 July; 57(7): B270-8 1079-5006
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Alcohol-induced congestive cardiomyopathy in adult turkeys: effects on myocardial antioxidant defence systems. Author(s): 2nd Department of Medicine, University Medical School, Szeged, Hungary. Source: Edes, I Piros, G Forster, T Csanady, M Basic-Res-Cardiol. 1987 Nov-December; 82(6): 551-6 0300-8428
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Anticoagulation in patients with dilated cardiomyopathy and sinus rhythm: a critical literature review. Author(s): Division of Cardiovascular Diseases, Department of Internal Medicine, University of Florida Health Science Center, Jacksonville, FL, USA. Source: Sirajuddin, Riaz A Miller, Alan B Geraci, Stephen A J-Card-Fail. 2002 February; 8(1): 48-53 1071-9164
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Axillary vein thrombosis complicating peripartum congestive cardiomyopathy. Source: Neill, P Cent-Afr-J-Med. 1987 December; 33(12): 292-4 0008-9176
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beta-Methyl-p-(123I)-iodophenyl pentadecanoic acid single-photon emission computed tomography in cardiomyopathy. Author(s): Osaka University, Medical School, Japan.
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Source: Nishimura, T Int-J-Card-Imaging. 1999 February; 15(1): 41-8 0167-9899 •
Calcium-activated protease in hamster cardiomyopathy. Source: Spalla, M Kuo, T H Wiener, J Muscle-Nerve. 1987 January; 10(1): 54-9 0148-639X
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Cardiac thrombus in dilated cardiomyopathy. Relationship between left ventricular pathophysiology and left ventricular thrombus. Author(s): First Department of Internal Medicine, Kobe University School of Medicine, Japan. Source: Yokota, Y Kawanishi, H Hayakawa, M Kumaki, T Takarada, A Nakanishi, O Fukuzaki, H Jpn-Heart-J. 1989 January; 30(1): 1-11 0021-4868
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Cardiomyopathy in children. Author(s): Department of Pediatrics, University of South Florida, Tampa, USA. Source: Gilbert Barness, E Marshall, R J W-V-Med-J. 2000 Jan-February; 96(1): 352-6 0043-3284
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Contractile responses of myocytes isolated from patients with cardiomyopathy. Author(s): Department of Cardiac Medicine, National Heart and Lung Institute, London, U.K. Source: Harding, S E MacLeod, K T Jones, S M Vescovo, G Poole Wilson, P A Eur-HeartJ. 1991 August; 12 Suppl D44-8 0195-668X
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Coronary flow reserve in patients with chest pain, angiographically normal coronary arteries and normal left ventricle, dilated cardiomyopathy, and hypertrophic cardiomyopathy. Author(s): Cardiovascular Diagnosis Section, National Heart, Lung, and Blood Institute, Bethesda, Md. Source: Cannon, R O 3rd Bibl-Cardiol. 1989; (44): 25-38; discussion 38-9 0067-7906
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Dilated cardiomyopathy in an American Cocker Spaniel with taurine deficiency. Source: Gavaghan, B.J. Kittleson, M.D. Aust-vet-j. Brunswick, Vic. : Australian Veterinary Association, 1927-. December 1997. volume 75 (12) page 862-868. 0005-0423
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Echocardiographic features of genetic diseases: part 1. Cardiomyopathy. Author(s): Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. Source: Alizad, A Seward, J B J-Am-Soc-Echocardiogr. 2000 January; 13(1): 73-86 08947317
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Experimental induction of cardiomyopathy in young bovine. Source: Kennedy, S. Rice, D.A. McMurray, C.H. Selenium in biology and medicine : proceedings of the Third International Symposium on Selenium in Biology and Medicine, held May 27-June 1, 1984, Xiangshan (Fragrance Hills) Hotel Beijing, People's Republic of China. New York : Van Nostrand Reinhold, c1987. page 853-856. ill. ISBN: 0442221088
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Familial hypertrophic cardiomyopathy and muscle carnitine deficiency. Author(s): Department of Neurology, Hospital Virgen del Rocio, Sevilla, Spain. Source: Bautista, J Rafel, E Martinez, A Sainz, I Herrera, J Segura, L Chinchon, I MuscleNerve. 1990 Mar; 13(3): 192-4 0148-639X
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Fulminant heart failure due to selenium deficiency cardiomyopathy (Keshan disease). Author(s): Victorian Institute of Forensic Medicine, Department of Forensic Medicine, Monash University, Southbank, Australia. Source: Burke, Michael Philip Opeskin, Kenneth Med-Sci-Law. 2002 January; 42(1): 10-3 0025-8024
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Glucose insulin potassium infusion improves systolic function in patients with chronic ischemic cardiomyopathy. Author(s): Cardiology Department, University Hospital, Dijon, France.
[email protected] Source: Cottin, Yves Lhuillier, Isabelle Gilson, Laurent Zeller, Marianne Bonnet, Caroline Toulouse, Christine Louis, Pierre Rochette, Luc Girard, Claude Wolf, Jean Eric Eur-J-Heart-Fail. 2002 Mar; 4(2): 181-4 1388-9842
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Growth hormone therapy in dilated cardiomyopathy monitored with MRI. Author(s): Franz-Volhard-Klinik, Max-Delbruck-Centrum for Molecular Medicine, Charite, Humboldt-University, Berlin, Germany. Source: Friedrich, M G Strohm, O Osterziel, K J Dietz, R MAGMA. 1998 September; 6(23): 152-4 0968-5243
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Growth hormone treatment in dilated cardiomyopathy. Author(s): Charitz/Franz-Volhard-Klinik am Max Delbruck Centrum fur Molekulare Medizin, Humboldt Universitat zu Berlin, Germany.
[email protected] Source: Perrot, A Ranke, M B Dietz, R Osterziel, K J J-Card-Surg. 2001 Mar-April; 16(2): 127-31 0886-0440
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Heart failure and Ca++ activation of the cardiac contractile system: hereditary cardiomyopathy in hamsters (BIO 14.6), isoprenaline overload and the effect of APP 201-533. Author(s): Department Research CVS, Ciba-Geigy Ltd., Basle, Switzerland. Source: Herzig, J W Gerber, W Salzmann, R Basic-Res-Cardiol. 1987 Jul-August; 82(4): 326-40 0300-8428
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Idiopathic dilated cardiomyopathy presenting in pregnancy. Author(s): Department of Anaesthesia & Intensive Care, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, China. Source: Chan, F Ngan Kee, W D Can-J-Anaesth. 1999 December; 46(12): 1146-9 0832610X
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Lack of effects of recombinant human growth hormone in a child with a complex cardiovascular malformation and dilated cardiomyopathy. Author(s): Cardiologia/Cardiochirurgia Pediatrica, Centro “E. Malan”, Ospedale San Donato, San Donato Milanese, Milano, Italy. Source: Rosti, L Cerini, E Festa, P Miola, A Brunelli, V Frigiola, A J-Endocrinol-Invest. 2000 January; 23(1): 28-30 0391-4097
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L-carnitine in children with idiopathic dilated cardiomyopathy. Author(s): Department of Cardiology, All India Institute of Medical Sciences, New Delhi. Source: Kothari, S S Sharma, M Indian-Heart-J. 1998 Jan-February; 50(1): 59-61 0019-4832
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Life-style related factors and idiopathic dilated cardiomyopathy--a case-control study using pooled controls. Author(s): Kurume University Medical Center, Japan. Source: Kodama, K Toshima, H Yazaki, Y Toyoshima, H Nakagawa, H Okada, R Kitabatake, A Serizawa, T Tanaka, H Hosoda, S Yano, K Yokoyama, M Fujita, Y Kasagi, F Yokoyama, T Tanaka, H Kawamura, T Ohno, Y Hashimoto, T J-Epidemiol. 1999 November; 9(5): 286-96 0917-5040
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Medical therapy of end-stage congestive and ischemic cardiomyopathy. Source: Leier, C V Unverferth, D V Cardiovasc-Clin. 1988; 19(1): 243-51 0069-0384
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Monocyte chemoattractant protein 1 (MCP-1) gene expression in dilated cardiomyopathy. Author(s): Department of Internal Medicine, Division of Cardiology, University of Jena, Jena, Germany. Source: Lehmann, M H Kuhnert, H Muller, S Sigusch, H H Cytokine. 1998 October; 10(10): 739-46 1043-4666
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Nemaline myopathy and cardiomyopathy. Author(s): Department of Pediatric Cardiology, University of Vienna, Austria. Source: Skyllouriotis, M L Marx, M Skyllouriotis, P Bittner, R Wimmer, M PediatrNeurol. 1999 April; 20(4): 319-21 0887-8994
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Opioid peptides in response to mental stress in asymptomatic dilated cardiomyopathy. Author(s): Dipartimento di Medicina Interna, Cardioangiologia, Epatologia, Ospedale S. Orsola, Bologna, Italy. Source: Fontana, F Bernardi, P Merlo Pich, E Tartuferi, L Boschi, S De Iasio, R Spampinato, S Peptides. 1998; 19(7): 1147-53 0196-9781
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Possible involvement of free radicals and antioxidants in the early stages of the development of cardiomyopathy in BIO 14.6 Syrian Hamster. Author(s): Third Department of Internal Medicine, Hamamatsu University School of Medicine, Japan. Source: Fukuchi, T Kobayashi, A Kaneko, M Ichiyama, A Yamazaki, N Jpn-Heart-J. 1991 September; 32(5): 655-66 0021-4868
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Pregnancy and peripartum cardiomyopathy. A comparative and prospective study. Author(s): Instituto do Coracao do Hospital das Clinicas - FMUSP, Sao Paulo, Brazil.
[email protected] Source: Avila, W S de Carvalho, M E Tschaen, C K Rossi, E G Grinberg, M Mady, C Ramires, J A Arq-Bras-Cardiol. 2002 November; 79(5): 484-93 0066-782X
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Primary systemic carnitine deficiency presenting as recurrent Reye-like syndrome and dilated cardiomyopathy. Author(s): Division of Medical Genetics, Department of Pediatrics, Chang Gung Children's Hospital, Taoyuan, Taiwan, ROC. Source: Hou, J W Chang-Gung-Med-J. 2002 December; 25(12): 832-7
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Propionyl-L-carnitine as protector against adriamycin-induced cardiomyopathy. Author(s): Pharmacology Unit, National Cancer Institute, Fum El-Khalig, Kasr El-Aini Street, Cairo, Egypt. Source: Sayed Ahmed, M M Salman, T M Gaballah, H E Abou El Naga, S A Nicolai, R Calvani, M Pharmacol-Res. 2001 June; 43(6): 513-20 1043-6618
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Protection from adriamycin-induced cardiomyopathy in rats. Author(s): Metabolic Research Laboratory, William S. Middleton Memorial Veterans Administration Hospital, Madison. Source: Shug, A L Z-Kardiol. 1987; 76 Suppl 546-52 0300-5860
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Rationale for clinical trials of selenium as an antioxidant for the treatment of the cardiomyopathy of Friedreich's ataxia. Author(s): John Tabor Laboratories, University of Essex, Colchester, UK.
[email protected] Source: Fryer, M J Med-Hypotheses. 2002 February; 58(2): 127-32 0306-9877
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Recirculating, retrograde heart perfusion according to Langendorff as a tool in the evaluation of drug-induced cardiomyopathy: effects of a high lipid diet. Author(s): Institute of Toxicology, Swiss Federal Institute of Technology. Source: Bachmann, E Weber, E Arch-Toxicol. 1991; 65(6): 474-9 0340-5761
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Relationship between dietary fatty acid, selenium, and degenerative cardiomyopathy. Author(s): Kenneth L. Jordan Heart Fund, Montclair, NJ. Source: Bierenbaum, M L Chen, Y Lei, H Watkins, T Med-Hypotheses. 1992 September; 39(1): 58-62 0306-9877
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Serum antioxidant capacity in neurological, psychiatric, renal diseases and cardiomyopathy. Author(s): Neuroscience and Phytochemical Laboratories, Jean Mayer USDA Human Nutrition Research Center on Aging, Tuft's University, Boston, MA, USA. Source: Sofic, E Rustembegovic, A Kroyer, G Cao, G J-Neural-Transm. 2002 May; 109(56): 711-9 0300-9564
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Serum selenium deficiency in myocardial infarction and congestive cardiomyopathy. Author(s): Unit of Cardiology, Bicetre Hospital, Paris. Source: Auzepy, P Blondeau, M Richard, C Pradeau, D Therond, P Thuong, T ActaCardiol. 1987; 42(3): 161-6 0001-5385
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Structural manifestations of diabetic cardiomyopathy in the rat and its reversal by insulin treatment. Author(s): Hornel Institute, University of Minnesota, Austin 55912. Source: Thompson, E W Am-J-Anat. 1988 July; 182(3): 270-82 0002-9106
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Sympathetic deactivation by growth hormone treatment in patients with dilated cardiomyopathy. Author(s): Department of Internal Medicine, IRCCS, NEUROMED, Pozzilli Isernia, Italy. Source: Capaldo, B Lembo, G Rendina, V Vigorito, C Guida, R Cuocolo, A Fazio, S Sacca, L Eur-Heart-J. 1998 April; 19(4): 623-7 0195-668X
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The addition of pentoxifylline to conventional therapy improves outcome in patients with peripartum cardiomyopathy. Author(s): Department of Cardiology, Baragwanath Hospital, University of the Witwatersrand, PO Bertsham 2013, Johannesburg, South Africa.
[email protected] Source: Sliwa, K Skudicky, D Candy, G Bergemann, A Hopley, M Sareli, P Eur-J-HeartFail. 2002 June; 4(3): 305-9 1388-9842
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The effects of L-carnitine treatment on left ventricular function and erythrocyte superoxide dismutase activity in patients with ischemic cardiomyopathy. Author(s): Department of Cardiology, Ankara University Faculty of Medicine, Ankara, Turkey. Source: Gurlek, A Tutar, E Akcil, E Dincer, I Erol, C Kocaturk, P A Oral, D Eur-J-HeartFail. 2000 June; 2(2): 189-93 1388-9842
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The role of selenium deficiency in occidental dilated cardiomyopathy. Author(s): Cardiology Department, Princess Margaret Hospital, Christchurch. Source: Ikram, H Crozier, I G Webster, M Low, C J N-Z-Med-J. 1989 March 8; 102(863): 100-2 0028-8446
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The role of the carnitine system in myocardial fatty acid oxidation: carnitine deficiency, failing mitochondria and cardiomyopathy. Author(s): Department of Biochemistry, Medical Faculty, Erasmus University, Rotterdam, The Netherlands.
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Source: Scholte, H R Luyt Houwen, I E Vaandrager Verduin, M H Basic-Res-Cardiol. 1987; 82 Suppl 163-73 0300-8428 •
The use of enalapril in the treatment of feline hypertrophic cardiomyopathy. Source: Rush, J.E. Freeman, L.M. Brown, D.J. Smith, F.W.K. Jr. J-Am-Anim-Hosp-Assoc. Lakewood, Colo. : The American Animal Hospital Association. Jan/February 1998. volume 34 (1) page 38-41. 0587-2871
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Thiamin, selenium, and copper levels in patients with idiopathic dilated cardiomyopathy taking diuretics. Author(s): Hospital Universitario Pedro Ernesto, IBRAG, Geologia - UERJ, Rio de Janeiro, RJ, Brazil.
[email protected] Source: da Cunha, S Albanesi Filho, F M da Cunha Bastos, V L Antelo, D S Souza, M M Arq-Bras-Cardiol. 2002 November; 79(5): 454-65 0066-782X
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To anticoagulate or not to anticoagulate patients with cardiomyopathy. Author(s): Division of Cardiology, Department of Medicine, State University of New York at Buffalo, Buffalo General Hospital, Buffalo, New York, USA.
[email protected] Source: Graham, S P Cardiol-Clin. 2001 November; 19(4): 605-15 0733-8651
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Transient dilated cardiomyopathy in a newborn exposed to idarubicin and all-transretinoic acid (ATRA) early in the second trimester of pregnancy. Author(s): Department of Pediatrics (Cardiology), Texas Children's Hospital, 6621 Fannin, MC 19345-C, Houston, TX 77030, USA. Source: Siu, B L Alonzo, M R Vargo, T A Fenrich, A L Int-J-Gynecol-Cancer. 2002 JulAugust; 12(4): 399-402 1048-891X
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Treatment of advanced heart failure in a young man with familial cardiomyopathy. Author(s): Department of Adult Cardiology, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston 77030, USA. Source: Massin, E K Tex-Heart-Inst-J. 1998; 25(4): 294-7 0730-2347
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Use of dexrazoxane and other strategies to prevent cardiomyopathy associated with doxorubicin-taxane combinations. Author(s): Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, NY 10467, USA. Source: Sparano, J A Semin-Oncol. 1998 August; 25(4 Suppl 10): 66-71 0093-7754
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Value of radionuclide assessment with thallium 201 scintigraphy in carnitine deficiency cardiomyopathy. Author(s): Service de Pediatrie Hopital Herold, Paris, France. Source: Taillard, F Mundler, O Tillous Borde, I Desbois, J C Paturneau Jouas, M EurHeart-J. 1988 July; 9(7): 811-8 0195-668X
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Warfarin for dilated cardiomyopathy: a bloody tough pill to swallow? Author(s): Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts 02111. Source: Tsevat, J Eckman, M H McNutt, R A Pauker, S G Med-Decis-Making. 1989 JulSeptember; 9(3): 162-9 0272-989X
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Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •
healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0
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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov
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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov
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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/
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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/
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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/
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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/
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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/
Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html
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Google: http://directory.google.com/Top/Health/Nutrition/
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Nutrition/
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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/
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WebMD®Health: http://my.webmd.com/nutrition
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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The following is a specific Web list relating to cardiomyopathy; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
Vitamins Vitamin B1 Source: Healthnotes, Inc.; www.healthnotes.com
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Minerals Carnitine Source: Prima Communications, Inc.www.personalhealthzone.com L-carnitine Source: Healthnotes, Inc.; www.healthnotes.com Selenium Source: Healthnotes, Inc.; www.healthnotes.com
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CHAPTER 3. ALTERNATIVE CARDIOMYOPATHY
MEDICINE
AND
Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to cardiomyopathy. At the conclusion of this chapter, we will provide additional sources.
National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to cardiomyopathy and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “cardiomyopathy” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to cardiomyopathy: •
A cohort study of childhood hypertrophic cardiomyopathy: improved survival following high-dose beta-adrenoceptor antagonist treatment. Author(s): Ostman-Smith I, Wettrell G, Riesenfeld T. Source: Journal of the American College of Cardiology. 1999 November 15; 34(6): 181322. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10577575&dopt=Abstract
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A physiological oral magnesium supplement does not influence total serum magnesium, left ventricular ejection fraction and prognosis in patients with dilated cardiomyopathy. Author(s): Fruhwald FM, Dusleag J, Fruhwald SM, Grisold M, Gasser R, Klein W. Source: Magnes Res. 1993 September; 6(3): 251-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8292499&dopt=Abstract
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Alteration of Na,K-ATPase isoenzymes in diabetic cardiomyopathy: effect of dietary supplementation with fish oil (n-3 fatty acids) in rats. Author(s): Gerbi A, Barbey O, Raccah D, Coste T, Jamme I, Nouvelot A, Ouafik L, Levy S, Vague P, Maixent JM. Source: Diabetologia. 1997 May; 40(5): 496-505. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9165216&dopt=Abstract
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Arrhythmogenic right ventricular cardiomyopathy and sudden cardiac death in young Koreans. Author(s): Cho Y, Park T, Yang DH, Park HS, Chae J, Chae SC, Jun JE, Kwak JS, Park WH. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2003 November; 67(11): 925-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14578598&dopt=Abstract
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Cardiomyopathies and oxidative stress. Author(s): Romero-Alvira D, Roche E, Placer L. Source: Medical Hypotheses. 1996 August; 47(2): 137-44. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8869930&dopt=Abstract
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Cardiomyopathy from ipecac administration in Munchausen syndrome by proxy. Author(s): Goebel J, Gremse DA, Artman M. Source: Pediatrics. 1993 October; 92(4): 601-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8105444&dopt=Abstract
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Cardiomyopathy of copper deficiency: effect of vitamin E supplementation. Author(s): Fields M, Lewis CG, Lure MD. Source: Journal of the American College of Nutrition. 1992 June; 11(3): 330-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1619185&dopt=Abstract
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Clinical and pathologic aspects of cardiomyopathy from ipecac administration in Munchausen's syndrome by proxy. Author(s): Schneider DJ, Perez A, Knilamus TE, Daniels SR, Bove KE, Bonnell H. Source: Pediatrics. 1996 June; 97(6 Pt 1): 902-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8657536&dopt=Abstract
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Dietary fish oil does not prevent doxorubicin-induced cardiomyopathy in rats. Author(s): Matsui H, Morishima I, Hayashi K, Kamiya H, Saburi Y, Okumura K. Source: The Canadian Journal of Cardiology. 2002 March; 18(3): 279-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11907617&dopt=Abstract
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Dilated cardiomyopathy due to type II X-linked 3-methylglutaconic aciduria: successful treatment with pantothenic acid. Author(s): Ostman-Smith I, Brown G, Johnson A, Land JM. Source: British Heart Journal. 1994 October; 72(4): 349-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7833193&dopt=Abstract
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Dilated cardiomyopathy in juvenile chronic arthritis. Author(s): Soylemezoglu O, Besbas N, Ozkutlu S, Saatci U. Source: Scandinavian Journal of Rheumatology. 1994; 23(3): 159-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8016592&dopt=Abstract
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Echocardiographic findings of the heart resembling dilated cardiomyopathy during hypokalemic myopathy due to licorice-induced pseudoaldosteronism. Author(s): Hasegawa J, Suyama Y, Kinugawa T, Morisawa T, Kishimoto Y. Source: Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. 1998 December; 12(6): 599-600. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10410830&dopt=Abstract
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Ephedra-associated cardiomyopathy. Author(s): Naik SD, Freudenberger RS. Source: The Annals of Pharmacotherapy. 2004 March; 38(3): 400-3. Epub 2004 January 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14742827&dopt=Abstract
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Experimental idiopathic dilated cardiomyopathy under low-calcium condition. Author(s): Yamaguchi H, Kaku H, Onodera T, Kurokawa R, Morisada M. Source: Experimental and Toxicologic Pathology : Official Journal of the Gesellschaft Fur Toxikologische Pathologie. 1994 August; 46(3): 223-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8000243&dopt=Abstract
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Genotypic and serotypic profile in dilated cardiomyopathy. Author(s): Wesslen L, Waldenstrom A, Lindblom B, Hoyer S, Friman G, Fohlman J. Source: Scand J Infect Dis Suppl. 1993; 88: 87-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8390721&dopt=Abstract
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Hypertrophic obstructive cardiomyopathy: alternative therapeutic options. Author(s): Cheng TO. Source: Clin Cardiol. 1997 July; 20(7): 667. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9220187&dopt=Abstract
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Impaired cardiac adrenergic innervation assessed by MIBG imaging as a predictor of treatment response in childhood dilated cardiomyopathy. Author(s): Acar P, Merlet P, Iserin L, Bonnet D, Sidi D, Syrota A, Kachaner J.
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Source: Heart (British Cardiac Society). 2001 June; 85(6): 692-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11359754&dopt=Abstract •
Induction of subaortic septal ischaemia to reduce obstruction in hypertrophic obstructive cardiomyopathy. Studies to develop a new catheter-based concept of treatment. Author(s): Kuhn H, Gietzen F, Leuner C, Gerenkamp T. Source: European Heart Journal. 1997 May; 18(5): 846-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9152655&dopt=Abstract
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Interferon and thymic hormones in the therapy of human myocarditis and idiopathic dilated cardiomyopathy. Author(s): Miric M, Miskovic A, Vasiljevic JD, Keserovic N, Pesic M. Source: European Heart Journal. 1995 December; 16 Suppl O: 150-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8682086&dopt=Abstract
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Ipecac myopathy and cardiomyopathy. Author(s): Dresser LP, Massey EW, Johnson EE, Bossen E. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 1993 May; 56(5): 560-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8099367&dopt=Abstract
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Iron overload cardiomyopathies: new insights into an old disease. Author(s): Liu P, Olivieri N. Source: Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. 1994 February; 8(1): 101-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8086319&dopt=Abstract
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L-carnitine administration in coronary artery disease and cardiomyopathy. Author(s): Singh RB, Aslam M. Source: J Assoc Physicians India. 1998 September; 46(9): 801-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11229253&dopt=Abstract
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L-carnitine supplementation in the therapy of canine dilated cardiomyopathy. Author(s): Keene BW. Source: The Veterinary Clinics of North America. Small Animal Practice. 1991 September; 21(5): 1005-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1949496&dopt=Abstract
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Long-term follow-up of patients with myocarditis and idiopathic cardiomyopathy after immunomodulatory therapy. Author(s): Miric M, Miskovic A, Brkic S, Vasiljevic J, Keserovic N, Pesic M.
dilated
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Source: Fems Immunology and Medical Microbiology. 1994 November; 10(1): 65-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7874080&dopt=Abstract •
Long-term survival effect of metoprolol in dilated cardiomyopathy. The SPIC (Italian Multicentre Cardiomyopathy Study) Group. Author(s): Di Lenarda A, De Maria R, Gavazzi A, Gregori D, Parolini M, Sinagra G, Salvatore L, Longaro F, Bernobich E, Camerini F. Source: Heart (British Cardiac Society). 1998 April; 79(4): 337-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9616339&dopt=Abstract
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Magnesium status and the effect of magnesium supplementation in feline hypertrophic cardiomyopathy. Author(s): Freeman LM, Brown DJ, Smith FW, Rush JE. Source: Canadian Journal of Veterinary Research = Revue Canadienne De Recherche Veterinaire. 1997 July; 61(3): 227-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9243004&dopt=Abstract
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Metabolic aspects of myocardial disease and a role for L-carnitine in the treatment of childhood cardiomyopathy. Author(s): Helton E, Darragh R, Francis P, Fricker FJ, Jue K, Koch G, Mair D, Pierpont ME, Prochazka JV, Linn LS, Winter SC. Source: Pediatrics. 2000 June; 105(6): 1260-70. Erratum In: Pediatrics 2000 September; 106(3): 623. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10835067&dopt=Abstract
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Nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy: one-year follow-up. Author(s): Lakkis NM, Nagueh SF, Dunn JK, Killip D, Spencer WH 3rd. Source: Journal of the American College of Cardiology. 2000 September; 36(3): 852-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10987610&dopt=Abstract
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Rapidly reversible cardiomyopathy associated with chronic ipecac ingestion. Author(s): Ho PC, Dweik R, Cohen MC. Source: Clin Cardiol. 1998 October; 21(10): 780-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9789704&dopt=Abstract
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Relationship between dietary fatty acid, selenium, and degenerative cardiomyopathy. Author(s): Bierenbaum ML, Chen Y, Lei H, Watkins T. Source: Medical Hypotheses. 1992 September; 39(1): 58-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1435394&dopt=Abstract
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Response of cats with dilated cardiomyopathy to taurine supplementation. Author(s): Pion PD, Kittleson MD, Thomas WP, Delellis LA, Rogers QR.
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Source: J Am Vet Med Assoc. 1992 July 15; 201(2): 275-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1500324&dopt=Abstract •
Reversal of Borrelia burgdorferi associated dilated cardiomyopathy by antibiotic treatment? Author(s): Gasser R, Fruhwald F, Schumacher M, Seinost G, Reisinger E, Eber B, Keplinger A, Horvath R, Sedaj B, Klein W, Pierer K. Source: Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. 1996 July; 10(3): 351-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8877079&dopt=Abstract
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Reversal of haemochromatotic cardiomyopathy in beta thalassaemia by chelation therapy. Author(s): Politi A, Sticca M, Galli M. Source: British Heart Journal. 1995 May; 73(5): 486-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7786668&dopt=Abstract
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Reversible dilated cardiomyopathy following treatment of atopic eczema with Chinese herbal medicine. Author(s): Ferguson JE, Chalmers RJ, Rowlands DJ. Source: The British Journal of Dermatology. 1997 April; 136(4): 592-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9155965&dopt=Abstract
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Reversible restrictive cardiomyopathy due to light-chain deposition disease. Author(s): Nakamura M, Satoh M, Kowada S, Satoh H, Tashiro A, Sato F, Masuda T, Hiramori K. Source: Mayo Clinic Proceedings. 2002 February; 77(2): 193-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11838655&dopt=Abstract
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Right ventricular cardiomyopathy in beta-thalassaemia major. Author(s): Hahalis G, Manolis AS, Apostolopoulos D, Alexopoulos D, Vagenakis AG, Zoumbos NC. Source: European Heart Journal. 2002 January; 23(2): 147-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11785997&dopt=Abstract
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Role of endothelin-1 in the development of a special type of cardiomyopathy. Author(s): Zsary A, Szucs S, Schneider T, Rosta A, Sarman P, Fenyvesi T, Karadi I. Source: Clinical Science (London, England : 1979). 2002 August; 103 Suppl 48: 272S-275S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12193102&dopt=Abstract
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Secondary and Infiltrative Cardiomyopathies. Author(s): Saltzberg MT.
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Source: Current Treatment Options in Cardiovascular Medicine. 2000 October; 2(5): 373384. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11096542&dopt=Abstract •
Selenium deficiency associated with cardiomyopathy: a complication of the ketogenic diet. Author(s): Bergqvist AG, Chee CM, Lutchka L, Rychik J, Stallings VA. Source: Epilepsia. 2003 April; 44(4): 618-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12681013&dopt=Abstract
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Successful treatment with an implantable cardioverter defibrillator for spontaneous ventricular fibrillation in dilated cardiomyopathy with very high defibrillation thresholds. Author(s): Tamura K, Abe H, Nagatomo T, Nakashima Y. Source: J Uoeh. 2001 December 1; 23(4): 363-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11789138&dopt=Abstract
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The effect of EGb 761 on the doxorubicin cardiomyopathy. Author(s): Timioglu O, Kutsal S, Ozkur M, Uluoglu O, Aricioglu A, Cevik C, Duzgun E, Sancak B, Poyraz A. Source: Res Commun Mol Pathol Pharmacol. 1999; 106(3): 181-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11485048&dopt=Abstract
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Use of dexrazoxane and other strategies to prevent cardiomyopathy associated with doxorubicin-taxane combinations. Author(s): Sparano JA. Source: Seminars in Oncology. 1998 August; 25(4 Suppl 10): 66-71. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9768827&dopt=Abstract
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Use of paclitaxel in patients with pre-existing cardiomyopathy: a review of our experience. Author(s): Gollerkeri A, Harrold L, Rose M, Jain D, Burtness BA. Source: International Journal of Cancer. Journal International Du Cancer. 2001 July 1; 93(1): 139-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11391633&dopt=Abstract
Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com®: http://www.drkoop.com/InteractiveMedicine/IndexC.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine
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Open Directory Project: http://dmoz.org/Health/Alternative/
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HealthGate: http://www.tnp.com/
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WebMD®Health: http://my.webmd.com/drugs_and_herbs
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
The following is a specific Web list relating to cardiomyopathy; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
General Overview Ascariasis Source: Integrative Medicine Communications; www.drkoop.com Cardiomyopathy Source: Healthnotes, Inc.; www.healthnotes.com Cardiomyopathy Source: Prima Communications, Inc.www.personalhealthzone.com Cardiovascular Disease Overview Source: Healthnotes, Inc.; www.healthnotes.com Congestive Heart Failure Source: Healthnotes, Inc.; www.healthnotes.com Guinea Worm Disease Source: Integrative Medicine Communications; www.drkoop.com Heart Attack Source: Healthnotes, Inc.; www.healthnotes.com HIV and AIDS Support Source: Healthnotes, Inc.; www.healthnotes.com Hookworm Source: Integrative Medicine Communications; www.drkoop.com
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Hypertension Source: Healthnotes, Inc.; www.healthnotes.com Loiasis Source: Integrative Medicine Communications; www.drkoop.com Lymphatic Filariasis Source: Integrative Medicine Communications; www.drkoop.com Pinworm Source: Integrative Medicine Communications; www.drkoop.com River Blindness Source: Integrative Medicine Communications; www.drkoop.com Roundworms Source: Integrative Medicine Communications; www.drkoop.com Shock Source: Integrative Medicine Communications; www.drkoop.com Threadworm Source: Integrative Medicine Communications; www.drkoop.com Trichinosis Source: Integrative Medicine Communications; www.drkoop.com Visceral Larva Migrans Source: Integrative Medicine Communications; www.drkoop.com Whipworm Source: Integrative Medicine Communications; www.drkoop.com •
Herbs and Supplements Coenzyme Q10 Source: Healthnotes, Inc.; www.healthnotes.com Coenzyme Q10 (CoQ10) Source: Prima Communications, Inc.www.personalhealthzone.com Coleus Alternative names: Coleus forskohlii Source: Healthnotes, Inc.; www.healthnotes.com Doxorubicin Source: Healthnotes, Inc.; www.healthnotes.com Glycyrrhiza Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org
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Hawthorn Alternative names: Crataegus laevigata, Crataegus oxyacantha, Crataegus monogyna Source: Healthnotes, Inc.; www.healthnotes.com Taurine Source: Healthnotes, Inc.; www.healthnotes.com Thymus Extracts Source: Healthnotes, Inc.; www.healthnotes.com
General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.
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CHAPTER 4. DISSERTATIONS ON CARDIOMYOPATHY Overview In this chapter, we will give you a bibliography on recent dissertations relating to cardiomyopathy. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “cardiomyopathy” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on cardiomyopathy, we have not necessarily excluded non-medical dissertations in this bibliography.
Dissertations on Cardiomyopathy ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to cardiomyopathy. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •
Cardiac Vasoactive Peptides in Hypertrophic Cardiomyopathy of Cats by Biondo, Alexander Welker, PhD from University of Illinois at Urbana-Champaign, 2003, 140 pages http://wwwlib.umi.com/dissertations/fullcit/3101799
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Effects of Pkc Phosphorylation and Mutations Linked to Familial Hypertrophic Cardiomyopathy in the Heart by Burkart, Eileen Marie, PhD from University of Illinois at Chicago, Health Sciences Center, 2003, 183 pages http://wwwlib.umi.com/dissertations/fullcit/3098349
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Erbb2 Is Essential for Maintenance of the Enteric Nervous System and Prevention of Dilated Cardiomyopathy by Crone, Steven Allen, PhD from University of California, San Diego, 2003, 129 pages http://wwwlib.umi.com/dissertations/fullcit/3071016
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Excitation-contraction Coupling in Hamster Model of Cardiomyopathy by Ma, Tony Sungnan; PhD from The University of Manitoba (Canada), 1978 http://wwwlib.umi.com/dissertations/fullcit/NK37811
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Initiation and Progression of Cardiomyopathy in Sarcoglycan Deficiency by Wheeler, Matthew Thomas, PhD from The University of Chicago, 2003, 250 pages http://wwwlib.umi.com/dissertations/fullcit/3097182
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Investigations of the Mechanism of Alcohol-induced Cardiomyopathy by King, David Christopher; PhD from The University of Western Ontario (Canada), 1989 http://wwwlib.umi.com/dissertations/fullcit/NL49328
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Pathophysiology of Bacterial Cardiomyopathy by Tomlinson, Charles W; PhD from The University of Manitoba (Canada), 1975 http://wwwlib.umi.com/dissertations/fullcit/NK26385
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Retrovirally Induced Dilated Cardiomyopathy in Murine Acquired Immunodeficiency Syndrome by Beischel, Julie Marie, PhD from The University of Arizona, 2003, 125 pages http://wwwlib.umi.com/dissertations/fullcit/3089910
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The Role of Cytoskeletal Lim Protein Deficiency in the Development of Dilated Cardiomyopathy by Lorenzen-Schmidt, Ilka, PhD from University of California, San Diego, 2003, 135 pages http://wwwlib.umi.com/dissertations/fullcit/3099547
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The Role of Lipid Abnormalities in the Development of Diabetic Cardiomyopathy by Rodrigues, Brian Baltzar; PhD from The University of British Columbia (Canada), 1989 http://wwwlib.umi.com/dissertations/fullcit/NL50580
Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.
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CHAPTER 5. CLINICAL TRIALS AND CARDIOMYOPATHY Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning cardiomyopathy.
Recent Trials on Cardiomyopathy The following is a list of recent trials dedicated to cardiomyopathy.8 Further information on a trial is available at the Web site indicated. •
Evaluation of Patients with Known or Suspected Heart Disease Condition(s): Chest Pain; Coronary Cardiomyopathy; Syndrome X
Disease;
Heart
Disease;
Hypertrophic
Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: In this study researchers will admit and evaluate patients with known or suspected heart disease referred to the Cardiology Branch of the National Heart, Lung, and Blood Institute (NHLBI). Patients participating in this study will undergo a general medical evaluation, including blood tests, urine, examination, chest x-ray and electrocardiogram (EKG). In addition, patients may be asked to have an echocardiogram (ultrasound scan of the heart) and to perform an exercise stress test. These tests are designed to assess the types and causes of patient's heart diseases and to determine if they can participate in other, specific research studies. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001313 •
Family Studies of Hypertrophic/Dilated Cardiomyopathy Condition(s): Hypertrophic Cardiomyopathy; Congestive Cardiomyopathy
8
These are listed at www.ClinicalTrials.gov.
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Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study will examine blood cells of patients (and their relatives) with hypertrophic cardiomyopathy or dilated cardiomyopathy for genes that may cause or modify the disease. Cardiomyopathy causes thickening or stretching of the heart muscle that can cause chest pain, shortness of breath, palpitations, and fainting. Cardiomyopathy sometimes runs in families and is caused by an abnormal gene or genes. Patients diagnosed with hypertrophic cardiomyopathy or dilated cardiomyopathy, or both, may enroll in this study. Relatives of patients will also be studied. Participants will have a review of their medical history and a brief physical examination, including and electrocardiogram (EKG) and echocardiogram-an ultrasound test of the heart. A small blood sample will be obtained for DNA (genetic) study. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00045825 •
Randomized Trial of a Telephone Intervention in Heart Failure Patients Condition(s): Heart Failure, Congestive; Cardiomyopathy Study Status: This study is currently recruiting patients. Sponsor(s): Department of Veterans Affairs; Department of Veterans Affairs Health Services Research and Development Service Purpose - Excerpt: In addition to medical treatment for heart failure (HF), a variety of non-pharmacological interventions have been demonstrated to benefit these patients. Some of these include systems for weight monitoring and medication reminders, exercise programs, and individually tailored evaluation and treatment plans with dieticians, social workers, psychologists, and nurse case managers. While many of these approaches have been shown to increase adherence to medication guidelines and result in decreased health care utilization, most rely heavily on a large team of specialized health care providers. It remains unknown whether or not an intervention with a lower intensity of specialized care using sophisticated automated computer tracking and Interactive Voice Response (IVR) techniques can impact the care of HF patients. The primary hypothesis of this study is that Heart Failure Telephone Intervention (HearT-I) will decrease hospitalizations and clinic visits in the veteran population with heart failure. The HearT-I intervention consists of three components: 1) computer-initiated medication refill and clinic appointment reminders; 2) IVR access to educational modules; and 3) weekly computer-initiated phone calls with a series of questions regarding weight and symptoms. Four hundred eighty-eight HF patients (NYHA class II-IV) will be randomized to HearT-I intervention vs. usual care. Upon enrollment, all patients will complete questionnaires assessing HF knowledge, behavior, self-efficacy, and perceptions of HF health care, and HF related Quality of Life (Kansas City Cardiomyopathy Questionnaire, KCCQ). Both groups also will receive a digital scale, educational materials, view an educational video about HF and perform a six-minute walk test. We will test the hypothesis that the HearT-I intervention will decrease health care utilization as measured by hospitalizations and unscheduled outpatient visits for HF over one year. Secondary endpoints include KCCQ score, patient satisfaction, adherence to medications, and general knowledge of heart failure and its management. Study Type: Interventional
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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00057057 •
The Role of Heart Stiff and Weak Atrium on Exercise Capacity in Patients with Hypertrophic Cardiomyopathy Condition(s): Cardiomyopathy, Hypertrophic Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study will examine how heart stiffness and a weak atrium affect exercise capacity and symptoms in patients with hypertrophic cardiomyopathy (HCM). The atrium is the booster pumping chamber of the heart that helps the ventricle (main pumping chamber), to fill properly. HCM is an inherited disease in which the ventricle becomes thickened and, in some patients, stiff. The stiffness makes it difficult for the ventricle to fill and empty, causing breathing difficulty, fatigue, and reduced exercise capacity. Scar formation and a weakened atrium can cause the heart to stiffen. Information gained from this study may guide doctors in prescribing medicines to reduce scarring or improve atrial function. Patients 21 years of age and older with hypertrophic cardiomyopathy may be eligible for this study. Candidates will be screened with a medical history and physical examination, electrocardiogram (EKG), blood tests, Holter monitor, and echocardiogram. A Holter monitor is a device about the size of a Walkman that is connected to three wires that are attached to the chest. It is worn for 24 hours to provide continuous monitoring of heart rhythm. An echocardiogram uses a small probe that emits sound waves to produce images of the heart. The probe is moved across the chest and the reflection of the sound waves from the chambers of the heart produce images showing the heart's thickness and function. Participants will undergo the following tests and procedures over 3 days: -Physical examination and echocardiogram. -Intravenous cannula insertion: A plastic tube is inserted into an arm vein for collecting blood samples to measure substances that the heart and circulatory system release at rest and during exercise. -Impedance cardiography: A small current of electricity is passed across the chest and electrodes similar to those used for an EKG test are placed to measure blood flow in the area of the current. -Pulmonary artery catheterization: A catheter (plastic tube) is inserted into a vein either in the arm, under the collarbone, or in the neck and advanced to the right atrium and ventricle. The catheter remains in place during the echocardiogram tilt and bicycle exercise tests (see below). -Echocardiogram tilt test: The patient lies flat on a table. After a few minutes, the table is tilted so that the patient's head is just above his or her feet for a short while, then is positioned flat again, and then tilted so the feet are just above the head. Echocardiographic measurements and blood samples are taken at intervals to examine heart function during changes in posture. -Echocardiogram bicycle stress test: The patient exercises for as long as possible on a bicycle-like machine while lying on his or her back. Echocardiographic measurements and blood samples are taken at intervals during the test. -Treadmill stress test: The patient runs for as long as possible on a treadmill that increases in difficulty. The patient wears a facemask or mouthpiece through which small amounts of gases are added in order to measure the ability of the heart and lung to increase their effectiveness with exercise. -Digoxin loading: Only patients who demonstrate limited exercise capacity and for whom digoxin is not a risk will undergo this procedure. A medicine that makes the heart contract more strongly, digoxin is used to treat certain heart abnormalities. Patients are given doses of either digoxin or placebo (a look-alike injection with no active ingredient) at 4-hour intervals
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over a 24-hour period and then repeat the tilt test and the bicycle and treadmill exercise tests Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00074880 •
Mapping Novel Disease Genes for Dilated Cardiomyopathy Condition(s): Cardiomyopathy, Congestive; Cardiovascular Diseases; Heart Diseases; Heart Failure, Congestive Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To identify new dilated cardiomyopathy genes by genetic linkage and mutational analyses. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00046618
•
Natural History and Results of Dual Chamber (DDD) Pacemaker Therapy of Children with Obstructive Hypertrophic Cardiomyopathy (HCM) Condition(s): Hypertrophic Cardiomyopathy Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Several studies have shown that specialized pacemaking devices (DDD pacing) can improve the symptoms associated with hypertrophic cardiomyopathy (HCM) in adults. In addition, studies have also shown that specialized pacemaking devices (DDD pacing) can improve conditions of HCM in children. However, growth of the body and organs, including the heart, is very rapid during childhood. Therefore the long-term effects of DDD pacing in children are unknown. The purpose of this study is to examine the growth rate and nutrition of children with HCM. Due to this heart condition and the restrictions that are often placed on the child's activity level, children with HCM may grow at a slower rat and may have a greater tendency to be overweight. Children participating in the study will have their growth rate and nutritional status measured before the study begins and throughout the course of the study. Findings in this research study will not directly benefit the patients participating in it. However, information gathered as a result of this study may lead to improvements in the management of children with HCM in the future. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001396
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Pediatric Cardiomyopathy Registry Condition(s): Cardiovascular Diseases; Heart Diseases; Myocardial Diseases
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Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To establish and maintain a national registry of children with different forms of cardiomyopathy. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005391 •
A Comparison of Two Treatments' Pacemaker and Percutaneous Transluminal Septal Ablation for Hypertrophic Cardiomyopathy Condition(s): Hypertrophic Cardiomyopathy Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study will compare two treatments: pacemaker implantation and percutaneous transluminal septal ablation (PTSA) for patients with hypertrophic cardiomyopathy (HCM), a condition in which the heart muscle thickens and obstructs the flow of blood out of the heart. The reduced blood flow can cause chest pain, shortness of breath, palpitations, tiredness, lightheadedness and fainting. Patients with HCM who cannot be helped by drug therapy may participate in the study. The standard treatment for such patients is septal myectomy, an operation in which the surgeon shaves the muscle obstructing the blood flow. Another treatment option is implantation of a type of pacemaker that causes the heart to contract in a certain way that reduces blood flow obstruction and improves symptoms. The pacemaker is implanted under local anesthesia and usually takes less than an hour. PTSA is an experimental treatment that may provide a third option. In PTSA, a thin tube (catheter) is inserted into the blood vessel that feeds the heart muscle causing the blood flow obstruction. A small amount of alcohol is injected through the catheter to destroy some of the muscle and relieve the obstruction. Candidates will have the following screening tests: chest X-ray, electrocardiogram, echocardiogram, exercise tests, exercise radionuclide angiography, exercise thallium scintigraphy, Holter monitoring, cardiac catheterization, electrophysiology study, and coronary angiography. Participants will be assigned to one of the two treatments groups: pacemaker implantation or PTSA. Patients in the PTSA group will also have magnetic resonance imaging scans at the start of the study, 3 to 7 days after PTSA, and at the end of the study, in order to observe changes in the heart's shape. All patients will fill out a questionnaire answering questions about their quality of life. Patients' progress will be followed with monthly phone calls. In addition, various tests, such as exercise tests and echocardiography, will be done during repeat visits at three and six months to measure treatment results. Patients will again complete qualityof-life questionnaires at both of those visits. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001894
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AIDS-Associated Cardiomyopathy Condition(s): Acquired Immunodeficiency Syndrome; Heart Diseases; Myocardial Diseases; HIV Infections Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To define the incidence and prevalence of AIDS-associated cardiomyopathy. Also, to conduct immunopathology and serologic studies in endomyocardial biopsies and autopsy tissues. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005227
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Alcohol Septal Ablation in Obstructive Hypertrophic Cardiomyopathy: A Pilot Study Condition(s): Hypertrophic Cardiomyopathy Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study will test the feasibility of a modified procedure for treating obstructive hypertrophic cardiomyopathy (OHC). Patients with OHC have a thickening of the heart muscle that obstructs blood flow out of the heart, causing breathlessness, chest pain, palpitations, tiredness, lightheadedness, and fainting. The current treatment for OHC is a procedure called alcohol septal ablation (also percutaneous transluminal septal ablation, or PTSA), which involves injecting a small amount of alcohol into a tiny artery that supplies the part of muscle causing blood flow obstruction. The success of PTSA is limited, however, by problems of heart anatomy and the ability to find the appropriate artery to inject. Modifying the procedure by injecting the alcohol through the wall of the lower right chamber of the heart may improve its safety and effectiveness. The new technique requires positioning a catheter (a flexible tube) into the appropriate area of the heart. This study will test the ability to accurately guide the catheter to that area. Patients with OHC 18 years of age and older who are scheduled to have a cardiac catheterization may be eligible for this study. At the end of the catheterization procedure, participants will undergo intra-cardiac echocardiographic imaging. For this test, one of the catheters placed in the femoral artery (at the top of the leg) for cardiac catheterization will be substituted for a larger one. Through this catheter, a special catheter will be introduced and advanced to the heart to provide images. This pilot feasibility study does not involve injection of alcohol. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00035386
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Analysis of Heart Muscle Function in Patients with Heart Disease and Normal Volunteers Condition(s): Cardiomyopathy, Hypertrophic; Coronary Disease; Healthy; Myocardial Ischemia; Syndrome X Study Status: This study is completed.
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Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Myocardial ischemia is a heart condition in which not enough blood supply and oxygen reaches the heart muscle. Damage to the major blood vessels of the heart (coronary artery disease), minor blood vessels of the heart (microvascular heart disease), or damage to the heart muscle (hypertrophic cardiomyopathy) can cause myocardial ischemia. Any of theses three conditions can cause patients to experience chest pain and other symptoms as well as cause the heart to function improperly. In order to detect myocardial ischemia researchers can use tests to measure the movement of the walls of the heart. Walls receiving inadequate supplies of blood often move less and occasionally move in the opposite direction. Some of the tests may require patients to receive injections of radioactive tracers. The radioactive material acts to enhance 3 dimensional pictures of the heart and helps to identify areas of ischemia. The purpose of this study is to determine whether 3-dimensional imaging (tomography) with radioactive tracers can provide more important information about heart wall function than routine diagnostic tests. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001459 •
Chagas Disease as an Undiagnosed Type of Cardiomyopathy in the United States Condition(s): Heart Diseases; Myocardial Diseases; Chagas Disease Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: A detailed review was made of data pertinent to the occurrence of chronic Chagas disease in the United States. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005455
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Cyclosporine A to Treat Hypertrophic Cardiomyopathy (HCM) Condition(s): Cardiomyopathy, Hypertrophic; Heart Hypertrophy Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study will examine the effectiveness of the drug cyclosporine in treating hypertrophic cardiomyopathy (HCM), a condition in which the heart muscle thickens. The thickened muscle can impair the heart's pumping action or decrease its blood supply, or both. Various symptoms, such as chest pain, shortness of breath, fatigue, and palpitations, may result. In animal studies, cyclosporine prevented heart muscle from thickening in mice that had been engineered to develop thick hearts. Patients with HCM 18 to 75 years old are screened for this study under protocol 98-H0102 and this protocol. Screening tests include blood tests, echocardiogram to measure heart thickness, Holter monitor to record heartbeats, treadmill exercise test, and various imaging tests including a thallium scan, radionuclide angiography, magnetic resonance imaging (MRI), and cardiac catheterization to examine heart function and blood supply. Patients admitted to the study will be randomly assigned to take either cyclosporine tablets or a placebo (a look-alike tablet with no active ingredient) twice a day for 6
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months. During a brief hospital stay at the start of the study, blood samples will be taken to measure cyclosporine levels. After discharge, heart rate and blood pressure will be checked and blood tests done during follow-up visits once a week for 2 weeks and then every two weeks until the end of the 6-month treatment period. At that time, patients will be hospitalized a second time for repeat tests to determine the effects of the drug on the heart condition. They include thallium scan, radionuclide angiogram, MRI, treadmill exercise test, cardiac catheterization, and echocardiogram. An echocardiogram and MRI will be repeated 1 year after the start of the study to evaluate long term effects of the drug, if any. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001965 •
Effect of Behavioral Management on Quality of Life in Heart Failure Condition(s): Heart Failure, Congestive; Cardiomyopathy, Dilated Study Status: This study is completed. Sponsor(s): Department of Veterans Affairs Purpose - Excerpt: Nurses play an important role in helping patients to manage symptoms, adhere to treatment, and change behavior. There has been a lack of research regarding nonpharmacologic interventions with patients with heart failure and other chronic conditions. The primary objective of this 4-year study was to determine the effect of a nurse-led behavioral management intervention on health-related quality in patients with medically-managed heart failure. The secondary objective was to assess the impact of the behavioral management intervention on health care resource utilization. DESIGN: randomized controlled trial. SETTING: single site, VA San Diego Healthcare System. SAMPLE: Patients were enrolled in 11 cohorts a total of 116 outpatients were randomly assigned to one of two treatment groups to evaluate the clinical impact of the intervention. Group 1 received usual care for patients with heart failure (n=58). Group 2 was an augmented group receiving usual care plus participation in the 15-week (4-month) behavioral management program (n=58). Inclusion criteria were that the patient had a primary diagnosis of heart failure, a VA primary care provider, stable symptoms for at least one month and was able to walk. INTERVENTION: The behavioral management program augmented usual care and consisted of establishing specific goals with patients related to healthier diet, increased quality and amount of exercise, smoking cessation, and increased social and interpersonal activities. DEPENDENT VARIABLES/OUTCOME MEASURES: The five major dependent variables for this study were psychological symptom distress (Multiple Affect Adjective Check List - MAACL), physical functioning (SF-36 physical component summary score), mental functioning (SF-36 mental component summary score), exercise capability (6-Minute Walk), and general health perceptions (SF-36 general health scale score). Dependent variables were assessed at baseline, at the end of treatment (at 4 months), and then at 10 and 16 months. DATA ANALYSIS: Initial analyses included all subjects who were randomized to treatment and completed all data collection time points in a series of 2 by 4 ANOVAs with time as a repeated measure. Study Type: Interventional Contact(s): see Web site below
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Web Site: http://clinicaltrials.gov/ct/show/NCT00012870 •
Epidemiology of Idiopathic Dilated Cardiomyopathy (Washington, DC Dilated Cardiomyopathy Study) Condition(s): Cardiovascular Diseases; Heart Diseases; Myocardial Diseases; Asthma; Diabetes Mellitus; Hypertension Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To identify risk factors for idiopathic dilated cardiomyopathy and to examine prognostic factors over a follow-up period of two to three years. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005262
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Factors Contributing to Increased Left Ventricle Size in Patients with Abnormally Enlarged Hearts Condition(s): Hypertrophic Cardiomyopathy; Left Ventricular Hypertrophy Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: The human heart is divided into four chambers. One of the four chambers, the left ventricle, is the chamber mainly responsible for pumping blood out of the heart into the circulation. There is an inherited condition affecting the heart, passed on through genetics, hypertrophic cardiomyopathy (HCM). HCM causes the left ventricle to become abnormally enlarged (left ventricular hypertrophy LVH). Some patients with the abnormal genes that may cause HCM do not have the characteristic LVH. Approximately 20 - 40% of patients with the genetic abnormality (missense mutation of genes encoding for sarcomeric protein) actually have an enlarged left ventricle. Because of this, researchers believe there may be other factors, along with the genetic abnormality that contribute to the development of HCM. Researchers are interested in learning more about several factors they suspect may play a role in the development of HCM. Specifically, researchers plan to study levels of a hormone and the protein it attaches to, which may contribute to the development of an abnormally enlarged heart. Insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein (IGFBP) work together with growth hormone (GH) in the development and maturation of many organ systems. Previous studies have suggested that these hormones affect the development and function of the heart. Patients participating in this study will undergo a variety of tests including collection of blood samples, echocardiogram of the heart, treadmill exercise test, and continuous electrical monitoring of heart activity (Holter monitor). Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001878
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Family Studies of Inherited Heart Disease Condition(s): Hypertrophic Cardiomyopathy
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Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Hypertrophic cardiomyopathy (HCM) is a genetically inherited heart disease. It causes thickening of heart muscle, especially the chamber responsible for pumping blood out of the heart, the left ventricle. Hypertrophic cardiomyopathy (HCM) is the most important cause of sudden death in apparently healthy young people. A genetic test called linkage analysis is used to locate genes causing inherited diseases like HCM. Linkage analysis requires large families to be evaluated clinically in order to identify the members with and without the disease. In this study researchers will collect samples of DNA from family members of patients with HCM. The diagnosis of the disease will be made by history and physical examination, electrocardiogram (12 lead ECG), and ultrasound of the heart (2-D echocardiogram). The ability of the researchers to locate the gene responsible for the disease improves with increases in the size of the family and members evaluated. In order to continue research on the genetic causes of heart disease, researchers intend on studying families with specific genetic mutations (beta-MHC) causing HCM. Researcher plan to also study families with HCM not linked to specific gene mutations (beta-MHC). Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001225 •
Genetic Analysis of Familial Hypertrophic Cardiomyopathy Condition(s): Cardiovascular Diseases; Cardiomyopathy, Hypertrophic
Heart
Diseases;
Myocardial
Diseases;
Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To map the genetic defect responsible for familial hypertrophic cardiomyopathy. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005251 •
Home Walking Exercise Training in Advanced Heart Failure Condition(s): Cardiomyopathy, Congestive Study Status: This study is completed. Sponsor(s): Department of Veterans Affairs; Department of Veterans Affairs Health Services Research and Development Service Purpose - Excerpt: Heart failure (HF) is a major public health burden in the United States. Despite considerable advances in the diagnosis and management of HF, it remains one of the leading causes of morbidity and mortality. HF is a progressive cardiovascular syndrome characterized by a reduction in exercise capacity with distressing symptoms of exertional fatigue and dyspnea. Currently, much of HF therapy is aimed at increasing survival. Yet, for many patients prolonged survival may be less critical than improved functional status and quality of life.38,39 Hence, a nursing intervention designed to ameliorate symptoms, maximize functional status, and achieve
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a high level of well-being is clinically relevant. Investigators have suggested that either a cardiac rehabilitation program or a home bicycle exercise training program may improve peak oxygen consumption, symptom scores and reverse autonomic imbalance. Improvement of peak oxygen consumption may not necessarily translate into improve functional status and quality of life. A cardiac rehabilitation program or bicycle ergometer may be costly for patients to perform. Utilizing a 2-group pre-test-post-test experimental design, the specific aim is to compare functional status (FS), quality of life (QOL) and neurohormonal activation in 2 groups of advanced HF patients (control group vs. home walking exercise (HWE) group). Will a 12-week HWE program decrease sympathetic activity, increase FS, and/or improve QOL? Heart failure patients from WLA-VAMC who meets inclusion criteria (dilated cardiomyopathy for 3 months, LVEF < 40%, NYHA Class II-III, 25-80 years) and exclusion criteria (i.e. MI or recurrent angina in past 3 months, orthopedic impediments, severe COPD, stenotic valvular disease, ventricular tachyarrhythmias, etc) are considered. Sample size will be 55 in each group. Consented patients are stratified by age: younger (< 60 years) and older (> 60 years); then, randomized into either control or experimental group. Control group performs "limited physical activity" for 12weeks; whereas, experimental group performs a 12week HWE program. The 12- week HWE program is once a day, 5x a week and initiated at 10 minutes and progressively increases in duration and intensity up to 45 minutes. Pre- and post-study measures are sympathetic activation (norepinephrine (NE)), FS (peak VO2 via cardiopulmonary exercise test and a Heart Failure Functional Status Inventory), and QOL (Cardiac Quality of life Index by Ferrans and Powers, and the Dyspnea-Fatigue Rating Index). Between group differences over time for FS (VO2max, and HFFSI scores), QOL (C-QLI and Dyspnea-Fatigue Rating Index scores), neurohormonal activation (NE levels) will be evaluated by repeated measures multivariate analysis of variance. Significance will be set at alpha=.05. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00012883 •
Idiopathic Dilated Cardiomyopathy Condition(s): Heart Diseases; Cardiomyopathy, Congestive Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the familial occurrence and pathogenesis of idiopathic dilated cardiomyopathy. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005201
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Investigation into the Use of Ultrasound Technique in the Evaluation of Heart Disease Condition(s): Healthy; Hypertrophic Cardiomyopathy; Left Ventricular Hypertrophy Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI)
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Purpose - Excerpt: The human heart is divided into four chambers. One of the four chambers, the left ventricle, is the chamber mainly responsible for pumping blood out of the heart into the circulation. Hypertrophic cardiomyopathy is a genetically inherited disease causing an abnormal thickening of heart muscle, especially the muscle making up the left ventricle. When the left ventricle becomes abnormally large, it is called left ventricular hypertrophy (LVH). Patients with HCM can be born with an enlarged left ventricle or they may develop the condition in childhood or adolescence, usually during the time when the body is rapidly growing. However, not all patients with the abnormal genes linked to HCM have the characteristic LVH. Currently, it is impossible to tell if a patient with the genes for HCM will develop LVH. A recently developed ultrasound tool called an integrated backscatter analysis (IBS), may allow researchers to determine those children who may later develop HCM and LVH. In order to test this, researchers plan to use IBS to study normal children with relatives diagnosed with HCM. This study will compare the results of IBS done on normal children with relatives diagnosed with HCM , normal children, and children with evidence enlarged heart muscle (HCM). Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001632 •
Long Term Effects of Enalapril and Losartan on Genetic Heart Disease Condition(s): Hypertrophic Myocardial Ischemia
Cardiomyopathy;
Left
Ventricular
Hypertrophy;
Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: The human heart is divided into four chambers. One of the four chambers, the left ventricle, is the chamber mainly responsible for pumping blood out of the heart into circulation. Hypertrophic cardiomyopathy (HCM) is a genetically inherited disease causing an abnormal thickening of the heart muscle, especially the muscle making up the left ventricle. When the left ventricle becomes abnormally large it is called left ventricular hypertrophy (LVH). This condition can cause symptoms of chest pain, shortness of breath, fatigue, and heart beat palpitations. This study is designed to compare the ability of two drugs (enalapril and losartan) to improve symptoms and heart function of patients diagnosed with hypertrophic cardiomyopathy (HCM). Researchers have decided to compare these drugs because each one has been used to treat patients with other diseases causing thickening of the heart muscle. In these other conditions, enalapril and losartan have improved symptoms, decreased the thickness of heart muscle, improved blood flow and supply to the heart muscle, and improved the pumping action of the heart muscle. In this study researchers will compare the effectiveness of enalapril and losartan when given separately and together to patients with hypertrophic cardiomyopathy (HCM). Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001534 •
Long-Term Results of DDD Pacing in Obstructive Hypertrophic Cardiomyopathy Condition(s): Cardiomyopathy, Hypertrophic Study Status: This study is completed.
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Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: DDD pacing improves symptoms and relieves LV outflow tract (LVOT) obstruction in most patients with hypertrophic cardiomyopathy (HCM). Notably, when pacing is temporarily discontinued, the beneficial effects of pacing are evident in sinus rhythm. The long term results of this novel therapy are, however, uncertain. We propose (1) to record the hemodynamic changes following >4 years of pacing; and (2) to determine whether DDD pacing continues to be necessary in patients who have had a substantial relief of their LVOT obstruction. Patients who have had >50% reduction in LVOT pressure gradients will be randomized to two pacing modalities: DDD at 70 beats per minute and AAI pacing at 70 beats per minute (DDD switched off), and reevaluated after a six-month period. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001530 •
Mortality Surveillance of MRFIT Screenees Condition(s): Cardiovascular Diseases; Heart Diseases; Cerebrovascular Accident; Coronary Disease; Hypertension; Cardiomyopathy, Congestive Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To ascertain the sixteen year mortality status of the 361,662 middleaged men screened in 1973-1975 for the Multiple Risk Factor Intervention Trial (MRFIT). Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005156
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Pirfenidone to Treat Hypertrophic Cardiomyopathy Condition(s): Hypertrophic Cardiomyopathy Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study will examine the effectiveness of the drug pirfenidone (Deskar) in improving heart function in patients with hypertrophic cardiomyopathy (HCM). Stiffening of the heart muscle in patients with HCM impairs the heart's ability to relax and thus fill and empty properly. This can lead to heart failure, breathlessness and excessive fatigue. The heart's inability to relax may be due to scarring, or fibrosis, in the muscle wall. This study will test whether pirfenidone can reduce fibrosis, improve heart relaxation and reduce abnormal heart rhythms. Men and women 20 to 75 years old with HCM may be eligible for this study. Participants will undergo a physical examination, blood tests, and other tests and procedures, described below, to assess heart function. When the tests are completed, patients will be randomly assigned to one of two treatment groups. One group will take a pirfenidone capsule and the other will take a placebo (a look-alike pill with no active ingredient) twice a day with meals for 6 months. For the pirfenidone group, the dose of drug will be increased gradually from 400 to 800 milligrams. At the end of 6 months, all patients will repeat the physical examination and heart tests that were done before starting medication. These include: -Electrocardiogram (ECG) - electrodes are attached to the heart to record the heart's electrical activity,
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providing information on the heartbeat. -Echocardiogram - a probe held against the chest wall uses sound waves to produce images of the heart, providing information on the function of the heart chambers. -24-hour Holter monitor - a 24-hour recording of the electrical activity of the heart monitors for abnormal heartbeats or conduction abnormalities. -Magnetic resonance imaging (MRI) - Radiowaves and a strong magnetic field are used to produce images of the heart, providing information on the thickness and movement of the heart muscle. -Radionuclide angiogram - a radioactive tracer is injected into a vein and a special camera is used to scan the heart, providing information on the beating motion of the heart. Scans are obtained at rest and after exercise. -Cardiac (heart) catheterization - a catheter (thin plastic tube) is inserted into a blood vessel in the groin and advanced to the heart to record pressures and take pictures inside the heart. Electrophysiology study - a catheter is inserted into a blood vessel in the groin and advanced to the heart to record electrical activity, providing information on abnormal heart rhythms. This procedure is done at the time of the heart catheterization. -Cardiac biopsy - a catheter is inserted into a blood vessel in the groin and advanced to the heart to remove a small sample of heart muscle for microscopic examination. This procedure is done at the end of the heart catheterization. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00011076 •
Screening for Inherited Heart Disease Condition(s): Heart Disease; Hypertrophic Cardiomyopathy Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Genetically inherited heart diseases like hypertrophic cardiomyopathy (HCM) are conditions affecting the heart passed on to family members by abnormalities in genetic information. These conditions are responsible for many heart related deaths and illnesses. Presently, there are several research studies being conducted in order to improve the understanding of disease processes and symptoms associated with genetically inherited heart diseases. This study is designed to determine the eligibility of patients diagnosed with or suspected to have inherited heart disease to participate in these research studies. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001746
•
Study of Blood Flow in Heart Muscle Condition(s): Coronary Disease; Healthy; Hypertrophic Cardiomyopathy; Myocardial Ischemia Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Blood flows to areas of the heart providing oxygen and fuel to the pumping muscle. Occasionally the arteries providing the fuel can become blocked. This occurs in coronary artery disease. Magnetic resonance imaging (MRI) can be used to
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evaluate the blood flow to different areas of the heart muscle. In this study magnetic resonance imaging will be compared to other diagnostic tests (radionucleotide perfusion studies) capable of measuring blood flow to heart muscle. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001631 •
Studying the Effectiveness of Pacemaker Therapy in Children who Have Thickened Heart Muscle Condition(s): Hypertrophic Cardiomyopathy Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: A heart condition called hypertrophic cardiomyopathy (HCM) causes abnormal thickening of the heart muscle, which obstructs the flow of blood out of the heart. The thickened muscle and the obstruction of blood flow are believed to cause chest discomfort, breathlessness, fainting, and a sensation of heart pounding. Treatment options for children with HCM include medicine, heart operation, and cardiac transplantation. However, there is no evidence that medicine prevents further thickening of heart muscle; operations carry the risk of death; and donor hearts are not always available. Several studies have shown that pacemaker treatment reduces the obstruction and improves heart complaints in patients with HCM. This study investigates further the efficacy of pacemaker treatment in children. Patients will have exercise tests after treatment with beta blocker and verapamil and will be eligible for the study if heart complaints or reduced exercise performance continue. A pacemaker that treats slow heart rhythms will be inserted. The patient will be sedated and local anesthesia will be administered to numb the area. The procedure takes about an hour. The study will last two years. Patients will be placed on one of two pacemaker programs for the first year and another the second year. At 3- and 6-month follow-up visits, a pacemaker check and echocardiogram will be performed. After 1 year, patients will be admitted to NIH for 2 to 3 days for exercise tests, echocardiogram, and cardiac catheterization. Also, the pacemaker will be changed to the second program. At 15- and 18-month follow-up visits, a pacemaker check and echocardiogram will be performed. After 2 years, patients will again be admitted for 2 to 3 days for exercise tests, echocardiogram, and cardiac catheterization. A pregnancy test will be given to females of child-bearing age before each cardiac catheterization and electrophysiology study. At the end of the study, the pacemaker will be set to the program that worked better. Risks of pacemaker insertion include lung collapse, infection, blood vessel damage, bleeding, heart attack, and death. Risks of cardiac catheterization include infection, bleeding, blood clots, abnormal heart rhythms, perforation of the heart, need for surgery, and death. However, the safety record for both these procedures at NIH has been excellent. The radiation exposure exceeds the NIH radiation guidelines for children, but this exposure in adults has not been associated with any definite adverse effects. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001960
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Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “cardiomyopathy” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •
For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/
•
For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html
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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/
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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm
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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm
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For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm
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For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp
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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm
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For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/
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For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm
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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm
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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm
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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm
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•
For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm
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For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials
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CHAPTER 6. PATENTS ON CARDIOMYOPATHY Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “cardiomyopathy” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on cardiomyopathy, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Cardiomyopathy By performing a patent search focusing on cardiomyopathy, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. 9Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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Cardiomyopathy
The following is an example of the type of information that you can expect to obtain from a patent search on cardiomyopathy: •
Actin mutations in dilated cardiomyopathy, a heritable form of heart failure Inventor(s): Keating; Mark T. (Salt Lake City, UT), Olson; Thomas M. (Salt Lake City, UT) Assignee(s): University of Utah Research Foundation (salt Lake City, Ut) Patent Number: 6,063,576 Date filed: June 29, 1998 Abstract: Two mutations in the human cardiac actin gene are disclosed which have been associated with idiopathic dilated cardiomyopathy (IDC) in two families. These mutations cosegregate with IDC in the two families. Both mutations affect universally conserved amino acids in domains of actin that attach to Z bands and intercalated discs. Analysis of the cardiac actin gene can be used to determine the presence in a patient of IDC resulting from mutations in this gene. Such analysis is useful in the diagnosis and prognosis of the disease in patients with mutations in this gene. Excerpt(s): Heart failure is a major medical problem that affects 700 thousand individuals per year in the United States and accounts for annual costs of 10 to 40 billion dollars (Abraham and Bristow, 1997). Heart failure is the primary manifestation of dilated cardiomyopathy, a group of disorders characterized by cardiac dilation and pump dysfunction. Half of patients with dilated cardiomyopathy are diagnosed with idiopathic dilated cardiomyopathy (IDC), isolated heart failure of unknown etiology (affecting 5 to 8 in 100,000 individuals) (Manolio et al., 1992; Kasper et al., 1994). Cardiac transplantation is the only definitive treatment for end-stage disease. The present invention is directed to ACTC and its gene products, mutations in the gene, the mutated gene, probes for the wild-type and mutated gene, and to a process for the diagnosis and prevention of idiopathic dilated cardiomyopathy. The instant work shows that some families with idiopathic dilated cardiomyopathy have mutations in ACTC. Idiopathic dilated cardiomyopathy is diagnosed in accordance with the present invention by analyzing the DNA sequence of the ACTC gene of an individual to be tested and comparing the respective DNA sequence to the known DNA sequence of normal ACTC. Alternatively, the ACTC gene of an individual to be tested can be screened for mutations which cause idiopathic dilated cardiomyopathy. The publications and other materials used herein to illuminate the background of the invention or provide additional details respecting the practice, are incorporated by reference, and for convenience are respectively grouped in the appended List of References. Web site: http://www.delphion.com/details?pn=US06063576__
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Adeno associated virus vectors for the treatment of a cardiomyopathy Inventor(s): Byrne; Barry J. (Baltimore, MD), Kessler; Paul D. (Baltimore, MD), Kurtzman; Gary J. (Menlo Park, CA), Podsakoff; Gregory M. (Fullerton, CA) Assignee(s): Avigen, Inc. (alameda, Ca), Johns Hopkins University (baltimore, Md) Patent Number: 6,610,290 Date filed: October 1, 2001
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Abstract: The use of recombinant adeno-associated virus (AAV) virions for delivery of DNA molecules to muscle cells and tissue is disclosed. The invention allows for the direct, in vivo injection of recombinant AAV virions into muscle tissue, e.g., by intramuscular injection, as well as for the in vitro transduction of muscle cells which can subsequently be introduced into a subject for treatment. The invention provides for sustained, high-level expression of the delivered gene and for in vivo secretion of the therapeutic protein from transduced muscle cells such that systemic delivery is achieved. Excerpt(s): The present invention relates generally to DNA delivery methods. More particularly, the invention relates to the use of recombinant adeno-associated virus (AAV) virions for delivery of a selected gene to muscle cells and tissue. The method provides for sustained, high-level expression of the delivered gene. Gene delivery is a promising method for the treatment of acquired and inherited diseases. Muscle tissue is an appealing gene delivery target because it is readily accessible, well-differentiated and nondividing. Barr and Leiden (1991) Science 254:1507-1509. These properties are important in the selection of appropriate delivery strategies to achieve maximal gene transfer. Several experimenters have demonstrated the ability to deliver genes to muscle cells with the subsequent systemic circulation of proteins encoded by the delivered genes. See, e.g., Wolff et al. (1990) Science 247:1465-1468; Acsadi et al. (1991) Nature 352:815-818; Barr and Leiden (1991) Science 254:1507-1509; Dhawan et al. (1991) Science 254:1509-1512; Wolff et al. (1992) Human Mol. Genet. 1:363-369; Eyal et al. (1993) Proc. Nat. Acad. Sci. USA 90:4523-4527; Davis et al. (1993) Hum. Gene Therapy 4:151-159. Web site: http://www.delphion.com/details?pn=US06610290__ •
Agent for gene therapy of dilated cardiomyopathy Inventor(s): Toyo-Oka; Teruhiko (23-3, Kamiogi 3-chome, Suginami-ku, Tokyo 167-0043, JP) Assignee(s): None Reported Patent Number: 6,589,523 Date filed: January 25, 2001 Abstract: According to the present invention, there is provided a gene expression vector which is obtained by inserting a gene encoding sarcoglycan into an adeno-associated virus (AAV) vector. By administering the gene expression vector of the present invention to a living body in vivo, a sarcoglycan can be continuously expressed in the living body, so that the restoration of.alpha.-,.beta.-,.gamma.- and.delta.-sarcoglycan components can be accompanied and the heart function of the patient of dilated cardiomyopathy can be improved. Excerpt(s): The present invention relates to an agent for gene therapy of dilated cardiomyopathy, more particularly, a gene expression vector which is obtained by inserting a gene encoding a sarcoglycan into an adeno-associated virus vector. Cardiomyopathy is one of the heart diseases which shows contraction dysfunction and electrophysiological dysfunction as symptoms, and includes a group of heart diseases which lead to a sever heart failure and a sudden death. Cardiomyopathy is classified into dilated cardiomyopathy and hypertrophied cardiomyopathy, and the study for revealing the causes of each cardiomyopathy has been made. In the case of dilated cardiomyopathy (DCM), in spite of progress in the therapy, the prognosis of the patients is still poor and cardiac transplantation is necessary in the deteriorated cases (V.
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V. Michels, et al., New Engl.J.Med. 326, 77 (1992); E. K. Kasper, et al., J.Am.Coll.Cardiol. 23, 586 (1994); M. Packer, et al., New Engl.J.Med. 334, 1349 (1996); M. Packer, et al. New Engl.J.Med. 335,1107 (1996); R. M. Graham, W. A. Owens, N.Engl.J.Med. 341, 1759 (1999)). Therefore, it is necessary to develop a novel method for therapy which can improve the patient's mortality and morbidity. Animal model is useful for developing such a novel method for therapy. Gene transfer will be promising for the therapy of some type of DCM which is caused by the gene deletion. It has been demonstrated that the deletion of.delta.-sarcoglycan (.delta.-SG) gene is the cause of DCM in hamsters (A. Sakamoto, et al., Proc.Natl.Sci.Acad.U.S.A. 94, 13873 (1997); V. Nigro, et al., Hum.Mol.Genet. 6, 601 (1997)). Also, it has been found that the breakpoint of.delta.-SG gene in TO-2 hamster which is a model animal of DCM is present in the first intron, and large region including its promoter and the first exon is deleted in TO-2 hamster (A. Sakamoto, et al., Proc.Natl.Sci.Acad.U.S.A. 94, 13873 (1997)). Furthermore, dystrophinassociated glycoprotein complex (DAGC) links intracellular contractile machinery with extracellular matrix (G. F. Cox, L. M. Kunkel, Curr.Opin.Cardiol. 12, 329 (1997); K. H. Holt, et al., Mol. Cell 1, 841 (1998); M. D. Henry, K. P. Campbell, Curr.Opin.Cell Biol. 11, 602 (1999)). Web site: http://www.delphion.com/details?pn=US06589523__ •
Aldose reductase inhibition in preventing or reversing diabetic cardiomyopathy Inventor(s): Johnson; Brian F. (East Lyme, CT) Assignee(s): Pfizer Inc. (new York, Ny) Patent Number: 5,990,111 Date filed: May 1, 1998 Abstract: This invention relates to the use of aldose reductase inhibitors in the treatment, prevention or reversal of diabetic cardiomyopathy in a human subject. Excerpt(s): This invention relates to the use of aldose reductase inhibitors in the treatment or reversal of diabetic cardiomyopathy in a human subject. Of all identified diabetic sequelae, perhaps the most physiologically deleterious are those complications involving the cardiovascular system. These may, for example, involve the blood or nervous supply to the heart or the heart muscle (myocardium) directly. An associated disease state related to myocardial abnormalities is diabetic cardiomyopathy, an affliction in which subjects afflicted therewith manifest such symptomes as, inter alia, an overall reduction in cardiac performance, reduced ventricular compliance as characterized by slowed, incomplete cardiac filling (diastolic dysfunction), an increased incidence of congestive heart failure and a markedly enhanced potential for death during episodes of myocardial infarction. Moreover, secondary indicators such as the development of interstitial and myocellular tissue abnormalities (including interstitial, perivascular and focal scar-like connective tissue accumulations) may be present in addition to microangiopathy (including thickening of the capillary basement membrane, pericapillary edema and capillary microaneurysms). These characteristic abnormalities define the syndrome of diabetic cardiomyopathy. Detailed discussions of this condition may be found, for example, in F. S. Fein, et. al., "Diabetic Cardiomyopathy", Cardiovascular Drugs and Therapy, Vol. 8, pp. 65-73, 1994, and D. S. H. Bell, "Diabetic Cardiomyopathy", Diabetes Care, Vol. 18, pp. 708-714, 1995 and pertinent references cited therein. Aldose reductase inhibitors constitute a class of compounds which have become well known for their utility in the treatment of certain diabetic complications such as ocular cataract formation and diabetic neuropathy and nephropathy. Such
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compounds are well known to those skilled in the art and may be identified by standard biological methodology. Web site: http://www.delphion.com/details?pn=US05990111__ •
Combination of aldose reductase inhibitors and selective serotonin reuptake inhibitors for the treatment of diabetic complications Inventor(s): Mylari; Banavara L. (Waterford, CT) Assignee(s): Pfizer, Inc. (new York, Ny) Patent Number: 6,380,200 Date filed: December 1, 2000 Abstract: This invention is directed to methods, pharmaceutical compositions and kits comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and selective serotonin reuptake inhibitor (SSRI), a prodrug thereof or a pharmaceutically acceptable salt of said SSRI or said prodrug. This invention further relates to methods of using those pharmaceutical compositions for the treatment of diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, myocardial infarction, cataracts and diabetic cardiomyopathy. Excerpt(s): This invention relates to methods, pharmaceutical compositions and kits comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and a selective serotonin reuptake inhibitor (SSRI), a prodrug thereof or a pharmaceutically acceptable salt of said SSRI or said prodrug. This invention further relates to methods of using such pharmaceutical compositions for the treatment of diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, myocardial infarction, cataracts and diabetic cardiomyopathy. Aldose reductase inhibitors function by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses, such as glucose and galactose, to the corresponding polyols, such as sorbitol and galactitol, in humans and other animals. In this way, unwanted accumulations of galactitol in the lens of galactosemic subjects and of sorbitol in the lens, peripheral nervous cord and kidneys of various diabetic subjects are prevented or reduced. Accordingly, aldose reductase inhibitors are of therapeutic value for controlling certain diabetic complications, e.g., diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataracts and diabetic retinopathy. Selective serotonin reuptake inhibitors function by inhibiting the reuptake of serotonin by afferent neurons. Web site: http://www.delphion.com/details?pn=US06380200__
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Combination of gaba agonists and sorbitol dehydrogenase inhibitors Inventor(s): Mylari; Banavara L. (Waterford, CT) Assignee(s): Pfizer Inc (new York, Ny) Patent Number: 6,544,998 Date filed: November 29, 2001
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Abstract: This invention relates to pharmaceutical compositions comprising combinations of a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug and a SDI, a prodrug thereof or a pharmaceutically acceptable salt of said SDI or said prodrug, kits containing such combinations and methods of using such combinations to treat mammals, including humans, suffering from diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic microangiopathy, diabetic macroangiopathy, cataracts or foot ulcers. Excerpt(s): This invention relates to pharmaceutical combinations of a.gamma.aminobutyric acid (GABA) agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug and a sorbitol dehydrogenase inhibitor (SDI), a prodrug thereof or a pharmaceutically acceptable salt of said SDI or said prodrug, kits containing such combinations and methods of using such combinations to treat mammals, including humans, suffering from diabetic complications such as, inter alia, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic microangiopathy, diabetic macroangiopathy, cataracts or foot ulcers. This invention also relates to additive and synergistic combinations of a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug and a SDI, a prodrug thereof or a pharmaceutically acceptable salt of said SDI or said prodrug, whereby those additive and synergistic combinations are useful in treating mammals, including humans, suffering from diabetic complications such as, inter alia, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic microangiopathy, diabetic macroangiopathy, cataracts or foot ulcers. By gating negative chloride (Cl.sup.31) ions into the interior of cells, GABA inhibits the presynaptic release of neurotransmitter due to a positive voltage polarization pulse. Such inhibition is extremely common: GABA receptors can be found in 60-80% of central nervous system neurons. Subtypes of GABA receptors can be activated by the mushroom toxin muscimol (at GABA.sub.A) as well as the antispasmodic amino acid baclofen (GABA.sub.B). These compounds directly mimic the action of GABA at the receptor. Allosteric facilitation of GABA receptors occurs at several distinct sites; the compounds which bind there are used as sedatives and anxiolytics. Progabide is a prodrug which decomposes to GABA after crossing the blood/brain barrier into the central nervous system. Vigabatrin (gamma-vinyl-GABA) promotes binding of GABA by inhibiting GABA-aminotransferase (GABA-T), the enzyme responsible for degrading GABA in the synapse. S. Ao et al., Metabolism, 40, 7787 (1991) have shown that significant functional improvement in the nerves of diabetic rats (based on nerve conduction velocity) occurs when nerve fructose levels are pharmacologically lowered, and that such improvement correlates more closely with the lowering of nerve fructose than the lowering of nerve sorbitol. Similar results were reported by N. E. Cameron and M. A. Cotter, Diabetic Medicine, 8, Suppl. 1, 35A-36A (1991). In both of these cases, lowering of nerve fructose was achieved using relatively high does of aldose reductase inhibitors, which inhibit the formation of sorbitol, a precursor of fructose, from glucose via the enzyme aldose reductase. Web site: http://www.delphion.com/details?pn=US06544998__
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Dual chamber pacing system having time-adaptive AV delay Inventor(s): Heynen; Henri G. M. (Geleen, NL), Struble; Chester (Eijsden, NL) Assignee(s): Medtronic, Inc. (minneapolis, Mn) Patent Number: 6,507,756 Date filed: April 3, 2000 Abstract: Rate responsive pacing systems that employ a time-dependent AV delay in the pacing hearts in Congestive Heart Failure (CHF) with Dilated Cardiomyopathy (DCM) (a CHF/DCM heart) during a post-implant Time-Adaptive period are disclosed. A starting or initial AV delay is set to an intrinsic AV delay time interval exhibited by the patient's heart at the time of implant. A chronic AV delay is then set to a therapeutic AV delay time interval that is shorter than the intrinsic AV delay time interval and alleviates symptoms of the CHF/DCM heart. A Time-Adaptive AV delay (TA-AV delay) is employed during a post-implant Time-Adaptive period that gradually changes the initial AV delay to the chronic AV delay at the end of the post-implant Time-Adaptive period. Excerpt(s): The present invention relates to dual chamber pacing systems, including rate responsive pacing systems, and more particularly to the employment of a timedependent AV delay for pacing hearts in Congestive Heart Failure (CHF) with Dilated Cardiomyopathy (DCM). Dual chamber pacing systems operating in the multiprogrammable, DDD and DDDR pacing modes have been widely adopted in implantable dual chamber pacemakers and certain implantable cardioverter/defibrillators (ICDs) for providing atrial and ventricular (AV) synchronized pacing on demand. A DDD pacemaker implantable pulse generator (IPG) includes an atrial sense amplifier to detect atrial depolarizations or P-waves and generate an atrial sense event (A-EVENT) signal, a ventricular sense amplifier to detect ventricular depolarizations or R-waves and generate a ventricular sense event (VEVENT) signal, atrial and ventricular pacing pulse generators providing atrial and ventricular pacing (A-PACE and V-PACE) pulses, respectively, and an operating system governing pacing and sensing functions. If the atria fail to spontaneously beat within a pre-defined time interval (atrial escape interval), the pacemaker supplies an A-PACE pulse to the atria through an appropriate lead system. The IPG supplies a V-PACE pulse to the ventricles through an appropriate lead system at the time-out of an AV delay timed from a preceding A-EVENT or generation of an A-PACE pulse unless a nonrefractory V-EVENT is generated in response to an R-wave during the AV delay. Such AV synchronous pacemakers which perform this function have the capability of tracking the patient's natural sinus rhythm and preserving the hemodynamic contribution of the atrial contraction over a wide range of heart rates. The rate-adaptive DDDR pacing mode functions in the above-described manner but additionally provides rate modulation of a pacing escape interval between a programmable lower rate and an upper rate limit (URL) as a function of a physiologic signal or rate control parameter (RCP) developed by one or more physiologic sensors and related to the need for cardiac output. In the DDDR pacing mode, reliance on the intrinsic atrial heart rate is preferred if it is appropriately between the URL and the programmed lower rate. At times when the intrinsic atrial rate is inappropriately high, a variety of "mode switching" schemes for effecting switching between tracking modes and non-tracking modes (and a variety of transitional modes) based on the relationship between the atrial rate and the sensor derived pacing rate have been proposed as exemplified by commonly assigned U.S. Pat. No. 5,144,949, incorporated herein by reference in its entirety.
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Web site: http://www.delphion.com/details?pn=US06507756__ •
Effects of IFN-.gamma. on cardiac hypertrophy Inventor(s): Jin; Hongkui (San Bruno, CA), Lu; Hsienwie (Needham, MA), Paoni; Nicholas F. (Belmont, CA), Yang; Renhui (San Bruno, CA) Assignee(s): Genentech, Inc. (south San Francisco, Ca) Patent Number: 6,187,304 Date filed: March 19, 1999 Abstract: The invention concerns the treatment of cardiac hypertrophy by interferongamma (IFN-.gamma.). Cardiac hypertrophy may result from a variety of diverse pathologic conditions, including myocardial infarction, hypertension, hypertrophic cardiomyopathy, and valvular regurgitation. The treatment extends to all stages of the progression of cardiac hypertrophy, with or without structural damage of the heart muscle, regardless of the underlying cardiac disorder. Excerpt(s): The present invention relates generally to the effects of IFN-.gamma. on cardiac hypertrophy. More particularly, the invention concerns the use of IFN-.gamma. for the prevention and treatment of cardiac hypertrophy and associated pathological conditions. Interferons are relatively small, single-chain glycoproteins released by cells invaded by viruses or certain other substances. Interferons are presently grouped into three major classes, designated leukocyte interferon (interferon-alpha,.alpha.-interferon, IFN-.alpha.), fibroblast interferon (interferon-beta,.beta.-interferon, IFN-.beta.), and immune interferon-gamma,.gamma.-interferon, IFN-.gamma.). In response to viral infection, lymphocytes synthesize primarily.alpha.-interferon (along with a lesser amount of a distinct interferon species, commonly referred to as omega interferon), while infection of fibroblasts usually induces.beta.-interferon.alpha.- and.beta.interferons share about 20-30 percent amino acid sequence homology. The gene for human IFN-.beta. lacks introns, and encodes a protein possessing 29% amino acid sequence identity with human IFN-.alpha.I, suggesting that IFN-.alpha. and IFN-.beta. genes have evolved from a common ancestor (Taniguchi et al., Nature 285, 547-549 [1980]). By contrast, IFN-.gamma. is not induced by viral infection, but rather, is synthesized by lymphocytes in response to mitogens, and is scarcely related to the other two types of interferons in amino acid sequence. Interferons-.alpha. and -.beta. are known to induce MHC Class I antigens, while IFN-.gamma. induces MHC Class II antigen expression, and also increases the efficiency with which target cells present viral peptide in association with MHC Class I molecules for recognition by cytotoxic T cells. Interferon-.gamma., along with other cytokines, has been implicated as an inducer of inducible nitric oxide (iNOS) which, in turn, has been described as an important mediator of the inflammatory mechanism underlying heart failure, of the cardiac response to sepsis or allograft rejection, as well as of the progression of dilated cardiomyopathies of diverse etiologies. Ungureanu-Longrois et al., Circ. Res. 77, 494502 (1995); Pinsky et al., J. Clin. Invest. 95, 677-685 (1995); Singh et al., J. Biol. Chem. 270, 28471-8 (1995); Birks and Yacoub, Coronary Artery Disease 8, 389-402 (1997); Hattori et al., J. Mol. Cell. Cardiol. 29, 1585-92 (1997). Indeed, IFN-.gamma. has been reported to be the most potent single cytokine with regard to myocyte iNOS induction (Watkins et al., J. Mol. & Cell. Cardiol. 27, 2015-29 [1995]). Web site: http://www.delphion.com/details?pn=US06187304__
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Inhibitors of UDP-G1cNAc:Ga1.beta.1-3Ga1NAc.alpha.R.beta.1-6 Nacetylglucosaminyltransferase (core 2 G1cNAc-T) and use of the inhibitors to prevent or treat cardiomyopathy associated with diabetes Inventor(s): Dennis; James W. (c/o Mount Sinai Hospital, Toronto, Ontario, CA), King; George L. (101 Centre St., Dover, MA 02030), Koya; Daisuke (30 Matsunoki-cho, Shimogamo, Sakyo-Ku, Kyoto 606, JP), Nishio; Yoshihiko (9-12-601 Ichiriyama, Ohtsu, Shiga 520-21, JP), Warren; Charles E. (c/o Mount Sinai Hospital, Toronto, Ontario, CA) Assignee(s): None Reported Patent Number: 6,131,578 Date filed: October 2, 1997 Abstract: Cardiomyopathy associated with diabetes and hyperglycemia can be treated by administering to a subject suffering from this condition a substance that inhibits UDP-GlcNAc:Gal.beta.1-3GalNAc.alpha.R.beta.1-6-N-acetylglucosaminyl transferase (core 2 GlcNAc-T) activity. Excerpt(s): The invention relates to methods for preventing or treating cardiomyopathy associated with diabetes mellitus and hyperglycemia by inhibiting UDPGlcNAc:Gal.beta.1-3GalNAc.alpha.R.beta.1-6 N-acetylglucosaminyltransferase (core 2 GlcNAc-T); methods for screening for substances that affect cardiomyopathy associated with diabetes mellitus and hyperglycemia; and methods and pharmaceutical compositions containing the substances for preventing or treating cardiomyopathy associated with diabetes mellitus and hyperglycemia. Cardiovascular diseases are the major cause of morbidity and mortality in diabetic patients, involving cardiac tissues as well as large vessels in the brain, heart, and lower extremities (1). In the heart, the majority of the cardiac failure is probably due to atherosclerotic processes in the coronary vessels, but multiple studies have documented that a sizeable number of diabetic patients suffer from congestive heart failure without significant coronary disease (2, 3). In addition, type I diabetic patients with
