TACHYCARDIA A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES
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., 1960Tachycardia: 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: 0-597-84646-4 1. Tachycardia-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 tachycardia. 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 TACHYCARDIA .......................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Tachycardia ................................................................................... 7 E-Journals: PubMed Central ....................................................................................................... 65 The National Library of Medicine: PubMed ................................................................................ 68 CHAPTER 2. NUTRITION AND TACHYCARDIA .............................................................................. 115 Overview.................................................................................................................................... 115 Finding Nutrition Studies on Tachycardia................................................................................ 115 Federal Resources on Nutrition ................................................................................................. 118 Additional Web Resources ......................................................................................................... 119 CHAPTER 3. ALTERNATIVE MEDICINE AND TACHYCARDIA ........................................................ 121 Overview.................................................................................................................................... 121 National Center for Complementary and Alternative Medicine................................................ 121 Additional Web Resources ......................................................................................................... 129 General References ..................................................................................................................... 131 CHAPTER 4. DISSERTATIONS ON TACHYCARDIA .......................................................................... 133 Overview.................................................................................................................................... 133 Dissertations on Tachycardia..................................................................................................... 133 Keeping Current ........................................................................................................................ 133 CHAPTER 5. PATENTS ON TACHYCARDIA .................................................................................... 135 Overview.................................................................................................................................... 135 Patents on Tachycardia.............................................................................................................. 135 Patent Applications on Tachycardia .......................................................................................... 158 Keeping Current ........................................................................................................................ 190 CHAPTER 6. BOOKS ON TACHYCARDIA ........................................................................................ 191 Overview.................................................................................................................................... 191 Book Summaries: Online Booksellers......................................................................................... 191 Chapters on Tachycardia............................................................................................................ 192 CHAPTER 7. PERIODICALS AND NEWS ON TACHYCARDIA .......................................................... 193 Overview.................................................................................................................................... 193 News Services and Press Releases.............................................................................................. 193 Academic Periodicals covering Tachycardia .............................................................................. 195 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 197 Overview.................................................................................................................................... 197 U.S. Pharmacopeia..................................................................................................................... 197 Commercial Databases ............................................................................................................... 198 Researching Orphan Drugs ....................................................................................................... 198 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 203 Overview.................................................................................................................................... 203 NIH Guidelines.......................................................................................................................... 203 NIH Databases........................................................................................................................... 205 Other Commercial Databases..................................................................................................... 207 The Genome Project and Tachycardia........................................................................................ 207 APPENDIX B. PATIENT RESOURCES ............................................................................................... 213 Overview.................................................................................................................................... 213 Patient Guideline Sources.......................................................................................................... 213 Finding Associations.................................................................................................................. 236 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 239 Overview.................................................................................................................................... 239
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Preparation................................................................................................................................. 239 Finding a Local Medical Library................................................................................................ 239 Medical Libraries in the U.S. and Canada ................................................................................. 239 ONLINE GLOSSARIES................................................................................................................ 245 Online Dictionary Directories ................................................................................................... 245 TACHYCARDIA DICTIONARY ................................................................................................ 247 INDEX .............................................................................................................................................. 327
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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 tachycardia 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 tachycardia, 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 tachycardia, 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 tachycardia. 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 tachycardia, 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 tachycardia. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON TACHYCARDIA Overview In this chapter, we will show you how to locate peer-reviewed references and studies on tachycardia.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and tachycardia, 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 “tachycardia” (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: •
Dentoalveolar Abscess in a Pediatric Patient With Ketoacidosis Caused by Occult Diabetes Mellitus Source: Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontics. 88(2): 164-166. August 1999. Summary: Oral health professionals are frequently asked to evaluate patients with routine odontogenic infections (infections arising from the dentition and its supporting structures). These patients can sometimes present with systemic signs and symptoms, including fever, malaise, tachycardia (racing heartbeat), and dehydration. In this article, the authors present the case of a pediatric patient with a routine canine space infection who exhibited classic clinical signs and symptoms of diabetic ketoacidosis. Their report illustrates the importance of a comprehensive approach to patient evaluation and diagnosis in a case that might otherwise have been interpreted as a simple odontogenic
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infection. Clues to the patient's underlying systemic problem came from the history obtained from the parents. It is also critical in a patient with a severe odontogenic infection who appears ill and dehydrated that electrolyte levels and a complete blood count be obtained to evaluate the fluid status. Information regarding the severity of the infection should be gathered, and the possibility of a systemic disease such as diabetes should be ruled out. The author concludes that oral health professionals need to be aware of the signs and symptoms of common systemic diseases that may initially manifest themselves in connection with a dental oral complaint. 1 figure. 4 references. •
Life-Threatening Retroperitoneal Sepsis After Hemorrhoid Injection Sclerotherapy: Report of a Case Source: Diseases of the Colon and Rectum. 42(3): 421-423. March 1999. Contact: Available from Williams and Wilkins. 352 West Camden Street, Baltimore, MD 21201-2436. Summary: This article reports a case of life threatening retroperitoneal sepsis after injection sclerotherapy for first degree hemorrhoids. A 50 year old man with symptomatic first degree hemorrhoids was seen in the outpatient department. An experienced surgical registrar injected three internal hemorrhoids with 3 to 5 mL of 5 percent oily phenol. Four days later, the patient was admitted as an emergency, complaining of tight central chest pain. For 6 hours he had experienced chills and pelvic pain radiating to his lower abdomen and the backs of his thighs. Anorectal instrumentation was not attempted, because the patient was reporting severe pelvic pain. Investigation revealed leukocytosis, raised creatinine kinase, and electrocardiographic changes suggestive of anteroseptal myocardial infarction. Streptokinase, cefotaxime, and metronidazole were administered. Later that day, his pelvic pain worsened. He remained pyrexial (having a fever), developed tachycardia (rapid heartbeat), and went into urinary retention. Computed tomography revealed extensive retroperitoneal fluid but no localized abscess. Blood culture isolated gram negative bacilli, but exploratory laparotomy found no colonic lesion. The fecal stream was diverted with an end sigmoid colostomy and the rectal stump was oversewn. Hyperbaric oxygen, antibiotics, and intensive inotropic and ventilatory support were continued in the postoperative period. The patient eventually made a good recovery. The authors note that life threatening sepsis after injection sclerotherapy for hemorrhoids has been reported only once previously. One table summarizes the cases of life threatening complications after rubber band ligation of hemorrhoids. 1 table. 9 references.
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Colitis: Key Components of the Evaluation Source: Consultant. 38(2): 375-378, 381-383. February 1998. Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Box 4010, Greenwich, CT 06831-0010. Summary: This article reviews the key components of the evaluation of colitis. Colitis is a nonspecific condition that has a variety of causes, including inflammatory bowel disease, infections, ischemia, radiation, and antibiotic therapy. The mainstays of evaluating patients who have colitis include the history and physical examination, sigmoidoscopy with mucosal biopsy, stool examination, and barium radiography. These tools are used to determine if colitis is present, how severe it is, the cause of the colitis, and the anatomic extent of the disease. In addition to the typical symptoms of colitis (diarrhea, abdominal pain, and tenesmus), the authors recommend that physicians look
Studies
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for signs of more severe disease, such as orthostasis, pallor, fever, fatigue, and tachycardia. Also, physicians should be alert for extraintestinal manifestations of chronic inflammatory bowel disease (IBD), such as mouth ulcers, erythema nodosum, and arthritis. Laboratory findings that may suggest severe colitis include a low hemoglobin level, leukocytosis, an elevated erythrocyte sedimentation rate, and hypoalbuminemia. After confirming the presence of colitis with proctosigmoidoscopy or flexible sigmoidoscopy, stool cultures and parasite testing should be ordered to identify the specific cause. Complications of colitis include toxic megacolon, perforation, hemorrhage, and obstruction in ischemic disease. 4 figures. 3 tables. 16 references. (AAM). •
Refeeding the Malnourished Patient (editorial) Source: Current Opinion in Gastroenterology. 15(2): 151-153. March 1999. Contact: Available from Lippincott Williams and Wilkins Publishers. 12107 Insurance Way, Hagerstown, MD 21740. (800) 637-3030. Fax (301) 824-7390. Summary: This editorial review article addresses refeeding of the severely malnourished patient, a technique that is necessary to reverse the adverse effects of malnutrition and to prevent death from starvation. The goal in refeeding such patients is to inhibit the mobilization of endogenous fuels, using ingested or infused nutrients to meet the body's nutritional requirements and to rebuild lost nutrient stores. The author cautions that, because of the structural, functional, and metabolic alterations caused by previously inadequate food intake, injudicious nutritional therapy can have adverse clinical consequences. Cardiovascular complications related to impaired muscle function are characteristic of the refeeding syndrome. The most worrisome electrolyte abnormality is hypophosphatemia, which can cause acute respiratory failure, arterial hypotension, tachycardia, and death. The author offers clinical recommendations, stating that it is important to be particularly cautious in providing nutritional therapy to cachectic, chronically semistarved patients to avoid complications during refeeding. Daily monitoring of body weight, fluid intake, urine output, and plasma glucose and electrolyte values is critical during early refeeding, because the risk of complications is greatest during the first week of therapy. 33 references (5 annotated).
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Treatment of Acute Porphyria Source: Hospital Medicine. 62(7): 422-425. July 2001. Summary: This journal article provides health professionals with information on the treatment of acute porphyria. Acute attacks are often triggered by drugs, hormones, alcohol, or calorie restriction. They are more common in women and usually first occur between the ages of 15 and 40 years. As soon as an acute attack is suspected, any drugs or other potential triggers should be withdrawn and appropriate supportive treatments started using drugs that are safe in acute porphyria. Opiates are the most effective analgesics for treating an acute attack. Hyponatremia is common, so careful management of intravenous fluids, with electrolyte measurement at least twice daily and avoidance of hypotonic solutions whenever possible, is important. Cardiovascular complications such as hypertension and tachycardia are rarely sufficiently severe to require therapy. Impaired nutrition may aggravate porphyria, so adequate calorie intake is also important. Attacks of acute porphyria are associated with increased activity of hepatic 5-aminolevulinate (ALA) synthase, overproduction of ALA, and relative haem (heme) deficiency. Carbohydrate loading and parenteral administration of haem (heme) are two procedures that have been used successfully for the specific treatment of attacks
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of acute porphyria. Carbohydrate loading with 2 liters of 20 percent glucose over 24 hours in divided doses of 500 milliliters was the recommended regimen for treating an acute attack prior to the introduction of hem. The introduction of haem (heme) arginate has substantially improved the treatment of acute attacks of porphyria. Haem (heme) arginate should be administered as soon as the diagnosis is established, preferably within 48 hours of symptom onset. Haem (heme) arginate has a greater metabolic effect and leads to a better clinical outcome than carbohydrate loading. In addition, it is easier to administer, avoids the danger of water overload, and has very few adverse effects. The article concludes that haem (heme) arginate should replace glucose loading as the specific treatment for acute porphyria. 3 tables and 18 references. •
Cardiovascular Autonomic Neuropathy: Clinical Manifestations and Measurement Source: Diabetes Reviews. 7(4): 342-357. 1999. Contact: Available from American Diabetes Association, Inc. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Summary: This review article provides information on the epidemiology, pathogenesis, clinical manifestations, measurement, and outcome of cardiovascular autonomic neuropathy (CAN). Several prospective studies have demonstrated an increased mortality among diabetic patients who have CAN. The overall mortality rates over periods up to 10 years were approximately 27 percent in diabetic patients with CAN detected by reduced heart rate variability (HRV) compared with 5 percent in those without evidence of CAN. However, reduced HRV is an independent indicator of poor prognosis in the absence of diabetes, as a consequence of common cardiovascular diseases such as coronary artery disease, myocardial infarction, and heart failure. Besides reduced HRV, the clinical manifestations of CAN include fixed heart rate, increased resting heart rate, sinus tachycardia, orthostatic hypotension with systolic blood pressure fall 30 mm Hg or greater, possibly increased susceptibility to silent myocardial ischemia or infarction, reduced circadian rhythm of heart rate and blood pressure, abnormal hormonal regulation to standing and exercise, antibodies to autonomic tissue, denervation hypersensitivity to alpha and beta adrenergic agonists, inadequate increase in heart rate or blood pressure to exercise, reduced left ventricular diastolic filling or ejection fraction, intraoperative cardiovascular instability, corrected QT interval prolongation, and increased QT dispersion. Sensitive and early assessment of CAN is currently possible by means of noninvasive autonomic function tests (AFTs), including time domain and frequency domain indices of HRV, aiming at prevention of the advanced stages. However, a generally accepted standardization of the various test procedures is needed. Despite this problem, it is estimated that CAN can be detected by abnormal AFTs in at least one fourth to one third of people who have type 2 diabetes. In some cases, autonomic dysfunction may be present at the time of manifestation of both type 1 and type 2 diabetes. There is increasing evidence suggesting that the statistical, geometric, frequency domain, and nonlinear measures of 24 hour HRV could be more sensitive and reliable in detecting CAN when compared with AFTs. Moreover, 24 hour recording of HRV provides insights into abnormal patterns of circadian rhythms modulated by sympathovagal activity. Recent studies using cardiac radionuclide imaging techniques have quantified myocardial adrenergic dysinnervation by diminished uptake of the norepinephrine analogs [123I]metaiodobenzylguanidine or [11C]hydroxyephedrine. These methods provide a unique and sensitive tool for direct assessment of the pathophysiology and progression of early sympathetic innervation defects not accessible to indirect autonomic function testing. The prognostic significance of these defects and that of reduced measures of 24 hour HRV in CAN need to be
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determined in large scale prospective clinical trials. 2 figures. 3 tables. 107 references. (AA-M). •
Ulcerative Colitis: A Rational Approach to Management Source: Consultant. 41(4): 541-548. April 1, 2001. Contact: Available from Cliggott Publishing Company. 330 Boston Post Road, Darien, CT 06820-4027. (203) 661-0600. Summary: Ulcerative colitis (UC), a type of inflammatory bowel disease can manifest as proctitis or proctosigmoiditis, left sided colitoss, or pancolitis. This article offers a rational approach to the management of patients with UC. Frequent low volume bowel movements, urgency, rectal bleeding, and tenesmus (ineffective spasms of the rectum) alone suggest proctitis. Prostration, fever, tachycardia (racing heartbeat), dehydration, and complications of blood loss (which may or may not be accompanied by symptoms of proctitis) suggest more severe disease or more extensive bowel involvement. For patients with mild to moderate disease, mesalamine is recommended to induce and maintain remission. Systemic corticosteroids can induce remission in patients with moderate to severe disease but are not useful for maintenance therapy. Azathioprine or 6 mercaptopurine can be used to wean patients with moderate to severe colitis from corticosteroids and to maintain remission. If severe colitis does not respond to corticosteroids, immunosuppressive therapy or colectomy may be needed. Other indications for surgery include development of acute complications related to disease activity and chronic complications, such as dysplasia, carcinoma, recurrent hemorrhage, or growth retardation in children. Annual surveillance colonoscopy with biopsy is recommended for patients with pancolitis and left sided colitis.
Federally Funded Research on Tachycardia The U.S. Government supports a variety of research studies relating to tachycardia. 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 tachycardia. 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 tachycardia. The following is typical of the type of information found when searching the CRISP database for tachycardia:
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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).
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Project Title: ADENOSINE & KATP CHANNEL CONTROL OF CORONARY BLOOD FLOW Principal Investigator & Institution: Feigl, Eric O.; Professor; Physiology and Biophysics; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 25-MAY-1993; Project End 30-APR-2006 Summary: (provided by applicant): When heart rate increases (as occurs during exercise), coronary blood flow must increase to provide oxygen to the heart to support the augmented myocardial oxygen consumption. The purpose of the proposed research is to discover the essential physiological mechanisms that couple coronary blood flow to myocardial oxygen consumption. Without these mechanisms, the heart becomes ischemic and dies. A new hypothesis, with supporting data, is presented where ATP released from red blood cells in the coronary circulation acts as the mediator of local metabolic coronary vasodilation. A plan is presented to quantitatively test the ATP hypothesis during tachycardia and exercise with a combination of ATP measurements and ATP-receptor blockade. The hypothesis that endothelin vasoconstriction in the outer layers of the left ventricle helps sustain blood flow to the vulnerable inner layers during exercise will be tested with measurements of plasma endothelin levels and endothelin receptor-blocking agents. The postulated role of P-450 enzymes acting on arachidonic acid in the heart to produce extremely powerful coronary vasodilator compounds called EETs and DHETs will be tested with measurements of these compounds and selective blocking agents. The proposed basic research is fundamental to understanding the normal coronary physiology that underlies coronary artery disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: AGE, HYPOTENSIO
EXERCISE,
THERMOGENESIS
AND
POSTPRANDIAL
Principal Investigator & Institution: Seals, Douglas R.; Professor; Integrative Physiology; University of Colorado at Boulder Boulder, Co 80309 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2005 Summary: In young adult humans, acute energy intake (feeding) evokes an integrative "postprandial" physiological response which includes an increase in metabolic rate (thermic effect of food intake--TEF) and a number of autonomic nervous system (ANS) and cardiovascular adjustments aimed at providing increased blood flow for digestion (splanchnic vasodilation) while maintaining arterial blood pressure (BP) at preprandial levels. Some older adults with chronic diseases demonstrate a reduced TEF and/or a postprandial fall in BP ("postprandial hypotension"), but it is unknown whether this occurs with age in healthy adults. If the latter is true, some evidence suggests that these changes may not occur with age in adult humans who exercise regularly. The specific aims of the present proposal are to determine if: (1) TEF is lower and postprandial BP declines occur in middle-aged and/or older sedentary adults compared with young adult controls; (2) the lower TEF is due to attenuated postprandial increases in sympathetic nervous system (SNS) activity associated with reduced CNS sympathoexcitatory responsiveness to acute hyperinsulinemia; (3) the postprandial hypotension also is associated with: a) an attenuated or absent whole-limb and skeletal muscle vasoconstriction; b) a smaller reduction in cardiac vagal modulation of heart rate and an attenuated tachycardia; and c) a lower baseline cardiac vagal tone and arterial baroreflex sensitivity; (4) middle-aged and older adults who exercise regularly do not demonstrate the lower TEF and postprandial hypotension observed with age in
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sedentary humans, and whether this is associated with augmented SNS responses, CNS sympathetic responsiveness to circulating insulin, limb vasoconstriction, vagallymediated tachycardia, baseline cardiac vagal tone and baroreflex sensitivity; and (5) the reduced TEF and postprandial hypotension associated with sedentary aging are related to elevated adiposity. Because TEF contributes significantly to daily energy expenditure and, therefore, energy balance, the expected results should provide new and clinically important information concerning the effects of sedentary aging, regular exercise and adiposity on TEF in the context of age-related obesity and its metabolic and cardiovascular co-morbidities. Moreover, postprandial hypotension is associated with post-meal dizziness, weakness, syncope, cerebrovascular ischemia, and angina pectoris. As such, the expected results should provide new insight into the effects of sedentary aging, habitual exercise and body fatness on this clinically-important cardiovascular disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AIRWAY SENSORY NERVES AND DYSPNEA IN HUMAN SUBJECTS Principal Investigator & Institution: Burki, Nausherwan K.; Professor of Medicine; Medicine; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-DEC-2004 Summary: (provided by applicant): Dyspnea, an unpleasant sensation of difficulty in breathing, is a common symptom in patients with cardiopulmonary diseases, but the underlying mechanisms are unclear. Amongst the various neural pathways, unmyelinated vagal C fibers arising from the lungs and airways have been implicated. The long-term objectives are to increase understanding of the mechanisms of dyspnea and specifically the role of pulmonary C fibers. Adenosine is a commonly used therapeutic intravenous drug for treatment of supraventricular tachycardia; it has been frequently reported to cause dyspnea. Recent studies from our laboratory reported the first evidence showing that adenosine stimulates pulmonary C fiber receptors in anesthetized rats. Preliminary human studies from our laboratory indicate that intravenous adenosine causes dyspnea and increase ventilation, and neither affect is associated with bronchoconstriction. Adenosine is known to increase ventilation by stimulating the carotid body chemoreceptors; such reflex stimulation would increase central motor command and could lead to the development of dyspnea. Our hypothesis is that adenosine causes dyspnea by direct activation of pulmonary C fiber, and it is not an indirect effect related to the increase in ventilation. The specific aims of the proposed study are: 1) to determine the latency and magnitude of dyspneic response, change in airway resistance, and ventilatory response to intravenous injection of adenosine in normal subjects and stable asthmatics; 2) to evaluate the effects of pretreatment with theophylline, and adenosine receptor antagonist, on the intensity of dyspnea and the ventilatory effects of intravenous adenosine; 3) to examine whether directly blocking pulmonary C fibers with inhaled lidocaine abolishes the sensation of dyspnea induced by adenosine in these subjects/patients; 4) to investigate if pretreatment with 100 percent O2, by reducing carotid chemoreceptor sensitivity, alters the dyspnogenic and ventilatory effects of intravenous adenosine. These studies should bring a better understanding of the underlying mechanism of adenosine-induced dyspnea and the role of bronchopulmonary C fibers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ANATOMICAL REMODELING AND ELECTRICAL CONDUCTION IN HEART 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 30-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): The fiber structure of the heart plays a critical role in shaping electrical propagation. Conduction is influenced by tissue geometric factors such as expansion and contraction, and is anisotropic, with current spread being most rapid in the direction of the fiber long axis. Spatial rate of change of fiber orientation also influences conduction properties. Remodeling of ventricular geometry and fiber organization, including development of interstitial fibrosis, is a prominent feature of several cardiac pathologies, and these alterations may figure importantly in arrhythmogenesis. A detailed knowledge of ventricular fiber structure, how it may be remodeled in cardiac pathology, and the effects of this remodeling on ventricular conduction is therefore of fundamental importance to the understanding of cardiac electro-mechanics in health and disease. We will investigate how anatomical remodeling of ventricular fiber structure influences ventricular conduction, using the canine tachycardia pacing-induced heart failure preparation as a model system. Several aims must be accomplished to do this. First, we will develop MR imaging methods for the rapid reconstruction of ventricular fiber structure. Second, we will use these methods to measure fiber structure in populations of normal and failing hearts. Third, we will develop mathematical methods for identifying statistically significant changes in fiber structure between normal and failing hearts. Fourth, we will measure electrical activation patterns in each heart that is anatomically reconstructed using MR imaging methods. Fifth, we will relate measured changes in fiber structure to measured changes of electrical propagation in each heart using both experimental approaches as well as computational models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ANTIARRHYTHMIC EFFECTS OF N-3 FATTY ACIDS Principal Investigator & Institution: Mcanulty, John H.; Professor and Head; Medicine; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-FEB-1999; Project End 31-JAN-2004 Summary: Ventricular tachycardia (VT) and ventricular fibrillation (VF) are common causes of the 300,000 sudden deaths occurring in the United States each year. Most of these victims have associated heart disease, most commonly coronary artery disease. Populations consuming considerable quantities of fish and marine mammals have lower than expected mortality rates from coronary disease. Interventional and observational trials have indicated that fatty fish consumption decreases the death rate from coronary artery disease, in part by reducing the number of sudden deaths. Animal and tissue culture studies both support the hypothesis that these beneficial effects are from the anti-arrhythmic properties of n-3 long chained polyunsaturated fatty acids (eicosapentaenoic and docosahexaenoic acids). In this prospective, randomized double blinded trial, survivors of VT and VF with an implantable defibrillator will be randomized to supplementation with these n-3 polyunsaturated fatty acids or with a placebo. Adherence to the supplement will be assessed by measurements of plasma, red cell, and adipose tissue n-3 fatty acid concentrations. The primary outcome variable will be the incidence of recurrent VT or VF, but secondary variables will also be assessed using serial ICD assessment, correlation of the rhythms with the biochemical
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measurements of n-3 fatty acids, hospitalization rates and quality of life. The ICD is the best protection available to patients and can store rhythm electrograms which will allow documentation of rhythm endpoints. If the dietary supplementation with n-3 fatty acids demonstrates a reduction of VT and VF in humans at high risk, this would be a stimulus to apply this inexpensive and safe form of treatment to the large populations who are at increased risk of sudden death. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ATRIONODAL BUNDLES:HISTOLOGIC AND PHYSIOLOGIC VALIDATION Principal Investigator & Institution: Racker, Darlene K.; Medicine; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2006 Summary: (provided by applicant): Radiofrequency (RF) catheter ablation of either the "slow" or "fast" AV nodal pathways can cure AV node reentrant tachycardia (AVNRT) and also modify ventricular response to atrial flutter and fibrillation. However, neither the tissues nor mechanisms underlying these arrhythmias are known. Recently, we demonstrated that two separate atrial circuits overlap in the AV junction region: components of the "muscular valvular apparatus", the "circumferential and the perpendicular laminae," which also form the inferior medial atrial wall; and, the collagen encased "multilimb input" to the AVN: the "atrionodal bundles (ABs) and the proximal AV bundle (PAVB)," which is outside of the medial atrial wall epicardium. We showed that each tissue possess unique extracellular (EAP) and transmembrane action potentials (TAP) and transmission properties; EAPs from the atrial and specialized tissues appear side-by-side in traces made at sites where the atrial and specialized tissues overlap; and atrial EAPs and contractions ceased with exposure to high potassium. HYPOTHESIS: A specialized multilimb AVN input with unique histologic and conduction properties is present in human and dog heart. SPECIFIC AIMS are to determine: 1) the position of the ABs and the PAVB in human heart; 2) the myocyte evoking the AB potential and its electrical pathway after iontophoresis of Lucifer Yellow (LY); 3) transmission properties of the ABs during program stimulation of the ABs and SAN by evalulation of the SAN-AB intervals; 4) each ABs role in AVN activation by alterations in the SAN-AVN interval due either to selective ablation of LY-fiUed myofibers or to transection of the AB/PAVB junctions. METHODS: Electrical potentials will be recorded using simultaneous (a) stationary catheter electrodes at the SAN, 3ABs, PAVB, and AVN to monitor electrical coupling, (b) wire electrodes to localize injection and recording sites, responses to photoablation, (c) multielctrode array plaque, (d) 1 percent LY or 3M KCI miropipet electrodes for recording and dye injection using current pulses. Ablations will be made using blue light and scalpel blades. The anatomy, LY pathways, and effects of photoloysis will be evaluated by 3D analysis and reconstructions. Alterations in morphology of electrical potentials, and conduction intervals will be confirmed via timing in the SAN trace and correlation of EAPs and TAPs. These studies are expected to provide a basis for evaluating transmission, arrhythmogenesis, and drug interactions at the tissue level. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CA+2 AND NA+ TRANSPORT AND ARRHYTHMIAS IN HEART FAILURE Principal Investigator & Institution: Bers, Donald M.; Professor and Chairman; Physiology; Loyola University Medical Center Lewis Towers, 13Th Fl Chicago, Il 60611
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Tachycardia
Timing: Fiscal Year 2002; Project Start 05-JUL-2000; Project End 30-JUN-2004 Summary: The goal of these studies is to define the role of altered Ca and Na transport in the development of ventricular tachycardia (VT) in heart failure (HF). We have recently shown that VT in the failing rabbit & human heart initiates by a nonreentrant" mechanism that may be due to triggered activity from delayed afterdepolarizations (DADs) (or early afterdepolarizations, EADs). We also find upregulation of Na/Ca exchange (NaCaX) mRNA, protein and current in HF which could underlie the transient inward current (I-ti) responsible for DADs. We hypothesize that in HF, prolongation of the action potential duration (APD) and increased [Na]1 (due to decreased Na/K ATPase activity) contribute to SR Ca overload and spontaneous SR Ca release. Further, a given SR Ca release in HF will produce greater I-ti (due to increased NaCaX) and larger DADs (due to increased I-ti and reduced 1-K1), resulting in more triggered APs and nonreentrant arrhythmias in HF. Specific Aims will focus on: l. The role of altered APD & ionic currents on both SR Ca load and DAD induction in HF. 2. The alterations in intracellular [Na] and Na/K-ATPase activity & expression in HF. 3. The relationship of SR Ca release to the genesis of arrhythmogenic I- ti's, DADs and triggered APs. 4. The possible contribution of spontaneous SR Ca release to EADs in HF. 5. The effects of blocking Ca influx via NaCaX (with KB-R7943) on E-C coupling, on prevention of I-ti and DADs in myocytes, and on prevention of VT in the intact failing heart in situ. The experimental approaches will include: in vitro patch clamping (voltage, AP & current clamp); fluorescence measurements of [Ca]i and [Na]i; measurement of mRNA & protein (of Ca transporters & Na/K ATPase subunit isoforms) and Na/K ATPase activity; and 3-dimensional cardiac mapping in vivo. Detailed studies in a novel arrhythmogenic rabbit model of nonischemic HF will be extended to include studies in isolated ventricular myocytes from failing and nonfailing human hearts. The results of these studies will provide the foundation for the development of effective therapeutic approaches to modulate nonreentrant initiation of VT and to decrease the high incidence of sudden death in patients with heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CA2+-MEDIATED MECHANISMS OF ATRIAL PACEMAKER ACTIVITY Principal Investigator & Institution: Lipsius, Stephen L.; Physiology; Loyola University Medical Center Lewis Towers, 13Th Fl Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 01-JUL-2000; Project End 30-JUN-2005 Summary: (adapted from the applicant's description): The long-range goal of the applicant is to understand the physiological mechanisms that determine and regulate atrial pacemaker activity, particularly with respect to latent atrial pacemakers and their contribution to atrial dysfunction. Latent atrial pacemakers are specialized cells localized in specific regions of the right atrium outside of the SA node region. They are thought to participate in a wide variety of atrial arrhythmias including brady-tachy syndrome, atrial tachycardia, supraventricular tachycardia and atrial fibrillation. Although of major clinical importance, the cellular mechanisms underlying latent atrial pacemaker activity are not well understood. Preliminary results by the applicant indicate that latent atrial pacemaker activity is regulated by bursting of local intracellular Ca2+ release, i.e., Ca2+ sparks, from the sarcoplasmic reticulum (SR) specifically during the late phase of diastolic depolarization. The mechanisms governing diastolic release of SR Ca2+ in atrial pacemaker cells is not clear. Whole-cell (perforated & ruptured patch) recording methods and measurements of intracellular Ca2+ concentration ((Ca)i) using laser scanning confocal microscopy will be used to determine
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the mechanism governing diastolic SR Ca2+ release in latent atrial and SA node pacemaker cells isolated from cat right atrium. The following hypotheses will be tested: 1) voltage-dependent activation of T-type Ca2+ current (ICa,T) during the late diastolic slope triggers SR Ca2+ release which in turn stimulates inward Na/Ca exchange current to depolarize the membrane to threshold, 2) both acetylcholine and norepinephrine regulate diastolic SR Ca2+ release triggered by ICa,T and thereby regulate atrial pacemaker activity, 3) by elevating (Ca)i, cardiac glycosides and low extracellular (K) enhance this normal mechanism of atrial pacemaker automaticity, and thereby elicit atrial dysrhythmias not dependent on Ca2+ overload of the SR, 4) low temperature inhibits atrial pacemaker activity by inhibiting diastolic SR Ca2+ release triggered by ICa,T, and 4) transitional atrial pacemaker cells lack diastolic time-dependent currents and therefore depend primarily on SR Ca2+ release triggered by ICa,T for their pacemaker mechanism. It is expected that the results gained from these studies will provide fundamental insight into the cellular mechanisms governing normal and abnormal atrial pacemaker function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CALCIUM IONS: AN INSIGHT TO CARDIAC FIBRILLATION Principal Investigator & Institution: Attin, Mina; None; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-MAY-2002 Summary: (provided by applicant): The objective of this proposal is to investigate the role of calcium (Ca) ions in initiation and maintenance of ventricular fibrillation (VF). This study will provide insight to scientists and clinicians about the mechanism of VF that leads to sudden cardiac death (SCD). Understanding the mechanism of VF is essential for developing new therapies and nursing interventions to prevent and to decrease the incidence of SCD. The specific aims of this study are to: 1) measure intracellular membrane potential while recording the Ca transients; 2) determine the extent to which intracellular membrane potential and the Ca transients are correlated; 3) analyze the spatial distance between membrane potential and the Ca transients, and 4) develop an optical mapping system to permit simultaneous mapping of membrane potential and Ca transients. This study will use the right ventricle (RV) of nine swine during four modes of pacing including regular, incremental, irregular and rapid pacing resembling the rate of ventricular tachycardia and VF. Action potential duration restitution and Ca transients restitution will be constructed for each pacing modes. Pharmacological agents will be given, the effects will be documented and then the agents will be washed out and the effects will be documented again. At each stage of the study, electrical recording will be taken and optical mapping will be performed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CARDIAC CONNEXINS IN IMPULSE PROPAGATION AND ARRHYTHMIAS Principal Investigator & Institution: Jalife, Jose; Professor of Pharmacology; Upstate Medical University Research Administration Syracuse, Ny 13210 Timing: Fiscal Year 2002 Summary: Intercellular communication is essential for normal cardiac impulse propagation. It is thought to be mediated by gap junction channels. Three gap junction proteins, known as connexins (Cxs), are expressed in the heart; these are Cx40, Cx43 and Cx45. However, the specific role of the individual connexins in normal and abnormal
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propagation is unknown. The recent development of connexin knockout mice now makes such knowledge possible. Our overall objective is to investigate the electrophysiological consequences of the absence of specific gap junction channels on impulse propagation in mice lacking either Cx43 or Cx40. We will combine electrocardiographic, microelectrode and patch- clamping techniques, with highresolution microscopic and macroscopic optical recordings of potentiometric dye fluorescence, to measure relevant electrophysiological parameters, which may be affected by Cx43 and Cx40 null mutation. Our Specific Aims are 1. To determine the electrophysiological consequences and pro-arrhythmic effects of reduced intercellular coupling in the ventricles of neonatal homozygote and heterozygote Cx43 knockout mice. We hypothesize that the lack of Cx43 results in a reduction of intercellular communication leading to discontinuous conduction, with an increase in the variability of local conduction times during both sinus rhythm and pacing. Moreover, we surmise that impulse blockade in the homozygote mice will occur preferentially in the direction transverse to fiber orientation and at much slower frequencies than in wildtype or heterozygous mice. 2. To determine the role of Cx40 in impulse propagation in the specialized conducting system, and ventricles of the adult mouse heart. Our hypothesis here is that the null mutation of Cx40 decreases intercellular communication in the specialized conduction system and slows Purkinje fiber conduction velocity, leading to an apparent bundle branch block configuration in the electrocardiogram, and facilitating the induction of reentrant arrhythmias. Further, because of source-sink relationships, we expect that conduction block is more likely to occur at branch points and the Purkinjemuscle than along the Purkinje bundles. 3. To determine the effects of Cx40 null mutation on sinus rhythm and impulse propagation in the atria of the adult mouse heart. Cx40 is expressed in both atria and the sinus node of the mouse. It has been shown that the lack of Cx40 results in P wave prolongation and atrial tachyarrhythmias, including fibrillation. However, in the absence of such arrhythmias, RR interval is unaffected in Cx40-/- mice. We postulate that Cx40 plays a crucial role in intercellular communication in the atria and helps maintain normal intraatrial conduction, but is not essential for synchronized pacemaker discharge in the sinus node. We propose also that the reduction in intercellular communication within the atria of the CX40 knockout mouse is accompanied by an increased susceptibility to reentrant arrhythmias. Overall, the studies proposed are highly significant in that they will provide definite proof or refutation to long-held assumptions regarding the fundamental role of connexins in cardiac electrophysiology and arrhythmias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CARDIAC IMPULSE INITIATION AND REPOLARIZATION Principal Investigator & Institution: Rosen, Michael R.; Gustavus A. Pfeiffer Professor of Pharma; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002 Summary: The general hypothesis for this Project is that sympathetic innervation contributes importantly to the changes in ion channels that occur developmentally and to the evolution of specific receptor-effector pathways. We hypothesize as well that in the setting of incomplete sympathetic innervation abnormalities of specific ion channels and signal transduction pathways set the stage for lethal arrhythmias. This hypothesis derives from our earlier work on both beta-and alpha-adrenergic signaling and developmental changes in electrophysiology in the normal canine, rat and rabbit heart. We now focus on two canine models of disordered innervation: (a) surgical interruption of the sympathetic nerves to the heart in the first 24 hours of life, and (b) familial failure
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of innervation to a portion of the anteroseptal left ventricle in Germ Shepherd Dogs. Important, surgical right stellectomy and thoracic sympathectomy is characterized by asystolic sudden death in the first weeks of life; whereas the familial failure of innervation results in ventricular tachycardia and sudden death at 4-5 months of life. We perform intact animal, isolated tissue and single myocyte experiments to study the electrophysiology (focussing on repolarization and impulse initiation), ionic currents (focussing initially on I/ks and I/kr), signal transduction (focussing on beta-receptors, G proteins and adenylate cyclase) and molecular physiology (focusing initially on mRNA for canine ERG and on KvLQT1 and minK), with a view towards working vertically from the ECG of the intact animal through the molecular mechanisms responsible for arrhythmic events. Moreover, in cooperation with all other Projects on the Program, we shall achieve an understanding of the relationship between nerve-myocyte interaction, evolution of signaling processes and evolution of electrophysiologic control mechanisms. The significance of the proposed research is that it not only utilizes multiple approaches in an attempt to understand the control of rhythm and arrhythmias in the proposed models, but the models, themselves, incorporate features important clinically, in that they are relevant to pause-dependent tachycardias, those triggered by delayed after depolarizations, and to catecholamine-or exercise-dependent tachycardias that tend to afflict otherwise healthy young individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CARDIOVASCULAR DISEASE MECHANISMS IN SLEEP APNEA Principal Investigator & Institution: Somers, Virend K.; Professor; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 29-FEB-2004 Summary: Obstructive sleep apnea is emerging as an important risk factor for hypertension, heart failure, and ischemic heart disease. The mechanisms linking obstructive sleep apnea to cardiac and vascular disease are poorly understood. Utilizing recent developments in neural circulatory control and in vascular biology, we have acquired exciting preliminary data that promise mechanistic insight into the association between sleep apnea and cardiovascular disease. These data suggest that patients with sleep apnea have: 1) increased sympathetic neural traffic, tachycardia, and marked impairment of heart rate and blood pressure variability; 2) impaired endothelial vasodilator function; 3) dramatic overnight increases in endothelin and cytokines, with reductions in both after acute continuous positive airway pressure (CPAP) therapy; and 4) a reduction in blood pressure and sympathetic drive after long-term CPAP therapy. These interesting findings have led us to propose the overall hypothesis that obstructive sleep apnea is associated with neural, vasoactive and inflammatory abnormalities, which may be implicated in cardiovascular dysfunction, and that these abnormalities are attenuated by long-term therapy with CPAP. We will test the following specific hypotheses: 1) That patients with sleep apnea have impaired neural mechanisms regulating circulatory control. 2) That patients with sleep apnea have impaired endothelial function, and increased production of endothelin, cytokines and leukocyte adhesion molecules. 3) That long term effective therapy with CPAP improves cardiovascular function by attenuation of these abnormalities in neural, vasoactive and inflammatory mechanisms. An important and novel strength of these studies is that the integrity of the hypotheses will be tested with careful exclusion of potential confounding variables such as obesity, hypertension, left ventricular dysfunction, exercise capacity and impaired glucose tolerance. This proposal builds on our broad experience in studies of both sleep apnea and neural circulatory control, and should
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contribute to the understanding and treatment of cardiac and vascular disease in patients with obstructive sleep apnea. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHAOS AND CARDIAC ARRHYTHMIAS Principal Investigator & Institution: Garfinkel, Alan J.; Associate Professor; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002 Summary: Multiple circulating wavefronts in an excitable medium produced by computer simulations are an example of spatio-temporal chaos. Their close similarity to experimentally-recorded activation patterns during atrial or ventricular fibrillation suggest that fibrillation may also be a form of spatio-temporal chaos, and raises the possibility that recently-developed chaos control strategies can be applied to fibrillation. We have previously shown that a pacing algorithm based on chaos control theory could successfully regularize a chaotic ventricular tachycardia induced by ouabain in isolated rabbit ventricle. The major objective of this project is to determine whether a similar strategy can be developed for ventricular fibrillation. We have modified the van Capelle & Durrer computer model of propagation in a two-dimensional excitable lattice, and have shown that multiple circulating wavefronts (spiral waves) simulating fibrillation can be induced. Local site recordings show clear evidence of chaotic behavior, and exhibit the dynamic features (fixed point and stable and unstable manifolds) necessary to apply the OGY chaos control method, which we successfully applied to the chaotic ouabain-induced arrhythmia. The model closely simulates the behavior of circulating reentrant wavefronts in the in vitro canine epicardial slice preparation described in Project 2, which also shows evidence of chaos at local recording sites. Criteria for detecting spatio-temporal chaos at individual elements in the lattice (equivalent to the information that could be obtained from a local intracardiac electrogram) will be developed in the van Capelle & Durrer model, and this information used develop a perturbation strategy based on chaos control theory (analogous to pacing at a one or more sites in the lattice) to determine whether local and global chaos control can be achieved. The results of computer simulations will be directly validated experimentally using the in vitro canine epicardial slice preparation and, if successful, adapted to the in vivo fibrillating canine heart. A second objective of the project is to further understand and improve the chaos control pacing algorithm which we have previously successfully applied to ouabain-induced ventricular tachycardia in the rabbit interventricular septum, a less spatially complex chaotic cardiac arrhythmia. Using high resolution activation mapping with extracellular electrodes, the ouabain-induced arrhythmia will be mapped to evaluate its mechanism and spatial properties, and to gain insight into the mechanism by which the chaos control pacing algorithm is effective. Improvements to our current chaos control algorithm will be further developed and tested in the septal preparation. These improvements to the chaos control pacing algorithm in the ouabaininduced arrhythmia will be essential for chaos control pacing algorithms designed for fibrillation. Ultimately, the goal is to develop an intelligent pacing strategy based on chaos control theory which will either terminate fibrillation or significantly decrease the defibrillation threshold. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CHRONIC MONITORING OF ISCHEMIC MODELS OF SUDDEN DEATH Principal Investigator & Institution: Smith, William M.; Professor; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: Most sudden cardiac death (SCD) is associated with coronary artery disease, but little is known about the exact sequence of events that leads up to it and the mechanisms responsible for it. There is a complex interplay between old myocardial infarcts, acute ischemia, the status of the autonomic system, mechanical viability, and electrophysiology that leads to SCD and influences whether tachycardia or bardycardia is the final rhythm. In this project, it is proposed to combine a unique set of technological and physiological resources to study the events surrounding sudden death. An animal model of infarct/ischemia leading to spontaneous SCD has been developing and will be studied in two complementary ways. One set of animals will be instrumented with a custom-developed telemetry system to acquire electrophysiologic and functional data during the conscious, ambulatory state, eliminating the confounding effects of thoracotomy and anesthesia and anesthesia on the incidence and nature of sudden death. Another set of animals will be studied with high resolution, three dimensional mapping to elucidate the mechanisms of the spontaneous arrhythmias that lead to SCD. It is hypothesized that the balance between the vagal and sympathetic arms of the autonomic system and that changes in repolarization properties of the myocardium are predictors of which animals die suddenly and spontaneously and spontaneously as well as the mode of death. It is also hypothesized that spontaneous tachycardia/fibrillation is initially reentrant and that the old infarct is involved in the arrhythmia maintenance. Further, it is hypothesized that bradycardia is associated with pump failure rather than a vagal reflex leading to hypotension. It is proposed to use the data from this research to develop, implement and validate measures that predict imminent SCD on the time scale of seconds to minutes. Because of the continuous nature of data acquisition over several days when no sustained arrhythmias are observed, it will be possible to determine the specificity as well as the sensitivity of derived predictors. Innovations in telemetry capability, cardiac mapping, and new animal models of spontaneous sudden cardiac death will provide information about the context and mechanisms of sudden death that has not been available before. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SYNDROME
CIRCULATORY
DYSFUNCTION
IN
CHRONIC
FATIGUE
Principal Investigator & Institution: Stewart, Julian M.; Professor; Pediatrics; New York Medical College Valhalla, Ny 10595 Timing: Fiscal Year 2002; Project Start 24-AUG-2001; Project End 31-JUL-2005 Summary: Chronic fatigue syndrome (CFS) is associated with orthostatic intolerance which often takes the form of postural orthostatic tachycardia syndrome (POTS) in adolescents. Preliminary data suggest the novel concept that defective vasoconstriction produces POTS in CFS with cardiac autonomic changes as a secondary response. CFS patients will be compared to healthy controls and to controls with simple faints to test 3 hypotheses: 1) Blood is redistributed peripherally and redistribution is enhanced during orthostasis producing increased microvascular filtration and dependent edema. Central hypovolemia causes decreased cardiac output, reflex tachycardia and reduced cerebral blood flow. This is enhanced during orthostasis producing increased microvascular
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filtration, dependent edema, and peripheral pooling. These changes alter the interstitium, and cause reflex tachycardia, reduced cerebral blood flow and often hypotension. Blood volume and cardiac output using the indocyanine green dye dilution technique will be measured supine, during conventional 700 head-up tilt, and during low angle head-up tilt. Cerebral blood flow velocity (CBFv) will be estimated by transcranial Doppler ultrasonography. Thoracic, splanchnic, and pelvic vascular volumes will be measured by impedance plethysmography, and limb blood flow, arterial flow, venous volume-pressure relation, and venous pressure will be measured by venous occlusion strain gauge plethysmography. These will show increased blood flow to lower extremities when upright. Central hypovolemia will occur and will reduce CBF and produce symptoms of CFS. Cardiac autonomic status including baroreflex will be assessed by heart rate and blood pressure variability and transfer function. Baroreflex and heart rate variability will be decreased and blood pressure variability will be increased related to circulatory deficit 2) The defect in vasoconstriction is heterogeneous comprising abnormal arterial baroreflex mediated sympathetic vasoconstriction in one subgroup of CFS patients and abnormal local vasoconstriction in a second subgroup with defective veno-arteriolar reflex (arterial baroreflex insensitive dysfunction). Low angle tilt will be used to activate baroreflex mediated and local reflexes. Local reflexes including myogenic, metabolic and veno-arteriolar will be sorted out through use of supine testing designed to specifically stimulate a specific reflex (limb hang, large pressure step and reactive hyperemia) and measuring peripheral resistance. 3) Cardiac autonomic findings are secondary to circulatory changes. Thus, tachycardia relates to vagal withdrawal because of circulatory insufficiency. CFS patients will be treated with midodrine or placebo in a cross-over study. Using supine and low angle tilt experiments, circulatory measurements and psychological instruments will be combined to demonstrate that circulatory abnormalities, autonomic abnormalities and symptoms correct in a subgroup of CFS patients with low resting peripheral resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SYNDROME
CLONIDINE
TREATMENT
FOR
NEONATAL
ABSTINENCE
Principal Investigator & Institution: Gauda, Estelle B.; Associate Professor; Pediatrics; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2006 Summary: (provided by applicant): In the United States, as many as 20,000 babies a year are born to opioid ("narcotic") addicted mothers. Like their mothers, these infants are opioid dependent. Following birth, the infant is removed from its opioid source, inducing a withdrawal syndrome in these infants. Withdrawal symptoms in newborns include vomiting, diarrhea, poor feeding, tachycardia, hypertension, diaphoresis, restlessness, insomnia, irritability, tremors, clonus, hyperphagia with poor growth and acidosis, reversible neurologic abnormalities, and even seizures. This complex of signs and symptoms is referred to as neonatal abstinence syndrome (NAS). Reinstitution of opioids followed by a slow tapering protocol is currently the standard of care, necessitating prolonged hospitalization from weeks to months. Clonidine is a nonnarcotic central alpha2-adrenergic receptor agonist that blocks the effects of overexcitation of the sympathetic nervous system and is an approved treatment for opioid withdrawal in adults. We currently have a physician sponsored IND (#63,781) to study the effect of clonidine as adjunct therapy to opioids for the treatment of NAS. This proposal will test the hypothesis that combination therapy of clonidine and opioids is 1) safe and efficacious, 2) allows reduced amount of opioid drug use, and 3) results in
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shorter time of treatment and hospitalization. This will be accomplished in a randomized, placebo controlled double blind clinical trial comparing diluted tincture of opium (DTO) combined with a placebo (control) vs. DTO combined with clonidine. Additional sub-studies include determination of 1) pharmacokinetics and pharmacodynamics of DTO and clonidine in the enrolled cohort and 2) further safety evaluation by evaluating developmental outcome on the Bayley Scale of Infant Development (BSID) at 6 and 12 months of age. Pharmacokinetics will be determined by measuring serum concentrations of clonidine and morphine and analyzing volume of distribution, elimination half-life and clearance. These results will have important clinical implications and may change the standards of care not only for management of infants with severe NAS, but also for the management of infants and children, after long-term iatrogenic opioid exposure for instance following prolonged analgesia for mechanical ventilation or multiple operations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COMPREHENSIVE DIAGNOSIS OF ISCHEMIC HEART DISEASE BY MRI Principal Investigator & Institution: Yang, Phillip C.; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: A new real-time, interactive cardiac magnetic resonance imaging system (RTIS) has been developed. The RTIS allows continuous dynamic acquisition, interactive selection of any scan plane, and real-time image display at 16 frames/second (6 complete images/second) without cardiac gating or respiratory breath-holding. A clinical trial of the RTIS demonstrates that the system provides clinically reliable evaluation of LV function. The goal of this proposal is to use the RTIS technology to develop a new imaging protocol for a comprehensive diagnosis of ischemic heart disease. The RTIS platform will be augmented by imaging sequences for coronary artery, stress-induced wall motion, and myocardial perfusion. The first phase will focus on optimizing each imaging sequence. Each optimization will be validated by systematic comparison to the respective diagnostic gold standard. High-resolution coronary artery imaging sequence will allow immediate screening, localization, and visualization of the desired coronary artery. Frame rate of 30 complete images/second will provide imaging of stress induced wall-motion in tachycardia range. Cardiac-gated single shot imaging will enable rapid acquisition of several frames per systole over multiple planes to cover the entire heart for first- pass perfusion imaging. The second phase will consist of a prospective clinical trial of each optimized sequence. During the final phase, the 3 imaging sequences will be integrated seamlessly into the RTIS to test the clinical utility of a rapid and robust comprehensive cardiovascular diagnostic system (CVMR). The wide range of tissue contrast mechanism of MRI creates a huge potential in cardiovascular imaging. Robust imaging sequences have been developed to display physiologic parameters to diagnose cardiac ischemia. The major thrust of this research plan is to develop an advanced, integrated imaging system to test the hypothesis whether such comprehensive approach will enhance non-invasive diagnosis of ischemic heart disease. The final product will be a diagnostic system that maximizes the MR tissue contrast properties coupled with real-time interactive capabilities and easy, intuitive user-interface. The CVMR will demonstrate optimal transfer of innovative technology to cardiovascular medicine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: COMPUTER MODEL OF THE CANINE VENTRICLE Principal Investigator & Institution: Gilmour, Robert F.; Professor of Physiology; Biomedical Sciences; Cornell University Ithaca Office of Sponsored Programs Ithaca, Ny 14853 Timing: Fiscal Year 2004; Project Start 15-DEC-2003; Project End 30-NOV-2007 Summary: (provided by applicant): Sudden death secondary to ventricular fibrillation (VF) remains a leading cause of mortality in the US. Therapy for VF has been largely ineffectual, principally because the underlying mechanisms for VF are not well understood and probing for potential mechanisms has been hindered by the inability to precisely modify specific ionic currents. To address these issues, we propose to develop a data-driven computer model of the electrical behavior of the canine ventricle. Specifically, we will: 1) Experimentally characterize IKr, ICa, IK1, INaCa, and the late sodium current INa in myocytes obtained from specific regions of the ventricles. These particular currents will be studied because they play a significant role in repolarization. They will be measured using action potentials recorded at rapid pacing rates as the command waveforms, to replicate current behavior during a tachyarrhythmias. 2) Develop deterministic Hodgkin-Huxley and Markov models for each ionic current for each anatomical region using the time series and steady state current data obtained under Specific Aim 1. Optimization routines will be used to determine unknown parameters in the models by comparing the model current to experimental data. 3) Incorporate the models of the individual currents into computer models of regionspecific single canine ventricular myocytes. Models of left and right ventricular epicardial, midmyocardial and endocardial myocytes of basal and apical origin and of right and left ventricular Purkinje myocytes will be developed. 4) Incorporate the single cell models into a 3-D computer model of the canine ventricle using a modified version of the phase field method. The model will be written using a portable parallel version of the code and run on a parallel computer and multi-node clusters. Initially, the model will consist of the left ventricle, with epicardial, midmyocardial and endocardial layers. More detailed anatomical models subsequently will be constructed to include the HisPurkinje system and the right ventricle. 5) Use the 3-D model to test candidate hypotheses for the development of VF. The initial test will determine whether suppressing dynamic electrical heterogeneity prevents VF. The computer model of ventricular electrical function we propose will provide an invaluable tool for drug discovery and the evaluation of algorithms for anti-tachycardia and anti-fibrillatory pacing and defibrillation. As such, the model is expected to have a significant impact on the diagnosis and treatment of lethal heart rhythm disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CORE--ANIMAL MODEL AND CELL Principal Investigator & Institution: Kass, David A.; Professor; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002 Summary: 1. Purpose, Core C, the animal model and cell isolation core, provides support for the central animal model used by Projects 1-4. This includes expert surgical instrumentation, follow-up care, and isolation of viable cardiomyocytes from several layers of the left ventricle. Myocytes are employed in projects 1-3 for molecular dissection of potassium and calcium channel physiology in normal and failing hearts. Myocytes are utilized in Project 4 for the purpose of studying neurohormonal modulation of ion channels in normal and failing hearts, and test the role of an altered
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extracellular matrix environment. Chunk tissues are also provided by Core C at time of animal sacrifice and are used for a variety of molecular assays and histochemical analyses. Two models are employed in Core C, the standard 4 week tachycardia-pacing model of dilated cardiomyopathy, and an accelerated model employing combined neurohumoral activation with relatively short-term tachycardia pacing (Project 4). The major roles of the core are 1) to provide a weekly supply of acutely isolated myocytes from control and abnormal (failing) left ventricles; 2) to provide a standardized hemodynamic/organ electrophysiologic characterization of hearts from which these cells are obtained; 3) to provide chronic surgery-instrumentation and post operative care for animals requiring chronic repetitive conscious hemodynamic assessment; and 4) to provide all required medical records for chronic care and animal maintenance, and to administer these protocols following policies set forth by the Animal Care and Use Policies of the Johns Hopkins University pursuant to guidelines established by the National Institute of Health. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CX43 IN A GENETIC MODEL OF ALTERED MYOCARDIAL CONDUCTION Principal Investigator & Institution: Saffitz, Jeffrey E.; Professor of Pathology & Immunology; Pathology and Immunology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAY-2005 Summary: The goal of the proposed research is to define the functional role of Cx43 in normal cardiac conduction and to delineate the role of altered coupling at gap junctions in the pathogenesis of conduction disturbances and arrhythmias. Proposed experiments will be performed using mice that are heterozygous for a null allele for the gene encoding the major cardiac gap junction protein, Cx43 (Cx43 plus/minus mice). These mice produce 50 percent of the wildtype level of Cx43 and have significant reduction in the number of gap junction interconnecting ventricular myocytes. The functional consequence of reduced Cx43 expression in adult mice is a 25-30 percent slowing of ventricular conduction velocity. Whereas the electrophysiological phenotype in Cx43 plus/minus mice is subtle under physiological conditions, a more dramatic phenotype can be elicited under pathophysiological condition. In response to acute regional ischemia, Cx43 plus/minus mice exhibit accelerated onset and increased incidence, frequency and duration of ventricular arrhythmias. The proposed research is focused on defining mechanisms by which reduced coupling promotes arrhythmias in accute and chronic ischemic heart disease. Studies in Specific Aim 1 will elucidate the mechanistic relationship between the rate and extent of electrical uncoupling at gap junctions and development of ventricular tachyarrhythmias induced by acute ischemia. Studies in Specific Aim 2 will define arrhythmia mechanisms in Cx43 plus/minus following acute coronary occlusion and delineate the roles of Cx43 and altered cell-to- cell coupling in electrical triggering events and sustained conduction abnormalities that underlie initiation and maintenance of ventricular arrhythmias in the setting of acute myocardial ischemia. In Specific Aim 3, the role of gap junction remodeling in the pathogenesis of arrhythmias in chronic ischemic heart disease will be elucidated by comparing arrhythmogenesis in Cx43 plus/minus and wildtype mice with healed myocardial infarcts. And in Specific Aim 4, molecular and structural determinants of conduction will be delineated using neonatal mouse ventricular myocytes grown in patterned arrays of defined structure and packing geometry, and analyzed by high resolution optical mapping. The results of the proposed research will define mechanisms by which
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reduced coupling promotes ventricular tachyarrhythmias in mouse models of acute and chronic ischemic heart disease in patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CYTOKINE-INDUCED ARRHYTHMIAS IN CONGESTIVE HEART FAILURE Principal Investigator & Institution: London, Barry; Associate Professor of Medicine; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 28-FEB-2005 Summary: (the applicant's description verbatim): Arrhythmias are a major health problem in cardiomyopathies of both ischemic and non-ischemic origin. As many as 50 percent of patients with congestive heart failure (CHF) die suddenly, accounting for more than 250,000 annual deaths. Pharmacological treatments of arrhythmias often fail, and internal defibrillators are expensive and limit quality of life. Inflammatory cytokines, including TNF-alpha, are increased in the serum and hearts of patients with CHF. TNF-alpha is also transiently increased following myocardial infarction, is elevated in inflammatory conditions such as sepsis, and increases with age and hypertrophy. All of these conditions are characterized by increased susceptibility to ventricular arrhythmias. The potential role of cytokines in the pathogenesis of arrhythmias has not been extensively studied. We have recently engineered mice that overexpress TNF-alpha in the heart and develop a cardiomyopathy characterized by atrial and ventricular dilatation, decreased ejection fraction, CHF, and decreased survival. Radio-telemetry monitoring of transgenic mice shows high-grade atrial and ventricular arrhythmias. Optical mapping studies of program-stimulated, Langendorffperfused hearts using voltage- and Ca2+-sensitive dyes show inducible ventricular tachycardia (VT), slow conduction of premature beats, elevated diastolic and decreased peak systolic Ca2+, and prolongation of the Ca2+ transient. Mating of these mice to long QT transgenic mice yields offspring that die suddenly, without evidence of CHF. The goals of this project are to determine the mechanism(s) by which cytokines may promote arrhythmias and sudden death in acute and chronic cardiac conditions, and to test whether treatments for CHF reverse the effects. To this end, we will study ambulatory telemetry-monitored mice, isolated Langendorff-perfused hearts stained with voltageand Ca2+-sensitive dyes, and isolated myocytes from control and transgenic mice. We will: 1) Test the hypothesis that acute exposure to TNF-alpha, IL-1 beta, and/or LPS predisposes to cardiac arrhythmias, and determine the mechanism(s) responsible; 2) Identify the mechanisms responsible for atrial and ventricular arrhythmias in the TNFalpha mouse model of CHF. 3) Determine to what extent and by what mechanisms treatments of CHF with beta-blockers, ACE inhibitors, and soluble TNF receptors decrease arrhythmias; and 4) Examine to what extent and by what mechanisms repolarization abnormalities exacerbate arrhythmias and sudden death in this mouse model of CHF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DATA COORDINATING CENTER FOR SCD IN HEART FAILURE TRIAL Principal Investigator & Institution: Lee, Kerry L.; Associate Professor of Biostatistics; Community and Family Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 01-MAY-1997; Project End 30-APR-2003
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Summary: The objective of this proposal is to establish the Statistical and Data Coordinating Center for the multicenter randomized clinical trial of prophylactic amiodarone or implantable defibrillator therapy vs. Conventional heart failure therapy in patients with Class II or Class III congestive heart failure (CHF) and an ejection fraction less than or equal to 35%. Qualifying patents (n=2,500) will be randomized in equal proportions to three treatments: conventional CHF therapy and placebo (control arm); conventional therapy combined with the use of amiodarone; and conventional therapy combined with a single lead, pectoral ICD that can be inserted on an outpatient basis. After discharge, all patients will be followed via clinic visits at 1 week, 4 weeks, 3 months, and every 3 months thereafter. Patients will be recruited over a period of 2.5 years, with a subsequent minimum follow-up of 2.5 years. The primary endpoint of the trial is all-cause mortality. Secondary endpoints include: 1) cardiac mortality and arrhythmic mortality; 2) ventricular tachycardia/fibrillation and bradyarrhythmias assessed via the ICD memory log; 3) morbidity; 4) quality of life; and 5) cost of care and cost effectiveness. In collaboration with the Clinical Coordinating Center (CCC) and the Economics and Quality of Life Center, the Data Coordinating Center will perform the following major functions: 1) participate in all phases of study planning; 2) coordinate the preparation of data collection forms; 3) prepare a manual of operations; 4) provide training/guidance in data collection procedures; 5) coordinate the randomization of patients; 6) organize the flow and management of all patient data; 7) establish high standards of quality control for data management; 8) perform on-site monitoring of completed data forms; 9) prepare regular status reports for the CCC and for all study committees; 10) dispense payments to clinical sites for enrolling and following patients; 11) perform appropriate statistical analyses of study data; and 12) participate in the preparation of study publications. Noteworthy features of this proposal include: a detailed assessment of sample size requirements; telephone randomization of patients; double data entry; on-site audits of data; economical and efficient computer hardware and software; state-of-the-art methods of data analysis; and an experienced team of investigators. Through the services it provides, the Data Coordinating Center will be a vital resource in the execution of this clinical trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DECOUPLING DYNAMICS OF THE AUTONOMIC NERVOUS SYSTEM Principal Investigator & Institution: Chon, Ki H.; Biomedical Engineering; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): The purpose of this R21 proposal is the development of a new nonlinear method that will be able to separate the dynamics of the sympathetic and parasympathetic nervous activities from noninvasive recordings of heart rate data. The cardiac autonomic nervous system (ANS) is an especially important control system that is responsible for maintaining [proper homeostasis of the cardiovascular system. Clinically-reliable assessment of the state of the ANS requires accurate nonlinear techniques that can separate the dynamics of sympathetic and parasympathetic nervous activities. Decoupling the dynamics of the two autonomic nervous activities based on heart rate data is important because it can be used as a powerful non-invasive marker for determining the state of the ANS balance. Experimental evidence suggests that myocardial infarction, chronic heart failure, ventricular tachycardia, and sudden cardiac death all exhibit signs of ANS imbalance. Currently, there is no method that can accurately characterize dynamics of the two branches of ANS using noninvasive
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approaches. One of the current standards in assessing the balance between the sympathetic and parasympathetic nervous systems is to compute the ratio of the low frequency (LF) to high frequency (HF) power obtained from spectral analyses of the heart rate data. The LF/HF ratio is inaccurate because it does not truly reflect the balance between the two branches of ANS activities, and is a linear approach despite the fact that the ANS involves nonlinear control. Consequently, characterization of the ANS using linear power spectra of the heart rate data may limit identification of subtle changes in dynamics from healthy to diseased states, for example. Preliminary results based on a limited database of healthy subjects suggest that our method is able to separate dynamics of the two ANS activities. The first aim of the R21 proposal is to further develop, modify, and enhance the capability of the method as the technique is applied to an existing clinical database to validate the efficacy of the approach. The second aim is to detect, quantify, and Interpret differences in dynamic characteristics of the ANS between normal and diseased subjects, in an attempt to find a marker for increased risk of sudden cardiac death. The final aim is to disseminate the developed software to the 9iomedical engineering community via the internet so that the algorithm can be tested with other researchers' own databases. Identifying and quantifying differences in the dynamic characteristics of ANS between normal and diseased conditions may lead to a better understanding of the role of the autonomic function imbalance in diseased conditions, and should have important clinical diagnostic and prognostic applications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DETERMINANTS OF CATHETER ABLATION FAILURE Principal Investigator & Institution: Po, Sunny S.; Medicine; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 30-NOV-2007 Summary: (provided by the applicant): The long-term objective of this project is to identify the determinants of catheter ablation failure in AV nodal reentrant tachycardia (AVNNRT) and accessory pathways (AP). Recently, the NASPE Catheter Ablation Registry showed that despite all the advances in mapping and ablation technology, the success rate of ablation has not improved between 1993 and 1998, suggesting that new strategies for selecting the ablation target are needed. The Specific Aim 1 of this project is to elucidate the causes of failed AP ablations. We hypothesize that the main cause of failure in AP ablation is inaccurate localization of the AP when the AP has an oblique course. We will test this hypothesis by reversing the activation wavefront using two different pacing sites to help identify an isolated AP potential, which will be targeted for ablation. The Specific Aim 2 of this project is to elucidate the causes of failed AVNRT ablations. We postulate that the main cause of failed AVNRT ablation is that the reentrant circuit in AVNRT is not well understood. Our working hypothesis is that identification of the reentrant circuit and atrial connections in AVNRT will facilitate appropriate target selection and improve success in AVNRT ablation. We will systemically examine the reentrant circuit by (1) map the earliest retrograde atrial activation to help identify the retrograde limb of the circuit in each variant of AVNRT. (2) establish the presence or absence of a lower common pathway in each variant of AVNRT to help localize the circuit. (3) deliver late atrial extrastimuli at different sites to identify the antegrade limb of the circuit. (4) ablate the reentrant circuit based on the mapping result to further confirm the location of the circuit. My past research has focused on basic electrophysiology (ion channel related research). My immediate career goal is to utilize this project to successfully change my research direction from basic to
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clinical electrophysiology. My long-term goal is to be a "linker" between basic and clinical electrophysiology and continue exploring the mechanism of cardiac arrhythmia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DOES VT BEGET VT? REMODELING IN HEALED INFARCTION Principal Investigator & Institution: Callans, David; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2004 Summary: Protracted atrial fibrillation (AF) conditions the atrium through electrical remodeling to perpetuate AF (AF begets AF). Whether this is true for episodic ventricular tachycardia (VT) due to healed myocardial infarction (MI) is not known so this proposal asks whether VT begets VT. A related issue is how VT electrically remodels the infarcted ventricle. Experimental and clinical evidence indicates that postNG VT is reentrant. While VT maintenance mechanisms are controversial, the role of refractoriness in VT initiation is usually not disputed. We therefore propose to study whether episodic VT affects VT inducibility and remodels refractoriness. Study hypotheses were based on the distinct properties of the infarcted (1Z), border (13Z), and normal (NZ) zone tissues associated with MI and on the phenomena of repolarization remodeling due to cardiac memory, failure or hypertrophy. Hypothesis 1 is that VT remodels refractoriness even in hearts already remodeled by MI. Hypothesis 2 is that refractoriness remodeling in the IZ, BZ and NZ differentially responds to the influence of VT rate versus site of origin. Hypothesis 3 is that VT-dependent changes in inducibility result from differences in refractoriness remodeling of the BZ with respect to the IZ or to the NZ. Hypothesis 4 is that changes in BZ and NZ plateau and repolarization currents are responsible for refractoriness remodeling in these tissues. To test these hypotheses we will use swine having healed MI caused by bead embolization. Fast or slow ventricular pacing (VP) from 1 of 3 test sites will simulate episodic VT. VT inducibility and peri-infarct endocardial refractoriness; will be assessed in vivo using CARTO electro-anatomic catheter mapping before and after MI and after VP of MI. Terminal in vitro studies will use whole cell voltage clamp to correlate remodeled BZ and NZ refractoriness with changes in plateau ion currents. We will measure steady state, peak activated and kinetic properties of Ik and ICaL and the current-voltage relations of Ik1 and InaCa. Indo-1 and fluo-3 recordings of the calcium transient will be used to determine the direction and relative magnitude of InaCa flux. Refractoriness due to INa reactivation will be detected via voltage and time-dependent recovery of upstroke velocity. If the study hypotheses are true then the labile and inhomogeneous remodeling properties of the post-MI heart may cause episodic VT to have either a positive or negative effect on VT inducibility. If the latter occurs then novel therapy based on pacing may be possible. If the former is true then preventive therapy could be directed against such remodeling. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DUAL GENE THERAPY FOR HEART FAILURE Principal Investigator & Institution: Nuss, H B.; Medicine; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2004 Summary: Heart failure is a multifactorial disease, having both electrical and contractile components. Downregulation of key potassium channels and concomitant prolongation and instability of repolarization, predispose the heart to arrhythmias. Meanwhile,
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downregulation of the sarcoplasmic reticulurn Ca2+ ATPase and concomitant calcium handling abnormalities contribute to depressed myocardial contractility. The electrical abnormalities and the contractile abnormalities are not mutually exclusive. Alterations in the control of membrane voltage will modulate the triggered release of Ca2+ from the sarcoplasmic reticulurn and, conversely, alterations in the intracellular calcium transient will influence membrane potential. It is the interplay between the electrical and contractile abnormalities of heart failure which compounds the complexity of abnormalities and confounds the design of successful treatments. Novel antiarrhythmic gene therapy based upon manipulation of a select K channel gene alone to decrease susceptibility to arrhythmias may lead to depressed contractility, which is already depressed in heart failure. Conversely, genetic manipulation of a SR Ca2+ ATPase protein alone, to amplify contractility, may create a proarrhythmic substrate in a failing heart which is already predisposed to fatal arrhythmic events. Thus, monogenic strategies, based upon selective overexpression of a single gene, may not suffice to correct heart failure abnormalities because of the interplay between excitation and contraction in cardiac muscle. This proposal seeks to offset abnormalities of tachycardia, pacing- induced heart failure in rabbits using combination gene therapy: overexpression of a select K channel gene and a SR Ca2+ ATPase gene in tandem. As a prelude we will test the hypotheses that gene therapy targeted to correct the electrical abnormalities alone or the calcium handling abnormalities alone will result in adverse conditions. The proposal focuses on potassium channels and SR Ca2+ ATPase's that are highly relevant to repolarization and contractility in the human heart failure. In vivo adenoviral mediated gene transfer, cellular and cardiac electrophysiology, and quantitative modeling will be used to investigate repolarization and calcium handling with the goal of correcting the electrical and contractile abnormalities in heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EFFECTS OF ETHANOL ON CARDIAC NEUROENDOCRINE DEVELOPMENT Principal Investigator & Institution: Mckenzie, James C.; Howard University Washington, Dc 20059 Timing: Fiscal Year 2002 Summary: Fetal Alcohol Syndrome (FAS) consists of a constellation of pathologies and functional/development abnormalities resulting from alcohol exposure in the womb. Medical problems related to FAS include retarded body and mental development, craniofacial abnormalties and cardiac structural and functional deficits. Some of these abnormalities appear due to alcohol-induced death of neural crest cells which migrate fromthe developing nervous system and give rise to structual and functional components of many organ systems, including the autonomic nervous system. It is hypothesized that underpopulation of the cardiac parasympathetic intrinsic nervous system may result from cell death and insufficient neural crest cell migration. This could explain the tachycardia and other functional cardiac pacing abnormalities observed in FAS infants. The population densities of cardiac intrinsic parasympathetic ganglion cells in ethanol- exposed and control rats will be assessed pre- and post-natally by histochemical and immunohistochemical techniques. It is also hypothesized that alcohol-induced redution in protein sysnthesis may inhibit the synthesis of Atrial Natriuretic peptide (ANP) in fetal atria and ventricles. ANP is a cardiovascular hormone with potent antihypertensive and vasoregulatory properties as well as antimitotic functions. Therefore, alteration in ANP content may affect cardiac development. Cardiac ANP content willb e monitored pre- and post- natally in ethanol-exposed and control
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rats by immunohistochemistry and radioimmunoassay. The results of the proposed studies should contribute significantly to understanding of the etiology of cardiac functional deficits related to FAS and lead to future studies at the molecular and cell biological levels of cardiac structural and functional abnormalities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ELECTRICAL THERAPY FOR PULSELESS ELECTRICAL ACTIVITY Principal Investigator & Institution: Ideker, Raymond E.; Jeanne V. Marks Professor; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: A serious problem during resuscitation to treat sudden cardiac arrest is that, even though defibrillation restores organized cardiac electrical activity, cardiac function is so poor that little or no blood is pumped, a condition called pulseless electrical activity (PEA). One is burst stimulation to restore a pulse pressure during PEA. The other is DC stimulation to improve function during chronic heart failure, which may also be beneficial during PEA. The other is DC stimulation to improve function during chronic heart failure, which may also be beneficial during PEA. In addition to their beneficial effects, these electrical stimuli may also have detrimental effects, the most serious of which is reinitiation of an arrhythmia. The goal of this project is to determine the mechanism of the beneficial and detrimental effects of burst and DC stimulation Electrical and optimal mapping will be used in animals to accomplish three specific aims. Specific Aim 1: To determine the effect of burst and DC stimulation on cardiac nerve activity. The hypothesis will be tested that the primary mechanism by which burst stimulation improves cardiac function is by increasing sympathetic nerve discharge. Specific Aim 2: To determine the effect of burst and DC stimulation on membrane polarization (Vm), action potential (APD), intracellular calcium (Cai/2+), and myocyte motion. The hypothesis will be tested that the primary mechanism by which DC stimulation improves cardiac function is by depolarizing Vm during the AP plateau, thus prolonging APD and increasing Cai2+. Specific Aim 3: To determine the mechanisms of the detrimental effects of burst and DC stimulation. The hypotheses will be tested that the mechanism for tachyarrhythmia induction by burst and DC stimulation are electroporation and creation of a Vm critical point. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ELECTRODE DESIGN FOR CARDIAC TACHYARRYTHMIA RF ABLATION Principal Investigator & Institution: Webster, John G.; Professor; Biomedical Engineering; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-SEP-1996; Project End 31-AUG-2004 Summary: (Adapted from Applicant's Abstract): The goal of this study is to optimize catheter design for the cure of atrial fibrillation and ventricular tachycardia by endocardial radiofrequency (RF) ablation. It is estimated that currently in the USA about 2 million people are affected by some form of atrial fibrillation. Also, each year about 200,000 patients are treated for ventricular tachycardia. Atrial fibrillation, although itself not fatal, is a frequent cause of stroke and is linked to a high degree of cardiovascular mortality. Ventricular tachycardia is the main cause of sudden cardiac death, affecting particularly patients suffering from myocardial infarction. To cure cardiac dysrhythmias, radiofrequency current flows through an electrode on a catheter in contact with the endocardium to ablate undesired arrhythmia substrates. This research
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will improve the electrodes and improve the procedure. In vitro tests on myocardium will yield physical parameters of electric conductivity, and thermal conduction, capacity, and heat convection variation throughout the endocardium. In vivo swine tests will improve accuracy of most parameters. The parameters will be used to improve a 3dimensional finite element computer model that simulates the electric power deposited, the myocardial temperature rise and the volume and distribution of the 50 degree Celsius contour that defines the lesion boundary. Further in vitro and in vivo tests will confirm the accuracy of the model. The model will predict lesion volumes resulting from proposed new electrodes. These are (1) uniform current density electrodes that prevent hot spots, steam generation "popping" and coagulum formation; (2) noncontact electrodes that generate larger lesions; (3) needle electrodes that generate larger lesions; (4) long electrodes that generate linear lesions for curing atrial fibrillation; (5) balloon electrodes that permit large imprints; (6) cooled electrodes; and (7) other novel electrodes. The model will aid in the design of new electrodes. The model will also predict the lesion volume at each ablation site. These volume predictions will form guidelines for setting tip temperature to achieve desired lesion volume at each ablation site and thus enhance present ablation techniques. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ENDOTOXIN ASSAY FOR ANALYSIS OF SEPTICEMIA DAMAGE Principal Investigator & Institution: Segal, Gershon; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002 Summary: In the United States, septicemia is the 13th leading cause of death, and accounts for $5 - 10 billion health care dollars spent annually. Patients at risk of developing sepsis frequently present initially to the Emergency Department (ED), with a 'preseptic' syndrome, known as 'systemic inflammatory response syndrome' (SIRS). Prompt recognition, evaluation and initiation of therapy in this group of patients is an area of intensive investigation, since early therapeutic intervention with well established modalities (intravenous fluids and antibiotics) has been shown to be associated with improved outcomes. Furthermore, advances in understanding of the pathophysiology of bacteremia has opened the door for the development of additional therapeutics (e.g. antiendotoxin antibodies) for interrupting the cascade of events associated with full blown sepsis. Establishing an early diagnosis of septicemia remains challenging however. Not all patients with SIRS (fever, tachycardia, tachypnea, and elevated white blood cell count) have a bacterial infection. SIRS can also occur in patients with severe trauma, pancreatitis, and burns without infections. Additionally, demonstration that an infection is the inciting stimulus for SIRS is complicated by the fact that culture reports are usually not available for 24-48 hours, and blood cultures are positive in only about 60% of cases of sepsis. A sensitive and specific clinical diagnostic test for earlier detection of infection would allow physicians to make the diagnosis of septicemia more rapidly, and identify patients who would benefit from specific therapy. Previous efforts toward the development of an assay for early detection of bacteremia have focused on gram-negative infections, as these bacteria are responsible for the majority of cases of sepsis in the United States. The only test currently available assay, the Limulus amebocte lysate test (LAL) is an indirect semiquantitative assay, which has variable sensitivity and specificity and is thus utilized only for industry and research purposes. Recent investigations from the sponsor of this protocol (LINK technology) have demonstrated that a ligand binding assay (LBA) exceeds the sensitivity and specificity of the LAL for the detection of endotoxin in plasma, and may therefore provide the first
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clinically useful test for early identification of patients with gram negative septicemia. LINK's endotoxin test is based on the core discovery that endotoxin binds to an A1 adenosine receptor. A sensitive and specific clinical diagnostic that quantitates the level of endotoxin in blood has a broad range of clinical uses including: (a) early diagnosis of gram negative septicemia allowing for antibiotic specific therapy; (b) early prediction of impending organ dysfunction; and (c) monitoring of the effectiveness of antibiotics or other therapeutic agents targeted at eradicating the infection and treating the complications associated with gram negative bacteremia. We hypothesize that the detection of endotoxin in human blood by a LBA is an early, sensitive, and specific predictor of organ dysfunction associated with gram negative septicemia. The following specific objectives for this pilot study are: 1) to establish the relationship between the LBA and organ dysfunction; 2) to estimate the correlation of diagnostic errors between the LBA and blood culture; and 3) to identify potential confounders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FACTORS THAT INITIATE ARRHYTHAMIAS IN LONG QT SYNDROME Principal Investigator & Institution: Salama, Guy; Professor; Cell Biology and Physiology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 01-FEB-1998; Project End 31-MAR-2007 Summary: (provided by applicant): The role of the autonomic nervous system in the genesis of life-threatening arrhythmias has been the subject of intense investigation yet remains incomplete and fragmented. Sympathetic imbalance has been implicated as a trigger of ventricular arrhythmias in the long QT syndrome (LQTS) by enhancing spatial heterogeneities of i) action potential durations (APDs), ii) dispersion of repolarization (DOR) and iii) perhaps conduction. The project will address fundamental questions regarding the neuromodulation of cardiac function by autonomic activity, the effects of intra-cardiac reflex responses and their role in LQT-related arrhythmias. Rabbit hearts will be isolated with bilateral innervation of sympathetic and parasympathetic branches, will be perfused, stained with voltage and Ca 2+ - sensitive dyes to simultaneously map action potentials (APs) and intracellular Ca 2v(Cai) transients from 256 sites at high spatial and temporal resolution. The sympathetic system will be stimulated bilaterally with electrodes inserted in the vertebral column and the parasympathetic system with electrodes on the right and left vagus nerves. Innervated hearts will be perfused with inhibitors of IKs (HMR 1556), IKr (E4031) or INa inactivation kinetics (Anthopleurin A) (e.g. models of LQTS types 1-3) to elucidate the role of autonomic activity on Torsade de Pointes (TdP). The specific aims are: 1) To test the hypothesis that autonomic activity to the heart modulates APDs, DOR and to determine the mechanisms underlying this neuromodulation by mapping simultaneously cardiac APs and Cai from 256 sites of innervated, Langendorff rabbit hearts. Sympathetic and parasympathetic modulation of heart rate, conduction of the specialized conduction system and ventricular myocardium, AP upstroke velocity, APDs, DOR, and Cai transients will be analyzed during various autonomic nerve stimulation paradigms. Stimulation nerve paradigms will be developed to obtain a spectrum of cardiac responses. Pharmacological interventions will be used to identify the receptors mediating the cardiac responses (131,132,cq-adrenergic receptors: AR; muscarinic cholinergic; peptidergic and puronergic) and the contribution of efferent and afferent fibers involved in this neuromodulation by blocking ganglionic transmission with hexamethonium. 2) To test the hypothesis that intra-cardiac reflexes via afferent and efferent neurons and ganglia
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in the heart muscle regulate electrical and contractile properties. We will apply a focal sensory stimulus (mechanical or chemical) at a site on the heart (i.e. the apex of the left ventricle) while recording changes in electrical and contractile parameters mediated by cardiac reflex responses in other regions of the heart. Pharmacological agents will then be per'fused to block specific neural pathways to identify the underlying neuronal mechanisms. 3) The synergistic effects of right and left sympathetic or right-left vagus nerves activation and the cross-interactions between the sympathetic and parasympathetic branches are central to our understanding of the neuromodulation of the heart. We will compare the changes in APs and Ca_ at a constant heart rate during i) bilateral versus unilateral (right or left) vagal stimulation; ii) vertebral column stimulation (bilateral sympathetic activation) and bilateral versus unilateral vagus stimulation; iii) vertebral column stimulation with right or left stellectomy. Sympathetic inputs to the heart are fractionated and emanate from different thoracic segments that target different regions of the heart. We will selectively stimulate a single sympathetic branch without activating the others inputs (up to 4) to identify the targets on the heart of each input. The convergence or divergence of sympathetic inputs to the heart may be important for normal cardiac function and enhance QT dispersion and TdP in the LQTS. 4) The role of 'autonomic imbalance' on the genesis of LQT-related arrhythmias will be determined in rabbit heart with LQTS type 1,2 or 3 by measuring changes in APDs, DOR, the propensity to fire early afterdepolarizations (EADs) and the initiation of TdP before and during various nerve stimulation paradigms (determined in aim 1). Stimulation paradigms that i) enhance DOR or ii) elicit a bradycardia followed by a tachycardia are more likely to increase the incidence of EADs and TdP. The specific aims are: 1) To test the hypothesis that autonomic activity to the heart modulates APDs, DOR and to determine the mechanisms underlying this neuromodulation by mapping simultaneously cardiac APs and CaI from 256 sites of innervated, Langendorff rabbit hearts. Sympathetic and parasympathetic modulation of heart rate, conduction of the specialized conduction system and ventricular myocardium, AP upstroke velocity, APDs, DOR, and CaI transients will be analyzed during various autonomic nerve stimulation paradigms. Stimulation nerve paradigms will be developed to obtain a spectrum of cardiac responses. Pharmacological interventions will be used to identify the receptors mediating the cardiac responses (beta1, beta2, alpha1-adrenergic receptors: AR; muscarinic cholinergic; peptidergic and puronergic) and the contribution of efferent and afferent fibers involved in this neuromodulation by blocking ganglionic transmission with hexamethonium. 2) To test the hypothesis that intra-cardiac reflexes via afferent and efferent neurons and ganglia in the heart muscle regulate electrical and contractile properties. We will apply a focal sensory stimulus (mechanical or chemical) at a site on the heart (i.e. the apex of the left ventricle) while recording changes in electrical and contractile parameters mediated by cardiac reflex responses in other regions of the heart. Pharmacological agents will then be perfused to block specific neural pathways to identify the underlying neuronal mechanisms. 3) The synergistic effects of right and left sympathetic or right-left vagus nerves activation and the crossinteractions between the sympathetic and parasympathetic branches are central to our understanding of the neuromodulation of the heart. We will compare the changes in APs and Cai at a constant heart rate during i) bilateral versus unilateral vagus stimulation; ii) vertebral column stimulation (bilateral sympathetic activation) and bilateral versus unilateral vagus stimulation; iii) vertebral column stimulation with right or left stellectomy. Sympathetic inputs to the heart are fractionated and emanate from different thoracic segments that target different regions of the heart. We will selectively stimulate a single sympathetic branch without activating the others inputs (up to 4) to identify the targets on the heart of each input. The convergence or divergence of sympathetic inputs to the heart may be important for normal cardiac function and
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enhance QT dispersion and TdP in the LQTS. 4) The role of 'autonomic imbalance' on the genesis of LQT-related arrhythmias will be determined in rabbit heart with LQTS type 1, 2, or 3 by measuring changes in APDs, DOR, the propensity to fire early afterdepolarizations (EADs) and the initiation of TdP before and during various nerve stimulation paradigms (determined in aim 1). Stimulation paradigms that i) enhance DOR or ii) elicit a bradycardia followed by a tachycardia are more likely to increase the incidence of EADs or TdP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENDER & ORTHOSTATIC INTOLERANCE: MECHANISMS AND THERAPY Principal Investigator & Institution: Fu, Qi; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): The global objective of this Mentored PatientOriented Research Career Development Award is to build my career as an academic physician-scientist and make the transition to become an independent investigator. To accomplish this goal, together with my mentor, i have developed a tightly integrated plan including cutting edge science, and advanced training in the techniques of patientoriented research. By participating in the K30 Curriculum in Patient-Oriented Research at UT Southwestern leading towards a MPH degree, I will receive in-depth instruction in research design, protection of human subjects, grantsmanship, and advanced level biostatistics. From my mentor and advisory committee, made up of senior scientists both at UT Southwestern and at the Brigham and Women's Hospital, I also will acquire critical new research skills regarding renal/neurohormonal mechanisms of blood pressure control, reproductive endocrinology, and clinical orthostatic intolerance. My research plan focuses on the mechanisms underlying gender differences in orthostatic tolerance, including neurohumoral influences on cardiovascular control processes and physical characteristics (primarily cardiac size and function) that determine orthostatic distribution of central blood volume. Menstrual cycle variability in young women, and differences among men, women, and women with chronic orthostatic intolerance (Postural Orthostatic Tachycardia Syndrome, or "POTS") will be examined. Finally, a specific intervention (exercise training) will be studied as treatment for patients with POTS and compared with standard pharmacologic therapies (13-blockers and volume expanders). Autonomic neural control of hemodynamic and sympathetic responses to the Valsalva maneuver, static handgrip, a cold pressor test, and prolonged head-up tilt will be investigated; the venoarteriolar response and neurohumoral responses to a longterm standing will be examined. After completion of the proposed project, we will know whether gender-specific factors such as the menstrual cycle or physical factors influencing cardiac size and function are among the determinants for orthostatic intolerance in young women, and whether physical exercise training can be considered an effective non-pharmacologic treatment for patients to improve their orthostatic tolerance. The combination of advanced training in patient-oriented research and indepth study of an important clinical problem will prepare me well for a career as an independent investigator. (End of Abstract) Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENE DISCOVERY IN A PUTATIVE MOUSE MODEL OF ADHD Principal Investigator & Institution: Mcdonald, Michael P.; Assistant Professor; Pharmacology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917
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Timing: Fiscal Year 2003; Project Start 15-JAN-2003; Project End 31-DEC-2004 Summary: (provided by applicant): Abnormal thyroid levels during gestation can have devastating effects on brain development and cognition. Resistance to thyroid (RTH) syndrome is a heritable condition caused by mutations in the TRbeta gene that typically result in elevated thyroid hormones, short stature, and tachycardia. More than half of RTH patients have attention deficit hyperactivity disorder (ADHD), with the incidence about 50% higher among males. Although the etiology of ADHD is unknown, considerable evidence implicates deficiencies in the dopaminergic and noradrenergic neurotransmitter systems. A normally functioning thyroid system is critical for proper development of the catecholaminergic systems, and thyroid abnormalities can result in behavioral and neurochemical features consistent with ADHD. We have recently found that a TRbeta transgenic mouse bearing a human mutant thyroid beta1 receptor reproduces all of the key symptoms of ADHD, such as juvenile hyperactivity, deficits in sustained and selective attention, impulsivity, and reduced catecholamine levels. Interestingly, the TRbeta transgenic mice have normal levels of thyroid hormones, thyroid stimulating hormone (TSH), and suppression of TSH. This is intriguing because it raises the possibility that modest developmental thyroid dysfunction may contribute to a larger proportion of ADHD cases than previously thought. In addition to the core symptoms of the disorder, mice demonstrate many of the more subtle features of ADHD, e.g., the hyperactivity dissipates in adulthood, the penetrance is greater among males than among females, and the deficit in sustained attention is attenuated with greater reinforcement levels. Another interesting feature of the TRbeta transgenic mice is that the hyperactivity phenotype depends on the maternal genotype, independent of the mouse's own genotype. This suggests a possible biological or behavioral basis for maternal or environmental effects on ADHD subtypes. This high degree of analogy between complex human behavioral disorders in an animal model is unparalleled for a complex, multigenic behavioral disorder. We propose to use microarray technology to examine differential gene expression in wild-types vs. transgenics, males vs. females, and offspring of transgenic dams vs. offspring of wild-type dams, in pups, adolescents, and adults. The TRbeta transgenic mouse model provides us with a rare opportunity to discover genes downstream of TRbeta activity that are able to produce all of the core symptoms and many adjunct features of ADHD-genes that may be differentially expressed in a large number of children with ADHD. In addition, we have an unprecedented opportunity to discover how the relationship between gene expression and behavior differs according to diagnostic subtype, gender, treatment refractoriness, and environmental (e.g., maternal) conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC AND RECEPTOR MECHANISMS IN HYPERTENSION Principal Investigator & Institution: Printz, Morton P.; Professor; Pharmacology; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2003; Project Start 01-MAR-1986; Project End 30-APR-2008 Summary: (provided by applicant): Research efforts of this Program Project are designed to identify and map genes in newly discovered quantitative trait loci (QTL) and to elucidate their contributions to susceptibility to genetic hypertension and target organ damage. Four projects supported by five cores comprise this Program. The Program theme emphasizes genomics of the effect of stressors on aberrant cardiovascular responses in the SHR, unique genetic rodent models, including the only colony of HXB-BXH rat Recombinant Inbred (RI) strains outside of Europe, and the pursuit of genes which (a) determine resting arterial pressure, (b) determine autonomic
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responses to environmental and behavioral stress, or (c) determine susceptibility to hypertension from repeated episodes of stress. The first subproject will seek candidate genes in new QTL discovered for mild airpuff startle stress-elicited tachycardia and pressor responses, for bradycardia associated with the Orienting Response, and for a cluster of blood pressure QTL on chromosome 2. Dr. Kurtz's subproject will build on its studies of the genes, Srebp-1 and CD36, and their role in abnormal lipid, glucose and plasma insulin in the SHR. Dr. Nigam's subproject will study the cell biology and mechanisms of action of new and unknown factors which exert inhibition on the formation of the developing ureteric tree and ultimately nephron number. Dr. Taylor's subproject will continue studies of hyper-responsiveness of spinal nicotinic receptors in the SHR and define the gene structure of nicotinic receptor subunit genes, which are in close proximity to a blood pressure locus. Cores will provide the folkowing functions: administration; breeding of rodents; telemetry and phenotyping, statistical genetic analyses, gene discovery, informatics and genotyping. The contributions of this Program should enhance our knowledge of genes, which determine susceptibility to repeated stress, to hypertension, to metabolic risk factors and to target organ damage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC DETERMINANTS OF SUDDEN CARDIAC DEATH Principal Investigator & Institution: Albert, Christine M.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 05-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): Sudden cardiac death (SCD) affects 400,000 individuals each year in the U.S. alone. Over half have no evidence of heart disease prior to death, and our ability to identify those at risk and therefore prevent SCD is poor. Mutations in cardiac ion channel genes including SCN5A, KVLQT1, HERG, KCNE1, KCNE2, and RyR2 have been implicated in monogenic traits with a high risk of SCD, such as the Iong-QT, Brugada, sudden infant death syndrome, and catecholaminergic polymorphic ventricular tachycardia. Alterations in ion channel function can result in life-threatening ventricular arrhythmias in diverse disease states. Therefore, sequence variants in these genes that alter function or transcription of these ion channels may confer a predisposition to ventricular arrhythmia and SCD in broader populations. This research program proposes to determine if sequence variants in the above candidate genes are associated with an increased risk of SCD in apparently healthy populations. Cases of SCD will be assembled from five NIH-funded prospective cohorts with a total of 106,314 individuals with existent blood samples. All cohorts are exceptionally wellcharacterized with respect to environmental exposures and have collected medical records on cardiovascular endpoints. We will characterize all coding sequence variation and selected non-coding sequence variation among 100 cases and controls from these cohorts. Using these novel markers, we will define the haplotype block structure (SNPs in linkage disequilibrium) for the six genes. We will then employ a nested case-control design and conditional logistic regression to test for associations between haplotypes (haplotype tag SNPs) in both coding and non-coding regions and SCD risk. We will also test directly for associations between single loci that may have functional significance and SCD risk. An estimated 600 cases of well-documented SCD will be confirmed over the first three years of the grant period, and these cases will be matched on age, sex, ethnicity, and geographic location to two control subjects from the same cohort. In addition, based upon known sex-differences in the phenotypic expression of the candidate genes in the primary arrhythmic disorders, we will specifically examine sexdifferences in the risk of SCD associated with sequence variation in these genes. The
34
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findings generated will have substantial implications for our understanding of the SCD syndrome and risk stratification in the general population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC SUSCEPTIBILITY IN ACQUIRED LONG QT SYNDROME Principal Investigator & Institution: Murray, Katherine T.; Associate Professor; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GUIDANT & CPI VENTAK FOR CONGESTIVE HEART FAILURE Principal Investigator & Institution: Birgersdotter, Ulrika; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: HYPOTHERMIA FOR PEDIATRIC CARDIAC ARREST PLANNING GRANT Principal Investigator & Institution: Moler, Frank W.; Pediatrics & Communicable Dis; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 24-JUL-2003; Project End 30-JUN-2005 Summary: (provided by the applicant): Cardiopulmonary arrest with apnea and loss of palpable pulse (CA) in childhood is a tragic event that very often results in either death or poor quality long-term neurological survival. Recent randomized clinical trials (RCT) in adult populations have reported improved neurologic outcome and survival in groups that received short term mild hypothermia following out of hospital ventricular fibrillation (VF) arrest. The efficacy of hypothermia in children following cardiac arrest is not known. CA in children is commonly secondary to a respiratory etiology that results in hypoxia, which after a period of time results in cardiac arrest. Asystole or pulseless electrical activity are the most common presenting cardiac rhythms when resuscitation is initiated. In adults by contrast, a sudden cardiac event (without a preceding period of hypoxia) most often occurs with VF or ventricular tachycardia, the common presenting rhythms. In this clinical trial planning grant application, 15 Pediatric Emergency Care Applied Research Network (PECARN) children's hospitals with intensive care units will obtain pilot data from the medical records of patients who have sustained a CA with return of spontaneous circulation in either the outpatient or inpatient setting. Characterization of this population will include arrest specific events and etiology, patient characteristics, hospital course, interventions received, hospital survival, and neurologic outcome. This information will be used to create inclusion and exclusion criteria, and to calculate sample size requirements for a future RCT of hypothermia following pediatric cardiac arrest. Duration of time to successfully enroll patients from this cohort of 15 children's hospitals for a future RCT will be estimated. This application will also result in creation of multiple documents needed to perform a RCT of hypothermia after cardiac arrest in childhood including study related data forms, study protocols, manuals of operation, institutional review board and informed
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consent related documents, and other materials. The PECARN will support all phases of this application with its existing clinical trials research infrastructure that includes a steering committee, five clinical trials supporting subcommittees, and a central data management coordinating center (CDMCC). The CDMCC will make operational all data and analysis related tasks of this application, and assure all study sites are compliant with regulations concerning data security and confidentiality. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LASER TACHYCARDIA
CATHER
FOR
ABLATION
OF
VENTRICULAR
Principal Investigator & Institution: Gowda, Ashok; Biotex, Inc. 8018 El Rio Houston, Tx 770544104 Timing: Fiscal Year 2002; Project Start 28-SEP-1999; Project End 31-JUL-2004 Summary: (provided by applicant): Ventricular Tachycardia (VT) is a life-threatening condition characterized by an abnormally high rate of ventricular contraction. During VT, the ventricles lack sufficient time to fill with blood prior to each contraction often resulting in dizziness, loss of consciousness and sudden cardiac arrest. Catheter ablation has been shown to be an effective means for curing many arrhythmias, but current approaches are not able to coagulate tissue in the midmyocardium or subepicardial regions where foci responsible for VT often originate. We have developed a cooled-tip laser catheter (CTLC) capable of creating large lesions that extend into these regions with little to no thermal damage to the endocardium. In our phase I study we designed, built, and tested prototypes of the CTLC system. The current system is comprised of an 8F deflectable catheter, which houses a fiber optic and a pathway for circulation of saline. We incorporated a low cost pump system and a low-power diode laser to complete the system. Acute and chronic animal studies were performed to test the prototype system and the results were indeed dramatic. Using our CTLC system, we successfully produced large (1 cm in diameter) lesions that began on average 1 mm below the irradiated surface. These lesions were free of char or carbonization and well circumscribed by a distinct border separating the lesion form normal tissue. Additional advantages of our approach include the ability to monitor real-time electrophysiological activity during delivery of laser energy. In Phase II we plan to refine the current CTLC by including functional mapping electrodes and improving maneuverability. Animal studies are designed to characterize in a thorough manner the dose response for our system, compare it against current state of the art ablation technologies, and acquire data necessary for submission of an investigational device exemption from the FDA for clinical trials. PROPOSED COMMERCIAL APPLICATION: This research is specifically targeted towards the development of an improved laser-based catheter for treatment of VT. Cardiac arrhythmias including ventricular tachycardia (VT) and ventricular fibrillation (VF) are responsible for 400,000 cases of sudden death in the U.S. each year. Unlike other therapies, our catheter has potential for providing a curative means for patients who suffer from VT, and therefore could become the treatment of choice in such patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LIGAND BINDING AND FUNCTIONAL ASSAY-BASED HERG DATABASE Principal Investigator & Institution: Perschke, Scott E.; Novascreen Biosciences Corporation 7170 Standard Dr Hanover, Md 21076
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Tachycardia
Timing: Fiscal Year 2002; Project Start 25-SEP-2002; Project End 24-MAR-2003 Summary: (provided by applicant): The HERG (human ether-a-go-go-related) gene encodes a membrane protein that functions as a K+ -channel. There is intense interest in the HERG protein because interactions between drugs and the HERG channel protein have become a major impediment in the development of new and safe pharmaceuticals. Interactions of drugs with the HERG channel alter the repolarization of the hearts' electrical system, causing tachycardia and occasionally heart failure. This has led to the removal of at least one drug from the market, and caused many others to fail in clinical trials. There is an increasing demand for methodologies that will allow prediction and identification of lead compounds with potential HERG channel activity early in the drug discovery process. The specific aims of this proposal are to develop multiple ligand binding assays and a functional assay for the HERG channel, as expressed in CHO cells. Once developed, approximately 20 known HERG inhibiting drugs will be screened for dose response in all assays developed and the data collected and assembled in a database. This database will then be used as the basis for a Phase 2 study that greatly expands the chemicals tested, to identify key molecular and chemical descriptors that are predictive of drug and protein interactions with the channel. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM TACHYCARDIA
AND
BEHAVIOR
OF
SYMPTOMATIC
Principal Investigator & Institution: Pritchett, Edward L.; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
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 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-, Beta1- and 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
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(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: MECHANISMS OF DEPRESSION AND CARDIOVASCULAR PATHOLOGY Principal Investigator & Institution: Grippo, Angela J.; Psychology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-APR-2002 Summary: (provided by applicant): This research proposal addresses physiological mechanisms and processes underlying the association between depression and cardiovascular disease. Human studies demonstrate a strong link between depression and coronary artery disease but have not progressed beyond correlational methods. The current proposal will examine the underlying mechanisms in depression and cardiovascular pathology by using a rodent model of depression (chronic mild stress) and a combination of behavioral, physiological, and pharmacological techniques. Rats will be exposed to chronic mild stress to induce the depression-associated sign of anhedonia (a reduced capacity to experience pleasure), and tested for cardiovascular impairments (Aim 1). Autonomic nervous system imbalance will be examined as a mechanism for the cardiovascular dysfunction (e.g., elevated heart rate and reduced heart rate variability) associated with the chronic mild stress model (Aim 2). In addition, central serotonin activity will be examined as a common pathophysiological factor underlying both depression and cardiovascular/autonomic dysfunction (Aim 3). This research will extend our knowledge of the interactions between psychological and physiological conditions, and possibly prompt the development of new treatments for patients with depression and/or cardiovascular disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISMS OF SYMPTOMS IN NEUROPATHIC PAIN & RSD Principal Investigator & Institution: Dotson, Rose; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002 Summary: The hypothesis and specific aims are focused on the pathophysiology of two different groups of conditions. The first group is orthostatic intolerance, specifically the postural tachycardia syndrome (POTS). The second group is neuropathic pain. The studies on neuropathic pain have been organized into 2 types of painfulness in response to a normally non-painful stimulus (allodynia) and to the enigma of reflex
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Tachycardia
symmpathetic dystrophy. The allodynias are in response to light touch (dynamic allodynia) and to pressure (static allodynia). The primary hypothesis is that patients with POTS develop a post-viral, presumably immune-mediated length-dependent autonomic neuropathy and that secondary brain-stem mechanisms supervene, resulting in a hyperadrenergic state. We will evaluate the pathophysiology of orthostatic intolerance using microneurographic recordings of muscle sympathetic nerve activity from peroneal nerves of patients with the postural tachycardia syndrome (POTS) and controls. We will specifically evaluate if resting muscle sympathetic nerve activity is increased (due t increased central drive) or reduced (due to denervation) and, to evaluate varoflex responsiveness, if the response to orthostatic stress and to induced blood pressure alterations are impaired. The hypothesis for the study of patients with neuropathic pain who have dynamic mechanical allodynia is that low threshold mechanoreceptor primary afferents propagate neural impulses to the central nervous system and result in the experience of pain with dynamic mechanical allodynia. The study will determine if rapid repetitive intraneural microstimulation of single low threshold mechanoreceptor primary afferents in patients with peripheral neurogenic pain and dynamic mechanical allodynia causes pain as the first perceived sensation with liminal intensity (the lowest intensity at which the subjects reports a perceived sensation) of electrical stimulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANO-ELECTRIC FEEDBACK IN THE HEART Principal Investigator & Institution: Trayanova, Natalia A.; Professor; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2006 Summary: SUBPROJECT ABSTRACT NOT PROVIDED Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MODE SELECTION TRIAL IN SINUS NODE DYSFUNCTION (MOST) Principal Investigator Washington, Dc 20059
&
Institution:
Williams,
Deborah;
Howard
University
Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MODULATION OF CARDIAC K+ CHANNELS BY DRUGS Principal Investigator & Institution: Sanguinetti, Michael C.; Associate Professor; Internal Medicine; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-JUL-1996; Project End 30-JUN-2005 Summary: Drugs that block the rapid delayed rectifier K+ current (Ikr) cause prolongation of cardiac action potentials and electrical refractoriness. These compounds were developed as antiarrhythmic agents based on positive findings in canine models of ischemia-induced ventricular tachycardia and fibrillation. Unfortunately, most class III antiarrhythmic drugs, as well as 70 other common mediations that block Ikr as a sideeffect, can cause an inhomogeneous prolongation of ventricular action potentials and induce long QT syndrome and its associated ventricular arrhythmia, torsades de pointes. It is unclear why so many structurally diverse compounds block Ikr, but this
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undesirable side effect is now recognized as a major hurdle in the development of new and safe drugs. The recent awareness that block of Ikr can induce arrhythmias prompted interest in the development of IKs blockers as antiarrhythmic agents. However, in the past 5 years it was discovered that mutations in any of the genes that encode the alpha- and beta-subunits that co assemble to form Ikr (HERG and MiRPl or IKs (KvLQT1 and minK) channels cause inherited long QT syndrome and sudden death. The overall goal of this project arises from our progress during the past four years where we defined the mechanisms of Ikr block and the molecular determinants of binding of a potent class III antiarrhythmic agent to the HERG channel. We now propose to characterize the blocking mechanisms and binding site for additional antiarrhythmic agents and other commonly used medications that block Kr and Ks channels. The specific aims are to characterize the molecular determinants of high affinity drug block of HERG and KvLQT1 channels, the role of the inactivated state in drug block of HERG channels, and how binding of accessory beta-subunits (minK, MiRP1 and MiRP2) enhances drug block of HERG and KvLQT1 channels. An understanding of the molecular determinants of drug binding to Kr and Ks channels will facilitate design of safer drugs that are devoid of the propensity to induce the long QT syndrome and potentially fatal arrhythmias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR MECHANISMS OF CARDIAC ARRHYTHMIAS Principal Investigator & Institution: Wang, Qing; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 30-JUN-2006 Summary: (provided by applicant): Cardiac arrhythmias account for more than 300,000 sudden deaths each year in the U.S. alone. Our laboratory is investigating the pathogenesis of cardiac arrhythmias. We focus on two arrhythmic disorders: long-QT syndrome (LQT) and idiopathic ventricular fibrillation (IVF), both of which cause sudden death in the young, otherwise healthy, individuals. During the past 8 years of this project, we focused on genetics and in vitro electrophysiology of LQT and IVF. Together with other scientists, we have defined a genetic pathway for pathogenesis of both LQT and IVF. Further exploration of pathogenic mechanisms of LQT and IVF at the tissue and organ level is impossible because of lack of fresh heart tissues from patients. In the proposed studies we plan to develop and characterize LQT- and IVF-animal models in which SCN5A (the cardiac sodium channel gene) mutations are engineered into the mouse genome to further explore the etiology of arrhythmogenesis. We have successfully established a mouse model for LQT and ventricular arrhythmias by targeting an SCN5A mutation (N1325S). Characterization of our arrhythmic mice has led to the working hypothesis that early and after depolarizations (EADs and DADs) are the substrate for ventricular tachycardia (VT) and ventricular fibrillation (VF). In the proposed studies we plan to continue to study the mouse model for LQT to uncover detailed molecular mechanisms of cardiac arrhythmias, and to generate and characterize mouse models for IVF and acquired LQT. Our specific aims are: (1) To investigate whether over-expression of an LQT-causing mutation of SCN5A in the mouse heart will trigger electrophysiological remodeling; (2) To systematically dissect EADs and DADs induced by a genetic LQT mutation; (3) To systematically determine the effects of representative agents from each class of antiarrhythmic drugs on VT/VF and correlate the findings with results on EADs/DADs; (4) To characterize SCN5A mutations associated with IVF and acquired LQT using the transgenic mouse technology. The successful accomplishment of goals in this proposal will provide a fundamental
40
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understanding of the pathogenic mechanisms of cardiac arrhythmias. Evaluation of animal models will help define the physiological and cellular processes involved in arrhythmogenesis, and bridge the gap between the in vitro biophysical defects and the in vivo whole animal phenotype characterized by arrhythmia susceptibility. These studies may provide a new framework for the rational design of therapeutic agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR STUDIES OF GAP JUNCTION REMODELING Principal Investigator & Institution: Fishman, Glenn I.; William Goldring Professor; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002 Summary: Description (Adapted from Applicant's Abstract) Several lines of investigation suggest that dysregulation of gap junction intercellular communication, or gap junctional remodeling, contributes to the substrate for ventricular arrhythmias. Using the canine infarct model, investigations in this Program have shown that changes in the structural location of gap junctions and the electrophysiological properties of gap junctions are associated with functional lines of block in reentrant circuits. Similar gap junctional remodeling has also been observed in human ischemic cardiomyopathy and in our studies of genetically modified mice with ventricular tachycardia and sudden cardiac death. Myopathic hearts, however, show a multitude of structural and functional perturbations, thus, the unique arrhythmias has been difficult to study in isolation from other contributory factors. The goal of the studies described in this proposal is to understand the molecular mechanisms of gap junctional remodeling and to determine the specific contribution of dysregulated intercellular coupling to the formation of the arrhythmogenic substrate. The applicant has, therefore, begun to elucidate mechanisms controlling gap junctional expression and remodeling and discovered that the Wnt signaling cascade, acting through beta-catenin via duel transcriptional and post-translational mechanisms, is an important regulatory pathway controlling connexin43 expression. Furthermore, they have prepared several conditions gene-targeted murine models to elucidate the role of remodeling in formation of the arrhythmogenic substrate. Their goals in junctional remodeling, conduction abnormalities and arrhythmogenesis, using gene-targeted and chimeric mice; 2) to determine the role of beta-catenin mediated signaling and its relationship with other signaling pathways in the regulation of Cx43 expression in normal and remodeled cardiomyocytes and hearts; 3) to determine the mechanisms responsible for gap junctional reentrant excitation appears to be related to changes in gap junction distribution. Elucidation of the mechanisms regulating gap junctional remodeling and its role in the arrhythmogenic substrate have significant implications for novel pharmacotherapy of lethal cardiac arrhythmias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MOLECULAR TARGETING OF CA2+ AND K+ CHANNELS IN HEART Principal Investigator & Institution: Kass, Robert S.; Professor of Pharmaclogy and Chairman; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002 Summary: Description (Adapted from Applicant's Abstract) The overall goal of the research proposed in this project is to identify molecular properties of cardiac ion channel proteins and organic drug molecules that will allow targeted control of calcium
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entry in cardiac myocytes in general and in myocytes surviving in the border zone of infarcted hearts in particular. Motivation for this goal comes from data in other projects of this program where it was shown that increasing L-type calcium channel current may prevent reentrant tachycardia in the infarcted canine heart, and that functional and molecular properties of key ion channels (Na+, Ca2+, and K+) are altered in epicardial cells that survive in the epicardial border zone (EBZ) of infarcted hearts. The overall goal of this project is thus to provide molecular insight into mechanisms that would permit more precise targeting of drugs to control calcium entry in these cells. There are thus three specific aims of this project. (1) to identify molecular determinants that target potentiation of calcium entry to cardiac vs. smooth muscle L-type calcium channels: (2) to test the hypothesis that drug-induced changes in L-type Ca2+ channel deactivation kinetics is a powerful mechanism of modulating calcium entry into targeted cells; and (3) to test the hypothesis that subunit assembly of 1Ks channel, which may differ between normal and EBZ cells, confers unique pharmacological and regulatory properties upon expressed channels. Together this information will provide a molecular basis for targeting control of calcium entry into cells of the EBZ which, in combination with the data obtained from other Projects of this program will provide the framework for the development of novel anti-arrhythmic therapy to control reentrant arrhythmias in ischemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MRI COMPATIBLE ELECTRODE CATHETER SYSTEM Principal Investigator & Institution: Gelfand, Yakov; Lexmed Technologies, Inc. 7708 Crossland Rd Baltimore, Md 21208 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2004 Summary: (provided by applicant): Atrial fibrillation and ventricular tachyarrhythmias occurring in patients with structurally abnormal hearts are the most important arrhythmias in contemporary cardiology. They represent the most frequently encountered tachycardias, account for the most morbidity and mortality, and, despite much progress, and remain therapeutic challenges. Invasive studies of the electrical activity of the heart (electrophysiologic study) are often used in the diagnosis and therapy of arrhythmias, and many arrhythmias can be cured by selective destruction of critical electrical pathways with radiofrequency (RF) catheter ablation. Attempts at applying ablation to atrial fibrillation and ventricular tachycardia have been made. Success has been limited, however, by the long time duration of procedures, resulting from the difficulty of creating continuous linear lesions in a setting where areas of ablated myocardium cannot be directly visualized. Continuous linear lesions, without gaps, can block critical arrhythmogenic circuits and reduce the amount of electrically contiguous arrhythmogenic substrate, thereby eliminating arrhythmias. We hypothesize that magnetic resonance imaging (MRI), with MRI-compatible diagnostic and therapeutic systems; can allow electrophysiology studies and catheter ablation to be performed without x-ray radiation. We also hypothesize that this technology will provide the ability to visualize ablation lesions, which should greatly simplify production of continuous linear lesions, and should improve the effectiveness of ablation procedures in general. In addition to electrophysiology, these methods may be applicable to guiding other diagnostic and therapeutic techniques. In Phase I, we will complete a prototype steerable ablation catheter that will allow us to target any area of the endocardial surface of the heart. We will also develop integral filters for protecting the catheters from excessive heating during MR imaging. We will test the prototype catheters in animals to show that electrophysiology studies can be done under MR
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guidance alone, that lesions can be produced and imaged, that linear lesions can be produced, and that MRI has sufficient resolution to allow detection of significant gaps in the lesions. In Phase II, we will develop, test, and prepare for manufacturing and marketing, a clinical-grade version of the ablation system, and apply for FDA approval for testing the technology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NERVE SPROUTING AND ELECTRICAL REMODELING Principal Investigator & Institution: Chen, Peng-Shen; Director, Pacemaker and Icd Clinic; Cedars-Sinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 900481804 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2004 Summary: The objective of this research project is to test the hypothesis that the interaction between neural remodeling (nerve sprouting) and electrical remodeling underlie the mechanisms of ventricular arrhythmogenesis after myocardial infarction (MI). We recently reported a positive correlation between the nerve density of native hearts of transplant recipients and a clinical history of ventricular arrhythmia. We also demonstrated in dogs that nerve growth factor (NGF) infusion to the left stellate ganglion could facilitate the development of ventricular tachycardia (VT), ventricular fibrillation (VF), and sudden cardiac death (SCD). Based on these findings, we propose Nerve Sprouting Hypothesis of ventricular arrhythmia and SCD. The hypothesis states that MI results in nerve injury followed by sympathetic nerve sprouting and regional myocardial hyperinnervation. The coupling between augmented sympathetic nerve sprouting with electrically remodeled ventricular myocardium results in VT, VF and SCD. Modification of nerve sprouting after MI may provide a novel opportunity for arrhythmia control. To test this hypothesis, we plan to pursue the following specific aims: (1) Mechanisms of cardiac nerve sprouting. We will use in-situ hybridization and immunocytochemical staining to detect NGF mRNA and the tenascin proteins in a canine model of MI. (2) Anatomical distribution and functional asymmeta of left and right stellate ganglia. We will study the differential electrophysiological effects of nerve sprouting of the left and right stellate ganglia. We will also use immunocytochemical techniques to demonstrate a differential anatomical distribution of nerves from these two ganglia. (3) Origin of nerves that sprout after MI. We will use recombinant lentivirus vectors (rLVs) to transfer fluorescent protein genes into the stellate ganglia. The cardiac nerve distribution will be determined by the location of positive immunocytochemical staining and fluorescent protein expression. (4) Induction of right stellate ganglion nerve sprouting by electrical current. We will use electrical current to induce cardiac nerve sprouting from the right stellate ganglion and to reduce the incidence of ventricular arrhythmia and SCD. These studies may lead to novel insights into the mechanisms of ventricular arrhythmogenesis after MI and may help develop new methods for arrhythmia control. 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
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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 •
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 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
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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: NOVEL CATHETER FOR TREATMENT OF VENTRICULAR TACHYCARDIA Principal Investigator & Institution: Curley, Michael G.; President; E.P., Ltd 35 Medford St, Ste 204 Somerville, Ma 02143 Timing: Fiscal Year 2002; Project Start 29-SEP-1999; Project End 31-AUG-2004 Summary: (provided by applicant): Sudden cardiac death kills 300,000 people in the United States yearly. More than half of these deaths are caused by arrhythmias including ventricular tachycardia. Radiofrequency ablation, which successfully treats supraventricular tachycardia, is not successful at treating ventricular tachycardia because conventional RF ablation catheters cannot treat a large enough volume of myocardium. In Phase 1 of this project, we have demonstrated the feasibility of salineenhanced ablation. We will have used infusion of warm saline through the myocardium (simultaneous with the application of radiofrequency or laser heating energy) to increase the tissue thermal transport by a factor of 20 or more. We have shown that this method can increase the volume of thermal lesions in myocardium by a factor of 12. These lesions are capable of treating the full thickness of the myocardium, and therefore show promise toward treatment of ventricular tachycardia. We will continue the development of this system during this Phase 2 project. Based on the Phase 1 results we will continue our development using saline enhanced radiofrequency ablations. We will develop a steerable catheter that will have a porous radiofrequency electrode at the tip, which will be inserted into the myocardium. The catheter will have a central lumen with an RF heater to heat the saline before injecting it into the myocardiurn. We will qualify this prototype catheter and system in preclinical studies of ventricular tachycardia in animal models at the Mayo Clinic and the Brigham and Women's Hospital. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ORTHOSTATIC INTOLERANCE IN AUTONOMIC NEUROPATHIES & POSTURAL TACHYCARDIA SYNDROME Principal Investigator & Institution: Low, Phillip A.; Professor; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002 Summary: The pathophysiology of orthostatic intolerance including orthostatic hypotension (OH) is poorly understood and hence its treatment has been unsatisfactory. The focus of this proposal is on the elucidation of mechanisms of orthostatic intolerance in the postural tachycardia syndrome (POTS) and neurogenic OH and develop pathophysiologically- based new treatment strategies. We will undertake a doubleblind, randomized, 4-way cross-over study of pyridostigmine in the treatment of neurogenic OH. This strategy of acetylcholinesterase inhibition to increase the safety factor of ganglionic transmission could improve OH without supine hypertension. A similar study will evaluate its efficacy in neurogenic POTS, where denervation is often also present. A blinded study will evaluate if sodium chloride will increase plasma volume and if urinary sodium secretion is a reliable surrogate measure of plasma volume. Seven studies will evaluate the pathophysiology of POTS. One is a power spectral analysis of autonomic rhythms that modulate the EEG. In particular, an ultralow frequency band (0.02-0.05 Hz) is reduced in POTS and may be of brainstem origin. One study will evaluate if carbonic anhydrase inhibition will improve cerebral perfusion and symptoms of POTS, since hypocapnia on head-up tilt is present. Two studies are focused on the venous capacitance bed in the legs and abdomen. One evaluates if the capillaries are excessively leaky, using plethysomographic techniques. The other evaluates, using a modified G- suit (compresses specific venous compartments), which capacitance beds are most responsible for orthostatic intolerance. Techniques are now available to study the systemic )beat-to-beat BP and impedance methodology), mesenteric (superior mesenteric blood flow ultrasonography), cerebrovascular (transcranial doppler) circulations simultaneously, and sympathetic discharges can be directly measured using microneurography. The hypothesis that pre-ganglionic lesions cause a different pattern of autonomic vascular involvement to post- ganglionic lesions will be tested. Finally, the independent predictors of auto-regulatory adaptation of the cerebrovascular circulation in neurogenic OH will be studied. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ORTHOSTATIC INTOLERANCE IN CFS Principal Investigator & Institution: Freeman, Roy; Associate Professor of Neurology; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 01-FEB-1998; Project End 30-JUN-2007 Summary: (provided by applicant): The chronic fatigue syndrome (CFS) is a common disorder of unknown cause that incapacitates young individuals in their most productive years. There is evidence that orthostatic intolerance may play a role in the fatigue of patients with CFS. The broad long-term objectives of the project are to delineate the pathophysiology and pathogenesis of orthostatic intolerance in the chronic fatigue syndrome (CFS); to investigate the role of orthostatic intolerance in producing the symptoms of CFS; to use this information to institute physiologically appropriate therapeutic interventions; and thereby decrease the symptoms of fatigue. The Specific Aims of the application are to enhance cardiovagal outflow with low dose atropine and Iosartan and examine the cardiovascular response to orthostatic stress; to characterizing sympathetic nervous transduction to vascular resistance in the lower limbs and
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characterize the sympathetic responses in the lower limbs to orthostatic stress; to measure transcapillary interstitial fluid filtration during orthostatic stress determine the relationship between capillary filtration and plasma volume; and characterize cerebral blood flow, systemic pressure maintenance, postural tachycardia and parasympathetic outflow. We will assess arterial baroreflex gain by measuring the heart rate and muscle sympathetic nerve activity response to pharmacological provocations; sympathetic transduction by relating muscle sympathetic nerve activity to peripheral resistance; plasma volume using the Evans Blue dye method; venous compliance using venous occlusion plethysmography; and cerebral blood flow velocity with transcranial Doppler. These measures, which comprise the elements of orthostatic tolerance, will be compared with healthy controls selected to match the gender, age and level of physical activity of the subjects. The relationships between these variables and role of covariates such as the level of physical activity and psychiatric state, determined with standardized instruments, will be analyzed using multivariate statistics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OVARIAN HORMONE METABOLITES & NEURAL CIRCULATORY CONTROL Principal Investigator & Institution: Heesch, Cheryl M.; Associate Professor; Veterinary Biomedical Sciences; University of Missouri Columbia 310 Jesse Hall Columbia, Mo 65211 Timing: Fiscal Year 2002; Project Start 01-SEP-1985; Project End 31-DEC-2003 Summary: (Adapted from the application) Normal pregnancy is associated with a 40% increase in blood volume and cardiac output, slight tachycardia, and a decrease in arterial blood pressure. Enhanced baroreflex sympathoinhibition and attenuated sympathoexcitation have been reported in pregnant animals, although the mechanisms have not been well defined. The primary metabolite of progesterone, 3-alpha-hydroxydihydroprogesterone (3-alpha-OH-DHP), which is elevated in pregnancy, is a potent positive modulator of central nervous system (CNS) inhibitory GABA-A receptors. Exogenous administration of 3-alpha-OH-DHP to virgin animals mimics the effects of pregnancy: sympathoinhibition is enhanced and sympathoexcitation is attenuated, most likely through a CNS mechanism. Importantly, blocking the formation of endogenous 3alpha-OH-DHP in pregnant reverses the attenuated sympathoinhibition. Previous studies focused mainly on enhanced arterial baroreflex sympathoinhibition. In the current proposal, experiments are designed to evaluate mechanisms for the attenuation of sympathoexcitatory responses (likely not arterial baroreflex mediated). The general hypothesis is to be tested that attenuated sympathoexcitation during pregnancy is associated with GABAergic mechanisms in central nervous system sites involved in regulation of cardiovascular function. Three possibilities will be evaluated: Increased inhibitory influences from peripheral receptors other than arterial baroreceptors, increased inhibitory influences from the CNS, and decreased excitatory effects in the rostral ventrolateral medulla (RVLM, brainstem site of cardiovascular sympathetic premotor neurons). Experiments in virgin and pregnant rats will evaluate the CNS expression of Fos protein in identified neuronal populations involved in central cardiovascular control following manipulations which normally increase or decrease efferent sympathetic nerve activity. Efferent sympathetic nerve activity will be recorded in other experiments in which inhibitory afferent inputs, CNS inhibitory influences, and excitatory inputs to the RVLM will be altered. Understanding the mechanism for suppressed sympathoexcitatory responses in normal pregnant animals will have
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important implications for hypertensive disorders or pregnancy which are associated with exaggerated sympathoexcitatory responses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PARTICLE-INDUCED CARDIAC EFFECTS IN SENESCENT MICE Principal Investigator & Institution: Tankersley, Clarke G.; Assistant Professor; Environmental Health Sciences; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2008 Summary: (provided by applicant): Plausible biological mechanisms remain elusive to explain the association between daily fluctuations in air pollution and increased mortality rates. Specifically, airborne particulate matter (PM) has been identified as the constituent of air pollution that is most culpable in correlating with increased mortality rates. Pathophysiologic mechanisms leading to tachycardia and bradycardia appear potential processes that increase PM-induced risk of mortality in humans and animal models. Because epidemiology studies also identify aging as a risk factor, we developed a unique model to define risk associated with terminal senescence based on a series of pathophysiological assays. HYPOTHESIS: Senescent-dependent changes in the neurohumoral regulation of the heart during PM exposure manifest acute instability in cardiac function resulting from imbalances in the autonomic nervous control and altered atrial natriuretic peptide regulation. Specific aim 1 characterizes specific pathophysiologic variables associated with loss of homeostasis in senescent mice of different inbred mouse strains. Specific aim 2 determines the interactive effects of terminal senescence and acute PM exposure on heart rate regulation and cardiac function. Here, we postulate that only terminally senescent animals are susceptible to the acute cardiac effects of PM exposure. Specific aim 3 determines the interactive role of innate susceptibility factors in acute PM-induced imbalances in autonomic neural regulation of heart rate, blood pressure and cardiac function. The focus of this aim considers PM-induced cardiac functional changes owing to genetic susceptibility factors. Specific aim 4 tests whether senescent-dependent susceptibility to PM-induced cardiovascular dysfunction evolves from adverse modifications in atrial natriuretic peptide (ANP) regulation. In the final aim, cardiac mechanisms surrounding right ventricular function and pulmonary hypertension are considered important factors in PM-induced susceptibility. The interaction between aging and PM exposure obliterates the cardioprotective effects of ANP leaving the heart acutely susceptible to instability. In summary, the proposed studies are significant because they represent a multidisciplinary approach that will advance our understanding of the adverse cardiac health effects of air pollution exposure in the elderly Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PH III: AZIMILIDE CONTROLLED TRIAL Principal Investigator & Institution: Bahnson, Tristram D.; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PHYSIOLOGIC BENEFITS OF BIVENTRICULAR PACING IN CHF Principal Investigator & Institution: Hamdan, Mohamed H.; Associate Professor of Internal Medicine; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 20-SEP-2000; Project End 31-AUG-2004 Summary: (The applicant's description verbatim): Acute biventricular (BV) pacing has been shown to result in hemodynamic improvement in patients with left ventricular dysfunction. Based on these studies, the effect of long term BV pacing on exercise tolerance and quality of life are being assessed in large prospective trials. What remains unknown are the effects of BV pacing on sympathetic activity, a known predictor of cardiac mortality, and on the incidence of ventricular arrhythmias. We hypothesize that in patients with LV dysfunction 1) BV pacing decreases sympathetic activity compared to intrinsic conduction in the presence of intraventricular conduction delay 2) BV and LV pacing improves hemodynamics and decreases sympathetic activity compared to right ventricular pacing 3) BV pacing decreases the inducibility of ventricular arrhythmias and 4) that this latter effect is due to preexcitation and prolongation of the coupling interval in the "slow" zone of the tachycardia circuit. To test these hypotheses, consecutive patients referred to the arrhythmia section at the Dallas VAMC with LV dysfunction and an indication for electrophysiologic evaluation will be enrolled in the study. During phase 1 and 2, arterial pressure, central venous pressure and muscle sympathetic nerve activity using microneurography will be recorded during sinus rhythm, atrial pacing (in patients with a QRS greater than 150msw) and atrialventricular pacing (RV, LV or BV). Pacing will be performed at a rate 10 beats faster than sinus rhythm. During phase 3 and 4, we will assess the effect of BV pacing on the inducibility of ventricular arrhythmias and the associated electrophysiologic changes. The outcome of this study will have a great impact on our management of patients with congestive heart failure. A reduction in sympathetic activity, demonstrated first with acute BV pacing and later with long term pacing, may have a beneficial effect on mortality. Similarly, a reduction in inducibility of ventricular arrhythmias, if present with long term pacing, may have an impact on the survival and on our management of patients with implantable defibrillators and frequent shocks. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PREVENTION OF INTRA ATRIAL REENTRANT TACHYCARDIA AFTER STAGED FONTAN REPAIR Principal Investigator & Institution: Law, Ian H.; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PROGNOSTIC VALUE OF REPOLARIZATION MEASURES Principal Investigator & Institution: Green, Larry S.; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002 Summary: This project is a clinical study of repolarization factors that predict arrhythmia risk. It consists of two related subprojects that both focus on quantitative measures of repolarization that will lead to clinically useful assessment of arrhythmia
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risk. The techniques used to measure repolarization will be derived from those developed in the animal experimental studies in Project 4 and they will then be applied to studies that evaluate therapeutic interventions in arrhythmia prone patients. Hence this project plays a pivotal role in linking the technical developments in experimental studies to the direct clinical application of monitoring and will prospectively evaluate repolarization abnormalities in over 2000 post-myocardial infarction patients using multi-read electrocardiography. Project 5.2 will study the role of the autonomic nervous system on repolarization in a group of patients with documented ventricular tachycardia. One study will measure repolarization changes leading up to arrhythmic events by means of QT interval, ARIs, and T- wave amplitudes measured from Holter ECGs. The second wave will induce repolarization changes by means of head-up tilt and compare the ECGs. The second study will induce repolarization changes by means of head-up tilt and compare the resulting repolarization change to those observed prior to spontaneous episodes of ventricular tachycardia. Success in these studies would provide robust electrocardiographic screening methods for arrhythmic sudden cardiac death. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROSPECTIVE ASSESSMENT AFTER PEDIATRIC CARDIAC ABLATION Principal Investigator & Institution: Van Hare, George F.; Pediatrics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-MAY-1998; Project End 30-APR-2004 Summary: (Adapted from Investigator's Abstract) Radiofrequency catheter ablation is a catheterization laboratory technique for the cure of cardiac arrhythmias, which has become common in pediatric cardiology practice. Recent analyses have suggested that ablation therapy is more cost-effective compared not only with surgery, but also with antiarrhythmic medication. Despite a good initial success rate of the technique, and a low initial complication rate, there is concern about possible long-term effects with the technique in the pediatric age group. There are reports not only of damage to cardiac valves, but also the development of new arrhythmias, including sudden death, as a result of ablations in children. Recurrences are observed frequently following initially successful procedures. Finally, there are animal data to suggest that immature myocardium is more prone to severe damage as a result of ablation procedures. Few, if any, data exist to support the long-term safety of these ablation techniques in children. Therefore, before ablation therapy becomes the standard approach in children, it is important to carefully assess the long-term risks in this patient group. The application presents plans to conduct a multi-center, prospective, 5-year study to evaluate children undergoing catheter ablation at pediatric centers in North America. The collection of these data is intended to provide the following information: 1) the incidence of serious cardiac damage as a result of ablation; 2) the incidence and time course of recurrence after initially successful ablation; and 3) the incidence of proarrhythmia following ablation. A total of 450 pediatric patients will be enrolled prospectively and evaluated both before ablation of supraventricular tachycardia and at intervals following ablation with clinical history and examination, electrocardiogram, 24-hour Holter monitor, and echocardiogram, with non-invasive studies read by outside consultants. In addition, a complete Registry of pediatric patients undergoing ablation at the participating centers will be established to allow comparisons with the study group and to provide population estimates of success and complication rates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: INFARCTION
PURKINJE-MYOCARDIAL
REENTRY
IN
ISCHEMIA
AND
Principal Investigator & Institution: Pollard, Andrew E.; Associate Professor; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: The contribution of the heart's specialized conduction system to arrhythmia initiation is not completely understood. While Purkinje fibers are considered a potent source for the initiating extrasystoles in focal and reentrant ventricular arrhythmias, recent suggests a contribution of Purkinje-myocardial reentry to polymorphic tachycardia that can precede fibrillation and sudden death. Our main objective is to investigate how reentrant circuits distribute between the peripheral conduction system and overlying myocardium during early cycles of sub-endocardially- induced ventricular arrhythmias. We believe those circuits circumscribe functional centers that are primarily located on the peripheral conduction system-myocardial interface, where the two components are weakly coupled via the system of discrete Purkinje-ventricular junctions (PVJs). We hypothesize this arrangement establishes peripheral conduction system and myocardial wavefronts that are out of phase with one another, which places critical importance about the ability of premature action potentials to propagate from peripheral conduction system to myocardium, i.e. antegrade PVJ conduction, for reentry maintenance. Antegrade PVJ conduction is inherent discontinuous because the myocardium imposes a large electrical load on peripheral conduction system. Experiments to test this hypothesis will use 1056-channel electrical mapping from perfused rabbit right ventricular free wall surfaces. Companion stimulations will incorporate membrane equations for ionic currents into detailed grids replicating the interface. The project has two aims. The first aim is to establish the relationship between antegrade PVJ PVJ conduction and subendocardially induced ventricular arrhythmias in macroscopically normal hearts. The second aim is to correlate regional acute ischemia and healing myocardial infarction with peripheral conduction system participation during subendocardially induced ventricular tachycardia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RANDOMIZED CLINICAL TRIALS FOR PEDIATRIC HEART DISEASE Principal Investigator & Institution: Saul, J P.; Pediatrics; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-AUG-2006 Summary: (provided by the applicant) The Children?s Heart Program of South Carolina is a statewide consortium of pediatric cardiologists, who care for 90% of the 3.7 million residents in the state. This consortium has all the critical elements for a center in the proposed research network: adequate patient volume, clinical research infrastructure, a track record of subject enrollment, and a demonstrated dedication to hypothesis driven clinical research. The applicant center, MUSC, is the tertiary referral center for the Children?s Heart Program. Current MUSC faculty have participated as PI?s in a total of 20 multicenter clinical trials or registries (10 open, 2 under IRB review). The PI of this application has been the lead investigator nationally in 4 of the 20. These protocols range from industry sponsored drug or device trials, to an NIH sponsored drug trial for fetal heart block, to an NIH prospective registry. The faculty also currently runs 11 local clinical research protocols. Participation in all of these protocols is supported by a dedicated pediatric cardiac research support group with 2 full time RN coordinators and
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an additional RN FTE. The combined resources of high volume and strong research infrastructure have enabled the PI?s at MUSC to be one of the top 2 subject recruiters in 6 of the 18 completed or active multicenter studies. As requested, the proposal contains a short-term and a long-term protocol. Short-Term. Randomized Trial of Aortopulmonary Collateral Coil Occlusion Prior to Fontan. Multiple factors influence morbidity and mortality for single ventricle patients undergoing Fontan operation. One considered recently is the presence of APC?s. However, multiple retrospective studies have failed to clearly delineate the role of APC?s or their optimum management. This protocol will prospectively evaluate the role of APC?s in postoperative Fontan hemodynamics and morbidity, and determine the importance of preoperative coil embolization in their management. Long-Term. Randomized Trial of Amiodarone vs Cooled- Tip Catheter Ablation for Treatment of Recurrent Intra-atrial Reentry Tachycardia (IART) in Patients with Congenital Heart Disease. IART, the single largest cause of morbidity late after repair of congenital heart disease, is often life-threatening, frustrating to treat and has no clearly superior therapy. This protocol will prospectively compare the most successful medical and catheter therapies for IART. The primary endpoint during a minimum of 2 years follow-up will be IART recurrence after successful ablation, or after drug loading and cardioversion. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REENTRANT MONOLAYERS
ACTIVITY
IN
CULTURED
CARDIAC
CELL
Principal Investigator & Institution: Tung, Leslie; Associate Professor; Biomedical Engineering; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 08-AUG-2001; Project End 30-JUN-2005 Summary: Reentrant mechanisms play a primary role in many types of arrhythmias, including tachycardia and flutter in the atria, ventricles, and atrioventricular node. Reentry may involve anatomical pathways, or it may be functional, with leading circle, figure-eight, anisotropic, and spiral wave variants. The primary goal of this research is to establish a simple and reproducible cultured cell model for the study of anatomical and functional cardiac reentry under well-controlled experimental conditions. We propose to use voltage-sensitive dyes and high- resolution optical mapping to monitor reentrant activity in monolayers of neonatal rat heart cells. A detailed computational model will be verified against experimental data drawn from action potential and intracellular calcium measurements, and their restitution and rate-dependent behavior in this experimental model. The computational model will be used to identify the ionic currents and biophysical mechanisms responsible for reentry behavior. New microfabrication and surface chemical approaches will also be used to develop patterned substrates that direct the growth of cells in the monolayers. The combined experimental and computational approach that is proposed in this study will permit a detailed quantitative analysis and dissection of tissue behavior down to the cellular level. We will, 1) formulate an experimentally-based, biophysical model of the neonatal rat cardiac cell monolayer 2) characterize reentry in confluent monolayers of cultured neonatal rat heart cells, and 3) determine the electrophysiological properties and role of the core of the reentrant circuits. Issues of critical mass, excitable gap, and leading circle vs. spiral wave reentry will be addressed. These aims will establish the cultured cell monolayer as a well-controlled, versatile and quantitative experimental model for basic studies of reentry- based arrhythmias. The simplicity and flexibility of this model system provides numerous advantages over existing tissue models of reentrant
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arrhythmia. Moreover, the cell culture is well suited for studies involving pharmacological, genetic and molecular manipulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF LATE INWARD CURRENT IN HUMAN HEART FAILURE Principal Investigator & Institution: Makielski, Jonathan C.; Professor of Medicine and Physiology; Medicine; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 26-SEP-2000; Project End 31-AUG-2004 Summary: Action potential prolongation in heart failure may contribute to the generation of arrhythmia in heart failure. The action potential could be prolonged either by decreasing outward currents or by increasing inward currents during the plateau phase. Nearly all studies of electrical remodeling underlying this prolongation have emphasized decreased outward current by down-regulation of potassium channels. Recent studies, including our own preliminary results, show an increase in late inward sodium current in animals models of heart failure, and we show in this application for the first time that it is also significantly increased in human heart failure. We propose to study this sodium current in ventricular cells from normal and failing hearts from a canine tachycardia pacing model of heart failure, and for normal and failing human hearts. Using whole cell and single channel voltage clamp techniques we will determine the amplitude and kinetics of this current under conditions important for physiological and pathophysiological interpretation including Ca and Na dependence, temperature dependence, regional and transmural distribution and heterogeneity, and antiarrhythmic drug block. We will also study the effect of sodium channel block on action potential duration for cells from epi, endo, and mid-myocardium. The potential mechanisms for the increase in late current in heart failure will be studied. These include alpha subunit isoform switching or beta subunit down-regulation, altered regulation by cell signaling pathways (alpha and beta adrenergic, endothelin and angiotensin), and other mechanisms such as altered free fatty acids, cytoskeleton, and nitric oxide regulation. These studies will produce the first detailed data on late sodium currents in humans and its regulation, and at the same time investigate the mechanism and the significance for this current in the electrical remodeling underlying arrhythmogenesis in heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REMODELING OF GAP JUNCTIONS IN REENTRANT CIRCUITS Principal Investigator & Institution: Wit, Andrew L.; Professor; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002 Summary: Description (Adapted from Applicant's Abstract) The applicant's have shown that structural remodeling of gap junctions, characterized by increased connexin43 along the lateral myocyte membranes, occurs in reentrant circuits that cause ventricular tachycardia in canine infarcted hearts. This discovery has led to this proposal in which the objectives are; 1) to determine the role of gap junction structural remodeling and altered gap junction physiology (electrophysiological remodeling) that occur as a consequence of myocardial infarction, in causing slow an discontinuous conduction necessary for reentrant excitation and 2) to determine how remodeled gap junctions in reentrant circuits affect the response of ventricular arryhthmias to anti-arrhythmic
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drugs. To accomplish these objectives, a canine infarct model of reentrant circuits in the epicardial border zone will be investigated with different methodologies designed to elucidate structured, electrophysiology and pharmacology of gap junctions. These include in vivo activation mapping, immunolocalization of connexin proteins, and measurements of transjunctional conductances in myocyte cell pairs from the infarct border zone. The different methods will be integrated to investigate the following questions. Does the pattern of structural gap junction remodeling determine the size, shape and location of reentrant circuits and the kinds of arrhythmias which occur? How does gap junctional remodeling of influence propagation of electrical activity i.e. does it cause discontinuous conduction and conduction block? Is structural remodeling associated with reduction in transjunctional conductance that contributes to slow conduction? Are remodeled gap junctions more sensitive to changes in intracellular calcium, possibly explaining the occurrence of conduction block during rapid heart rates or after pharmacologically increasing the L-type calcium current? Does an increased sensitivity of remodeled gap junctions to pH play a role in causing slow activation and conduction in regions with poor gap junction coupling? And, are remodeled gap junctions a sensitive target for drug induced termination of reentrant arrhythmias? When the answers to those questions are obtained, the applicants assert that they will have a comprehensive picture of the electrophysiological and pharmacological consequences of gap junctional remodeling in ischemic heart disease. Gap junctions will be shown to be an important target for drug development to prevent sudden arrhythmic death. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RENAL DENERVATION IN ORTHOSTATIC INTOLERANCE Principal Investigator & Institution: Biaggioni, Italo; Professor of Medicine and Pharmacology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SELECTIVE MODULATION OF THYROID RECEPTOR ACTION Principal Investigator & Institution: Baxter, John D.; Professor and Director of Medicine; Diabetes Center; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2007 Summary: (provided by applicant): Nuclear receptors (NRs) regulate numerous medically important processes in humans and include receptors for thyroid (TH) and steroid hormones, vitamin D, retinoids and prostaglandins. Selective modulation of NR function is an emerging concept in NR ligand design. While there is progress, many concepts are poorly understood. Many TH actions would have medical utility in reducing cardiovascular disease risk. TH stimulates metabolism, promotes weight loss, and lowers plasma levels of cholesterol, triglycerides, and lipoprotein (a). However, TH benefits are offset by deleterious influences, including effects on heart that include lifethreatening tachycardia and arrhythmia. It is desirable to block TH in hyperthyroidism, but current blockade by inhibiting TH production is slow in onset. Thus, it is important to identify selective TR modulators (STRMs). We used structure-activity profiling and TR X-ray crystal structures for designing: (i) selective TR modulators (STRMs) that preferentially bind the TRbeta-form, and may be prototype drugs for treating obesity
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Tachycardia
and lipid disorders; and (ii) novel TR antagonists and partial agonists. Preliminary studies indicate that these ligands could have further potentially useful selective properties, including differences in cell uptake, activation and suppression of individual promoter elements, and abilities of their activities to be regulated by coactivators and corepressors. In the proposed studies we plan to examine properties of a spectrum of ligands to better understand their activities. We will determine effects of individual STRMs on: (i) TR conformation; (ii) TR interactions with cofactors in cell-free conditions and in cells; (iii) individual TR activation functions; (iv) TR-mediated gene expression at model promoters; and (v) gene expression profiles in intact cells. The information obtained will be integrated to provide profiles for individual and combinatorial features that may be ultimately exploited for rational design of ligands with more desirable profiles than either pure agonists or antagonists. This study will expand our understanding of selective TR modulation in specific and NR action in general. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SOTALOL IN CHILDREN WITH TACHYARRHYTHMIAS Principal Investigator & Institution: Triedman, John K.; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SPECIALIZED CENTER OF RESEARCH IN SUDDEN CARDIAC DEATH Principal Investigator & Institution: Marban, Eduardo; Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 20-JAN-1995; Project End 31-DEC-2004 Summary: Sudden cardiac death accounts for 30-50% 0f heart failure mortality. This proposal, which is the continuation of an existing SCOR program in Sudden Cardiac Death, investigates the biological basis of altered excitability in heart failure and how predisposes to fatal ventricular arrhythmias. The SCOR is motivated by the following central hypothesis: Abnormalities of ionic currents and calcium handling render repolarization unstable in failing myocardium, increasing spatiotemporal variability of repolarization and predisposing patients with heart failure to sudden death. This hypothesis has been tested and validated extensively in the first five years of the program. We now propose to probe the biological basis of the abnormal repolarization, with a view to developing novel strategies for the identification of patients at high risk. Our program features a central animal model (pacing tachycardia canine heart failure) as well as tissue and myocytes from explanted human hearts. The program consists of five projects and five cores. Project 1, directed by Eduardo Marban, will use gene transfer and cell fusion to dissect the molecular determinants of cardiac repolarization. Project 2 focuses on L- type calcium channel inactivation. Project 2 focuses on L-type calcium channel inactivation under the leadership of David Yue. Project 3, directed by Gordon Tomaselli, investigates the relative roles of voltage- dependent and calciumdependent mechanisms in the action potential prolongation of heart failure. Project 4 probes the neurohumoral modulation of electromechanical remodeling in heart failure, under the directorship of David Kass. Project 5, led by Ronald Berger, examines temporal QT interval variability as a predictor of severe arrhythmias and sudden cardiac death in patients. The five cores will provide support in the following areas:
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administrative matters, molecular genetics and vectors, animal models and cells, human cells and tissue, and quantitative modeling. The program in its first five years has been highly productive and interactive. The proposed continuation combines existing strengths with new approaches in a strongly synergistic manner. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
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: SUBCUTANEOUS MONITOR/ALARM FOR CARDIAC ARREST Principal Investigator & Institution: Arzbaecher, Robert C.; Professor and Director; Aj Medical Devices, Inc. 155 N Harbor Dr, Ste 2804 Chicago, Il 60601 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 30-MAY-2004 Summary: It is estimated that 220,000 people suffer cardiac arrest each year in the US, of whom only 10,000 survive to hospital discharge. The number of survivors could increase 10-fold if paramedical attention and/or defibrillation were available within a new minutes of the attack. It is the goal of our company to develop and deploy new and innovative technology that improves survival of cardiac arrest by lessening the time to treatment. This is a proposal to design, develop, and test the feasibility of an implanted monitor that notifies bystanders and emergency medical services (EMS) of an incipient
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Tachycardia
cardiac arrest and/or acute myocardial ischemia. Such notification can shorten materially the time to defibrillation of most witnessed, and all unwitnessed, episodes of cardiac arrest, thereby improving survival manyfold. The tiny device will automatically detect the lethal event and signal transcutaneously to a cellphone-size purse, pocket, belt-worn or night stand unit which gives voice instructions to bystanders, spouse, or other witnesses and transmits victim location to the nearest EMS. Candidates for the implanted device are those readily identifiable cardiac patients whose medical condition and/or history puts them at particularly high risk of cardiac arrest. PROPOSED COMMERCIAL APPLICATIONS: The monitor/alarm will address the problem of 220,000 cardiac arrests a year of which only 3-5% presently survive. An implanted monitor/alarm could speed life saving rescuers to a victim of cardiac arrest, summon EMS automatically, and provide instant victim location. The US market for such a device could exceed 100,000 units, as our ability to define the population at risk improves. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SUBSTRATE TACHYCARDIA
MAPPING
&
ABLATION OF
VENTRICULAR
Principal Investigator & Institution: Reddy, Vivek Y.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 30-JUN-2007 Summary: (provided by applicant): In patients with coronary artery disease at risk for sudden cardiac death, malignant ventricular tachycardia (VT) is treated with a combination of implantable defibrillators and antiarrhythmic drugs. While effective in preventing sudden cardiac death, this strategy is plagued with medication side-effects and toxicities, and device related iatrogenic complications. The ideal treatment for VT would be eradication of the arrhythmia. This can be accomplished with greater than 90% efficacy through surgical resection of the infarcted arrhythmogenic tissue; however, this is an open surgical procedure associated with significant morbidity and mortality. Radiofrequency (RF) catheter ablation is an effective less-invasive alternative, but is largely limited to hemodynamically-tolerated VT-which accounts for less than 10% of all VT. However, the approach to catheter ablation of VT is undergoing a paradigm shift. Instead of trying to precisely identify the critical portions of the VT circuit during tachycardia, "substrate mapping" is performed in sinus rhythm to identify the arrhythmogenic tissue. Then, a probabilistic approach to catheter ablation is undertaken using strategically-placed linear RF lesions. While this strategy has proven to be successful in small non-randomized studies, the safest and most efficacious method to deliver the RF ablation is not known. Also, the role of substrate ablation in the primary prevention of ICD shocks is unknown. We now propose to conduct prospective randomized clinical trials: a) comparing the standard non-irrigated to the salineirrigated RF ablation catheter for substrate-mapping and ablation in the treatment of patients with multiple ICD shocks (the THERMO COOL IDE trial), and b) examining the role of substrate-mapping and RF ablation in the primary prevention of ICD shocks (the SMASH-VT trial). Furthermore, the abilitv of a new 3-dimensional mapping system to rapidly identify the arrhythmogenic substrate will be examined in a porcine model of healed myocardial infarction with inducible VT. Finally, using this advanced mapping system to identify the substrate, the effect of catheter-mediated cryoablation will be compared to RF ablation using a saline-irrigated catheter on the inducibility of VT in this animal model system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SURGICAL TREATMENT OF CARDIAC ARRHYTHMIAS Principal Investigator & Institution: Boineau, John P.; Medical Science Service; Surgery; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 08-AUG-1983; Project End 31-JUL-2003 Summary: This renewal application requests five years' support for work now in continuous progress for over 15 years at Washington University. Dr. John Boineau, the new PI, has replaced Dr. James Cox, the former P1, who transferred to Georgetown University Hospital. Dr. Cox remains as a special consultant. The broad aims continue to be the direct or surgical ablation of cardiac arrhythmias. The emphasis of the current renewal is focused upon the development of a new procedure, the radial incisions approach (RIA), to eradicate atrial fibrillation (AF) and restore atrial transport function and is directed primarily toward patients undergoing surgery for valvular or ischemic heart disease. Conventional valve or CABG surgery does not eliminate and may not prevent AF in these patients. The availability of an effective means of eradicating this arrhythmia in these patients at the time of surgery would permit control of rate and rhythm, limit embolic stroke, and improve cardiac performance, outcome, and the quality of life. Whereas the Maze and RIA assume randomly distributed and changing reentry which are eliminated without prior activation mapping, new data indicate that some forms of AF result from (spatially) stable reentry which can be identified by new mapping methods and focally ablated. Thus, a second project is directed toward map guided, focal cryoablation of AF. This could be performed off bypass as a more limited and rapid alternative to the more extensive and (bypass) time consuming RIA procedure. A third project is targeted at prevention and correction of postoperative atrial flutter (AFL) after the Fontan operation in congenital heart patients or after lung transplant surgery. Studies will be performed in both realistic animal models with atrial enlargement and patients with AF and AFL and will center about the use of new automated, 3-D mapping techniques and rapid numerical analysis of potentials recorded simultaneously from to 512 electrodes during the arrhythmias. Preliminary observations indicate that the proposed studies are feasible, will provide new information regarding the different mechanisms of AF and AFL that are related to atrial enlargement and/or atrial surgery, and this data will be used to develop the new surgical ablation techniques to control or prevent these arrhythmias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SWELLING ACTIVATED CURRENTS AND MYOCYTE VOLUME IN CHF Principal Investigator & Institution: Baumgarten, Clive M.; Professor of Physiology; Internal Medicine; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2004; Project Start 30-SEP-2000; Project End 31-JAN-2005 Summary: (the applicant's description verbatim): Congestive heart failure (CHF) induces significant changes in cardiac myocyte size. Increased myocyte volume (hypertrophy) ultimately requires intracellular accumulation of osmolytes and water. Intracellular osmolarity is regulated in myocytes by multiple mechanisms, including transmembrane flux of ions through channels that are sensitive to changes in cell volume. We discovered that one of these ionic currents, the cell swelling-activated Clcurrent (IC,lswell) is chronically activated under isosmotic conditions in ventricular myocytes from dogs with tachycardia-induced and rabbits with aortic regurgitationinduced CHF. Furthermore, we showed that the activity of ICl,swell and cell volume in CHF and control myocytes were regulated by protein kinase C (PKC) and protein
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Tachycardia
phosphatases thought to control phosphorylation of ion channels responsible for lCl,swell. The overall objective is to understand how Icl,swell and cell volume are regulated in volume and pressure overload models of CHF and how hormonal and autocrine-paracrine factors implicated in the genesis of CHF contribute to this regulation. The effects of catecholamines, autocrine-paracrine factors including angiotensin II and cardiotrophin-1, and selected growth factors on Icl,swell and cell volume will be examined. Intracellular signaling pathways, including protein kinase C, tyrosine kinases, mitogen-activated protein kinases, and phosphatases, will be examined to evaluate their influence on lCl,swell and myocyte volume. Perforated patch voltage clamp and digital video microscopy will be used concurrently to quantify ionic currents and their effect on cell volume. Single myocytes isolated acutely from either sham operated or CHF animals will be studied because these cells better reflect the in vivo state during CHF than do cell culture models. Because no single model of CHF fully represents clinical CHF, pressure, tachycardia, and volume overload models of CHF will be used. Where appropriate, the effect of interventions on cell signaling pathways will be confirmed with western blot with phospho-antibodies. The following questions will be addressed: 1. Are lCl,swell behavior and its effect on myocyte volume different in pressure than volume overload CHF? 2. Is Icl,swell activated prior to onset of clinically apparent CHF in pressure and volume overload models? 3. Are lCl,swell and myocyte volume regulated by autocrine-paracrine factors that are important in the genesis of CHF? 4. Do intracellular signaling pathways that are important in CHF influence lCl,swell and myocyte volume? Knowledge of swelling-activated ion currents and how they influence myocyte volume in CHF may provide important insights into the pathophysiology of tachyarrhythmias and contractile and diastolic dysfunction that occur in CHF. Further, this work may lead to new approaches to treat or prevent CHF and thereby, reduce the morbidity and mortality of this common disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SYMPATHETIC TACHYCARDIA
RESPONSES
DURING
VENTRICULAR
Principal Investigator & Institution: Weiss, James N.; Kawata Professor Med. & Physiol.; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002 Summary: Objective. The longterm goal of this project is to investigate further the role of the sympathetic nervous system in determining sudden cardiovascular death during ventricular tachycardia in humans, and thereby improve survival. Background. In humans, sympathetic nerve activation during ventricular tachycardia is an important determinant of hemodynamic stability during ventricular tachycardia, independent of ventricular function and tachycardia rate. In animal models, the arterial baroreflex and cardiopulmonary baroreflex have important, yet opposing, effects on sympathetic activation during ventricular tachycardia. The relative contributions of these control mechanisms in humans is unknown. Specific Aims. The immediate aim o this study is to determine the roles of the arterial and cardiopulmonary baroreflexes, and the additional contributions of ventricular dysfunction and orthostatic stress, in determining sympathetic activation and hemodynamic stability during ventricular tachycardia in humans. Design. Using microneurography of the peroneal nerve, sympathetic nerve activity directed to muscle and to skin will be measured and compared in patients with hemodynamically stable and unstable ventricular tachycardia. A series of interventions which selectively activate arterial and cardiopulmonary baroreceptors will be performed
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to determine the contribution of each to sympathetic responses observed during induced ventricular tachycardia or rapid ventricular pacing. Patients with a wide range of ventricular function will be studied, including those with advanced heart failure and patients who have undergone orthotopic heart transplant (which denervates cardiopulmonary baroreceptors). Chaos theory will be used to analyze sympathetic recordings in the different patient groups, based on preliminary results suggesting qualitative differences between normal subjects and heart failure patients. Significance. The knowledge gained from these studies may serve as a basis for the development of medical and surgical therapies directed at the correction of the underlying abnormalities that predispose the patient to hemodynamically unstable ventricular tachycardia degenerating into ventricular fibrillation and sudden cardiovascular death. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SYSTOLIC CARDIAC FUNCTION IN OBESITY AND EXERCISE Principal Investigator & Institution: Carroll, Joan F.; Integrative Physiology; University of North Texas Hlth Sci Ctr Fort Worth, Tx 761072699 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: (Adapted from applicant's abstract) The candidate's immediate career goals are to study the role of the beta-receptor signaling pathway in mediating systolic dysfunction in obesity, and the role of exercise training in attenuating obesity-related cardiovascular defects. The Department of Integrative Physiology at the University of North Texas Health Science Center is uniquely suited to help the candidate achieve these goals. Within the department, there is a wide variety of expertise in human, animal, in vivo, and in vitro studies in cardiovascular physiology and endocrinology. This will aid in developing expertise with a variety of surgical, laboratory, and assay techniques to study cardiac function. Further, the Cardiovascular Research Institute at the University of North Texas Health Science Center provides access to research efforts of molecular biologists, pharmacologists, physiologists and physicians from within the institution and from nearby institutions. This will benefit career development by providing opportunities to integrate knowledge from many fields which impact cardiovascular research. The current proposal has three major goals: 1) to determine mechanisms associated with reduced cardiac contractile responsiveness to betaadrenergic stimulation in obesity, 2) to determine the role of exercise training in attenuation of obesity-induced abnormalities in cardiac function, and 3) to determine the role of obesity, separate from hypertension, in contributing to systolic dysfunction in sedentary and trained animals. The investigators hypothesize that there are multiples sites of decreased activity in the beta- signaling pathway in obesity. Thus, they will use the rabbit method of dietary-induced obesity to compare function of lean animals with that of obese animals after 12 weeks of a high fat diet. They will use the Langendorff isolated heart preparation and appropriate assay and western blotting techniques to analyze the role of the beta-receptor and four sites of post- receptor activity in contributing to cardiac abnormalities in obesity. The investigators also hypothesize that exercise training during the development of obesity will attenuate or prevent obesityrelated cardiovascular abnormalities. They will determine whether exercise training will 1) reduce obesity-related hypertension, resting tachycardia, and neurohumoral activation, and 2)attenuate obesity-related decreases in responsiveness to betaadrenergic stimulation. They will examine hemodynamics and neurohumoral activation in vivo and use the isolated heart preparation to determine the role of exercise training in increasing responsiveness to beta-adrenergic stimulation. Finally, they hypothesize that obesity has an independent effect on cardiac hypertrophy and systolic dysfunction.
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They will test this hypothesis by maintaining blood pressure at control levels as obesity develops before testing for responsiveness to beta-adrenergic stimulation. Insight into mechanisms whereby obesity increases risk for congestive heart failure may lead to advances in therapeutic modalities for prevention and treatment of heart failure in obese patients. Information on mechanisms whereby exercise training may improve cardiovascular risk profile and cardiac performance in obesity may help reduce risk for development of cardiovascular diseases in obesity. Because such a large segment of the American population is overweight or obese, the knowledge and insight gained from these studies can have far-reaching effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE PATHOPHYSIOLOGY OF T-WAVE ALTERNANS Principal Investigator & Institution: Narayan, Sanjiv M.; Medicine; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 17-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant) This Mentored Patient-Oriented Research Career Development Award application focuses on a program of research designed to study the intracardiac mechanisms underlying T-wave alternans (TWA) of the electrocardiogram in individuals with prior myocardial infarcts and depressed cardiac systolic function in order to improve its computation and therefore its ability to predict those who are at risk for ventricular tachycardia (VT) or fibrillation (VF). This work will build on the applicant?s prior research and training in clinical cardiology and invasive electro-physiology, as well as in basic science, computer science and numerical methods. The proposed research will test the hypothesis that programmed ventricular stimulation in patients with ischemic heart disease and left ventricular dysfunction induces proarrhythmic nonuniformities in ventricular repolarization, and results in redistribution of TWA late in the T-wave, and TWA phase reversal, that are detectable by novel analyses of the ECG. There are two specific aims: 1) To establish that an increased magnitude of TWA late in the T-wave and TWA phase reversal parallel changes in the endocardial dispersion of ventricular repolarization measured, using monophasic action potentials, during progressive programmed ventricular stimulation leading to the induction of VT/VF. 2) To prospectively test, in patients with ischemic heart disease and left ventricular dysfunction, the performance of a new index of myocardial electrical instability, derived from the data calibrating TWA late magnitude and phase to the dispersion of monophasic action potential duration obtained in the research performed to fulfill Specific Aim 1, in predicting the incidence of spontaneous VT/VF. The applicant will perform this work under the supervision and guidance of his Mentor, and with guidance from a Scientific Advisory Committee comprising experts in basic and clinical electrophysiology, in the interpretation of monophasic action potentials, in numeric modeling and signal processing, in statistics and in clinical research. This structured approach will ensure the successful completion of this project and, in this way, the development of the applicant into an independent clinicianinvestigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THREE DIMENSIONAL VORTEX LIKE REENTRY IN CORONARY PERFUSED VENTRICULAR WALL Principal Investigator & Institution: Pertsov, Arkady M.; Associate Professor; Upstate Medical University Research Administration Syracuse, Ny 13210
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Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2003 Summary: The electrophysiological mechanisms of polymorphic ventricular tachycardia and fibrillation remain poorly understood. The surface manifestations as well as limited three-dimensional (3D) information obtained using arrhythmias. In the proposed study, we will utilize a new experimental method (transillumination) that should significantly enhance our ability to study 3D reentrant activity via visualization of its organizing center-filament. Using transillumination in combination with conventional optical mapping we will test the following major hypotheses: 1. In 3D ventricular myocardium, the filament tends to align parallel to myocardial fibers. 3. Sustained polymorphic ventricular tachycardia and fibrillation are maintained by stable filaments concealed in the depth of myocardial wall. Hypotheses 1 and 2 are based on preliminary computer simulations of 3D myocardial wall with realistic fiber geometry. Hypotheses 3 is supported by electrically induced tachycardia or fibrillation. The specific aims of our study are as follows: 1. To identify the mechanisms controlling spatial orientation and dynamics of the filament in computer models of ventricular wall with realistic fiber organization. 2. To study the evolution of the scroll-wave filament during sustained and non-sustained arrhythmias in isolated coronary-perfused preparations of sheep right and left ventricles using a transillumination technique. 3. To determine the role of stable filaments in the maintenance in the maintenance mechanisms of complex reentrant ventricular arrhythmias. The ultimate goal of this study is to assess the possibility of terminating those arrhythmias by controlling the evolution of the scroll wave filament. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TOWARDS FIBRILLATION
A
NON-INVASIVE
THERAPY
FOR
ATRIAL
Principal Investigator & Institution: Scherlag, Benjamin J.; Medicine; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Atrial fibrillation (AF) has been called the arrhythmia of the 21st century since it is the most common arrhythmia whose prevalence increases as the population ages. Recent clinical studies have suggested that trains of rapid electrical discharges from the pulmonary veins induce paroxysmal (P) or episodic AF. The mechanism by which this focal activity leads to PAF is unknown. Therefore, our initial studies have concentrated on this mechanism providing for a 4 step strategy towards developing a non-invasive therapy for PAF 1) Demonstration that local autonomic nerve stimulation at the base of the pulmonary veins can cause the conversion of rapid focal firing from the pulmonary veins into PAF. 2) Demonstration that low level electrical stimuli applied to the vagosympathetic trunks can condition the cardiac ganglia so that stimuli applied to the latter will manifest a significant alteration in the threshold for induction of PAF. 3) Utilize time varying electromagnetic fields (EMFs) applied to the cervical vagosympathetic trunks in order to significantly alter the AF threshold. 4) Since magnetic components of EMFs penetrate soft tissues and bone unattenuated, our final approach will employ a large 18" Helmholtz coil by which the EMF will be applied across the chest to induce low-level electrical stimulation of intrinsic cardiac nerves. Again, the objective is to demonstrate electrical conditioning of the local cardiac autonomic nerves in order to alter baseline conditions for AF induction. In this developmental phase, all of these studies will be acutely performed in Napentobarbital anesthetized dogs. Our long-term objectives relate to the extension of the previously described strategies to animal models of chronic or sustained AF which if applied to the clinical arena would profoundly alter the treatment of these arrhythmias
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in man. This new therapeutic approach could be utilized as a non-invasive application or incorporated into an implantable device for treatment of patients with PAF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TREATMENT OF ORTHOSTATIC TACHYCARDIA Principal Investigator & Institution: Robertson, David H.; Professor of Medicine, Pharmacology And; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: T-TUBULES AND L-TYPE CALCIUM CHANNELS IN HEART FAILURE Principal Investigator & Institution: Kamp, Timothy J.; Assistant Professor; Medicine; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-JUL-1999; Project End 31-MAY-2004 Summary: (adapted from the applicant's description): Congestive heart failure results in substantial structural and functional changes at the level of cardiac myocytes. Preliminary results indicate that the t-tubular network is severely depleted or absent in failing canine and human myocytes. This observation has important functional consequences for excitation-contraction (E-C) coupling (which requires close opposition between surface membrane L-type Ca channels (DHPRs) in the t-tubule membrane and Ca release channels (RyRs) in the SR) and beta-adrenergic signal transduction. The general hypothesis of the proposed research is that sub-cellular remodeling of the ttubule system and junctional domains results in contractile failure and abnormal betaadrenergic regulation in failing ventricular myocytes. This general hypothesis will be tested in myocytes obtained from a tachycardia pacing-induced dog model and confirmed on human cells obtained from patients undergoing cardiac transplantation. The 5 specific aims of the proposed research are: 1) characterization of the t-tubule system density in failing and control hearts using 2-photon and confocal microscopy, 2) quantification of DHPRs in failing and control hearts using electrophysiological and biochemical techniques, 3) define the mechanism of uncoupling of the DHPR and RyR in failing myocytes, 4) determine the mechanism of uncoupling of beta-adrenergic receptors and DHPRs, and 5) perform confocal immunolocalization studies of DHPR subunits, RyR, beta-adrenergic receptors and G-proteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: UTILIZING ETHYL NITRATE GAS IN LAPAROSCOPIC SURGERY Principal Investigator & Institution: Reynolds, James D.; Anesthesiology; Duke University Durham, Nc 27706 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2007 Summary: The principal goal of this project is to evaluate the ability of ethyl nitrate to attenuate the reduced tissue perfusion and respiratory acidosis produced during carbon dioxide pneumoperitoneum. The studies will use a novel method of drug delivery: inclusion of ethyl nitrate in the insufflating gas. Laparoseopy has rapidly become the method of choice for surgical intervention to correct abdominal pathologies. However, pneumoperiteneum, the act of insufflating the peritoneal cavity with gas, is not without physiologic consequence: pulmonary function is impaired and organ blood flows
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altered. In addition, due to its plasma solubility, insufflation with CO2 will increase pCOz and decrease blood pH, actions that can produce respiratory acidosis, tachycardia, and arrhythmia. The overall effects can become profound in the presence of underlying vascular disease, in[ the elderly, if the patient is pregnant, and/or when the duration of surgery is extended. In all situations, tissue ischemia and fetal ischemia (where applicable) can produce significant morbidity. To control this, it is a logical supposition that administration of a vasoactive agent to increase tissue blood flow and gas exchange would be beneficial. For the purposes of this study, we propose to introduce a nitric oxide donator (ethyl nitrate; E-NO) into the insufflating gas. As the released nitric oxide can act locally (i.e. within the peritoneum) as well as entering the systemic circulation and, in the case of the gravid patient, the fetal circulation (either by diffusion or maternal-fetal exchange), this would appear to be an ideal methodology to abate the CO2 pnenmoperiteneum-mediated changes in physiologic status. Such abatement is expected to be of long-term benefit to all laparoscopic patients including the parturient and her fetus. To evaluate this novel therapy, we will test two research hypotheses: 1. In the non-gravida, inclusion of E-NO in the insufflating gas attenuates the tissue perfusion changes produced by CO2 pneumoperitoneum; and 2. In the parturient, inclusion of E-NO during maternal pneumoperitoneum stabilizes fetal physiologic status. Studies will utilize adult swine and pregnant sheep. Completion of this investigation will produce clinically-relevant information that will be of significant interest to surgeons With patients in need of laparoscopic surgery and to obstetricians who are presented with parturients in abdominal distress. It is expected that the results of these studies will be used to further develop and refine standards of care for human laparoscopy and will lead to a novel therapy for controlling the blood flow changes produced during pneumoperitoneum. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: VIDEO INITIATION/TERMINATION
IMAGING
OF
CARDIAC
REENTRY
Principal Investigator & Institution: Gray, Richard A.; Biomedical Engineering; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: Sudden cardiac death is the leading cause of fatalities in the industrialized world. Ventricular fibrillation (VF) is the underlying cause of the majority of these deaths. The only effective means to save the lives of these individuals is to apply high energy electric fields from widely spaced electrodes to terminate VF. These high energy "shocks" can also induce VF, if they are applied during the "vulnerable period" of normal sinus or pace rhythms. The outcome following a shock is determined largely by the charges in transmembrane potential (Vm) during the shock. However, very little is known about the shock- induced changes in Vm in the whole heart and how they relate to the events following a shock. It is thought that the changes in Vm during applied electric fields is a nonlinear function of: 1) the Vm pattern immediately before the sock; 2) the strength and time course (waveform) of the electric field; and 3) the dynamic response of cardiac cells to stimuli. We hypothesize that: I Electric fields greater than some critical strength prevent wave front propagation throughout the heart, and if these shocks are sufficiently long in duration, a steady state pattern of Vm will be established. Vm at the end of short duration shocks, for a constant electric field above this critical strength, can be predicted from Vm at the beginning of the shock and the steady state Vm pattern achieved during long duration shocks. II) The nonlinear response of cardiac cells, most importantly all-or-none depolarization and repolarization, plays an
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important role in the generation of new wave fronts at the end of the shock which may lead to reentry. III) The spatial pattern of Vm at the end of the shock can be related to reentry formation and hence the outcome resulting from the shock. In particular, spatial patterns of cardiac phase can be formally related to reentry via phase singularities and reentry will only occur following a shock if a phase singularity exists at the end of the shock. Our overall goal is to provide the first precise understanding of the factors that determine the changes in Vm during a shock and how the pattern of Vm at the end of the applied electric field affects the outcome of the shock. This goal will be achieved by: 1) recording Vm from the surface of the heart during and following electric shocks given during pacing, monomorphic tachycardia, and fibrillation; 2) recording them response to stimuli in isolated ventricular myocytes; and 3) relating the patterns of membrane potential at the end of shocks to outcome. Furthermore, changes in Vm in single cells and patterns of Vm from the heart surface will be analyzed in terms of a cardiac phase variable which provides a mathematical framework for the examination of cellular dynamics and reentrant waves. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: VIRTUAL ELECTRICAL-ANATOMICAL IMAGING OF THE HEART Principal Investigator & Institution: Khoury, Dirar Shafiq.; Assistant Professor; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2005 Summary: (Provided by Applicant): Atrial fibrillation (AF) is the most common heart rhythm disorder: it affects more than two million Americans, is responsible for one-third of all strokes over the age of 65 years, and annually costs 9 billion dollars to manage. Furthermore, about 300,000 Americans die of sudden cardiac death annually, primarily due to ventricular rhythm disorders (ventricular tachycardia (VT and fibrillation) which result in intractable, extremely rapid heartbeats. Unfortunately, current pharmacological therapy for managing these disorders is often ineffective, thereby shifting emphasis to nonpharmacological therapy (e.g. ablation and pacing). Catheter ablation has been successful in managing many atrial and a few ventricular rhythm disorders. However, due to limitations in present mapping techniques, brief, chaotic, or complex rhythms such as AF and VT cannot be mapped adequately, resulting in their unsuccessful elimination. Advancing the management of abnormal heartbeats is contingent on developing mapping techniques that identify their mechanisms, localize their sites of origin, and elucidate effects of therapy. Our objective is to develop a catheter-based, cardiac electrophysiological imaging technique that simultaneously maps multiple endocardial electrograms on a beat-by-beat basis and combines three-dimensional activation-recovery sequences with endocardial anatomy. The hypothesis is that virtual electrical-anatomical imaging of the heart based on (1) cavitary electrograms that are measured with a noncontact, multielectorde probe and (2) three-dimensional endocardial anatomy that is determined with integrated, intracardiac echocardiography (ICE), provides an effective and efficient means to diagnose abnormal heartbeats and deliver therapy. Therefore, we will: (1) build a noncontact, electrical-anatomical imaging catheter-system that carries both a multielectrode catheter-probe for acquiring cavitary electrograms from multiple directions, and a central ICE catheter for acquiring endocardial anatomical images; (2) advance novel mathematical methods to compute endocardial electrograms and reconstruct three-dimensional activation-recovery sequences based on noncontact cavitary probe electrograms and geometry determined by ICE; and, (3) prove the utility of virtual electrical-anatomical imaging in the canine beating heart by characterizing models of AF, myocardial infarction, and VT and
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identifying their components, and by quantifying ablation lesions as assessed by both electrical and echocardiographic criteria. The proposed catheter can be introduced into the blood-filled cavity without surgery and provides three-dimensional electricalanatomical images on a beat-by-beat basis. With this approach, one can pinpoint the site of origin and type of abnormal heartbeats and advance their therapy. In line with a Bioengineering Research Grant, the research develops a system the outcome of which is to improve the benefit-risk and benefit-cost relationships of patient care and advance heart rhythm-related research. 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 “tachycardia” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for tachycardia in the PubMed Central database: •
ABLATIVE TECHNIQUES FOR SURGICAL TREATMENT OF PAROXYSMAL TACHYCARDIA. by Cooley DA, Ott DA, Gillette PC, Garson A Jr.; 1979 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=287815
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Active Lymphocytic Myocarditis Treated with Murine OKT3 Monoclonal Antibody in a Patient Presenting with Intractable Ventricular Tachycardia. by Bilinska ZT, Grzybowski J, Szajewski T, Stepinska J, Michalak E, Walczak E, Wagner T, Kwiatkowska B, Ruzyllo W.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116737
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Amiodarone for control of recurrent ventricular tachycardia secondary to cardiac metastasis. by Leak D.; 1998; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325549
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Assessment and Treatment of Tachycardias in Ischemic Heart Disease. by Fontaine G.; 1982 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=351675
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Assessment of Tachycardia in Preexcitation Syndromes. by Gallagher JJ, Orgain ES.; 1982 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=351673
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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Assessment of Tachycardia-Prone Individuals. by Wellens HJ.; 1982 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=351672
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Cardiac Sarcoidosis: Two Cases with Ventricular Tachycardia and Review of Cardiac Involvement in Sarcoid. by Wilkins CE, Barron T, Lowrimore MG, Massumkhani GA, Klima T, Younis AC, Treistman B, Hall RJ.; 1985 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=341894
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Cardiac Sarcoidosis: Two Cases With Ventricular Tachycardia and Review of Cardiac Involvement in Sarcoid. by Lam CR.; 1986 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=324640
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Catheter Ablation Techniques in Patients with Supraventricular Tachycardia. by Scheinman MM.; 1986 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=324673
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Cryoablation of Incessant Ventricular Tachycardia: Case Report and Long-Term Follow-Up. by Afshar H, Rasekh A, Treistman B, Leeuwen CV, Duncan JM, Massumi A.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101020
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Cryosurgical Modification of the Atrioventricular Node for Treatment of Atrioventricular Junctional Reentrant Tachycardia. by Perin EC, Petersen F, RizoPatron C, Ott DA, Massumi A.; 1991; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=324964
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Difference in end-tidal CO2 between asphyxia cardiac arrest and ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest in the prehospital setting. by Grmec S, Lah K, Tusek-Bunc K.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=374361
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Electrophysiologic characteristics of sudden QRS axis deviation during orthodromic tachycardia. Role of functional fascicular block in localization of accessory pathway. by Jazayeri MR, Caceres J, Tchou P, Mahmud R, Denker S, Akhtar M.; 1989 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=303771
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Electrophysiologic Testing: Predictive of Amiodarone Efficacy in Recurrent Sustained Ventricular Tachycardia? by Mas IJ, Massumi A, Harlan M, Seger JJ, Hall RJ.; 1987 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=324762
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Exercise-Induced Right Ventricular Tachycardia and Arrhythmogenic Right Ventricular Dysplasia: Electrophysiologic and Therapeutic Considerations. by Solomon SL, Van Osdol KD, Massumi A, Warda M, Hall RJ.; 1983 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=344364
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Increased Sympathetic Nervous System Activity as Cause of Exercise-Induced Ventricular Tachycardia in Patients with Normal Coronary Arteries. by Ozdemir O, Soylu M, Demir AD, Topaloglu S, Alyan O, Geyik B, Kutuk E.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161893
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Neonatal presentation of ventricular tachycardia and a Reye-like syndrome episode associated with disturbed mitochondrial energy metabolism. by Scaglia F, Scheuerle AE, Towbin JA, Armstrong DL, Sweetman L, Wong LJ.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140035
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Prevention of AV Nodal Reentry Tachycardia by Oral Amiodarone: An Alternative Mechanism of Action. by Gold RL, Haffajee CI, Entes KL.; 1987 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=324700
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Programmed electrical stimulation and Amiodarone therapy for the control of persistent junctional tachycardia. by Critelli G, Adinolfi L, Perticone F, Condorelli M.; 1981 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=287922
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Rapid Ventricular Tachycardias Associated with Cilostazol Use. by Gamssari F, Mahmood H, Ho JS, Villareal RP, Liu B, Rasekh A, Garcia E, Massumi A.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116744
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Role of Retrograde His Purkinje Block in the Initiation of Supraventricular Tachycardia by Ventricular Premature Stimulation in the Wolff-Parkinson-White Syndrome. by Akhtar M, Shenasa M, Schmidt DH.; 1981 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=370663
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Role of Tachycardia as an Inotropic Stimulus in Man. by Ricci DR, Orlick AE, Alderman EL, Ingels NB Jr, Daughters GT II, Kusnick CA, Reitz BA, Stinson EB.; 1979 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=372004
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Sinus versus nonsinus tachycardia in the emergency department: Importance of age and heart rate. by Pinto DS, Ho KK, Zimetbaum PJ, Pedan A, Goldberger AL.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=184452
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Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a. by Papadatos GA, Wallerstein PM, Head CE, Ratcliff R, Brady PA, Benndorf K, Saumarez RC, Trezise AE, Huang CL, Vandenberg JI, Colledge WH, Grace AA.; 2002 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122928
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Surgical Treatment of Tachycardias in Preexcitation Syndromes. by Sealy WC.; 1982 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=351660
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Surgical Treatment of Tachycardias in Preexcitation Syndromes. by Sealy WC.; 1982 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=351676
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Tachycardia associated with moxifloxacin. by Siepmann M, Kirch W.; 2001 Jan 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26602
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Transesophageal electrocardiography and adenosine in the diagnosis of wide complex tachycardia. by Lopez JA, Lufschanowski R, Massumi A.; 1994; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325147
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Treatment of Resistant Ventricular Tachycardia with Endocavitary Fulguration and Antiarrhythmic Therapy, Compared to Antiarrhythmic Therapy Alone: Experience in 111 Consecutive Cases with a Mean Follow-up of 18 Months. by Fontaine G, Frank R, Tonet JL, Gallais Y, Touzet I, Todorova M, Baraka M, Grosgogeat Y.; 1986 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=324671
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Ventricular tachycardia during repair of gastroschisis. by Saidi AS, Friedman RA, el Said H, Nuchtern JG, Fenrich AL.; 1998; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325578
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 tachycardia, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “tachycardia” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for tachycardia (hyperlinks lead to article summaries): •
A Long RP' Interval Tachycardia: what is the mechanism? Author(s): Intini A, Stambler B, Varma N. Source: Journal of Cardiovascular Electrophysiology. 2003 December; 14(12): 1379-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678118
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A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel. Author(s): Eldar M, Pras E, Lahat H. Source: Cold Spring Harb Symp Quant Biol. 2002; 67: 333-7. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12858557
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 narrow QRS complex tachycardia: what is the mechanism? Author(s): Okumura Y, Watanabe I, Kofune T, Takagi Y, Saito S, Ozawa Y, Kanmatsuse K. Source: Pacing and Clinical Electrophysiology : Pace. 2003 September; 26(9): 1897-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12930506
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A narrow-QRS tachycardia: what is the mechanism? Author(s): Vijayaraman P, Kok LC, Ellenbogen KA. Source: Journal of Cardiovascular Electrophysiology. 2003 June; 14(6): 670-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12875432
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A not-so-narrow complex tachycardia. Author(s): Indik JH. Source: Cardiology in Review. 2003 September-October; 11(5): 247-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12943599
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A novel form of familial bidirectional ventricular tachycardia. Author(s): Nof E, Lahat H, Constantini N, Luria D, Rosenfeld G, Eldar M, Pras E, Glikson M. Source: The American Journal of Cardiology. 2004 January 15; 93(2): 231-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14715357
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A wide QRS tachycardia inducible only by atrial pacing and terminable only by ventricular pacing. Author(s): Li H, Rovang K, Hee T. Source: Pacing and Clinical Electrophysiology : Pace. 2003 November; 26(11): 2170-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14622321
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Ablation of epicardial macroreentrant ventricular tachycardia associated with idiopathic nonischemic dilated cardiomyopathy by a percutaneous transthoracic approach. Author(s): Swarup V, Morton JB, Arruda M, Wilber DJ. Source: Journal of Cardiovascular Electrophysiology. 2002 November; 13(11): 1164-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12475110
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Ablation of postinfarction ventricular tachycardia guided by isolated diastolic potentials. Author(s): Strohmer B, Hwang C. Source: Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 2003 October; 5(4): 375-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14753635
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Acute blood pressure effects at the onset of supraventricular and ventricular tachycardia. Author(s): Taneja T, Kadish AH, Parker MA, Goldberger JJ. Source: The American Journal of Cardiology. 2002 December 15; 90(12): 1294-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12480037
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Acute results of transvenous cryoablation of supraventricular tachycardia (atrial fibrillation, atrial flutter, Wolff-Parkinson-White syndrome, atrioventricular nodal reentry tachycardia). Author(s): Rodriguez LM, Geller JC, Tse HF, Timmermans C, Reek S, Lee KL, Ayers GM, Lau CP, Klein HU, Crijns HJ. Source: Journal of Cardiovascular Electrophysiology. 2002 November; 13(11): 1082-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12475096
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Advances in ablation therapy for complex arrhythmias: atrial fibrillation and ventricular tachycardia. Author(s): Lin D, Marchlinski FE. Source: Current Cardiology Reports. 2003 September; 5(5): 407-14. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12917057
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Amiodarone therapy for drug-refractory fetal tachycardia. Author(s): Strasburger JF, Cuneo BF, Michon MM, Gotteiner NL, Deal BJ, McGregor SN, Oudijk MA, Meijboom EJ, Feinkind L, Hussey M, Parilla BV. Source: Circulation. 2004 January 27; 109(3): 375-9. Epub 2004 Jan 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14732753
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An 82-year-old man with an implantation of a CPI Ventak AV II DR device for sustained ventricular tachycardia. Author(s): Marieb MA, Schwartz KV. Source: Pacing and Clinical Electrophysiology : Pace. 2003 November; 26(11): 2209. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14622330
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An unusual cause of tachycardia. Author(s): Klafkowski G, Newall N, Sampson C. Source: The British Journal of Radiology. 2003 June; 76(906): 427-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12814932
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Anterograde slow pathway is not the same as retrograde slow pathway conducted in the reverse direction in patients with uncommon atrioventricular nodal reentrant tachycardia. Author(s): Ooie T, Tsuchiya T, Ashikaga K, Honda T, Takahashi N. Source: Journal of Cardiovascular Electrophysiology. 2003 July; 14(7): 722-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12930252
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12807832
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Atrioventricular block during atrioventricular nodal reentrant tachycardia is not always benign. Author(s): Tokano T, Nakata Y, Sasaki A, Mineda Y, Sumiyoshi M, Nakazato Y, Daida H. Source: Japanese Heart Journal. 2003 September; 44(5): 789-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14587661
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Atrioventricular nodal reentry tachycardia with multiple AH jumps: electrophysiological characteristics and radiofrequency ablation. Author(s): Kuo CT, Luqman N, Lin KH, Cheng NJ, Hsu TS, Lee YS. Source: Pacing and Clinical Electrophysiology : Pace. 2003 September; 26(9): 1849-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12930499
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Automatic discrimination between supraventricular and ventricular tachycardia using a multilayer perceptron in implantable cardioverter defibrillators. Author(s): Rojo-Alvarez JL, Garcia-Alberola A, Arenal-Maiz A, Pineiro-Ave J, ValdesChavarri M, Artes-Rodriguez A. Source: Pacing and Clinical Electrophysiology : Pace. 2002 November; 25(11): 1599-604. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12494618
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Baseline reconstruction for localization of rapid ventricular tachycardia from body surface potential maps. Author(s): Jokiniemi T, Simelius K, Nenonen J, Tierala I, Toivonen L, Katilal T. Source: Physiological Measurement. 2003 August; 24(3): 641-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14509302
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Becker muscular dystrophy with bundle branch reentry ventricular tachycardia. Author(s): Negri SM, Cowan MD. Source: Journal of Cardiovascular Electrophysiology. 1998 June; 9(6): 652-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9654233
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Benefit of pacing and beta-blockers in idiopathic repetitive polymorphic ventricular tachycardia. Author(s): Perez-Castellano N, Rodriguez JC, Medina O, Nieto V. Source: Journal of Cardiovascular Electrophysiology. 2001 November; 12(11): 1304-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11761421
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Best approach to nonsustained ventricular tachycardia? Author(s): Tak T. Source: Postgraduate Medicine. 2002 November; 112(5): 99. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12462189
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Bidirectional tachycardia eliminated with radiofrequency ablation. Author(s): Li JM, Welch PJ, Zagrodzky JD, Hamdan MH. Source: Pacing and Clinical Electrophysiology : Pace. 2002 December; 25(12): 1786-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12520685
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Bidirectional tachycardia: two cases and a review. Author(s): Al-Khafaji A, Corwin HL, Adhar GC, Greenberg ML. Source: Anesthesia and Analgesia. 2002 August; 95(2): 310-5, Table of Contents. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12145041
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Bidirectional ventricular tachycardia after radiofrequency ablation of idiopathic left ventricular tachycardia. Author(s): Kuo JY, Tai CT, Lin YK, Yu WC, Chen SA. Source: Pacing and Clinical Electrophysiology : Pace. 2001 September; 24(9 Pt 1): 1412-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11584465
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Bidirectional ventricular tachycardia and channelopathy. Author(s): Laohakunakorn P, Benson DW, Yang P, Yang T, Roden DM, Kugler JD. Source: The American Journal of Cardiology. 2003 October 15; 92(8): 991-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14556882
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Bidirectional ventricular tachycardia. Author(s): Ito S, Tada H, Naito S, Taniguchi K. Source: Journal of Cardiovascular Electrophysiology. 2002 December; 13(12): 1312. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12521355
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Biventricular implantable cardioverter defibrillator use in a patient with heart failure and ventricular tachycardia secondary to Emery-Dreifuss syndrome. Author(s): Walker S, Levy T, Rex S, Paul VE. Source: Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 1999 July; 1(3): 206-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11225801
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Blunt cardiac injury presenting as unsuspected ventricular tachycardia. Author(s): Vogler A, Seaberg DC. Source: The American Journal of Emergency Medicine. 2001 November; 19(7): 607-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11699018
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Broad complex tachycardia--Part I. Author(s): Edhouse J, Morris F. Source: Bmj (Clinical Research Ed.). 2002 March 23; 324(7339): 719-22. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11909791
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Brugada syndrome with monomorphic ventricular tachycardia in a one-year-old child. Author(s): Sastry BK, Narasimhan C, Soma Raju B. Source: Indian Heart J. 2001 March-April; 53(2): 203-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11428478
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Brugada syndrome with ventricular tachycardia and fibrillation related to hypokalemia. Author(s): Araki T, Konno T, Itoh H, Ino H, Shimizu M. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2003 January; 67(1): 93-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12520160
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Brugada syndrome: a case report of monomorphic ventricular tachycardia. Author(s): Boersma LV, Jaarsma W, Jessurun ER, Van Hemel NH, Wever EF. Source: Pacing and Clinical Electrophysiology : Pace. 2001 January; 24(1): 112-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11227955
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Brugada-type ECG with polymorphic ventricular tachycardia: a red herring for isolated right ventricular infarction. Author(s): Hsu LF, Ding ZP, Kam R, Teo WS, Lim YL. Source: International Journal of Cardiology. 2003 October; 91(2-3): 255-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14559142
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Bundle branch reentrant tachycardia in patients with apparent normal His-Purkinje conduction: the role of functional conduction impairment. Author(s): Li YG, Gronefeld G, Israel C, Bogun F, Hohnloser SH. Source: Journal of Cardiovascular Electrophysiology. 2002 December; 13(12): 1233-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12521339
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Bundle branch re-entrant ventricular tachycardia in a patient with structurally normal heart. Author(s): Gupta AK, Vajifdar BU, Vora AM. Source: Indian Heart J. 1999 January-February; 51(1): 80-2. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10327786
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Bundle branch reentrant ventricular tachycardia in a patient with the Brugada electrocardiographic pattern. Author(s): Mazur A, Iakobishvili Z, Kusniec J, Strasberg B. Source: Annals of Noninvasive Electrocardiology : the Official Journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2003 October; 8(4): 352-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14516293
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Bystander cavo-tricuspid isthmus activation during post-incisional intra-atrial reentrant tachycardia. Author(s): Tritto M, De PR, Zardini M, Spadacini G, Salerno-Uriarte JA. Source: Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 2002 January; 4(1): 91-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11846322
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Cardiology patient pages. Supraventricular tachycardia. Author(s): Wang PJ, Estes NA 3rd. Source: Circulation. 2002 December 17; 106(25): E206-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12485968
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Cardiovascular magnetic resonance of iatrogenic ventricular scarring due to catheter ablation for left ventricular tachycardia. Author(s): Sievers B, Brandts B, Moon JC, Pennell DJ, Trappe HJ. Source: International Journal of Cardiology. 2003 October; 91(2-3): 249-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14559140
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Case reports and review of Postural Orthostatic Tachycardia syndrome (POTS). Author(s): Carothers B, Schmidt L, Puri V. Source: J Ky Med Assoc. 2003 December; 101(12): 549-52. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14689686
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Cases from the Osler Medical Service at Johns Hopkins University. Digitalis toxicity with bidirectional ventricular tachycardia. Author(s): Piccini J, Zaas A. Source: The American Journal of Medicine. 2003 July; 115(1): 70-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12867240
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Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death. Author(s): Sumitomo N, Harada K, Nagashima M, Yasuda T, Nakamura Y, Aragaki Y, Saito A, Kurosaki K, Jouo K, Koujiro M, Konishi S, Matsuoka S, Oono T, Hayakawa S, Miura M, Ushinohama H, Shibata T, Niimura I. Source: Heart (British Cardiac Society). 2003 January; 89(1): 66-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12482795
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Catheter ablation of sinoatrial re-entry tachycardia in a 2 month old infant. Author(s): Simmers T, Sreeram N, Wittkampf F. Source: Heart (British Cardiac Society). 2003 January; 89(1): E1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12482811
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Catheter ablation of subepicardial ventricular tachycardia using electroanatomic mapping. Author(s): Ouyang F, Bansch D, Schaumann A, Ernst S, Linder C, Falk P, Hachiya H, Kuck KH, Antz M. Source: Herz. 2003 November; 28(7): 591-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14689119
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Catheter ablation of supraventricular tachycardia in the transplanted heart: a case series and literature review. Author(s): Magnano AR, Garan H. Source: Pacing and Clinical Electrophysiology : Pace. 2003 September; 26(9): 1878-86. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12930504
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Catheter ablation of ventricular tachycardia in patients with ischemic heart disease. Author(s): Soejima K, Stevenson WG. Source: Current Cardiology Reports. 2003 September; 5(5): 364-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12917050
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Catheter ablation of ventricular tachycardia in remote myocardial infarction: substrate description guiding placement of individual linear lesions targeting noninducibility. Author(s): Kottkamp H, Wetzel U, Schirdewahn P, Dorszewski A, Gerds-Li JH, Carbucicchio C, Kobza R, Hindricks G. Source: Journal of Cardiovascular Electrophysiology. 2003 July; 14(7): 675-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12930243
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Characterization of endocardial electrophysiological substrate in patients with nonischemic cardiomyopathy and monomorphic ventricular tachycardia. Author(s): Hsia HH, Callans DJ, Marchlinski FE. Source: Circulation. 2003 August 12; 108(6): 704-10. Epub 2003 July 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12885746
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Chronic inappropriate sinus tachycardia in elderly females. Author(s): Lopera G, Castellanos A, Moleiro F, Huikuri HV, Myerburg RJ. Source: Annals of Noninvasive Electrocardiology : the Official Journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2003 April; 8(2): 139-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12848795
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Clinical and electrophysiological characteristics in patients with atrioventricular reentrant and atrioventricular nodal reentrant tachycardia. Author(s): Bottoni N, Tomasi C, Donateo P, Lolli G, Muia N, Croci F, Oddone D, Menozzi C, Brignole M. Source: Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 2003 July; 5(3): 225-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12842632
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Clinical course of atrial ectopic tachycardia is age-dependent: results and treatment in children < 3 or > or =3 years of age. Author(s): Salerno JC, Kertesz NJ, Friedman RA, Fenrich AL Jr. Source: Journal of the American College of Cardiology. 2004 February 4; 43(3): 438-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15013128
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Clinical results with catheter ablation: AV junction, atrial fibrillation and ventricular tachycardia. Author(s): Weinstock J, Wang PJ, Homoud MK, Link MS, Estes NA 3rd. Source: Journal of Interventional Cardiac Electrophysiology : an International Journal of Arrhythmias and Pacing. 2003 October; 9(2): 275-88. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14574041
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Clinical usefulness of electrophysiologic testing in patients with ventricular tachycardia and chronic chagasic cardiomyopathy treated with amiodarone or sotalol. Author(s): Leite LR, Fenelon G, Simoes A Jr, Silva GG, Friedman PA, de Paola AA. Source: Journal of Cardiovascular Electrophysiology. 2003 June; 14(6): 567-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12875414
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Coincidence of idiopathic ventricular outflow tract tachycardia and atrioventricular nodal reentrant tachycardia. Author(s): Kautzner J, Cihak R, Vancura V, Bytesnik J. Source: Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 2003 July; 5(3): 215-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12842630
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Cor triatriatum with unroofed coronary sinus and persistent left superior vena cava associated with atrial tachycardia. Author(s): Sato T, Suzuki K, Umemura J, Takahashi Y, Tomimoto K. Source: Pediatric Cardiology. 2003 September-October; 24(5): 520-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14627330
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Coronary no-flow and ventricular tachycardia associated with habitual marijuana use. Author(s): Rezkalla SH, Sharma P, Kloner RA. Source: Annals of Emergency Medicine. 2003 September; 42(3): 365-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12944889
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Correlates of functional disability in patients with postural tachycardia syndrome: preliminary cross-sectional findings. Author(s): Benrud-Larson LM, Sandroni P, Haythornthwaite JA, Rummans TA, Low PA. Source: Health Psychology : Official Journal of the Division of Health Psychology, American Psychological Association. 2003 November; 22(6): 643-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14640863
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Decreased skeletal muscle pump activity in patients with postural tachycardia syndrome and low peripheral blood flow. Author(s): Stewart JM, Medow MS, Montgomery LD, McLeod K. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2004 March; 286(3): H1216-22. Epub 2003 October 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14576081
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Definition of the reentry circuit with demonstration of a low frequency diastolic potential in a patient with verapamil-sensitive idiopathic left ventricular tachycardia. Author(s): Wen MS, Yeh SJ, Wu D. Source: Journal of Electrocardiology. 2002 October; 35(4): 357-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12395364
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Delineation of intra-atrial reentrant tachycardia circuits after mustard operation for transposition of the great arteries using biatrial electroanatomic mapping and entrainment mapping. Author(s): Zrenner B, Dong J, Schreieck J, Ndrepepa G, Meisner H, Kaemmerer H, Schomig A, Hess J, Schmitt C. Source: Journal of Cardiovascular Electrophysiology. 2003 December; 14(12): 1302-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678105
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Demonstration of the exact anatomic tachycardia circuit in the fast-slow form of atrioventricular nodal reentrant tachycardia. Author(s): Yamabe H, Shimasaki Y, Honda O, Kimura Y, Hokamura Y. Source: Circulation. 2001 September 11; 104(11): 1268-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11551878
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Demonstration of the exact anatomic tachycardia circuit in the fast-slow form of atrioventricular nodal reentrant tachycardia. Author(s): Patterson E, Scherlag BJ. Source: Circulation. 2002 April 9; 105(14): E80-1; Author Reply E80-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11940558
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Detection of enteroviral RNA (poliovirus types 1 and 3) in endomyocardial biopsies from patients with ventricular tachycardia and survivors of sudden cardiac death. Author(s): Klein RM, Jiang H, Du M, Niederacher D, Picard F, Brehm M, Vester EG, Strauer BE. Source: Scandinavian Journal of Infectious Diseases. 2002; 34(10): 746-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12477325
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Detection of ventricular fibrillation and tachycardia from the surface ECG by a set of parameters acquired from four methods. Author(s): Jekova I, Mitev P. Source: Physiological Measurement. 2002 November; 23(4): 629-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12450264
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Development and validation of an ECG algorithm for identifying the optimal ablation site for idiopathic ventricular outflow tract tachycardia. Author(s): Ito S, Tada H, Naito S, Kurosaki K, Ueda M, Hoshizaki H, Miyamori I, Oshima S, Taniguchi K, Nogami A. Source: Journal of Cardiovascular Electrophysiology. 2003 December; 14(12): 1280-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678101
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Difference in end-tidal CO2 between asphyxia cardiac arrest and ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest in the prehospital setting. Author(s): Grmec S, Lah K, Tusek-Bunc K. Source: Critical Care (London, England). 2003 December; 7(6): R139-44. Epub 2003 September 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14624688
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Differences in inducibility and prognosis of in-hospital versus out-of-hospital identified nonsustained ventricular tachycardia in patients with coronary artery disease: clinical and trial design implications. Author(s): Pires LA, Lehmann MH, Buxton AE, Hafley GE, Lee KL; Multicenter Unsustained Tachycardia Trial Investigators. Source: Journal of the American College of Cardiology. 2001 October; 38(4): 1156-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11583897
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Differential effects of adenosine on focal and macroreentrant atrial tachycardia. Author(s): Markowitz SM, Stein KM, Mittal S, Slotwiner DJ, Lerman BB. Source: Journal of Cardiovascular Electrophysiology. 1999 April; 10(4): 489-502. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10355690
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Differential effects of atropine and isoproterenol on inducibility of atrioventricular nodal reentrant tachycardia. Author(s): Stellbrink C, Diem B, Schauerte P, Brehmer K, Schuett H, Hanrath P. Source: Journal of Interventional Cardiac Electrophysiology : an International Journal of Arrhythmias and Pacing. 2001 December; 5(4): 463-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11752915
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Differentiation of atypical atrioventricular node re-entrant tachycardia from orthodromic reciprocating tachycardia using a septal accessory pathway by the response to ventricular pacing. Author(s): Michaud GF, Tada H, Chough S, Baker R, Wasmer K, Sticherling C, Oral H, Pelosi F Jr, Knight BP, Strickberger SA, Morady F. Source: Journal of the American College of Cardiology. 2001 October; 38(4): 1163-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11583898
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Differentiation of narrow QRS complex tachycardia types using the 12-lead electrocardiogram. Author(s): Erdinler I, Okmen E, Oguz E, Akyol A, Gurkan K, Ulufer T. Source: Annals of Noninvasive Electrocardiology : the Official Journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2002 April; 7(2): 120-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12049683
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Diltiazem to treat sinus tachycardia in critically ill patients: a four-year experience. Author(s): Gabrielli A, Gallagher TJ, Caruso LJ, Bennett NT, Layon AJ. Source: Critical Care Medicine. 2001 October; 29(10): 1874-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11588443
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Discrimination of ventricular tachycardia from supraventricular tachycardia by a downloaded wavelet-transform morphology algorithm: a paradigm for development of implantable cardioverter defibrillator detection algorithms. Author(s): Swerdlow CD, Brown ML, Lurie K, Zhang J, Wood NM, Olson WH, Gillberg JM. Source: Journal of Cardiovascular Electrophysiology. 2002 May; 13(5): 432-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12030523
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Dissimilar atrial rhythms: coexistence of reentrant atrial tachycardia, atrioventricular nodal reentrant tachycardia and interatrial conduction block. Author(s): Schreieck J, Zrenner B, Dong J, Ndrepepa G, Schmitt C. Source: Zeitschrift Fur Kardiologie. 2002 January; 91(1): 68-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11963210
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Distinction between atrioventricular reciprocating tachycardia and atrioventricular node re-entrant tachycardia in the adult population based on P wave location; should we reconsider the value of some ECG criteria according to gender and age? Author(s): Maury P, Zimmermann M, Metzger J. Source: Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 2003 January; 5(1): 57-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12504642
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Does tachycardia correlate with hypotension after trauma? Author(s): Victorino GP, Battistella FD, Wisner DH. Source: Journal of the American College of Surgeons. 2003 May; 196(5): 679-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12742195
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Dual-loop intra-atrial re-entry tachycardia in a patient with ischaemic cardiomyopathy. Author(s): Ott P. Source: Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 2002 April; 4(2): 207-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12135255
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ECG of the month. Idiopathic ventricular tachycardia with a left bundle branch block morphology and right axis deviation. Author(s): Belhassen B, Glick A, Herz I, Berger M, Swissa M. Source: Isr Med Assoc J. 2003 September; 5(9): 679-80. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14509167
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ECG of the month. Regular wide-QRS tachycardia. Ventricular tachycardia. Author(s): Glancy DL, Mendoza D, Starnes S, Mills TA, Greer RW. Source: J La State Med Soc. 2003 May-June; 155(3): 125-7. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12873094
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Effect of beta-blocking therapy on outcome in the Multicenter UnSustained Tachycardia Trial (MUSTT). Author(s): Ellison KE, Hafley GE, Hickey K, Kellen J, Coromilas J, Stein KM, Lee KL, Buxton AE; Multicenter UnSustained Tachycardia Trial Investigators. Source: Circulation. 2002 November 19; 106(21): 2694-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12438295
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Effect of elevated heart rate preceding the onset of ventricular tachycardia on antitachycardia pacing effectiveness in patients with implantable cardioverter defibrillators. Author(s): Kouakam C, Lauwerier B, Klug D, Jarwe M, Marquie C, Lacroix D, Kacet S. Source: The American Journal of Cardiology. 2003 July 1; 92(1): 26-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12842240
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Effect of radiofrequency catheter ablation of ventricular tachycardia on left ventricular function in patients with prior myocardial infarction. Author(s): Khan HH, Maisel WH, Ho C, Suzuki M, Soejima K, Solomon S, Stevenson WG. Source: Journal of Interventional Cardiac Electrophysiology : an International Journal of Arrhythmias and Pacing. 2002 December; 7(3): 243-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12510135
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Electroanatomic mapping of the endocardium. Implication for catheter ablation of ventricular tachycardia. Author(s): Wetzel U, Hindricks G, Dorszewski A, Schirdewahn P, Gerds-Li JH, Piorkowski C, Kobza R, Tanner H, Kottkamp H. Source: Herz. 2003 November; 28(7): 583-90. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14689118
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Electrocardiographic criteria still useful for mapping of idiopathic right ventricular tachycardia. Author(s): Mounsey JP. Source: Journal of Cardiovascular Electrophysiology. 2003 January; 14(1): 8-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12625603
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Electrocardiographic differentiation of typical atrioventricular node reentrant tachycardia from atrioventricular reciprocating tachycardia mediated by concealed accessory pathway in children. Author(s): Jaeggi ET, Gilljam T, Bauersfeld U, Chiu C, Gow R. Source: The American Journal of Cardiology. 2003 May 1; 91(9): 1084-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12714151
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Electrocardiographic manifestations: wide complex tachycardia due to accessory pathway. Author(s): Nelson JA, Knowlton KU, Harrigan R, Pollack ML, Chan TC. Source: The Journal of Emergency Medicine. 2003 April; 24(3): 295-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12676301
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Electrophysiological and electrocardiographic characteristics of focal atrial tachycardia originating from the pulmonary veins: acute and long-term outcomes of radiofrequency ablation. Author(s): Kistler PM, Sanders P, Fynn SP, Stevenson IH, Hussin A, Vohra JK, Sparks PB, Kalman JM. Source: Circulation. 2003 October 21; 108(16): 1968-75. Epub 2003 Oct 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14557361
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Electrophysiological features of orthodromic atrioventricular reentry tachycardia in patients with wolff-Parkinson-white syndrome and atrial fibrillation. Author(s): Kalarus Z, Kowalski O, Lenarczyk R, Prokopczuk J, Pasyk S. Source: Pacing and Clinical Electrophysiology : Pace. 2003 July; 26(7 Pt 1): 1479-88. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12914625
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Electrophysiology of inducible atrial flutter in patients with atrioventricular nodal reentrant tachycardia. Author(s): Liu S, Yuan S, Hertervig E, Kongstad O, Ljungstrom E, Bertil Olsson S. Source: Clinical Physiology and Functional Imaging. 2004 January; 24(1): 19-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14717744
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Electrophysiology of ventricular tachycardia: a historical perspective. Author(s): Josephson ME. Source: Pacing and Clinical Electrophysiology : Pace. 2003 October; 26(10): 2052-67. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14516353
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Electrophysiology of ventricular tachycardia: an historical perspective. Author(s): Josephson ME. Source: Journal of Cardiovascular Electrophysiology. 2003 October; 14(10): 1134-48. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14521677
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Elevated troponin levels in absence of coronary artery disease after supraventricular tachycardia. Author(s): Zellweger MJ, Schaer BA, Cron TA, Pfisterer ME, Osswald S. 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 August 9; 133(31-32): 439-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14562187
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Endocardial mapping of right ventricular outflow tract tachycardia using noncontact activation mapping. Author(s): Ribbing M, Wasmer K, Monnig G, Kirchhof P, Loh P, Breithardt G, Haverkamp W, Eckardt L. Source: Journal of Cardiovascular Electrophysiology. 2003 June; 14(6): 602-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12875421
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Epidural haematoma presenting as polymorphic ventricular tachycardia. Author(s): Webb TR, Morgan JM, Roberts PR. Source: Heart (British Cardiac Society). 2003 March; 89(3): 316. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12591840
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Evidence that nonsustained polymorphic ventricular tachycardia causes syncope (data from implantable cardioverter defibrillators). Author(s): Farmer DM, Swygman CA, Wang PJ, Mark Estes NA 3rd, Link MS. Source: The American Journal of Cardiology. 2003 March 1; 91(5): 606-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12615273
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Excessive charge time delaying ventricular tachycardia therapy. Author(s): Panchal VR, Groh WJ. Source: Journal of Cardiovascular Electrophysiology. 2001 September; 12(9): 1078-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11573700
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Extracorporeal life support as a treatment of supraventricular tachycardia in infants. Author(s): Walker GM, McLeod K, Brown KL, Franklin O, Goldman AP, Davis C. Source: Pediatric Critical Care Medicine : a Journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2003 January; 4(1): 52-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12656543
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12600890
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Familial orthostatic tachycardia due to norepinephrine transporter deficiency. Author(s): Robertson D, Flattem N, Tellioglu T, Carson R, Garland E, Shannon JR, Jordan J, Jacob G, Blakely RD, Biaggioni I. Source: Annals of the New York Academy of Sciences. 2001 June; 940: 527-43. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11458707
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Familial polymorphic ventricular tachycardia--intracellular calcium channel disorder. Author(s): Swan H, Laitinen PJ. Source: Cardiac Electrophysiology Review. 2002 February; 6(1-2): 81-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11984023
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Fascicular tachycardia: uncommon or just unrecognised? Author(s): Eynon CA, Howe L, Firoozan S. Source: Emergency Medicine Journal : Emj. 2002 September; 19(5): 477-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12205019
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Fast pathway ablation in patients with common atrioventricular nodal reentrant tachycardia and prolonged PR interval during sinus rhythm. Author(s): Reithmann C, Hoffmann E, Grunewald A, Nimmermann P, Remp T, Dorwarth U, Steinbeck G. Source: European Heart Journal. 1998 June; 19(6): 929-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9651718
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Feasibility of a noncontact catheter for endocardial mapping of human ventricular tachycardia. Author(s): Schilling RJ, Peters NS, Davies DW. Source: Circulation. 1999 May 18; 99(19): 2543-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10330386
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Fetal hydrops due to supraventricular tachycardia--successful outcome in a difficult case. Author(s): Doherty G, Bali S, Casey F. Source: Ir Med J. 2003 February; 96(2): 52-3. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12674156
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Fetal supraventricular tachycardia diagnosed and treated at 13 weeks of gestation: a case report. Author(s): Porat S, Anteby EY, Hamani Y, Yagel S. Source: Ultrasound in Obstetrics & Gynecology : the Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2003 March; 21(3): 302-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12666229
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Filtered QRS duration on signal-averaged electrocardiography predicts inducibility of ventricular tachycardia in arrhythmogenic right ventricle dysplasia. Author(s): Nasir K, Tandri H, Rutberg J, Tichnell C, Spevak P, Crossan J, Baughman KL, Kasper EK, Tomaselli GF, Berger R, Calkins H. Source: Pacing and Clinical Electrophysiology : Pace. 2003 October; 26(10): 1955-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14516335
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Flecainide and sotalol: a new combination therapy for refractory supraventricular tachycardia in children