Heart Catheterization - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

HEART

CATHETERIZATION 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

ii

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., 1960Heart Catheterization: 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: 0-497-00516-6 1. Heart Catheterization-Popular works. I. Title.

iii

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.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

iv

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 heart catheterization. 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.

v

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.

vi

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

vii

Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON HEART CATHETERIZATION ...................................................................... 3 Overview........................................................................................................................................ 3 Federally Funded Research on Heart Catheterization.................................................................... 3 The National Library of Medicine: PubMed ................................................................................ 51 CHAPTER 2. PATENTS ON HEART CATHETERIZATION ................................................................... 81 Overview...................................................................................................................................... 81 Patent Applications on Heart Catheterization............................................................................. 81 Keeping Current .......................................................................................................................... 82 CHAPTER 3. PERIODICALS AND NEWS ON HEART CATHETERIZATION ......................................... 83 Overview...................................................................................................................................... 83 News Services and Press Releases................................................................................................ 83 Academic Periodicals covering Heart Catheterization................................................................. 85 APPENDIX A. PHYSICIAN RESOURCES ............................................................................................ 89 Overview...................................................................................................................................... 89 NIH Guidelines............................................................................................................................ 89 NIH Databases............................................................................................................................. 91 Other Commercial Databases....................................................................................................... 93 APPENDIX B. PATIENT RESOURCES ................................................................................................. 95 Overview...................................................................................................................................... 95 Patient Guideline Sources............................................................................................................ 95 Finding Associations.................................................................................................................... 97 APPENDIX C. FINDING MEDICAL LIBRARIES .................................................................................. 99 Overview...................................................................................................................................... 99 Preparation................................................................................................................................... 99 Finding a Local Medical Library.................................................................................................. 99 Medical Libraries in the U.S. and Canada ................................................................................... 99 ONLINE GLOSSARIES................................................................................................................ 105 Online Dictionary Directories ................................................................................................... 105 HEART CATHETERIZATION DICTIONARY........................................................................ 107 INDEX .............................................................................................................................................. 151

1

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 heart catheterization 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 heart catheterization, 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 heart catheterization, 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 heart catheterization. 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 heart catheterization, 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 heart catheterization. The Editors

1

From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

3

CHAPTER 1. STUDIES ON HEART CATHETERIZATION Overview In this chapter, we will show you how to locate peer-reviewed references and studies on heart catheterization.

Federally Funded Research on Heart Catheterization The U.S. Government supports a variety of research studies relating to heart catheterization. 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 heart catheterization. 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 heart catheterization. The following is typical of the type of information found when searching the CRISP database for heart catheterization: •

Project Title: 3D CORONARY RECONSTRUCTION AND MULTIMODALITY FUSION Principal Investigator & Institution: Chen, Shiuh-Yung J.; Assistant Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 05-MAY-2000; Project End 30-APR-2004

2

Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

4

Heart Catheterization

Summary: Clinicians usually assess the three-dimensional (3-D) characteristics of the cardiac anatomy and function by mentally reassembling data acquired from different modalities using the two-dimensional (2-D) display format such as coronary angiography, echocardiography, computed tomography (CT), magnetic resonance (MR) imaging, or radionuclide tomography. Our major goal in the proposed research is to develop computer-based techniques for 3-D reconstruction and integration using complementary imaging modalities to facilitate diagnostic and interventional procedures. The initial effort will be concentrated on the 3-D reconstruction and correlation of coronary vascularture of human heart based on x-ray angiography and intravascular ultrasonography (IVUS). Specifically, the spatial 3-D geometry of coronary arteries and the morphology of coronary disease will be generated from respective routine angiograms and IVUS cross-sectional images to facilitate diagnostic and therapeutic cardiac catheterization by (i) suggesting optimal views with minimal vessel overlap and foreshortening, (ii) comprehending the composition, morphology, and distribution of coronary atherosclerotic plaques, and (iii) optimizing input for quantitative coronary analysis and interventional device selection. In a single patient examination, multiple coronary angiograms will be acquired during several cardiac cycles either by using a single-plane or biplane imaging system. The initial 3-D coronary arterial tree will be reconstructed based on an initial pair of angiograms. With the reconstructed 3-D patient-specific coronary arterial tree model, optimal views that minimize vessel overlap and foreshortening with respect to a selected arterial segment or a bifurcation will be predicted and employed for subsequent image acquisition to continue the diagnostic and therapeutic procedure. The initially reconstructed 3-D coronary arterial tree model can then be refined by using the subsequently acquired angiograms. The calculated optimal views will be utilized to facilitate IVUS examination for advancing the IVUS catheter. The 3-D vascular lumen and plaques will be reconstructed from a sequence of IVUS cross-sectional images acquired by means of a systematic, timed pull-back of the ultrasound catheter through the respective arterial segments. The reconstructed 3-D coronary arterial tree and vascular plaque will then be correlated and integrated. The cardiologist can then incorporate the prediction of optimal views and the well-defined morphology and composition of coronary disease to continue the study during the fluoroscopic or ultrasound based interventional procedure. With the 3-D coronary processing techniques, we expect that the prospective clinical study can accomplish: a) reduction in radiation exposure and contrast volume, b) reduction of interventional procedure time by initially optimizing visualization and quantification of stenosis, and c) accurate assessment of coronary vascular pathology and histology for guidance of interventional therapy to improve and provide safer health care. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: 5-D IMAGE GUIDED CARDIAC ABLATION THERAPY Principal Investigator & Institution: Robb, Richard A.; Scheller Professor in Medical Research; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2003; Project Start 20-SEP-2003; Project End 31-AUG-2006 Summary: (provided by applicant): Cardiac arrhythmias are a major clinical problem. We propose a significant and unique solution. Based on our preliminary results and progress with minimally invasive, multi dimensional image-guided interventions for myocardial ablation of cardiac arrhythmias in experimental animals, we have developed a theoretical basis and shown significant promise for proving the hypothesis that realtime, anatomy-based imaging and accurate fusion with electrophysiologic recordings

Studies

5

will significantly improve the outcomes of catheter-based ablation of cardiac arrhythmias. In addition to greater success with less risk of morbidity/mortality, other important benefits will include reduced procedure time, less x-ray exposure, and lower cost. Our multi-disciplinary team (biomedical engineering, cardiology, radiology, computer science) will focus on atrial fibrillation (AF) where current treatment strategies are ineffective. However, our approach and system will be adaptable to treatment of any cardiac arrhythmias that can be reached by a catheter. The target goal is to achieve outcomes with catheter-based ablation comparable to surgical procedures, which can be 80-90% effective for AF, primarily due to direct visualization of the target cardiac anatomy through the surgically opened chest. But surgical procedures are undesirably invasive and accompanied by significant risk and cost. We will test our hypothesis by developing and validating a complete prototype system for image-guided catheterbased cardiac ablation featuring accurate real-time and on-line localization, visualization and targeting of the treatment region. This new system will be based on rapid volume image acquisition, real-time computer image processing and interactive display of threedimensional anatomical images registered and mapped with electrophysiological data during successive cardiac cycles - a five-dimensional image guided intervention system. The system will be constructed using currently available microprocessors, display technology, mapping hardware and standard interfaces for 3D imaging modalities, including electron beam, CT, multirow spiral CT, MRI and ultrasound. Image processing steps, including segmentation, registration, modeling and rendering will be performed by customizing and optimizing algorithms previously developed and evaluated in our laboratory. The systems engineering task will essentially be one of designing, assembling and testing the integration of physical components (hardware, software and data) and procedural components (tasks) which have been separately developed and successfully demonstrated. This prototype system will then be thoroughly validated in the animal laboratory, with modifications and refinements for improved performance and user interface incorporated as these are indicated during the evaluation studies. We firmly believe that development, validation and optimization of this prototype system will herald a new generation of advanced technology for minimally invasive treatment of cardiac arrhythmias that will dramatically and positively impact the field. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: A INTERVENTIONS

MICROFABRICATED

SYSTEM

FOR

IMAGE

GUIDED

Principal Investigator & Institution: Prinz, Friedrich B.; Mechanical Engineering; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2003; Project Start 20-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): The development of minimally invasive technologies for treating disease has significantly reduced the morbidity of treating coronary artery disease. The presence of totally coronary arteries is significant factor in preventing broader application of minimally invasive techniques. To address this important clinical problem new methods must be developed for visualizing the arteries of the heart and for manipulating devices within the heart. This proposal presents a new methodology for creating new devices that will address the visualization and guidance needs to solve these problems. More specifically a novel machining and fabrication technique will be created that will allow the creation of an ultrasound scanner small enough to fit in coronary arteries and will allow the physician to see where he is going in two planes as he advances the device through the arteries of the heart. Furthermore

6

Heart Catheterization

this same fabrication technique will be used to create building blocks will be used to construct catheters that can be steered to direct devices such as lasers and atherectomy through occluded arteries without risk of puncturing the artery. Finally the project will develop a set of core integrated electronics and control algorithms that will allow these complex devices to be manipulated in a user friendly through the body. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADULT-DERIVED STEM CELL DIFFERENTIATION IN THE HEART Principal Investigator & Institution: Anderson, Page a W.; Professor; Pediatrics; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 30-JUN-2007 Summary: (provided by applicant): Heart failure is a major cause of premature death and disability in the United States. Adult-derived stem cells could provide a basis for effective therapies. This proposal is based on our finding that a well characterized adultderived stem cell line (WB-F344), isolated from the adult rat liver, differentiates in vivo in the adult heart into heart cells. We will use the WB-F344 stem cell line and Fischer 344 (F344) rats in the normal heart and left anterior descending (LAD) coronary artery ligation model. We will test:Hypothesis 1. WB-F344 cells engraft in the heart, acquire a structural cardiac phenotype, and differentiate into mature cardiac myocytes in vivo. These processes will be affected by the different host cardiac microenvironments in the two models. We will examine these processes qualitatively and quantitatively. Bgalactosidase activity will be used to identify WB-F344-derived myocytes. The commitment to a cardiac lineage and acquisition of a cardiac phenotype will be examined using expression of transcription factors, myofilament proteins, and membrane proteins and the remodeling of anatomical couplings, and their distribution. Hypothesis 2. WB-F344-derived myocytes acquire the functional phenotype of adult cardiac myocytes. These functional properties will be affected by the host cardiac microenvironments in the two models. We will examine the mechanical and electrophysiological properties of isolated single WB-F344-derived myocytes and host myocytes in vitro and their communication with host cells in situ. Hypothesis 3. WBF344-derived cardiac myocytes affect ventricular function in vivo. Left ventricular dysfunction in the post myocardial infarction heart will be moderated by WB-F344derived myocytes. The effects of WB-F344 cell engraftment and differentiation on in vivo left ventricular function and size will be examined, using echocardiography and cardiac catheterization. The proposed studies will provide new and important information about the functional properties of stem cell-derived cardiac myocytes and the potential value of stem cell-based approaches to treating heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ALTERED GENE EXPRESSION IN THE FAILING HUMAN HEART Principal Investigator & Institution: Bristow, Michael R.; Professor of Medicine; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-MAY-1993; Project End 30-NOV-2003 Summary: The mechanisms responsible for progressive myocardial dysfunction and remodeling of the cardiomyopathic, failing human heart are unknown. In general, these pathophysiologic mechanisms are likely to involve signaling mechanisms which alter myocardial gene expression. Numerous recent studies have demonstrated that, in order to be meaningful, gene regulation and expression must be examined in the intact heart.

Studies

7

The overall objective of this proposal is to test, in human subjects with myocardial failure, the general hypothesis that compensatory mechanisms activated to support the failing heart ultimately decrease systolic function through signaling alterations in myocardial gene expression, which then leads to chamber remodeling. The proposal 1) tests two specific hypotheses for the molecular basis of systolic dysfunction (myosin heavy chain isoform changes and altered Beta- adrenergic signal transduction), and 2) investigates the roles of four signaling pathways (increased wall stress, increased cardiac alpha1- and Beta-adrenergic drive, and increased activity of the reninangiotensin system) in effecting changes in these two candidate molecular mechanisms. The 3rd aim of the proposal is to establish the temporal relationship between changes in contractile dysfunction and remodeling. The strategy employed in Aims 1 and 2 is to investigate the right ventricle in human subjects with idiopathic dilated cardiomyopathy (IDC) compared to nonfailing controls without cardiomyopathy, and to study dynamic changes in signaling, gene expression and chamber phenotype in IDC subjects treated with a Beta- blocker or placebo. The primary analysis in Aim 3 is in the left ventricle. We have developed techniques to measure the expression of a large number of target genes in small quantities of human ventricular myocardium that can be obtained serially from the intact heart by right ventricular (RV) endomyocardial biopsy, using reverse transcription-quantitative PCR. We have demonstrated that in situations where left and right ventricular function are concordant, directional changes in gene expression are similar in RV septal endomyocardium, RV free wall and LV free wall, indicating that RV endomyocardial biopsy samples may be used to investigate changes in RV or LV free wall gene expression. We have also developed methods to precisely define chamber phenotypic characteristics of the intact human RV, using magnetic resonance imaging and cardiac catheterization. Finally, we have developed methods to precisely measure the four signaling pathways under investigation. Thus, this proposal has the ability to determine some of the mechanisms likely to be responsible for progression in human myocardial failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTICOAGULATION POST-FONTAN/CLOSURE OF ASDS Principal Investigator & Institution: Mccrindle, Brian W.; Hospital for Sick Chldrn (Toronto) 555 University Ave Toronto, On Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant) Patient-related research in heart problems in children has been of limited quality, because of lack of collaboration and emphasis on information provided in medical charts. Important problems remain controversial and unsolved. The Fontan operation is designed for patients who have only one pumping chamber, and guides blood from the major veins returning to the heart directly into the lung arteries, with the pumping chamber reserved to pump blood into the arteries of the body. Afterwards, blood flows differently and more slowly in the veins and lungs, and clots may form, which can cause strokes. The proposed study aims to determine the risk of clots and the best way to prevent them. The study will consist of a review medical charts on a large number of patients who have had Fontan to help determine the risk of clots. For patients who will have Fontan, they will be enrolled in a study where they will be randomly assigned to different types of medications to prevent clots, which will be compared. For patients who have already had the Fontan, they will be enrolled in a similar study where they will randomly assigned to either aspirin or a medication called warfarin. In both the studies, the patients will have regular check-ups and tests for a two year period to see if clots occur and which type of medicine best prevents the clots.

8

Heart Catheterization

Atrial septal defects, or holes between the two collecting chambers of the heart, can lead to heart failure and heart rhythmn problems. They can be closed with surgery, or by placing a special patch or device with a catheter. The proposed study aims to determine whether closure is better with surgery or the catheter method, and whether there are any differences in closure with different types of catheter devices. The study will review medical charts of children who have had closure of these holes, and compare surgery and catheter methods. A second part of the study will enroll children with holes which need to be closed, and randomly assign them to either surgery or the catheter method. For patients assigned to the catheter method, they will be further randomly assigned to one of two types of catheter devices. Comparisons will be made between surgery and the two catheter methods regarding the completeness of closure and complications. A further analysis will look at patient preferences and the costs for these different types of procedures, to help determine the best way to close these holes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ATRIONODAL BUNDLES:HISTOLOGIC AND PHYSIOLOGIC VALIDATION Principal Investigator & Institution: Racker, Darlene Katie.; 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

Studies

9

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 •

Project Title: CARDIOPULMONARY HYPERTENSION

EXERCISE

TESTING:

PULMONARY

Principal Investigator & Institution: Oudiz, Ronald J.; Associate Professor of Medicine; Harbor-Ucla Research & Educ Inst 1124 W Carson St Torrance, Ca 905022052 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (Revised Abstract) Pulmonary arterial hypertension (PAH) is a devastating, rapidly progressive disease of the pulmonary vasculature that typically affects young women between the ages of 21 and 40. Untreated, the median survival time is 2.8 years. Only lung transplantation relieves the pulmonary hypertension. Methods currently used to assess the clinical course are either subjective or do not correlate well with symptoms and life expectancy. Right heart catheterization is widely-used to measure disease severity and response to therapy, but repeated catheterization causes morbidity and is a potential barrier to needed changes in therapy. Also, catheterization is performed at rest, not during exercise, when the patient is symptomatic. In contrast, preliminary data from the PI and his mentor show that noninvasive measures of aerobic function and ventilatory efficiency during exercise are closely related to disease severity and response to therapy in patients with PAH. This has broad implications for determining prognosis, selection of treatment, and making decisions on the timing of lung transplantation. The broad objectives of this proposal are to define optimal methods for noninvasively assessing patients with PAH, and to develop a prognostic model using cardiopulmonary exercise testing (CPET). The specific aims are: 1) To establish peak exercise oxygen consumption (peak VOz) and other CPET measurements as independent predictors of survival time, need for tung transplantation, or hospitalization for symptoms of PAH. 2) To use CPET parameters to further subclassify patients with NYHA II and III functional class symptoms, and patients with 6-minute walk distances of 250-400 m 3) To establish the relationship between peak VO2 and other CPET measurements in tracking the response to vasodilator therapy. This study will help determine the most useful parameter(s) to follow for making critical clinical decisions, including determining the need for and timing of lung transplantation. From our large PAH referral clinic, we will perform CPET in 72 human subjects with PAH, as defined by the World Health Organization. We will examine how the pulmonary vasculopathy of PAH affects exercise aerobic capacity and ventilatory efficiency in PAH, and how these important reflections of cardiac and pulmonary vascular function relate to clinical indices used in the conventional evaluation of these patients. Our hypotheses are based on the concept that CPET measurements provide objective, quantitative measures of disease severity and response to therapy. Therefore important therapeutic decisions can be based on objective measures of the circulatory and ventilatory responses to exercise, This proposal will enable the PI to participate in a structured, graded career development program leading to the acquisition of skills needed for a career in patient-oriented cardiovascular research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CARDIOPULMONARY SURGERY RESEARCH Principal Investigator & Institution: Kadowitz, Philip J.; Professor; Pharmacology; Tulane University of Louisiana New Orleans, La New Orleans, La 70112

10

Heart Catheterization

Timing: Fiscal Year 2004; Project Start 20-JUL-2000; Project End 31-JUL-2008 Summary: (provided by applicant): The broad long-term objectives of the proposed research are to improve our current understanding of the regulation of the pulmonary vascular bed by humoral factors, including vasoactive products in the cyclooxygenase pathway. Cyclooxygenase (COX) is the initial step in the formation of prostaglandins (PGs) and thromboxane A2 (prostanoids). The prostanoids have marked effects on the pulmonary vascular bed, and PGI2 is used in the treatment of pulmonary hypertension. It is known that there are two COX isoforms in the lung. COX-1 is believed to be a constitutive enzyme involved in physiologic regulation, whereas COX-2 is an inducible isoform upregulated by inflammatory cytokines. Although it is believed that COX-2 Is not present or expressed in low levels in normal tissue, recent studies in the literature and in our laboratory show that COX-1 and COX-2 are abundantly expressed in the normal healthy rodent lung and have the capacity to generate vasoactive prostanoids from the precursor, arachidonic acid. It is our hypothesis that vasoactive prostanoids that increase pulmonary vascular resistance and decrease systemic vascular resistance are generated by COX-1 and COX-2. The first specific aim is to determine the role of COX-1 and COX-2 in the generation of vasoactive prostanoids in the intact-chest mouse using a recently developed right-heart catheterization procedure to measure pulmonary vascular pressures and blood flow. These studies will involve the use of selective COX-1 and COX-2 inhibitors, a platelet aggregation assay to determine COX-1 selectivity, and enzyme immunoassay to measure prostanoid levels in lung tissue. The second specific aim is to determine the role of COX-1 and COX-2 in the generation of vasoactive prostanoids when arachidonic acid is released from endogenous pools by agents or stimuli reported to release prostaglandins from the lung. In these experiments, the effects of the COX-1 and COX-2 inhibitors on responses to ventilatory hypoxia, angiotensin II, and ionophore A23187 will be investigated in the intact-chest mouse. These experiments will test the hypothesis that responses to ionophore A23187 are mediated by the formation of prostanoids in the COX-1 and COX-2 pathway and that COX-1 and COX-2 modulate pulmonary vasoconstrictor responses to angiotensin II and ventilatory hypoxia. The experiments in specific aims 1 and 2 involve the use of selective COX inhibitors which may be problematic, therefore, specific aim three is to determine the role of COX-1 and COX-2 in the generation of vasoactive prostanoids and in the regulation of the pulmonary vascular bed in COX-1 and COX-2 knockout mice. The results of these experiments will provide new information about the role of COX-1 and COX- 2 in the regulation of the pulmonary vascular bed and may lead to new strategies for the treatment of pulmonary hypertensive disorders. 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 Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2004; Project Start 30-SEP-1999; Project End 28-FEB-2009 Summary: (provided by applicant): Obstructive sleep apnea (OSA) has been linked to hypertension, heart failure and other cardiac and vascular diseases. Endothelial dysfunction is an important contributor to cardiac and vascular pathophysiology and predicts the development of future cardiovascular disease. Hypoxemia, blood pressure surges, oxidative stress and metabolic and inflammatory dysregulation in OSA may contribute to impairment of endothelial function. However, whether endothelial dysfunction is indeed present in OSA is controversial, and the mechanisms of any such dysfunction are unclear. This proposal tests the overall hypotheses that there are distinct

Studies

11

abnormalities in endothelial mediated dilation of conductance and/or resistance arterial blood vessels in OSA patients, that the endothelial dysfunction may be explained by neural, vasoactive, inflammatory and/or progenitor cell mechanisms, and that effective therapy with continuous positive airway pressure (CPAP) attenuates these abnormalities, with consequent improvement in endothelial dysfunction. Specific Aims are: 1) To test the hypothesis that patients with OSA have an impairment in tonic endothelial function, as well as impaired endothelial responses to provocative stimuli such as flow-mediated dilation and acetylcholine. 2) To test the hypothesis that neural, vasoactive, inflammatory and/or progenitor cell mechanisms contribute to impaired endothelial function in patients with OSA, and that these mechanisms and consequent endothelial dysfunction are more manifest after overnight untreated OSA. 3) To test the hypothesis that long-term effective therapy of OSA using CPAP improves endothelial function by attenuation of abnormalities in neural, vasoactive, inflammatory and endothelial progenitor cell mechanisms described in Specific Aims # 1 and #2. These studies apply novel developments in vascular biology to the understanding of cardiovascular disease in a multi-system disorder with a high and rising prevalence. The integrity of the hypotheses will be tested with careful exclusion of potential confounding variables such as obesity, hypertension and left ventricular dysfunction. Exciting preliminary data support the feasibility and promise of the hypotheses to be tested. Identification of the mechanisms mediating vascular disease in OSA will enhance our understanding of disease pathophysiology, and may provide opportunities for new therapeutic strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CARDIOVASCULAR PHENOTYPING IN MICE Principal Investigator & Institution: Weiss, Robert M.; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 28-FEB-2008 Summary: (provided by applicant): This Award will provide support for the establishment and operation of a core facility for mouse cardiovascular phenotyping. It will also support three projects with implications for aging research: 1) adult-onset cardiomyopathy in mice; 2) age-induced placental insufficiency in mice; and 3) functional tumor vasculogenic mimicry. The application includes specific plans to mentor young investigators who select careers in translational cardiovascular research. Specific long-term career goals: 1) Operate an internationally recognized cardiovascular mouse phenotyping core facility; 2) advance the understanding of the cellular basis of heritable dilated cardiomyopathy, and develop diagnostic and therapeutic modalities with the potential for clinical application; 3) determine the nature and magnitude of impairment of maternal-placental circulation in murine disease states which recapitulate important clinical conditions, and develop therapeutic strategies which have potential for clinical application; 4) apply newfound knowledge about the function of tumor vasculogenic mimicry channels toward improved cancer diagnosis and treatment; and 5) develop and implement a training program in translational mouse cardiovascular research, dedicated toward fostering the careers of future independent investigators. These goals will be pursued by application of current methods and development of new methods for investigation of mouse cardiovascular function in vivo. The project will initially rely on ultrasonography and cardiac catheterization to achieve its Specific Aims. During the course of the Award, new methods for cardiovascular studies in mice will be tested and implemented. Ultimately, the information gained by these studies in mice

12

Heart Catheterization

will form the foundation for the development of novel and feasible advances in the diagnosis and treatment of patients with cardiovascular disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CARDIOVASCULAR STIFFENING IN AGED PATIENTS WITH CHF Principal Investigator & Institution: Kass, David A.; Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Heart failure predominantly affects individuals of advanced age, and is currently reaching epidemic proportions. Nearly half the patients with symptoms of heart failure have preserved systolic ejection fraction (EF>50 percent), and are generally thought to suffer from ventricular diastolic dysfunction. However, most of these same individuals are over 65 years of age and have systolic hypertension, both factors that can themselves adversely impact on diastolic function. An additional mechanism that may prominently contribute to failure symptoms despite preservation of EF is ventricular-arterial stiffening. Vascular stiffening is common with aging, and results in increased arterial pulse pressure and systolic hypertension, both dominant risk factors for the development of coronary artery disease and heart failure. We have shown that ventricular systolic stiffening with or without cardiac hypertrophy accompanies progressive vascular stiffening with age. When combined, these changes can limit cardiac reserve capacity, enhance blood pressure fluctuations with daily activities of living, and limit coronary flow reserve. The studies in this proposal test the novel hypothesis that ventricular-vascular stiffening is a potent contributor to cardiac failure with preserved EF by reducing exercise capacity due to limited systolic reserve, enhancing blood pressure lability, and inducing abnormal coronary flow and myocardial energy balance with increased stress. The studies employ new methods for non-invasive quantitation of ventricular/vascular stiffening recently developed and validated in the P.I.'s laboratory. The first two specific aims test whether ventricularvascular stiffening is greater in patients with "non-systolic" heart failure versus a control group of similar age, blood pressure, hypertrophy, and sex, and tests its impact on blood pressure lability, reduced systolic reserve, and exercise performance. The third aim focuses on the impact of ventricular/vascular stiffening on coronary flow regulation and high energy phosphate metabolism. These studies test the influence of combined stiffening on cardiac supply/demand balance with stress. This research should provide major new insights regarding the pathophysiology of heart failure with preserved EF and specifically the importance of ventricular-vascular stiffening. This could lead to new therapeutic approaches to this difficult clinical problem that affects a growing aged patient population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CLOPIDOGREL THERAPY IN HEART CATHETERIZATION Principal Investigator & Institution: King, Spencer B.; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002 Summary: This study is a modification of SPID 4230. The effects of the primary loading dose of 525 mg Clopidogres have been carefully studied. The dose was well tolerated and produced partial inhibition of platelet function within 2 hours of administration. This amendment proposes to now add a second loading dose of clopidogrel (525 mg) to

Studies

13

be administered 12 hours after a primary loading dose (525 mg) to aspirin-treated coronary artery disease patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMPREHENSIVE ASSESSMENT OF VALVULAR FUNCTION WITH MRI Principal Investigator & Institution: Pauly, John M.; Associate Professor; Electrical Engineering; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): The goal of this proposal is to develop and validate a comprehensive examination of valvular heart diseases. Valvular heart disease affects approximately 10% of the general population in the United States. Over the past 20 years, valvular diagnosis has undergone a revolution due to advances in cardiac ultrasound. However, ultrasound has inherent limitations with respect to tissue characterization, spatial resolution, and the need for acoustic windows. Particularly difficult are the evaluation of valvular morphology, quantitation of valvular stenosis and identification and quantitation of valvular regurgitation. The examination of valvular heart disease includes the assessment of valvular morphology, cardiac output, intracardiac pressures, ventricular volume and volume regurgitations. Magnetic resonance imaging (MRI) is potentially the most appropriate technique for addressing all of these areas in a single examination. Current MR techniques for valvular imaging suffer from poor temporal and spatial resolutions, require prolonged acquisitions, and frequently require laborious post processing. As a result, there is a gap between what is scientifically feasible and what is currently applied clinically. Our goal in this proposal is to eliminate this gap between the potential of MRI and current clinical practice. Our group has pioneered many of the components that will be useful for the diagnosis of valvular heart disease, including real-time imaging, real-time color flow, and MR Doppler. In this proposal we will integrate and extend these components along with new developments to provide an integrated and comprehensive assessment of valvular function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: COMPUTER INTERVENTION

ASSISTED

SURGERY

PRENATAL

CARDIAC

Principal Investigator & Institution: Nikou, Constantinos; Casurgica, Inc. 4815 Liberty Avenue, Ste M50 Pittsburgh, Pa 15224 Timing: Fiscal Year 2004; Project Start 01-MAR-2004; Project End 31-AUG-2004 Summary: (provided by applicant): Approximately 1% of babies born require operative treatment for congenital heart diseases. Worldwide, 80,000 pediatric cardiac procedures are performed annually. These procedures are all performed postnatally. However, based on a growing recognition that earlier anatomic repair is beneficial to the health of the child, it has become clear that prenatal cardiac intervention (PCI), though revolutionary, is highly desirable to correct aortic valve stenoses and other abnormalities that lead to hypoplastic left heart syndrome (HLHS). At the same time the technology available for PCI is clearly deficient. Ours is a proposal to begin a multiphase effort to realize technologies and interventional techniques that will make it possible to perform extraordinarily delicate and intricate cardiac procedures on a fetus while it is in the mother's womb, i.e., using minimally invasive in utero techniques. The overall concept is to provide the interventionalist graphical displays, navigation aids

14

Heart Catheterization

and in vivo sensing capabilities that enable a PCI and confirm its efficacy. The essence of our approach is to make minor augmentations of the equipment and devices currently used for PCI, but in so doing to make a significant increase in the information content provided to the interventionalist. The specific research proposed here is to develop an optical position tracking solution for instruments used in PCI that will enable their relative locations to be measured with high accuracy and in real time. Based on those data, a graphical display that combines ultrasound imagery and navigation data will readily created. With this real time display, the interventionalist will have the means to visualize the exact location of catheters and introducers even if they not clearly evident in the ultrasound images. Further, the display will show other salient geometric features, such as the trajectory a catheter will follow if it is inserted further and distances and angles between that tool path and the ultrasound image. The prototype system will be based on three technologies we have developed for orthopaedic surgery. This research will be conducted in partnership with Carnegie Mellon University's Robotics Institute and the Cardiology Department of Children's Hospital of Pittsburgh. In Phase Two, we will conduct in vivo tests of the sensors in appropriate animal models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMPUTER-GUIDED FIBRILLATION

DESIGNER

ABLATION

OF

ATRIAL

Principal Investigator & Institution: Cherry, Elizabeth M.; Physics; Hofstra University 200 West Library Wing Hempstead, Ny 115491440 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2005 Summary: (provided by applicant): Catheter ablation techniques to treat chronic reentrant atrial fibrillation (AF) have been largely unsuccessful. We postulate that a major determinant of failure is the extreme variability in atrial structure among patients, so that no single catheter ablation strategy will be successful; rather, therapy must be individualized for a given patient. We hypothesize that incorporating specific anatomic information about an individual patient's atrial structure into the ablation strategy will increase the likelihood of success. In this project, we propose to perform the fundamental research necessary to bring patient-specific ablation therapy to the animal laboratory and, ultimately, to human patients. Using three-dimensional endocardial mapping techniques during electrophysiologic diagnostic studies, patient-specific atrial anatomy will be reconstructed from data sets containing the locations and electrogram characteristics of atrial points obtained by a catheter probe. Simulations of AF will be performed using the reconstructed atria. Within this framework, different ablation strategies will be tested in silico to determine how ablation lesions can be successfully performed for each specific individual anatomic structure. This work is designed to lead directly to testable ablation strategies and to novel clinical paradigms in the treatment of AF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--MOUSE CARDIOVASCULAR PHYSIOLOGY Principal Investigator & Institution: Kelly, Daniel P.; Professor of Pediatrics; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2002 Summary: Significant advances in the development of genetically engineered mice lacking or over-expressing specific proteins has proven to be a powerful research tool. As described in this SCOR proposal, a number of interesting transgenic and gene

Studies

15

"knockout" models will be developed to explore the role of specific enzymes and proteins in the physiology and pathophysiology of the cardiovascular system. The mouse cardiovascular Physiology Core will assist with the characterization of the mouse models. This Core will provide rigorous physiologic evaluation of mouse models including; 1) characterization of the structure and function of the heart and great vessels using trans-thoracic echocardiography, 2) cardiovascular hemodynamic measurements of the mouse circulatory system using open- and closed-chest cardiac catheterization, 3) identification and characterization of cardiac rhythm disturbances in mice using ambulatory telemetric electrocardiographic monitoring, and 4) to evaluate the responses to short-term and long-term exercise studies in mice. The Mouse Cardiovascular Physiology Core will accomplish these goals in dedicated space within the Clinical Sciences Research Building at Washington University School of Medicine. It is anticipated after the evaluation of the mouse models developed in this proposal will identify cardiovascular abnormalities relevant to the pathogenesis of pediatric cardiovascular disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--MOUSE PHENOTYPING CORE Principal Investigator & Institution: Hsueh, Willa A.; Professor of Medicine and Chief; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 01-DEC-2002; Project End 30-NOV-2007 Summary: The overall objectives of the Mouse Phenotyping Core will be to provide DERC investigators with consultation, accurate and easily accessible mouse phenotyping, and the availability of both standard and certain unique mouse models of diabetes and its complications. Services provided by the Mouse Phenotyping Core to DERC investigators concentrate heavily on mouse metabolic, cardiovascular and pathologic phenotyping. These services particularly focus on interests of DERC members: 1) metabolic phenotyping relevant to the genesis of insulin resistance and the progression to type 2 diabetes; 2) cardiovascular physiological phenotyping relevant to models of atherosclerosis, diabetic cardiomyopathy and hypertension; 3) renal phenotyping relevant to hypertension and diabetic nephropathy. The existing strengths at UCSD in metabolic phenotyping and at UCLA in renal-cardiovascular phenotyping will be standardized and merged into one central, partially mobile Core. Seamless integration of phenotyping among DERC investigators at UCLA and UCSD will be facilitated by the Mobile Mouse Physiology Unit. This exciting and innovative concept permits delivery of many phenotyping services directly to the laboratory of DERC investigators, as well as provides needed transport of animals, cryopreserved embryos, equipment and other precious materials. Increased quality of data and substantial savings in costs to individual DERC investigators and the Core are anticipated through implementation of this unique concept. Dr. Gerald Levey, Provost UCLA, has committed to purchasing and equipping this Unit. Currently, the most heavily used services of the DERC include: oral glucose tolerance testing, plasma glucose determinations, renal function tests, non-invasive blood pressure measurements, osmotic minipump placement, cardiac fibrosis quantification, echocardiography, cardiac catheterization, and quantification of atherosclerosis. DERC funding will allow expansion of services and development of a new assay development component of this Core. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

16

•

Heart Catheterization

Project Title: CORONARY VASCULAR RESPONSE TO ISCHEMIA Principal Investigator & Institution: Bache, Robert J.; Professor of Medicine; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 01-JUL-1992; Project End 30-NOV-2007 Summary: (provided by applicant): The studies in this proposal will examine responses of the coronary vessels to myocardial ischemia, and determine whether alterations of nitric oxide (NO) or superoxide (O2-) influence vascular or myocardial responses in ischemic regions. Studies will be performed in chronically instrumented dogs in which coronary artery blood flow is measured with a Doppler flowmeter while regional systolic wall thickening is assessed with ultrasonic microcrystals. Myocardial perfusion is measured with microspheres; aortic and coronary venous catheters will allow measurements of coronary NO production. Three different groups of studies are planned. The first group will examine collateral vessel development in response to five daily 2-minute coronary artery occlusions; collateral development will be assessed from blood flow measurements obtained by administering microspheres during occlusion. Myocardial interstitial fluid will be collected using a chronically implanted catheter for measurement of vascular endothelial growth factor, NO metabolites and mitogenic activity in cultured endothelial and smooth muscle cells. Since NO is an important mediator for collateral vessel growth, and since superoxide (O2-) produced during ischemia and reoxygenation consumes NO, a study will determine whether scavenging O2- with a superoxide dismutase (SOD) mimetic can augment collateral growth. Since HMG CoA reductase inhibitors increase NO bioavailability in cultured endothelial cells, another study will determine whether the HMG CoA reductase inhibitor atorvastastin can augment collateral vessel development. A second group of studies will examine mechanisms responsible for endothelial dysfunction in collateral vessels and microvessels perfused through collateral channels. In vivo and in vitro studies will determine whether NO production is decreased and/or O2- production increased in coronary microvessels in collateral-dependent regions. The role of O2- will be examined by determining whether the SOD mimetic can improve endothelial function in microvessels perfused through collateral channels. A final group of studies will examine bioenergetic alterations in myocardium perfused through collateral channels. These studies will determine whether viable collateral-dependent myocardium with persistent contractile dysfunction ("hibernating myocardium") demonstrates a unique pattern of high energy phosphate (HEP) content at rest or during stress different from ischemic or stunned myocardium. Interrogation of myocardial deoxymyoglobin content will demonstrate whether contractile abnormalities in collateralized myocardium at rest or during catecholamine-induced stress are the result of oxygen insufficiency. A final study will examine the influence of NO on the energy supply/demand relationship in collateralized myocardium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: COST-EFFECTIVE MANAGEMENT OF CATHETER RELATED INFECTION Principal Investigator & Institution: Rothaar, Robert C.; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2003; Project Start 31-JAN-2004 Summary: Central venous catheters are essential to the management of the hospitalized patient, especially when critically ill, but catheters do result in substantial morbidity, mortality and expense. Infectious complications alone are responsible for as many as

Studies

17

70,000 deaths annually with an estimated cost to the healthcare system projected at over $2 billion. Large, randomized controlled trials are currently lacking for the majority of interventions considered standard for diagnosis and treatment of catheter related infection (CRI). The proposed research project will pool the best available published evidence for diagnostic accuracy and management of catheter related infection (Aims I & 2), perform a case-control study to examine the economics associated with infection (Aim 3) and lastly, synthesize all of these data elements into a decision analysis model to examine the risks, benefits and costs associated with alternative diagnostic and management strategies (Aim 4). The results of this study are expected to provide a rational, cost effective approach to catheter management decisions in the ICU and could help to identify critical data or strategies that should be examined in future clinical trials. 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 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: DETERMINANTS OF PROCEDURE USE IN MYOCARDIAL INFARCTION Principal Investigator & Institution: Jollis, James G.; Medicine; Duke University Durham, Nc 27710

18

Heart Catheterization

Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: A six-fold variation in the use of cardiac procedures by U.S. geographic region suggests that medical decisions are neither approached in a standard fashion, nor informed by medical evidence. The decision between a patient and their physician is key to efforts aimed at understanding this variation, and at translating medical evidence into clinical practice. In considering the factors that lead to treatment decisions, both patient and physician must be examined together. Lacking knowledge and experience, patients presented with treatment decisions must rely on their physicians to act as their advocate. How physicians frame information will strongly influence the patient's decision process. The objective of this research will be to examine the patient and physician factors involved in the selection of diagnostic and therapeutic procedures in the management of coronary artery disease, and to compare procedural strategies related to patient and physician influences to strategies suggested by clinical trials. The study will encompass two main approaches. The first approach will be to directly examine the patient decision process by administering the Shared Decision Program (SDP) to patients facing treatment decisions following cardiac catheterization. The SDP is a computer based interactive video device that provides patients with easily understood information about their disease and potential therapeutic options in a neutrally framed format. The program also provides viewers with individualized comparisons of survival according for angioplasty, bypass surgery, and medical therapy. If patients are given sufficient information about their disease process and treatment options, they have a greater potential to actively participate in decisions about procedures, possibly selecting those therapies most consistent with medical evidence. The second approach will involve an examination of the physician factors related to differences in cardiac procedure use following acute myocardial infarction. For this approach, we will take advantage of the data available at Duke to develop a longitudinal description of myocardial infarction care from hospital admission through long term follow up, including detailed patient descriptors, inpatient and outpatient cardiac procedures, daily records of physician care, rehospitalizations, and survival status. Using this information, we will examine procedural variation according to the characteristics of the admitting physician. We will also examine "which rate is right?" by comparing adjusted outcomes (mortality, resource use, and costs), and by comparing procedure use to approaches based on medical evidence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIASTOLIC MECHANISMS

HEART

FAILURE:

DEFINING

CARDIOCYTE

Principal Investigator & Institution: Zile, Michael R.; Professor; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: The diagnosis of diastolic congestive heart failure (CHF) can be made when patients have symptoms and signs of fluid overload, a normal ejection fraction, and pronounced abnormalities in diastolic function. In a general population of patients with CHF, the prevalence of diastolic CHF is 30-35% and the 5 year mortality rate is 25%. In patients over 70 years old, the prevalence of diastolic CHF increases to 50% and the 5 year mortality rate approaches 50%. Therefore, diastolic CHF is a major health care problem, especially in our aging population. Despite its importance, the basic underlying mechanisms that cause diastolic CHF and the impact that aging makes on these mechanisms are not completely understood. For these reasons, the primary focus of my research has been to define the mechanisms, which cause abnormal diastolic

Studies

19

function. Diastolic CHF develops when there has been a fundamental alteration in the passive material properties of the cardiac muscle tissue (i.e., increased diastolic myocardial stiffness). Three of the possible mechanisms which may cause this increase in myocardial stiffness include changes in the cardiac muscle cell (cardiocyte), changes in the extracellular matrix (ECM), and changes in neurohumoral activation. I believe that changes in each of these three mechanisms, individually and in combination, cause the abnormalities in diastolic function that lead to diastolic CHF. Studies examining the ECM and neurohumoral activation are the subject of my ongoing Department of Veterans Affairs Merit Review grant. Studies examining mechanisms within the cardiocyte will be the focus of this Program Project Proposal. The purpose of Project 6 is to prove the hypothesis that basic cardiocyte mechanisms play a significant cause and effect role in the development of the diastolic CHF. This hypothesis will be tested using three specific aims: 1) Determine whether, and to what degree, changes in the viscoelastic properties of the cardiocyte occur in, and are causally related to the increased myocardial stiffness produced by pressure-overload hypertrophy (POH) and advanced age, 2) Define the basic cellular mechanisms which cause increased cardiocyte viscoelastic stiffness, and 3) Determine whether transgenic modulation of these basic cellular mechanisms will prevent or correct the increases in diastolic stiffness produced by POH and advanced age. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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 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

20

Heart Catheterization

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: FEASIBILITY STUDY PAROXYSMAL ATRIAL FIBRILLATION

OF

CATHETER

Principal Investigator & Institution: Haines, David; Charlottesville Box 400195 Charlottesville, Va 22904

ABLATION

University

of

FOR

Virginia

Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HIGH FREQUENCY ULTRASOUND ARRAYS : INTRACARDIAC IMAGING Principal Investigator & Institution: Sahn, David J.; Professor; Pediatrics; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-JAN-2007 Summary: (provided by applicant): lnvasive applications of echocardiography, including transesophageal echo, intravascular echo and intracardiac echo have been one of the most fertile areas driving new technology for ultraminiaturization and very high resolution. Among the most prolonged and detailed interventional catheterization procedures, electrophysiological mapping and ablation for recurrent atrial and ventricular arrhythmias have received recent attention because of the now-recognized need for spatial mapping in addition to fluoroscopic catheter localization, and because of the increased frequency of these debilitating rhythm problems in an aging population. We propose to design, develop and test a family of 2D and 3D ultrasound imaging devices which, at 10-15MHz operating frequency, will provide spatial localization, and both tissue velocity and strain rate estimates of mechanical activation in atrial and ventricular walls, to guide electrical mapping. This should greatly shorten time to localize critical areas. Our devices will be integrated with the EP electrode and RF ablation devices so that they can anatomically monitor the ablation procedure, visualize the lesion, and map the distribution of temperature during RF delivery focus. The devices we will build can also assess the heart before, during and after surgery as well as monitor anatomical catheter interventions for coronary artery, valvular or congenital heart disease. Our partnership is a multidisciplinary group of clinicians, surgeons, echocardiographers and electrophysiologists at OHSU, led by David J. Sahn, MD, Director of the Interdisciplinary Program For Cardiac Imaging, combined with bioengineers including: Matthew O'Donnell, PhD, Chair of the Department of Biomedical Engineering at the University of Michigan, Ann Arbor; Kirk Shung, PhD, director of an NIH Research Resource for Development of High Frequency Arrays at Pennsylvania State University, University Park; Kal Thomenius, PhD, Program Manager of Ultrasound Research at the General Electric Corporate Research and Development Center in Schenectady, New York; Douglas Stephens, Vice President of Strategic Technology at the Imaging Division of JOMED (formerly Endosonics Corporation) in Rancho Cordova, California, a pioneer in miniaturized array devices for intravascular and intracardiac imaging catheters; and Raymond Chia, PhD, of Irvine Biomedical, a small agile company with expertise in steerable multipolar electrode and ablation devices and their combination with other imaging modalities. The design and

Studies

21

development of these devices combined with advanced functional imaging methods should open new vistas for applications in invasive echocardiography and ultrasound in general. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMAGING AND LASER REVASCULARIZATION IN HIBERNATION Principal Investigator & Institution: Johnson, Lynne L.; Director, Nuclear Cardiology; Rhode Island Hospital (Providence, Ri) Providence, Ri 029034923 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-MAY-2004 Summary: (Provided by Applicant): Identifying chronically ischemic dysfunctional or hibernating myocardium is an important clinical endeavor. Patients who are not candidates for CABG or PICA are now being considered for new methods of revascularization such as direct myocardial revascularization with laser channels using catheter based approach (DMR). Electromechanical endocardial (UPV) mapping is used to guide DMR but is not fully validated. Perfusion imaging and dobutamine echocardiography are being used clinically to identify dysfunctional viable myocardium and assess results of novel revascularization techniques. The accuracy of these imaging techniques for these indications have never been fully validated in an animal model. Gold standards for viability used in clinical studies are imperfect. A double ameroid constrictor/swine model for hibernating myocardium shows promise as a good model to compare these technologies against one another and against histopathology and to investigate the efficacy and mechanisms of DMR. In the first aim we propose to use swine models of extensive hibernation and of scar to validate UPV mapping to identify viability vs scar and to compare thallium imaging and dobutamine echocardiography against histopathology to identify viability and sear. Under aims 2 and 3 the double vessel ameroid model will be used to investigate mechanisms for DMR. The effect of laser therapy on angiogenesis will be assessed using combined morphometric tissue analysis and angiographic techniques. The efficacy of noninvasive imaging (adenosine Tc-99m sestamibilrest Tl-201 and dobutamine echo) to detect neovascularization will be assessed. In aim 4 radioiodinated MIBG autoradiography will be used to look at the effects of DMR on regional innervation. The results of these experiments should better define the accuracy of methods to image viability and image angiogenesis, and lead to a better understanding of whether DMR revascularizes the heart and whether or not it denervates the heart. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: IMPROV OF RES FACIL: EXERCISE & AGING Principal Investigator & Institution: Coleman, James S.; Phd; None; University of Missouri Columbia 310 Jesse Hall Columbia, Mo 65211 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2003 Summary: (provided by applicant): Expansion of prominent biomedical research at the UMC is a campus and legislative priority. The SOM adopted a new strategic plan that increases external funding for diabetes and cardiovascular research. A CDCH was formed to meet the goal of translating basic science to clinical research. The CDCH will facilitate recruitment of four highly qualified faculty; three are budgeted through special state funding targeted for life sciences mission enhancement, the fourth through an endowed professorship. CDCH faculty recruitments are delayed due to lack of research space. Renovation of existing space on the fourth (8,900 sq. ft. and first (500 sq. ft.) floors of the SOM solves CDCH's immediate space needs. The space proposed for renovation

22

Heart Catheterization

is 30-years-old. It never has been updated. The renovation will: 1) house and promote collaborations between four National Institutes of Health (NIH)-funded investigators (Drs. Virginia Huxley, Kerry McDonald, Michael Sturek, and Richard Tsika); 2) free 4,600 sq. ft. of laboratory space on the fourth floor to be renovated (an institutional commitment beyond the required cost match) for the recruitment of four clinical scientists; 3) enhance collaborations with clinical scientists and advance training of clinical fellows by placing quality laboratories near the hospital; and 4) renovate an animal cardiac catheterization facility on the first floor. In FY 2001-02 investigators impacted by this renovation held active NIH awards totaling $6,469,602. The CDCH will function as an incubator leading to program and center applications. CDCH will serve as a focal point for a capital fund raising campaign. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPROVED ACCURACY FOR SPECT CARDIAC PERFUSION IMAGING Principal Investigator & Institution: King, Michael A.; Professor of Radiology; Nuclear Medicine; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2002; Project Start 01-APR-1994; Project End 31-DEC-2003 Summary: The goal of the proposed research is to improve the accuracy in identifying patients with coronary artery disease by single photon emission computed tomographic (SPECT) myocardial perfusion imaging. To attain this goal the investigations will complete the development of the corrections for the degradations inherent in imaging (non-uniform attenuation, scatter, distance-dependent resolution (DDR), physiological motion, and noise) begun during the original grant period. The specific aims are: 1) to investigate the limits imposed by variations in cardiac wall thickness, motion, and contractility, and to determine to what extent alterations in acquisition and reconstruction strategies can overcome the current limitations; 2) to investigate the impact of respiratory motion on defect detection and develop strategies to diminish this impact; 3) to investigate methods to reduce the influence of noise in reconstructed static (3D) and gated (4D) slices; and 4) to conduct two receiver operating characteristics (ROC) studies using clinical images to determine the relative detection accuracy of the acquisition and reconstruction strategies developed herein. The investigations of the first three specific aims will use simulations based on anatomical models of the left ventricle (LV) derived from the segmentation and fitting of gated, breath-held magnetic resonance imaging (gMRI) slices from normal subjects. By utilizing simulation studies we can systematically evaluate acquisition and reconstruction strategies which may not yet be clinically feasible. The comparison criteria used in the simulation studies will include the degree of uniformity of maximal-count circumferential-profile polar-maps, and defect detection by numerical-observers, human-observers, and quantitative analysis. The first clinical human-observer ROC study will compare stress images reconstructed by filtered backprojection (FBP) with no compensation, and those rendered using iterative reconstruction with compensation for: 1) attenuation; 2) attenuation and scatter; and 3) attenuation, scatter and DDR. The second ROC study will compare: 1) iterative reconstruction with the best combination of compensations, as determined in the first ROC study, versus FBP reconstruction with no compensation; 2) expert readers (board certified physicians) versus readers with more limited expertise (cardiology fellows); and 3) reading only the stress slices versus using all of the scintigraphic information which is routinely clinically available. Overall, the proposed investigations should permit us to develop an optimal imaging strategy for myocardial

Studies

23

perfusion imaging, and determine whether this strategy enhances clinical interpretation for readers with differing skill levels. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN SIGNALING AND THE HEART IN DIABETES Principal Investigator & Institution: Abel, Evan Dale.; Assistant Professor; Internal Medicine; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-DEC-2007 Summary: (provided by applicant): The pathogenesis of cardiac dysfunction in diabetes is partially understood. Our goal is to determine the mechanisms by which reduced insulin signaling in cardiomyocytes and vascular endothelium contributes to the pathogenesis of diabetic cardiomyopathy. Our overall hypotheses are: (1) In diabetes, deficient or reduced insulin signaling in cardiomyocytes leads to an initial defect in glucose/pyruvate oxidation, and a secondary increase in fatty acid oxidation that leads to increased production of reactive oxygen species (ROS) that ultimately causes progressive mitochondrial injury. Increased fatty acid delivery to insulin resistant cardiomyocytes during diabetes will accelerate mitochondrial dysfunction. (2) In the heart the (acute and chronic) regulation of cardiac muscle substrate metabolism by insulin involves paracrine interactions between cardiomyocytes and other cells in the heart such as endothelial cells. Thus, impaired insulin signaling in these cells and in cardiomyocytes both contribute to altered cardiac metabolism and function. The consequences of these defects will be exaggerated when cardiac energy requirements are increased such as during left ventricular hypertrophy. Aim 1: will determine the mechanisms by which chronic deficiency of insulin signaling in cardiomyocytes impairs mitochondrial oxidative capacity and predisposes the heart to lipotoxic injury. Studies will be performed in mice with constitutive and inducible deletion of insulin signaling in cardiomyocytes. We will determine the mechanisms for changes in PDH activity, the mechanisms that lead to increased fatty acid utilization in these models and the role of increased ROS generation in precipitating mitochondrial dysfunction and lipotoxic cardiomyopathy. Aim 2: will determine the mechanisms by which non-myocyte cells in the heart modulate cardiomyocyte metabolism. We will determine if loss of insulin signaling in these compartments will accelerate or exacerbate the metabolic and functional impairment in hearts that lack insulin signaling in cardiomyocytes by studying hearts deprived of insulin signaling in endothelial cells and cardiomyocytes under basal conditions and following pressure overload hypertrophy. The role of nitric oxide in the paracrine regulation of myocardial metabolism by insulin will be determined. These studies will shed important insight into the regulation of cardiac function and metabolism by insulin and the role of impaired insulin signaling in the pathogenesis of diabetic cardiomyopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: INVASIVE MICROCIRCULATION

ASSESSMENT

OF

THE

CORONARY

Principal Investigator & Institution: Fearon, William F.; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2009 Summary: (provided by applicant): Traditionally, evaluation of patients with suspected coronary artery disease has focused on the epicardial coronary system. More recently, investigators have come to appreciate better that the status of the coronary

24

Heart Catheterization

microcirculation can influence significantly long-term morbidity and mortality. Although cardiac transplant recipients commonly develop microcirculatory dysfunction, its timing and its effect on outcomes is unclear. Patients with acute myocardial infarction, despite successful recanalization of an occluded epicardial artery, suffer from microcirculatory dysfunction, both in the infarcted region, as well as in myocardium remote from the infarction. However, the incidence and implications of micro-circulatory dysfunction in areas remote from an acutely infarcted territory are poorly understood. To date, evaluation of the coronary microcirculation has been limited by techniques which incorporate the epicardial system into their assessment. Additionally, most methods require specialized equipment and/or analyses. Others are limited by their qualitative nature. Finally, the majority of methods are noninvasive, yet many patients first present for evaluation of their coronary arterial system in the cardiac catheterization laboratory. The first goal of this project is to demonstrate that an invasive, coronary wire-based method for evaluating the coronary microcirculation is easy to perform and interpret, quantitative, and correlates well with standard methods for assessing the microcirculation. The technique will be validated in a porcine model of epicardial artery and microcirculatory disease. It's correlation with PET imaging, the current gold standard noninvasive method of evaluating the microcirculation, will then be tested in patients with and without microcirculatory dysfunction. The second and third goals of this study will be to apply this technique to gain a better understanding of the role of the microcirculation in the outcomes of cardiac transplant patients and those suffering from acute myocardial infarction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IR AND ULTRASOUND CATHETER SYSTEMS Principal Investigator & Institution: Hooper, Brett A.; Assistant Research Professor; Biomedical Engineering; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 02-MAY-2001; Project End 30-APR-2004 Summary: (Verbatim from Applicant's Abstract): Cardiovascular disease is the leading cause of death in the United States. Techniques to address this problem such as laser angioplasty showed promise early on, but enthusiasm waned in the face of inadvertent vascular perforation, restenosis, and thrombosis. The overall objective of the proposed research is to develop and test a new class of broadband endoscopic and catheter based systems for the diagnosis and therapy of cardiovascular disease. This new generation of catheter based devices is designed to overcome the problems associated with laser angioplasty and extend the frequency range of IR which can be administered. We also propose to develop, for the first time, multiple energy catheters that will permit simultaneous imaging with JR and ultrasound (U/S). Simultaneous, multi-energy images may permit a more accurate assessment of vascular plaque type. The proposed imaging systems will be forward-Jooking rather than side-looking unlike all conventional intravascular ultrasound scanners. To address the overall objective we propose the following specific aims: 1) measure IR absorbance spectra of various atherosclerotic plaque (in vitro and in vivo) in the 2 to 10 um range, 2) perform tissuespecific, evanescent optical wave ablation of atherosclerotic plaque (in vitro and in vivo) at wavelengths determined from aim 1, using the continuously tunable IR free-electron laser (FEL) at Duke University, 3) design, construct, and test a broadband multi-energy catheter that permits simultaneous forward-looking JR and U/S imaging, and 4) design, construct, and test a broadband multi-energy catheter that permits sequential JR imaging and ablation. Perhaps the most profound advantage of this approach is the combined use of evanescent waves and multiple energy endoscopic delivery for precise,

Studies

25

controlled laser surgery and diagnosis in a minimally invasive setting. The program will evolve from benchtop experiments using the JR FEL to advanced fiber optics that incorporate specialized optical micro-electro-mechanical systems (MEMS) sources and sensors for diagnostic and therapeutic devices. Results from aims 1 and 2 will guide the construction phase of the advanced MEMS source and detection arrays. The integration of MEMS and smart pixel arrays has the potential of making available to cardiovascular medicine high performance, inexpensive and unique catheters. Such catheters could have a major impact on the treatment of cardiovascular disease and may find application in other disease entities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: KANGAROO CARE EFFECTS ON POST/CATH STABILIZATION Principal Investigator & Institution: Torowicz, Deborah L.; None; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 30-SEP-2002 Summary: (provided by applicant) Infants undergoing cardiac cath are at risk for complications due to cardiac instability in the post cath period. Current pediatric practice is based on adult standards of care. An established intervention called kangaroo care (KC) skin-to-skin contact between a mother and her infant is known to increase cardio respiratory stability and may be useful for infants post cath. The purposes of the proposed study are to determine l) the nature of cardio respiratory and behavioral effects of KC following cardiac catheterization and 2) the efficacy of KC by examining its? effect on cardio respiratory stabilization during the post cath period. Infants admitted for cardiac catheterization will be placed into one of two groups; one group will receive KC for five hours in the post cath period and the other group will receive the standard care of bed rest. A randomized control pretest-posttest design will be used that controls for all threats to internal validity. Baseline data will be collected from each group on heart rate, respiratory rate, oxygen saturation, and cardiac output. ABSSS will be used for behavioral state. Student t test will be used to compare post cath means between groups. 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; President; Biotex, Inc. 8018 El Rio St 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

26

Heart Catheterization

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: LEFT VENTRICULAR GEOMETRY AND CARDIAC RISK IN BLACKS Principal Investigator & Institution: Keane, Martin G.; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: LEFT VENTRICULAR REMODELING IN AORTEC INSUFFICIENCY Principal Investigator & Institution: Pasque, Michael K.; Surgery; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 10-APR-2000; Project End 31-MAR-2004 Summary: (Verbatim from the application): Introduction. Over the last nine years, our laboratory has helped develop and validate the mathematical modeling capabilities that are necessary to clinically evaluate the function of the heart by assessing the systolic and diastolic stress-strain relationships of the in vivo myocardium. This proposal would extend the application of these clinical tools to the comprehensive evaluation of the pathological left ventricular (LV) remodeling associated with severe aortic valvular insufficiency and the time course, degree, durability and prognostic significance of the reversal of this remodeling that occurs after aortic valve replacement (AVR). The accurate characterization of left ventricular remodeling and its reversal would have direct clinical relevance to a large number of clinically significant disease processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: LINEAR LESION DEVICE Principal Investigator & Institution: Sherman, Jon A.; Vice-President; Enable Medical Corporation 6345 Centre Park Dr West Chester, Oh 45069 Timing: Fiscal Year 2003; Project Start 30-SEP-2001; Project End 30-NOV-2004

Studies

27

Summary: (provided by applicant): Atrial Fibrillation is an electrical malfunction of the upper pumping chambers of the heart causing major medical and lifestyle problems. The current treatments are pharmaceutical (side effects and minimal effectiveness), pacemakers (after destroying the electrical system of the heart, expensive and moderately effective), and electrically isolating areas of the heart using the MAZE procedure - surgically cutting the heart and sewing back together creating scar tissue to block malfunctioning electrical pathways. This MAZE procedure has proven to be nearly 100 percent effective, however it is long and extraordinarily difficult. Due to the promising concept, this approach is aggressively being investigated using ablation catheters and probes to create lesions. However, to isolate electrical pathways, a complete electrical block in the tissue must be made and these technologies are limited in their ability to create transmural lesions. With these technologies, charring and extensive atrial damage occur, which can increase risk of stroke. Our technology addresses these issues by incorporating RF Bipolar energy into a device that will quickly and safely create a transmural linear lesion, from endocardium to epicardium, in a single application while protecting the surrounding tissue. In Phase I we will fabricate a prototype and evaluate our lesions for transmurally and ability to electrically isolate tissue. PROPOSED COMMERCIAL APPLICATION: Our technclogy will overcome the limitations of the current methods of treating atrial fibrillation (AF) and can be used to treat AF during open-heart procedures and to reduce the occurrence of post-operative AF episodes. This market alone exceeds $1.2 BB/year. The devices that can be developed using this technology have a strong potential of being incorporated into minimally invasive procedures adding an additional $1.5 BB to the market potential. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MCAP: ENABLING TECHNOLOGY FOR MRI VISIBLE POLYMERS Principal Investigator & Institution: Burke, Thomas M.; Phantoms by Design, Inc 1507 175Th Pl Se Bothell, Wa 980126460 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 31-DEC-2004 Summary: (provided by applicant): Efforts to establish MRI guided intervention as clinically practical are hampered by a lack instruments that are safe and exhibit clinically useful MRI visibility. We propose to introduce and develop an advanced class of microcapsule (mCAP) contrast additives optimized for use with medical grade polymers, mCAP enhanced polymers will allow MRI compliant instruments exhibit clinically relevant MRI visibility while retaining existing mechanical and manufacture properties. Although the proposed enabling technology is applicable to many devices, this grant application focuses primarily upon developing MR-visible vascular catheters. This will be accomplished by: 1) Identifying base materials and encapsulation procedures to: establish feasibility and set performance baseline. 2) Explore variations in material formulations and polymer processing to: a) Demonstrate ability to optimize performance. b) Identify paths for in depth Phase II development. 3) Lastly, three (3) different prototypes devices are constructed and tested to demonstrate: a) mCAP compatibility with a range of polymers. b) Direct MR visibility with contemporary MR imaging sequences. Mechanical properties and image performance are quantified for each prototype. Results are compared with quantitative criteria to establish proof-ofconcept. If successful, mCAP enhanced polymers should enjoy broad applicability and contribute to the adoption of minimally invasive, MRI guided interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

28

•

Heart Catheterization

Project Title: MECHANISM OF CHD IN HIGH RISK FAMILIES Principal Investigator & Institution: Becker, Lewis C.; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002 Summary: In a group at high risk for CAD, we hypothesize that non-invasive testing will accurately detect the presence of occult asymptomatic CAD and thereby identify individuals at higher risk for future CAD events, such as sudden death, myocardial infarction and unstable angina. Coronary angiography will reveal significant flowlimiting coronary stenoses in most individuals with abnormal treadmill tests or thallium scans but in others, angiographic lesions in the proximal coronary arteries will be relatively mild and exercise-induced ischemia will be explained by reduced coronary flow reserve or impaired endothelium-dependent coronary artery dilatation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: MECHANISMS OF MYOCARDIAL RADIOFREQUENCY SCAR EXPANSION Principal Investigator & Institution: Mukherjee, Rupak; Pediatrics; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2005 Summary: Transcatheter radiofrequency (RF) ablation is an important modality for the control of pharmacologically refractory arrhythmias in pediatric patients. While RF ablation effectively terminates arrhythmias in children, the myocardial remodeling that occurs following the creation of a RF lesion remains poorly understood. Clinical case reports have provided evidence to suggest that scar expansion occurs following RF ablation in infants. Furthermore, in a pediatric animal model, RF scars have been demonstrated to increase in a time dependent manner. Thus, significant RF scar expansion may occur in the myocardium of pediatric patients following RF ablation. Accordingly, the overall goal of this study is to define determinants responsible for myocardial remodeling which results in RF scar expansion in a pediatric animal model and to determine the physiological consequences of this event. Furthermore, a potential molecular mechanism which contributes to expansion of the RF ablative scar will be defined. Expansion of the RF ablative scar must be accompanied by myocardial remodeling. An endogenous enzyme system responsible for extracellular collagen degradation and remodeling is the matrix metalloproteinases (MMPs). Therefore, the overall hypothesis of this project is that heightened MMP activity occurs following the creation of a RF ablative lesion, and which remains elevated along the border zone of the RF scar and directly contributes to scar expansion. Direct interruption of MMP activation during and following RF lesion creation will result in an attenuation of RF scar expansion and the physiological consequences of this process. To test this hypothesis, the degree of MMP expression and activity at the border of the RF scar will be measured and related to temporal changes in RF scar size. Furthermore, in order to more precisely define the role of MMP activity in RF scar expansion, two sets of experiments will be performed. First, MMP inhibition will be instituted in a set of animals at the time of RF lesion creation and continued through the follow up period. Second, the RF scar expansion characteristics will be examined in transgenic mice lacking the genes responsible for MMP expression or endogenous control of MMP activity. Thus, results of this study will define the physiological consequences of RF lesion expansion in a pediatric model, determine the molecular basis for RF scar expansion, as well as identify a potential therapeutic modality to attenuate this process.

Studies

29

Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MENTORED DEVELOPMENT AW

PATIENT-ORIENTED

RESEARCH

CAREER

Principal Investigator & Institution: Robbins, Ivan M.; Medicine; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-JUL-2000; Project End 30-JUN-2005 Summary: (Adapted from the applicant's abstract): PPH is a disease of high morbidity and mortality occurring predominately in young adult women. The etiology of this illness remains unknown, but increased production of thromboxane A(2) [TxA(2)] and decreased synthesis of prostacyclin [prostaglandin I] provide clues to the pathogenesis. Over the past decade, intravenous epoprostenol, the synthetic analogue of prostacyclin, has emerged as the most effective treatment of PPH. However, tolerance to the effects of epoprostenol occurs in the majority of patients necessitating progressive dose escalation to maintain efficacy. Furthermore, only 70% of patients benefit from treatment. Preliminary data derived from clinical studies of patients with PPH demonstrate that epoprostenol increases circulating levels of angiotensin II (AII), a potent vasoconstrictor and smooth muscle mitogen, which can stimulate production of both plasminogen activator inhibitor 1 (PAI- 1), a procoagulant protein, and vascular endothelial growth factor (VEGF), permeability and angiogenic growth factor. This proposal will explore two hypotheses: 1) activation of the renin- angiotensin system (RAS) during chronic administration of epoprostenol is the cause of increasing dose requirements; 2) direct and indirect effects of RAS activation and persistent TxA(2) production limit the clinical efficacy of epoprostenol. To evaluate these hypotheses, the applicant will: a) delineate the relationship between epoprostenol-induced RAS activation and compare biochemical changes with hemodynamic data obtained during right heart catheterization; b) delineate clinical data obtained from measurement of distance walked in six minutes, and structural changes obtained by wedge angiography of pulmonary circulation; and c) determine, in a collaborative study with other medical centers, whether concomitant treatment with and angiotensin converting enzyme inhibitor will improve the clinical efficacy of epoprostenol and prevent the need for chronic dose escalation. These studies will advance our knowledge of the mechanism of action of epoprostenol and pulmonary hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METHOD TO EVALUATE AND QUANTIFY MYOCARDIAL INJECTIONS Principal Investigator & Institution: Reinhardt, Christopher P.; Biophysics Assay Lab, Inc. (Biopal, Inc) 80 Webster St Worcester, Ma 016031914 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2004 Summary: (provided by applicant): Direct intra myocardial injection may permit local delivery of protein and gene therapy agents for myocardial and coronary artery disease. However, little is known about the immediate fate of materials administered via percutaneous endomyocardial catheters or via surgical epicardial injection. Unrecognized loss of injected material can negatively influence the outcome of a preclinical trial. Both pharmaceutical developers have long privately discussed this problem and developers of drug delivery systems. A recent publication demonstrates that myocardial retention of injected material can vary greatly. We hypothesize that a commercial reagent can be developed to provide both detection and quantitation of

30

Heart Catheterization

cardiac drug delivery systems in vivo models, as well as provide the means to uniquely identify experimental subgroups during double blind animal trials. In addition, this reagent can be used as a teaching tool and as a means to certify clinicians in myocardial injection techniques. Our Phase I application seeks support to develop a set of reagents, co-labeled with both a stable isotope and a fluorescent marker. Our proposed reagent will allow validation of cardiac injection methods, allow monitoring of technical competence during preclinical trails, allow identification of subject groups, and assure higher quality of in vivo data. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MICRONEEDLE ARRAY FOR CATHETER DRUG DELIVERY Principal Investigator & Institution: Roy, Shuvo; Co-Director; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2003; Project Start 12-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): The ultimate goal of this project is the development of a catheter that can inject drugs directly into the wall of the coronary artery to prevent restenosis after angioplasty. MEMS (microelectromechanical systems) technology will be used to prototype miniature hollow needles from silicon substrates. Microneedle arrays will be integrated with low profile catheter delivery systems for transport to and from the deployment site within arteries. Finite element modeling will be used to generate robust needle designs, which will be subsequently fabricated using deep reactive ion etching and wet anisotropic etching of silicon. Different microneedle geometries and array layouts will be fabricated and evaluated for mechanical strength and penetration characteristics into filleted rabbit lilac and porcine coronary arteries. Two low profile catheter delivery systems will be developed to transport the microneedle array to the coronary artery. One approach will rely on a low profile balloon to house the microneedle array inside molded pockets within the balloon. The other approach will investigate a novel suction catheter that would house the microneedle during transport. Once at the deployment site within the artery, suction would be applied via a syringe to pull the vascular wall towards the catheter and force the microneedles into the tissue. Fluid delivery will be demonstrated by injecting Evan's Blue dye into the arterial wall. Experiments and computer modeling will be conducted to optimize the microneedle geometry and array layout for penetration and fluid delivery. Results of this R21 project will establish the feasibility for further development of microneedles for local drug delivery catheters that could be used to investigate the efficacy and delivery characteristics of anti-restenosis therapy delivered directly into the vascular wall. 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-2005 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

Studies

31

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 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: MULTIDIMENSIONAL HEART IMAGING WITH ULTRASOUND Principal Investigator & Institution: Greenleaf, James F.; Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2003; Project Start 01-APR-1989; Project End 31-AUG-2006 Description (provided by applicant): The long-term goal of this research program continues: to evaluate myocardial function and physiology with high temporal and spatial resolution using advanced multidimensional ultrasound methods. The specific goals of this proposed project for the next five years are: 1) to relate localized in-plane wall stress, to the vibroacoustography signal in excised perfused slabs of myocardium and later, in open chest pigs, 2) to relate local myocardial in-plane strain, measured with tissue Doppler gradients from our intra-cardiac ultrasound catheter, to vibroacoustography signals, 3) to measure myocardial perfusion (ml gram-1 min about') from contrast bubble concentration, with vibro-acoustography using high ultrasound intensity to clear out bubbles, and then 4) to apply these methods to characterizing localized myocardial conditions of normal, ischemia, infarct, and reperfusion, in the hearts of open chest pigs validated with gross vital staining and histology. These specific goals will be accomplished with two new imaging methods, both recently developed at Mayo Clinic. The first is an intracardiac ultrasound imaging catheter developed in collaboration between the Mayo echocardiography group and Acuson Corporation (AcuNav, Acuson, Inc., Mountain View, CA). The intracardiac catheter (ICE) can measure tissue myocardial Doppler velocity gradients, which are a rough estimate of strain rate along the direction of the ultrasound beam. The second recently developed imaging method is "vibro-acoustographic emission" or VAE. VAE uses radiation force induced vibration of myocardium, detected with a hydrophone, to estimate stiffness with high spatial and temporal resolution (-0.7cc, 200 samples/second, respectively). In

32

Heart Catheterization

controlled in vitro and in vivo studies we will validate the ability of VAE to estimate wall stress from measurements of stiffness and of ICE to estimate strain. We also propose that VAE can assess inflow rates of contrast microbubbles, and thus provide an estimate of blood perfusion, within localized (-0.7cc) regions in the myocardium. When VAE, validated in this program, is combined with the ICE catheter in a future clinical instrument, highly localized stress, strain and perfusion could be estimated within the mvocardium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NATRIURETIC PEPTIDES, GENES, AND DIASTOLIC HEART FAILURE Principal Investigator & Institution: Wang, Thomas J.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Plasma natriuretic peptide levels are markedly elevated in individuals with left ventricular hypertrophy (LVH), one of the key precursors of diastolic heart failure (DHF). However, experiments using gene knockout mice indicate that natriuretic peptide deficiency (not excess) leads to progressive LVH. This apparent paradox is explained by the important counter-regulatory function of the natriuretic peptides, which are secreted in response to atrial and ventricular wall stress. In experimental models, natriuretic peptides have two paracrine effects on the heart: enhanced lusitropy and inhibition of myocyte hypertrophy and fibrosis. It is hypothesized that deficiency of natriuretic peptides contributes to the development of LVH and DHF in humans. Two clinically relevant approaches to testing this hypothesis are to examine the impact of genetic variations in the natriuretic peptide axis on left ventricular structure and function and to study the effects of acute administration of these peptides. The proposed research has 3 specific aims: (1) to examine the influence of selected polymorphisms in natriuretic peptide genes on plasma natriuretic peptide levels and LVH, using multivariable analyses; (2) to examine the association of genetic variation in natriuretic peptides and natriuretic peptide levels with incident heart failure, using proportional hazards models; (3) to assess the effects of exogenous B-type natriuretic peptide on myocardial function in patients with DHF, using serial hemodynamic and echocardiographic assessments. The first 2 aims will be addressed by studying a large, community-based cohort (Framingham Heart Study) with extensive clinical, echocardiographic, and genetic characterization. Aim 3 will be carried out in the cardiac catheterization laboratory and coronary care unit of a large, referral hospital. The goal of these studies is to elucidate the role of the natriuretic peptides and their genes in ventricular remodeling and diastolic dysfunction, in the hopes of identifying more specific strategies for treating and preventing congestive heart failure. This research and the associated career development activities will provide the candidate with specific training in genetic epidemiology, the hemodynamic and non-invasive assessment of ventricular function, the use of biomarkers, and clinical trials. Each of these skills will be critical to the candidate's long-term goal of becoming an independent clinical investigator with a focus on heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: NEUROHUMORAL CONTROL IN HYPERTENSION Principal Investigator & Institution: Fink, Gregory D.; Associate Professor; Michigan State University 301 Administration Bldg East Lansing, Mi 48824

Studies

33

Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: This Program Project will compare control of arteries and veins by the sympathetic nervous system (SNS), endothelin (ET-1), and superoxide anions in normotensive and hypertensive animals. A major goal is to determine if abnormalities in venous function contribute to the etiology of hypertension. Project 1 involves studies in rats instrumented to allow long-term recording of blood pressure, blood volume and mean circulatory filling pressure. This latter variable is an in vivo index of venoconstriction or venomotor tone. Most experiments will be in rats with DOCA-salt hypertension. In this model the SNS, ET-1 and superoxide anions all participate in hypertension development. We have produced in vivo evidence that the SNS, ET-1 and superoxide each increase venomotor tone in DOCA-salt hypertension, in vitro data from other projects in the Program have revealed important differences in control of veins by these factors in normotensive and DOCA-salt hypertensive rats. This information has been used to formulate four Specific Aims for Project 1. Specific Aim 1 is to determine if increased venomotor tone due to sympathetic venoconstriction, ET-1 and/or superoxide anions contributes to the development of DOCA-salt hypertension. Specific Aim 2 is to determine if increased venomotor tone due to sympathetic venoconstriction, ET-1 and/or superoxide anions help support established DOCA-salt hypertension by regulating cardiac output. Specific Aim3 will evaluate ET-1 levels and sympathetic activity in the splanchnic bed of DOCA-salt hypertensive rats. Specific Aim 4 capitalizes on our novel observation that chronic infusion of the selective ETB receptor agonist sarafotoxin 6c causes hypertension associated with increased venomotor tone and neurogenic pressor activity. Studies will characterize the role of ET receptor regulation, superoxide generation and sympathetic activity to veins in this new model of hypertension. This Project is unique in highlighting the veins and their role in vascular capacitance as an important component of the pathophysioiogy of hypertension. New findings here could suggest novel approaches to therapy of this important and prevalent disease. They also could provide insights into numerous other conditions involvinq venous dysfunction, including orthostatic disorders and heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEW SCANNING MODALITIES FOR 3-D CARDIAC ULTRASOUND Principal Investigator & Institution: Smith, Stephen W.; Professor; Biomedical Engineering; Duke University Durham, Nc 27710 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2007 Summary: (provided by applicant): Real time trans-thoracic volumetric scanning, using 2-D array transducers based on Duke University designs, offers potential to increase the accuracy of cardiac measurements such as ventricular volumes and improve the diagnosis of coronary heart disease. The objective of this proposal is to extend the advances of real time volumetric scanning to transesophageal endoscopes, surgical endoscopes for applications in minimally invasive cardiac surgery. In this research, we will develop new 2D array transducers including cylindrical and hemispherical curvilinear probes operating from 5-10 MHz which produce a panoramic 3-D field of view approaching 1800. We will also develop an intracardiac catheter which combines 3D ultrasound imaging and endocardial ultrasound thermal ablation system integrated within a single catheter delivery device for applications to the cardiac arrhythmias and interventional cardiology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

34

•

Heart Catheterization

Project Title: NEW TECHNOLOGIES IN ELECTROPHYSIOLOGY INTERVENTION Principal Investigator & Institution: Halperin, Henry R.; Associate Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): The focus of Dr. Halperin's research career has been extending basic and applied investigation to patient-oriented research. His work has been primarily in the fields of cardiopulmonary resuscitation and electrophysiology, where he continues to apply scientifically-based technology development to clinical medicine. He first studied the mechanisms whereby blood moved during cardiopulmonary resuscitation. That work led to the development of pneumatic vest CPR, which provides high-force circumferential chest compressions. After pre-clinical studies showed that pneumatic vest CPR improved blood flow and survival over that obtained with manual CPR, Dr. Halperin developed a clinical pneumatic vest CPR system, developed protocols for clinical studies, obtained FDA approval for the clinical studies, and published the results in the New England Journal of Medicine. Dr. Halperin's interests broadened from cardiopulmonary resuscitation to include electrophysiology, given that the arrhythmias that cause cardiac arrest are a major interest of electrophysiologists. A major limitation in studying arrhythmias in patients, however, is the lack of ability of current technology to accurately correlate anatomical and electrical information. Anatomy is derived from x-ray images, which are twodimensional and have substantial anatomic ambiguity. Another major limitation is the lack of ability to visualize ablated areas of myocardium during catheter ablation procedures. Dr. Halperin has invented ways of combining the anatomic information from magnetic resonance imaging (MRI), with electrophysiologic testing and catheter ablation. After pre-clinical studies demonstrated the feasibility of performing MRIguided electrophysiologic studies and catheter ablation, Dr. Halperin is extending this technology to patient-oriented research. Dr. Halperin has been awarded a Bioengineering Research Partnership grant from NHLBI to pursue this project, which is the current focus of his research. Dr. Halperin?s continued application of scientificallybased technology development to clinical medicine shows his commitment to patientoriented research and his ability to perform that research. All technology has been sufficiently developed to allow the studies to proceed, but continued improvements will likely occur. This award would help free protected time to do these studies that would otherwise be used for performing standard clinical duties. By providing 50% salary support, this award would allow at least 50% of Dr. Halperin's time to be protected from standard patient care activities. That protected time would allow him more time to pursue the patient-oriented studies outlined in this proposal, and help train young clinical investigators. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: NF-AT3 IN CARDIOVASCULAR BIOLOGY Principal Investigator & Institution: Kaji, Eugene H.; Medicine; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2005 Summary: Left ventricular hypertrophy is an adaptive response by the heart to many stresses including hypertension, genetic mutations in cardiac contractile proteins, and mechanical stress. This initially compensatory response may also cause morbidity and mortality secondary to diastolic dysfunction and arrhythmias. Despite the clinical importance of cardiac hypertrophy, the molecular pathways leading to its development

Studies

35

are poorly understood. The long-term objectives of this project are to define the regulatory mechanisms involved in cardiac hypertrophy and apply these paradigms to develop therapeutic strategies appropriate for the clinical arena. Previously, others have implicated the serine phosphatase calcineurin and the transcription factor NF-AT3 as central mediators of cardiac hypertrophy. The initial aim of this proposal is to investigate the role of NF-AT3 in cardiac biology by generating mice deficient in NFAT3. These mice will be characterized using molecular, histological, and cardiac catheterization techniques providing an understanding of NF- AT3 which is necessary prior to designing clinical therapeutic strategies involving this factor. Inhibiting NF-AT3 activity may have untoward effects that may be uncovered by characterizing mice deficient in NF- AT3. Our secondary aim1or this proposal is to identity what role NFAT3 plays in the hypertrophic response to various stimuli using three separate mouse models: aortic banding, chronic over-exposure to angiotensin II, and a transgenic mouse expressing a constitutively active form of calcineurin. In summary, we hope to better understand the role of NF-AT3 permitting us to target rationally clinical strategies involving its inhibition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NMR DETECTION OF GENE EXPRESSION Principal Investigator & Institution: Roman, Brian B.; Research Assistant Professor; Physiology and Biophysics; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Non-invasive monitoring of transient and stable gene expression would be a potent technique to evaluate normal and pathological processes as well as the efficacy of disease treatment. The "biosensor" proposed will take advantage of well known early patterns of gene transcription which occur in response to pathologic stimuli. Promoter sequences of native genes that are transcriptionally activated in ventricular myocardium under pathologic conditions will drive expression of an NMR sensitive reporter gene. This DNA sequence will be transfected and characterized in isolated cells to establish its patho-sensitivity. Subsequently, these constructs will be used to create transgenic mice for in vivo studies. Detection of the biosensor will require novel NMR RF microcoils of two general designs: 1)planar or cylindrical geometry amenable to isolated cell conditions and 2) an interventricular catheter coil of solenoid or Maxwell design. Since both the reporter and detectors are being developed simultaneously, the result will be a truly integrated detection system. Specific Aim I. - NMR Sensitive Reporter Genes and Transfection into Cardiocytes: Hypothesis 1: Endogenous genes and gene products can be combined to non-invasively monitor cellular status. Hypothesis 2: Specifically engineered cells can act as endogenous biosensors of physiological stress. Specific Aim II. - Mouse Cardiac Catheter MR Microcoil: Hypothesis: A MR cardiac catheter microcoil can detect localized 31P NMR spectra from inside the mouse ventricle. Specific Aim II1. - Cell Culture Microcoil: Hypothesis: A MR microcoil can detect gene expression defined 31P NMR spectra from isolated cells or cell lines. Specific Aim IV. - Endogenous Biosensors Expressed in Hearts of Transgenic Mice: Hypothesis: NMR sensitive reporters (Biosensors) can be expressed and detected in the heart of a mouse in response to transient and stable hypertrophic stimuli. The importance of this approach suggests it is now possible to provide a very early detection of intracellular events prior to tissue remodeling or mechanical failure. This opens the window to early treatments such that a

36

Heart Catheterization

reversal of the process is possible. This system will also be able to evaluate therapeutic regimens as the activity of the biosensor (CK) will modulate with the disease process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NMR STUDIES OF MYOCARDIAL METABOLISM Principal Investigator & Institution: Ugurbil, Kamil; Director; Radiology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-DEC-1984; Project End 30-APR-2005 Summary: This abstract is not available. 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

•

Project Title: OPTICAL THERMAL MAPPING CATHETER FOR VULNERABLE PLAQUE Principal Investigator & Institution: Ho, Winston Z.; Director, Clinical Diagnostic Devices; Maxwell Sensors, Inc. 10020 Pioneer Blvd, Ste 103 Santa Fe Springs, Ca 906706213 Timing: Fiscal Year 2004; Project Start 16-DEC-2003; Project End 15-JUN-2004 Summary: (provided by applicant): Cardiovascular events remain largely unpredictable. However, recently, inflammation has been recognized as being associated with the formation and progression of vulnerable plaque. It has been observed that the inflamed necrotic core of a vulnerable plaque deposit, is a fraction of a degree to a few degrees higher than the surrounding tissue. MSI proposes to develop an optical thermal

Studies

37

mapping catheter (OTMC) for real-time temperature monitoring of a vessel wall, with high sensitivity, accuracy, and ease of use. The technology is based on ultra thin optical fibers, encoded with optical gratings derived from state-of-the-art optical fiber communication. Fiber gratings reflect light of particular bandwidths and can act as highperformance optical thermal sensors. The reflected bandwidths are extremely narrow. A minute temperature change around the fibers, changes the effective refractive index, and leads to modulation of reflective wavelengths. The proposed OTMC, incorporates multiple optical fibers into a basket catheter that can simultaneously map thermal distribution in-situ. Phase I work will focus on the design & fabrication fiber gratings, constructing a basket catheter with built-in optical fibers, integration of the optoelectronics, followed by the testing and characterization of the system's performance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PARADIGM SHIFTS IN CLINICAL ISCHEMIA DETECTION Principal Investigator & Institution: Binkley, Philip F.; Professor of Medicine; Internal Medicine; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 15-MAR-2000; Project End 28-FEB-2005 Summary: The advent of novel angiogenic therapies for ischemic heart disease has created the need for innovative strategies of ischemia detection that will accurately direct the application of these therapies in the settings in which they are administered. This investigation tests the accuracy of two new methods of ischemia detection, contrast echocardiography and endocardial catheter mapping of electromechanical coupling, as compared to established nuclear perfusion studies. Furthermore, it will test molecular and clinical measures of ischemia and inflammation is a component of all forms of heart failure. Patients with ischemic cardiomyopathy will each be evaluated by dobutamine thallium perfusion studies, adenosine sestaMIBI studies, contrast echocardiography, and endocardial catheter mapping of electromechanical coupling. The results of contrast echocardiography and endocardial catheter mapping will be compared to the two standard nuclear perfusion techniques to evaluate agreement in definition of zones of ischemia, infarction, and viable myocardium. A cohort of patients with ischemia cardiomyopathy and a matched group of patients with patent coronary arteries and left ventricular failure will under go endomyocardial biopsy. Quantification of gene expression of angiogenic factors, mediators of inflammation, and markers of left ventricular dysfunction will be performed by Real Time PCR on the endomyocardial biopsy samples. These measures will be compared between the two groups for evidence of similar ischemic and inflammatory mechanisms despite differences in coronary occlusive disease. The two groups will be compared in terms of the four clinical markers of ischemia to further test for the role of functional ischemia in patients with cardiomyopathy and patent coronary arteries as well as those with ischemic cardiomyopathy. A similar group of patients with and without patent coronary arteries will undergo seventy-two hour dobutamine infusions which purportedly augments subendocardial blood flow. This intervention serves as a model in which to test the relative capacity of the techniques examined in this protocol to detect significant changes in myocardial ischemia in these different patient groups. This protocol will thus provide the foundation for implementing effective novel measures of ischemia that provide immediate information for implementing effective novel measures of ischemia that provide immediate information for the targeting of and evaluation of response to novel angiogenic therapies in setting in which they are administered. This, in addition to the definition of a potential role of ischemia in all forms of heart failure, will amplify the

38

Heart Catheterization

role of these new strategies for revascularization making them feasible for a broad range of patients including those compromised by chronic ventricular systolic dysfunction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEDIATRIC CARDIAC PROCEDURES: ACCESS, RATES AND OUTCOMES Principal Investigator & Institution: Gray, Darryl T.; Research Associate Professor of Health; Health Services; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2004; Project Start 17-JAN-2004; Project End 31-DEC-2005 Summary: (provided by applicant): Congenital malformations of the heart and great vessels (hereafter referred to as congenital cardiac malformations) are the most common and the most commonly fatal class of birth defects. Approximately one million Americans have such defects. Annual hospital charges for inpatient procedures performed on patients