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

CORONARY HEART DISEASE A 3-IN-1 MEDICAL REFERENCE Medical Dictionary Bibliography & Annotated Research Guide TO I NTERNE...

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CORONARY HEART DISEASE A 3-IN-1 MEDICAL REFERENCE Medical Dictionary Bibliography & Annotated Research Guide TO I NTERNET

R EFERENCES

CORONARY HEART DISEASE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

J AM ES N. P ARK ER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2004 by ICON Group International, Inc. Copyright ©2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Coronary Heart Disease: 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: 0-497-00303-1 1. Coronary Heart Disease-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

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.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on coronary heart disease. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON CORONARY HEART DISEASE .................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Coronary Heart Disease.............................................................. 11 E-Journals: PubMed Central ....................................................................................................... 68 The National Library of Medicine: PubMed ................................................................................ 70 CHAPTER 2. NUTRITION AND CORONARY HEART DISEASE ........................................................ 115 Overview.................................................................................................................................... 115 Finding Nutrition Studies on Coronary Heart Disease............................................................. 115 Federal Resources on Nutrition ................................................................................................. 119 Additional Web Resources ......................................................................................................... 119 CHAPTER 3. ALTERNATIVE MEDICINE AND CORONARY HEART DISEASE .................................. 123 Overview.................................................................................................................................... 123 The Combined Health Information Database............................................................................. 123 National Center for Complementary and Alternative Medicine................................................ 124 Additional Web Resources ......................................................................................................... 132 General References ..................................................................................................................... 137 CHAPTER 4. DISSERTATIONS ON CORONARY HEART DISEASE .................................................... 139 Overview.................................................................................................................................... 139 Dissertations on Coronary Heart Disease.................................................................................. 139 Keeping Current ........................................................................................................................ 141 CHAPTER 5. PATENTS ON CORONARY HEART DISEASE ............................................................... 143 Overview.................................................................................................................................... 143 Patents on Coronary Heart Disease........................................................................................... 143 Patent Applications on Coronary Heart Disease ....................................................................... 153 Keeping Current ........................................................................................................................ 163 CHAPTER 6. BOOKS ON CORONARY HEART DISEASE .................................................................. 165 Overview.................................................................................................................................... 165 Book Summaries: Federal Agencies............................................................................................ 165 Book Summaries: Online Booksellers......................................................................................... 171 Chapters on Coronary Heart Disease......................................................................................... 173 CHAPTER 7. MULTIMEDIA ON CORONARY HEART DISEASE........................................................ 177 Overview.................................................................................................................................... 177 Video Recordings ....................................................................................................................... 177 CHAPTER 8. PERIODICALS AND NEWS ON CORONARY HEART DISEASE..................................... 179 Overview.................................................................................................................................... 179 News Services and Press Releases.............................................................................................. 179 Newsletter Articles .................................................................................................................... 181 Academic Periodicals covering Coronary Heart Disease ........................................................... 182 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 185 Overview.................................................................................................................................... 185 NIH Guidelines.......................................................................................................................... 185 NIH Databases........................................................................................................................... 187 Other Commercial Databases..................................................................................................... 189 APPENDIX B. PATIENT RESOURCES ............................................................................................... 191 Overview.................................................................................................................................... 191 Patient Guideline Sources.......................................................................................................... 191 Finding Associations.................................................................................................................. 195 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 197 Overview.................................................................................................................................... 197

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Preparation................................................................................................................................. 197 Finding a Local Medical Library................................................................................................ 197 Medical Libraries in the U.S. and Canada ................................................................................. 197 ONLINE GLOSSARIES................................................................................................................ 203 Online Dictionary Directories ................................................................................................... 203 CORONARY HEART DISEASE DICTIONARY ..................................................................... 205 INDEX .............................................................................................................................................. 275

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with coronary heart disease 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 coronary heart disease, 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 coronary heart disease, 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 coronary heart disease. 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 coronary heart disease, 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 coronary heart disease. The Editors

1 From

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

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

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and coronary heart disease, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “coronary heart disease” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

NCEP-Defined Metabolic Syndrome, Diabetes, and Prevalence of Coronary Heart Disease Among NHANES III Participants Age 50 Years and Older Source: Diabetes. 52(5): 1210-1214. May 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Although the individual components of the metabolic syndrome are clearly associated with increased risk for coronary heart disease (CHD), the authors of this study wanted to quantify the increased prevalence of CHD among people with metabolic syndrome. The authors used the Third National Health and Nutrition Examination Survey (NHANES III) to categorize adults over 50 years of age by presence

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Coronary Heart Disease

of metabolic syndrome, with or without diabetes. Metabolic syndrome is very common, with approximately 44 percent of the United States population over 50 years of age meeting the criteria. In contrast, diabetes without metabolic syndrome is uncommon (13 percent of those with diabetes). Older Americans over 50 years of age without metabolic syndrome, regardless of diabetes status, had the lowest CHD prevalence. The prevalence of CHD markedly increased with the presence of metabolic syndrome. Among people with diabetes, the prevalence of metabolic syndrome was very high, and those with diabetes and metabolic syndrome had the highest prevalence of CHD. 2 figures. 4 tables. 31 references. •

Does Chronic Periodontitis cause Coronary Heart Disease?: A Review of the Literature Source: JADA. Journal of the American Dental Association. 133 (Supplement 6): 31S-36S. June 2002. Contact: Available from American Dental Association. ADA Publishing Co, Inc., 211 East Chicago Avenue, Chicago, IL 60611. (312) 440-2867. Website: www.ada.org. Summary: Chronic periodontitis (CP) has been associated with coronary heart disease (CHD). This article reviews the evidence to support this connection. The author found that in 9 cohort studies, CP was associated with a 15 percent greater risk of developing CHD. Conclusions from individual studies depended on the study's characteristics. Summary risk estimates for studies controlling for smoking intensity (five of nine studies) or health awareness (two of nine studies) or studies with more than 600 CHD events (three of nine studies) suggest that CP is either not at all or only weakly associated with CHD. These data suggest that the CP-CHD associations observed in smaller studies are due to insufficient control for lifestyle differences. In addition, one cohort study reported that edentulous (without teeth) people had a CHD risk similar to that of people with CP. Therefore, the plausibility of dental infection elimination affecting CHD risk appears limited. 1 table. 44 references.

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Role of Cigarette Smoking in the Association Between Periodontal Disease and Coronary Heart Disease Source: Journal of Periodontology. 73(9): 988-994. September 2002. Contact: Available from American Academy of Periodontology. Suite 800, 737 North Michigan Avenue, Chicago, IL 60611-2690. (312) 573-3220. Fax (312) 573-3225. Summary: Cigarette smoking is a significant risk factor for both coronary heart disease and periodontal disease. This article reports on a study undertaken to better understand the role of smoking in the relationship between periodontal disease and heart attack history. The study population consisted of 5,285 participants in the Third National Health and Nutrition Examination Survey (NHANES) during 1988 to 1994 and who were age 40 years or older when examined. After adjustment for potential confounders, the authors only found significant associations between periodontal loss of attachment (LOA) and heart attack history for smokers. When the analysis was stratified by smoking status and age at heart attack, the statistically significant associations were limited to smokers who had a heart attack between the ages of 25 and 50 years. These results suggest that cigarette smoking is a necessary cofactor in the relationship between periodontal disease and coronary heart disease, and the increase in risk appears to be age dependent. However, the key role played by smoking in the etiology of both periodontal and heart diseases makes it difficult to determine how much of the observed association resulted from periodontal disease. 5 tables. 45 references.

Studies

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Risk Factors for Mortality from All Causes and from Coronary Heart Disease among Persons with Diabetes. Findings from the National Health and Nutrition Examination Survey I. Epidemiologic Follow-up Study Source: American Journal of Epidemiology. 133(12): 1220-1230. 1991. Summary: Coronary heart disease is the leading cause of mortality among people with diabetes mellitus, but the factors that account for this high coronary heart disease mortality remain unclear. This article reports on an epidemiologic follow-up study conducted from 1982-1984 as part of the National Health and Nutrition Examination Survey. Ninety-two deaths from coronary heart disease were found to have occurred among 602 people with diabetes and 558 deaths from coronary heart disease were found to have occurred among 12,562 nondiabetic participants during the follow-up period (1971-1984; average follow-up, 10 years). The authors found age, male sex, severe overweight, and non-leisure-time physical inactivity to be significantly associated with coronary heart disease mortality among people with diabetes. The strength of the associations between risk factors and all-cause and coronary heart disease mortality did not differ significantly among persons with and without diabetes. These results reinforce the importance of controlling coronary heart disease risk factors among persons with diabetes. 4 tables. 23 references. (AA-M).

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Age, Dental Infections, and Coronary Heart Disease Source: Journal of Dental Research. 79(2): 756-760. February 2000. Contact: Available from International Association for Dental Research. Subscription Department, 1619 Duke Street, Alexandria, VA 22314. (703) 548-0066. Fax (703) 548-1883. Summary: Epidemiological and intervention studies have suggested that infections are risk factors for coronary heart disease (CHD). This article reports on a case control study aimed at detailed assessment of the dental pathology found in various CHD categories (including elderly patients). Altogether, 85 patients with proven coronary heart disease and 53 random controls, matched for sex, age, geographic area, and socioeconomic status, were compared with regard to dental status, and were assessed on four separate scores and the classic coronary risk factors. The dental indices were higher among CHD patients than in the controls, but, contrary to previous studies, the differences were not significant. This result could not be explained by potential confounding factors. The participants in the present study were older and had more often undergone recent dental treatment in comparison with subjects in our earlier studies. Age correlated with the severity of dental infections only in the random controls but not in the coronary patients who, although young, already had high dental scores. The authors contend that the higher age of the participants in this study is the most likely reason for the results. Other possible explanations include an age related selection bias among older CHD patients, and the fact that those participating in studies like this may have better general health and thus also less severe dental infections. The authors conclude that the role of dental infections as a coronary risk factor varies according to the characteristics of the population studied. 2 tables. 24 references.

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Long-term Intake of Dietary Fiber and Decreased Risk of Coronary Heart Disease Among Women Source: JAMA. 281(21):1998-2004; June 2, 1999. Contact: American Medical Association, (800) 621-8335.

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Summary: Epidemiological studies of men suggest that dietary fiber intake protects against coronary heart disease, but data on this association in women are sparse. Using a group of 68,782 women aged 37 to 64 without previously diagnosed angina, myocardial infarction, stroke, cancer, hypercholesterolemia, or diabetes, the study examined the association between long-term intake of total dietary fiber as well as fiber from different sources and risk of coronary heart disease in women. The findings support the hypothesis that higher fiber intake, particularly from cereal sources, reduces the risk of coronary heart disease. •

Diabetes and Coronary Heart Disease Risk in Mexican Americans Source: Annals of Epidemiology. 2(1/2): 101-106. January-March 1992. Summary: Mexican Americans have a high prevalence of diabetes relative to nonHispanic whites but paradoxically experience a lower prevalence of myocardial infarction and cardiovascular mortality (at least in men). This article reports on a study undertaken to determine whether Mexican Americans might be more resistant to the atherogenic effects of diabetes than nonHispanic whites, by examining the associations between diabetes and myocardial infarction and selected coronary heart disease (CHD) risk factors in these two ethnic groups. The study population consisted of 5,149 Mexican Americans and nonHispanic whites who were 25 to 64 years old. Data showed that in both sexes, the association between myocardial infarction and diabetes was nearly identical between the two ethnic groups. These associations were at least as strong, if not stronger, in Mexican Americans as in nonHispanic whites. The authors stress that their data provide no evidence to suggest that Mexican Americans are resistant to the lipid-altering effects of diabetes. They conclude that the protective effect against CHD conferred by Mexican American ethnicity may be obscured in part by the high prevalence of diabetes in this ethnic group. 3 tables. 17 references. (AA-M).

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Periodontal Disease and Coronary Heart Disease Risk Source: JAMA. Journal of the American Medical Association. 284(11): 1406-1410. September 20, 2000. Contact: Available from American Medical Association. P.O. Box 10946, Chicago, IL 60610-0946. (800) 262-2350 or (312) 670-7827. Fax (312) 464-5831. Website: jama.amaassn.org. Summary: Research has suggested a relationship between periodontal disease and coronary heart disease (CHD), but data on the association between these 2 common conditions are inconclusive due to the possibility of confounding. This article reports on a study undertaken to evaluated the risk of CHD in persons with periodontitis, gingivitis (inflamed gums), or no periodontal disease. The prospective cohort study used data from the First National Health and Nutrition Examination Survey Epidemiologic Follow up Study, conducted in 1982 to 1984, 1987, and 1992. The study comprised a total of 8,032 dentate adults aged 25 to 74 years with no reported history of cardiovascular disease, including 1,859 individuals with periodontitis, 2,421 with gingivitis, and 3,752 with healthy periodontal tissues. The outcome measure was first occurrence of death from CHD or hospitalization due to CHD, or revascularization procedures, obtained from death certificates and medical records, by baseline periodontal status. During follow up, 1,265 individuals had at least 1 CHD event, including CHD fatality (n = 468) or at least 1 hospitalization with a diagnosis of CHD (n = 1,022), including coronary revascularization procedures (n = 155). After adjustment for known cardiovascular risk factors, gingivitis was not associated with CHD, while

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periodontitis was associated with a nonsignificant increased risk for CHD event. The authors conclude that this study did not find convincing evidence of a causal association between periodontal disease and CHD risk. 3 tables. 34 references. •

Prevalence of Nontraditional Risk Factors for Coronary Heart Disease in Patients with Chronic Kidney Disease Source: Annals of Internal Medicine. 140(1): 9-17. January 2004. Summary: Risk for coronary heart disease is high among patients with chronic kidney disease (CKD). This article reports on a study undertaken to compare the prevalence of nontraditional risk factors for coronary heart disease in patients with CKD. The authors considered the prevalence of low apolipoprotein A1 levels and elevated apolipoprotein B, plasma fibrinogen, lipoprotein (a), homocysteine, and C-reactive protein levels by estimated glomerular filtration rate (GFR, a measure of kidney function). After standardization for age, race or ethnicity, and sex, lower estimated GFR was associated with lower average levels of apolipoprotein A1, and higher levels of apolipoprotein B, plasma fibrinogen, homocysteine, and C-reactive protein in patients with CKD. These findings imply that these risk factors may be important underlying causes of an excess risk for cardiovascular disease among patients with CKD. 1 figure. 4 tables. 48 references.

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Assessing the Relationship Between Dental Disease and Coronary Heart Disease in Elderly U.S. Veterans Source: JADA. Journal of American Dental Association. 129(3): 301-311. March 1998. Summary: Several recent studies have shown a link between dental disease and coronary heart disease. This article reports on a study of 320 U.S. veterans undertaken to assess the relationship between oral health and systemic diseases among older people. They present cross-sectional data confirming that a statistically significant association exists between a diagnosis of coronary heart disease and certain oral health parameters, such as the number of missing teeth, plaque benzoyl-DL-argininenaphthylamide (BANA) test scores (a test for bacteria), salivary levels of Streptococcus sanguis, and complaints of xerostomia (dry mouth). The oral parameters in these subjects were independent of and more strongly associated with coronary heart disease than were recognized risk factors, such as serum cholesterol levels, body mass index, diabetes, and smoking status. However, because of the convenience sample studied, these findings cannot be generalized to other populations. 5 tables. 40 references. (AAM).

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Risk Factors for Coronary Heart Disease Mortality Among Persons with Diabetes Source: Annals of Epidemiology. 3(1): 27-34. January 1993. Summary: This article reports on a study in which the authors used data from two large surveys to perform a case-control analysis of risk factors for coronary heart disease (CHD) mortality among persons with diabetes. They focused on three modifiable risk factors: cigarette smoking, high blood pressure, and obesity. Results showed that women younger than 55 years with diabetes and with no other risk factors for CHD had a 16-fold higher risk of dying from CHD than did women without diabetes. About onethird of younger women who died of CHD had diabetes. Men with diabetes less than 45 years old with no other risk factors for CHD had an eight-fold higher risk of CHD mortality. Among older white men and women, diabetes increased the risk of mortality from CHD about two-fold. In younger people with diabetes, current cigarette smoking

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was associated with a 50-percent increase in risk, and high blood pressure increased the risk more than three-fold. In the older age group, risk factors for CHD mortality were similar among those with and those without diabetes. The authors stress that smoking and blood pressure control represent major opportunities to reduce the risk of CHD among persons with diabetes. 4 tables. 26 references. (AA-M). •

Cardiovascular Risk Factors in Confirmed Prediabetic Individuals: Does the Clock for Coronary Heart Disease Start Ticking Before the Onset of Clinical Diabetes? Source: JAMA. Journal of the American Medical Association. 263(21): 2893-2898. June 6, 1990. Summary: This article reports on a study that documented the cardiovascular risk factor status of 614 initially nondiabetic Mexican Americans who later participated in an 8-year follow-up of the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Individuals who were nondiabetic at the time of baseline examination, but who subsequently developed NIDDM, had higher levels of total and low-density lipoprotein cholesterol, triglyceride, fasting glucose and insulin, 2-hour glucose, body mass index, and blood pressure and lower levels of high-density lipoprotein cholesterol than subjects who remained nondiabetic. Most of these differences persisted after adjustment for obesity and/or level of glycemia, but were abolished after adjustment for fasting insulin concentration. These results indicate that prediabetic subjects have an atherogenic pattern of risk factors (possibly caused by obesity, hyperglycemia, and especially hyperinsulinemia), which may be present for many years and may contribute to the risk of macrovascular disease as much as the duration of clinical diabetes itself. 5 tables. 46 references. (AA-M).

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Prospective Study of Obesity and Risk of Coronary Heart Disease Among Diabetic Women Source: Diabetes Care. 25(7): 1142-1148. July 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study undertaken to examine the relationship of obesity, measured as BMI, and weight change to incidence of coronary heart disease (CHD) among women with diabetes. The authors followed 5,897 women with type 2 diabetes in the Nurses' Health Study for up to 20 years. Women were aged 40 to 74 years and had no history of cardiovascular disease or cancer at the beginning of the follow up period. During follow up, the authors document 418 incident cases of CHD (236 of nonfatal myocardial infarction and 182 of fatal CHD). After adjustment for age, smoking, and other coronary risk factors, current BMI (body mass index) was strongly associated with increased risk of CHD among women with diabetes. Increasing BMI values from age 18 years to 1976, before diagnosis of diabetes, were also positively associated with risk of CHD. Weight gain before the diagnosis of diabetes was related to increased risk of CHD. In contrast, weight change after diagnosis of diabetes was not associated with risk of CHD. The authors conclude that these findings provide strong evidence that obesity and weight gain before diagnosis of diabetes are associated with future risk of CHD among women with type 2 diabetes. 1 figure. 2 tables. 34 references.

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Risk Factors for Coronary Heart Disease in Diabetes Mellitus Source: Diabetes. 41(Supplement 2): 1-3. October 1992.

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Summary: This article reviews the putative risk factors associated with the development of coronary heart disease (CHD) in diabetes. The author emphasizes to the effect of nephropathy (persistent proteinuria) and hypertension on cardiovascular mortality in insulin-dependent diabetes (IDDM). Risk factors associated with CHD in noninsulindependent diabetes (NIDDM) are also reviewed. Finally, possible reasons to explain the increased incidence of CHD associated with proteinuria in IDDM patients, including lipoprotein abnormalities, increased fibrinogen levels, increased platelet adhesiveness, and altered hemostatic variables, are discussed. 1 table. 32 references. (AA-M). •

Periodontitis: A Risk Factor for Coronary Heart Disease? Source: Annals of Periodontology. 3(1): 127-141. July 1998. Contact: Available from American Academy of Periodontology. Suite 800, 737 North Michigan Avenue, Chicago, IL 60611. (312) 787-5518. Fax (312) 787-3983. Website: www.perio.org. Summary: This paper evaluates the current information on the relationship between oral disease (specifically, periodontitis) and atherosclerosis (coronary heart disease or CHD) to determine whether there is sufficient information to conclude that periodontitis is a risk factor for CHD. The authors first define the term risk factor and review the 3 criteria used to establish exposures as risk factors. In addition, epidemiologic criteria for defining an exposure as causal are presented. The available evidence then is evaluated according to the criteria for causality, which are extensions of the criteria for establishing a risk factor. The authors also present new findings which indicate that the extent of the periodontal infection, a measure reflecting microbial burden, also is related to onset of new CHD events. The authors conclude that the available evidence does allow an interpretation of periodontitis being a risk factor for atherosclerosis or CHD. This conclusion is made with some qualifications, however, which the authors outline. 9 figures. 4 tables. 40 references. (AA-M).

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Diagnosing Coronary Heart Disease in Patients with Diabetes: How and Why Source: Consultant. 39(2): 556-557, 561. February 1999. Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Box 4010, Greenwich, CT 06831-0010. Summary: This review article presents highlights from a consensus statement developed by the American Diabetes Association and the American College of Cardiology that offers insights into the importance of diagnosing coronary heart disease in patients with diabetes. Although patients who have type 1 diabetes may not have the usual risk factors for coronary artery disease (CAD), patients who have type 2 diabetes frequently have many of the usual risk factors for CAD. The question of whether the atherosclerotic process is different in diabetes has not been definitively determined, but early diagnosis of asymptomatic CAD has many benefits. The article presents indications for cardiac testing and highlights various intervention measures. Beneficial treatment modalities include control of hypertension, aspirin therapy, lipid lowering therapy, improved glycemic control, and beta-blocker therapy. 1 figure. 6 references.

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Dyslipidemia, Morbidity, and Mortality in Non-Insulin-Dependent Diabetes Mellitus: Lipoproteins and Coronary Heart Disease in Non-Insulin-Dependent Diabetes Mellitus Source: Journal of Diabetes and Its Complications. 11(2): 137-141. March-April 1997.

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Contact: Available from Elsevier Science, Inc. Journal Fulfillment Department, 655 Avenue of the Americas, New York, NY 10010. (212) 633-3950. Fax (212) 633-3990. Summary: This review article summarizes typical characteristics of dyslipidemia in noninsulin dependent diabetes mellitus (NIDDM, or Type II) and its association with the risk of macrovascular complications. Lipid and lipoprotein abnormalities in NIDDM include particularly elevated levels of total and very-low-density lipoprotein (VLDL) triglycerides and reduced levels of high-density lipoprotein (HDL) cholesterol. Total and low-density lipoprotein (LDL) cholesterol levels are usually normal if glycemic control is adequate. The worsening of glycemic control deteriorates lipid and lipoprotein abnormalities and particularly total and LDL cholesterol levels are often elevated in patients with poor glycemic control. According to prospective population-based studies, total cholesterol is a powerful risk factor for coronary heart disease (CHD) in NIDDM patients as in nondiabetic subjects. In contrast, high total triglycerides and low HDL cholesterol may be even stronger risk factors for CHD in NIDDM patients than in nondiabetic individuals, but more prospective studies are needed to substantiate this view. Compositional changes in LDL and VLDL particles may further increase the risk for CHD but epidemiologic data are missing to support this notion. Preliminary data from the Scandinavian Simvastatin Survival Study including 202 patients with diabetes seem to indicate that patients with diabetes benefit from simvastatin treatment equally to nondiabetic subjects. 31 references. (AA-M). •

Impact of Coexistent Diabetes on the Prevalence of Coronary Heart Disease Source: Journal of Diabetes and Its Complications. 11(5): 268-273. September-October 1997. Contact: Available from Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010. Summary: This study is designed to examine the overall prevalence of coronary heart disease (CHD) and the impact of diabetes on ischemic heart disease at the time of diagnosis. The authors compared the impact of diabetes on ischemic heart disease in people hospitalized in a public hospital over a 10-year period. In comparison with the nondiabetic population, the prevalence of CHD was consistently higher among people with noninsulin-dependent diabetes mellitus (NIDDM, or Type II). The prevalence was similar in both genders, increased with age, and was independent of body-mass index, a history of smoking, metabolic control, or lipid pattern. In people with NIDDM and CHD, heart rate and blood pressure levels were significantly higher. In addition, even in subjects with impaired glucose tolerance, there was a significant association between ischemic heart disease and atherosclerotic peripheral artery disease prevalence. The authors conclude that diabetes has a harmful effect on general risk factors of atherosclerosis and increases susceptibility to cardiovascular disease by itself. Based on the epidemiological evidence of an excessive occurrence of NIDDM in people with preexisting vascular diseases, a genetically determined link between metabolic disturbances and cardiovascular disease is possible. 2 figures. 6 tables. 42 references. (AA-M).

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Examining the Link Between Coronary Heart Disease and the Elimination of Chronic Dental Infections Source: JADA. Journal of the American Dental Association. 132(7): 883-889. July 2001. Contact: Available from American Dental Association. ADA Publishing Co, Inc., 211 East Chicago Avenue, Chicago, IL 60611. (312) 440-2867. Website: www.ada.org.

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Summary: While it has been suggested that periodontal disease may be associated with coronary heart disease (CHD), there are no data to suggest that the elimination of chronic dental infections actually lowers the risk of developing chronic CHD. This article reports on a study undertaken to determine whether people with a definitive elimination of all potential dental infections (i.e., edentulous people, who are at the optimum endpoint of dental infection elimination as they have no teeth) lower their CHD risk over time when compared with people who have a specific dental infection, periodontitis. The authors examined data from a prospective cohort of 4,027 people who participated in the First National Health and Nutrition Examination Survey (NHANESI) Epidemiologic Follow up Study. The primary outcome measure was the first CHD event. During a mean follow up of 17 years, there were 1,238 CHD events (538 fatal). The confirmed elimination of chronic dental infections did not lead to a decreased risk of experiencing a CHD event. The CHD risk among people with and without chronic dental infections remained constant over time with respect to each other. The authors concluded that people who had a complete, definitive and long term elimination of all potential dental infections through extraction of all teeth did not have lower CHD risk when compared with people with diagnosed periodontitis. Until evidence is found to the contrary, the authors suggest that prevention of CHD should not be used as the basis for recommending treatment to eliminate chronic dental infections. 3 tables. 35 references.

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

Project Title: A RANDOMIZED, CONTROLLED TRIAL FOR HOMOCYSTEINE Principal Investigator & Institution: Bostom, Andrew G.; Associate Professor of Medicine; Rhode Island Hospital (Providence, Ri) Providence, Ri 029034923 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JAN-2006 Summary: (Adapted from the application) This multicenter, randomized, double-blind controlled clinical trial has been designed to determine whether total homocysteine

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

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(tHcy)-lowering treatment with a standard multivitamin augmented by a high dose combination of folic acid, vitamin B12, and vitamin B6, versus treatment with a standard multivitamin devoid of these three B-vitamins, reduces the pooled rate of recurrent and de novo cardiovascular disease outcomes (i.e., pooled occurrence of non-fatal and fatal arteriosclerotic outcomes, including coronary heart, cerebrovascular, and peripheral vascular disease events= primary outcome), among clinically stable renal transplant recipients who have mild to moderately elevated tHcy levels. The basic eligibility criteria are age 35 to 75 years old, functioning renal allograft for greater than six-months with serum creatinine based creatinine clearance greater than 30 mL/min, and a screening random tHcy level greater than12 uM/L. Patients will be stratified based on the presence/absence of clinical CVD, and randomly assigned to treatment with a standard multivitamin containing a high dose combination of folic acid, vitamin B6, and vitamin B12, or an identical multivitamin devoid of these three micronutrients. Randomized patients will also undergo a methionine loading test. All patients will receive standard clinical management for traditional CVD risk factor reduction. The study is designed to recruit 4000 patients (2000 in each group) over a two-year period for 83% power to detect a 25% treatment effect. Follow-up continues until occurrence of de novo or recurrent non-fatal CVD, or death, or a maximum of four-years. Data analysis will be performed on the basis of original randomization (intention to treat) using the log-rank test of difference in survival-without-endpoint curves. In the current era of cereal grain flour fortified with physiologic amounts of folic acid, RTRs comprise a patient population particularly well-suited to test the tenable hypothesis that tHcylowering treatment will reduce CVD outcomes, given: a) their persistent excess prevalence of mild hyperhomocysteinemia post-fortification, in contrast, for example, to coronary heart disease patients with normal renal function; b) the demonstrated capability of B-vitamin treatment regimens featuring supraphysiologic amounts of folic acid to successfully "normalize" tHcy levels in RTRs. Furthermore, overall "conditions" in the RTR population (i.e., renal impairment, mild to moderate hyperhomocysteinemia which can be normalized by supraphysiologic dose B-vitamin supplements, and high CVD event rates) are representative of the larger population of patients with chronic renal insufficiency, who are not yet dialysis-dependent. Accordingly, findings from the proposed trial are very likely to be generalizable to the much more sizable population of patients with renal insufficiency progressing to end-stage renal disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AMINOSTEROL MSI-1436 AS A THERAPEUTIC FOR OBESITY Principal Investigator & Institution: Mclane, Michael; Genaera Corporation 5110 Campus Drive Plymouth Meeting, Pa 19462 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2005 Summary: (provided by applicant): Obesity is a disease that has increased at an alarming rate. Today, 64.5 percent of adult Americans (about 127 million) are categorized as being overweight (body mass index >25) or obese (body mass index >30). Obesity is strongly associated with type 2 diabetes, hypertension, coronary heart disease, respiratory conditions, increased incidence of certain forms of cancer, and many other diseases. Each year, obesity causes at least 300,000 excess deaths in the U.S. and healthcare costs of American adults with obesity amount to approximately $100 billion. Diet and exercise are stalwart anti-obesity therapies but success is variable. With the valvular heart disease associated with fenfluramine and phentermine in the late 1990's and subsequent withdrawal of fenfluramine and dexfenfluramine anti-obesity agents from the market, there has been a reduction in use of products that have similar

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pharmacological activities. Currently approved anti-obesity therapies (see Table 1) work by stimulating noradrenergic receptors, inhibiting serotonin and norepinephrine reuptake, or inhibiting absorption of fats via inhibition of Iipase but results are variable and there are some associated side effects. Major advances in understanding the homeostatic system and neural pathways that regulate body weight have led to potential therapeutic agents with novel activities, such as leptin, ghrelin antagonists, and ciliary neurotrophic factor (CNTF). We have discovered a natural occurring (in dogfish sharks), novel aminosterol, MS1-1436, that causes body weight reduction in genetically obese or diet-induced obese rodents when administered via various routes and in dogs. This compound, also re-established normoglycemia in diabetic obese animals and lowered serum cholesterol levels. Two steps are necessary to elevate this compound to clinical development and will be the aims of this grant: 1) the mechanism(s) of action(s) or neural pathways used by this compound need to be elucidated and 2) a minimal dose/frequency and formulation that allows subcutaneous implantable, intranasal or oral bio-availability needs to be developed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANXIETY & VAGAL CONTROL OF THE HEART IN CORONARY DISEASE Principal Investigator & Institution: Watkins, Lana L.; Psychiatry; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-JUN-1999; Project End 31-MAY-2004 Summary: Coronary heart disease continues to be the leading cause of death in the United States, despite risk factor reduction and technological advances in treatment options. Prospective studies implicate chronic anxiety as an independent risk factor for fatal coronary heart disease. In particular, anxiety increases the risk of sudden cardiac death substantially. The primary objective of the proposed research is to examine the role of reduced vagal control of heart rate in the increased risk of cardiac mortality associated with anxiety in a population with established coronary artery disease (CAD). A second objective is to determine whether the effects of anxiety are independent of the effects of depression. Nine hundred and fifty CAD patients will be recruited for this study from patients hospitalized for elective cardiac catheterization. Anxiety will be measured by the Hospital Anxiety Scale, the Spielberger Trait Anxiety Inventory, and the Crown-Crisp Phobic Anxiety Scale. Symptoms of depression will be measured by the Montgomery-Asberg Depression Rating Scale, the Hospital Depression Scale, and the Beck Depression Inventory. Vagal control of heart rate will be determined using power spectral analysis to measure two indices of vagal control: baroreceptor-mediated vagal reflex cardiac control, and respiratory sinus arrhythmia. Patients will be followed at 6 months, l year, 2 years, and 3 years postcatheterization, and cardiac mortality data will be obtained, including non-sudden and sudden cardiac death. The data generated by this study will be used to examine the involvement of impaired vagal cardiac control in the risk of fatal coronary heart disease and sudden cardiac death associated with anxiety. Specifically, the proposed study will examine: (1) the relationship between anxiety and cardiac mortality; (2) the relationship between anxiety and vagal control; (3) the role played by reduced vagal control in mediating anxiety-related risk; and (4) the relationship between depression, vagal control and cardiac risk. Findings of a relationship between anxiety, reduced vagal control and sudden cardiac death would suggest the potential importance of early intervention in cardiac patients with anxiety disorders and would underscore the benefit of aggressive monitoring of arrhythmias in this population, which may ultimately translate to reduced mortality rates.

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

Project Title: BIOLOGY OF PHAGE INFECTION IN CHLAMYDIA Principal Investigator & Institution: Bavoil, Patrik M.; Oral & Craniofacial Biol Scis; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-MAY-2006 Summary: (provided by applicant): Chlamydial disease of humans includes predominant ocular, genital and respiratory tract infections, with sequelae ranging from blindness, to female infertility, arthritis and asthma. Chronic infection with the respiratory pathogen, Chlamydia pneumoniae is also associated with coronary heart disease, the number one killer disease of humans. In spite of their public health magnitude, chlamydiae are reputed for their elusiveness as infectious microorganisms to clinicians and molecular biologists alike. This owes to several factors, prominent among which are a unique obligate intracellular developmental lifestyle and the fact that chlamydiae have resisted genetic manipulation to this day. We have isolated a bacteriophage, phiCPG1 from the model Chlamydia psittaci strain ?Guinea Pig Inclusion Conjunctivitis?. A member of the single-stranded DNA microviridae family, phiCPG1 is nearly identical to a ?virtual? phage of C. pneumoniae that was revealed by genome sequence analysis. The infection of an intracellular pathogen by its own parasitic bacteriophage is a unique biological phenomenon, with potentially important implications in infection and disease. Moreover, phages offer unique opportunities for the development of molecular and genetic tools for research. The objectives of this application are therefore to gain a broad understanding of Chlamydia phage biology in the context of chlamydial infection. We will determine the molecular basis of the interaction of the phage with its host and comparatively evaluate gene expression in phage-free and phage-infected bacteria. The availability of well-established models of infection and disease in the guinea pig will allow for the first time to study the impact of phage infection on the natural infection of a vertebrate animal by an obligate intracellular pathogen. Finally, the information gained in these studies will be exploited toward the development of genetic methodologies in Chlamydia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BLACK POOLING PROJECT Principal Investigator & Institution: Lackland, Daniel T.; Professor and Director of Graduate Train; Biometry & Epidemiology; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2006 Summary: (provided by applicant): Over the last three decades a sustained and marked decline in death rates from coronary heart disease (CHD) has occurred for all major demographic groups of the US population. Recently, however, the decline has proceeded less rapidly in blacks than in whites, and in women than men. These trends have focused further attention on possible heterogeneity in the risk factor patterns among the demographic sub-groups. As is well recognized, the knowledge on CHD risk factors and statistical models used to predict personal risk of CHD have been based on studies among white populations. In some epidemiological studies with samples from black populations, large variation in the effect of specific factors has been noted. Given the small sample of blacks under investigation, however, low statistical power exists for many of the black-white comparisons. The fundamental obstacle to progress in this area remains the absence of the cohorts of sufficient size that is representative of all four

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major groups. Hence, a strong rationale exists to undertake a "pooling project" to clarify a set of important unanswered questions in cardiovascular disease epidemiology. We propose to conduct a person-level meta-analysis by pooling 9 US studies with both black and white samples: the First National Health and Nutrition Examination Survey (NHANES I) Epidemiological Follow-up Study, the NHANES II Mortality Follow-up Study, the Charleston Heart Study, the Evans County Heart Study, the Chicago Heart Association Detection Project in Industry, the Atherosclerosis Risk in Communities Study (ARIC), the Follow-up Study of the screenees for the Multiple Risk Factors Intervention Trial (MRFIT), the Follow-up Study of the participants from the MRFIT, and the Follow-up Study of the participants from the Hypertension Detection and Follow-up Program (HDFP). We will perform black-white comparison on the CHD incidence and mortality, exposure-outcome relationship, patterns of co-morbidity (or coexistence of risk factors) and population attributable risk. We will also examine the multivariate risk functions in blacks and whites in the three contexts: ordering risk, magnitude of relative risks, and estimation of absolute risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BORDER EPIDEMIOLOGY STUDY ON AGING (BESA) Principal Investigator & Institution: Bastida, Elena M.; Professor; Univ of Texas-Pan American Edinburg, Tx Timing: Fiscal Year 2002; Project Start 01-JUN-1977; Project End 31-JUL-2006 Summary: (provided by applicant): The Border Epidemiologic Study of Aging (BESA) offers the unique opportunity to investigate intra-group health disparities in a longitudinal study of 1133 middle aged and older Mexicans Americans. The proposed study builds and extends on three earlier waves of data and expands previous research to include two new emphases: the investigation of diabetes and health disparities. In exploring health disparities two additional dimensions of social stratification have been added, social trust and work productivity and conditions. Five Specific Aims are proposed: 1)To examine and compare the dynamic association between socioeconomic status (SES) and disease, mainly diabetes and coronary heart disease which disproportionately affect the Mexican American population along the border; 2)To identify predictors of risk factors for diabetes and to explore the economic, social and psychological consequences of diabetes for this population over time; 3)To identify predictors and patterns of change, particularly, incidence rates for major diseases, changes in risk factors for major diseases; changes in productivity and earnings, family dynamics, acculturative status, and changes in social support and other ways of coping over time; 4)To identify predictors of mortality for each wave; 5)To identify predictors of survival for the 80+ in Waves 3 & 4. The proposed research strategies include: (1) Conducting extensive longitudinal analyses on the three waves of available data; (2) Building on the current three waves by collecting a fourth wave; (3) Increasing the current sub-sample of the 39-44 years old to 250 participants; and, (4) Gathering qualitative data through a series of focus groups and in-depth interviews with selected participants in the established BESA sample and in the younger sub-sample. A Social stratification theoretical model of Health is proposed. This model is used in drawing a set of hypotheses for each of the listed aims above. Various statistical methods are proposed in discussing hypotheses testing and evaluation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CARDIAC AND RENAL DISEASE STUDY (CARDS) Principal Investigator & Institution: Iribarren, Carlos; Physician / Scientist; Kaiser Foundation Research Institute 1800 Harrison St, 16Th Fl Oakland, Ca 946123433 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Mild-to-moderate chronic renal insufficiency (CRI) is reaching epidemic proportions in the US. Studies relating mild-to-moderate CRI and cardiovascular risk are limited and inconsistent. Although we have learned much about the natural history and adverse outcomes associated with end-stage renal disease (ESRD), we have little specific information regarding risk factors for the development or progression of renal disease. Using a population-based, ethnically diverse large cohort of male and female health plan enrollees with extended follow-up, we propose: Aim 1: To evaluate: a) whether baseline and decline in renal function overtime are independent predictors of coronary heart disease (CHID), stroke, heart failure and peripheral vascular disease; b) effect modifiers of these relationships, including baseline hypertension and diabetes status. Aim 2: To determine whether baseline and increase over time in blood pressure level (as well as prevalent and incident hypertension) are predictive of the subsequent risk of ESRD after adjusting for diabetes and for baseline serum creatinine, proteinuria and hematuria. Aim 3: To examine other potential predictors of ESRD including demographic factors (race/ethnicity, level of education) total cholesterol level, family history of renal disease, body mass index, sagittal abdominal diameter, cigarette (as well as cigar and pipe) smoking, coffee intake, alcohol consumption, family history of renal disease and self-reported occupational exposures. We will take advantage of existing longitudinal data resources at the Northern California Kaiser Permanente Division of Research and available patient-level crosslinkage with the US Renal Data System end-stage renal disease registry to obtain comprehensive renal and cardiovascular outcomes. A de novo prospective study of this magnitude and duration will be prohibitively expensive and time-consuming. This proposal will leverage unique resources and methodological expertise to provide novel insights into the epidemiology of renal disease and its association with cardiovascular events. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CARDIAC MR OF SUBCLIN CVD: IMPACT OF AGE Principal Investigator & Institution: Manning, Warren J.; Assistant Professor; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-AUG-2005 Summary: (Verbatim from the Applicant's Abstract): Coronary heart disease and stroke are leading causes of mortality for men and women in the United States. Our current understanding of the pathogenesis of and the risk factors for cardiovascular disease (CVD) is derived largely from prospective studies of clinically overt disease. Unfortunately, clinical risk factors for CVD defined by these methods fail to predict a large proportion of CVD events, and some subjects at high clinical risk fail to develop overt disease. Subclinical disease precedes clinical events by years/decades but is difficult to quantify. For example, left ventricular hypertrophy (LVH) and aortic atherosclerosis are strong predictors of CVD events, but are difficult to accurately noninvasively quantify, especially among the elderly and overweight subjects (both growing populations in the U.S.). MRI perrnits accurate assessment of cardiac anatomy/function and subclinical aortic atherosclerosis. The underlying hypothesis of this proposal is that subclinical CVD is a precursor to overt CVD, and that MRI

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measures of subclinical aortic and cardiac anatomic disease are superior for the characterization of risk as compared with current measures of risk factors as well as more conventional imaging (e.g., carotid ultrasound, echo). Longitudinal/timeaveraged indexes of all established risk factors for CVD have been collected in the Framingham Heart Study (FHS). These time-averaged indexes are stronger predictors of clinical CVD than single measures. In a Pilot study of 312 FHS Offspring subjects, MRI measures of LV mass were successfully acquired in a larger proportion of subjects than echo, and MR evidence of LVH and subclinical aortic disease correlated more strongly (than echo and carotid ultrasound measures) with these time-averaged indexes. Application of MRI methods in the FHS offers an opportunity to identify subclinical atherosclerosis and LVH in this well-characterized cohort and to relate these data with conventional imaging measures already acquired in this cohort. Importantly, the nearconcurrent acquisition of brain MRI/neuropsychologic examination in the same FHS cohort offer the unique contemporaneous opportunity to examine subclinical cerebrovascular disease with MRI indexes of subclinical atherosclerosis. We propose to expand our Pilot study to perform heart and thoracic/abdominal aorta MRI studies in 2400 FHS participants to allow for identification of individual CVD risk factors for subclinical atherosclerosis. These population-based data will extend our knowledge of the distribution and severity of atherosclerosis in adult men and women and their relations to existing echo, carotid ultrasound and brain MRI measures. This study provides the rare opportunity to examine associations of quantitative MRI measures of aortic atherosclerosis and LVH with both cross-sectional and time-averaged measures of individual atherosclerotic risk factors (e.g., blood pressure, cigarette smoking, and cholesterol) and with novel inflammatory markers (e.g., C-reactive protein, MCP-1). Further, because the FHS consists of hundreds of sibships for which a DNA repository has been established, we propose to determine the heritability of MRI indexes of atherosclerosis and LVH, laying the groundwork for future genetic studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CARDIOVASCULAR DISEASE IN THE PIMA INDIANS Principal Investigator & Institution: Howard, Barbara V.; President; Medstar Research Institute Hyattsville, Md 20783 Timing: Fiscal Year 2002; Project Start 30-SEP-1988; Project End 31-MAY-2005 Summary: MedStar (formerly Medlantic) Research Institute proposes to continue its participation in the Strong Heart Study to manage the Arizona field center and the core laboratory. For the field center, this proposal describes methodology for 1) morbidity and mortality surveillance of the original Strong Heart Study cohort (1099 surviving out of 1500 original men and women ages 45-74 years in Phase I); 2) recruitment and examination of 30 families of at least 30 members, each 15 years and older; and 3) reexamination of the 900 family members from the Phase Ill pilot study. The Arizona field center comprises three American Indian communities: Gila River, Salt River, and Ak Chin. The Arizona center had a 71% recruitment rate in Phase I and 90%+ completion rates in Phases II and III. Morbidity and mortality surveillance obtained data on 99% of the participants. The core laboratory will provide accurate, reliable, stable, and comparable phenotypic measures of coronary heart disease risk factors in blood and urine samples. Measurements to be made for the family cohort include lipoprotein profile, glucose, HbA1c, insulin, LDL size, fibrinogen, PAI-1, apoE phenotype, apoB, apoA1, chemistry profile, and urinary albumin and creatinine. In addition, some exciting new markers of evolving importance in the etiology of atherosclerosis will be evaluated on stored baseline samples using a case-cohort design. sVCAM and

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endothelin-1 will be measured in approximately 400 definite cardiovascular disease cases and suitable controls. TSH also will be measured in these samples to allow evaluation of its role in cardiovascular disease in American Indians. The core laboratory will store blood, urine, and DNA in a safe and organized manner for effective inventory so that the resources will be retrievable for other scientists and the American Indian communities. Laboratory performance during the previous exams has been excellent, with high completion rates and precision and accuracy exceeding those of most core laboratories. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CASE CONTROL STUDY OF STATIN USE AND LARGE BOWEL CANCER Principal Investigator & Institution: Coogan, Patrica F.; Epidemiology; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 18-SEP-2000; Project End 31-AUG-2005 Summary: (Adapted from applicant's abstract): Cancer of the large bowel is a leading cause of cancer morbidity and mortality in the United States. Our previous epidemiologic studies played a key role in documenting an inverse association between the use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDS) and the incidence of large bowel cancer. Those studies were inspired by laboratory data suggesting that NSAIDs may reduce colon carcinogenesis. Now a growing body of laboratory data indicates that the commonly used, relatively new class of cholesterollowering drugs, the "statins" may have a similar chemopreventive potential: statins inhibit the growth of colon cancer cells in vitro and in vivo. There is also some evidence that statins may enhance the chemopreventive effect of NSAIDS. The statins (e.g., lovastatin, simvastatin) were first marketed in 1987, and are now among the most commonly prescribed drugs in the United States. At this time there is little epidemiologic data concerning their potential protective effect against large bowel cancer. Two randomized trials of statin use as preventives of coronary heart disease had nonsignificant deficits of large bowel cancer in the treated groups. We propose to conduct a population-based case-control study in Massachusetts of the relation of statin use to the risk of large bowel cancer. We will identify 2050 incident cases aged 50-74 through participating hospitals and 2050 age, sex, and precinct matched community controls from Massachusetts town lists. Cases and controls will be interviewed to obtain information on demographic factors, risk factors for large bowel cancer, detailed histories of statin and NSAID use, and data useful for addressing potential biases. The study is large enough to assess the influence of characteristics of statin use (timing, duration, dose) on the risk of large bowel cancer and to assess consistency of findings across subgroups of age, sex, and cancer site. The joint effect of statins and NSAIDs will also be assessed. The proposed study will provide informative epidemiologic data on a potential chemopreventive of large bowel cancer. Because the incidence of the disease and prevalence of statin use by U.S. men and women are high, an inverse association would be of considerable public health importance. Moreover, it would shed light on a mechanism of colon carcinogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CELLULAR DISORDERS IN FAMILIAL HDL DEFICIENCIES Principal Investigator & Institution: Oram, John F.; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105

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Timing: Fiscal Year 2002; Project Start 15-APR-1996; Project End 31-MAR-2004 Summary: Population studies have shown an inverse correlation between plasma HDL levels and risk for coronary heart disease, suggesting that HDL protects against atherosclerosis. This protection may be related to the ability of HDL to stimulate clearance of cholesterol from peripheral cells, particularly those of the artery wall. Lipidpoor HDL apolipoproteins such as apoAI remove excess cholesterol and phospholipids from cells by an active process that may account for the cardioprotective effects of HDL. This pathway is virtually absent in fibroblasts from subjects with Tangier disease (TD), a genetic disorder characterized by extremely low plasma levels of HDL, deposition of cholesteryl esters in tissue macrophages, and a high prevalence of cardiovascular disease. Other forms of familial HDL deficiency (FHD) have a less severe impairment of the same pathway. Thus a failure of apoAI to acquire cellular lipids may account for the rapid catabolism of nascent HDL particles, low HDL levels, and increased atherosclerosis in TD and other FHDs. Using microarray gene expression technology, we identified the probable TD gene product, called ABC1 , that appears to play a critical role in the apolipoprotein-mediated lipid removal pathway. We have prepared the necessary cell lines, cDNAs, antibodies, and assays for studying this protein and its gene. With these tools, we will characterize the biologic properties of ABC1 and other newly-discovered proteins using cultured cells, and we will establish the role of ABC1 in whole-body lipoprotein metabolism and atherogenesis using genetically-manipulated mouse models. Characterization of ABC1 and related proteins will advance significantly our understanding of cellular processes involved in clearing excess cholesterol from tissues by HDL apolipoproteins. These studies will help design therapeutic approaches for correcting cellular disorders associated with low plasma HDL and increased risk for heart disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CENTER FOR AFRICAN AMERICAN URBAN HEALTH Principal Investigator & Institution: Flack, John M.; Professor; Internal Medicine; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2003; Project Start 18-SEP-2003; Project End 31-MAY-2008 Summary: The Wayne State University (WSU) Center for African American Urban Health is a 5-year proposal that consists of five Cores and four Projects with participation of 34 investigators from various Departments, Centers, and Programs across the WSU campus. The Center has invested heavily in coalescing and expanding a shared research infrastructure that is widely accessible to investigators. The four Cores represent specialized areas of expertise and services required to undertake testing of multi-level hypotheses related to research in racial health disparities. These Cores form the foundation of our application. The Cores are: 1) Psychosocial and Community Measures; 2) Recruitment and Clinical Assessment; 3) Biostatistics and Research Database; and 4) Genomics Core. These Cores allow the investigators to test a broader range of Project-specific study hypotheses in a more cost-efficient manner than would be possible with stand-alone Projects. African Americans were selected as the exclusive study population for the Center because of their high burden of obesity-related disease such as breast cancer and cardiovascular diseases (hypertension, heart failure, diabetes mellitus, and coronary heart disease). Also, while Detroit has the third largest population of African Americans, it has the highest percentage (81.6%) of African Americans of any major city in the USA. The four Projects are: 1) Project 1: Obesity, Nitric Oxide, Oxidative Stress and Salt Sensitivity, 2) Project 2: Weight Loss in Breast Cancer Survivors, 3) Project 3: A Dyadic Intervention for Cardiac Rehabilitation

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Patients, and 4) Project 4: Promotion of Healthy Behavior in African American Women. These Projects are thematically linked through obesity, diet and other lifestyle factors including physical activity, and obesity-related cardiovascular disease and cancer. Our research efforts are focused on understanding the mechanisms operating at multiple levels (environment, lifestyle, physiology, genetics) mediating known disparate chronic conditions and their precursors. We also seek to identify preventive strategies and therapeutic approaches that might alleviate the disproportionate burden of disease. Primary as well as interactive effects of environmental exposures (household and community-level) and psychobehavioral characteristics with physiological measures (e.g., 24-hour BP burden and oxidative stress), genes, and body composition will be explored in relation to their impact on study outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHLAMYDIA ATHEROSCLEROSIS

PNEUMONIAE

AND

MACROPHAGES

IN

Principal Investigator & Institution: Byrne, Gerald I.; Professor & Chairman; Medical Microbiol & Immunology; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 15-FEB-1999; Project End 30-SEP-2002 Summary: (Adapted from the Applicant's Abstract): Chlamydia pneumoniae, a causative agent in human community acquired pneumonia, also has been implicated in a variety of sequelae associated with chronic disease and re-exposure to the organism. One important sequel associated with C. pneumoniae infection is the development of atherosclerotic lesions that define the pathology of cardiovascular disease in people. Cardiovascular disease due to atherogenic processes is a major health problem in most of the world, accounting for about 50% of all deaths. It is clear that vascular injury is crucial in the development and progression of atherosclerosis and that this injury can result from a variety of causes, including infection. Several lines of evidence support the hypothesis that C. pneumoniae infection is linked to the development of atherosclerosis. Initially, seroepidemiological evidence was generated to establish a relationship between C. pneumoniae and cardiovascular disease. Subsequently, evidence for the presence of the organism in atherosclerotic lesions was obtained using either direct antigen detection methods or probes specific for C. pneumoniae nucleic acids. In addition, the organism has been isolated from an aortic lesion and grown in cell culture. Finally, two pilot secondary prevention antibiotic treatment trials have provided evidence to suggest that treatment of C. pneumoniae in individuals with coronary heart disease significantly reduces cardiac events in treated versus placebo administered populations. Thus, although the association of C. pneumoniae and atherosclerosis is well-established, existing data do not prove an etiology or pathogenic role for the organism in disease, although both rabbit and murine animal models have been developed to determine if C. pneumoniae is causally associated with development or progression of atherosclerotic lesions in vivo. Activation and modification of mononuclear phagocyte function is associated with atherosclerotic lesion development. Characteristic changes include development of cholesteryl ester-laden monocytes (foam cells) and oxidation of lipids to form tissue-damaging derivatives. The hypothesis to be tested here is that infection of human monocytes, monocyte-derived macrophages or murine monocyte cell lines with C. pneumoniae results in changes in macrophage morphology and function that are consistent with a role for C. pneumoniae in the pathogenesis of atherosclerosis. This hypothesis will be tested by determining if C. pneumoniae causes mononuclear phagocytes to form foam cells in the presence of low

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density lipoprotein (LDL) or other cholesterol-containing serum lipoprotein complexes. Studies also will be conducted to determine if C. pneumoniae contributes to the oxidative modification of LDL and molecular characterization of C. pneumoniae antigens involved in these processes will be identified. Finally, a murine model will be developed to provide in vivo correlates to cell culture observations. Results will help establish links between C. pneumoniae infection and the atherosclerotic disease process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHLAMYDIA SIGNIFICANCE

PNEUMONIAE

ANTIGENS

OF

BIOLOGICAL

Principal Investigator & Institution: Campbell, Lee Ann.; Professor; Pathobiology; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2007 Summary: (provided by the applicant): Chlamydia pneumoniae is a human respiratory pathogen that causes 5 percent to 10 percent of pneumonia, bronchitis, and sinusitis. Virtually everyone is infected in his or her lifetime and reinfection is common. Infection is difficult to treat even with sensitive antibiotics. Chronic infection is common and has been associated with asthma, reactive airway disease, Reiter's syndrome, erythema nodosum, and sarcoidosis. The potential public health impact of infection with this pathogen is underscored by the association of C. pneumoniae with atherosclerosis and related clinical manifestations such as coronary heart disease, carotid artery stenosis, aortic aneurysm, claudication, and stroke. If C. pneumoniae infection plays a role in atherogenesis, there will be an urgent need to facilitate diagnosis and develop strategies for intervention and prevention. The overall goal of this proposal is two fold. First, C. pneumoniae specific antigens that are recognized during human infection will be exploited to facilitate serodiagnosis and identify putative vaccine candidates. The second goal is to define chlamydial/host cell interactions that lead to entry and survival of C. pneumoniae in host cells relevant to atherosclerosis. The specific focus will be on the interaction of the chlamydial glycan moiety with carbohydrate binding receptors on the host cell. Importantly, infection of epithelial cells can be inhibited with N-linked high mannose type oligosaccharide, the major component of the glycan. The novel hypothesis to be tested is that C. pneumoniae enters through the mannose-6 phosphate receptor by binding to the site involved in transport of phosphomannosylated residues to the lysosome and this differs from C. trachomatis, which utilizes the mannose receptor. The ultimate goals of these studies are to identify C. pneumoniae specific antigens to facilitate laboratory diagnosis and virulence factors playing a role in pathogenesis to guide vaccine development or develop anti-adhesive strategies for prevention of infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHLAMYDIA PNEUMONIAE VACCINE CANDIDATES Principal Investigator & Institution: Kaltenboeck, Bernhard; Assistant Professor; Vet Pathobiology; Auburn University at Auburn Auburn University, Al 36849 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-MAY-2005 Summary: (Provided by Applicant): Chlamydia (C.) pneumoniae is a major agent of community-acquired upper and lower respiratory infection and pneumonia. Increasing evidence suggests that C. pneumoniae infection plays an integral role in atherosclerotic coronary heart disease in developed countries, making C. pneumoniae a major public health concern. This clearly merits an effort to develop a vaccine against C. pneumoniae

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for prevention or treatment of respiratory disease, and possibly coronary heart disease and atherosclerosis. Using our new genetic immunization technologies, we are able to deconvolute the genomes of pathogens into the best vaccine candidates, and have recently validated this in a mouse model of C. psittaci infection in which we found 10 protective genes that also protect the original host animal. Perusing the complete genome sequence of C. pneumoniae, we propose as first step towards a C. pneumoniae vaccine to i) examine the C. pneumoniae homologs of the protective C. psittaci genes for protective efficacy in a mouse model of C. pneumoniae respiratory infection; ii) conduct a C. pneumoniae genome-wide search for the best antigens mediating prophylactic immunity against respiratory infection; and iii) perform experiments to understand the mechanisms for the success of such immunological intervention. We propose the following specific aims: 1) Test the C. pneumoniae homologs of the 10 protective C. psittaci genes in a mouse prophylactic respiratory model of C. pneumoniae infection. 2) Screen all approximately 1,000 C. pneumoniae genes for their protective efficacy in the mouse prophylactic model. 3) To understand the spectrum of possible responses in an outbred human population, dissect the immunological mechanisms of disease protection mediated by the C. pneumoniae vaccine candidate proteins in respiratory disease models using several inbred mouse strains. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHRONIC DENTAL DISEASE AND CARDIOVASCULAR DISEASE Principal Investigator & Institution: Joshipura, Kaumudi J.; Assistant Professor; Oral Health Policy & Epidem; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 30-SEP-1998; Project End 31-JUL-2004 Summary: Several recent reports have found significant associations between periodontal disease, tooth loss and increased coronary heart disease (CHD). Possible associations between dental caries and CHD and between dental disease and stroke have also been reported. Recent literature also supports the possible role of other chronic bacterial and viral infection, fibrinogen and other inflammatory mediators in increasing CHD risk. We propose to study the relation between periodontal disease, caries and tooth loss, and risk of incidence of coronary heart disease and stroke and to assess if these associations are independent of common risk factors including behavioral factors. Additionally, we propose to evaluate two possible explanations for these associations: (1) tooth loss leads to reduced masticatory efficiency, which could lead to reduced intake of dietary antioxidant and fiber, which in turn has been associated with increased risk for cardiovascular disease; and (2) chronic dental disease could lead to hyperfibrinogenemia which is strongly and probably causally associated with increased risk of CHD. We will also evaluate C-reactive protein, von Willebrand factor, tissue plasminogen activator, and Factor VII as additional mediators. Participants include 51,529 men enrolled in the Health Professionals Follow-Up Study since 1986 and 90,000 females enrolled in the Nurses Health Study since 1976 who reported their dental status in 1992. The follow-up in these cohorts is excellent and has been consistently over 90 percent. The outcome measures will include incident cases of CHD and stroke in 15 years of follow-up among men and 9 years of follow-up among women free of cardiovascular disease and cancer at baseline. Over 4500 incident cases of CHD and stroke are anticipated. Biomarker assays will be performed for a sub-population consisting of new CHD cases incident after the time of initial blood collection, and one matched control per case. Blood samples were provided by 32,000 nurses in 1989-90 and by 18,100 male health professionals in 1993-94, allowing for sufficient follow-up to

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include an estimated 600 incident cases among males and 600 cases among females for the biomarker analyses. The high prevalence of dental infection makes its potential association with inflammatory and dietary mediators, and ultimately increased risk of CHD and stroke very important with implications for millions of Americans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHRONIC ISCHEMIC MR-MECHANISMS & NOVEL SURGICAL THERAPY Principal Investigator & Institution: Miller, D Craig.; Professor; Cardiothoracic Surgery; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: (Verbatim from Applicant's Abstract):.Ischemic mitral regurgitation (IMR), or "functional" MR as a consequence of coronary heart disease, continues to defy surgical attempts to repair the mitral valve in a predictable fashion because we still do not understand the mechanisms responsible for IMR. Postoperative survival is only about 55 percent after 5 years, and debate continues as to whether repair is preferable to replacement. While ring annuloplastyworks in most patients with annular dilation and normal leaflet motion, such an approach can be unreliable in those who have "complex" MR jets and/or apical leaflet tethering, which results in restricted systolic leaflet motion. Our ignorance of the mechanisms responsible for IMR has been reduced by work in experimental models of acute IMR, but the real clinical problem and surgical challenge is patients with chronic I1\IR. Chronic animal experiments are rare due to high cost and the inescapable animal attrition that these preparations entail. Clinical progress, however, will continue to be tentative and empirical until controlled studies of chronic IMR are performed which tell us how and why these morphologically normal valves leak. We propose to apply our myocardial marker technology (which can measure submillimeter instantaneous changes in leaflet, annular, papillary muscle, and left ventricular 3-D geometry and dynamic motion throughout the cardiac cycle on a beatto-beat basis) to determine the mechanisms responsible for chronic IMR in an ovine myocardial infarction model and to define how the therapeutic effects of ring annuloplasty differ from those of a novel trans-annular suture reparative technique (Septal-Lateral Annular Cinching, or "SLAC"), which we have shown can eliminate acute IMR. To address these issues, we set forth the following Specific Aims: #1) To elucidate the basic pathophysiology o chronic ischemic mitral regurgitation, with particular emphasis on the 3-D geometry of the mitral leaflets in relation t about one another and to the other components of the mitral valvular-ventricular complex. This work will define for the frst time the causal basis of chronic IMR as a function of the evolving interrelationships between leaflet, annular, and ventricular pathologic abnormalities. #2) To investigate in a randomized, controlled fashion a new surgical treatment, "SLAC," for chronic IMR and to determine the mechanistic basis for the beneficial effects conferred by either the conventional surgical approach (undersized ring annuloplasty) or this new SLAC technique based on differences in LV remodeling, interactions between leaflet, annular, and ventricular 3-D dynamics, and valvular competency. Comparison of the effects of ring annuloplasty and SLAC on LV geometry as well as leaflet and annular 3-D motion and dynamics will reveal why patients might benefit from one approach versus the other, beyond simply eliminating the MR. These experiments promise to add fundamental knowledge which will lead to more intelligent design of new, more effective, and more predictable surgical approaches for patients with CAD and chronic ischemic mitral regurgitation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLINICAL UTILITY OF ENDOTHELIAL FUNCTION IN PAD Principal Investigator & Institution: Vita, Joseph A.; Professor; Boston Medical Center Gambro Bldg, 2Nd Fl, 660 Harrison Ave, Ste a Boston, Ma 02118 Timing: Fiscal Year 2003; Project Start 22-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Peripheral arterial disease (PAD) produces considerable morbidity and mortality, and the precise factors that determine disease progression and the responses to therapy remain largely unknown, In addition to their risk for critical limb ischemia or graft failure, PAD patients also have markedly increased risk for coronary heart disease, particularly during the stress of vascular surgery, It is clear that new approaches are needed for optimal risk assessment and therapy. Targeting endothelial function represents a major new departure from traditional methods for assessing cardiovascular disease risk. The central hypothesis of this proposal is that endothelial dysfunction is a critical mediator of both PAD and coronary heart disease events and measuring endothelial function will enhance both the risk assessment and therapy in PAD patients. Recent studies by the applicants strongly support this contention and establish the prognostic value of endothelial dysfunction in PAD patients undergoing vascular surgery. A key unresolved question is whether reversing endothelial dysfunction will directly reduce risk. This finding would more firmly establish endothelial dysfunction as a mediator of both PAD and coronary heart disease risk and further validate its clinical utility. We propose the following specific aims: 1. To determine whether reversing endothelial dysfunction ameliorates perioperative risk in PAD patients. Patients referred for elective vascular surgery will be treated with high dose atorvastatin (80 mg/day), ascorbic acid (500 mg/day), or placebo in a randomized, double blind, fashion beginning a month prior to surgery and continuing for a month after surgery. Non-invasive assessment of vascular function will be performed at baseline and immediately prior to surgery. Patients will be monitored for cardiovascular events (cardiac death, myocardial infarction, unstable angina, and stroke) in the 30-day postoperative period. The goal is to determine whether improvement in vascular function independently predicts outcome (irrespective of which treatment produces the improvement). 2. To determine whether endothelial dysfunction predicts long-term (2-year) PAD and coronary heart disease risk in PAD patients. 3. To determine whether systemic markers of oxidative stress and inflammation relate to endothelial dysfunction and long-term PAD and coronary heart disease risk. This work will provide novel information about the pathogenesis and management of PAD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMMUNITY SURVEILLANCE OF CHD AND SUDDEN DEATH (MHS) Principal Investigator & Institution: Luepker, Russell V.; Mayo Professor and Head; Epidemiology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 30-JUN-2005 Summary: The Minnesota Heart Survey (MHS) is among the few population- based longitudinal studies to monitor and explain trends in coronary heart disease (CHD) mortality and morbidity; the leading cause of death and disability in the United States. It encompasses a large and well defined community, the Minneapolis/St. Paul (Twin Cities) metropolitan area of Minnesota, comprising a population of 2.3 million (1990 census). For almost two decades, MHS has made contributions to: 1) understanding the

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components of the decline of coronary heart disease mortality including incidence rate, hospitalized attack rate, case fatality, and population levels of CHD risk factors; and 2) the methodology of disease surveillance in a time when classification and diagnostic technologies are constantly changing. In the last grant period, MHS morbidity and mortality surveillance has found: 1) a continued decline in age-adjusted CHD death rates through 1995 for both men and women; 2) continued improved survival of hospitalized AMI patients in the first half of the 1990's; 3) more modest declines of outof-hospital sudden cardiac death during the 1990's resulting in an increasing preponderance of out-of-hospital compared to in-hospital CHD mortality; 4) declining rates of hospitalized AMI including incident and recurrent events for both men and women in the 1990's; 5) a modest change in event severity for AMI; 6) dramatic improvements in two year case fatality after validated hospitalized AMI; and 7) significant increases in the use of appropriate medications, diagnostic procedures and therapeutic procedures during AMI in the setting of dramatic declines in length of hospital stay. In this application, we propose to continue efficient MHS data collection in the following domains: 1) continue surveillance of coronary heart disease mortality through the year 2002; 2) monitoring trends in AMI occurrence and survival by surveillance of hospitalized AMI in the year 2000; 3) evaluation of the effect on AMI diagnosis of the widespread use of new, highly sensitive and specific biomarkers (troponins); and 4) evaluation of out-of- hospital sudden cardiac death (SCD) through an autopsy in a population sample of victims utilizing modern anatomical, histological, toxicologic and interview-based data to better characterize this fatal condition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONVECTIVE FLOW TISSUE ASSEMBLY OF VASCULAR GRAFTS Principal Investigator & Institution: Frangos, John A.; Principal Scientist; Applied Tissue and Materials, Inc. 505 Coast Blvd S, Ste 402 La Jolla, Ca 920374614 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2005 Summary: Coronary heart disease accounts for the largest fraction of heart disease (the leading cause of death in the United States, affecting 12 million Americans) and has an annual cost to society that exceeds 110 billion dollars. There is a great clinical need for small diameter vascular artery grafts, as patients requiring multiple or repeat bypass procedures frequently lack adequate autogenous vessels to serve as bypass conduit. Tissue engineering clearly has the potential to provide relief in this area, however, present attempts have had limited clinical potential, due to practicality and feasibility issues or involvement of foreign materials. As such, a novel tissue assembly methodology that avoids these pitfalls is proposed. The new methodology relies upon drag-induced convective flow to assemble tissue on an inert porous mandrel, which is later removed, yielding completely biological constructs. The flow will be generated by a transmural pressure gradient, which in turn will generate shear stresses that will mimic the mechanical environment of native arteries. The tissue assembly methodology will allow for multiple seedings, such that the culture of layered tissues is possible, and will be readily scaled up and automated, allowing for wide-scale commercial and clinical application. The present Phase I proposal seeks to test the ability of the novel bioreactor design to assemble human smooth muscle cells into thick, healthy threedimensional tissue constructs. These constructs will be evaluated in terms of physical and morphological properties. The ultimate goal is to develop a tissue assembly method that produces autologous and completely biological vascular grafts, which are produced with consistent biological and mechanical properties, by a manufacturing process that can be readily scaled-up in an economic manner.

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

Project Title: CORE-CONTRIBUTION OF NEIGHBORHOOD TO HEALTH DISPARITIES IN CARDIOVASCULAR DISEASE Principal Investigator & Institution: Diez Roux, Ana V.; Assistant Professor; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 10-FEB-2003; Project End 31-JAN-2008 Summary: Recent epidemiologic studies have found that living in socioeconomically disadvantaged neighborhoods is associated with increased prevalence and incidence of coronary heart disease, even after controlling for measures of personal income, education, and occupation. There is also abundant evidence of important differences in neighborhood environments by race and ethnicity. For example, African Americans are significantly more likely to live in disadvantaged neighborhoods than whites, even when persons of similar personal income and education are compared. Predominantly African-American neighborhoods (and disadvantaged neighborhoods generally) have been shown to have greater density of tobacco advertising and greater availability of tobacco products. The availability and quality of recreational spaces and the availability and quality of healthy foods may also differ across neighborhoods. These data suggest that neighborhood characteristics, and access to health community environments generally, may contribute to race and ethnic differences in cardiovascular risk. Neighborhood differences may also be relevant in understanding differences in cardiovascular health among other race/ethnic groups. The proposed project will build on existing research in both cardiovascular disease epidemiology and neighborhood effects at Columbia, allowing increased focus on the examination of neighborhood effects on cardiovascular disease in minority populations and on the contributions of neighborhood differences to disparities in cardiovascular health. This increased focus will include (1) enhanced analyses of neighborhood effects on cardiovascular health in minority groups using existing cohort data and data from the US Census, (2) support for the development of operational measures of neighborhood characteristics including both survey-based and geographic information-based (GIS) approaches, and (3) support for methodological approaches which will enhance our ability to more rigorously examine neighborhood effects as well as the contribution of neighborhood differences to health disparities in cardiovascular diseae. Confirming that neighborhood characteristics are relevant to disease risk (through health damaging or health enhancing features of neighborhoods) could have important implications for the prevention of cardiovascular disease and for the reduction of persistent (and often increasing) social and race/ethnic disparities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORONARY RELATIONSHIP

HEART

DISEASE

ANXIETY:

PREVALENCE,

Principal Investigator & Institution: Carmin, Cheryl N.; Psychiatry; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2004; Project Start 01-DEC-2003; Project End 30-NOV-2008 Summary: (provided by applicant): The goals of this career development award are designed enable the candidate to develop a program of independent research examining the relationship between anxiety disorders and coronary heart disease (CHD). This study would contribute to the investigator's long-term career goal of examining the relationship between anxiety disorders and medical illness, such as CHD. There is a

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relatively well-established link between emotional and behavioral variables and the risk for CHD. Despite the comorbidity of anxiety and depressive disorders, the lines of research investigating these conditions and CHD have remained largely independent of one another. Further, despite it being more prevalent than and often pre-dating the onset of depression, less attention has been paid to the relationship between anxiety and CHD. The existing research focusing on anxiety disorders in those at risk for or who have CHD is limited by the use of descriptive, rather than state-of-the-art diagnostic measures of psychopathology. It remains unclear to what extent clinically significant anxiety disorders serve as independent risk factors and may be influential in the development of CHD. In order to address the risk that anxiety disorders pose in CHD prone individuals, the initial phase of this award will allow the investigator to develop background in areas related to the interface between cardiology and psychology including psychosocial epidemiology, biostatistics, psychophysiological assessment, and scanning technology related to CHD. Existing epidemiological databases that assess CHD will be utilized to determine whether anxiety disorders are independently related to the development of CHD. The 2 nd phase of the award will be used to apply the skills acquired in coursework and in analyzing existing data to execute a study comparing a sample of anxiety disordered subjects to a matched control group based on anxiety symptoms (severity, frequency, duration), cardiac calcium as assessed by electron beam tomography, lipid levels, and heart rate variability. The investigator is in the unique position of having access to individuals who are being screened for CHD using EBT as well as having access mentors and collaborators involved in multicenter cardiovascular research (Drs. Lynda Powell, Peter Buttrick, Kiang Liu, George Kondos), psychophysiological research (Dr. Stephen Porges) and who are experienced in the psychopathology and treatment of anxiety disorders (Dr. Richard Heimberg). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORONARY HEART DISEASE: WOMEN'S VALUES, BELIEFS AND COGNITIVE PROCESSES Principal Investigator & Institution: Arslanian-Engoren, Cynthia; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 30-JUN-2007 Summary: Coronary heart disease, which includes acute and old myocardial infarction, angina pectoris, and other acute, subacute, and chronic forms of ischemic heart disease, is the single largest killer of American women. In 1999, 262,391 United States women, of all ethnic and racial groups, lost their lives to coronary heart disease. However, Black women have the highest overall death rates from coronary heart disease, followed by White and Hispanic women. Despite these findings and the fact that women are more likely than men to die after a myocardial infarction, women are less likely than men to seek medical attention after the onset of initial symptoms. Explanations for these delays have been linked to low perceptions of susceptibility to heart disease, the lack of association of initial symptoms as significant indicators of an acute cardiac event, low socioeconomic status, and patient race. While not negating the importance of these variables, they do not speak to the values attitudes or beliefs that underlie women's decision to seek emergency care. Guided by The Health Belief Model, this triangulated, descriptive study will examine the values, beliefs, and cognitive process of a total of 78 women (26 Hispanic, and 26 white) relative to the manifestation and presentation of an acute myocardial infarction, while the quantitative phase will focus on the symptoms women believe most likely indicate an acute myocardial infarction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORTISOL, CENTRAL OBESITY, AND INSULIN RESISTANCE Principal Investigator & Institution: Purnell, Jonathan Q.; Associate Professor; Medicine; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 15-AUG-2000; Project End 31-JUL-2004 Summary: (adapted from the application) Central (visceral) obesity contributes to an excess risk of diabetes, dyslipidemia, hypertension, and premature death from coronary heart disease. A feed-back loop model of weight regulation has emerged from recent studies of animals and humans: afferent hormones signal amount of fat mass to the central nervous system; weight regulation centers in the hypothalamus interpret these signals and control efferent systems including appetite, energy expenditure, and enzymes in the fat cell, such as lipoprotein lipase, that facilitate partitioning of energy into lipid storage. It is proposed in this grant that the hypothalamic-pituitary-adrenal axis is an effector system of hypothalamic weight regulatory centers and that increased cortisol production rates in the obese state directly regulate enzyme transcription in the fat cell to promote lipid uptake and central fat distribution. Cross sectional data from lean and obese humans using stable isotope enrichment determined by mass spectroscopy demonstrate that increases in cortisol production rates across the physiological range are associated with increased adipocyte lipoprotein lipase activity, accumulation of fat mass independent of non-fat mass, increased visceral fat, and increased insulin resistance. These findings, however, do not establish whether increased cortisol production causes, or is simply associated with these variables. To directly test whether cortisol enhances lipid uptake, fat mass accumulation, increased visceral fat mass, and insulin resistance, it is proposed to study the effect of administration of increasing doses of hydrocortisone (including doses within the physiological replacement range) in subjects with complete adrenal failure on these parameters. Finally, leading cellular candidates for the regulation of adipocyte lipoprotein lipase gene expression and fat cell differentiation, including PPAR-gamma and C/EBP, will be measured in adipose samples from the subjects in these studies to provide a mechanistic link between peripheral signaling systems such as cortisol and the adipocyte enzymes involved with fat partitioning. These studies will not only provide insight into the mechanisms of central obesity and its metabolic consequences, they also have great importance to clinicians who care for subjects with adrenal insufficiency as to the consequences of recommended replacement doses of cortisol on risk factors for heart disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DETECTING CHANGES IN MYOCARDIAL PERFUSION AND FUNCTION Principal Investigator & Institution: Faber, Tracy L.; Associate Professor; Radiology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 15-JUL-2002; Project End 30-JUN-2006 Summary: Coronary heart disease caused 476,124 deaths in 1996 and continues to be the leading cause of death in America today. Over 12 million people alive today have a history of myocardial infarction, angina pectoris, or both. Every year in the US about 5 million perfusion studies are performed to evaluate extent and severity of CAD, thereby enabling clinical decisions regarding diagnosis, prognosis, and therapy for patients with heart disease. Of these, 1 million undergo angioplasty and about 500,000 have bypass surgery, and millions of others undergo drug therapy and or lifestyle changes to prevent progression of cardiac disease. It is widely recognized that computer quantification of

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myocardial perfusion images improves diagnostic accuracy and enhances confidence and reproducibility of interpretation. Theses quantitative approaches are wellestablished for assessing abnormalities in myocardial perfusion and function. However, they have not been developed or optimized for detecting changes in serial studies of the same patient such as is needed for assessing the effect of interventions, medical therapy, or disease progression. In this project, we will develop and validate computer-based methods to automatically quantify and visualize serial changes in myocardial perfusion and function from perfusion SPECT. The work can be separated into 4 projects: 1) To assess changes in myocardial perfusion, 2) to assess changes in myocardial function, 3) to design a virtual heart suitable for creating simulation data for optimizing and analyzing our algorithms, and 4) to validate the methods using both simulations and animal studies. Important subprojects include: a) development of 3-d and 4-d surface detection methods for defining LV endocardial and epicardial surfaces, b) development of algorithms for non-rigid alignment of static and/or dynamic serial SPECT images so that they may be more directly compared, c) development of motion analysis methods using similar non-linear alignment techniques to measure regional myocardial function and also to correct ungated SPECT scans for motion blur, and d) creation of new statistical approaches to determine significant changes in both global and regional perfusion and functional variables. The ultimate goal of this project is to create a clinically useful tool for detecting changes in serial SPECT studies. Most importantly, the tools will be extremely well characterized as to their sensitivity in detecting small changes as well as for overall accuracy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIETARY ETIOLOGIES OF HEART DISEASE AND CANCER Principal Investigator & Institution: Rimm, Eric B.; Associate Professor; Nutrition; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 01-DEC-1985; Project End 31-MAY-2007 Summary: (provided by applicant): We propose to continue the biennial follow-up of cardiovascular disease among 51,529 male health professionals, age 40 to 75 years in 1986, to address a series of new dietary hypotheses related to risk of a coronary heart disease and stroke. We project over 4,000 incident MI, fatal CHD, and stroke cases through the end of the follow-up period. Nested within this cohort, over 18,000 participants provided blood samples in 1994 from which we propose to investigate several biological (plasma and genetic) determinants of disease. We will concentrate on several hypotheses related to nutritional and genetic determinants of cardiovascular disease (CVD). With this exceptional resource of repeated assessments of diet and lifestyle characteristics tied to potential genetic markers of disease, we will prospectively evaluate in relation to coronary heart disease 1) n-6 fatty acids across a wide range of n3 fatty acid intake from fish and vegetable sources, 2) foods with a high glycemic load, specifically among men with a BMI > 25kg/m^2, 3) protein intake as a replacement for carbohydrate, and 4) putative functional variants and haplotypes in candidate genes thought to be insulin targets. Within this metabolic domain we seek to determine if lifestyle practices such as physical activity or a low glycemic load diet can modify underlying genetic risk. To investigate further the effect of diet on mediators of CHD we will investigate a) the interaction between n- 3 and n-6 fatty acids on inflammatory risk factors for CVD and b) glycemic load on adiponectin and the associated risk of this adipocyte-derived cytokine on risk of MI and fatal CHD. Also, we propose further to examine aims 1-3 with respect to stroke. Finally, within a small exploratory aim, we propose to document basic risk factors for congestive heart failure by utilizing the

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innovative methods we designed to study coronary heart disease. The ongoing Health Professionals Follow-up Study will provide follow-up of non-CVD endpoints (CA55075) in addition to information on important covariates for the proposed study. Overall, the large size of the prospective cohort, the high follow-up rate, the repeated assessment of dietary and lifestyle information, and the availability of archived bloods provide a unique cost-effective opportunity to test hypotheses related to CVD risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIETARY PATTERN INDEXES: RELATION WITH CVD RISK FACTORS Principal Investigator & Institution: Kant, Ashima K.; Professor; Family, Nutrition & Exercise Scis; Queens College Flushing, Ny 113671597 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Although many studies have examined the role of single nutrients, foods, or food groups in the etiology of disease, relatively little research has addressed the health effects of dietary patterns comprising multiple interdependent dietary factors. Research on dietary patterns is warranted on several grounds. First, complex diets consumed by free-living individuals do not consist of single nutrients or foods but rather a combination of foods containing multiple nutrients and nonnutrients. Second, intercorrelation of dietary variables makes it difficult to isolate effects of single nutrients or foods. Third, biological activities of nutrients in vivo are interdependent. Finally, recommendations for disease prevention implicitly reflect the dietary pattern approach by emphasizing the simultaneous change of several dietary behaviors such as increasing fruit, vegetable, and grain intake, and decreasing fat intake. However, the exact mechanisms through which healthy diet patterns modify the risk of heart disease are not known. Intuitively, such patterns may be effective at several levels, but little is known about it. This proposal will test the hypothesis that two diet indexes intended to represent healthy eating patterns may be associated with several major, lifehabit, and emerging risk factors of coronary heart disease (CHD) risk identified by the ATP III in a representative sample of adult Americans. We will use dietary, anthropometric, biochemical, and health data from the third National Health and Nutrition Examination Survey, 1988-1994 (>15,000), to address these issues. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DISLIPIDEMIA DETECTION IN WV FAMILIES Principal Investigator & Institution: Harris, Carole V.; Behavioral Med and Psychiatry; West Virginia University P. O. Box 6845 Morgantown, Wv 265066845 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): West Virginians are at high-risk for developing coronary heart disease due to high rates of biomedical risk factors, low socio economic status, and a rural geography with limited access to health care. West Virginian's health beliefs influence participation in health care programs and must be considered in the development of interventions to improve health. The long-range goal of this research program is to prevent the development and progression of coronary heart disease in atrisk children and their parents. The objective for this application is to identify and reduce the health belief barriers to an existing cholesterol screening program in this high-risk, rural, poor population. The existing program, Coronary Artery Risk Detection in Appalachian Communities (CARDIAC) has a four year history of providing no cost dyslipidemia testing to fifth grade children and their parents. The specific aims for this

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proposal are: (1) To identify health beliefs that act as barriers to participation in the dyslipidemia screening program and to develop belief-based strategies to reduce those barriers, and (2) To improve the identification of children and families who are at-risk for the development of CHD. Research Design and Methods: The Theory of Planned Behavior will provide the theoretical framework for identifying beliefs barriers and developing interventions to address them. Belief barriers to participation in the dyslipidemia detection program will be initially identified through interviews with children, parents, and community leaders in rural West Virginia. The reliability and validity of interview responses will be assessed through administration of general and study-specific health beliefs questionnaires to a larger, random sample of children and adults. A Health Beliefs (HB) approach will be developed for the screening and diagnosis phases of the dyslipidemia detection program. The new HB approach will be compared to the standard CARDIAC (SC) approach in a randomized controlled trial. Three thousand fifth grade students in fourteen counties will be randomly assigned to receive either the HB or SC approach. Participants will be followed through screening and diagnosis. The HB and SC approaches will be compared on participation rates for children and parents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EDUCATION AND AWARENESS FOR LIFE THAT'S HEALTHY Principal Investigator & Institution: Addison, Clifton; Jackson State University Jackson, Ms 39217 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2007 Summary: Purpose and Specific Aims of the PROJECT. Mississippi has not developed any comprehensive programs to address CVD disparities even though many researchers have reported that overall mortality and cardiovascular disease mortality are higher in African Americans than whites. One important challenge for preventing the onset of cardiovascular disease is to decrease the number of people who are engaged in unhealthy lifestyle behaviors, such as sedentary lifestyle practices, inappropriate dietary practices, and the incidence of overweight among young people. Project HEALTH will provide intervention programs that are designed to increase intrinsic motivation for youth to participate in fitness activity, in achieving this goal the intervention also hopes to increase participant self-esteem, establish more harmonious relationships with peers and educate youth on the necessity of fitness to promote health and prevent debilitating diseases, which afflict minority populations at higher rates than the general population. Project HEALTH will design intervention programs to change the trends that currently exist relating to cardiovascular disease among African Americans in Mississippi. This study hopes to reduce overweight in children because it is well known that being overweight during childhood and adolescence has been associated with increased adult mortality 1. Weight in adolescence is considered to be a good measure of future adult weight status and is a good predictor of the occurrence of later adverse health reports, hence the importance of preventing obesity in children. Researchers conclude that school intervention, especially the case of classroom-based intervention, is effective for preventing future cardiovascular disease. It is predicted that there would be a reduction of 5% to 25% in the rate of coronary heart disease if all sedentary individuals could become physically active 2. One primary benefit of regular physical activity is protection against cardiovascular disease. A well designed exercise program can increase stamina and endurance, lower blood pressure, improve blood cholesterol levels, help with weight control, help lower abnormal blood sugar levels, reduce stress, improve sleep, and help prevent osteoporosis 3 Harshfield et al. (1990) found that less fit African

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American males and females had higher systolic and diastolic pressures than more fit adolescents 4 Danforth et al. (1990) found that in low socio-economic African American youth, a 12-week aerobic exercise program could decrease blood pressure readings significantly. Furthermore, exercise seemed to lower cholesterol and helped to maintain recommended weight, particularly when combined with good nutrition. Given the problem of health disparities in minority populations and its prevalence and acute nature in Mississippi, ways and means of successfully motivating youth to a fit, active lifestyle becomes a desired goal. The study also seeks to decrease the development of cardiovascular disease by decreasing the number of students who are engaged in unhealthy lifestyle behaviors, such as inappropriate dietary practices, and to increase students' self-esteem. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTS OF MEDITATION ON MECHANISMS OF CHD Principal Investigator & Institution: Bairey Merz, C. Noel.; Associate Professor and Medical Director; Cedars-Sinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 900481804 Timing: Fiscal Year 2000; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Coronary heart disease (CHD) is the leading cause of death, disability, and health care costs in the US. The majority of CHD patients continue to have acute cardiac events, many sudden and unexpected, despite identification and treatment of their disease and attention to the traditional risk factors. The pathophysiologic bases of these cardiac events are not fully established, but substantial evidence indicates that psychosocial stress and resulting sympathetic nervous system imbalance are major contributors. Evidence indicates that psychosocial stress and a hyperresponsive sympathetic nervous system have adverse effects on both vasomotor function and longterm autonomic balance. Recent advances in our understanding of the pathophysiology of acute cardiac events-specifically, identification of the roles that arterial vasomotor dysfunction and autonomic nervous system imbalances play in the interplay of psychosomatic stress and CHD. Preliminary evidence further suggests that Complementary and Alternative Medicine (CAM) practices, such as the Transcendental Meditation (TM) technique, can not only reduce stress but also reduce acute cardiac events in patients with CHD. Based on these and related data, we propose a randomized, blinded, controlled study of the effects of one CAM practice, the TM technique, compared to a control group, on the primary outcomes of (1) arterial vasomotor dysfunction (brachial artery reactivity); (2) autonomic nervous system imbalances (heart rate variability); (3) transient ambulatory myocardial ischemia (ST segment depression); and (4) the secondary outcomes of psychological stress and quality of life (anger, hostility, anxiety, depression, perceived health, disease-specific symptoms, and life stress/social resources). We hypothesize that significance effects on these physiological and psychological mechanisms associated with practice of the TM program will elucidate the known effectiveness of certain CAM techniques as additive/alternative approaches to prevention of acute cardiac events in CHD patients. Results of this randomized controlled trial will: (a) yield new data regarding the reversal of pathophysiological mechanisms underlying CHD, (b) provide mechanism data to complement our ongoing NIH- sponsored trial of this CAM practices on CVD-related mortality, and (c) provide pilot data for an expanded study of the effect of the TM technique on the pathophysiological mechanisms underlying acute cardiac events. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OUTCOMES

ENDODONTIC

INFLAMMATION

AND

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CARDIOVASCULAR

Principal Investigator & Institution: Caplan, Daniel J.; Assistant Professor; Dental Ecology; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 10-JUL-2001; Project End 30-JUN-2004 Summary: Several large-scale epidemiologic investigations have uncovered relationships between chronic periodontal disease and adverse cardiovascular outcomes such as coronary heart disease and stroke. To date, endodontic inflammation has not received the same attention despite its being a commonly found sequel to bacterial infection of the Dental pulp space and its having several important characteristics in common with inflammation of periodontal origin. These similarities form the basis of the proposed epidemiologic study, which seeks to test the hypothesis that a greater history of endodontic inflammation is associated with 1) increased risk of coronary heart disease and stroke; and 2) increased carotid artery intimal-medial thickness and prevalence of coronary heart disease. These hypotheses will be addressed by linking data from three large, well-established, ongoing epidemiologic studies of aging populations with newly collected variables involving endodontic disease and treatment. Two of the three sub-studies (from populations of adult men in Boston and adult women in Sweden) will employ a review of existing intra- and extra-oral radiographs to assess variables related to apical periodontitis and frequency and quality of root canal therapy, and will relate these exposures to subsequent incidence of coronary heart disease and stroke. The third sub-study (from adult populations in four U.S. communities) will compare self-reports of endodontic treatment with prevalence of coronary heart disease and thickened carotid arterial walls in a cross-sectional fashion. Given the relatively high frequency of endodontic inflammation among adult populations, the proposed study describes a straightforward, fast, and inexpensive way to gain preliminary insight into the relationship between endodontic and cardiovascular disease. It also will serve as the epidemiologic foundation for future investigations into endodontic disease and other systemic outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENDOTHELIN-1-CARDIOMYOPATHY

A

NEW

PLAYER

IN

DIABETIC

Principal Investigator & Institution: Schwartz, Dean D.; Vet Microbiology and Pathology; Auburn University at Auburn Auburn University, Al 36849 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2003 Summary: Applicant's Abstract Diabetes mellitus is a metabolic disorder recently identified as a strong independent risk factor for cardiovascular disease. Both Type 1 and 2 diabetes mellitus have been linked to a marked increase in the incidence of heart failure and mortality associated with coronary heart disease. Diabetic cardiomyopathy, an independent clinical syndrome, is characterized by diastolic dysfunction, abnormalities in systolic function and histological changes that occur with or without coronary artery disease. The specific etiological mechanism(s) responsible for the cardiormyopathy observed in diabetic patients and experimental models of diabetes has not been clearly defined. However, the direct effects of abnormal carbohydrate metabolism and excessive fatty acid oxidation have been implicated as important proximate causes in diabetic cardiomyopathy. We propose that another factor contributing to altered cardiac energy metabolism and function associated with diabetic

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cardiomyopathy is the bioactive peptide, endothelin-1 (ET-1). In this application, we present preliminary data demonstrating that diabetic rats have elevated plasma and tissue levels of ET-1, decreased cardiac mechanical function and decreased tissue fructose-2,6-bisphosphate (F26P2) levels compared to vehicle-treated rats eight weeks after induction with streptozotocin. Furthermore, in isolated ventricular myocytes. ET-1 inhibits glucose uptake, glycolysis and F26P2 production, possibly by a protein kinase C (PKC)-dependent mechanism. We therefore hypothesize that the progressive decline in cardiac metabolism and function observed in the diabetic patient is due in part to the metabolic effects of ET-1, which augment the already altered cardiac metabolism produced by insulin deficiency/resistance and subsequent elevations in free fatty acid levels. To test this hypothesis, the following specific aims will be examined in streptozotocin (STZ)- and vehicle-treated rats: 1) Determine the cellular effects of ET-1 on cardiac glucose uptake and utilization in isolated ventricular myocytes; 2) Examine endothelin-insulin myocardial receptor signaling crosstalk in isolated ventricular myocytes and the effect of protein kinase C activation on this crosstalk; and 3) Determine the time course for the pathological effects of ET-1 on cardiac metabolism, PKC activation and function in vivo in diabetic rats using the endothelin receptor antagonist bosentan. In summary, this application will delineate the connections between altered intracellular signaling between ET-1 and insulin as they relate to glucose utilization, protein kinase C activation and myocyte function, and examine the relation between altered energy metabolism and myocardial function in diabetes mellitus. (End of Abstract) Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENHANCING SUPPORT FOR WOMEN AT RISK FOR HEART DISEASE Principal Investigator & Institution: Toobert, Deborah J.; Research Scientist; Oregon Research Institute Eugene, or 97403 Timing: Fiscal Year 2002; Project Start 12-APR-1999; Project End 31-MAR-2005 Summary: ABSTRACT=The overall goal of this project is to test a practical, theorybased intervention to achieve long-term behavior change for women with Type 2 diabetes at high risk for developing coronary heart disease (CHD). Epidemiological and clinical studies suggest that diabetes is associated with increased risk for CHD that is greater in women than in men. CHD is a major cause of death and functional limitations in women, but the vast majority of CHD studies have primarily involved middle-aged men. There is convincing research evidence that healthy lifestyle behaviors, including low-fat diet, physical activity, stress management, smoking cessation, and social support, can reduce CHD risk. We will conduct a randomized trial to compare shortterm (6-month) outcomes in women receiving usual care compared to a modified Ornish-type comprehensive lifestyle management (CLM) intervention. After 6 months, women in the CLM condition will be randomized to one of two approaches for providing support either lay-led group support or personalized computer-based support - to evaluate these strategies in enhancing longer-term maintenance of effects. Outcomes will include multiple CHD lifestyle behaviors (e.g., dietary intake, exercise levels, stress management, smoking cessation), physiological risk factors associated with CHD (e.g., serum lipids, hypertension, weight, vascular reactivity), HbA1c and quality of life (e.g., depression, functioning). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EPIDEMIOLOGY OF CAROTID ARTERY ATHEROSCLEROSIS IN YOUTH Principal Investigator & Institution: Davis, Patricia H.; Neurology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 30-SEP-1995; Project End 31-MAR-2004 Summary: (Adapted from Investigator's Abstract) The atherosclerotic process begins in childhood and progresses through adult life resulting in coronary heart disease (CHD), stroke, and peripheral vascular disease. There is a need to identify young people at risk for premature atherosclerosis so that preventive measures can be instituted before occlusive vascular disease occurs. The ultrasonic measurement of carotid intimal-medial thickness (IMT) allows detection of early atherosclerosis and is related to incident CHD and stroke in older adults. In 1970, a population of school age children and adolescents was first examined in Muscatine, Iowa. A sample of 776 members of this longitudinal cohort, who are representative of the initial childhood population, is now aged 37 to 45 years. Their risk factors were measured in childhood, young adulthood and twice in later adult life, and they have undergone measurement of carotid IMT as well as electron beam computed tomography to identify coronary artery calcification (CAC). In this cohort, carotid IMT is significantly associated with CAC as well as current LDL cholesterol and systolic blood pressure, but only 14 percent of carotid IMT variability can be explained by these risk factors. Parents of the cohort have been assessed for cardiovascular morbidity and mortality. In this application the investigators propose to do the following: (1) examine the third generation to determine whether the offspring of cohort members with premature atherosclerosis and/or a familial history of cardiovascular disease have increased carotid IMT or elevated risk factors; (2) identify risk factors for progression of carotid IMT over four years in this cohort; and (3) measure putative risk factors for increased IMT (serologic evidence of Clamydia pneumoniae or cytomegalovirus infection, high sensitivity C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 and glycosylated hemoglobin). The investigators state that the study has the potential of providing information which would allow identification of subjects at risk for atherosclerosis at an early age and may lead the way to interventions to halt or slow progression of atherosclerosis prior to the development of clinical disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EPIDEMIOLOGY OF CHD OF MEN AGED 40+ IN US, HAWAII, JAPAN Principal Investigator & Institution: Curb, J David.; Pacific Health Research Institute 846 S Hotel St, Ste 303 Honolulu, Hi 96813 Timing: Fiscal Year 2003; Project Start 05-SEP-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Substantial change toward a more Westernized lifestyle has taken place among younger individuals who were born after World War II (WWII) in non-Western countries including Japan. Data from national sample surveys in Japan clearly demonstrate that risk factor profiles for coronary heart disease (CHD) are very similar to those in the United States (US) in this post WWII cohort. Men in Japan do have a considerably higher prevalence of cigarette smoking and men in the US have a higher prevalence of obesity. CHD mortality among men in Japan is, however, still less than a half of that in the US. Careful review of mortality statistics confirms this. This difference remains unique among industrialized countries. The investigators propose to test the null hypothesis that there are no differences in the extent of atherosclerosis

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among Japanese men in Japan, Japanese American men in Hawaii, and US white and black men in this post WWII birth cohort. This project will be based on recent and ongoing successful Japan/US collaborations in the INTERMAP, INTERLIPID and Honolulu Heart Program studies including development of the first standardized US/Japan diet tables. We will examine 300 white men and 100 black men aged 40-49, randomly selected from Allegheny County, PA, 300 Japanese American men aged 40-49 from the population-based sample recruited from the offspring of the members of the Honolulu Heart Program cohort, and 300 Japanese men aged 40-49, randomly selected from Kusatsu City, Japan. The Japanese recruitment and examination has already been supported in Japan. The extent of atherosclerosis and risk factor profiles for CHD will be evaluated and compared, as well as the relationship of specific risk factors to the measures of atherosclerosis. The measures of subclinical disease proposed include calcium scores of coronary artery and aorta measured by electron beam computed tomography (EBCT) and carotid intima thickness measured by ultrasound. Other proposed measures include dietary intake by food frequency questionnaire, total cholesterol, LDLc, HDLc, lipids by NMR spectroscopy, blood pressure, cigarette smoking, thiocyanate, omega-3 fatty acid, alcohol consumption, body mass index (BMI), intra-abdominal fat, and others. Better understanding the reasons for the low Japanese rates may help us find new methods for prevention of CHD in all populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EPIDEMIOLOGY OF CORONARY CALCIFICATION IN THE ELDERLY Principal Investigator & Institution: Newman, Anne B.; Associate Professor of Medicine and Epid; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 15-AUG-1999; Project End 31-JUL-2006 Summary: Recent studies indicate that coronary artery calcium is a strong predictor of coronary heart disease events in middle- aged men and women. We examined the extent and predictors of coronary artery calcium and its relationship to other noninvasive measures of atherosclerosis in 614 (89 percent) of the surviving cohort from the Pittsburgh center of the Cardiovascular Health Study (CHS). These individuals were ages 67-99 (mean 80). Key findings have been reported and include: 1) Coronary artery calcium scores were strongly age related, yet the range of scores was quite broad. Ten percent had scores of zero. 2) Other noninvasive vascular tests missed many of those with high coronary calcium scores. 3) Other than age, gender and race, traditional risk factors were relatively weak predictors of calcification. We now propose to follow these individuals to determine whether coronary artery calcification predicts cardiovascular disease and mortality in old age, and whether this is independent of other non-invasive measures of disease and traditional risk factors. The alternative hypothesis is that the risk is attenuated in old age, as it may represent stable plaque that is less prone to occlusion or rupture. The CHS is ending the ascertainment of outcomes at the end of 2001, necessitating additional funding for local follow-up of this cohort. In addition to monitoring cardiovascular events, we will evaluate the functional significance of the extent of calcification by an exercise test and will assess progression after 4 years by repeating the EBT scan, and determine the rate of new calcification in those with scores of zero at baseline. Such individuals with no calcium might be regarded as "immune from coronary artery disease." The specific aims are: 1) To determine whether the extent of coronary artery calcium is an independent predictor of total and incident myocardial infarction and total CVD morbidity and mortality in older adults. 2) To determine the

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functional significance of coronary artery calcification in about 312 of these older adults without clinical cardiovascular disease. 3) To determine the rate of progression over 4 years in coronary artery calcium score in an estimated 424 survivors and to determine if those with zero (n=47) develop any calcification. This study can determine the risk of cardiovascular disease events in relationship to coronary artery calcium in older adults in a time-efficient and cost- effective manner that capitalizes on the rich CHS database. This is the largest population study of coronary artery calcium in this older age group, and can rapidly produce definitive data to determine the potential for benefit of screening older adults for coronary artery calcium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EPIDEMIOLOGY OF CORONARY HEART DISEASE OF MEN AGED 40+ Principal Investigator & Institution: Sekikawa, Akira; Epidemiology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 05-SEP-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Substantial change toward a more Westernized lifestyle has taken place among younger individuals who were born after World War II (WWII) in non-Western countries including Japan. Data from national sample surveys in Japan clearly demonstrate that risk factor profiles for coronary heart disease (CHD) are very similar to those in the United States (US) in this post WWII cohort. Men in Japan do have a considerably higher prevalence of cigarette smoking and men in the US have a higher prevalence of obesity. CHD mortality among men in Japan is, however, still less than a half of that in the US. Careful review of mortality statistics confirms this. This difference remains unique among industrialized countries. The investigators propose to test the null hypothesis that there are no differences in the extent of atherosclerosis among Japanese men in Japan, Japanese American men in Hawaii, and US white and black men in this post WWII birth cohort. This project will be based on recent and ongoing successful Japan/US collaborations in the INTERMAP, INTERLIPID and Honolulu Heart Program studies including development of the first standardized US/Japan diet tables. We will examine 300 white men and 100 black men aged 40-49, randomly selected from Allegheny County, PA, 300 Japanese American men aged 40-49 from the population-based sample recruited from the offspring of the members of the Honolulu Heart Program cohort, and 300 Japanese men aged 40-49, randomly selected from Kusatsu City, Japan. The Japanese recruitment and examination has already been supported in Japan. The extent of atherosclerosis and risk factor profiles for CHD will be evaluated and compared, as well as the relationship of specific risk factors to the measures of atherosclerosis. The measures of subclinical disease proposed include calcium scores of coronary artery and aorta measured by electron beam computed tomography (EBCT) and carotid intima thickness measured by ultrasound. Other proposed measures include dietary intake by food frequency questionnaire, total cholesterol, LDLc, HDLc, lipids by NMR spectroscopy, blood pressure, cigarette smoking, thiocyanate, omega-3 fatty acid, alcohol consumption, body mass index (BMI), intra-abdominal fat, and others. Better understanding the reasons for the low Japanese rates may help us find new methods for prevention of CHD in all populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ESTROGEN AND EXERCISE--VASCULAR BENEFITS AFTER MENOPAUSE Principal Investigator & Institution: Brownley, Kimberly A.; Psychiatry; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 15-SEP-2000; Project End 31-AUG-2005 Summary: (Adapted from the applicant's abstract) This application describes a 5-year career development training program for Dr. Kim Brownley. The program includes extensive research and pedagogical training designed to facilitate her growth as an independent researcher investigating combination modality therapies in high-risk cardiac patient populations. The plan is structured around a randomized placebocontrolled study of raloxifene and aerobic exercise training in hypertensive postmenopausal women. Dr. Kathleen Light, whose expertise is in cardiovascular stress responses, hypertension, and hormone (estrogen) replacement therapy (HRT), will serve as mentor. A collaborative support team is also in place, including: 1) Dr. James Blumenthal, who specializes in exercise training interventions in coronary heart disease (CHD); and 2) Alan Hinderliter, M.D. (Cardiology consultant), who will provide training in ultrasound measurement of cardiovascular function, and oversee data interpretation from a clinical perspective. The proposed study will investigate cardiovascular, neuroendocrine, and metabolic functioning in borderline and stage I hypertensive postmenopausal women. This patient group is at increased CHD risk due to elevations in blood pressure (BP), insulin resistance, and low-density lipoproteins. HRT and exercise training can offset these harmful effects by enhancing vasodilatory processes, and their effects may be additive when combined. HRT improves cardiovascular and neuroendocrine function; yet despite these benefits, HRT use and compliance are low because of added cancer risks in some women. Raloxifene, a secondgeneration nonsteroidal selective anti-estrogen, has beneficial lipid and osteogenic effects but does not confer added cancer risks. However, the cardiovascular effects of raloxifene are unspecified. Also, HRT has only modest BP-reducing effects and is thus insufficient antihypertensive therapy for hypertensive postmenopausal women. In contrast, exercise training has robust BP-reducing potential, especially in hypertensive individuals. Therefore, after all subjects complete a 3-month intervention with raloxifene alone, they will be randomized to either an additional 3-month treatment with raloxifene alone or treatment with raloxifene plus exercise training. Pre- and posttreatment assessments will include: 1) impedance cardiography measures of hemodynamic responses to laboratory challenge, 2) 24-hour ambulatory BP and impedance cardiography monitoring, 3) echocardiography assessment of left-ventricular geometry and function, 4) B-mode ultrasound assessment of flow-mediated brachial artery dilatation, 5) assay of neuroendocrine and lipid levels at rest and in response to laboratory stress, and 6) euglycemic insulin clamp to assess insulin sensitivity. Implementation of this training will provide a unique and highly advantageous opportunity for Dr. Brownley to work with this team of senior scientist- practitioners within the collaborative environments of the University of North Carolina and Duke University. This investigation, coupled with the didactic experiences outlined in this plan, will lay the foundation for her future endeavors as a scientific advocate for the systematic investigation of underlying mechanisms of hypertensive heart disease, and for the delivery of effective combination behavioral and pharmacological interventions for stressrelated cardiovascular disorders in patients at increased risk for CHD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ESTROGEN, INFLAMMATION AND CARDIOVASCULAR RISK Principal Investigator & Institution: Reuben, David B.; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): The effects of exogenous estrogen on coronary heart disease are controversial. Substantial observational data support a protective effect and several randomized clinical trials have demonstrated that estrogen produces a more favorable lipid profile. Yet, when administered for secondary prevention in the Heart and Estrogen/Progestin Replacement Study (HERS) and Estrogen Replacement and Atherosclerosis (ERA) trials, estrogen had no overall benefit. In HERS, estrogen use was associated with an increase in early events but a late reduction in risk. These conflicting data suggest the need for additional exploration of the effect of estrogen on the risk factors and precipitants of coronary heart disease. Peripheral blood markers of inflammation, specifically C-reactive protein (CRP) and interleukins, have been increasingly recognized as predictors of cardiovascular events and suggest new pathophysiologic mechanisms. However, the effects of estrogen upon inflammatory markers and their subsequent impact upon endothelial function are still unclear. This study will use data from the NHLBI-funded Postmenopausal Estrogen Progestin Intervention (PEPI) randomized clinical trial to assess the effect of conjugated equine estrogens (CEE) with or without progestins upon two peripheral blood inflammatory markers, CRP and IL-6, and their subsequent effects on other cardiovascular risk factors. We will also examine the relation of exogenous CEE on sex hormone-binding globulin (SHBG), a hepatic protein whose production is independent of inflammation but is stimulated by CEE. Assays for IL-6, CRP, and SHBG will be performed on longitudinal stored serum samples and these results will be linked to extensive socio-demographic, lifestyle, and clinical information already collected in the PEPI clinical trial. We hypothesize that CEE will create unfavorable risk profiles of inflammatory markers (higher IL-6 and higher CRP) during the first year of therapy but these patterns will change toward more favorable profiles (lower IL-6 despite continued higher CRP) with continued treatment. We also hypothesize that the continued stimulation of CRP beyond the first year will be through a non- inflammatory effect on liver protein production (similar to estrogen's stimulation of sex hormone-binding globulin SHBG) rather than IL-6 mediated. These findings may provide substantial insight into why CEE appears to promote early but protect against late cardiovascular effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ETHANOL, NITRIC OXIDE AND CORONARY HEART DISEASE Principal Investigator & Institution: Demaster, Eugene G.; Pharmacology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 30-SEP-2003 Summary: Epidemiological studies conducted over the last several decades consistently show that light to moderate alcohol consumption protects the heart against coronary artery disease. The major protective properties of alcoholic beverages reside with ethanol itself rather than with bioflavinoids/ antioxidants present in some of these beverages, although the latter may possess certain beneficial biological properties distinct from ethanol. Historically, this protection has been attributed to an ethanolinduced increase in one of the subfractions of HDL in plasma; however, this increase in HDL is now regarded to account for only a minor part of the observed protection by ethanol. The antithrombotic properties of alcohol also continue to it beneficial effect, but

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a specific molecular mechanism connecting these properties to alcohol has not been forthcoming. We are proposing that nitric oxide (NO) mediates the protective effects of ethanol on the cardiovasculature, including the antithrombotic properties of ethanol, through the NO-cyclic GMP (cGMP) signal transduction pathway. According to our mechanism, protection by ethanol occurs via an enhancement of the NO activation of guanylate cyclase by products of ethanol metabolism. The key specific objectives of this proposal are to show that (a) ethanol metabolism promotes the catalase-catalyzed oxidation of NO to NO2 and (b) NO2 is a more potent activator of guanylate cyclase than NO itself. We propose that ethanol drives the catalase-mediated NO oxidation reaction via a cascade of well established metabolic conversions that result in increased production of hydrogen peroxide. The two-electron oxidation of NO to NO2 by catalase and the subsequent activation of guanylate cyclase by NO2 are two biochemical steps that we have undertaken to establish as fact. These two steps are critical to our understanding of the overall mechanism for the protection of the cardiovasculature provided by ethanol. Moreover, because ethanol and its metabolites as well as NO alter or regulate cellular processes in almost every tissue and body organ, we anticipate that the biochemical mechanisms described here for the interaction between ethanol and the NO-cGMP signaling pathway likely have relevance beyond the cell types located within the cardiovascular system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EVALUATION OF CHD IN MEN AND WOMEN PRIOR TO FIRST AMI Principal Investigator & Institution: Yawn, Barbara P.; Director of Research; Olmsted Medical Group Box 4300, 210 9Th St Se Rochester, Mn 55904 Timing: Fiscal Year 2002; Project Start 29-SEP-2000; Project End 31-AUG-2004 Summary: Coronary heart disease (CHD) is the leading cause of death in women in the United States. The recent proliferation of studies of woman and heart disease suggest that women may receive less aggressive treatment and thereby missing the important pre- and peri-CHD diagnostic phase. A recent vignette study confirmed a gender bis in proposed evaluation rather than actual practice information. No studies have addressed the possible the possible existence of gender differences in the critical pre- CHD diagnostic phase nor incorporated observed practice data across the total spectrum of primary to tertiary care. This study will focus on the important pre-diagnostic or differential diagnosis (hypothesis activation) phase. We will describe and compare the recorded CHD-related symptoms and their evaluation as well as timing of the CHD diagnosis in women and men during the ten years prior to their first acute myocardial infarction (AMI). In addition, we will describe and compare the evaluation and treatment of CHD risk factors in the ten years prior to the first AMI. These data will allow us to identify gender differences in timing of CHD diagnoses prior to AMI and differences in physician response to men and women's symptoms. Our extensive data collection will allow exploration of the association of other factors such as risk status, comorbidity and age with gender differences in CHD-related testing or treatment. Control subjects (both men and women) who do not have known CHD will provide information on the role of prior probabilities on non-cardiac disease in gender differences in the evaluation of possible cardiac symptoms. The retrospective of look-back design starting at the time of the subject's first AMI, assures that subjects have CHD and will achieve greater efficiency in design than would be possible using a prospective cohort study. It also avoids the Hawthorne effect that might be observed in a clinical trial. Using a unique community population-based dataset maintained for > 70 years on all residents

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of Olmsted County avoids referral bias and will allow access to data from the entire spectrum of care, from primary ambulatory to tertiary hospital care. The information obtained will help fill important gaps in existing knowledge regarding gender differences in the recognition and evaluation of CHD. In addition, we will provide specific information on current gender-related practice patterns. This information can be used to inform future practice recommendations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FHS--CENTRAL LABORATORY Principal Investigator & Institution: Eckfeldt, John H.; Lab Medicine and Pathology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 1999; Project Start 15-AUG-1996; Project End 31-JUL-2004 Summary: (Adapted from the applicants' abstract) FHS: Molecular Genetics and Genetic Epidemiology is submitted collaboratively by seven research groups including four clinical sites (University of North Carolina; Boston University; University of Minnesota; and University of Utah), a molecular biology laboratory (University of Utah), a coordinating center (Washington University, St. Louis, MO), a chemistry laboratory (University of Minnesota). The proposed study will perform state-of-the-art molecular genetic and genetic epidemiology studies using the extensive data on family and medical histories, risk factors, life style, blood specimens and banked DNA, previously collected by the Family Heart Study (FHS). The purpose is to identify and characterize genes of coronary heart disease (CHD) and atherosclerosis, familial environmental factors and behavioral characteristics, and to advance our understanding of how they interact with one another in the development of clinical outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FOLIC ACID & HOMOCYSTEINE-- DOSE RESPONSE STUDY Principal Investigator & Institution: Beresford, Shirley A.; Professor; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: We will examine chronically stressed individuals (spouse caregivers of persons with Alzheimer's disease (AD). Spouse caregivers lose the companionship and support of their AD spouses. These losses, coupled with chronic physical, emotional and financial demands (1, 2) as well as biobehavioral vulnerabilities, put spouse caregivers at increased risk for psychophysiological distress and physical health problems (3). In previous work with caregivers and matched controls, we studied a variety of psychobehavioral (e.g., hassles, anger/hostility, exercise, diet) and physiological measures. Of the metabolic, cardiovascular (CV), and immune measures examined, metabolic variables (Body Mass Index/obesity, insulin, and glucose) showed the strongest relationships with caregiving, whereas CV measures showed some relationships. These results lead us to focus now on metabolic/neuroendocrine measures. Such measures qualify as mediators of the relationship between caregiving and coronary heart disease (CHD) because they are related to both stress and CHD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FRAMINGHAM OFFSPRING STUDY: PSYCHOSOCIAL RISK FACTORS Principal Investigator & Institution: Eaker, Elaine D.; Eaker Epidemiology Enterprises, Llc 8975 County Rd, V Chili, Wi 544209506 Timing: Fiscal Year 2002; Project Start 01-MAY-2001; Project End 31-OCT-2003 Summary: (Provided by Applicant) The outstanding design and methods of the Framingham Offspring Study offers the next major step in understanding how behavioral, psychological, and social factors not only contribute to health and illness, but also interact with biological factors to influence health outcomes. A unique data set of social, psychological, and behavioral measures were collected at the third examination of the Offspring Study from 1984 through 1987 (which results in 14 to 17 years of follow-up). Hypotheses for this research are focused toward understanding the sex and age differences in the effects these variables have on health endpoints. The research questions involve the prediction of three separate endpoints: incidence of coronary heart disease; the incidence and prognosis of atrial fibrillation; and total mortality. The analyses of psychosocial predictors for these outcomes are divided into four conceptual areas: 1) occupational status and strain, income, and employment status; 2) type A behavior, expressions of anger, hostility, and rate; 3) symptoms of depression, tension, anxiety, and feelings of aloneness; and 4) marital relationships and marital strain. These psychosocial variables will be analyzed jointly with the physiological risk factors collected at the same time to assess independence and interaction of effects. To date these psychosocial data have not been analyzed or published. There are many studies that have examined the associations between psychological and social characteristics and cardiovascular morbidity and mortality. Findings from these studies, however, are often conflicting and may result from inadequate study designs (e.g., case-control where psychosocial assessment takes place after the health event of interest), use of different measures or scales, study of noncomparable populations, or defining different outcomes. The strength of the Framingham Study involves longitudinal data collection; large numbers of both men and women; a standard and thorough follow-up protocol; careful assessment of heart disease and mortality endpoints; collection of information on other risk factors for disease and death concurrently with psychosocial risk factors (enabling the examination of and control for confounding or causal pathways); and the ability to examine the interrelationships between a number of different psychosocial risk factors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE-BY-SMOKING ATHEROSCLEROSIS

INTERACTION

AND

RISK

OF

Principal Investigator & Institution: North, Kari E.; Epidemiology; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2006 Summary: (provided by applicant): While cigarette smoking is a well-established and potent risk factor for atherosclerotic vascular disease, individual susceptibility to smoking varies considerably, suggesting modifiers such as genomic variation. Several key enzymes involved in the activation and detoxification of mutagenic tobacco smoke compounds, oxidative stress, and DNA damage are expressed in the tissues of the heart and vasculature and represent mechanistic pathways for tobacco-induced pathology. Many of these enzymes have common polymorphisms (greater than or equal too 10% prevalence in the population) with known functional effects. Although restricted to a

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few enzymes and hampered by shortcomings in design, a small number of studies have suggested that enzymatic activation and detoxification of tobacco smoke modifies the risk of certain cardiovascular outcomes associated with cigarette smoking. The main goal of the proposed study is to evaluate common genetic polymorphisms that, in combination with exposure to tobacco smoke, may modify the risk of atherosclerosis and its clinical sequelae. An average of six polymorphisms, selected on the basis of their prevalence and functional significance, expression in relevant tissues, evaluation in previous studies and biologic plausibility, within 19 genes involved in activation, detoxification, oxidative stress, and DNA repair pathways will be evaluated as an ancillary study to the Atherosclerosis Risk in Communities (ARIC) study. In this wellcharacterized, bi-ethnic cohort of 15,792 men and women under active follow-up since 1987-89 (completeness of follow-up 96%), five endpoints quantifying subclinical atherosclerosis and validated clinical atherosclerotic events will be studied in casecohort/case-control mode: incident coronary heart disease, carotid atherosclerosis, peripheral arterial disease, incident stroke, and MRI-detected cerebral infarcts. The proposed investigation is well designed to study how DNA sequence polymorphisms can promote or inhibit the atherogenic effects of smoking and the risk of clinical events, and to contribute new knowledge on the role of genetic variation in the response to environmental insults and toxicants. The findings are expected to be of clinical and public health significance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE-DIET INTERACTIONS AND HEART DISEASE Principal Investigator & Institution: Campos, Hannia; Nutrition; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: Evidence is building from epidemiological and laboratory investigations to support the hypothesis that genetic variation can modulate the effect of dietary intake on metabolic parameters to promote atherosclerosis and increase the incidence of coronary heart disease (CHD). Technological advances in molecular and nutritional epidemiology now make it possible to study gene-diet interactions and CHD in human populations at a new level of sophistication. The overall goal of this project is to carry out a population-based case-control study in 2,150 cases of myocardial infarction and 2,150 matched controls from Costa Rica, to test specific hypotheses relating gene-diet induced atherosclerosis susceptibility (GDAS) markers to CHD. Twelve GDAS markers were selected for this study. GDAS markers are defined as common genetic variants that modulate the effect of intake of specific fatty acids, tocopherols, and carotenoids on atherosclerosis. We will determine whether carriers of the GDAS marker variants are at increased risk of CHD compared to wild type homozygotes when exposed to high intakes of lauric 12:0, myristic 14:0, and palmitic 16:0, and trans fatty acids particularly 18:2 trans from partially hydrogenated soybean oil. We will study whether high intakes of alpha-linolenic acid, vitamin E, carotene, particularly alpha- carotene, lutein, and lycopene reduce the risk of CHD, and whether the GDAS marker variants alleles lessen this protective effect. In secondary analyses, we will test the hypotheses that the GDAS variant alleles influence the effect of dietary fiber, cholesterol, physical activity, and smoking on CHD. Haplotypes of metabolically related GDAS markers that are better predictors of CHD than individual markers alone will be established, and for each haplotype, we will determine specific adverse dietary patterns. Dietary exposure variables will be evaluated by simultaneous analyses of a semi-quantitative food frequency questionnaire, and biochemical measures of intake including adipose tissue

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tocopherols and carotenoids by HPLC, and fatty acids, including trans isomers of partially hydrogenated soybean oil by GC. This study will provide the most complete data set to study numerous hypotheses relating genes, diet, and CHD, and could lead to specific targeted interventions for reducing the development of CHD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETICS OF INSULIN RESISTANCE IN PCOS: THE PPAR PATHWAY Principal Investigator & Institution: Talbott, Evelyn O.; Faculty; Epidemiology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 30-JUN-2005 Summary: (provided by applicant): Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by chronic anovulation, hyperandrogenism, and insulin resistance with an estimated prevalence of 5-10% among all women. Family studies have indicated a genetic predisposition to the development of PCOS and several candidate PCOS susceptibility genes have been explored. Thus far, pedigree studies have mainly focused on steroidogenic pathway dysfunction in women with little success in determining a genetic basis for PCOS. It has more recently been postulated that insulin resistance, rather than hyperandrogenism, is the central defect in PCOS. Peroxisome proliferator-activated receptor gamma (PPAR [gamma]) has been indicated as a potential candidate gene for insulin resistance in Type 2 diabetes. No studies to date have focused on the PPAR. pathway and insulin resistance in PCOS probands and their family members. Given the high prevalence of PCOS and its association with coronary heart disease, PCOS may represent the largest, unique group of women at high-risk for the development of coronary heart disease (CHD). Thus understanding the etiology of PCOS may have a large public health impact for women. This pilot study will examine extended pedigrees by analyzing linkage using both parametric and non-parametric methods in five multigeneration, multiplex families (N= 125). We will explore genetic mechanisms through the following specific aims by: (1) demonstrating our ability to enroll both PCOS probands and their multi generation, multiplex family members to study insulin resistance markers in families with PCOS and (2) genotyping five probands and their multigeneration, multiplex family members for single nucteotide polymorphisms (SNPs) at or near candidate genes P12A and IRS-1 and microsatellite markers near candidate genes lipoprotein lipase and acetyI-CoA carboxylase, to test for linkage of PCOS with these candidate genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TREATMENTS

GENHAT-GENETICS

OF

HYPERTENSION

ASSOCIATED

Principal Investigator & Institution: Arnett, Donna K.; Associate Professor; Epidemiology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 31-AUG-2004 Summary: The Genetics of Hypertension Associated Treatments (GenHAT) is proposed as a prospective study to examine whether the association between selected hypertensive genes and combined fatal coronary heart disease and nonfatal myocardial infarction in high-risk hypertensives is modified by the type of antihypertensive treatment, leading to differential risks of coronary heart disease (CHD). Such genetreatment interactions might shed important light On the variation in patient response

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to antihypertensive agents, and improve our ability to pick the right antihypertensive for specific patients. GenHAT will be an ancillary study to ALLHAT (the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial). ALLHAT recruited 42,515 hypertensives and randomized them to one of four antihypertensive agents (lisinopril, chlorthalidone, amlodipine, and doxazosin); followup will be completed in March, 2002. GenHAT will characterize hypertension genetic variants and determine their interaction with antihypertensive treatments in relation to CHD. DNA from frozen clots stored at the ALLHAT Central Laboratory will be used to genotype variants of hypertension genes (angiotensinogen -6, angiotensin converting enzyme insertion/deletion, angiotensin type- 1 receptor, alpha-adducin, beta2 adrenergic receptor, lipoprotein lipase, and 10 new hypertension variants expected to be discovered during the course of the study). In addition to the primary aim, a number of secondary aims will be undertaken to evaluate genetreatment interactions in relation to other endpoints, including all-cause mortality, stroke, heart failure, left ventricular hypertrophy, decreased renal function, peripheral arterial disease, and blood pressure lowering. Because of the ethnic and gender diversity of ALLHAT, we will also assess effects of these variants on outcomes in key subgroups (age >65 years, women, African Americans, Type II diabetics), and whether the gene-treatment interactions in relation to outcomes are consistent across subgroups. This proposal has the advantages of (1) incorporation into an already funded clinical trial, and (2) collaboration with experienced investigators in genetic analysis (Drs. Boerwinkle and Eckfeldt) and clinical trials (Drs. Davis and Ford). It will, therefore, provide an important and cost-efficient contribution to the knowledge and understanding of the treatment of hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEART DISEASE IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Gabriel, Sherine E.; Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: (Applicant's Abstract) The hypotheses to be tested in this proposal are built on findings from two intriguing, but rather disparate lines of investigation. The first is the recent data suggesting that the excess mortality experienced by people with rheumatoid arthritis (RA) may result from increased rates of coronary heart disease (CHD) among RA patients compared to the general population. The second is the rapidly growing body of evidence indicating that chronic systemic inflammation (such as that which occurs in RA) plays an important role of chronic inflammation in CHD. We propose 3 specific aims to investigate this subject: First, we will use a cohort study to test the hypothesis that the incidence of acute MI (the central manifestation of CHD) is higher in RA subjects compared to controls. Second, we will identify high-risk RA subgroups and, using a novel adaptation of the case-cohort design, investigate interactions between RA and the major CHD risk factors (e.g. smoking, hyperlipidemia, exogenous estrogens). Third, we will conduct studies on archived autopsy heart tissue to test the hypothesis that coronary atherosclerosis is more extensive in RA subjects compared to matched controls. A unique set of circumstances allows us to address each of these aims rigorously and efficiently. We will incorporate and extend our already assembled population-based RA incidence cohort and identify validated definite acute MI outcomes using the cardiovascular surveillance techniques developed through out NIH-funded companion study, "Coronary Disease Morbidity and Mortality in a Population" (HL59205). Our population-based data resources, with essentially complete enumeration of a geographically defined population, allowed us to design an analytic

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plan which nearly quadruples the statistical power of our risk factor analyses, compared with typical cohort analyses. Third, the availability of extensive autopsy material (the autopsy rate in this community is four-fold higher than the national rate and all autopsies have been performed at the same center since 1930) provides us with a unique opportunity to assess the pathologic characteristics of atherosclerosis among RA subjects compared to controls. When combined with our experienced multidisciplinary investigative team, these resources lend us a capability, not available elsewhere, to rigorously examine the risks and determinants of coronary heart disease in patients with RA. These results will lay the foundation for a program of research aimed at elucidating the mechanisms for CHD in RA patients and at improving our understanding of the role of inflammation in the pathogenesis of CHD in the general population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEART FAILURE IN THE COMMUNITY Principal Investigator & Institution: Roger, Veronique L.; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2003; Project Start 15-JAN-2003; Project End 31-DEC-2006 Summary: (provided by applicant): Heart failure (HF) is designated as an emerging epidemic. Yet, it is not fully characterized. Most data, derived from hospital discharges, cannot measure incidence, have uncertain validity and cannot capture the full burden of HF because of the shift towards outpatient care. Regarding its etiology, the respective role of hypertension and coronary heart disease (CHD) is controversial. Moreover, the prevalence of obesity and diabetes mellitus is increasing, both conditions linked to HF via several mechanisms such that their contribution to HF could conceivably be increasing but remains to be examined. Finally, while the existence of diastolic HF is recognized, its diagnosis is exclusionary based on symptoms of HF in the absence of LV systolic dysfunction. This approach is unsatisfactory, thus the contribution of DHF to HF remains contentious. These striking gaps in knowledge underscore the necessity of a rigorous investigation of the HF epidemic. Through surveillance of the Olmsted County community, we demonstrated the postponement of CHD towards older ages and the decline over time in the severity of hospitalized MI and the incidence of HF after MI. This implies that, if CHD is the main cause of HF, HF should be postponed towards older ages and its incidence rate relatively stable. During the same period, preliminary findings on HF surveillance suggest that the incidence of first clinical diagnosis of HF may not be increasing as much as implied by hospital discharges and that adverse trends may be occurring preferentially among younger ages. These data from the same community are challenging to reconcile with the concept of an ongoing major contribution of CHD to an epidemic of HF, thereby underscoring the need to rigorously study the epidemiology of HF, which is the focus of this application. We propose 3 specific aims and a community surveillance approach, integrated with our ongoing work on CHD surveillance to investigate the HF epidemic in Olmsted County by characterizing its magnitude and determinants and studying prospectively the contribution of DHF. Aim 1 will estimate the secular trends in the incidence and in the outcome of validated HF to test the hypotheses that there has been an increase in the incidence of HF, which differs by age and sex and that the survival of HF improved while hospitalization for HF has increased. Aim 2 will use a case-control approach to characterize the etiology of HF and its changes over time to test the hypotheses that CHD and hypertension confer an excess risk of HF, the magnitude of which is declining over time, that obesity and diabetes mellitus confer an excess risk of HF the magnitude

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of which is increasing and that the population attributable risk of CHD and hypertension for HF is declining, while that of obesity and diabetes mellitus is increasing over time. Aim 3 will prospectively characterize the contribution of DHF to HF using brain natriuretic peptide (BNP) among persons with HF and define the prognostic value of BNP in all cases of HF. Thus, the completion of these aims will provide important insights into the epidemiology of HF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEART CARDIOVASCULAR

RATE

VARIABILITY

AND

OUTCOME

IN

THE

Principal Investigator & Institution: Stein, Phyllis K.; Professor; Barnes-Jewish Hospital Ms 90-94-212 St. Louis, Mo 63110 Timing: Fiscal Year 2002; Project Start 05-FEB-2000; Project End 31-AUG-2003 Summary: We will investigate whether standard and newer indices of heart rate variability (HRV) enhance the prediction of clinical and functional outcomes in the Cardiovascular Health Study (CHS). The CHS, an NIH-sponsored population-based longitudinal study of the risk factors for coronary heart disease and stroke in 5,201 men and women aged 65 years and older, includes ambulatory ECG recordings on a subset of 1432 participants at baseline, repeated in 862 during exam year 7-8, and recordings in an additional 387 minority participants in exam year 5. Although measurement of HRV, which quantifies beat-to-beat changes in the normal rhythm of the heart, was among the original purposes of the ambulatory ECG monitoring, only a limited index (5-minute averaged time domain HRV) was determined, and beat-to-beat data were not saved. Thus a more in depth analysis of HRV is impossible without re-analyzing the tapes. Time domain indices of HRV provide generalized information about cardiac autonomic modulation, but frequency domain indices of HRV, because they partition the variance in the heart rate into distinct frequency bands, provide a more precise picture and can provide insights into circadian patterns of the autonomic modulation of the heart. Also, frequency domain HRV has been a better predictor of outcome than time domain HRV. Heart rate tachograms will be generated which reveal periodic and other heart rhythms. The prognostic value of newer HRV indices which provide information independent of that from standard HRV will be determined. To perform frequency domain and other analysis of HRV in the CHS, the tapes will be re-scanned and the beat-to-beat data saved in electronics format. In addition to determining if HRV enhances prediction of outcome in the CHS, the detailed relationship between cardiac autonomic modulation and clinical and functional health in the CHS will be investigated. The changes in HRV over time in healthy older adults will be determined. We will investigate whether there is an effect of gender or race on the relationship between HRV and aging in healthy adults. Clinical outcomes will include cardiovascular and non-cardiovascular morbidity and mortality. Health may also be defined as maintaining the ability to carry out activities of daily living for as long as possible. Therefore, we will also consider the predictive value of HRV for functional status and describe the detailed HRV profile of those who are functionally healthy at baseline and remain so upon follow up. Furthermore, the data generated will provide the basis for a number of studies about HRV and clinical and functional parameters that otherwise would require a large number of separate investigations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HOSTILITY, MARITAL INTERACTION AND HEALTH IN AGING Principal Investigator & Institution: Smith, Timothy W.; Department Chair; Psychology; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: Hostility confers increased risk of coronary heart disease, presumably through the mechanism of cardiovascular reactivity to interpersonal stressors. Marriage is an important context for this mechanism. However, an adult developmental perspective suggests that marital conflict may be a more central issue for trait hostility among middle- aged spouses, whereas the stress of collaboration may be important for hostility in older couples. Guided by a model of individual, spouse, and couple effects of hostility, the proposed study examines the effects of hostility on immediate behavioral and psychophysiological responses to marital conflict and collaboration, and on health outcomes of ambulatory blood pressure, coronary artery disease, marital adjustment, and cognitive functioning. The major aims are to examine (a) how the effect of hostility on behavioral and cardiovascular responses may differ for middle-aged and older adults, during conflict and collaborative problem solving, (b) the effect of hostility on ambulatory blood pressure and coronary artery disease, and (c) the role of hostility in the frequency and quality of collaborative problem solving. One-hundred and fifty middle-aged (40-50 years) and 150 older married couples (60-70 years) will be involved in a 4-day study. Hostility will be measured in a multi-method approach with interview, self-report, and spouse report measures. Marital interaction will be examined as couples discuss a source of marital conflict and solve a planning task. Interaction will be coded for components typical of interactions of hostile persons and also detrimental to collaborative cognition. Psychophysiological reactivity will be examined via blood pressure, heart rate, and impedance cardiography during the two tasks. The effects of hostility will be examined on health outcomes such as coronary artery disease (assessed via computed tomography) ambulatory blood pressure, marital adjustment, and general cognitive function (e.g., fluid and crystallized intelligence). The long-term goal of the research is to identify potentially modifiable determinants of cardiovascular risk, marital adjustment, and cognitive aging in adulthood. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMPACT OF LIFESKILLS TRAINING ON BLOOD PRESSURE IN YOUTH Principal Investigator & Institution: Barnes, Vernon A.; Williams Lifeskills, Inc. 2020 W Main St, Ste 100 Durham, Nc 27705 Timing: Fiscal Year 2003; Project Start 25-SEP-2003; Project End 31-AUG-2004 Summary: (provided by investigator): Essential hypertension (EH) affects one out of four adults and is a primary risk factor for coronary heart disease (CHD), the leading cause of death in the US. Essential hypertension (EH) has its patho-biologic origins in childhood. Since blood pressure (BP) ranking tracks from late childhood onward, adolescents with high normal BP are at risk for development of EH. Clinical research has shown behavioral interventions to have great promise in reducing BP levels. To date few such programs targeting students have been implemented in the high school setting. This application requests support to adapt the Williams LifeSkills (WLS) workshop (a protocol-driven 12-session stress/anger management workshop) for use in high schools. This study will develop an innovative intervention designed to reduce ambulatory BP, BP reactivity to stress, hostility, anger, and school-related problem behaviors among a population of adolescents with high normal BP. The specific aim of

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Phase I is to identify adaptations in format and timing necessary to successfully conduct the 12-session WLS Workshop in a high school setting. This aim will be accomplished through-- a) focus groups and interviews with students to guide fine-tuning of the program content; b) conducting two pilot cycles of workshop, to obtain feedback from the students regarding course content, style of presentation and materials. This project will adapt a highly developed anger/stress management program that will become available for Health Education curriculums in schools across the country. If successful, this project presents a tremendous potential for not only reduction in hostility, anger and school-related conduct problems, but more importantly for prevention of cardiovascular disease via reduced BP and a concomitant enormous reduction in health care costs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INFLAMMATORY MARKERS AND IMPROVING CHD RISK ASSESSMENT Principal Investigator & Institution: Wilson, Peter W.; Professor of Endocrinology; Medicine; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2003; Project Start 19-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): This application responds to laboratory, analytical, and collaborative components mentioned in the RFA. Specifically, we propose to integrate epidemiological risk factor information with a decision analytical approach, using existing data sets and stored biological specimens, and establishing a multidisciplinary collaboration between the FHS, Boston University Medical Center, Boston University Mathematics Department and the Tufts University Human Nutrition Research Center on Aging. Aim 1. To test the utility of homocysteine (tHcy) (to be measured), C-reactive protein (CRP) (to be measured), lipoprotein (a) [Lp(a] (already determined) as predictors of coronary heart disease (CHD) over and above traditional risk factor measures. Levels of these markers will be determined with a nested case cohort design, utilizing a baseline examination that includes already obtained information on conventional risk factors for the Framingham Offspring and 12 years of follow up for cardiovascular disease events. New measurements of hsCRP will be made in the Framingham laboratory and homocysteine will be done at Tufts University by Dr. Jacob Selhub. Aim 2. To test the ability of new factors (tHcy, CRP and Lp[a]) at different levels of coronary risk as assessed by using the traditional risk factors alone, considering 0-6%, 6-20% and >20% initial risk of a coronary event. The utility of newer risk measures to predict an increase in the absolute risk of coronary events at pre-specified absolute levels of risk will be estimated. Aim 3. To develop new CHD risk prediction equations that will incorporate CRP and homocysteine measurements to assess the risk of coronary heart disease. This aim will include estimates of CHD risk over 12 years for the second generation Offspring and will incorporate data from the older first generation cohort where homocysteine and CRP have already been measured and 12 years of follow up for coronary disease events is also available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: JAPANESE AMERICAN COMMUNITY DIABETES STUDY Principal Investigator & Institution: Boyko, Edward J.; Professor; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002

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Summary: This longitudinal study examines the relationship of environmental factors in the development of the insulin resistance syndrome (hyperinsulinemia, central obesity, glucose intolerance, hypertension, dyslipidemia, and coronary heart disease) in Japanese Americans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LAY CHD REPRESENTATIONS AND WOMEN'S SELF REFERRAL FOR MI Principal Investigator & Institution: Martin, Rene E.; Psychology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: This application seeks three years of support to investigate how lay people's cognitive representations of coronary heart disease (CHD) contribute to delays in seeking medical are for symptoms of myocardial infarction (MI), with an emphasis on female victims. In a correlational study, 1,114 post-MI patients and approximately 777 support providers will be interviewed. Analyses will (1) identify gender differences in pre- hospital symptom perceptions, symptom attributions, self-care activities, treatmentseeking behaviors, and perceptions of CHD vulnerability and the implications of such gender differences in self-referral for acute MI; (2) examine the impact of social influence processes in the lay evaluation of cardiac symptoms, including gender differences in information- seeking, advice received from support providers, and pre-hospital interactions with individual possessing medical expertise; and (3) determine whether gender differences in the response to acute MI symptoms are manifested even after controlling for victim age, ethnicity, education, prior CHD knowledge and experience, socioeconomic status, medical status, living arrangements, social support network, and other individual differences. The proposed research will focus on differences in lay CHD cognitive representations that may account for intervention after the onset of cardiac-related symptoms. The proposed project will provide fundamental information to nurses and other health care providers about how the lay interpretation of cardiac symptoms is influenced by the victim's gender, age, and other factors. Finally, the knowledge gained from the proposed project is likely to represent a vital contribution in the development of programmatic nursing interventions targeted at the facilitation of self-referral behaviors and the provision of optimal health care to both women and men at risk of CHD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MARITAL ADJUSTMENT, DEPRESSION AND MYOCARDIAL INFARCTION Principal Investigator & Institution: Gallo, Linda C.; Psychology; San Diego State University 5250 Campanile Dr San Diego, Ca 92182 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Depression and Coronary Heart Disease (CHD) are each prevalent disorders, which frequently co-occur. Approximately 15-23% of individuals recovering from a heart attack (e.g., myocardial infarction; MI) will meet criteria for major depression and up to 65% will experience elevations in depressive symptoms. Yet, history of depression and disease severity are only moderately predictive of this co-morbidity. Importantly, depression is embedded within social context and, in particular, depression is strongly associated with marital adjustment. The primary goal of the current research is to examine if individuals with worse marital

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adjustment experience higher levels and a more persistent course of depressive symptoms following MI, in a 6-mo, 3-wave, prospective study of 150 men and women. Some research suggests that marital distress and depressive symptoms are more closely linked in women than in men. Therefore, the current research will examine if gender moderates the associations between marital adjustment and level and course of depression, with the hypothesis that associations will be stronger for women than for men. Previous research suggests that depression and possibly marital adjustment represent risk factors for negative physical health outcomes following MI. Further, when psychosocial risk factors occur in combination, the probability of negative outcomes is likely to increase substantially due to additive or synergistic effects. A secondary goal of the study will therefore be to examine the joint and independent effects of depression and marital adjustment on quality of life, functional status, and the probability of recurrent events following Ml. Women may experience worse outcomes following MI, and psychosocial factors could contribute to this trend. The proposed research will therefore examine if gender moderates the relationships between depression, marital adjustment, and health outcomes following CHD, with the hypothesis that effects will be stronger for women than for men. The broader goal of the proposed research is to identify aspects of social functioning that could represent potent, modifiable risk factors for CHD and depression co-morbidity, in the hopes of informing more effective prevention and intervention efforts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODERATE ALCOHOL USE & HEALTH: PREFERENCES & OUTCOMES Principal Investigator & Institution: Mukamal, Kenneth J.; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 25-SEP-1999; Project End 31-AUG-2004 Summary: This proposal seeks a Mentored Patient-Oriented Research Career Development Award. The candidate proposes to use this award to foster a research career in the study of the effect of moderate alcohol consumption on specific health measures. The aims of the career development plan are fourfold: (1) to develop methodologic expertise in eliciting personal preferences and values from individuals, particularly related to alcohol use; (2) to gain experience in quantifying the effect of behavioral factors on designated health outcomes amongst groups of patients; (3) to develop expertise in the use of decision analysis to inform patient decision-making by combining personal preferences and outcomes data; and (4) to use the results of these studies to establish research independence. In a structured program, the applicant will receive formal training at the Harvard School of Public Health and graduated supervision from Murray Mittleman, MD, DrPH, an active investigator in the behavioral determinants of heart disease at Beth Israel Deaconess Medical Center in Boston. These career development goals closely parallel the research plan, which will employ them as they are mastered in succession. The overall aim of the research program is to understand how individuals view the competing risks and benefits of moderate alcohol consumption and how those competing factors actually influence health. The research program will comprise three related studies: (1) development of a survey instrument to be administered by the applicant to patients in different outpatient settings to determine their preferences about moderate alcohol consumption and its effects; (2) analysis of the effect of alcohol use on survival following acute myocardial infarction in the Determinants of Myocardial Infarction Onset Study; and (3) assessment of the populationwide effect of moderate alcohol use on total mortality with the Coronary

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Heart Disease Policy Model, using the survey results to refine the applicability of the Policy Model findings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR EPIDEMIOLOGY OF ESSENTIAL HYPERTENSION Principal Investigator & Institution: Boerwinkle, Eric A.; Professor; Human Genetics Center; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 08-JUL-1994; Project End 31-MAY-2004 Summary: Increased arterial blood pressure [BP] in the absence of known causes, essential hypertension [EHYT], is a significant risk factor for coronary heart disease, cerebrovascular disease and renal disease, and reaches epidemic proportions in both non-Hispanic Whites and African-Americans in the United States. In the previous cycle of this research, we evaluated the influence of variation in established candidate genes on variation in BP levels in the population at large and carried out the first genome wide linkage analysis to identify new BP candidate genes (i.e. positional candidate genes). In this proposed cycle of research, we will use DNA sequencing to identify variation in the coding and regulatory regions of newly identified positional candidate genes, and carry out association analyses between this DNA sequence variation and BP levels and EHYT status. In Aim 1, we will use high through-put DNA sequencing in 24 non-Hispanic Whites and 24 African-Americans to identify DNA sequence variation in the coding and 5' regulatory regions of each positional candidate gene. To accomplish Aim 2, we will type the variable sites identified in Aim 1 in a sample of 573 randomly ascertained threegeneration pedigrees containing 3,938 individuals from Rochester, MN, and 515 hypertension cases and 471 normotensive controls from Jackson, MS. We will then use graphical and statistical methods, including transmission disequilibrium tests [TDTs] and regression tree methods, to evaluate the relationship between the DNA sequence variation and the distribution of systolic and diastolic BP and EHYT status. We will also determine whether the influence of the genetic variation is homogeneous among strata defined by gender, age, body size, smoking status and population. The studies proposed here will move us one step closer to defining functional allelic variation influencing interindividual variation in BP levels and the risk of developing EHYT in the population-at-large. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MONITORING COMMUNITY TRENDS IN HEART FAILURE Principal Investigator & Institution: Goldberg, Robert J.; Professor; Medicine; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): Heart failure is a syndrome of profound clinical and public health importance. Heart failure (HF) is estimated to contribute to nearly 1 million hospitalizations and approximately 250,000 deaths annually in the U.S. The number of new cases of HF in the U.S. is estimated to exceed 400,000 annually. Though reliable estimates of the magnitude, incidence, and mortality of HF remain sorely lacking, HF is associated with a grim prognosis. However, little recent data exist, particularly from a community-wide perspective, to determine whether the incidence or survival associated with HF, and the management of this clinical syndrome, has changed over time. This study proposes to examine temporal trends (1995 and 2000) in the incidence rates of HF, its therapeutic management, and changes over time in the hospital and long-term survival of patients with HF from a multi-hospital, population-

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based perspective. The study will take place in residents of the Worcester (MA) metropolitan area (1990 census 437,000) and will examine changes over time in these and additional outcomes for patients with validated HF during 1995 and 2000. Complimenting the hospital surveillance of HF, newly diagnosed cases of HF occurring in members of the largest HMO in Central Massachusetts during 1995 and 2000 will be identified and monitored over time. The proposed project will build on the investigators' clinical and epidemiological experience and on data collection efforts and methodologies used in the ongoing community-wide study of coronary heart disease in greater Worcester residents. To accomplish the study objectives, the medical records of residents of the Worcester metropolitan area hospitalized with a discharge diagnosis of HF and related diagnostic rubrics will be individually reviewed and validated according to pre-established diagnostic criteria. The use of traditional criteria for HF as well as development of new criteria for the epidemiological study of HF will be an important focus of this observational study. Records for additional hospitalizations and death certificates will be reviewed to examine trends in long-term survival of discharged hospital patients through the year 2005. The results of this study will provide much needed information about the epidemiology of HF from a more generalizable population-based perspective. Information would be provided about the clinical and descriptive epidemiology of this prevalent and disabling condition in men and women and individuals of different age groups. The proposed surveillance system will provide insights and guidance to public health and clinical efforts of HF and in monitoring trends in this newly emerging chronic disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NURSING INTERVENTIONS TO REDUCE CORONARY RISK Principal Investigator & Institution: Becker, Diane M.; Professor of Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: A. Hypotheses Studies, primarily in white populations, have demonstrated that only 50-70% of premature coronary heart disease (CHD) is accounted for by known traditional risk factors (hypertension, dyslipidemias, and smoking). Several newly identified "nontraditional" risk factors appear promising in explaining a greater portion of CHD. We have shown that occult disease can be identified in asymptomatic apparently healthy siblings of persons with CHD prior to 60 years of age. Certain risk profiles discriminate those with and without occult disease. Further, occult disease at baseline has predicted subsequent CHD events. Virtually no family studies have included a sufficient sample of African Americans. Our hypotheses are proposed for the 480 African American brothers and sisters of persons with premature CHD being accrued in a new National Heart Lung and Blood (NHLBI) Intervention Study commencing April 1, 1998. Hypothesis 1: Traditional risk factors (hypertension, hypercholesterolemia, low HDL cholesterol, obesity (BMI >27), current smoking, increased left ventricular mass and glucose will be significantly associated with occult coronary ischemia. Hypothesis 2: Nontraditional risk factors elevated levels of serum insulin, fibrinogen, apolipoprotein B, homocysteine, and Lp(a)) will be significantly associated with occult coronary ischemia. Hypothesis 3: There will be a significant relationship between abnormal carotid wall intimal thickness and /or carotid plaque and the presence of occult coronary ischemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OCCUPATIONAL HEALTH GRADIENTS IN HOSPITAL WORKERS: THE Principal Investigator & Institution: Blanc, Paul D.; Professor of Medicine; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 28-SEP-2000; Project End 31-AUG-2005 Summary: (Taken from the Investigators' Abstract) Socioeconomic gradients in health status are ubiquitous in space, persistent in time, and pervasive across diverse health outcomes. Yet little is known of how they arise, and specifically, how great a contribution is made to them by working conditions during adult life. Existing occupational cohort studies, such as the landmark Whitehall publications, have failed to convince some observers that work-related "psychosocial" exposures, e.g., the degree of control felt by employees over their jobs, constitute the key causal influences responsible for socioeconomic gradients in the health of the general adult population, especially gradients in chronic disease. Largely missing in the debate thus far is high-quality evidence on gradients from workplaces with a wide range of jobs -- Whitehall, for example, is fundamentally an office worker study. The present proposal is premised on the view that rich insights into the genesis of such health "gradients" may be gained by studying in detail, over some years, a workplace, such as a hospital, that has a very wide range of jobs, and of employees from different social classes. By far the major "shortterm" occupational health problem of this workforce, and many others, is work-related musculoskeletal disorders (WRMSDs) -- a broad class of outcomes including low back pain and upper extremity injuries, such as tendinitis and carpal tunnel syndrome. Both psychosocial and physical-ergonomic exposures at work are now thought to be joint determinants of these musculoskeletal problems. Thus, psychosocial aspects of work are increasingly recognized as risk factors for both sorts of illness processes: traumatic and chronic disease. Yet there appears to be a dearth of research linking socioeconomic and job-category disparities in the risk of WRMSDs, with well-known gradients in many longer-term health outcomes, particularly coronary heart disease and its risk factors (such as hypertension). The investigators propose a study to shed light on the nature and multi-factorial etiology of hospital gradients, across job categories and employee social class backgrounds, in the occurrence of several potentially work-related health outcomes in hospitals. The outcomes studied will be lost-time, work-related musculoskeletal disorders, non-invasive measures of allostatic load (salivary cortisol and blood pressure), overall health-related quality-of-life and injury-specific functional status, mental health status, and total sickness/injury absence from work. The influence of both directly observed physical-ergonomic factors at work and psychosocial occupational exposures on socioeconomic gradients in the risk of these conditions will be assessed. Finally they propose to examine, through qualitative research methods, the social contextual factors within participating hospitals, which influence working conditions. The study team will also work with a labor-management team to develop possible interventions for the problems that are identified by this study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OXIDATIVE MODIFICATIONS OF PROTEINS AND FIBRINOGEN IN ATHEROGENESIS Principal Investigator & Institution: Ischiropoulos, Harry; Associate Professor; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 31-MAR-2007

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Summary: (provided by the applicant): A potential major cause of vascular injury leading to the development of atherosclerosis is oxidative stress. Oxidative stress is the result of overproduction of reactive species that overwhelms the cellular antioxidant capacity leading to inactivation of key cellular functions and ultimately to cell death. Proteins are major targets of reactive species, and nitration of tyrosine residues is a selective protein modification induced by reactive nitrogen species in human disorders as well as animal and cellular models of disease. We have discovered that circulating fibrinogen is nitrated in patients with acute respiratory distress syndrome (ARDS). Nitration of fibrinogen significantly altered the function of fibrinogen by accelerating the rate of fibrin clot formation producing of fibrin clot with abnormal structure upon electron microscopic examination. Fibrin deposits are abundant in the lungs of patients with ARDS, a common complication of hemorrhagic injury and sepsis, and likely the result of abnormal clotting rather than failure in the fibrinolytic pathways, which are functioning normally in ARDS patients. A number of epidemiological studies have indicated that high levels of circulating fibrinogen is an independent predictor of coronary heart disease and in some cases of premature death from cardiovascular and heart disease although a causative correlation between high levels of fibrinogen and cardiovascular disease has not been established. Based on these data we developed the hypothesis that plasma protein nitration is a marker of oxidative stress and independent predictor of coronary heart disease and that nitration of fibrinogen is a critical posttranslational modification responsible for abnormal functioning of the hemostatic system in atherosclerosis. To test the critical aspects of this hypothesis we propose to: 1) Quantify by the use of LC-MS the levels of 3-nitrotyrosine, dityrosine, the oxidation product of tyrosine and 3- chlorotyrosine, a marker of inflammation, in plasma proteins of smokers and nicotine users (Project 1), subjects in the prospective study of progression in coronary plaque burden (Project 5), the Apobec-l/LDLR double knock out mouse (Project 1) and in the plasma of mice with altered ApoA-I levels (Project 5). Evaluate the degree of nitration of specific proteins, fibrinogen, LDL/ApoB-100, and determine the site(s) of tyrosine nitration by the use of the Proteomics Core. 2) Evaluate the effects of nitration and/or oxidation on the biochemical, biophysical and viscoelastic properties of fibrinogen and fibrin clots by the use of scanning and transmission electron microscopy, and a Plazek torsion pendulum. 3) Determine the effect of nitration on critical functional aspects of fibrinogen and fibrin clot, ADP-induced platelet aggregation, endothelial cell gene expression (Genomics Core), endothelialinflammatory cell interaction (in collaboration with Project 3), and kinetics of fibrinolysis. Overall this project is focused on investigating the possible biochemical and biophysical mechanisms that may underline abnormalities in the hemostatic factors that regulate critical pro- and anti-thrombotic functions in human cardiovascular disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PDAY CARDIOVASCULAR SPECIMEN AND DATA LIBRARY Principal Investigator & Institution: Strong, Jack P.; Boyd Professor and Head; Pathology; Louisiana State Univ Hsc New Orleans New Orleans, La 70112 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JUL-2003 Summary: (Adapted from the applicant's abstract) This project is for the maintenance of the specimen and data base emanating from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) and Risk Factors in Early Human Atherogenesis (RFEHA) studies (PDAY Archive) so that it can be used effectively by investigators for continued study of atherosclerosis during the next five years. PDAY and RFEHA were investigator-initiated multi-center cooperative studies based on a rigidly developed

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protocol, which had anatomically standardized samples of aorta and coronary arteries of 3,000 young black and white subjects, age 15-34, who died suddenly of trauma. Risk factor data was also obtained in a majority of the cases. So far these studies have yielded over 75 publications by the PDAY group. These reports in turn have generated a widespread enthusiastic response from investigators throughout the scientific community in the U.S. and abroad. Many of these investigators are currently utilizing or planning to utilize the PDAY Archive as a resource for their studies on atherosclerosis and coronary heart disease. This unique resource, the PDAY Archive, should continue to contribute in important ways to our understanding of atherosclerosis, the underlying cause of coronary heart disease (CHD) and most strokes. CHD and stroke are by far the leading cause of debilitating illnesses and death in this country. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PERIODONTAL DISEASE AND RECURRENT CHD EVENTS Principal Investigator & Institution: Trevisan, Maurizio M.; Professor and Chair; Social and Preventive Medicine; State University of New York at Buffalo Suite 211 Ub Commons Buffalo, Ny 14228 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 30-JUN-2005 Summary: (Adapted from the Investigator's Abstract) This study will analyze the association between periodontal disease and recurrent coronary heart disease (CHD) in individuals who have survived a myocardial infarction (MI). The overall goal is to test the hypothesis that periodontal disease is a significant and independent risk factor for recurrent CHD events. In addition potential mechanisms linking periodontal disease to CHD events will be investigated. At baseline 1,200 participants will undergo a detailed interview and health examination that will include information on lifestyle, sociodemographic, and anthropometric variables and CVD risk factors, and a complete oral health examination including measurement of clinical attachment levels and radiographic assessment of interproximal alveolar crestal height. The two aims are to examine the association between recurrent heart disease and periodontal disease as measured by gingival attachment level and radiographic assessment, and to examine the association between recurrent heart disease and levels of bacterial infection. Participants will be followed prospectively annually for an average of 3 years. The investigators state that the proposed study should provide important new information about the temporal association between periodontal disease and CHD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PLANT-BASED DIETRY INTERVENTION IN TYPE 2 DIABETES Principal Investigator & Institution: Barnard, Neal D.; Physicians Committee for Responsible Med Responsible Medicine Washington, Dc 20016 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Diabetes often leads to serious complications, including coronary heart disease, kidney disease, and blindness, among others. Previous studies have suggested that low-fat, plant-based diets can have a strongly favorable effect on the management of type 2 diabetes mellitus, as well as on the elevations of body weight and serum cholesterol that often accompany it, reducing the risk of complications, and raising the possibility of reducing or even eliminating medication use for many individuals. Evidence suggests that the dietary recommendations that are most effective in diabetes management may be similar to the low-fat, vegetarian diets that have demonstrated utility in reversing coronary artery

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blockages. However, no study to date has examined the effect of a low-fat, vegetarian diet as an intervention for diabetes in a substantial number of participants, and most studies using plant-based (near-vegetarian) diets have also included exercise as a major intervention component, making it impossible to separate the effects of physical activity from those of diet or to reach any definitive conclusion as to which type of dietary intervention is best. This study, which follows an encouraging preliminary trial reported in Preventive Medicine in 1999, will test the hypothesis that a low-fat, vegetarian diet yields significant improvements in key indices of diabetic control, including glycosylated hemoglobin, fasting serum glucose and insulin concentrations, microalbuminuria, and medication requirements, as well as in cardiovascular risk factors, such as body weight, serum lipids, and blood pressure, in a 22-week intervention controlled throughout for exercise, with a 1-year follow-up. Sixty-eight volunteers with type 2 diabetes will be randomly assigned to a low-fat, vegan (intervention) diet or a control diet deriving 15-20percent of energy from protein and < 7percent of energy from saturated fats, with carbohydrate and monounsaturated fats together providing 60-70percent of energy intake, based on current American Diabetes Association guidelines. Participants in both groups will be asked to attend weekly meetings for nutrition and cooking instruction and group support, and will be asked not to alter their exercise patterns. Physical activity will be monitored by use of the Bouchard 3-Day Physical Activity Record. (Bouchard 1983) Diets will be assessed at baseline and 11, 22, and 74 weeks, using a 3-day dietary record. Fasting serum glucose will be monitored for the study duration and will be used to adjust medications according to a set protocol. Glycosylated hemoglobin, insulin concentrations, 24-hour urinary albumin, body weight, blood pressure, serum lipids, and related cardiovascular risk factors will be measured at baseline, 22 weeks, and 74 weeks. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREDICTING SYSTOLIC BP CONTROL IN THE ELDERLY Principal Investigator & Institution: Bailey, Kent R.; Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2004 Summary: NHANES III data show that fewer than 30% of patients who are hypertensive have been treated to the goal blood pressure of less than 140/90 mm Hg. Older patients are more likely to have uncontrolled blood pressure than are younger patients. The SHIELD Study revealed that 41% of people over the age of 65 years and 65% of African Americans over that age have poorly controlled hypertension. Poor blood pressure control also disproportionately causes cardiovascular disease in patient over 60. Systolic blood pressure is the primary predictor in this age group for the development of stroke, congestive heat failure (most common reason for hospitalization in the elderly), renal failure and coronary heart disease. There is even exciting new data showing that control of systolic blood pressure in the elderly reduces the risk for the development of Alzheimer?s dementia. Failure to achieve blood pressure control is determined by three factors: physician practice (behavior), antihypertensive medication efficacy, and adherence to the prescribed medications (patient factors). Our study proposes to develop models that describe each of these factors independently and then develop a model that encompasses all three factors. Specific Aim 1 will identify and quantify differences in physician response to elevated systolic blood pressure in hypertensive patients greater than 60 years of age compared to their younger counterparts. Specific Aim 2 will analyze the differences in responsiveness of systolic blood pressure to treatment regimens using one or more antihypertensive medications. Specific Aim 3

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examines adherence and postulates that adherence is the same between younger and older hypertensives. This study is to be conducted using a unique clinical database. Over 7,000 patients with more than 25,000 observations are present in the Mayo Clinic Rochester Hypertension Continuity Clinic Database. This Sybase database is well constructed to answer the important questions posed in Aims 1-3 regarding the management of hypertension. This study will provide significant and generalizable answers to the question of why control rates for systolic hypertension remain low and will provide direction for altering clinical practice to reduce cardiovascular morbidity and mortality among older hypertensives. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROSPECTIVE STUDY OF HEALTH IN RUNNERS AND WALKERS Principal Investigator & Institution: Williams, Paul T.; Nuclear Science Division; University of Calif-Lawrenc Berkeley Lab Lawrence Berkeley National Laboratory Berkeley, Ca 94720 Timing: Fiscal Year 2002; Project Start 01-JUN-1998; Project End 31-MAY-2004 Summary: (Adapted from Investigator's Abstract) Current government physical fitness guidelines state that: 1) the majority of the health benefits from physical activity can be obtained by walking 2 miles briskly on most days of the week; and 2) the health benefits of physical activity depend principally on the total amount of activity rather than the intensity of the activity. Nevertheless, there are currently no prospective epidemiological studies extant, designed specifically to directly contrast the health benefits and costs of moderate exercise (e.g., walking) versus vigorous exercise (e.g., running). The proposed study plans to compare rates of coronary heart disease (CHD), cancer, total mortality and exercise injuries in 68,000 runners and 68,000 walkers during four years of surveillance. Questionnaires concerning running and other physical activities in 56,000 runners have already been obtained, and additional questionnaires from 13,000 runners are expected before March 1997. The runners will be resurveyed in 1997 along with 68,000 walkers. The walkers will also be solicited through the publication of the questionnaire in Walking magazine followed by a direct mailing of the questionnaire to 425,000 subscribers. Total and cause-specific mortality will be determined from the National Death Index; fatal and nonfatal cancers will be identified from the SEER and 46 state registries; nonfatal coronary heart disease and injuries will be determined from questionnaires. Survival analyses will be used to test whether runners have greater reduction in heart disease, total mortality, and cancer per unit of exercise. Exercise-related injuries from walking and running will also be examined. Power calculations suggest that detection of differences between runners and walkers, as small as 11% for total mortality, 16% for CHD, 12% for total cancers, and 36% for breast cancer, will be possible. The differences will be adjusted for weekly kilocalories expended by walking and running, for walking and running distance, and for time spent on each activity to test whether these variables account for differences in disease rates between walkers and runners. Before the start of the study, 233,000 person-years of follow-up in 56,000 runners (between 1991 and 1997) will have been accumulated. By the end of the study, 517,000 person years in 68,000 runners (between 1991 and 2001) will be available for analysis. Survival analysis will be used to test for a dose-response relationship between running mileage and CHD and cancer risk, and whether this relationship is affected by running intensity, running frequency, running history, gender, adiposity, age or medication use. Using conservative rates (25% below published values), statistical power calculations suggest that detectable reduction in coronary heart disease risk as small as 0.71% per mile will be possible, which is far

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below the estimated reduction from other published studies (2.1%). Additionally, a detectable reduction in breast cancer risk as small as 1.5% per mile run in women is calculated, which is below the 1.7% reduction in risk estimated from other published data. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTECTION FROM CARDIAC REPERFUSION INJURY BY ETHANOL Principal Investigator & Institution: Gray, Mary O.; Assistant Professor of Medicine; Northern California Institute Res & Educ 4150 Clement Street (151-Nc) San Francisco, Ca 941211545 Timing: Fiscal Year 2002; Project Start 30-SEP-1996; Project End 31-MAR-2007 Summary: (provided by applicant): Moderate alcohol intake has been shown to reduce coronary heart disease in numerous epidemiological studies. We propose that moderate ethanol consumption causes cardioprotection by increasing epsilonPKC protein expression in cardiac myocytes. To test this hypothesis, we will use multiple approaches to examine resistance of ischemia-reperfusion injury in hearts receiving ethanol in drinking water for at least 12 weeks. In addition, we will investigate the requirement for epsilonPKC function in ethanol-mediated cardioprotection using techniques routinely available in our laboratory with the following specific aims: Aim A: Examine epsilonPKC enzyme activity and subcellular localization in hearts from ethanol-fed mice and age-matched controls. We plan to identify ethanol-induced changes in epsilonPKC kinase function and distribution among subcellular compartments in adult cardiac myocytes and in left ventricular tissue from ethanol-fed mice and age-matched controls using immunofluorescence staining, confocal microscopy, immunoprecipitation, and western blotting techniques. Aim B: Determine whether acute isozyme-selective inhibition of epsilonPKC function blocks sustained ethanol-mediated cardioprotection. We will examine the effects of peptide modulators of PKC isozyme translocation and function introduced acutely into cultured adult cardiac myocytes or intact hearts on chronic ethanol-induced resistance to ischemia-reperfusion injury and PKC interactions with other signaling proteins. Aim C: Investigate the effects of moderate alcohol consumption on cardiac function and resistance to ischemia-reperfusion injury in epsilonPKC knockout mice. We will use adult cardiac myocytes and intact hearts to determine whether cardioprotection develops in epsilonPKC knockout mice in response to ethanol feeding and whether ethanol-mediated regulation of related signaling pathways is altered by the absence of epsilonPKC. One overall goal of this research is to understand the cellular mechanisms of cardioprotection mediated by chronic moderate alcohol consumption. A second goal is to identify therapeutic targets for sustained protection against coronary heart disease that do not require ethanol ingestion because of concerns regarding alcohol abuse and potential adverse effects on other organ systems in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: QUANTIFICATION OF HEART BETA ADRENERGIC RECEPTORS Principal Investigator & Institution: Muzic, Raymond F.; Radiology; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2005 Summary: (Adapted from applicant's abstract): Health Relevance: Beta-adrenergic receptors (beta-ARs) play a fundamental role in the regulation of heart function.

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Changes in the amount and binding properties of beta-ARs are implicated in coronary heart disease, congestive and ischemic heart failure, cardiomyopathy, sudden death, arrhythmia, and mitral valve disease. Drugs that interact with the beta-ARs, betablockers, are widely prescribed to treat heart disease. Since the in vitro behavior of receptors often differs from their in vivo behavior, a method to assess beta-ARs in vivo is essential for improving our understanding and treatment of heart diseases. Moreover, a relatively noninvasive test could be used to assess patients individually. Proposed Work: a significant component of the tissue uptake of (S)-[18F]fluorocarazolol as measured by positron emission tomography (PET) reflects specific binding to beta-ARs. However, it also reflects nonspecific uptake, radioactive metabolites in the myocardium, and possibly uptake related to the norepinephrine transporter. Therefore, quantitative assessment of beta-AR specific binding and of beta-AR concentration requires a mathematical model of fluorocarazolol pharmacokinetics. To formulate this model, details of fluorocarazolol pharmacokinetics will be clarified via in vitro and in vivo experiments (Aims 1 to 2) and via computer simulation to compare compartmental and distributed pharmacokinetic models (Aim 3). A mathematical model of fluorocarazolol pharmacokinetics will be formulated in accordance with the results of Aims 1 to 3. This model will then be used to analyze PET data collected from pigs with normal and elevated concentrations of beta-AR. The validity of the model and its utility to assess beta-AR concentration and binding properties in vivo will be evaluated based on comparison to results obtained via in vitro assay of myocardial samples (Aim 4). Significance: Although [11C]CGP 12177 has been used to estimate myocardial beta-AR concentration in vivo, there are numerous advantages for using [18F]fluorocarazolol. Perhaps the most significant is that fluorocarazolol reaches internalized receptors whereas CGP 12177 does not. Completion of the proposed work could lead to a method for estimating the fraction of receptors that are internalized. It would entail two PET experiments using [18F]fluorocarazolol; one at baseline and one following administration of unlabeled 9commercially available) CGP 12177 to block surface receptors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RESPONSIVITY OF HOMOCYSTEINE TO BEHAVIORAL STRESS Principal Investigator & Institution: Emery, Charles F.; Associate Professor; Psychology; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 10-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Homocysteine is putative risk factor for coronary heart disease (CHD). It is an amino acid associated with endothelial damage, which may cause direct injury to intimal cells and assist in the deposition of lipoproteins within atherosclerotic lesions. Homocysteine is bound to lipoproteins. Although several psychological characteristics are associated with CHD, few investigations of psychological risk factors and homocysteine exist. We have shown that homocysteine increases during stress, and that hostility is positively associated with resting homocysteine. The major goals of this proposal are to investigate the etiological significance of stress-induced and personality-associated elevations in homocysteine; to evaluate the relationship between lipids and homocysteine during stress; and to test one viable mechanism for homocysteine reactivity. Study 1 will test whether the stressassociated increases in homocysteine are etiologically meaningful, by comparing individuals with above average risk for CHD (based on American Heart Association/American College of Cardiology recommendations and family history), to those at below average risk. This study will also build on our earlier findings, by

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comparing homocysteine reactivity among high hostile individuals to low hostile individuals. Study 2 will test whether individuals with exaggerated homocysteine reactivity have greater stress-induced alterations in vitamin B6, vitamin B12, and folate than do those with smaller homocysteine reactivity. An additional purpose of this study will be to test whether individuals given B vitamin supplements for 4 weeks prior to an acute stressor display smaller elevations in stress-induced homocysteine, relative to individuals given placebo. Because homocysteine is bound to lipoproteins, and because it appears to modify the atherogenicity of low density lipoprotein, both studies will test the relationships between homocysteine and lipid reactivity. The results of this research will extend the available but limited data testing the impact of stress and hostility on homocysteine concentrations; will allow one test of the etiological significance of stressrelated homocysteine elevations; will allow us to examine the relationship between lipid reactivity and homocysteine reactivity; and will test a viable mechanism for the homocysteine elevations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE ATHEROGENESIS

OF

CHLAMYDIA

PNEUMONIAE

INFECTION

IN

Principal Investigator & Institution: Kuo, Cho-Chou; Professor; Pathobiology; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-APR-1997; Project End 31-MAR-2004 Summary: (Adapted from the Applicant's Abstract): Chlamydia pneumoniae (TWAR) is a common human respiratory pathogen. In recent years, there has been mounting evidence showing that this organism might play a role in atherosclerosis. Because coronary heart disease is a leading cause of death in this country, the overall goal is to investigate the immunopathogenic mechanisms by which C. pneumoniae infection contributes to the development of vascular disease. The proposed studies will exploit our recent findings from mouse model studies linking C. pneumoniae infection and atherosclerosis and in vitro cell culture studies on C. pneumoniae infection of arterial wall cells. The mouse models that will be used are C57BU6 and strains derived from this background strain including, apoE-deficient and TNF-A receptor and apoE double knockout mice. Atherosclerosis in C57BU6 mice can be induced by feeding with a high fat/high cholesterol diet, while apoE mice develop atherosclerosis spontaneously on a regular diet. The specific aims are to 1) further evaluate the synergistic effect of C. pneumoniae infection and hyperlipidemia on atherogenesis by infecting mice with C. pneumoniae followed by feeding animals with a high fat/high cholesterol diet and measuring the atherosclerotic lesion development using computer assisted morphometry; 2) study the effects of C. pneumoniae infection on key components in the inflammatory process of atherosclerosis that promote atherosclerotic lesion development by recruiting lymphocytes/macrophages and eliciting inflammatory responses at lesion sites. In vitro, in vivo, and ex vivo systems will be used to assay the expression of leukocyte adhesion molecules and adherence of macrophages to the endothelial surface. The effect of TNF-A on lesion development will be investigated by infecting TNF-A receptor and apoE double knockout mice and measuring lesion development using computer assisted morphometry; 3) assess the role of macrophages in the establishment of persistent C. pneumoniae infection of atheromatous lesions using cell culture to analyze vascular cell interactions and the effect on infectivity, growth and persistence of C. pneumoniae, and characterize the growth of C. pneumoniae in macrophages loaded with low density lipoproteins (foam cells). The proposed studies should prove invaluable for understanding the disease process and

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developing better measures for eradication or prevention of C. pneumoniae infection and for reducing atherosclerosis and coronary heart disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SLEEP HEART HEALTH STUDY Principal Investigator & Institution: O'connor, George T.; Associate Professor; Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 30-SEP-1994; Project End 31-AUG-2004 Summary: The Sleep Heart Health Study (SHHS) was started in 1994 as a multicenter cohort study of the cardiovascular consequences of sleep-disordered breathing (SDB). The study's principal aims are to assess SDB as a risk factor for adverse cardiovascular outcomes, including incident coronary heart disease events, stroke, and hypertension, and accelerated increase in blood pressure with age. The SHHS protocol added an assessment of SDB to ongoing cohort studies of cardiovascular and other diseases, including the Framingham Offspring and Omni cohorts, the Hagerstown and Minneapolis/St. Paul sites of the Atherosclerosis Risk in Communities (ARIC) Study, the Hagerstown, Sacramento, and Pittsburgh sites of the Cardiovascular Health Study (CHS), the Strong Heart Study (SHS) sites South Dakota, Oklahoma, and Arizona, and cohort studies of respiratory disease in Tucson and of hypertension in New York. During its first four years (1994-1998), the SHHS was successfully started with full and high quality polysomnography (PSG) data obtained in the home from 6,440 participants, exceeding the recruitment target. The SHHS cohort, includes 3,039 men and 3,401 women 40 years of age or more, of whom 8.2 percent are African American, 9.6 percent are Native American, 1.3 percent are Asian, and 4.2 percent are Hispanic. In addition to PSG, data collection covered snoring and sleepiness and quality of life (QOL). Outcome assessment protocols are in place for all cohorts and the second SHHS examination is now in progress. Initial cross-sectional findings show that SDB is common and associated with hypertension and self-reported cardiovascular disease (CVD). This application requests five years additional support to continue the SHHS. Further followup is needed to have sufficient power to test the primary SHHS hypotheses. Additionally in Years 7-9, PSG will be repeated to further characterize SDB in the participants and to describe the natural history of SDB. During the first five years, the SHHS has shown that large-scale research on sleep, SDB, and disease risk can be conducted in the community. Follow-up of the SHHS cohort will provide the data needed to characterize the cardiovascular consequences of SDB, along with its natural history. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: STRESS REDUCTION AND CVD MORBIDITY AND MORTALITY-II Principal Investigator & Institution: Schneider, Robert H.; Dean; None; Maharishi University of Management Db 1133 Fairfield, Ia 52556 Timing: Fiscal Year 2003; Project Start 15-AUG-1992; Project End 31-JUL-2007 Summary: (provided by applicant): African Americans suffer from disproportionately high rates of cardiovascular disease morbidity and mortality compared to white Americans. Substantial evidence indicates that high levels of psychosocial and socioenvironmental stress contribute to the excessive morbidity and mortality in this population. In earlier controlled trials with African Americans and other populations at high risk for CVD, the current collaborative team demonstrated that a selected stress reduction approach, the Transcendental Meditation (TM) program, was associated with

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significant reductions in CVD risk factors and surrogate markers for clinical CVD. These include clinically significant decreases in hypertension, myocardial ischemia and carotid atherosclerosis, as well as improvements in psychosocial stress and quality of life. In the previous NHLBI-sponsored clinical trial, 201 African American men and women with documented coronary heart disease (mean age 59 years) were randomized to either stress reduction with the TM program or a health education control. The results showed 50 percent lower risk of combined mortality and CVD morbidity in the stress reduction group compared to control (RR =.50, p

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

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End-Stage Renal Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

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Tay-Sachs Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Cushing's Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

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Gallbladder Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

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