NATIONAL HEART, LUNG, AND BLOOD INSTITUTE NATIONAL INSTITUTES OF HEALTH MINUTES OF THE SPECIAL EMPHASIS PANEL ON HEART AND VASCULAR DISEASES RESEARCH OPPORTUNITIES March 26, 1997 Conference Room 6, Building 31 National Institutes of Health Bethesda, Maryland Panel Members Present: Dr. Peter Libby (Chairperson) Dr. H. Scott Baldwin Dr. Robert O. Bonow Dr. Bernard Gersh Dr. Gary H. Gibbons Dr. Richard P. Lifton Dr. Suzanne Oparil Dr. Thomas A. Pearson Dr. Robert Roberts Dr. Renu Virmani Dr. Samuel A. Wickline Dr. Michael J. Horan (Executive Secretary) National Heart, Lung, and Blood Institute Staff Present: Ms. Shirley Agnew Dr. Frank D. Altieri Dr. Deborah Applebaum-Bowden Dr. Winifred Barouch Dr. Alan Berson Dr. Michael Commarato Dr. Patrice Desvigne-Nickens Dr. Paul Didisheim Dr. Rosalie Dunn Dr. Paula Einhorn Dr. Abby Ershow Dr. John Fakunding Ms. Janet George Dr. Stephen Goldman Dr. David Gordon Dr. Marie Green Ms. Tina Higginbotham Dr. Christine Kelley Dr. Alan Levine Dr. Isabella Liang Dr. Michael Lin Dr. Teri Manolio Dr. Judith Massicot-Fisher Dr. Stephen C. Mockrin Dr. Susan Old Dr. Gail Pearson Dr. Leslie Reinlib Dr. Basil Rifkind Dr. David M. Robinson Ms. Beth Schucker Dr. Sonia Skarlatos Dr. Alfred Small Dr. George Sopko Dr. Peter Spooner Dr. Paul Velletri Dr. Lan Hsiang-Wang Dr. Momtaz Wassef Dr. John T. Watson Dr. Constance Weinstein Visitors: Dr. Jeffrey Moak, Childrens National Medical Center, Washington D.C. Call to Order and Opening Remarks Dr. Michael Horan, Director of the Division of Heart and Vascular Diseases, called the meeting to order at 8:30am, March 26, 1997. The meeting had been announced in the Federal Register and was open to the public. This Special Emphasis Panel (SEP) was organized to advise the National Heart, Lung, and Blood Institute (NHLBI) and the Division of Heart and Vascular Diseases (DHVD) on NHLBI's extramural research program in heart and vascular diseases. Dr. Horan reviewed the objectives and operational format of the meeting. The Conflict of Interest Statement was read. The Panel members, staff and meeting attendees were introduced. Dr. Horan also reviewed the agenda and the material provided to the Panel. Consideration of Initiatives Dr. Peter Libby, chairperson of the Special Emphasis Panel, reviewed the agenda and the organizational aspects of the meeting. The Panel members had been invited to identify scientific areas within the Division's purview which may need further stimulation and represent exciting new opportunities. DHVD had specifically invited each Panel member to be prepared to propose a research initiative(s) (written or oral) or topic. The Panel discussed each initiative in detail and provided the following comments. 1. Cardiac Cell Apoptosis in Heart Failure (RFA) The objective of this initiative is to foster research on molecular, cellular, and genetic approaches to elucidate the role of apoptosis in the pathological processes leading to heart failure. The goals of this research are to assess the degree to which apoptosis contributes to cardiac dysfunction in heart failure and to elucidate the apoptotic signaling pathways that operate the myocardium. Dr. Roberts stated that apoptosis is an important event and its role in heart failure is uncertain at present. He also stated that apoptosis is a normal part of cardiac growth development. There is increasing evidence that stimuli that induce cardiac growth such as pressure, or myocardial infarction are consistently associated with simultaneous upregulation of genes that induce apoptosis. Our level of knowledge on the role of apoptosis in the heart and the growth response is probably where hypertrophy was 20 years ago. While everyone on the panel agreed that research on apoptosis is very exciting and timely, the question was raised as to whether there is a need for an initiative since there is considerable research being performed in this area. Nevertheless, the work currently being performed is diffuse and most of it is not concerned with the heart. Dr. Roberts added that the proposed initiative should also deal with cardiac development model (e.g. chick) and an appropriate large animal model. Dr. Gibbons concluded that this was an important question, it has a good clinical application, the literature is at a descriptive stage and much needs to be done with respect to the cardiovascular system as well as the heart. 2. Institutional Research Training Program in Integrative Research (PA) The objective of the Institutional Research Training Program in Integrative Research is to support hands-on training programs in the area of heart, blood vessels, lung, and blood diseases designed to integrate and coordinate the methods of classical in vivo physiology in relevant whole animal models and/or tissues, and clinical investigations, with the new techniques of basic cellular and molecular research. Trainees would conduct research projects which include the use of the most modern techniques in cellular and molecular biology, biochemistry, cell physiology, immunology, isolated tissues, and whole animals. Dr. Oparil stated that there is a "tremendous need" for this type of research, and enthusiastically supported the initiative. She suggested the possibility of some type of cooperation or partnership with industry since many of the candidates doing integrative research will go to industry. Other Panel members were highly supportive of this initiative and gave it the highest priority. 3. Cellular and Genetic Interrelationship of Atherosclerosis and Hypertension The goal of this initiative is to encourage basic research on cellular and genetic mechanisms leading to: 1) the concurrent development of high blood pressure and atherosclerosis or 2) pathways by which either one of these conditions might influence the severity of the other. Research efforts at the molecular level are ongoing for each of these conditions separately, but little investigation is currently directed at studying the interaction of high blood pressure and atherosclerosis. Dr. Libby stated that although there are various research groups focused in this area, there is definitely a need to take this research to the next level integrating the different research groups. Dr. Oparil agreed that integrative research was needed. 4. Pediatric Arrhythmia Registry of RF Catheter (RFP) This proposed initiative intends to establish a five year follow-up registry for pediatric cardiology patients who have undergone cardiac catheterization procedures for the ablation of an arrhythmia using radiofrequency (RF) energy. The objective of this follow-up is to determine whether: 1) RF ablation can be safely used in all age subgroups of pediatric patients, 2) the arrhythmia originally treated with RF ablation will recur, and 3) whether the incidence of other cardiovascular abnormalities is higher in children treated with RF ablation. This initiative was developed a few years ago and enthusiastically recommended. Several members of the pediatric electrophysiology community who originally helped develop this initiative have contacted NHLBI to say that they believe that a registry of patients who suffer lethal arrhythmias as a sequela of open heart surgery for certain congenital heart malformations is more important than the RF ablation registry. A pilot registry has been initiated without NIH support and the details of the study design were supplied with Dr. Moak's letter to the Panel. The Panel was asked to review the new proposal. The Panel stated that there have been large NHLBI supported registries for adults with arrhythmias but none for children. RF ablation is being performed on children under one year of age. The Panel asked whether there is a minimum age below which this procedure should not be performed. Also, what are the long term effects on a growing heart? For children who have had corrective surgery for congenital heart disease there is no way to predict which of them will suffer arrhythmias and sudden cardiac death, often years after surgery. A registry could provide long term study data and possibly lead to rational bases for prognosis. The Panel concluded a design should be created to combine these two concepts into one registry. 5. Developmental Aspects of Blood Pressure Control The goal of this initiative is to encourage research on factors that influence how blood pressure is controlled during the maturation process, how these factors may lead to hypertension, and how their detection and correction early in life may help alleviate or prevent high blood pressure. There was general agreement that this initiative addresses a neglected area of research. However, this initiative was thought to be too broad and that the areas of scientific research should be rewritten to focus the scope of proposed work. Emphasis should be placed on adult animal models. The initiative therefore requires editing but should be ready to move forward within the near future. 6. Unstable Plaque For some time the NHLBI has been considering possible approaches to encourage work in this important area. With the recent arrival of the Report of the Working Group on Arterial Thrombosis, interest has been reawakened. An initiative developed by the DHVD, entitled "Molecular and Physical Characterization of the Unstable Atherosclerotic Plaque" deals with some aspects of the cell biology and physiochemistry involved, and includes new ways of imaging. A separate initiative, developed by DECA, entitled, "Etiology of Unstable Plaque" as the title implies, deals with the epidemiology of the phenomenon. Dr. Wassef reviewed the materials provided to the Panel. He described the DHVD initiative on "Molecular and Physical Characterization of the Unstable Atherosclerotic Plaque". The objective of this initiative is to support research into the properties of the unstable atherosclerotic plaque, especially those that relate to its tendency to progress and to rupture, leading to unstable angina, thromboembolic events, myocardial infarction, and/or sudden death. Dr. Manolio presented the DECA initiative entitled "Etiology of Unstable Plaque". Rupture and subsequent thrombosis of unstable coronary plaques have been implicated in the majority of acute myocardial infarctions, but little is known about the factors leading to development of unstable plaque. The proposed study is designed to identify potential etiologic factors for unstable plaque, as identified by fibrous cap thinning and echolucency of plaque core on intravascular coronary ultrasound (IVUS), in coronary disease patients undergoing invasive procedures. The Panel was asked to consider whether the two initiatives may be merged. The Panel concluded that each of the two initiatives is taking a different perspective, but they are complementary to each other and address an important area of research. Both initiatives were favorably recommended, but they should remain separate. For the DHVD initiative, the Panel endorsed the need for a multidisciplinary approach, and pointed out that it is a high pay inclusion of research dealing with mechanistic issues underlying superficial plaque erosion and gender differences. They concluded that the initiative is "ripe" and ready for implementation. The panel pointed out that the DECA initiative was focused, but will provide useable information. Some panel members raised a number of technical problems and questioned the ability of the intravascular ultrasound instrumentation to adequately define plaque morphology, specifically to measure the thickness of the fibrous cap. In summary, the Panel recommended further development of these initiatives with enthusiasm. 7. Optimal Treatment of Chest Pain with Endothelial Dysfunction and No Coronary Atherosclerosis The syndrome of chest pain and "normal" coronary arteries is known to carry significant morbidity and medical care cost and to be minimally controlled with standard anti-ischemic therapy. The overall objective of this study is to determine if risk factor modifications, with or without arginine supplementation, will reestablish normal endothelial function and reduce the chest pain syndrome in patients with arteriographically insignificant coronary atherosclerosis. The study would enroll patients 35-65 years old with angina as defined as typical or minimally atypical by the Rose Questionnaire after arteriography documenting coronary arteries with no stenosis > 50%. A study to measure a defective endothelial-dependent vasomotor response of the brachial or other arterial bed will be performed at baseline and at intervals after therapy. Patients will be characterized as to their risk factors and those with LDL-cholesterol levels >120 mg/dl will be randomized to placebo or an HMG-CoA inhibitor. The groups will further be randomized to arginine therapy. Vasomotor response, chest pain diary, and medical care utilization and cost for 12 months after randomization will be the study endpoints. This initiative was presented by Dr. Pearson who emphasized that this is an orphan disease in which appropriate clinical data/evidence is lacking. He also stated that this problem is more acute in women and blacks. Dr. Bonow agreed that this is an important area. Dr. Virmani stated that these patients do not have plaques, but there is coronary disease. Unfortunately, we cannot define it at present. She recommended that emphasis be placed on the development of techniques to diagnose this disease. Dr. Libby agreed this is a significant problem and Dr. Gibbons stated that the heterogeneity of this patient population may complicate patient selection and interpretation of the results of such a study. 8. Development and Evaluation of Novel Approaches for Noninvasive Delineation of Myocardial Perfusion, Angiography, and Specific Tissue Targeting and Characterization with Magnetic Resonance and Ultrasound Imaging Techniques Dr. Alan Berson reviewed the recommendations of a NHLBI sponsored Working Group which met on October 28-29, 1996 to explore the potential of MR for imaging the heart, lung, and participant in that workshop, recommended aninitiative for further development of ultrasound and MRI technologies. Dr. Wickline showed atape which used MR to examine the coronary arteries of a pig. Dr. Wickline outlined the need for further efforts in three areas, namely: 1) training, 2) clinical validation of current MRI methods for imaging structure and function and, 3) research support for more exotic areas for which there is great potential but very little practical application of MRI and MR spectroscopy. This initiative was highly supported by other Panel members. This initiative requires further development and refinement by staff. Panel members considered this an important area. 9. Imaging Studies in Patients with Left Ventricular Dysfunction Dr. Fakunding summarized the recommendations of an NHLBI Workshop held on July 2-3, 1996 entitled "Molecular and Cellular Implications of Stunning, Hibernation, and Preconditioning". One of the recommendations that came from the Workshop dealt with imaging studies in patients with left ventricular dysfunction. Specifically, it was recommended that the NHLBI conduct observational studies of patients with left ventricular dysfunction, utilizing echocardiography and radionuclide ventriculography. This would involve utilizing dobutamine echocardiography and thallium redistribution to assess functional viability in (PET) studies could be used as a reference to assess both coronary flow and myocardial function in a group of these patients. A central core laboratory would be utilized and a registry maintained to assist in data clearing and future studies. Follow up of patients would be for a minimum of six months for left ventricular function, quality of life, cardiac events, and mortality. An objective of the study would be to compare the ability of the imaging methods to assess myocardial viability and predict which patients would benefit from revascularization or other treatment. Dr. Bonow indicated that such a study should be considered as an ancillary study to a heart failure clinical study or trial or possibly a study of heart transplant patients. The question would be whether a proportion of heart failure patients exhibit hibernating myocardium due to reduced coronary flow. It would include assessing by state-of-the-art diagnostic techniques whether these patients suffer from blocked arteries and whether opening of the arteries may alleviate or ameliorate the heart failure. 10. Opportunities and Obstacles to Genetic Research in NHLBI Clinical Studies Dr. Old reviewed the purpose and goals of the NHLBI sponsored Special Emphasis Panel (SEP) meeting on Opportunities and Obstacles in Genetic Research in NHLBI Clinical Studies which took place on February 5, 1997. Dr. Lifton reviewed a few of the recommendations of this SEP and specifically emphasized the need to establish an Immortalization Service for important NHLBI studies. The Immortalization Service would allow permanent preservation of genetic material and expedite the sharing of samples. Dr. Lifton stressed the significance of NHLBI taking the lead in this area, as this is an activity that will not be initiated on its own. The Panel expressed high enthusiasm for this initiative. 11. Regulation of Vascular and Hematopoietic Stem Cell Differentiation Dr. Weinstein reviewed the results of a NHLBI sponsored Workshop held September 1996 entitled "From Developmental Biology to Molecular Medicine". She stated that the subject initiative resulted from this workshop. The goal of this initiative is to foster research into genetic mechanisms which control development of the vascular and hematopoietic components of the cardiovascular system that may be involved in heart, lung, and blood diseases. More specifically, this initiative is focused on the pluripotent stem cell or precursor cell populations of endothelial, blood, and vascular smooth muscle cells and the regulatory mechanisms which determine and maintain their diverse phenotypes. Dr. Baldwin summarized the need for this initiative and described it in more detail. He stated that this is an underserved gap area. The study of the origin of a putative smooth muscle stem cell is a total black box at present and research into endothelial cell differentiation has been ignored. The Panel concluded that this was an exciting research area and recommended it with high enthusiasm. 12. Molecular Genetic Determinants of Diet on Atherosclerosis Dr. Applebaum-Bowden introduced the topic. She noted that NHLBI had sponsored a Working Group on September 1996 entitled "Interaction of Diet and Genes in Atherogenesis". She stated that the initiative entitled "Molecular Genetic Determinants of Diet on Atherosclerosis" resulted from this Working Group. Dr. Wassef reviewed the other recommendations of the Working Group. Epidemiological, clinical, and biochemical studies have shown that dietary components can induce atherosclerosis. Nevertheless, there is considerable variability with some individuals being much more sensitive than others. Understanding this variability has profound implications for predicting an individual's susceptibility to atherosclerosis and its complications, as well as for predicting whether an individual will respond favorably to dietary treatment. Progress in the Human Genome Project provides the opportunity for discovering genes that play an important role in the dietary contributions to atherogenesis. The goal of this initiative would be to map and identify the genes contributing to genetic-dietary interactions in atherogenesis utilizing mouse or rat animal models and then to test the homologous genes in human populations. Dr. Pearson expressed concern regarding the proposed testing of genetic components in human populations, because there is such a limited understanding of human diet responsiveness. Dr. Lifton stated that the human component may be difficult to do, but that candidate genes certainly can be identified in animal studies. 13. The Role of Inflammation in Cardiovascular, Pulmonary, and Hematological Diseases Dr. Applebaum-Bowden introduced this initiative. Recent advances in determining the biochemical and molecular basis underlying the pathophysiology of inflammation have revealed common themes in cardiovascular, hematologic, and pulmonary diseases. The unifying concept in this "convergence" is identification of the adhesion molecules with their complex interactions and cell signaling capabilities. The new information argues for the development of a program which encourages research utilizing the modern approaches and the wealth of information from the Human Genome Project. Dr. Massicot-Fisher reviewed the relationship of adhesion molecules to cardiac transplantation and transplant atherosclerosis. Dr. Libby stated that while adhesion molecules are important in inflammation they are only one part of the process. He suggested that this initiative should be broadened to include other aspects of inflammation. He added that this is an important area and the initiative should undergo further refinement. 14. Impact of Viral Genes on the Pathogenesis of Atherosclerosis and Pulmonary Diseases Dr. Skarlatos introduced this topic. She stated that the initiative resulted from an NHLBI sponsored Special Emphasis Panel on "The Role of Infectious Agents in Atherosclerosis and Restenosis" held on September 19, 1996. Recent epidemiologic and pathologic evidence suggests that viral agents such as cytomegalovirus (CMV), a member of the herpes virus group, may play an important role in the initiation and progression of atherosclerosis. Herpes virus infections, which are widespread in the general population, are found in most tissues of the body including lesion-bearing areas of the arterial wall. In vitro models of viral infection show a variety of effects on cellular metabolism that may parallel in vivo events of the atherosclerotic lesion. In addition, recent observations in immunosuppressed heart transplant patients infected with CMV have shown that atherosclerosis develops rapidly in the transplanted hearts. Several opportunities exist for increasing the application of genetic and molecular approaches to dissect the viral mechanisms of cardiovascular and pulmonary diseases. Use of gene transfer approaches, genomic technology, and transgenic and knockout models offer such opportunities. Dr. Libby stated that this is an exciting area of research. The main issue is whether this is causal or commensal. Clinical trials were considered premature at this time and pre-clinical work in animal models was recommended. 15. Women and Coronary Diseases Dr. Virmani reviewed a recent study she had performed. She stated that high cholesterol levels correlated with plaque rupture in women but HDL does not correlate. The leading cause of death in woman continues to be coronary heart disease. It has been assumed that men and women have similar clinical and morphologic expression of the disease. It has been shown in some studies that women are more likely to present with angina and less likely to present with myocardial infarction. Chest pain is a poor predicator of epicardial coronary disease in women. It has been reported that age adjusted mortality in women with myocardial infarction or angina is lower than men while others report that prognosis of CAD in women is not as benign. There are rare morphologic studies in women with CAD to determine if differences in atherosclerotic plaque exists in men and women. The goal of this initiative is to stimulate new research that incorporates the advances made in cellular, structural, and molecular biology to the understanding of coronary artery disease in women. The Panel concluded that this was an important area and discussed integrating this initiative with the unstable plaque initiative. 16. Angiotensin II - Dependent Oxidant Production in Cardiovascular Disease Dr. Oparil introduced this initiative and reviewed recent data in this area. The renin-angiotensin system plays a role in the pathophysiology of hypertension, atherosclerosis, and also perhaps in left ventricular hypertrophy and heart failure. It is well appreciated that high-renin hypertensives have an increased incidence of coronary disease. Oxidant stress is also believed to play a pathogenic role in a variety of diseases. Emerging evidence suggests that renin-dependent cardiovascular disease is linked to increased oxidative stress. The goal of this research initiative is to develop integrative approaches to study the relationship(s) between the renin-angiotensin system and oxidative stress in the heart and vasculature. Activation of these cellular response pathways may facilitate the development of secondary cardiovascular complications including an enhanced risk for development of atherosclerosis. These interactions represent an under-investigated area of cardiovascular research and reflect the need for development of a multidisciplinary program which will address these issues. The SEP Panel recommended adding portions of this initiative to the RFA initiative entitled "Cellular and Genetic Interrelationships of Atherosclerosis and Hypertension". 17. Alternative Mechanisms of Action of ACE Inhibitors Dr. Oparil submitted this initiative. She stated that ACE inhibitors have become a primary and first line of defense against hypertension; however, the mechanisms underlying the beneficial and deleterious effects of these agents remains ambiguous. The use of ACE inhibitors is historically based on the assumption that these agents reduce the levels of circulating angiotensin II and thereby decrease arterial pressure in hypertensive patients. But many recent studies demonstrate that ACE inhibition does not chronically eliminate the formation of angiotensin II in patients, suggesting that there are alternate mechanisms through which it reduces arterial pressure. The present initiative solicits applications to study the alternative pathways by which ACE inhibitors produce these effects. It is proposed that the elucidation of the basic mechanisms underlying these beneficial and deleterious consequences of ACE inhibitors will facilitate more effective, long-term treatment of hypertensive individuals. It is envisioned that both clinical and animal studies will be funded through this mechanism. The Panel concluded that this initiative was too focused for an RFA. While some panelists suggested that the NHLBI should explore collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), little enthusiasm was voiced for the initiative as currently written. 18. Origins of Structural Remodeling Leading to Cardiac Dysfunction Dr. Reinlib introduced this initiative. He stated that this initiative resulted from the previously discussed NHLBI Workshop held in July 2-3, 1996 entitled "Molecular and Cellular Implications of Stunning, Hibernation, and Preconditioning". The goal of this initiative is to encourage research elucidating the mechanisms of cardiac restructuring as it occurs in heart failure following ischemic events such as myocardial infarction, coronary artery disease, or the condition known as hibernation. Development of appropriate animal models is proposed to facilitate further studies to understand the mechanisms of ischemia-related cardiac dysfunction. Dr. Bonow described clinical and pathological reports of cardiac restructuring following prolonged hypoperfusion. Inquiries into the mechanisms of de-differentiation of mature cardiac cells would lead to insights into the progression of hypertrophy and cardiac dysfunction in heart failure, coronary artery disease, and occurrences of persistent reduced perfusion. Dr. Renu Virmani added that a link between hypoperfusion and cardiac hypertrophy has been reported, justifying further investigation into the mechanisms of cardiac restructuring under these conditions. Drs. Robert Roberts and Samuel Wickline also voiced their support for multi-faceted studies and indicated the results would have considerable clinical impact. Among the critical steps the Panel recommended were multi-disciplinary efforts directed at cell, molecular, and organ levels; development of appropriate animal models--either restrictive of general to a variety of interventions; and studies targeted both at cellular signaling and at function of the cardiac molecular motor. The Panel members recommended refining the initiative, but enthusiastically endorsed it. 19. Heart Failure with Normal Systolic Function Dr. Bonow submitted this initiative. The objective of the initiative is to elucidate the mechanisms and implications of diastolic dysfunction in heart failure. Dr. Bonow reported on the wide-spread incidence of diastolic dysfunction which occurs in up to 50% of heart failure patients. Many fatal cases of heart failure are distinguished by a lack of systolic dysfunction. The issue is particularly relevant to older Americans, who utilize the majority of health care resources. The progression of diastolic abnormalities appears to follow different natural histories in individuals and its mechanisms and clinical implications are unclear. Dr. Bonow suggested a battery of NHLBI initiatives including improved detection, definition of better indices of diastolic function, and studies to understand the progression of diastolic dysfunction. The Panel was generally supportive of Dr. Bonow's initiatives. It was uniformly believed that diastolic dysfunction has not received adequate attention, possibly due to the imprecise nature of existing parameters and measures. Dr. Peter Libby noted this as a challenging area and remarked that indices of diastolic dysfunction rise and fall. Dr. Samuel Wickline agreed the parameters are nebulous and advocated development of new techniques to correlate intrinsic properties of the heart with practical parameters. He also forecast the emergence of novel tools, such as intravascular ultrasound, in the next five years to improve the measurements of accurate diastolic parameters. Dr. Gary Gibbons added that the initiative could complement the working tools of cardiologists and also should include and compare full measures of left ventricular dysfunction. This initiative received positive support from the Panel. 20. Randomized Trial Evaluating the Role of Magnesium in High Risk Patients Undergoing Thrombolytic Therapy Dr. Bernard Gersh reviewed the results of the studies using magnesium to treat high risk patients undergoing thrombolytic therapy. This discussion included the result of the ISIS-4 trial which showed no benefits using magnesium, as well as results of several smaller studies which showed significant benefit. Animal data in swine also shows positive effects. Dr. Gersh concluded that in view of different timing of magnesium application during the acute MI among the studies, the optimal use of magnesium has not been adequately tested and thus benefit may have been obscured. Dr. Gersh strongly supported the conduct of a randomized trial evaluating the role of magnesium in high risk patients such as the MAGIC trial conducted in DECA. Dr. Bonow agreed that we need an answer to this problem. 21. A Randomized Trial of Transcatheter Technologies Versus Medical Therapy Dr. Gersh recommended a randomized trial evaluating revascularization technologies in low risk patients (1-2 vessel disease). This randomized trial should specifically include all new catheter-based technology, such as stents. Aggressive lipid lowering therapy should apply to both arms. It was pointed out by staff that this issue would be addressed by the Institute developed initiative (ACIP-2) as well as the proposal by applicants (SMART trial). 22. The Impact of the Open Artery Dr. Gersh provided background information about the beneficial impact of early opening of the infarct related artery and indicated that the benefit may extend beyond the current strategy (within 12 hours of acute MI). It is anticipated, based on experimental and non-randomized study data, that opening of infarct-related closed artery within 3-5 days of acute MI may prevent negative left ventricle remodeling and positively impact future events such as chronic heart failure and reinfarction. He and other panel members strongly supported a randomized trial testing the "late opening of the infarct-related artery" hypothesis. Adjournment The meeting adjourned at 2:35pm on March 26, 1997. We hereby certify that, to the best of our knowledge, the foregoing minutes are accurate and complete. Peter Libby, M.D. Chairperson Michael J. Horan, M.D., Sc.M. Executive Secretary ROSTER HEART, LUNG, AND BLOOD SPECIAL EMPHASIS PANEL ON HEART AND VASCULAR DISEASES RESEARCH OPPORTUNITIES March 26, 1997 Bethesda, Maryland Chair: Peter Libby, M.D. Professor of Medicine Director, Vascular Medicine and Atherosclerosis Unit LMRC, Room 307 Brigham and Women's Hospital 221 Longwood Avenue Boston, MA 02115 Phone: 617-732-6628 Fax: 617-732-6961 E-mail: plibby@bustoff.bwh.harvard.edu Members: H. Scott Baldwin, M.D. Assistant Professor of Pediatrics University of Pennsylvania School of Medicine 1102 B Abramson Research Building 3615 Civic Center Boulevard Children's Hospital of Philadelphia Philadelphia, PA 19104 Phone: 215-590-2938 Fax: 215-590-3324 E-mail: sbaldwin@mail.med.upenn.edu Robert O. Bonow, M.D., FACC Goldberg Professor of Medicine Chief, Division of Cardiology Northwestern University Medical School 250 E. Superior Street, Suite 524 Chicago, IL 60611 Phone: 312-908-1052 Fax: 312-908-1434 E-mail: r-bonow@nwu.edu Bernard Gersh, M.D. Chief, Division of Cardiology Georgetown University Medical Center 3800 Reservoir Road, N.W., PHC 5 Washington, D.C. 20007-2197 Phone: 202-687-2043 Fax: 202-687-6545 E-mail: gersh@gunet.georgetown.edu Gary H. Gibbons M.D. Cardiovascular Division Brigham and Women's Hospital Thorn-1223 75 Francis Street Boston, MA 02115 Phone: 617-732-8912 Fax: 617-975-0995 E-mail: ggibbons@bustoff.bwh.harvard.edu Richard P. Lifton, M.D., Ph.D. Associate Professor, Internal Medicine and Genetics Yale University School of Medicine BCMM 136E 295 Congress Avenue New Haven, CT 06510 Phone: 203-737-4420 Fax: 203-624-8213 E-mail: richard_lifton@QM.yale.edu Suzanne Oparil, M.D. Director, Vascular Biology and Hypertension Program of the Division of Cardiovascular Disease University of Alabama at Birmingham 1034 Zeigler Research Building 703 S. 19th Street Birmingham, AL 35294 Phone: 205-934-2580 Fax: 205-975-5119 E-mail: soparil@uab.edu Thomas A. Pearson, M.D., Ph.D. Director, The Mary Imogene Bassett Research Institute One Atwell Road Cooperstown, NY 13326 Phone: 607-547-3048 Fax: 607-547-3061 E-mail: tapearson@guno.com Robert Roberts, M.D. Don W. Chapman Professor of Medicine and Professor of Cell Biology Baylor College of Medicine 6550 Fannin, MS SM677 Houston, TX 77030 Phone: 713-790-4864 Fax: 713-790-4348 E-mail: dweaver@bcm.tmc.edu Gustav Schonfeld, M.D. * Professor and Chairman Washington University Department of Internal Medicine Campus Box 8046 660 S. Euclid Avenue St. Louis, MO 63110 Phone: 314-362-8060 Fax: 314-362-3513 E-mail: gschonfe@imgate.wustl.edu Renu Virmani, M.D. Chairperson, Cardiovascular Pathology Armed Forces Institute of Pathology 14th and Alaska Avenues, N.W. Building 54, Room 2005 Washington, D.C. 20306 Phone: 202-782-2844 Fax: 202-782-9021 E-mail: NA Samuel A. Wickline, M.D. Associate Professor of Medicine Codirector, Cardiovascular Division Washington University School of Medicine Barnes-Jewish Hospital North Campus 216 S. Kingshighway St. Louis, MO 63110 Phone: 314-454-8635 Fax: 314-454-5265 E-mail: saw@howdy.wustl.edu Executive Secretary: Michael J. Horan, M.D., Sc.M. Director Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Two Rockledge Centre, Suite 9044 6701 Rockledge Drive, MSC 7940 Bethesda, MD 20892-7940 Phone: 301-435-0466 Fax: 301-480-1336 E-mail: horanm@gwgate.nhlbi.nih.gov * Unable to attend meeting. .