Boston University Medical Campus
Medicine

Research Activities
Founded in 1974 as the Cardiovascular Institute of Boston University School of Medicine, the Whitaker Cardiovascular Institute conducts, stimulates, and coordinates research and training related to the etiology, prevention, control, and treatment of cardiovascular disease. More than 125 full-time investigators and technical staff are involved in research, training, and education. Total research support from federal and non-federal sources is in excess of $31 million per year.

The Institute is currently overseeing five major research programs. Under the direction of Haralambos Gavras, M.D., Chief of the Section of Hypertension, and Professor of Medicine, the Specialized Center of Research (SCOR) in Hypertension is focusing on “Molecular Genetics of Hypertension.”

Recently renewed, the “Structural and Cell Biology in Cardiovascular Disease” program project seeks to understand the structural biology of the macromolecules and the macromolecular complexes involved in the transport of lipids into and out of cells. It is under the direction of Donald M. Small, M.D., Professor of Biophysics.

Directed by Herbert Kagan, Ph.D., Professor of Biochemistry, the “Role of the Arterial Wall in Atherogenesis” Program Project is an in-depth study of the causes and prevention of arteriosclerosis at the gross tissue, cellular, and subcellular levels.

Joseph Loscalzo, M.D., Ph.D., Director of the Whitaker Cardiovascular Institute, and Professor and Chair of Medicine, is overseeing the “Biological Effects of Nitric Oxide” program. Industry- and National Institutes of Health (NIH)-funded, this research program studies the endothelial factor nitric oxide and its role in vascular biology. Also under Dr. Loscalzo’s direction is the recently renewed SCOR, “Ischemic Heart Disease in Blacks.” Investigators test the hypothesis that oxidative stress and a relative insufficiency of nitric oxide production or action by the endothelial cell underlies the microvascular diathesis known to exist in African Americans.

The recently awarded Program Project, “Role of Apoptosis in Heart Failure,” is under the direction of Wilson Colucci, M.D., Chief of Cardiology, and Professor of Medicine. It focuses on molecular and cellular mechanisms of remodeling in the failing heart. Joseph Vita, M.D., Director of Clinical Research in the Department of Medicine and Professor of Medicine, is overseeing the “Vitamin C and GSH: Roles in Vascular Function” Program Project, which focuses on the role of antioxidants in protection from vascular disease.

The NIH is the principal funding source for several other active research efforts, including Dr. Loscalzo’s investigation of thrombotic determinants in atherosclerosis. Working with John Keaney, M.D., Associate Professor of Medicine, Dr. Loscalzo is also involved in studying the role of homocysteine in atherothrombosis. Drs. Vita and Keaney are investigating the function of oxidative stress in atherosclerosis; Katya Ravid, Ph.D., Professor of Medicine and Biochemistry, is conducting research on gene regulation in megakaryocytes, and Carl Apstein, M.D., Professor of Medicine, is investigating determinants of ventricular function.

Vassilis Zannis, Ph.D., Professor of Medicine is actively involved with research on gene regulation of apoproteins. Working with Drs. Vita and Kearney, Richard Cohen, M.D., Professor of Medicine, is studying endothelial function.

Jane E. Freedman, M.D., was appointed Associate Professor of Medicine and Pharmacology, joining the Institute in September 2001. Dr. Freedman returns to Whitaker after spending four years as an assistant professor at Georgetown University. She brings with her an NIH award, a Pharmaceutical Research and Manufacturers foundation award, and an Established Investigator award from the American Heart Association. She studies the impact of platelet function and thrombosis in acute coronary syndromes.

Kenneth Walsh, Ph.D., was appointed Professor of Medicine, and Director of the Institute’s Molecular Cardiology Unit in November 2001. Dr. Walsh comes to Boston University Medical Center from St. Elizabeth’s Medical Center and brings with him six NIH awards as well as a staff of sixteen. His interests focus on molecular events that drive cardiovascular cell growth, cell pathology, apoptosis, and angiogenesis.

In addition, promising junior investigators continue to be successful in obtaining career development awards, such as the National Institutes of Health Clinical Investigator Award and the American Heart Association’s Clinical Scientist Development Award and Established Investigatorship.

Clinical Activities
Over the past year, the Whitaker Cardiovascular Institute continued its activities in National Heart, Lung, and Blood Institute (NHLBI)-sponsored clinical trials of cardiovascular disease.

Led by Alice Jacobs, M.D., Director of the Cardiac Catheterization Laboratory, and Professor of Medicine, the “Bypass Angioplasty Revascularization Investigation” (BARI) trial is an NHLBI-sponsored trial investigating the benefits of coronary artery bypass surgery versus those of percutaneous transluminal coronary (balloon) angioplasty.

Under Dr. Vita’s direction, “Antioxidants and Vascular Function” explores the effects of oxidative stress on endothelium-derived relaxing factor (EDRF) action and the potential protective effects of lipid-soluble and water-soluble antioxidants in atherosclerosis. Dr. Vita studies these issues in patients undergoing cardiac catheterization using intracoronary infusion of vasoactive agents; intracoronary Doppler and quantitative angiography; and noninvasively in peripheral arteries of patients using Doppler studies and plethysinography.

“Intracoronary Dobutamine Echocardiography for the Functional Assessment of Coronary Artery Stenoses,” led by Dr. Jacobs, aims to develop the use of intracoronary infusion of dobutamine to assess the functional significance of individual coronary artery stenoses in patients undergoing therapeutic coronary interventional procedures.

In studies of vasopressin, a pressor hormone that elevates blood pressure, Dr. Gavras and his associates have developed peptides that counteract the vasopressin-1 (V1) receptor. These researchers have demonstrated that approximately 30% of patients with severe heart failure have an improvement in circulatory function following administration of the peptide antagonist. Recently, the laboratory has synthesized several other peptides inhibiting both V1 and V2 receptors, the V2 receptors being responsible for water absorption by the kidney. Clinical trials are now underway for studies of the new V1 antagonist in patients with hypertension or heart failure and for the dual V1-V2 blocker in patients with fluid retention or edema. In addition, Dr. Gavras and Irene Gavras, M.D., Professor of Medicine, have carried experimental testing through Phase 3 clinical studies on the effects of new renin inhibitors, ACE inhibitors, and calcium channel blockers.

Studies led by Dr. Colucci and Flora Sam, M.D., are examining the role of nitric oxide in regulating myocardial systolic and diastolic function, pulmonary vascular tone and coronary blood flow reserve under physiologic and pathophysiologic conditions, and, in particular, in patients with dilated cardiomyopathy. By using the intra-coronary infusion of an inhibitor of nitric oxide synthesis, this group has demonstrated that increased nitric oxide activity in the myocardium contributes to myocardial depression in patients with clinical heart failure.

Dr. Colucci’s group is also conducting several trials of new therapeutic agents for patients with heart failure. Drugs under study include adrenergic receptor and endothelin receptor antagonists, natriuretic peptides, and drugs that increase myocardial cell calcium sensitivity.

Drs. Gavras, Ryan, Apstein and Rodney Falk, M.D., Director of Clinical Cardiology Research at Boston University Medical Center, and Professor of Medicine, have performed several trials on the benefits of ACE inhibitors and of inotropic agents (drugs that exert pressure on cardiac muscle) in patients with moderate and severe congestive heart failure. Dr. Falk has also conducted several important trials in the treatment of atrial fibrillation and in cardiac amyloidosis.

Education
Educational programs, particularly in research training of both pre- and postdoctoral students, are consistent with the Institute’s mission to further the conquest of cardiovascular diseases through the preparation of research leaders. Now in its twenty-fifth year and recently renewed for another five years, the Basic Science Cardiovascular Postdoctoral Training Program, under the direction of Dr. Apstein, offers research training in hypertension, atherosclerosis, and ischemic heart disease. This single program has graduated more than 100 alumni, most of whom hold academic positions.

Major Accomplishments
The Whitaker Cardiovascular Institute counts among its major accomplishments the appointment of two new faculty members, as well as the addition of new technology to its research facility.

As a major occupant of the Center for Advanced Biomedical Research Building (CABR), the Institute occupies its fifth and sixth floors, which contain approximately 40,000 square feet of research space, including a fully equipped fluoroscopy lab. The seventh floor of the Evans Biomedical Research Center (EBRC) contains more than 20,000 square feet of research space for Institute investigators. A new dual-photon real-time confocal microscopy imaging center is under construction on this floor; in addition, a state-of-the- art magnetic resonance imaging center (both NMR and EPR) has now opened in 880 square feet of space on the EBRC’s third floor. Both new facilities comprise a cardiovascular imaging center supported by a recent grant from the Whitaker Foundation.

Michael Kirber, Ph.D., Associate Professor of Medicine, was recently recruited to run the microscopy facility, and James Hamilton, M.D., Professor of Biophysics, has been appointed to direct the magnetic resonance facility.