Cardiovascular Research Institute

The Cardiovascular Research Institute is the formal Research Center responsible for coordinating and performing the cardiovascular research of the MedStar Research Institute (MRI). MedStar Health is the non-profit corporation that owns Washington Hospital Center and Georgetown Hospital, and MedStar Research Institute is the entity through which clinical research is conducted at these hospitals and basic research is conducted at Washington Hospital Center. In addition, Georgetown has additional resources which support basic research at the University.

The goal of the Cardiovascular Research Institute (CRI) is to develop new technologies and strategies to enhance the cardiovascular care of patients. This goal is implemented by a commitment to a strong basic research program to further our understanding of the causative mechanisms responsible for cardiovascular disease, and an equally strong commitment to translating the fruits of this research in clinically relevant ways.

One important concept that drives CRI is the recognition that fundamental to achieving the goals of CRI is the creation of an environment in which there is a continuing interaction and collaboration among outstanding clinical cardiologists, cardiovascular surgeons, clinical investigators, epidemiologists and basic scientists. The success of CRI is due, in part, to the development of an environment that allows senior investigators to independently pursue their area of interest (i.e., develop novel concepts and creative applications within their field of expertise) while maintaining strong communication and collaboration across investigators. Collaboration is easy at CRI. Among the senior investigators, there is a wide diversity of research interests and a very broad range of settings in which to test hypotheses (basic, animal, clinical or epidemiologic). The intellectual integration of collaborators is enhanced by physical integration. The basic scientists literally sit in the same office area as clinical investigators and clinical interventional cardiologists; research and clinical labs sit side-by-side within the hospital (e.g. the dedicated endothelial function research laboratory is next to the clinical non-invasive laboratory); and free-standing research labs (e.g. cardiovascular animal lab) are within a few feet of the Washington Hospital Center (the largest inner-city hospital in Washington, DC). This physical integration, along with the CRI mindset, facilitates and encourages collaboration and translational research.

The effectiveness of this unique environment, which blends basic, animal, clinical and epidemiologic resources, is evidenced in many ways. CRI/MRI publishes hundreds of abstract and over a hundred original publications each year (including publications in NEJM, JAMA and Lancet). CRI/MRI senior investigators are recognized leaders in their field and actively involved in professional societies and national educational forums. CRI also conducts approximately 50 educational activities per year; these activities range from small forums (50 people), visiting speakers/professors, to tutorial / preceptor training, to large scale (over 700 attendees) educational meetings. The Cardiology fellowships at both hospitals are well established and have produced leaders in the field of cardiology.

Since there are diverse research interests and numerous research accomplishments, the following will just highlight a few of the lines of research that exemplify the collaborative and transitional nature of research at CRI.

Angiogenesis Research:
Dr. Epstein and his colleagues were the first to demonstrate that infusion of certain proteins (VEGF and bFGF) enhance collateral flow in a canine model of coronary artery occlusion. They were also first to demonstrate that cytokines having the capacity to augment angiogenesis can also increase the vascular response to injury, and thereby increase atherogenesis.

More recently, Dr. Epstein and his CRI associates developed the concept that the presently accepted paradigm for therapeutic angiogenesis--the delivery of a single angiogenesis gene or protein to ischemic tissue--will probably not produce an optimal angiogenesis effect. The reason for this is that blood vessel development is an extremely complex process requiring dozens, probably hundreds, of gene products that must be expressed in appropriate concentrations and in appropriate sequence. The approach to this conundrum that these investigators pioneered is based on the concept that nature has imbued certain cells with the capacity to express multiple angiogenesis factors in appropriate sequence and concentration. The CRI investigators studied the potential angiogenic effects of bone marrow cells. They found that in culture these cells do in fact secrete angiogenesis factors, including VEGF, MCP-1, and bFGF, and that when the conditioned medium derived from these cells is applied to endothelial cells, the endothelial cells proliferate, migrate, and form tubes.

These findings were first applied by injecting bone marrow cells into ischemic myocardium (amaroid constrictor porcine model) or into an ischemic hind limb (murine model). Enhanced collateral flow and myocardial contractility was consistently observed. This work recently led to a Phase I clinical trial of intramyocardial injection of autologous bone marrow in CAD patients—this study, to date, provides preliminary clinical data indicating feasibility and safety. They anticipate that a Phase II trial will be initiated within the next 6-10 months.

Parallel Tumor Angiogenesis Research:
In parallel to the CV angiogenesis research described above, Dr Wellstein’s lab has been centered around the understanding of mechanisms that induce and drive tumor angiogenesis and metastasis. For example, this lab has shown biologic function, expression in tumors and release of pleiotrophin (PTN) into serum of cancer patients (lung, pancreas, brain, GI-tract, breast cancers). Furthermore, they found insertion of an endogenous human retrovirus as a major regulator of the human gene. More recently, they identified a receptor for this growth factor, the orphan tyrosine kinase ALK (=anaplastic lymphoma kinase) and have focused significant amounts of effort on studying the signaling via this pathway. The ALK intracellular kinase domain is closely related to the insulin receptor/IGF-IR family and utilizes very similar and parallel signaling molecules whereas the extracellular domain is unique. A major focus of the lab is characterizing inhibitors and activators of this pathway. As this work increases our understanding of the biology and pathology of such molecules and as more tools are developed, the lab is translating such findings into clinical utility in diagnostics and therapeutics of cancer and cardiovascular disease.

Infection and atherosclerosis:
Because many CAD pts have no traditional risk factors, and because inflammation is an essential component of atherogenesis, CRI investigators postulated infection may be one of the triggers of this inflammatory response. While still at the NIH, Dr. Epstein’s group was the first to demonstrate that cytomegalovirus (CMV) infection increases atherosclerosis in a mouse model of atherosclerosis (apoE -/-), that CMV infection increases the neointimal response to vascular injury of the rat carotid artery, and that CMV seropositivity is associated with an increased rate of restenosis in pts undergoing angioplasty.

More recently CRI investigators demonstrated that mechanisms other than those deriving from direct infection of the vessel wall play a role in atherogenesis; whereas CMV infection increases the neointimal response to injury, virus is not present in the injured vessel (despite its presence in other tissues). Of relevance are their findings that serum from CMV-infected mice induces pro-atherosclerotic changes in endothelial cells (mediated in part by IFNg), and infection induces cross-reactive immunological responses involving heat shock proteins.

This line of study was extended to the clinical arena by examining autoantibodies to heat shock protein 60 (HSP60) in patients presenting for cardiac catheterization. CRI investigators found that atherosclerosis may, in part, be an autoimmune disease since these autoantibodies were present in a higher percentage of patients with CAD and correlated with the extent of CAD, as assessed by quantitative coronary angiography. These studies further demonstrated that CAD risk, and the event rate in pts with established CAD, are related to the aggregate number of certain intracellular pathogens with which an individual is infected ("pathogen burden"). Most recently, these investigators have demonstrated that increasing pathogen burden is associated with an increased likelihood of having endothelial dysfunction of the coronary arteries, one of the earliest manifestations of CAD. This body of work provides great insight into the role of infection on atherosclerotic burden and (potentially) restenosis after catheter based intervention.

Investigation of endothelial dysfunction:
Dr. Panza’s endothelial function laboratory has been dedicated to the study of endothelial function in healthy subjects and in patients with risk factors for atherosclerosis. Initial investigations, conducted when he was at the NIH, demonstrated the role of NO in the abnormal response to acetylcholine (Ach) in hypertensive and hypercholesterolemic patients. They also showed that the impaired vasodilator response was not related to a decreased availability of the NO precursor L-arginine, or to an isolated defect of the muscarinic receptor or its signal transduction pathway.

Subsequent research addressed the role of endothelin-1 (ET-1) in the microvasculature of hypertensive, hypercholesterolemic, and type 2 diabetic patients, and showed an increased vascular ET-1 activity in these conditions. CRI investigators also explored the role of cyclooxygenase (COX)-derived prostanoids in the maintenance of basal vascular tone and in the endothelium-dependent relaxation to Ach. During COX blockade with intraarterial aspirin, they demonstrated decreased blood flow and improved response to Ach, indicating a contribution of prostacyclin to basal vascular tone and an Ach-induced secretion of vasoconstrictor prostanoids.

More recently, these CRI investigators are focusing their attention on the vascular actions of insulin, and its effects on the NO and ET-1 systems. In healthy subjects, they demonstrated that systemic hyperinsulinemia induces NO-mediated vasodilation of the microcirculation, whereas insulin infusion in the forearm circulation does not affect vascular tone, but stimulates both ET-1 and NO activity. Further work has shown that systemic hyperinsulinemia impairs endothelium-dependent dilation of the brachial artery independent of insulin sensitivity or lipid profile. Their data support the independent epidemiological link between hyperinsulinemia and cardiovascular risk and sheds new light on the potential role of insulin in atherogenesis. Based on the aforementioned work, Dr. Panza proposes to assess the effects on endothelial function on improved insulin sensitivity induced by PPAR agonists. The results of these studies should have direct clinical application when optimizing diabetes treatment to alter subsequent cardiovascular risk.

Cardiovascular Risk Factor Epidemiologic Trials:
Dr Howard, President of MRI, has had extensive experience in the study of risk factors for CVD, with a particular emphasis on diabetes. She participated in the development of the multi-compartmental modeling techniques for the study of human lipoprotein metabolism, and used them to define the influences of diet, obesity and diabetes on lipand prevention trials focusing on CVD and diabetes. She is a PI and chair of the steering committee of the Strong HEart Study, funded for the past 13 years by NHLBI to examine CVD, its risk factors, and the interactions among insulin resistance, diabetes and CVD in American Indians. She is also a PI for the WOmen's Health INitiative, which includes both an observational study and clinical trials to examine strategies for the prevention of CVD, cancer and osteoporosis in postmenopausal women. Recently she was funded by NHLBI to conduct the SANDS study, an intervention to examine the effect of lower targets for LDL and blood pressure on CVD in people with diabetes.

Brachytherapy and Device Technology to Treat Atherosclerosis
The Washington Hospital Center has a long history of excellence in interventional cardiology and has long been the leader in the study of new catheter-based devices (coronary, carotid and peripheral interventions). Many of the CRI clinical investigators are national and international PI’s for multicenter trials device trials (involved in study design, implementation and data analysis). In addition, many forms of novel device technology and treatment strategies for restenosis arose from pre-clinical work performed by CRI investigators. Dr. Waksman and colleagues have led an intensive preclinical and clinical investigation in the field of vascular brachytherapy to prevent restenosis. Utilizing the porcine model of restenosis, new isotopes and careful dosimetry studies led to the initiation of several single center and multicenter clinical trials. Over 2000 patients were enrolled in approximately 10 single-center brachytherapy studies (WRIST = Washington Radiation for In-Stent Treatment) at the Washington Hospital Center. The outcome of these studies (published in multiple journals including NEJM) was used to support PMA submission and approval of gamma radiation for the treatment of in-stent restenosis. This monumental task was possible because of the CRI infrastructure for clinical research, which includes strong regulatory and database/statistical support and angiographic and intravascular ultrasound core laboratories. This very active line of device investigation is simultaneously conducted at both Georgetown and Washington Hospital Center.

Cardiovascular Kidney Institute:
Under the direction of Dr. Christopher Wilcox at Georgetown, there is an active center of investigation focusing on hypertension, renal and cardiovascular disease. The current NIH Program Project Grant on “Renovascular Oxidative Stress and Hypertension” explores the roles of nitric oxide and vasoconstrictor prostaglandins and this group is actively exploring the basis and treatment of cardiovascular disease in patients with kidney disease. This is accomplished through collaboration of basic scientists, pharmacologists, and clinical nephrologists and cardiologists and is focused on three lines of research: 1) vascular biology and hypertension, 2) heart failure and 3) kidney failure.

Cardiac and Coronary Imaging:
Because of the strong history in interventional cardiology, Washington Hospital Center / CRI has become a leader in the field of coronary ultrasound. Intravascular ultrasound (IVUS) work done by CRI has advanced our understanding of the pathogenesis/mechanism of atherosclerotic disease, interventional devices and restenosis. In addition to performing 3000 IVUS examinations each year, CRI has a very active IVUS Core Lab, responsible for study design, interpretation and analysis of IVUS examinations from multicenter, international trials studying brachytherapy, local drug delivery, sonotherapy and novel stent designs. Over 150 IVUS studies from WHC have been published in the cardiology literature.

CRI investigators have also been instrumental in using cardiac ultrasound to advance our knowledge on the effects of numerous pharmaceutical agents and intra-cardiac devices (e.g., novel prosthetic valves). For example, Dr. Weismann’s group was responsible for designing a multicenter, double blind, placebo-controlled study to assess the effect of dexfenfluramine (diet pill) on valvular function. This 1000 patient study was published in NEJM approximately one year after trial initiation and the results, along with subsequent studies from this group (published in Annals of Int Med, JACC and JAMA), allows cardiologists to better appreciate the true prevalence and extent of diet pill-associated valvulopathy.

CRI Database and Gene Discovery:
The CRI database consists of demographic and clinical information on over 20,000 patients that have had procedures at the Washington Hospital Center. While initially developed in conjunction with the catheterization laboratory, the database has recently been expanded to capture similar demographic, procedural and outcome data on cardiac patients with acute coronary syndromes. Retrospective use of this database has already resulted in over 75 publications (e.g., effect of mild renal insufficiency on long term outcomes or the effect of obesity on interventions).

Collaborations between scientists in the molecular, animal and clinical research areas are now using this enormous database to facilitate an exciting gene discovery project. Large number of patients presenting to the clinical laboratories are volunteering to donate blood samples for subsequent gene analysis. Using information derived from animal model and state-of-the-art technology for SNP discovery, candidate genes are identified. With a large bank of patient genetic data, associations between candidate SNPs and atherosclerosis burden (by angiography and/or IVUS and/or MRI), restenosis, and/or the propensity for infection to contribute to atherosclerosis and atherosclerosis-related events can be investigated. This line of research further exemplifies the collaborative and translational nature of research at CRI.