CVRI Scientists

Prediction and prevention of cardiovascular disease

Brian L Black, Ph.D.
Professor

Research Interests:
Cardiac and skeletal muscle development, differentiation, and function

Summary:
Congenital heart anomalies are the most common form of birth defect in the United States, affecting nearly one percent of all babies, yet the molecular and developmental basis for these defects is largely unknown. Tissues and organs form during mammalian embryonic development because of the integration of numerous signaling and transcriptional pathways. Our major goal is to define these pathways in order to understand the molecular causes of congenital anomalies and potential mechanisms for organ regeneration and repair. Using the mouse as a model system, the current work in the lab is focused on defining the pathways regulating the development of cardiac and skeletal muscle, the vascular endothelium, and neural crest. Specific projects focus on the regulation and function of genes that are known to be critical for cardiac development. These include Mef2c, Islet1, Gata4, Bmp4, and Fgf8. Each of these genes is involved in cardiac development, and we are defining their regulation and function specifically during the formation of the cardiac outflow tract, one of the most commonly and severely affected regions of the heart observed in babies. The long-term scientific goal of these studies is to define the how tissues and cells are integrated during organogenesis and how cells receive and interpret positional information. We are using a combination of conditional gene knockouts, transgenic reporter assays, and fate mapping techniques in mice to define the embryological origins of the outflow tract and the reciprocal signaling between tissues that is required for proper heart development. The ultimate goal of these studies is to development diagnostic and therapeutic interventions for birth defects of the heart and other organ systems.

Elias H Botvinick, M.D.
Professor In Residence

Research Interests:
Nuclear medicine, nuclear cardiology, PET/CT, MRI, CT, cardiac cardiology, echocardiology, nuclear magnetic resonance, cardiovascular imaging, stress testimg, heart, myocardial perfusion, scintigraphy, coronary, sychrony, sychronization

Summary:
My research centers on a collaborative effort to develop noninvasive imaging methods for the identification and evaluation of cardiac anatomy and pathophysiology, and apply them to the diagnosis, risk stratification and monitoring of clinical disease. The work is centered on nuclear medicine methods, PET and SPECT, as well as echocardiography, MRI, and CT.

Michael S Conte, M.D.
Chief, Vascular Surgery

Research Interests:
Aortic reconstruction, carotid artery disease, lower extremity arterial occlusive disease, diabetic vascular disease

Summary:
Our laboratory studies the healing process in blood vessels which currently limits the long term success of procedures like angioplasty and bypass surgery. Our goals are to develop new drug and molecular therapies to prevent failures due to vessel re-narrowing, and to better identify patients at increased risk.

Rahul C Deo, M.D., Ph.D.
Assistant Professor

Research Interests:
Genetic variants underlying cardiovascular and metabolic disease

Summary:
We are now surrounded by an unprecedented amount of information about the human genetic variation that influences who will develop cardiovascular disease. Although more variants are likely to be found, we can now turn our attention to deciphering the mechanisms by which this variation in DNA ultimately governs the differences from individual to individual. My research is focused on tackling this problem in several ways, combining experimental and emerging computational approaches to take advantage of the enormous amount of new molecular information in the public domain. Specifically, I hope to adapt the sorts of statistical learning tools used in finance and engineering (and consumer marketing!) to narrow the list of likely genes that determine our cholesterol levels. Guided by this information, I hope to move to the experimental laboratory to then decipher how individual variation affects the amount of these genes, and to break down how common environmental exposures influence their levels. My ultimate aim is to identify potential new drug targets and develop new means to classify patients according to their "molecular fingerprints" under stress.

Jeffrey R Fineman, M.D.
Professor in Residence

Research Interests:
Endothelial regulation of the pulmonary circulation during normal development and during the development of pediatric pulmonary hypertension disorders. Endothelial dysfunction in pediatric pulmonary hypertension

Summary:
Pulmonary hypertension, high blood pressure in the lungs, is a serious disorder in subsets of neonates, infants, and children. These include newborns with persistent pulmonary hypertension of the newborn (PPHN), children with congenital heart defects, and teenagers and young adults with primary pulmonary hypertension. The vascular endothelium (the cells that line the blood vessels in the lungs), via the production of vasoactive factors such as nitric oxide and endothelin-1, are important regulators of the tone and growth of pulmonary blood vessels. We utilize an integrated physiologic, biochemical, molecular, and anatomic approach, to study the potential role of aberrant endothelial function in the pathophysiology of pulmonary hypertensive disorders. To this end, we utilize fetal surgical techniques to create animal models of congenital heart disease, and investigate the early role of endothelial alterations in the pathophysiology of pulmonary hypertension secondary to congenital heart disease with increased pulmonary blood flow. Our clinical research interests include the use of pulmonary vasodilator therapy for pediatric pulmonary hypertension, and the use of peri-operative BNP levels as marker of outcome following repair of congenital heart disease.

Guo Huang, Ph.D.
Assistant Prof in Residence

Research Interests:
Comparative study of heart development and regeneration, ischemic heart diseases, stem cell, cardiomyocyte proliferation, regenerative biology

Summary:
The ability to regenerate damaged or lost tissues varies dramatically across organisms and developmental stages. For example, heart regeneration is robust in adult zebrafish and newborn mouse while very limited in adult mouse and human. This presents a particular problem for patients with a heart attack who suffer from a significant loss of heart muscle cells and subsequent life-threatening functional deterioration of the heart.

By taking a comparative approach to study regenerative versus non-regenerative heart repair processes in zebrafish and mouse, we seek to uncover ancestrally conserved injury responses and more importantly, to identify the signals blocking regeneration in the mammalian heart and consequently new treatment strategies for heart diseases.

Yuet W Kan, M.D. , D.Sc.
Professor

Research Interests:
The mechanisms of globin production and exploring novel ways of inserting genes into mammalian cells; investigating newer approaches for fetal diagnosis of genetic disorders

Summary:
Sickle cell anemia and thalassemia are the most common genetic diseases and affect people of African, Mediterranean, Middle Ease and Southeast Asian origins. Our laboratory has pioneered the diagnosis of these conditions by DNA tests and is currently investigating the use of patient specific stem cells for their treatment.

John P Kane, M.S., M.D., Ph.D.
Professor

Research Interests:
Structure and function of lipoproteins; genetic determinants of arteriosclerosis

Summary:
The Kane laboratory focuses on the discovery of the native structures of lipoproteins ( proteins that carry cholesterol so that we can better understand how they are involved in the development of heart disease and stroke. We are also active in the discovery of alterations in genes that lead to heart disease and stroke.

Ronald M Krauss, M.D.
Adjunct Professor

Research Interests:

Summary:
Lipoprotein metabolism and risk of cardiovascular disease

Despite recent advances in treatment, cardiovascular disease (CVD) remains the leading cause of death in the US and will soon achieve this status globally. Our group's research is aimed at addressing three major challenges for reducing this enormous disease burden. First, standard diagnostic procedures do not identify a high proportion of children and adults who are at risk for CVD. We have developed and implemented a sophisticated new procedure that, by analyzing individual lipoprotein particles, provides more specific information than that afforded by ordinary cholesterol testing, and hence is capable of improving both the assessment and management of CVD risk. Second, dietary and lifestyle guidance has failed to substantially impact CVD risk factors, particularly those related to overweight and obesity. We have demonstrated that carbohydrate restriction can reverse the high risk lipid profile found in a high proportion of overweight and obese individuals even without weight loss, and that this effect is independent of saturated fat intake. These findings have helped support dietary guidelines that place a greater emphasis on limiting refined carbohydrates than fats. Third, despite the awareness of wide interindividual variability in response to treatments aimed at reducing CVD risk, the potential benefits of applying genomic tools for developing personalized approaches for maximizing CVD risk reduction have not been realized. A major component of our research program has been the application and development of genomic methodology for dissecting genetic influences on the therapeutic responses to statins, the most widely prescribed class of drugs for reducing CVD risk.

Theodore W Kurtz, M.D.
Prof in Res & Vice Chair

Research Interests:
Molecular Genetics of Complex Disease, Genetic Models of Hypertension and the Metabolic Syndrome, Transcription Modulating Drugs

Summary:
Hypertension affects 30% of the population and is a major cause of stroke, kidney failure, and heart disease. Patients with hypertension are also at increased risk for diabetes. Our laboratory is studying genetic mechanisms that promote increased blood pressure with the goal of identifying new opportunities for the prevention and treatment of hypertension, diabetes, and cardiovascular disease.

Pui-Yan Kwok, M.D., Ph.D.
Professor

Research Interests:
Genetic analysis of complex traits, DNA technology development

Summary:
We are developing efficient methods to analyze single DNA molecules and applying molecular genetic tools to identify genetic factors associated with complex human traits such as longevity, sudden cardiac arrest, stroke, psoriasis, lupus, and kidney transplantation outcome. We are also conducting studies to identify genetic factors associated with drug response. The overall goal of our research is to develop the tools for genetic analysis of whole genomes and apply these tools to elucidate the genetic factors associated with common human diseases and phenotypes. The sequencing of the human genome and the mapping of common genetic variation by the International HapMap Consortium, in which our lab participated, have inspired an explosion of new technologies, accelerating identification of genetic susceptibility loci. Our phenotypes of interest include kidney transplantation outcomes, longevity, pharmacogenetics of membrane transporters, sudden cardiac death, psoriasis, skin cancer and brian vascular malformations and hemorrhage.

Robert W Mahley, B.S., Ph.D., M.D.
Director

Research Interests:
I. Plasma lipoprotein metabolism Hepatic and intestinal origin of plasma lipoproteins; Apolipoprotein structure and function, especially apolipoprotein (apo) E and apoB; Characterization of cell surface receptors for lipoproteins; Role of the liver in cholesterol homeostasis. II. Relationship of plasma lipoproteins to the development and progression of atherosclerosis Role of diet in progression of coronary artery heart disease; Effect of apoE production in the artery wall on inhibition of atherogenesis. III. Role of apoE in the nervous system Effect on peripheral nerve injury and repair; Role in the pathogenesis of Alzheimer's disease; Effect on neuronal cytoskeleton. IV. Turkish Heart Study Director of epidemiological study to determine the risk factors responsible for coronary artery disease in Turkey; Characterization of genetic polymorphisms responsible for low HDL-C levels and metabolic syndrome in Turks; Co-director of physician continuing education program for Turkish doctors and medical students in the area of cardiovascular disease.

Summary:
My research has focused on the structure and function of apolipoprotein (apo) E, specifically its critical role in cholesterol homeostasis and atherosclerosis and, more recently, in Alzheimer's disease and neurodegeneration. ApoE regulates the clearance of plasma lipoproteins by mediating their binding to lipoprotein receptors and is also involved in peripheral nerve regeneration, lipid transport in the nervous system, and cytoskeletal stability and neurite extension and remodeling. A goal of our research is to develop a drug that will block the detrimental effects of apoE4 in cardiovascular and neurodegenerative disorders.

Mary J. Malloy, M.D.
Senate Emeritus

Research Interests:
Molecular mechanisms in lipoprotein metabolism; genetic basis of metabolic disorders of lipoproteins and of arteriosclerosis

Summary:
My chief research foci are the discovery of previously unknown disorders that affect the metabolism of cholesterol and other lipids, and the discovery of genes that are associated with the risk of heart attack and stroke. Identification of these diseases and genetic markers of risk will lead to improved prevention and treatment of coronary disease and stroke.

Jeffrey E Olgin, M.D.
Professor and Chief

Research Interests:
Cardiac Electrophysiology, Arrhythmias, Mechanisms, Remodeling, Cardiac Fibrosis, Atrial Fibrillation, Cardiac Ablation, Mouse models, animal models, mouse electrophysiology, optical mapping, atrial fibrillation ablation, clinical trials.

Summary:

Nelson B Schiller, M.D.
Professor of Cardiology

Research Interests:
Dr. Schiller specializes in the use of echocardiography in the diagnosis and treatment of heart disease. His research interests center around the quantitation of left ventricular function by quantitative two-dimensional echocardiography and Doppler.

Summary:
Measuring the heart has been a preoccupation of civilizations since ancient Egypt. Measuring the heart using noninvasive techniques that are free of ionizing radiation has riveted the attention of modern medicine because knowledge of the size of the heart's anatomic parts provides powerful diagnostic and therapeutic information. Dr. Nelson B. Schiller a member of the Department of Medicine, Cardiology Division, CVRI and John J. Sampson-Lucie Stern Endowed Chair in Cardiology, has spent his career investigating the application of echocardiography to the precise measurement and clinical application of the volume, weight and hemodynamics of the chambers and valves of the heart. His work is currently centered on the Heart and Soul Study (Mary Whooley, MD PI), where echocardiography measurements are being related to outcomes of heart disease.

Arthur Weiss, M.D., Ph.D.
Chief of Rheumatology

Research Interests:
Cell Surface Molecules and Molecular Events Involved in Lymphocyte Activation

Summary:
Dr. Weiss studies on how the functions of cells of the immune system are regulated. The immune system protects individuals from infections and malignancies. However, it is also involved in undesirable destructive responses, such as in autoimmune and allergic diseases as well as atherosclerosis and transplant rejection.

Ethan J Weiss, M.D.
Associate Professor

Research Interests:
Coagulation, thrombosis, hemostasis, fibrinolysis, genetics, platelet, sexual dimorphism, growth hormone signaling, fatty liver disease, regulation of energy metabolism and obesity

Summary:
Our group has two main interests. The first is to understand the mechanisms underlying the regulation of energy metabolism by growth hormone. Growth hormone is well-known to promote lipolysis as a means of mobilizing energy from stores in the form of free fatty acids. To accommodate tissues and organs with increased energy needs, fatty acid uptake is also regulated by growth hormone. The precise molecular mechanisms driving these two processes remain unclear. With an aim toward understanding mechanisms of obesity and related conditions, we use a molecular and cellular approach combined with mouse genetic models to understand how growth hormone regulates lipolysis and the uptake of fatty acid by cells and tissues.

Our second interest is in defining novel mechanisms of thrombosis susceptibility. Our group has had a long interest in thrombosis. Recently, we have focused on understanding ways to modulate thrombosis risk without increasing the risk of bleeding. Here, we also use molecular, cellular, and mouse genetics approaches.

Prescott G Woodruff, M.D., M.P.H.
Associate Professor

Research Interests:
Genomics, Asthma, Chronic Obstructive Pulmonary Disease, Stereology, Epidemiology, Clinical Trials, Medical Education

Summary:
My research relates to two common lung diseases, asthma and chronic obstructive pulmonary disease, and falls into three specific categories: 1) the identification of molecular sub-phenotypes of these diseases, 2) the elucidation of mechanisms of inflammation and remodeling in these diseases and 3) clinical trials of novel therapies.

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