Roger J. Hajjar, MD
Molecular, Cellular, Clinical Approaches to Heart Failure
Dr. Roger Hajjar was recruited from Massachusetts General Hospital and Harvard Medical School to head the Cardiovascular Research Center at Icahn School of Medicine.
Prior to coming to Mount Sinai, Dr. Hajjar was an Associate Professor of Medicine at Harvard Medical School and Staff Cardiologist in the Heart Failure & Cardiac Transplantation Center at Massachusetts General Hospital. He was the director of the Cardiology Laboratory of Integrative Physiology & Imaging at Massachusetts General Hospital. He received his medical degree from Harvard Medical School and trained in Internal Medicine and Cardiology at Massachusetts General Hospital in Boston.
Congestive heart failure (CHF) represents an enormous clinical problem demanding effective therapeutic approaches. Our laboratory focuses on targeting molecular and cellular pathways to improve contractile function and survival in failing cardiac myocytes. We are targeting specific abnormalities that have been identified in failing hearts at the cellular level by gene transfer. These targets involve membrane channels, intracellular transporters involved in calcium homeostasis, and intracellular pathways involved in cell survival.
1. Targeting Calcium Cycling Proteins
Contraction and relaxation in cardiac myocytes are tightly regulated by intrinsic mechanisms that govern the sequential rise and fall of cytosolic Ca2+. During depolarization, Ca2+ entry through the L-type Ca2+ channels triggers the release of Ca2+ from the sarcoplasmic reticulum (SR) through ryanodine receptors resulting in activation of the contractile proteins. In human cardiomyocytes, the removal of Ca2+ from the cytoplasm is governed mainly by the SR Ca2+ ATPase (SERCA2a) pump and to a lesser extent the Na/Ca exchanger as shown. Cardiomyocytes isolated from failing human hearts are characterized by contractile dysfunction including prolonged relaxation, reduced systolic force and elevated diastolic force. These contractile abnormalities are paralleled by abnormal Ca2+ homeostasis such as reduced SR Ca2+ release, elevated diastolic Ca2+ and reduced rate of Ca2+ removal. In addition, failing human myocardium is characterized by a frequency-dependent decrease in systolic force and Ca2+ as opposed to normal myocardium where an increase in pacing rate results in potentiation of contractility and an increase in SR Ca2+ release. In the failing heart, the decrease in SR Ca2+ load has been linked to a decrease in SR Ca2+ ATPase function. We have recently shown that overexpression of SERCA2a by adenoviral gene transfer restores contractile function in cardiac myocytes from failing human hearts. In addition, we have shown that overexpression of SERCA2a in a model of pressure-overload hypertrophy in transition to failure improves contractile function and reserve in these animals. We are currently exploring the effect of long-term expression of SERCA2a in failing animals along with the energy cost of SERCA2a expression using NMR methods. We are also using a different strategy to improve SR Ca2+ ATPase activity, which involves decreasing the expression of phospholamban by antisense strategies to enhance SR Ca2+ ATPase activity.
2. Clinical Trials in Gene Therapy for Heart Failure
Our laboratory has extended these studies in large animal models and is developing novel molecular imaging techniques to better track gene transfer. In addition, our laboratory is using both genomics and proteomics approaches to identify new targets based on the restoration of contractile function following SERCA2a gene transfer. The large body of data generated by our laboratory to establish SERCA2a as a key target for gene transfer in heart failure has culminated in the initiation of two key clinical trials: 1) Calcium Up-Regulation by Percutaneous Administration of Gene therapy In Cardiac Disease (CUPID Trial), A Phase 1 Trial of Intracoronary Administration of MYDICAR™ (AAV1/SERCA2a) in Subjects with Heart Failure Divided into Two Stages: Stage One Open-Label, Sequential Dose-Escalation Cohorts Followed in Stage Two by Randomized, Double-Blind, Placebo-Control, Parallel Cohorts and 2) the NIH-funded clinical trial "Gene Therapy with Adeno-associated Virus Carrying SERCA2a in Patients With Advanced Heart Failure Undergoing Ventricular Assist Device Placement." These trials will demonstrate the bench-to-bedside application of his research.
3. Targeting the Transient Outward Current
Action potential prolongation is attributed to reductions in transient outward current (Ito) density in human heart failure. This prolongation can improve contractility but can also cause after depolarization. Using gene transfer of various K channels responsible for Ito, we are investigating the molecular and the ionic basis of action potential prolongation in cardiac hypertrophy and failure and we are examining how intracellular calcium handling changes in response to alterations in action potential duration.
4. Gene Transfer in Aging Myocardium
Gene therapy in heart failure has the biggest potential in the aging population where the disease is rampant. However adenoviral gene transfer is less effective in aging cardiac cells than in younger cells. We are examining the molecular mechanisms responsible for this decrease in infectivity.
5. Viral Vectors
Scientists in Dr. Hajjar's research team are involved in the design and construction of novel viral vectors including mosaics of adeno-associated viruses (a collaboration with Dr. Jude Samulski of the University of North Carolina, Chapel Hill), and lentiviruses with promoters that infer cardiac specificity and long-term expression of targeted genes and their protein products.
6. Tracking Stem Cells in the Cardiovascular System
Dr. Hajjar's group is using newly developed molecular probes to track stem cells and to understand the biology of integration and the cellular fate of stem cells in large animal model of myocardial infarction and remodeling. These novel molecular probes generate contrast simultaneously for both magnetic resonance imaging (MRI) and near-infrared (NIR) fluorescent optical imaging. MRI permits stem cells to be identified in the normal and diseased hearts of large animals over time, non-invasively, and without sacrifice of the animal. NIR fluorescent optical imaging provides high sensitivity, and in some cases single cell sensitivity, which can be used for intraoperative physiological studies, and for histological correlation with other markers of cardiomyocyte function.
Hina Chaudhry, MD
Dr. Hina Chaudhry is Associate Professor of Medicine at Icahn School of Medicine and Director of Cardiovascular Regenerative Medicine. She was recruited from Columbia University College of Physicians and Surgeons where she was Florence Irving Assistant Professor of Medicine. Dr. Chaudhry is an NIH-funded physician-scientist whose basic research interests are focused on cardiac regeneration utilizing both cell cycle regulation and endogenous cardiac progenitors. Dr. Chaudhry received her medical degree with honors from Harvard Medical School, trained in internal medicine at Duke and cardiology at the Hospital of the University of Pennsylvania. She has trained in genetics and developmental biology at Columbia University. Her laboratory is focused on the function of cyclin A2, a cell cycle regulator, in cardiac development. Cardiomyocyte death with the ensuing loss of cardiac pump function is noted in many forms of cardiovascular disease. This decline of cardiovascular function might be partially abated if the surviving myocardium retained even a limited ability to proliferate. In mammalian hearts, cardiomyocytes proliferate throughout fetal development and into the early neonatal period. In the neonatal heart, DNA replication declines quickly and cardiomyocyte division ceases. Therefore, in adulthood, cardiac tissue cannot regenerate after injury such as myocardial infarction. A thorough understanding of the mechanisms of this process may potentiate therapeutic strategies for cardiomyocyte regeneration. Cell cycle progression in both normal and cancer cells is regulated by the expression of cyclins and the activation of their associated Cdks. Her research efforts are focused on the role of cyclin A2 in cardiac development and disease.
Fadi Akar, PhD
The Akar laboratory is dedicated to the investigation of arrhythmia mechanisms in structural heart disease at multiple levels of integration. Dr. Fadi Akar's group specializes in the development of novel imaging technologies using voltage, calcium and sodium fluorescent probes for the investigation of cardiac excitability and arrhythmias. A major focus resides in the study of abnormalities in action potential conduction and repolarization at the multicellular tissue network level using high-resolution optical mapping, and the elucidation of underlying mechanisms, using state-of-the-art cellular electrophysiological and molecular biological techniques. Specific areas of active research include mechanisms of mechano-electrical feedback, the electrophysiology of mechanical dysfunction during progression from compensated hypertrophy to end-stage heart failure in small and large animal models, the interaction of myocardial energetics and electrical function in post-ischemic remodeling and reperfusion related arrhythmias, the role of altered gene expression in transgenic mouse models or using gene transfer approaches on ion channel function, intracellular calcium handling, arrhythmogenesis and the development of realistic computational models of cardiac bioelectric properties.
Djamel Lebeche, PhD
Molecular and Cellular Approaches to Heart Failure
Dr. Djamel Lebeche, currently an Assistant Professor of Medicine, was recruited to the Cardiovascular Research Center from Massachusetts General Hospital where he was an instructor of Medicine at Harvard Medical School. Dr. Lebeche's research is focused on targeting molecular and cellular pathways to improve contractile function and survival in failing cardiac myocytes with particular interested in diabetes-induced left ventricular dysfunction. Using gene therapy approaches to target specific abnormalities, the genetic and cellular mechanisms underlying the pathophysiology of diabetic cardiomyopathy are being investigated in his laboratory. In addition, proteomic and genomic approaches are used to identify new targets in heart failure.
Yoshiaki Kawase, MD
Arrhythmias in Ischemic Cardiomyopathy
Dr. Yoshiaki Kawase was recruited from Massachusetts General Hospital and Harvard Medical School to join the Cardiovascular Research Center.
Prior to coming to Mount Sinai, Dr. Kawase was a research fellow of Medicine at Harvard Medical School. He was director of operations of the Cardiology Laboratory of Integrative Physiology & Imaging at Massachusetts General Hospital. He received his medical degree from Gifu University School of Medicine, Gifu, Japan, and trained in Internal Medicine and Cardiology at Gifu University School of Medicine. He also trained as an interventional cardiologist at National Toyohashi Higashi Hospital, Toyohashi, Aichi, Japan, and Toyohashi Heart Center, Toyohashi, Aichi, Japan. Dr. Kawase is focused on large animal models of arrhythmia caused by ischemic cardiomyopathy.
Zahi A. Fayad, PhD
Advanced Imaging in Cardiovascular Disease
Dr. Zahi Fayad is Director, Imaging Science Laboratories and Director, Cardiovascular Imaging Research. His is Professor of Medicine (Cardiology) and Radiology. Dr. Fayad's current research is in the development and use of multimodality cardiovascular imaging including magnetic resonance (MR), computed tomography (CT), positron emission tomography (PET) and molecular imaging using nanotechnology to study cardiovascular disease. His recent focus has been on the noninvasive assessment of atherosclerosis. He holds several patents in the field of imaging. Clinical and experimental observations have established the importance of atherosclerotic plaque composition, rather than size, in lesion vulnerability and subsequent thrombosis upon disruption.
Dr. Fayad has developed several techniques for the in vivo assessment of atherosclerotic plaques and for the study of cardiovascular morphogenesis and function using innovative imaging method. The work is currently focused on preclinical studies in animal models and human studies and clinical trials using multimodality (MR, CT, PET) imaging techniques.
Juan José Badimon, PhD
Atherothrombosis: Basic Mechanisms and Translational Research
Dr. Juan José Badimon is internationally recognized for his work on the role of lipids and thrombosis in cardiovascular disease. He was the first to demonstrate in experimental models the effect of HDL cholesterol in the removal of LDL cholesterol from the vessel wall, a discovery that has led to a better understanding of lipid metabolism and of such pharmacological potential for atherosclerotic plaque regression in humans. His animal models of experimental atherothrombotic disease have led to new discoveries regarding its nature. His Atherothrombosis Research Unit builds a bridge from bench studies to early clinical studies (Phase I and IIa) by combining multidisciplinary expertise (biochemical, pharmacology, physiology, imaging) and applying it to the research of the pathophysiologic processes involved in the genesis and progression of cardiovascular diseases. The laboratory has wide expertise in the use of several animal models of atherothrombosis (pigs, rabbits and mice). At the clinical level, Dr. Badimon's laboratory is actively involved in the performance of Phase I and Phase IIa and IIb clinical trials to test new therapeutic interventions (antithrombotic and lipid-altering) for cardiovascular diseases.
Martin A. Schwarz, PhD
Cardiovascular Research Development and Training
Dr. Martin A. Schwarz is Assistant Director of Cardiovascular Research Development and Training and Assistant Professor of Medicine. In 2008, Dr. Schwarz was recruited to the Cardiovascular Research Center (CVRC). Dr. Schwarz holds a doctoral degree in cell biology and immunology from the University of Texas Health Science Center-Houston. Prior to joining the CVRC at Mount Sinai he held the position of Director of the Office of Research and Sponsored Programs at the University of Medicine and Dentistry of New Jersey-New Jersey Medical School (UMDNJ-NJMS). At New Jersey Medical School, in addition to his administrative responsibilities, Dr. Schwarz was instrumental in establishing the NJMS Bridge Grant and Junior Faculty Mentoring Programs. As a basic scientist Dr. Schwarz spent his career in the pharmaceutical industry at the Schering-Plough Research Institute where he focused on drug discovery and pre-clinical development of small molecule and protein-based therapeutics for diseases of the immune system, such as rheumatoid arthritis. Several of the projects in which he was involved progressed through early and late phase clinical trials. For over 10 years, Dr. Schwarz has served on review panels for the K-series of Mentored Career Development Awards administered through the NHLBI of the NIH. Within the Cardiovascular Institute, Dr. Schwarz is developing programs to foster the basic, clinical or translational cardiovascular research activities of fellows in cardiology at Mount Sinai. One of the goals of these endeavors is to enable cardiology fellows to submit highly competitive applications for extramural support of their research activities.