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Heart failure and sudden cardiac death is the leading cause of mortality in the US. Development of effective therapies has been hampered by a lack of understanding of the mechanisms that cause these disorders. This symposium reviews the biology and current therapeutic approaches for treating sudden cardiac death, and discusses current research efforts to identify useful molecular targets and useful therapeutic approaches to combat this disease. The goal is to provide a review of current clinical treatments, and a discussion of new approaches to address this unmet medical need.
Sponsors
This meeting is part of our Translational Medicine Initiative, sponsored by the Josiah Macy Jr. Foundation.
Agenda
*Presentation times are subject to change.
Tuesday, September 28, 2010
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1:00 PM
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Clinical Overview of Heart Failure - The Unmet Medical Need
Mariell Jessup, MD, University of Pennsylvania College of Medicine
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1:40 PM
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Future G Protein-coupled Receptor Targets for Treatment of Heart Failure
Walter J. Koch, PhD, Thomas Jefferson University
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2:20 PM
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What is New in Targeted Molecular Therapy
Roger J. Hajjar, MD, Mount Sinai School of Medicine
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3:00 PM
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Coffee Break
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3:40 PM
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Targeting Signalling Circuits that Control Calcium in Heart Failure
Evangelia Kranias, PhD, University of Cincinnati College of Medicine
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4:20 PM
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Novel Mitochondrial Targets for Preventing Arrhythmias
Fadi G. Akar, PhD, Mount Sinai School of Medicine
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SpeakersOrganizers
Charles A. Lunn, PhD
Merck Research Laboratories Charles A. Lunn received his BA and PhD degrees from Johns Hopkins University in 1985. Following postdoctoral training with Masayori Inouye, he joined Schering-Plough‘s Department of Immunology in 1986. Now with New Lead Discovery at Merck, he has recently published on cannabinoid inverse agonists, and on screening using high throughput mass spectrometry. He is program coordinator for the Biochemical Pharmacology Steering Committee at the New York Academy of Sciences, and chair of the Society for Biomolecular Sciences Education Committee.
Martin A. Schwarz, PhD
Mount Sinai School of Medicine Dr. Schwarz holds a PhD in cell biology from the University of Texas Health Science Center in Houston. As the recipient of an Individual National Research Service Award from the NIH he completed postdoctoral training at the University of California, Irvine. As a basic researcher and laboratory head in the pharmaceutical industry his scientific portfolio includes over 15 years experience in preclinical drug development of novel therapeutics for treatment of diseases of the immune system and malignancies. From 2005-2008, he was Director of Research and Sponsored Programs at the University of Medicine & Dentistry of New Jersey, New Jersey Medical School. In this capacity he collaborated on developing a formal mentoring program for early career stage faculty in the basic and clinical sciences with an emphasis on developing independent investigators. In 2008, Dr. Schwarz joined the Cardiovascular Institute at the Mount Sinai School of Medicine where he is Assistant Director of Cardiovascular Research Development and Training and Assistant Professor of Medicine. At Mount Sinai, Dr. Schwarz, Dr. Valentin Fuster and Dr. Roger Hajjar have established a program to assist clinical fellows in the Cardiology Training Program and postdoctoral fellows in the basic sciences in pursuing academic careers. This program focuses on developing the next generation of independent investigators pursuing basic, translational and clinical cardiovascular research. In addition to his research and administrative activities, for over 10 years, Dr. Schwarz has served on numerous review panels for the Mentored Scientist Career Development and Institutional Training Awards sponsored through the National Heart Lung and Blood Institute of the NIH.
Jennifer Henry, PhD
The New York Academy of Sciences
Speakers
Fadi G. Akar, PhD
Mount Sinai School of Medicine Fadi G. Akar is Assistant Professor of Medicine at the Mount Sinai School of Medicine in New York and an adjunct Assistant Professor in the Division of Cardiology and Computational Medicine at Johns Hopkins University. Dr. Akar received a Bachelors of Science degree in Electrical Engineering from The Pennsylvania State University, and Masters and PhD degrees in Biomedical Engineering from Case Western Reserve University in Cleveland, where he trained in the laboratory of Dr. David Rosenbaum. Dr. Akar then completed a Post-doctoral Research Fellowship in the Institute of Molecular Cardiobiology at Johns Hopkins University under the supervision of Dr. Gordon Tomaselli. Dr. Akar was then a Research Associate and an Assistant Professor in Cardiology at Johns Hopkins. Dr. Akar joined the Cardiovascular Research Institute at Mount Sinai School of Medicine in 2007, where he established an experimental cellular electrophysiology and arrhythmia program. His work is aimed at uncovering mechanisms underlying sudden cardiac death across a variety of clinically relevant structural heart diseases. Specific areas of active research in the lab include mechanisms of mechano-electrical feedback during the early progression of heart failure, the interaction between mitochondrial function, myocardial energetics and electro-mechanical properties in post-ischemic remodeling and reperfusion related arrhythmias, and the role of altered gene expression and targeted gene delivery on ion channel function and arrhythmogenesis.
Roger J. Hajjar, MD
Mount Sinai School of Medicine
Dr Hajjar is the Director of the Cardiovascular Research Institute, and the Arthur & Janet C. Ross Professor of Medicine at Mount Sinai School of Medicine, New York, NY. He received his BS in Biomedical Engineering from Johns Hopkins University and his MD from Harvard Medical School and the Harvard-MIT Division of Health Sciences & Technology. He completed his training in internal medicine, cardiology and research fellowships at Massachusetts General Hospital in Boston.
Dr. Hajjar is a pioneer and internationally renowned scientific leader in the field of cardiac gene therapy for heart failure. His laboratory has validated the cardiac sarcoplasmic reticulum calcium ATPase pump, SERCA2a, as a target in heart failure, developed methodologies for cardiac directed gene transfer that are currently used by investigators throughout the world, and examined the functional consequences of SERCA2a gene transfer in failing hearts. His basic science laboratory remains one of the preeminent laboratories for the investigation of calcium cycling in failing hearts and targeted gene transfer in various animal models. The significance of Dr Hajjar’s research has been recognized with the initiation and recent completion of phase 1 and phase 2 First-in-Man clinical trials of SERCA2a gene transfer in patients with advanced heart failure under his guidance.
Dr. Hajjar has won numerous awards and distinctions, including the Young Investigator Award of the American Heart Association. He was awarded a Doris Duke Clinical Scientist award and has won first prize at the Astra Zeneca Young Investigator Forum. He is a member of the American Society for Clinical Investigation. Dr. Hajjar holds five NIH research grants (R01s), a Program project grant and multiple foundation grants including a Transatlantic Leducq Foundation award.
Dr Hajjar is the scientific co-founder of a number of biotechnology companies including Celladon Inc., Nanocor Co and Stemheal Inc.
Mariell Jessup, MD
University of Pennsylvania College of Medicine
Dr. Jessup is Professor of Medicine at the University of Pennsylvania School of Medicine, Associate Chief-Clinical Affairs, Cardiovascular Division of Medicine, and Medical Director of the Heart and Vascular Center at Penn Medicine. Her focus throughout her career has been on the optimal management of patients with heart failure, including the appropriate selection of patients for heart transplant or ventricular assist devices (VADs). Dr. Jessup has been a member of the committee to revise ACC/AHA Guidelines for the Management of Congestive Heart Failure, published in 2001 and most recently in 2005. She is now the Chair of the ACC/AHA Guidelines focused update for heart failure; the newest version of the guidelines were published in March, 2009. Dr. Jessup served on the American Heart Association’s Council of Clinical Cardiology Program Committee, and is currently Chair of the Committee for Scientific Sessions Program of the AHA. She is a member of the Board of Directors of the national AHA, and recently completed a 4-year term as an ABIM representative for the Residency Review Committee-Internal Medicine of the ACGME, and a 6-year term on the ABIM’s Cardiovascular Board. She has just joined the Board of the Advanced Heart Failure and Transplant cardiology secondary subspecialty. She served as the Co-chairman of the ISHLT’s Heart failure Council, and served on the Board of Directors of the ISHLT for 3 years. She is a member of the Executive Council of the Heart Failure Society of America, and currently serves as the secretary for the HFSA. She is on the Steering committee of the INTERMACs registry for ventricular assist devices.
Walter J. Koch, PhD
Thomas Jefferson University Dr. Koch is the W. W. Smith Professor of Medicine and currently serves as Director of the Center for Translational Medicine and Vice Chair for Research in Department of Medicine at Thomas Jefferson University. After receiving his Ph.D. in Pharmacology in 1990 in the Lab of Dr. Arnold Schwartz at the University of Cincinnati, Dr. Koch began at Duke in 1991 as a Howard Hughes Post-Doctoral Fellow in the Laboratory of Dr. Robert J. Lefkowitz. In 1995 he was recruited to start a cardiovascular biology laboratory in the Department of Surgery at Duke and rose through the ranks to tenured full Professor in 2001. Dr. Koch moved to Jefferson in 2003 to build the Center for Translational Medicine. The goal of the Center is to use cutting-edge laboratory research to create the best in clinical care and move laboratory discoveries “from the bench to bedside”. Specifically in the Koch Laboratory, studies are focused on the role of the G protein-coupled receptor kinases (GRKs), GRK2 and GRK5 in the heart. Recent studies have revealed that these GRKs not only act on receptors via phosphorylation and desensitization but they have novel roles that appear important in cardiac hypertrophy and failure. For example, GRK5 is also a HDAC kinase after nuclear translocation. GRK2 also appears to have non-receptor roles in the heart that appear pathological and make its inhibition a therapeutic target for heart diseases such as heart failure. These studies and current data will be discussed during this presentation.
Evangelia Kranias, PhD
University of Cincinnati College of Medicine Dr. Evangelia (Litsa) Kranias received her B.S. degree from the University of Chicago (1970) and her Masters and Ph.D. degrees from Northwestern University in Chicago (1974). She served as a postdoctoral fellow at Northwestern University Medical School, Chicago (1974-77). In 1978, she started her faculty career at the University of Cincinnati Medical Center, where she is currently a Distinguished University Research Professor, Hanna Professor of Cardiology, Chair of the Department of Pharmacology and Cell Biophysics, and co-Director of the Cardiovascular Center of Excellence. Dr. Kranias’ internationally recognized program in Molecular Cardiovascular Biology has provided key fundamental insights into the regulation of the normal and failing heart. The overall goal of Dr. Kranias’ research program has been to elucidate the regulatory mechanisms and signaling pathways in cardiac physiology and pathophysiology with special emphasis in heart failure. Her studies span from the laboratory bench to the clinical arena and have identified genes that may predispose to heart failure or even sudden death. Dr. Kranias has published over 210 original articles and 70 book chapters/review articles and has been invited to 130 National and over 100 International conferences. Her research has been continuously funded by National Institute of Health for the past 30 years and often with multiple grants. Dr. Kranias has received many awards and honors and has been elected as a Council Member to several Societies.
Sponsors
For sponsorship opportunities please contact Cristine Barreto at cbarreto@nyas.org or 212.298.8652.
This meeting is part of our Translational Medicine Initiative, sponsored by the Josiah Macy Jr. Foundation.
Academy FriendAbcam Inc.
Bristol-Myers Squibb Research and Development
Abstracts
Clinical Overview of Heart Failure - The Unmet Medical Need
Mariell Jessup, MD, University of Pennsylvania College of Medicine
Despite ongoing, active investigations there have been no major new medical therapies for chronic heart failure-either systolic or heart failure with preserved ejection fraction- in many years. Moreover, the field of new pharmacotherapies for acute heart failure has only included levosimendan and tolvaptan. Nevertheless, there continue to be many exciting possibilities with new drug classes, and novel mechanisms. These include agents to promote diuresis, facilitate myocardial relaxation, enhance inotropy or vasodilatation. What seems to be clear is that we have reached the limit of therapeutic benefit that may be derived from antagonism of the renin-angiotensin and sympathetic systems. Thus, drugs that exert influence on other pathways have been the focus of intense interest. Alternatively, more molecular based therapies are increasingly being explored. In addition, gene therapy, specifically targeted to increase myocardial levels of SERCA2 are now proceeding in phase II studies. An additional challenge in new drug development is a failure of the clinical research community to agree on end-points for clinical trials, making comparative effectiveness statements problematic. International consensus is needed to move the field forward.
Future G Protein-coupled Receptor Targets for Treatment of Heart Failure
Walter J. Koch, PhD, Thomas Jefferson University
For over 15 years, our laboratory has been researching the role of the G protein-coupled receptor kinases (GRKs) in myocardial function. This includes how GRKs are involved in the cardiovascular pathological processes of hypertension, ventricular hypertrophy and heart failure. Studies with GRK2 (also known as ßARKct) have shown from cell studies to whole animal studies that the increased activity of this kinase is pathological to the cardiomyocyte. Importantly, lowering its expression or activity has led to beneficial effects in several animal models of heart failure. Most recently, studies in myocyte-specific GRK2 knockout mice have revealed that the loss of GRK2 in heart cells prevents the development of heart failure after a myocardial infarction. In separate animal studies, gene therapy with a GRK2 inhibitor peptide has shown that lowering the activity of this kinase can reverse ventricular contractile failure and also adverse remodeling. Large animal pre-clinical studies are being done with gene therapy, however, development of small molecule inhibitors of GRK2 are warranted. Recent studies have revealed that these GRKs not only act on receptors via phosphorylation and desensitization but they have novel roles that appear important in cardiac hypertrophy and failure. For example, GRK5 is also a HDAC kinase after nuclear translocation and this activity promotes maladaptive hypertrophy. This lecture will focus on GRK2 and GRK5 as targets for heart failure therapy.
What is New in Targeted Molecular Therapy
Roger J. Hajjar, MD, Mount Sinai School of Medicine
Congestive heart failure remains a progressive disease with a desperate need for innovative therapies to reverse the course of ventricular dysfunction. Recent advances in understanding the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology have placed heart failure within reach of gene-based therapies. One of the key abnormalities in both human and experimental HF is a defect in sarcoplasmic reticulum (SR) function, which is responsible for abnormal intracellular Ca2+ handling. Deficient SR Ca2+ uptake during relaxation has been identified in failing hearts from both humans and animal models and has been associated with a decrease in the activity of the SR Ca2+-ATPase (SERCA2a). Over the last ten years we have undertaken a program of targeting important calcium cycling proteins in experimental models of heart by somatic gene transfer. This has led to the completion of a first-in-man phase 1 clinical trial of gene therapy for heart failure using adeno-associated vector (AAV) type 1 carrying SERCA2a. In this Phase I trial, there was evidence of clinically meaningful improvements in functional status and/or cardiac function which were observed in the majority of patients at various time points. The safety profile of AAV gene therapy along with the positive biological signals obtained from this phase 1 trial has led to the initiation and recent completion of a phase 2 trial of AAV1.SERCA2a in NYHA class III/IV patients. In the phase 2 trial, gene transfer of SERCA2a was found to be safe and associated with benefit in clinical outcomes, symptoms, functional status, NT-proBNP and cardiac structure.
Targeting Signalling Circuits that Control Calcium in Heart Failure
Evangelia Kranias, PhD, University of Cincinnati College of Medicine
A clinical hallmark of human and experimental heart failure is impaired sarcoplasmic reticulum (SR) calcium (Ca)-cycling, leading to depressed function. Thus, efforts have concentrated on elucidating the mechanisms contributing to aberrant SR Ca-homeostasis to uncover new therapeutic targets. The efficacy of restoring Ca-ATPase levels or inhibiting phospholamban activity has been tested in animal models of heart failure and human failing cardiomyocytes. Collectively, these studies indicate that both SERCA and phospholamban may represent attractive targets for correcting the deteriorated function in failing hearts. In addition, targeting the phospholamban-phosphatase through its Inhibitor-1 appeared to represent another therapeutic intervention. Indeed, gene delivery of inhibitor-1 restored function and reversed remodeling in failing hearts. Recently, we identified two new proteins associated with regulation of SR Ca-transport and overall Ca-homeostasis in the cardiomyocyte. One of them is HAX-1, the anti-apoptotic protein, which interacts with PLN and alters the PLN inhibitory function. The other one is the SR intraluminal histidine-rich Ca-binding protein (HRC), which interacts with SERCA and regulates the enzyme’s maximal Ca-transport velocity. Thus, HAX-1 and HRC may represent potential therapeutic targets in correcting the elevated diastolic Ca-levels in heart failure. Collectively, these studies indicate that increases in Ca-ATPase levels or activity (through PLN or HRC) and/or decreases in phospholamban levels or activity (through inhibitor-1 or HAX-1) may be beneficial in restoring SR Ca-cycling and function in the failing cardiomyocyte. Furthermore, human mutations have been identified in these SR Ca-cycling genes, which may serve as prognostic or diagnostic indicators for arrhythmias and heart failure development.
Novel Mitochondrial Targets for Preventing Arrhythmias
Fadi G. Akar, PhD, Mount Sinai School of Medicine
Mitochondrial dysfunction is a hallmark of many important cardiovascular diseases, including left ventricular hypertrophy, diabetic cardiomyopathy, heart failure, atherosclerosis, and other age-related disorders. Our long-term goal is to identify the mechanistic interplay between altered mitochondrial energetics and structural, contractile, and electrophysiological dysfunction at multiple levels of integration. We will discuss the development of new metabolic imaging techniques that allow the investigation of mitochondrial function within the intact heart and their implications for altered electrical and contractile function. Specifically, we will demonstrate how these integrative tools have led to the identification of new “metabolic fingerprints” for arrhythmias based on dynamic spatio-temporal changes in the the mitochondrial membrane potential. Finally, recent advances in the characterization of novel therapeutic targets for improving electro-mechanical properties by modulating mitochondrial function, in general and the mitochondrial membrane potential, specifically will be highlighted.
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