Dr. Marbán received his M.D./Ph.D. (Physiology) degree from Yale University and completed his doctoral dissertation with Richard Tsien. Even as a graduate student, Marbán distinguished himself by performing the first reliable measurements of intracellular calcium concentration in heart muscle (1), work which is still widely quoted. Following completion of his clinical training at the Johns Hopkins Hospital in 1985, Dr. Marbán joined the faculty there and started his own laboratory. He was tenured and promoted to full professor six years later and eventually served as Chief of Cardiology at Johns Hopkins. In 2007, Dr. Marbán moved to Los Angeles to become the founding Director of the Heart Institute at Cedars-Sinai Medical Center, the birthplace of the Swan-Ganz catheter. His scientific accomplishments have been remarkable for their innovation, impact on his field, and their uniform high quality, as reflected in the prestige of the journals where he has published, and in outstanding peer-reviewed research support over the span of 26 years. Marbán served for ten years (1999-2009) as Editor in Chief of Circulation Research, is Consulting Editor for Circulation and Journal of Molecular and Cellular Cardiology, and an editorial board member of various other journals. He served on and chaired the Cardiovascular Study Section and was a member of the Program Project Review Committee of the National Heart, Lung and Blood Institute. Dr. Marbán is a member of various honorary societies, and is a regularly-invited speaker at national and international meetings (including talks at four Plenary Sessions of the American Heart Association). Previous major awards include the Lucian Award in Cardiovascular Diseases of McGill University (1999), the Basic Research Prize of the American Heart Association (2000), the Research Achievement Award of the International Society for Heart Research (2001), the Distinguished Scientist Award of the American Heart Association (2004), the Gill Heart Institute Award (2006), and the Award of Meritorious Achievement of the American Heart Association (2009). In recognition of his scientific and programmatic accomplishments, Dr. Marbán served as President of the Cardiac Muscle Society (1999-2003), and as Chairman (2000-2002) of the Basic Cardiovascular Sciences Council of the American Heart Association, which we are proud to note represents the largest group of cardiovascular scientists in the world. Finally, a particularly noteworthy feature of Dr. Marbán's career has been his outstanding record as a mentor. More than 25 of his trainees have gone on to become productive, independent full professors nationally and internationally. Dr. Marbán serves as Professor in Residence in the Departments of Medicine and Physiology at UCLA.
Dr. Marbán's research revolves around tightly-interwoven central themes: What are the molecular determinants of cardiac excitability and contractility, how do they go awry in disease states, and what can we do therapeutically? His productivity can be subdivided into the following categories:
Heart failure. This important disease entity has been a focus of Dr. Marbán's interest since his time at Yale, where he elucidated a novel mechanism of action for cardiotonic steroids such as digitalis. Later, he went on to characterize the basic defects of excitation-contraction coupling and of electrical stability in failing heart cells. Until Dr. Marbán's pioneering work, there was little pathophysiological understanding of the basis of such heart failure arrhythmias. His work has led to a systematic program of investigation that has culminated in a novel, widely-accepted hypothesis for the pathogenesis of sudden death in heart failure. Dr. Marbán directed (1995-2005) the NIH-funded Specialized Center of Research at Hopkins, the major international center focused on sudden death in heart failure, spanning all the way from basic biology to clinical studies. Currently, Dr. Marbán is working on a variety of innovative cell therapy strategies for the treatment of heart failure.
Arrhythmias. Dr. Marbán has extensively investigated the fundamental questions of how ion channels open and close, and how selective ion flux is generated. His studies were the first to provide specific constraints for intramolecular dimensions of the sodium channel pore (2). Dr. Marbán has successfully leveraged his expertise in fundamental ion channel biology to achieve important translational advances. Notably, his team has pioneered somatic gene transfer methods to modify excitability in heart and nerve (3), laying the groundwork for gene therapy of cardiac arrhythmias and other disorders of excitability. His laboratory has single-handedly defined the latter field, with the development of approaches to correct both the lesion of contractility and that of arrhythmogenesis in heart failure, proof of the principle that gene therapy can be used to treat a common cardiac arrhythmia (atrial fibrillation) in vivo (4), and the creation of a biological pacemaker by gene transfer (5). Finally, Dr. Marbán founded and directed the largest academic program in the world focused on sudden cardiac death research, which has identified several new genes involved in the regulation of the electrocardiographic QT interval and in risk for sudden death, using novel whole genome association methods.
Interactions of energy metabolism with excitability and contractility. Dr. Marbán has discovered a number of novel pathways whereby changes in cellular energy metabolism feed back upon and influence cardiac function (6). He discovered that myocardial cells subjected to modest energetic stress exhibit profound oscillations of energy metabolism that result in oscillations of cellular excitability (7). These oscillations constitute a previously unrecognized mechanism of the fatal ventricular arrhythmias that complicate cardiac ischemia.
Ischemic injury and excitation-contraction coupling. Dr. Marbán has shaped our contemporary understanding of the pathogenesis and pathophysiology of stunned myocardium, a common acquired form of heart failure that follows ischemia. He was the first to demonstrate that the primary lesion of excitation-contraction coupling resides at the level of contractile proteins, thereby refuting the commonly-held belief that stunning is caused by insufficient availability of activator Ca2+. His subsequent work has led to the widely-accepted hypothesis that proteolytic injury to the myofilaments, and specifically to troponin I, accounts for the phenotype of stunned myocardium. This hypothesis has been decisively validated by Dr. Marbán's creation of the first transgenic model of stunned myocardium in mice expressing a troponin I degradation fragment in the heart (8). Dr. Marbán has expanded his interests in the area of ischemic injury to include the cellular basis of ischemic preconditioning, where he produced the first evidence for a key role of mitochondrial ATP-dependent potassium channels as the effectors of preconditioning in intact cells.
Stem cells. For the last 14 years, Dr. Marbán has concentrated on the use of stem cells for therapeutics. The work ranges from skeletal myoblasts, where he pioneered the concept of anti-arrhythmic engineering by forced ectopic expression of connexin 43, to human embryonic stem cells, which his team transplanted into hearts to create biological pacemakers (9). Marbán's major interest now lies in resident cardiac stem cells. Dr. Marbán's laboratory was the first to isolate and characterize a type of cardiac stem cell called cardiosphere-derived cells (CDCs) from patients using minimally-invasive endomyocardial biopsies. In a systematic bench-to-bedside approach, Dr. Marbán isolated human CDCs and characterized their physiological properties in vitro, went on to demonstrate their engraftment, differentiation and functional benefit in various animal models of heart injury (10-13), then undertook all the complex regulatory filings required to initiate clinical studies. The NIH-funded randomized CADUCEUS study, which was reported recently (14), administered autologous CDCs to patients with recent heart attacks. Intracoronary infusion of CDCs was found to be safe and effective in regenerating infarcted myocardium and improving regional function in post-MI patients with ventricular dysfunction. The work is conceptually important in providing the first evidence for therapeutic regeneration in a controlled clinical trial. Scar tissue was reduced, while new healthy tissue was generated, in response to therapy with CDCs. This discovery challenges the conventional wisdom that, once established, scar is permanent and that, once lost, healthy heart muscle cannot be restored.
3. Summary. Dr. Marbán is a physician-scientist who has made many seminal contributions to our understanding of heart disease, and who has trained a remarkable number of accomplished faculty. His work on stunning is the first example of the identification of the molecular basis of an acquired form of heart failure. His work on the role of mitochondrial KATP channels in preconditioning has major potential therapeutic implications. Marbán's discoveries in stem cell research and regenerative medicine are already shaping the future of cardiology.