SCOR IN HEART FAILURE

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Heart failure is a leading cause of disability and death in the U.S., affecting at least 2.5 million individuals, with an estimated 400,000 new cases per year. Progress in the prevention and treatment of heart failure has been limited in magnitude, due in large part to an incomplete understanding of basic biologic phenomena and mechanisms that underlie the clinical syndrome. This Heart Failure SCOR proposal attacks the problem across a spectrum from basic to clinical studies. Our unifying theme views heart failure as a continuum of basic phenomena and mechanisms that underlie the progression of events from an inciting cause e.g., a single base substitution in the DNA sequence of an individual or kindred with familial dilated or hypertrophic cardiomyopathy -- to the disturbances of cell and organ function and regulation that comprise the clinical syndrome of heart failure irrespective of the initial inciting cause. The participating Project Leaders have an extensive record of prior productive collaboration, and have focused their efforts on six interactive projects with substantial areas of interface. Project I seeks to test the hypothesis that nitric oxide (NO) produced in the myocardium regulates the contractile responsiveness of cardiac muscle to autonomic influences, and that inappropriate or excessive NO production contributes to contractile dysfunction and heart failure. This project interacts extensively with Project 2 which examines in humans the role of NO in normal myocardial and vascular regulation, and tests the hypothesis that disturbances of NO regulation contribute to the pathogenesis of clinical heart failure. Project 3 combines biophysical, biochemical, and molecular biological (transgenic) tools to test the hypothesis that decreased energy reserve via the creatine kinase system impairs contractile reserve in the failure myocardium. Project 4 also makes extensive use of transgenic technology to define the role of individual GTP-binding proteins in the normal and pathological function of cardiac cells, seeking to elucidate the role of G proteins in the disturbed transmembrane signalling processes known to exist in heart failure. We believe that a forward-looking program should address genetic factors that are primary in leading to heart failure, especially if the design of these studies is informed by new findings from patients with genetically-based forms of heart failure. Thus, Project 5 attacks the genetic basis of familial dilated cardiomyopathy seeking first to identify the chromosome(s) and causal gene(s) and mutations that form the basis of this cause of heart failure. Project 6 proposes to study heart failure in beta cardiac MHC gene missense mutations, using homologous recombination to produce well-defined mouse models of specific base substitutions known to cause the clinical manifestations of familial hypertrophic cardiomyopathy. Projects 1, 3, 4 and 6 will make extensive use of Core B for isolated cardiac myocyte preparation and functional characterization, while Projects 2 and 5 will use Core B later in the course of these studies. In all of these interactive projects, the collaborating investigators will maintain constant vigilance for opportunities to bring an enhanced understanding of fundamental biological and pathobiological phenomena and mechanisms to bear on improved prevention and treatment of patients at risk. The aggregate productivity of coordinated SCOR project efforts is expected to exceed that of the individual parts due to facilitation of the flow of ideas and technologies among investigators and projects.