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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
1P50HL052320-01
Application #
2229639
Study Section
Special Emphasis Panel (ZHL1-CSR-J (S1))
Project Start
1995-01-15
Project End
1999-12-31
Budget Start
1995-01-15
Budget End
1995-12-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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Pinz, Ilka; Zhu, Ming; Mende, Ulrike et al. (2011) An improved isolation procedure for adult mouse cardiomyocytes. Cell Biochem Biophys 61:93-101
Shen, Weiqun; Vatner, Dorothy E; Vatner, Stephen F et al. (2010) Progressive loss of creatine maintains a near normal DeltaG approximately (ATP) in transgenic mouse hearts with cardiomyopathy caused by overexpressing Gsalpha. J Mol Cell Cardiol 48:591-9
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Gnecchi, Massimiliano; He, Huamei; Melo, Luis G et al. (2009) Early beneficial effects of bone marrow-derived mesenchymal stem cells overexpressing Akt on cardiac metabolism after myocardial infarction. Stem Cells 27:971-9
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Pinz, Ilka; Robbins, Jeffrey; Rajasekaran, Namakkal S et al. (2008) Unmasking different mechanical and energetic roles for the small heat shock proteins CryAB and HSPB2 using genetically modified mouse hearts. FASEB J 22:84-92
Pinz, Ilka; Wax, Stephen D; Anderson, Paul et al. (2008) Low over-expression of TNFalpha in the mouse heart increases contractile performance via TNFR1. J Cell Biochem 105:99-107
Hoyer, Kirsten; Krenz, Maike; Robbins, Jeffrey et al. (2007) Shifts in the myosin heavy chain isozymes in the mouse heart result in increased energy efficiency. J Mol Cell Cardiol 42:214-21

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