The hypothesis that the failing heart is energy starved is both long- standing and controversial. There is now convincing evidence from both failed human myocardium and animal models of severe heart failure that the [ATP] is as much as 25% lower than in normal myocardium and animal models of severe heart failure that the [ATP] is as much as approximately 25% lower than in normal myocardium. We present evidence showing that the decrease is due to a loss of the purine pool. Based on results using NMR spectroscopy and chemical assay, we and others have shown that the tissue contents of phosphocreatine (PCr) and creatine and the capacity of the CK reaction (Vmax) are also lower. These observations increase our understanding of two important aspects of cardiac energetics (PCr) and creatine and the capacity of the CK reaction (Vmax) are also lower. These observations increase our understanding of two important aspects of cardiac energetics: the kinetics of ATP synthesis and the thermodynamics of ATP utilization, i.e. the chemical driving force for the ATP-consuming reactions. Our observations that the creatine and purine pools are lower in the failing heart have important implications for understanding the energetics of the failing heart. Because the concentrations of these substrates are lower, the velocities of the reactions they support must be lower. However, the driving force for ATPases of muscle contraction may not be compromised. This new information leads to the following hypothesis: that the loss of creatine in the failing myocardium is an important compensatory mechanism preserving the driving force of the ATPase reactions. Little is known about the regulation of either creatine transport or de novo purine synthesis in the failing heart. Accordingly, the primary goal of the proposed research plan is to define the mechanisms whereby creatine and purine pools are depleted in the failing heart. A closely related goal is to manipulate the ATP/ADP and PCr/creatine ratios in normal and failing hearts (due to prolonged aortic banding in the rat), and in hearts with low CK Vmax caused by gene deletions of specific CK isozymes, to define the energetic state of the failing heart no longer capable of supporting normal contractile performance and contractile reserve.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL052320-07
Application #
6421861
Study Section
Project Start
2001-02-01
Project End
2002-01-31
Budget Start
Budget End
Support Year
7
Fiscal Year
2001
Total Cost
$214,676
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Herman, Daniel S; Lam, Lien; Taylor, Matthew R G et al. (2012) Truncations of titin causing dilated cardiomyopathy. N Engl J Med 366:619-28
Alcalai, Ronny; Wakimoto, Hiroko; Arad, Michael et al. (2011) Prevention of ventricular arrhythmia and calcium dysregulation in a catecholaminergic polymorphic ventricular tachycardia mouse model carrying calsequestrin-2 mutation. J Cardiovasc Electrophysiol 22:316-24
Pinz, Ilka; Zhu, Ming; Mende, Ulrike et al. (2011) An improved isolation procedure for adult mouse cardiomyocytes. Cell Biochem Biophys 61:93-101
Saltzman, Adam J; Mancini-DiNardo, Debora; Li, Chumei et al. (2010) Short communication: the cardiac myosin binding protein C Arg502Trp mutation: a common cause of hypertrophic cardiomyopathy. Circ Res 106:1549-52
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
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
Pinz, Ilka; Ostroy, Sanford E; Hoyer, Kirsten et al. (2008) Calcineurin-induced energy wasting in a transgenic mouse model of heart failure. Am J Physiol Heart Circ Physiol 294:H1459-66
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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