The failing heart is unable to transfer effectively the chemical energy from the combustion of foodstuffs to contractile work. The consequences of metabolic dysfunction in heart failure are poorly understood, but there is strong evidence that impaired energy metabolism contributes to contractile dysfunction and to the progressive left ventricular remodeling that are characteristic of the heart failure state. The theme of this Program Project is the identification of abnormalities of myocardial energy substrate metabolism that occur with heart failure, and the effects of these abnormalities on left ventricular function and remodeling, and the progression of the disease. This Program consists of four projects and three core facilities. The projects are: Project 1: """"""""Metabolic Regulation in Heart Failure"""""""" Project 2: """"""""Fatty Acid Oxidation in Heart Failure Progression"""""""" Project 3: """"""""Metabolic Phenotype Switch in Heart Failure"""""""" Project 4: """"""""Mitochondrial Dysfunction in Heart Failure"""""""" The goal of all four projects is to identify the mechanisms regulating the metabolic changes that occur over the course of heart failure, and to elucidate the effects of these metabolic changes on contractile function and the progression of heart failure. Common questions are addressed by all projects regarding the mechanisms responsible for the alterations in metabolic phenotype in heart failure, and the consequences of these changes on cardiac function and progression of the disease. All studies will be performed in well-established large animal models of heart failure, and short and long-term manipulations of substrate metabolism will be used to elucidate the precise consequences of energy metabolism in the pathophysiology of heart failure. The major strength of this Program is the combination of in vivo studies on cardiac function and metabolism with the detailed assessment of biochemical regulators of cardiac phenotype and energy substrate metabolism.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL074237-04
Application #
7099673
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Evans, Frank
Project Start
2003-07-15
Project End
2007-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$1,791,520
Indirect Cost
Name
Case Western Reserve University
Department
Physiology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Lanfear, David E; Gibbs, Joseph J; Li, Jia et al. (2017) Targeted Metabolomic Profiling of Plasma and Survival in Heart Failure Patients. JACC Heart Fail 5:823-832
Maruyama, Sonomi; Nakamura, Kazuto; Papanicolaou, Kyriakos N et al. (2016) Follistatin-like 1 promotes cardiac fibroblast activation and protects the heart from rupture. EMBO Mol Med 8:949-66
Sabbah, Hani N; Gupta, Ramesh C; Kohli, Smita et al. (2016) Chronic Therapy With Elamipretide (MTP-131), a Novel Mitochondria-Targeting Peptide, Improves Left Ventricular and Mitochondrial Function in Dogs With Advanced Heart Failure. Circ Heart Fail 9:e002206
Ardell, J L; Andresen, M C; Armour, J A et al. (2016) Translational neurocardiology: preclinical models and cardioneural integrative aspects. J Physiol 594:3877-909
Lanfear, David E; Li, Jia; Abbas, Raza et al. (2015) Genetic Factors Influencing B-type Natriuretic Peptide-Mediated Production of Cyclic Guanosine Monophosphate and Blood Pressure Effects in Heart Failure Patients. J Cardiovasc Transl Res 8:545-53
Kop, Willem J; Galvao, Tatiana F; Synowski, Stephen J et al. (2015) Effects of environmental stress following myocardial infarction on behavioral measures and heart failure progression: The influence of isolated and group housing conditions. Physiol Behav 152:168-74
Roul, David; Recchia, Fabio A (2015) Metabolic alterations induce oxidative stress in diabetic and failing hearts: different pathways, same outcome. Antioxid Redox Signal 22:1502-14
Flori, Alessandra; Liserani, Matteo; Frijia, Francesca et al. (2015) Real-time cardiac metabolism assessed with hyperpolarized [1-(13) C]acetate in a large-animal model. Contrast Media Mol Imaging 10:194-202
Recchia, Fabio A (2015) Revascularization of hibernating myocardium: uneven reflorescence after the drought. J Am Coll Cardiol 65:698-700

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