title: Influence of metabolic dysfunction on cardiac mechanics in decompensated hypertrophy and heart failure.
abstract: Alterations in energetic state of the myocardium are associated with decompensated heart failure in humans and in animal models. However, the functional consequences of the observed changes in energetic state on mechanical function are not known. The primary aim of the study was to quantify mechanical/energetic coupling in the heart and to determine if energetic dysfunction can contribute to mechanical failure. A secondary aim was to apply a quantitative systems pharmacology analysis to investigate the effects of drugs that target cross-bridge cycling kinetics in heart failure-associated energetic dysfunction. Herein, a model of metabolite- and calcium-dependent myocardial mechanics was developed from calcium concentration and tension time courses in rat cardiac muscle obtained at different lengths and stimulation frequencies. The muscle dynamics model accounting for the effect of metabolites was integrated into a model of the cardiac ventricles to simulate pressure-volume dynamics in the heart. This cardiac model was integrated into a simple model of the circulation to investigate the effects of metabolic state on whole-body function. Simulations predict that reductions in metabolite pools observed in canine models of heart failure can cause systolic dysfunction, blood volume expansion, venous congestion, and ventricular dilation. Simulations also predict that myosin-activating drugs may partially counteract the effects of energetic state on cross-bridge mechanics in heart failure while increasing myocardial oxygen consumption. Our model analysis demonstrates how metabolic changes observed in heart failure are alone sufficient to cause systolic dysfunction and whole-body heart failure symptoms.
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Shivendra G
authors.initials: SG
authors.lastname: Tewari
authors.affiliation: Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, United States.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Bugenhagen
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Kalyan C
authors.initials: KC
authors.lastname: Vinnakota
authors.affiliation: Functional Genomics and Systems Biology Group, IBM T.J. Watson Research Center, New York, United States.
authors.forename: J Jeremy
authors.initials: JJ
authors.lastname: Rice
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH 43210, United States.
authors.forename: Paul M L
authors.initials: PML
authors.lastname: Janssen
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, United States. Electronic address: beardda@umich.edu.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Beard
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000465:Algorithms; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D003198:Computer Simulation; D004734:Energy Metabolism / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D006334:Heart Function Tests; D006801:Humans; D006868:Hydrolysis; D008954:Models, Biological; D009210:Myofibrils / Q000378:metabolism; D009929:Organ Size; D010641:Phenotype; D018754:Ventricular Dysfunction / Q000188:drug therapy
chemical_list: D000255:Adenosine Triphosphate
keywords: Congestive heart failure; Frank-Starling law; Metabolism; Myofilaments; Omecamtiv mecarbil