TY - JOUR
T1 - Influence of metabolic dysfunction on cardiac mechanics in decompensated hypertrophy and heart failure
AU - Tewari, Shivendra G.
AU - Bugenhagen, Scott M.
AU - Vinnakota, Kalyan C.
AU - Rice, J. Jeremy
AU - Janssen, Paul M.L.
AU - Beard, Daniel A.
N1 - Funding Information:
The authors acknowledge the financial support by the National Institutes of Health ( National Institute of General Medical Sciences award P50-GM094503 and National Heart, Lung, and Blood Institute award HL072011 ).
Publisher Copyright:
© 2016 Published by Elsevier Ltd.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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.
KW - Congestive heart failure
KW - Frank-Starling law
KW - Metabolism
KW - Myofilaments
KW - Omecamtiv mecarbil
UR - http://www.scopus.com/inward/record.url?scp=84963527079&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2016.04.003
DO - 10.1016/j.yjmcc.2016.04.003
M3 - Article
C2 - 27085901
AN - SCOPUS:84963527079
SN - 0022-2828
VL - 94
SP - 162
EP - 175
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -