Influence of metabolic dysfunction on cardiac mechanics in decompensated hypertrophy and heart failure

Shivendra G. Tewari, Scott M. Bugenhagen, Kalyan C. Vinnakota, J. Jeremy Rice, Paul M L Janssen, Daniel A. Beard

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)162-175
Number of pages14
JournalJournal of Molecular and Cellular Cardiology
Volume94
DOIs
StatePublished - May 1 2016
Externally publishedYes

Fingerprint

Mechanics
Hypertrophy
Heart Failure
Myocardium
Calcium
Hyperemia
Myosins
Blood Volume
Oxygen Consumption
Pharmaceutical Preparations
Heart Ventricles
Canidae
Dilatation
Animal Models
Pharmacology
Pressure
Muscles

Keywords

  • Congestive heart failure
  • Frank-Starling law
  • Metabolism
  • Myofilaments
  • Omecamtiv mecarbil

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Influence of metabolic dysfunction on cardiac mechanics in decompensated hypertrophy and heart failure. / Tewari, Shivendra G.; Bugenhagen, Scott M.; Vinnakota, Kalyan C.; Rice, J. Jeremy; Janssen, Paul M L; Beard, Daniel A.

In: Journal of Molecular and Cellular Cardiology, Vol. 94, 01.05.2016, p. 162-175.

Research output: Contribution to journalArticle

Tewari, Shivendra G. ; Bugenhagen, Scott M. ; Vinnakota, Kalyan C. ; Rice, J. Jeremy ; Janssen, Paul M L ; Beard, Daniel A. / Influence of metabolic dysfunction on cardiac mechanics in decompensated hypertrophy and heart failure. In: Journal of Molecular and Cellular Cardiology. 2016 ; Vol. 94. pp. 162-175.
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