Origin of contractile dysfunction in heart failure: Calcium cycling versus myofilaments

N. Gustavo Pérez, Katsuji Hashimoto, Sylvia McCune, Ruth A. Altschuld, Eduardo Marbán

Research output: Contribution to journalArticlepeer-review

Abstract

Background - Chronic congestive heart failure is a common, often lethal disorder of cardiac contractility. The fundamental pathophysiology of the contractile failure remains unclear, the focus being on abnormal Ca2+ cycling despite emerging evidence for depressed myofilament function. Methods and Results - We measured intracellular Ca2+ concentration ([Ca2+](i)) and contractile force in intact ventricular muscle from SHHF rats with spontaneous heart failure and from age-matched controls. At physiological concentrations of extracellular Ca2+ ([Ca2+](o)), [Ca2+](i) transients were equal in amplitude in the 2 groups, but [Ca2+](i) peaked later in SHHF muscles. Twitch-force peaked slowly and was equivalent or modestly decreased in amplitude relative to controls. Steady-state analysis revealed a much greater (53%) depression of maximal Ca2+-activated force in SHHF muscles, which, had other factors been equal, would have produced an equivalent suppression of twitch force. Phase-plane analysis reveals that the slowing of Ca2+ cycling prolongs the time available for Ca2+ to activate the myofilaments in failing muscle, partially compensating for the marked dysfunction of the contractile machinery. Conclusions - Our results indicate that myofilament activation is severely blunted in heart failure, but concomitant changes in [Ca2+](i) kinetics minimize the contractile depression. These results challenge prevailing concepts regarding the pathophysiology of heart failure: the myofilaments emerge as central players, whereas changes in Ca2+ cycling are reinterpreted as compensatory rather than causative.

Original languageEnglish (US)
Pages (from-to)1077-1083
Number of pages7
JournalCirculation
Volume99
Issue number8
StatePublished - Mar 2 1999

Keywords

  • Calcium
  • Contractility
  • Heart failure
  • Myocardium

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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