Origin of Contractile Dysfunction in Heart Failure

Publisher Website
Google Scholar
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 Ca 2+ cycling despite emerging evidence for depressed myofilament function. Methods and Results —We measured intracellular Ca 2+ concentration ([Ca 2+ ] 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 Ca 2+ ([Ca 2+ ] o ), [Ca 2+ ] i transients were equal in amplitude in the 2 groups, but [Ca 2+ ] 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 Ca 2+ -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 Ca 2+ cycling prolongs the time available for Ca 2+ 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 [Ca 2+ ] 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 Ca 2+ cycling are reinterpreted as compensatory rather than causative.