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

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.