Properties of Atrial Myocyte Calcium Handling in Canine Model of Chronic Heart Failure

Abstract

Weakened atrial contractility is a common comorbidity in heart failure (HF) that increases severity of HF symptoms. The role of intracellular calcium (Ca) handling remodeling in pathogenesis of ventricular contractile failure has been well established. However, the relationship between Ca signaling and atrial dysfunction in HF is not well recognized. We studied intracellular Ca handling in atrial myocytes isolated from control dogs and dogs with tachypacing-induced chronic HF. Ca transients and cellular shortening were reduced, while sarcoplasmic reticulum (SR) Ca content was increased in field-stimulated myocytes from HF compared to controls. Both control and HF myocytes have scarce t-tubule density, and Ca transients originated predominantly at the periphery of myocytes in both groups. Diminished Ca transients in HF myocytes were associated with decreased peripheral Ca release and impaired propagation of Ca signal from sarcolemma to the central areas of the myocyte. Peak density of the L-type Ca currents and gain of excitation-contraction coupling were reduced in voltage-clamped HF myocytes compared to control myocytes. Analysis of decay of caffeine- and electrically-induced Ca transients suggests reduced Na/Ca exchanger activity and increased SR Ca ATPase (SERCA) activity in HF myocytes. SERCA inhibition with cyclopiazonic acid did not improve centripetal propagation of Ca signal in HF myocytes. In contrast, L-type Ca channel agonist BayK 8644 increased peripheral Ca release, improved centripetal Ca wave propagation and restored shortening of HF myocytes to control levels.We conclude that defective activation and impaired propagation of the SR Ca release in atrial myocytes contribute to compromised atrial contractility in chronic HF. Our results suggest L-type Ca channels as a therapeutic target for treatment of atrial contractile dysfunction in HF.