Enhanced sarcolemmal Ca2+ efflux reduces sarcoplasmic reticulum Ca2+ content and systolic Ca2+ in cardiac hypertrophy

Objective: Recent work has identified reductions in the systolic Ca2+ transient in cardiac disease states. The aim of the present study was to identify the mechanisms responsible for perturbations of intracellular calcium homeostasis in isolated cardiac myocytes and determine if such changes can quantitatively explain the reduced systolic Ca2+ transient. Methods: Left ventricular hypertrophy (LVH) was induced by aortic coarctation in adult ferrets. Changes in intracellular Ca2+ regulation, sarcolemmal Ca2+ fluxes and SR function were measured in single left ventricular cardiac myocytes. Results: Cardiac hypertrophy was associated with a 29% increase in action potential duration (APD90); a 48% reduction in the amplitude of and 19% slowing in the rate of decay of the systolic Ca2+ transient; a 20% decrease in SR Ca2+ content and a 36% increase in inward Na+–Ca2+ exchange current for a given change in [Ca2+]i (all P<0.05). Peak L-type Ca2+ current density, integrated Ca2+ influx and SERCA2a protein levels remained unchanged in hypertrophy. By determining the relationship between SR Ca2+ content and systolic Ca2+, the reduction in SR Ca2+ content quantitatively explained the smaller systolic Ca2+ transient. The reduced SR Ca2+ content also accounted for a smaller fractional release of Ca2+ from the SR and lower gain of excitation contraction coupling in cardiac hypertrophy. The increased sarcolemmal-mediated Ca2+ efflux was sufficient to explain the reduction in SR Ca2+ content. Conclusions: The findings indicate that the primary mechanism underlying the smaller systolic Ca2+ transient amplitude in cardiac hypertrophy is decreased SR Ca2+ content occurring as a consequence of reduced SR Ca2+-ATPase-mediated Ca2+ uptake and increased sarcolemmal-mediated Ca2+ efflux from the cell. The increased Na+–Ca2+ exchange-mediated current for a given change in intracellular Ca2+ concentration provides a mechanism for the development of arrhythmias in the face of a reduced SR Ca2+ load in cardiac hypertrophy.