Alteration of Ryanodine Receptor-Mediated Calcium Release in Heart Failure

Abstract

The decrease in contractility in heart failure associates with impaired cellular Ca2+ homeostasis that is in part due to altered ryanodine receptor (RyR) function. We studied properties of sarcoplasmic reticulum (SR) Ca2+ release in normal and failing rabbit ventricular myocytes using simultaneous measurements of cytosolic ([Ca2+]i) and intra-SR free Ca2+ ([Ca2+]SR). At a given SR Ca2+ content, fractional SR Ca2+ release during action potential stimulation was higher in failing than nonfailing myocytes, suggesting increased sensitivity of RyRs in heart failure. In permeabilized myocytes, SR Ca2+ content and Ca2+ spark frequency were decreased in heart failure, while Ca2+ spark amplitude was similar between failing and nonfailing myocytes. To compare these two groups further, SR Ca2+ content was experimentally decreased in nonfailing myocytes to the level observed in failing myocytes using SERCA inhibition. When SR Ca2+ content was matched, both Ca2+ spark frequency and amplitude were markedly increased in failing myocytes, showing that RyRs are more sensitive to release activation. By monitoring [Ca2+]SR during Ca2+ sparks, we also observed that the [Ca2+]SR level for spark termination was significantly lower in myocytes from failing hearts. Because Ca2+ sparks are a major contributing factor to diastolic SR Ca2+ leak, we compared the properties of SR Ca2+ leak in normal and failing myocytes. In failing myocytes SR Ca2+ leak was significantly faster, particularly at high [Ca2+]SR where Ca2+ sparks are the predominant pathway for SR Ca2+ leak. These data show that during the progression of heart failure, modifications to RyRs alter both activation and termination of local SR Ca2+ release events. At a given SR Ca2+ content these effects may increase fractional SR Ca2+ release and preserve contractility during systole, however at the cost of increased diastolic SR Ca2+ leak and SR depletion.