Slow Ca2 + sparks de-synchronize Ca2 + release in failing cardiomyocytes: Evidence for altered configuration of Ca2 + release units?

Abstract

In heart failure, cardiomyocytes exhibit slowing of the rising phase of the Ca2+ transient which contributes to the impaired contractility observed in this condition. We investigated whether alterations in ryanodine receptor function promote slowing of Ca2+ release in a murine model of congestive heart failure (CHF). Myocardial infarction was induced by left coronary artery ligation. When chronic CHF had developed (10weeks post-infarction), cardiomyocytes were isolated from viable regions of the septum. Septal myocytes from SHAM-operated mice served as controls. Ca2+ transients rose markedly slower in CHF than SHAM myocytes with longer time to peak (CHF=152±12% of SHAM, P<0.05). The rise time of Ca2+ sparks was also increased in CHF (SHAM=9.6±0.6ms, CHF=13.2±0.7ms, P<0.05), due to a sub-population of sparks (≈20%) with markedly slowed kinetics. Regions of the cell associated with these slow spontaneous sparks also exhibited slowed Ca2+ release during the action potential. Thus, greater variability in spark kinetics in CHF promoted less uniform Ca2+ release across the cell. Dyssynchronous Ca2+ transients in CHF additionally resulted from T-tubule disorganization, as indicated by fast Fourier transforms, but slow sparks were not associated with orphaned ryanodine receptors. Rather, mathematical modeling suggested that slow sparks could result from an altered composition of Ca2+ release units, including a reduction in ryanodine receptor density and/or distribution of ryanodine receptors into sub-clusters. In conclusion, our findings indicate that slowed, dyssynchronous Ca2+ transients in CHF result from alterations in Ca2+ sparks, consistent with rearrangement of ryanodine receptors within Ca2+ release units. This article is part of a Special Issue entitled “Calcium Signaling in Heart”.