Abstract 16425: Slow Ca2+ Sparks De-synchronize Ca2+ Release in Failing Cardiomyocytes: Evidence for Altered Ryanodine Receptor Distribution?
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 the underlying mechanisms in a murine model of congestive heart failure (CHF). Myocardial infarction was induced by left coronary artery ligation, and at 10 weeks post-infarction, mice exhibited symptoms of CHF with reduced cardiac function and increased lung weight. Cardiomyocytes were isolated from viable regions of the septum, and septal myocytes from SHAM-operated mice served as controls. Ca2+ transients (fluo-4 AM, 1Hz) rose markedly slower in CHF than SHAM myocytes with longer time to peak (CHF=172±13% of SHAM, P<0.05). The rise time of Ca2+ sparks was also increased in CHF (SHAM=9.6±0.6 ms, CHF=13.1±0.6 ms, 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 FFT analyses, but slow sparks were not associated with orphaned ryanodine receptors located at gaps between T-tubules. Rather, mathematical modeling predicted that slowed spark kinetics were caused by altered composition of Ca2+ release units, including a reduction in ryanodine receptor density and/or distribution of ryanodine receptors into sub-clusters. Thus, our findings indicate that slow rise of the Ca2+ transient in failing cardiomyocytes results from dyssynchronous Ca2+ release due to T-tubule loss and altered ryanodine receptor configuration in Ca2+ release units.
- © 2012 by American Heart Association, Inc.