Simulating cardiac Ca release units: effects of RyR cluster size and Ca buffers on diastolic Ca leak.

Leak of Ca out of the cardiac sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) during diastole is vital to regulate SR Ca levels. This leak can become deleterious when large spontaneous RyR-mediated Ca release events evoke proarrhythmic Ca waves that can lead to delayed after-depolarizations. Here, we model diastolic SR Ca leak at individual SR Ca release sites using computer simulations of RyR arrays like those in the dyadic cleft. The results show that RyR arrays size has a significant effect on SR Ca leak, with bigger arrays producing larger and more frequent Ca release events. Moreover, big RyR arrays are more susceptible to small changes in the levels of dyadic Ca buffers. Such changes in buffering shift Ca leak from small Ca release events (involving few open RyRs) to larger events (with many open RyRs). Moreover, by analyzing a large parameter space of possible buffering and SR Ca loads, we find further evidence for the hypothesis that SR Ca leak by RyR arrays can undergo a sudden phase transition.