Simulating cardiac Ca 2+ release units: effects of RyR cluster size and Ca 2+ buffers on diastolic Ca 2+ leak

Leak of Ca 2+ out of the cardiac sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) during diastole is vital to regulate SR Ca 2+ levels. This leak can become deleterious when large spontaneous RyR-mediated Ca 2+ release events evoke proarrhythmic Ca 2+ waves that can lead to delayed after-depolarizations. Here, we model diastolic SR Ca 2+ leak at individual SR Ca 2+ 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 2+ leak, with bigger arrays producing larger and more frequent Ca 2+ release events. Moreover, big RyR arrays are more susceptible to small changes in the levels of dyadic Ca 2+ buffers. Such changes in buffering shift Ca 2+ leak from small Ca 2+ 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 2+ loads, we find further evidence for the hypothesis that SR Ca 2+ leak by RyR arrays can undergo a sudden phase transition.