Role of coupled gating between cardiac ryanodine receptors in the genesis of triggered arrhythmias

Abstract

Mutations in the ryanodine receptor (RyR) have been linked to exercise-induced sudden cardiac death. However, the precise sequence of events linking RyR channel mutations to a whole heart arrhythmia is not completely understood. In this paper, we apply a detailed, mathematical model of subcellular calcium (Ca) release, coupled to membrane voltage, to study how defective RyR channels can induce arrhythmogenic-triggered activity. In particular, we show that subcellular Ca activity, such as spontaneous Ca sparks and Ca waves, is highly sensitive to coupled gating between RyR channels in clusters. We show that small changes in coupled gating can induce aberrant Ca release activity, which, under Ca overload conditions, can induce delayed afterdepolarization (DAD). We systematically investigate the properties of subcellular Ca during DAD induction and show that the voltage time course during a DAD is dependent on the timing and number of spontaneous Ca sparks that transition to Ca waves. These results provide a detailed mechanism for the role of coupled gating in the genesis of triggered arrhythmias.