Submitted on January 28, 2009
Revised on April 20, 2009
Accepted on May 4, 2009
Role of Coupled Gating Between Cardiac Ryanodine Receptors in the Genesis of Triggered Arrhythmias
Wei Chen1, J. Andrew Wasserstrom2, and Yohannes Shiferaw3*
1 California State University Northridge
2 Northwestern University
3 california state northridge
* To whom correspondence should be addressed. E-mail: yshiferaw{at}csun.edu.
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, are 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 after depolarization (DADs). 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 which transition to Ca waves. These results provide a detailed mechanism for the role of coupled gating in the genesis of triggered arrhythmias.
