Roles of Delayed Repolarization and Altered Calcium Handling in Determining Regional Arrhythmia Propensity Under Conditions of Reduced Inward-Rectifier Potassium Current

Andersen-Tawil syndrome Type 1 (ATS1) is a disorder linked to a loss of function of the inward rectifier current IK1. Such a reduction in repolarization reserve has an established link with heterogeneous action potential duration (APD) prolongation. This in turn can serve as a substrate for reentrant arrhythmias. While APD prolongation and increased dispersion have been reported in pharmacological models of ATS1 they have not been linked with arrhythmogenesis. APD prolongation secondary to reduced IK1 can increase Ca entry into myocytes. The resultant accumulation of cytosolic Ca has been linked with ventricular ectopies which can trigger arrhythmias. Indeed this mechanism of arrhythmogeneis has been proposed in ATS1 based on previous in silico and ex vivo studies. However, ATS1associated cytosolic Ca overload and increased arrhythmia propensity has not been demonstrated in tissue preparations. The overall goal of this research was to characterize the factors that underlie arrhythmia propensity in a pharmacological model of ATS1. To this end we performed two studies. The first study analyzed APD gradients to determine whether they were sufficient for induction of reentrant arrhythmias. The results indicated they were not. However, this study revealed increased arrhythmia propensity which correlated with cytosolic Ca overload. Therefore, the second study focused on Ca handling and showed that ectopic activity originated from regions of higher Na/Ca exchanger