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 Ca2+ entry into myocytes. The resultant accumulation of cytosolic Ca2+ 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, ATS1- associated cytosolic Ca2+ 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 Ca2+ overload. Therefore, the second study focused on Ca2+ handling and showed that ectopic activity originated from regions of higher Na+/Ca2+ exchanger iv (NCX) functional expression relative to sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), which we term "NCX dominant" regions of the heart. In support of the idea that NCX is an important determinant of ectopy, we were able to modulate both the timing as well as the frequency of ectopy by pharmacologically modulating NCX dominance. The data presented in this dissertation provide an insight into the factors by which Ca2+ handling contributes to ectopy under conditions of partial loss of IK1 function. This concept may aid in the identification of novel targets for antiarrhythmic therapy when IK1 is reduced in ATS1, as well as more prevalent disorders such as heart failure.