Abstract 3505: Heterogeneous Calcium Handling Modulates Spatio-Temporal Initiation of Premature Beats During Conditions of Calcium Overload
Heart failure and Andersen-Tawil syndrome Type 1 (ATS1) are associated with inward-rectifier potassium current (IK1) abnormalities and ventricular arrhythmias. We previously demonstrated increased arrhythmia propensity in a guinea pig model of ATS1 and marginal action potential duration (APD) gradient increases. Therefore, we hypothesized that abnormal calcium handling underlies arrhythmogenesis in ATS1. ATS1 was modeled in an isolated guinea pig ventricle preparation by perfusion of 10μ M BaCl2 and 2mM [K+]o. APD and intracellular Ca2+ from the anterior epicardium were quantified by ratiometric-optical mapping of voltage (di-4-ANEPPS) or Ca2+ (Indo-1) during RV pacing with or without pinacidil (15μM). Repolarization gradients during ATS1 were insufficient for arrhythmia induction by premature stimuli (S1-S2), but 75% (15/20) of animals exhibited ventricular couplets or longer arrhythmias. Pinacidil significantly decreased APD in all regions (17±5%, p<0.05), APD dispersion (4.5±0.4%, p<0.05) and incidence of couplets and arrhythmias (27.8%, 5/18 of animals) compared to ATS1. Increased arrhythmia propensity during ATS1 was associated with greater left ventricular (LV) diastolic intracellular calcium (Cadias) (12±2%, p<0.05) and Ca2+ transient amplitude (Caamp) (17±4%, p<0.05) relative to RV. Reduction of arrhythmia propensity by pinacidil was associated with reduced Cadias in all ventricular regions (by 14.2±1.5%, p<0.05) but not Caamp. During ATS1, DADs preferentially originated from the basal LV (38% of total), which also manifested the largest Cadias levels. While pinacidil decreased the incidence of arrhythmias, it unmasked ectopic activity (97 ± 26 ms later, p<0.05) stemming from regions with highest Caamp (apical LV). These data suggest that loss of IK1 function leads to DADs with different onset times via at least two different mechanisms. One mechanism is associated with elevated Cadias and the other is associated with increased Caamp alone. The latter however, is unmasked by pinacidil. Importantly, ventricular tachycardias arising from multiple ectopic foci may result from two different substrates, which strongly suggests that Cadias elevation is not the only mechanism of calcium mediated spontaneous activity.