Calcium oscillations and T-wave lability precede ventricular arrhythmias in acquired long QT type 2

BackgroundAlternans of intracellular Ca2+ (Cai) underlies T-wave alternans, a predictor of cardiac arrhythmias. A related phenomenon, T-wave lability (TWL), precedes torsades de pointes (TdP) in patients and animal models with impaired repolarization. However, the role of Cai in TWL remains unexplored.ObjectiveThis study investigated the role of Cai dynamics on TWL in a noncryoablated rabbit model of long QT syndrome type 2 (LQT2) using simultaneous measurements of Cai transient (CaT), action potentials (APs), and electrocardiogram (ECG) during paced rhythms and focused on events that precede ventricular ectopy.MethodsAPs and CaTs were mapped optically from paced Langendorff female rabbit hearts (n = 8) at 1.2-s cycle length, after atrioventricular node ablation. Hearts were perfused with normal Tyrode solution, then with dofetilide (0.5 μM), and reduced [K+] (2 mM) and [Mg2+] (0.5 mM) to elicit LQT2. Lability of ECG, voltage, and Cai signals were evaluated during regular paced rhythm, before and after dofetilide perfusion.ResultsIn LQT2, lability of Cai, voltage, and ECG signals increased during paced rhythm, before the appearance of early afterdepolarizations (EADs). LQT2 resulted in AP prolongation and multiple (1 to 3) additional Cai upstrokes, whereas APs remained monophasic. When EADs appeared, Cai rose before voltage upstrokes at the origins of propagating EADs. Interventions (i.e., ryanodine and thapsigargin, n = 3 or low [Ca]o and nifedipine, n = 4) that suppressed Cai oscillations also abolished EADs.ConclusionIn LQT2, Cai oscillations (CaiO) precede EADs by minutes, indicating that they result from spontaneous sarcoplasmic reticulum Ca2+ release rather than spontaneous ICa,L reactivation. CaiO likely produce oscillations of Na/Ca exchange current, INCX. Depolarizing INCX during the AP plateau contributes to the generation of EADs by reactivating Ca2+ channels that have recovered from inactivation. TWL reflects CaTs and APs lability that occur before EADs and TdP.