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

BACKGROUND Alternans of intracellular Ca2+ (Ca-i) 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 Ca-i in TWL remains unexplored. OBJECTIVE This study investigated the role of Ca-i dynamics on TWL in a noncryoablated rabbit model of long QT syndrome type 2 (LQT2) using simultaneous measurements of Ca-i transient (CaT), action potentials (APs), and electrocardiogram (ECG) during paced rhythms and focused on events that precede ventricular ectopy. METHODS APs 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 mu M), and reduced [K+] (2 mM) and [Mg2+] (0.5 mM) to elicit LQT2. Lability of ECG, voltage, and Ca-i signals were evaluated during regular paced rhythm, before and after dofetilide perfusion. RESULTS In LQT2, lability of Ca-i, 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 Ca-i upstrokes, whereas APs remained monophasic. When EADs appeared, Ca-i 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 Ca-i oscillations also abolished EADs. CONCLUSION In LQT2, Ca-i oscillations (CaiO) precede EADs by minutes, indicating that they result from spontaneous sarcoplasmic reticulum Ca2+ release rather than spontaneous I-Ca,I-L reactivation. CaiO likely produce oscillations of Na/Ca exchange current, I-NCX. Depolarizing I-NCX 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.