Diastolic Spontaneous Calcium Release from the Sarcoplasmic Reticulum Increases Beat-to-Beat Variability of Repolarization in Canine Ventricular Myocytes after β-Adrenergic Stimulation
Rationale: Spontaneous Ca2+ release from the sarcoplasmic reticulum (SCR) can cause delayed afterdepolarizations (DADs) and triggered activity, contributing to arrhythmogenesis during β-adrenergic stimulation. Excessive beat-to-beat variability of repolarization duration (BVR) is a proarrhythmic marker. Previous research has shown that BVR is increased during intense β-adrenergic stimulation leading to SCR.
Objective: We aimed to determine ionic mechanisms controlling BVR under these conditions.
Methods and Results: Membrane potentials and cell shortening or Ca2+ transients were recorded from isolated canine left-ventricular myocytes in the presence of isoproterenol. Action-potential (AP) durations following DADs were significantly prolonged. Addition of IKs blockade led to further AP prolongation after SCR and this strongly correlated with exaggerated BVR. Suppressing SCR via inhibition of ryanodine receptors, CaMKII inhibition, or by using Mg2+ or flecainide, eliminated DADs and decreased BVR independent of effects on AP duration. Computational analyses and voltage-clamp experiments measuring ICaL with and without prior SCR indicated that ICaL was increased during Ca2+-induced Ca2+ release after SCR, and this contributes to AP prolongation. Prolongation of QT, Tpeak-Tend intervals and left-ventricular monophasic AP duration of beats following aftercontractions occurred prior to torsades de pointes in an in-vivo dog model of drug-induced long-QT1 syndrome.
Conclusions: SCR contributes to increased BVR by interspersed prolongation of AP duration, which is exacerbated during IKs blockade. Attenuation of Ca2+-induced Ca2+ release by SCR underlies AP prolongation via increased ICaL. These data provide novel insights into arrhythmogenic mechanisms during β-adrenergic stimulation besides triggered activity and illustrate the importance of IKs function in preventing excessive BVR.
- Received June 16, 2012.
- Accepted November 13, 2012.
- Copyright © 2012, American Heart Association