Diastolic Spontaneous Calcium Release From the Sarcoplasmic Reticulum Increases Beat-to-Beat Variability of Repolarization in Canine Ventricular Myocytes After β-Adrenergic Stimulation

Johnson, Daniel M.; Heijman, Jordi; Bode, Elizabeth F.; Greensmith, David J.; van der Linde, Henk; Abi-Gerges, Najah; Eisner, David A.; Trafford, Andrew W. and Volders, Paul G.A. (2013). Diastolic Spontaneous Calcium Release From the Sarcoplasmic Reticulum Increases Beat-to-Beat Variability of Repolarization in Canine Ventricular Myocytes After β-Adrenergic Stimulation. Circulation Research, 112(2) pp. 246–256.

DOI: https://doi.org/10.1161/CIRCRESAHA.112.275735

Abstract

Rationale:
Spontaneous Ca2+ release (SCR) from the sarcoplasmic reticulum can cause delayed afterdepolarizations 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 after delayed afterdepolarizations were significantly prolonged. Addition of slowly activating delayed rectifier K+ current (IKs) blockade led to further AP prolongation after SCR, and this strongly correlated with exaggerated BVR. Suppressing SCR via inhibition of ryanodine receptors, Ca2+/calmodulin-dependent protein kinase II inhibition, or by using Mg2+ or flecainide eliminated delayed afterdepolarizations and decreased BVR independent of effects on AP duration. Computational analyses and voltage-clamp experiments measuring L-type Ca2+ current (ICaL) with and without previous 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 after aftercontractions occurred before 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.

Viewing alternatives

Metrics

Public Attention

Altmetrics from Altmetric

Number of Citations

Citations from Dimensions

Item Actions

Export

About

Recommendations