Abstract
Rationale: Spontaneous Ca2+ release (SCR) from the sarcoplasmic reticulum can cause delayed afterdepolarizations and triggered activity, contributing to arrhythmogenesis during beta-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 beta-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 (I-Ks) 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 (I-CaL) with and without previous SCR indicated that I-CaL was increased during Ca2+-induced Ca2+ release after SCR, and this contributes to AP prolongation. Prolongation of QT, T-peak-T-end 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 I-Ks blockade. Attenuation of Ca2+-induced Ca2+ release by SCR underlies AP prolongation via increased I-CaL. These data provide novel insights into arrhythmogenic mechanisms during beta-adrenergic stimulation besides triggered activity and illustrate the importance of I-Ks function in preventing excessive BVR. (Circ Res. 2013;112:246-256.)
Original language | English |
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Pages (from-to) | 246–256 |
Journal | Circulation Research |
Volume | 112 |
Issue number | 2 |
DOIs | |
Publication status | Published - 18 Jan 2013 |
Keywords
- action potentials
- arrhythmia
- beta-adrenergic receptors
- calcium
- sarcoplasmic reticulum