In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 112, No. 2 ( 2013-01-18), p. 246-256
Abstract:
Spontaneous Ca 2+ 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 Ca 2+ 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 Mg 2+ or flecainide eliminated delayed afterdepolarizations and decreased BVR independent of effects on AP duration. Computational analyses and voltage-clamp experiments measuring L-type Ca 2+ current (I CaL ) with and without previous SCR indicated that I CaL was increased during Ca 2+ -induced Ca 2+ 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 Ca 2+ -induced Ca 2+ release by SCR underlies AP prolongation via increased I CaL. These data provide novel insights into arrhythmogenic mechanisms during β-adrenergic stimulation besides triggered activity and illustrate the importance of I Ks function in preventing excessive BVR.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/CIRCRESAHA.112.275735
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2013
detail.hit.zdb_id:
1467838-X
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