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 ORCID: 0000-0002-7376-7101, Heijman, Jordi ORCID: 0000-0002-1418-108X, Bode, Elizabeth F ORCID: 0000-0003-3754-6026, Greensmith, David J, van der Linde, Henk, Abi-Gerges, Najah, Eisner, David A ORCID: 0000-0002-7002-3748, Trafford, Andrew W ORCID: 0000-0002-2770-445X and Volders, Paul GA (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.

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Abstract

<h4>Rationale</h4>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.<h4>Objective</h4>We aimed to determine ionic mechanisms controlling BVR under these conditions.<h4>Methods and results</h4>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, Ca(2+)/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.<h4>Conclusions</h4>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.

Item Type:	Article
Uncontrolled Keywords:	Sarcoplasmic Reticulum, Heart Ventricles, Myocytes, Cardiac, Animals, Dogs, Calcium, Adrenergic beta-Agonists, Action Potentials, Heart Rate, Female
Depositing User:	Symplectic Admin
Date Deposited:	15 Jun 2017 06:18
Last Modified:	21 Mar 2024 07:20
DOI:	10.1161/circresaha.112.275735
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3006881