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Diastolic spontaneous calcium release from the sarcoplasmic reticulum increases beat-to-beat variability of repolarization in canine ventricular myocytes after β-adrenergic stimulation

Johnson, DM, Heijman, J, Bode, EF, Greensmith, DJ, van der Linde, H, Abi-Gerges, N, Eisner, DA, Trafford, AW and Volders, PGA 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. 246-56.

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Abstract

RATIONALE 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, 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. 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.

Item Type: Article
Themes: Health and Wellbeing
Subjects outside of the University Themes
Schools: Schools > School of Environment and Life Sciences > Biomedical Research Centre
Journal or Publication Title: Circulation research
Publisher: American Heart Association
Refereed: Yes
ISSN: 1524-4571
Related URLs:
Funders: Netherlands Organization for Scientific Research, British Heart Foundation, AstraZeneca Ltd
Depositing User: D Greensmith
Date Deposited: 10 Feb 2015 20:47
Last Modified: 10 Feb 2015 20:47
URI: http://usir.salford.ac.uk/id/eprint/33383

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