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; Volders, PGA

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.

Citation

Johnson, D., Heijman, J., Bode, E., Greensmith, D., van der Linde, H., Abi-Gerges, N., …Volders, P. (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), 246-56. https://doi.org/10.1161/CIRCRESAHA.112.275735

• Journal Article Type: Article
• Publication Date: Jan 18, 2013
• Deposit Date: Feb 10, 2015
• Journal: Circulation research
• Print ISSN: 0009-7330
• Publisher: American Heart Association
• Peer Reviewed: Peer Reviewed
• Volume: 112
• Issue: 2
• Pages: 246-56
• DOI: https://doi.org/10.1161/CIRCRESAHA.112.275735
• Publisher URL: http://dx.doi.org/10.1161/CIRCRESAHA.112.275735
• Related Public URLs: http://circres.ahajournals.org/
• Additional Information: Funders : Netherlands Organization for Scientific Research;British Heart Foundation;AstraZeneca Ltd