Title: Increased ICaL Underlies Ventricular Action-Potential Prolongation After Spontaneous Ca2+ Release From The Sarcoplasmic Reticulum
Authors: Johnson, Daniel
Heijman, Jordi
Bode, Elizabeth
Greensmith, David
Abi-Gerges, Najah
Eisner, David
Trafford, Andrew
Volders, Paul #
Issue Date: Nov-2011
Publisher: Elsevier
Host Document: Heart Rhythm vol:8 issue:11 pages:1823
Conference: Cardiac Electrophysiology Society
Abstract: Background: Spontaneous Ca2+ release from the sarcoplasmic reticulum (SCR) can cause delayed afterdepolarizations (DADs) and triggered activity, contributing to arrhythmogenesis during Ca2+ overload. Excessive beat-to-beat variability of repolarization duration (BVR) is a proarrhythmic marker. Previous research has shown that BVR is increased during Ca2+ overload in isolated myocytes. We aimed at determining ionic mechanisms controlling BVR during abnormal Ca2+ handling.

Methods: Membrane potentials, ionic currents and cell shortening or Ca2+ transients were recorded from isolated canine left-ventricular myocytes in the presence of the β-adrenergic agonist isoproterenol to induce Ca2+ overload.

Results: Action-potential (AP) durations following DADs were significantly prolonged. Addition of IKs blockade led to further AP prolongation after SCR and this strongly correlated with exaggerated BVR. Suppressing SCR via inhibition of ryanodine receptors, CaMKII inhibition, or by using Mg2+ or flecainide eliminated DADs and decreased BVR, which was independent of effects on AP duration. Caffeine led to a similar decrease in BVR, due to the occurrence of SCR before every AP. Computational analyses and voltage-clamp experiments measuring ICaL with and without prior SCR demonstrated that ICaL was increased during Ca2+-induced Ca2+ release after SCR, contributing to AP prolongation.

Conclusions: SCR promotes BVR by interspersed prolongation of myocyte AP duration, which is exacerbated during IKs blockade. Attenuation of Ca2+-induced Ca2+ release by SCR underlies AP prolongation via increased ICaL. These data provide insight into arrhythmogenic mechanisms during Ca2+ overload besides triggered activity, as well as illustrating the importance of IKs function in preventing excessive BVR.
Publication status: published
KU Leuven publication type: IMa
Appears in Collections:Non-KU Leuven Association publications
# (joint) last author

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