Shortened Ca2+ Signaling Refractoriness Underlies Cellular Arrhythmogenesis in a Postinfarction Model of Sudden Cardiac Death
Rationale: Diastolic spontaneous Ca2+ waves (DCWs) are recognized as important contributors to triggered arrhythmias. DCWs are thought to arise when [Ca2+] in sarcoplasmic reticulum ([Ca2+]SR) reaches a certain threshold level, which might be reduced in cardiac disease as a consequence of sensitization of ryanodine receptors (RyR2s) to luminal Ca2+.
Objective: We investigated the mechanisms of DCW generation in myocytes from normal and diseased hearts, using a canine model of post–myocardial infarction ventricular fibrillation (VF).
Methods and Results: The frequency of DCWs, recorded during periodic pacing in the presence of a β-adrenergic receptor agonist isoproterenol, was significantly higher in VF myocytes than in normal controls. Rather than occurring immediately on reaching a final [Ca2+]SR, DCWs arose with a distinct time delay after attaining steady [Ca2+]SR in both experimental groups. Although the rate of [Ca2+]SR recovery after the SR Ca2+ release was similar between the groups, in VF myocytes the latency to DCWs was shorter, and the [Ca2+]SR at DCW initiation was lower. The restitution of depolarization-induced Ca2+ transients, assessed by a 2-pulse protocol, was significantly shorter in VF myocytes than in control. The VF-related alterations in myocyte Ca2+ cycling were mimicked by the RyR2 agonist, caffeine. The reducing agent, mercaptopropionylglycine, or the CaMKII inhibitor, KN93, decreased DCW frequency and normalized restitution of Ca2+ release in VF myocytes.
Conclusions: The attainment of a certain threshold [Ca2+]SR is not sufficient for the generation of DCWs. Postrelease Ca2+ signaling refractoriness critically influences the occurrence of spontaneous Ca2+ waves in the diastolic period. Shortened Ca2+ signaling refractoriness due to RyR2 phosphorylation and oxidation is responsible for the increased rate of DCWs observed in VF myocytes.
- Received November 8, 2011.
- Revision received December 6, 2011.
- Accepted December 29, 2011.
- © 2012 American Heart Association, Inc.