Shortened Ca2+ Signaling Refractoriness Underlies Cellular Arrhythmogenesis in a Postinfarction Model of Sudden Cardiac Death

[摘要]：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+. Rationale: 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 beta-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 faster in VF myocytes than in controls. 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 DCWs. Shortened Ca2+ signaling refractoriness due to RyR2 phosphorylation and oxidation is responsible for the increased rate of DCWs observed in VF myocytes and could provide a substrate for synchronization of arrhythmogenic events at the tissue level in hearts prone to VF. (Circ Res. 2012;110:569-577.)

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