In a canine model of post-MI VF, shortened Ca2+ signaling refractoriness due to RyR2 phosphorylation and oxidation increased the rate of arrhythmogenic diastolic spontaneous Ca2+ waves.
Shortened Ca2+ signaling refractoriness due to RyR2 phosphorylation and oxidation underlies increased diastolic spontaneous Ca2+ waves in a post-MI VF model.
Rationale: Diastolic spontaneous Ca 2+ waves (DCWs) are recognized as important contributors to triggered arrhythmias. DCWs are thought to arise when Ca 2+ in sarcoplasmic reticulum (Ca 2+ SR ) reaches a certain threshold level, which might be reduced in cardiac disease as a consequence of sensitization of ryanodine receptors (RyR2s) to luminal Ca 2+ . 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 Ca 2+ SR , DCWs arose with a distinct time delay after attaining steady Ca 2+ SR in both experimental groups. Although the rate of Ca 2+ SR recovery after the SR Ca 2+ release was similar between the groups, in VF myocytes the latency to DCWs was shorter, and the Ca 2+ SR at DCW initiation was lower. The restitution of depolarization-induced Ca 2+ transients, assessed by a 2-pulse protocol, was significantly faster in VF myocytes than in controls. The VF-related alterations in myocyte Ca 2+ cycling were mimicked by the RyR2 agonist, caffeine. The reducing agent, mercaptopropionylglycine, or the CaMKII inhibitor, KN93, decreased DCW frequency and normalized restitution of Ca 2+ release in VF myocytes. Conclusions: The attainment of a certain threshold Ca 2+ SR is not sufficient for the generation of DCWs. Postrelease Ca 2+ signaling refractoriness critically influences the occurrence of DCWs. Shortened Ca 2+ 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.
Belevych et al. (Fri,) conducted a other in Post-myocardial infarction ventricular fibrillation. Isoproterenol, caffeine, mercaptopropionylglycine, and KN93 (in vitro) vs. Normal controls was evaluated on Frequency of diastolic spontaneous Ca2+ waves (DCWs) and restitution of depolarization-induced Ca2+ transients. In a canine model of post-MI VF, shortened Ca2+ signaling refractoriness due to RyR2 phosphorylation and oxidation increased the rate of arrhythmogenic diastolic spontaneous Ca2+ waves.
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