Affiliation:
1. From the Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, College of Medicine (A.E.B., D.T., R.T., H.-T.H., I.G., I.B. C.A.C., G.E.B., S.G.), and College of Pharmacy (I.B., C.A.C.), The Ohio State University, Columbus, OH.
Abstract
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
99 articles.
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