High Incidence of Lethal Ventricular Arrhythmia-Sudden Cardiac Death in Early Myocardial Ischemia: Critical Roles of Cross-Regulation Between Stresses and Calcium Imbalance

Abstract

Aims:

Early myocardial ischemia (MI) predisposes to lethal ventricular arrhythmias (LVA) and subsequent sudden cardiac death (SCD). This study aims to elucidate the roles of cross-regulation between oxidative stress, endoplasmic reticulum (ER) stress, and calcium (Ca²⁺) disturbances in the increased risk of LVA-SCD in early MI.

Results:

Both clinical and animal model data showed a higher incidence of SCD within 30 min of MI. In MI animals, T-wave alternans and conduction slowing were observed prior to LVA onset. Optical mapping revealed spatiotemporal electrophysiological discordances, including conduction slowing and alternans in both action potentials and Ca²⁺ transients before LVA, peaking 5–15 min after ischemia onset, with the ischemic zone most affected. Reentrant cycles were observed in isolated MI hearts that developed LVA. SCD animals exhibited elevated mitochondrial and cytosolic reactive oxygen species and Ca²⁺, mitochondrial damage, ER stressors upregulation, and activation of the Ca²⁺/calmodulin-dependent protein kinases (oxidized)-RyR2, ryanodine receptor 2 (CaMKII-RyR2) pathway. These results were partly validated in hypoxic and undernourished myocytes. Targeted interventions, such as MitoTEMPO to mitigate oxidative stress, 4-phenyl butyric acid to inhibit ER stress, and dantrolene or RyR2-S2814A to suppress Ca²⁺ leakage, attenuated disturbances and reduced SCD incidence.

Innovation and Conclusion:

We identify a critical 30-min window post-MI, during which redox/ER stress and Ca² imbalance synergistically drive LVA and SCD via the CaMKII-RyR2 pathway. Targeting this pathway could offer a promising strategy to prevent LVA and SCD in early MI. Antioxid. Redox Signal. 43, 547–565.