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- W2028991655 abstract "Sudden cardiac death (SCD) resulting from ventricular arrhythmia remains a leading cause of death in the USA. The underlying molecular and structural mechanisms of arrhythmic SCD, however, are still unclear. We have recently reported that oxidative stress can trigger the abrupt collapse of mitochondrial inner membrane potential (ΔΨm), reverse of ATP synthase and decrease of ATP concentration. This could activate the sarcolemmal ATP sensitive potassium channel (KATP), affecting cellular electrical excitability and electrical wave propagation in the cardiac tissue. To test this hypothesis, we investigated the effect of regional mitochondrial depolarization on electrical wave propagation using combined optical mapping and computer simulations. The regional mitochondrial depolarization was induced in the center of cardiac cell monolayer by oxidative stress or mitochondrial uncoupler. The results show a coupling between ΔΨm depolarization, activation of KATP current and shortening of action potentials. When this effect is amplified, regional mitochondrial depolarization could form a metabolic current sink, preventing electrical wave propagation on the cardiac tissue. The overall influence involves a combination of a decrease in the action potential amplitude and shortening of the action potential duration. This mechanism introduces both temporal and spatial dispersion of electrical excitability and heterogeneous conduction, leading to wave breaks and spontaneous arrhythmia when the mitochondrial energetics within the metabolic current sink zone is recovering. In summary, this study illustrates the mechanism by which “metabolic” sinks can contribute the formation of fatal reentrant arrhythmias and reveal a novel way that reentry may be triggered in tissues recovering from metabolic inhibition (e.g., ischemia-reperfusion). The findings underscore the importance of considering mitochondrial targets for developing new therapies for SCD in the context of cardiovascular disease." @default.
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- W2028991655 date "2011-02-01" @default.
- W2028991655 modified "2023-10-12" @default.
- W2028991655 title "Regional Mitochondrial Depolarization Causes Spontaneous Ventricular Arrhythmia in Cardiac Tissue" @default.
- W2028991655 doi "https://doi.org/10.1016/j.bpj.2010.12.2568" @default.
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