Abstract 20902: Emergent Ventricular Fibrillation caused by Regional Mitochondrial Depolarization in Cardiac Muscle
Sudden cardiac arrest (SCA) is a leading cause of death nationwide that involves sustained ventricular arrhythmias and can be terminated only if therapy is initiated within minutes. The mechanisms underlying the transition from normal to uncoordinated electrical propagation remain poorly understood. We have recently reported that oxidative stress can trigger the abrupt collapse of mitochondrial inner membrane potential (ΔΨm), which activates KATP current and alters the cardiac action potential. We propose that this mechanism could introduce both temporal and spatial dispersion of electrical excitability in tissue, formatting a ”metabolic current sink” and leading to heterogeneous conduction and arrhythmia. To test this hypothesis, we developed a 2D computational model of the myocardial syncytium incorporating cellular electrophysiology, Ca2+ dynamics, mitochondrial energetics and reactive oxygen species (ROS) balance. In the model, oxidative stress was initiated in a central circular zone of tissue by increasing the fractional ROS production from 2% to 15%. This single parameter change caused the mitochondria in this area to undergo a dynamic bifurcation towards slow limit cycle oscillations of ΔΨm. Within the metabolic sink, action potentials dramatically shorten and refractory period was abbreviated. In addition, fibrillation was observed when an S2 stimulus was introduced near the border of the metabolic sink. Even more remarkable was the observation of wavebreak and fibrillation occurring in the absence of S2, triggered solely by the inhomogeneous recovery of mitochondrial energetics within the metabolic current sink zone. A similar phenomenon was also observed on neonatal rat ventricular myocytes that were locally perfused with the mitochondrial oxidative phosphorylation uncoupler, FCCP (1μM). The present results illustrate the mechanism by which can contribute the formation of fatal reentrant arrhythmias and also reveal a novel way that reentry may be triggered in tissues recovering from metabolic inhibition. The findings underscore the importance of considering mitochondrial targets for developing new therapies for SCA in the context of cardiovascular disease.
- Cardiac metabolism
- Oxidative stress
- Ventricular arrhythmia
- Mitochondrial energetics, heart failure, arrhythmias
- © 2010 by American Heart Association, Inc.