The mitochondrial origin of postischemic arrhythmias

Abstract

Recovery of the mitochondrial inner membrane potential (∆Ψ m ) is a key determinant of postischemic functional recovery of the heart. Mitochondrial ROS-induced ROS release causes the collapse of ∆Ψ m and the destabilization of the action potential (AP) through a mechanism involving a mitochondrial inner membrane anion channel (IMAC) modulated by the mitochondrial benzodiazepine receptor (mBzR). Here, we test the hypothesis that this mechanism contributes to spatiotemporal heterogeneity of ∆Ψ m during ischemia-reperfusion (IR), thereby promoting abnormal electrical activation and arrhythmias in the whole heart. High-resolution optical AP mapping was performed in perfused guinea pig hearts subjected to 30 minutes of global ischemia followed by reperfusion. Typical electrophysiological responses, including progressive AP shortening followed by membrane inexcitablity in ischemia and ventricular fibrillation upon reperfusion, were observed in control hearts. These responses were reduced or eliminated by treatment with the mBzR antagonist 4′-chlorodiazepam (4′-Cl-DZP), which blocks depolarization of ∆Ψ m . When applied throughout the IR protocol, 4′-Cl-DZP blunted AP shortening and prevented reperfusion arrhythmias. Inhibition of ventricular fibrillation was also achieved by bolus infusion of 4′-Cl-DZP just before reperfusion. Conversely, treatment with an agonist of the mBzR that promotes ∆Ψ m depolarization exacerbated IR-induced electrophysiological changes and failed to prevent arrhythmias. The effects of these compounds were consistent with their actions on IMAC and ∆Ψ m . These findings directly link instability of ∆Ψ m to the heterogeneous electrophysiological substrate of the postischemic heart and highlight the mitochondrial membrane as a new therapeutic target for arrhythmia prevention in ischemic heart disease.

Reduced susceptibility to ventricular tachyarrhythmias in rats selectively bred for high aerobic capacity

“…These investigators reported a 12% increase in survival for each 1-metabolic equivalent increase in aerobic exercise capacity. In accord with this view, the work of Akar et al (1) suggests that ischemia-related electrophysiological alterations and arrhythmias in intact hearts are, at least in part, a consequence of the failure of the cellular mitochondrial network to maintain membrane electrical potential. They found that preventing membrane depolarization by blocking the mitochondrial benzodiazepine receptor stabilized the action potentials of metabolically stressed cardiomyocytes, blunted ischemia-induced action potential shortening, improved postischemic recovery of the action potential, and prevented the occurrence of spontaneous arrhythmias on reperfusion of the heart.…”

Mitochondrial Ion Channels in Cardiac Function and Dysfunction

“…In more than 90% of the control hearts, ventricular tachycardia and fibrillation was induced upon reperfusion. Exposure of the hearts to 4′Cl-diazepam, which was shown to stabilize both ΔΨ m and the action potential duration of cardiac cells undergoing oscillations after a laserinduced flash, completely eliminated post-ischaemic arrhythmias (Akar et al 2005). We proposed that clusters of cells that have reached mitochondrial criticality in the heart during ischaemia constitute metabolic current sinks that will impede electrical propagation due to their high K ATP conductance.…”

“…In recent studies, we have provided evidence that failure of the mitochondrial network not only scales to the level of the whole cell, but also underlies global electrical dysfunction in the whole heart during ischaemia and reperfusion (Akar et al 2005). Isolated-perfused guinea-pig hearts were subjected to 30 minutes of global ischaemia followed by reperfusion while epicardial electrical activity was followed using a multichannel optical mapping system.…”

Persistent Oxidative Stress after Myocardial Infarction Treated by Percutaneous Coronary Intervention

“…The action of ROS and the ensuing lipid peroxidation exhaust the organism's antioxidant capacity (Frei 1994). During early reperfusion oxidative stress might also lead to myocardial stunning and arrhythmia (Ferrari et al 1993;Akar et al 2005). The reaction of ROS with polyunsaturated fatty acids (PUFA) of low-density lipoproteins (LDL) leads to the formation of oxidized LDL (oLDL).…”