The mitochondrial origin of postischernic arrhythmias
The mitochondrial origin of postischernic arrhythmias
复制标题
DOI：
10.1172/jci25371
复制
发表时间：
2005-12-01
影响因子：
15.9
通讯作者：
O'Rourke, B
中科院分区：
文献类型：
--
作者：
Akar, FG;Aon, MA;O'Rourke, B
Recovery of the mitochondrial inner membrane potential (Delta Psi(m)) is a key determinant of postischemic functional recovery of the heart. Mitochondrial. ROS-induced ROS release causes the collapse of Delta Psi(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 Delta Psi(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 Delta psi(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 Delta Psi(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 Delta Psi(m). These findings directly link instability of Delta Psi(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.
