Myocardial ischemia results in metabolic changes, which collapse the mitochondrial network, that increase the vulnerability of the heart to
ventricular fibrillation (VF). It has been demonstrated at the single cell level that uncoupling the mitochondria using
carbonyl cyanide p-(tri-fluoromethoxy)phenyl-
hydrazone (
FCCP) at low concentrations can be cardioprotective. The aim of our study was to investigate the effect of
FCCP on arrhythmogenesis during
ischemia in the whole rabbit heart. We performed optical mapping of isolated rabbit hearts (n = 33) during control and 20 min of global
ischemia and reperfusion, both with and without pretreatment with the mitochondrial uncoupler
FCCP at 100, 50, or 30 nM. No hearts went into VF during
ischemia under the control condition, with or without the electromechanical uncoupler
blebbistatin. We found that pretreatment with 100 (n = 4) and 50 (n = 6) nM
FCCP, with or without
blebbistatin, leads to VF during
ischemia in all hearts, whereas pretreatment with 30 nM of
FCCP led to three out of eight hearts going into VF during
ischemia. We demonstrated that 30 nM of
FCCP significantly increased interventricular (but not intraventricular) action potential duration and conduction velocity heterogeneity in the heart during
ischemia, thus providing the substrate for VF. We showed that wavebreaks during VF occurred between the right and left ventricular junction. We also demonstrated that no VF occurred in the heart pretreated with 10 μM
glibenclamide, which is known to abolish interventricular heterogeneity. Our results indicate that low concentrations of
FCCP, although cardioprotective at the single cell level, are arrhythmogenic at the whole heart level. This is due to the fact that
FCCP induces different electrophysiological changes to the right and left ventricle, thus increasing interventricular heterogeneity and providing the substrate for VF.