Doxorubicin, one of the most effective anticancer drugs, is characterized by severe cardiotoxic effects, which induce cardiac remodeling and congestive heart failure. The aim of the study was to evaluate remodeling of ventricular repolarization heterogeneity in chronic doxorubicin cardiotoxicity in rats. Doxorubicin cardiotoxicity was produced by six equal intraperitoneal injections of the drug in a cumulative dose of 15 mg/kg in a 2-week period. Electrophysiological mapping of the ventricular epicardium in situ was performed 6 weeks after the last injection of doxorubicin. Activation-recovery intervals (ARIs) were used for the evaluation of the heterogeneity in repolarization durations. The major findings were as follows: (1) ARIs on the ventricular epicardium of both ventricles were significantly prolonged in the doxorubicin group and (2) this inhomogeneous prolongation of ARIs on the ventricular epicardium resulted in (i) the increase in the dispersion of repolarization across the ventricular epicardium and (ii) the inhomogeneous alterations of the regional ARI gradients on the ventricular epicardium. These changes in repolarization could explain the electrocardiographic alterations, that is, the prolongation of the QT interval and flattening of the T wave.

Antiarrhythmic effects of melatonin have been demonstrated ex vivo and in rodent models, but its action in a clinically relevant large mammalian model remains largely unknown. Objectives of the present study were to evaluate electrophysiological and antiarrhythmic effects of melatonin in a porcine model of acute myocardial infarction. Myocardial ischemia was induced by 40-min coronary occlusion in 25 anesthetized pigs. After ischemia onset, 12 animals received melatonin (4 mg/kg). 48 intramyocardial electrograms were recorded from left ventricular wall and interventricular septum (IVS). In each lead, activation time (AT) and repolarization time (RT) were determined. During ischemia, ATs and dispersion of repolarization (DOR = RTmax − RTmin) increased reaching maximal values by 3–5 and 20–25 min, respectively. Ventricular fibrillation (VF) incidence demonstrated no relations to redox state markers and was associated with increased DOR and delayed ATs (specifically, in an IVS base, an area adjacent to the ischemic zone) (p = 0.031). Melatonin prevented AT increase in the IVS base, (p < 0.001) precluding development of early VF (1–5 min, p = 0.016). VF occurrence in the delayed phase (17–40 min) where DOR was maximal was not modified by melatonin. Thus, melatonin-related enhancement of activation prevented development of early VF in the myocardial infarction model.