ABSTRACT
Isoproterenol in high doses induces infarction-like myocardial damage and structural and functional remodelling of the ventricular myocardium. The purpose of the present study was to investigate ventricular repolarization in a rat model of isoproterenol-induced heart failure. Isoproterenol was administered twice to female Wistar rats (170 mg/kg, s.c., 24 h apart). Four weeks after the injections, cardiac output was measured and unipolar epicardial ventricular electrograms were recorded in situ. Activation-recovery intervals were calculated to assess repolarization. Histological examination of the heart ventricles was also performed. Heart failure in rats treated with isoproterenol was indicated by myocardial histopathological damage and reduced cardiac output. In rats with heart failure, the regional differences in activation-recovery interval prolongation over the ventricular epicardium resulted in increasing heterogeneity in the activation-recovery interval distribution and increasing repolarization heterogeneity of the ventricular subepicardium. Myocardial damage and haemodynamic changes in heart failure induced by isoproterenol were accompanied by significant changes in ventricular repolarization, which were not associated with myocardial hypertrophy.
Subject(s)
Heart Failure/physiopathology , Heart Ventricles/physiopathology , Action Potentials/drug effects , Action Potentials/physiology , Animals , Cardiac Output/drug effects , Cardiac Output/physiology , Disease Models, Animal , Electrocardiography/methods , Female , Heart Ventricles/drug effects , Hypertrophy/physiopathology , Isoproterenol/pharmacology , Myocardium/pathology , Pericardium/drug effects , Pericardium/physiopathology , Rats , Rats, WistarABSTRACT
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.
Subject(s)
Antibiotics, Antineoplastic/toxicity , Doxorubicin/toxicity , Heart Diseases/chemically induced , Heart/drug effects , Pericardium/drug effects , Ventricular Remodeling/drug effects , Animals , Electrocardiography/methods , Female , Heart Ventricles/drug effects , Rats , Ventricular Function/drug effectsABSTRACT
Anthracycline chemotherapy produces cardiac repolarization abnormalities and arrhythmias because of cardiac toxicity of drugs. Ventricular arrhythmogenesis is attributable to increase in repolarization heterogeneity that is characterized by spatial dispersion of repolarization. The purpose of this work was to study the delayed effects of doxorubicin, the most frequently used anthracycline, on repolarization heterogeneity of the ventricular epicardium. Doxorubicin was administered to rats in a cumulative dose of 15 mg/kg (six equal intraperitoneal injections over a period of 2 weeks). Six weeks after the last injection, electrophysiological mapping of the ventricular epicardium was performed by sequential superimposition of a 64-electrode array on the left ventricular base, left ventricular apex, right ventricular base, and right ventricular apex. Activation-recovery intervals (ARIs) were measured. In doxorubicin-treated rats, ARIs were inhomogeneously prolonged, the overall ARI dispersion and local ARI dispersions were increased, and the interregional differences in ARI dispersion were decreased. These data demonstrate that doxorubicin-induced inhomogeneous prolongation of repolarization of the ventricular epicardium results in increasing heterogeneity of ventricular repolarization because of increasing intraregional heterogeneity while interregional differences are lost. Repolarization of the right ventricle is more sensitive to doxorubicin than that of the left one.
