Article

Cardiovascular Toxicology

, Volume 12, Issue 4, pp 312-317

Doxorubicin-induced Changes of Ventricular Repolarization Heterogeneity: Results of a Chronic Rat Study

  • Sergey N. KharinAffiliated withLaboratory of Cardiac Physiology, Institute of Physiology, Komi Science Centre, Ural Branch, Russian Academy of Sciences Email author 
  • , Valeria V. KrandychevaAffiliated withLaboratory of Cardiac Physiology, Institute of Physiology, Komi Science Centre, Ural Branch, Russian Academy of Sciences
  • , Marina V. StrelkovaAffiliated withLaboratory of Cardiac Physiology, Institute of Physiology, Komi Science Centre, Ural Branch, Russian Academy of Sciences
  • , Aliona S. TsvetkovaAffiliated withLaboratory of Cardiac Physiology, Institute of Physiology, Komi Science Centre, Ural Branch, Russian Academy of Sciences
  • , Dmitry N. ShmakovAffiliated withLaboratory of Cardiac Physiology, Institute of Physiology, Komi Science Centre, Ural Branch, Russian Academy of Sciences

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Abstract

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.

Keywords

Activation–recovery interval Anthracyclines Doxorubicin Heart ventricles Heterogeneity Rat model Repolarization