Doxorubicin and its proarrhythmic effects: A comprehensive review of the evidence from experimental and clinical studies

The cancer burden on health and socioeconomics remains exceedingly high, with more than ten million new cases reported worldwide in 2018. The financial cost of managing cancer patients has great economic impact on both an individual and societal levels. Currently, many chemotherapeutic agents are available to treat various malignancies. One of these agents is doxorubicin, which was isolated from Streptomyces peucetius in the 1960s. Doxorubicin is frequently administered in combination with other agents as a mainstay chemotherapeutic regimen in many settings, since there is well-documented evidence that it is effective in eliminating malignant cells. Doxorubicin exerts its anti-tumor properties through DNA intercalation and topoisomerase inhibition. It also contains a quinone moiety which is susceptible to redox reactions with certain intracellular molecules, thereby leading to the production of reactive oxygen species. The oxidative stress following doxorubicin exposure is responsible for its well-documented cardiotoxicity, impairing cardiac contractility, ultimately resulting in congestive heart failure. Despite the cumulative evidence noting its adverse effects on the heart, limited information is available regarding the mechanistic association between doxorubicin and cardiac arrhythmias. There is compelling evidence to suggest that doxorubicin also causes proarrhythmic effects. Several case reports and studies in cancer patients have attributed many arrhythmic events to doxorubicin, some of which are life-threatening such as complete heart block and ventricular fibrillation. In this review, reports regarding the potential arrhythmic complications associated with doxorubicin from previous studies investigating the effects of doxorubicin on cardiac electrophysiological properties are comprehensively summarized and discussed. Consistencies and controversial findings from in vitro, in vivo, ex vivo, and clinical studies are presented and mechanistic insights regarding the effects of doxorubicin are also discussed.