Drug-Induced Cardiotoxicity

Drug-induced cardiotoxicity is damage to the heart or its electrical activity caused by medications. It spans two broad problems: structural injury that weakens the heart muscle, classically seen with anthracycline chemotherapy and some targeted cancer drugs, and electrophysiological effects such as QT-interval prolongation that predispose to dangerous arrhythmias.

Definition

Drug-induced cardiotoxicity is adverse injury to the heart attributable to a drug, including structural injury to cardiomyocytes that can impair cardiac function and electrophysiological effects, such as blockade of cardiac ion channels, that disturb the heart's rhythm.

Scope

This entry covers the concept and main categories of drug-induced cardiac injury, the mechanisms of anthracycline and targeted-therapy cardiomyopathy, and the electrophysiological toxicity underlying drug-induced QT prolongation. It is a reference-educational overview of how cardiotoxicity is understood and studied, not clinical guidance on prevention, monitoring, or treatment.

Core questions

• What distinguishes structural (myocardial) cardiotoxicity from electrophysiological (arrhythmic) cardiotoxicity?
• How do anthracyclines injure cardiomyocytes at the molecular level?
• Why do some targeted cancer therapies affect the heart?
• How does blockade of cardiac ion channels lead to QT prolongation and arrhythmia risk?

Key concepts

• Structural (myocardial) cardiotoxicity
• Anthracycline-induced cardiomyopathy
• Topoisomerase IIβ-mediated injury
• Oxidative stress and mitochondrial damage
• Targeted-therapy cardiotoxicity
• hERG potassium channel block
• QT prolongation and torsades de pointes

Mechanisms

Structural cardiotoxicity is exemplified by the anthracyclines (such as doxorubicin), which generate oxidative stress and mitochondrial injury in cardiomyocytes; work in animal models identified topoisomerase IIβ in cardiomyocytes as a key mediator of doxorubicin-induced cardiac injury, linking the drug's anticancer mechanism to its cardiotoxicity (Zhang et al., 2012; Vejpongsa & Yeh, 2013). Targeted cancer therapies can injure the heart by interfering with signalling pathways that cardiomyocytes depend on for survival and function (Moslehi, 2016). Electrophysiological cardiotoxicity arises when drugs block cardiac ion channels, particularly the hERG potassium channel that governs repolarisation; this prolongs the QT interval and can precipitate the polymorphic ventricular arrhythmia torsades de pointes (Witchel, 2011).

Clinical relevance

Cardiotoxicity is a major consideration in oncology and in drug safety more broadly: it shapes how cardiac function and heart rhythm are conceptually monitored during therapy, and hERG-related QT risk is a standard part of cardiac safety evaluation in drug development. This entry explains how cardiotoxicity is conceptualised and studied and is not a basis for individual monitoring, diagnosis, or treatment decisions.

Epidemiology

Anthracycline cardiotoxicity is dose-related, with risk rising at higher cumulative exposure, while the cardiotoxicity of targeted therapies varies by agent and pathway (Vejpongsa & Yeh, 2013; Moslehi, 2016). Drug-induced QT prolongation is an important cause of acquired long QT syndrome and a leading reason for restricting or withdrawing drugs; the magnitude of risk depends on the drug, dose, and host factors (Witchel, 2011).

History

Anthracycline cardiomyopathy was recognised soon after these drugs entered cancer therapy and became a model for dose-dependent structural cardiotoxicity, later refined by the identification of topoisomerase IIβ as a mediator (Zhang et al., 2012). Separately, high-profile arrhythmias from non-cardiac drugs that block the hERG channel drove the field of cardiac safety pharmacology and regulatory attention to QT prolongation (Witchel, 2011). The growth of targeted cancer therapies subsequently expanded the scope of cardio-oncology (Moslehi, 2016).

Debates

Can anticancer efficacy be separated from anthracycline cardiotoxicity?

Because topoisomerase IIβ in cardiomyocytes appears central to anthracycline cardiac injury while topoisomerase IIα is implicated in the antitumour effect, whether the two can be pharmacologically separated to preserve efficacy while reducing cardiotoxicity is an active question.

Key figures

• Edward T. H. Yeh
• Javid J. Moslehi
• Harry J. Witchel

Seminal works

• zhang2012
• witchel2011

Frequently asked questions

What are the two main types of drug-induced cardiotoxicity?

One type is structural injury to the heart muscle, which can weaken the heart, as seen with anthracycline chemotherapy. The other is electrophysiological toxicity, in which drugs disturb the heart's electrical activity, for example by prolonging the QT interval and raising the risk of dangerous arrhythmias.

Why do many drugs need to be tested for QT prolongation?

A wide range of drugs can block the hERG potassium channel that controls cardiac repolarisation. Blocking it prolongs the QT interval, which can trigger a serious arrhythmia, so cardiac electrical safety is routinely evaluated during drug development.