Cardiotoxicity: Mechanisms and Prevention
Drug-induced cardiotoxicity can manifest as arrhythmias, cardiomyopathy, or heart failure. Recognizing mechanisms enables safer prescribing.
## Overview
Drug-induced cardiotoxicity encompasses a spectrum from asymptomatic ECG changes to fatal arrhythmias and irreversible heart failure. It is a leading reason for drug withdrawal from the market, with over 40 drugs removed since 1990 due to cardiac safety concerns.
## Types of Cardiotoxicity
**Cardiomyopathy** can be classified as Type I (irreversible, dose-dependent) or Type II (reversible, dose-independent). Anthracyclines like doxorubicin cause Type I injury through topoisomerase IIb inhibition and free radical generation in cardiomyocytes. The lifetime cumulative dose limit for doxorubicin is 450-550 mg/m2. Trastuzumab causes Type II injury by blocking HER2 signaling in cardiac cells, which is generally reversible upon discontinuation.
**Arrhythmias** result from ion channel blockade. hERG potassium channel inhibition causes QT prolongation and risk of torsades de pointes. Sympathomimetics and digitalis glycosides can cause tachyarrhythmias.
**Myocardial ischemia** occurs with vasospastic agents (5-fluorouracil, cocaine) and drugs causing demand ischemia (amphetamines).
**Pericarditis** and **myocarditis** are seen with immune checkpoint inhibitors (1-2% incidence) and have high mortality rates when unrecognized.
## Major Drug Classes
- **Anthracyclines**: Dose-dependent cardiomyopathy; dexrazoxane is cardioprotective
- **Tyrosine kinase inhibitors**: Sunitinib, sorafenib cause hypertension and LV dysfunction
- **Immune checkpoint inhibitors**: Myocarditis with 25-50% fatality if untreated
- **Fluoropyrimidines**: 5-FU causes coronary vasospasm in 1-18% of patients
- **Antipsychotics**: Metabolic syndrome, QT prolongation
- **Stimulants**: Cocaine and amphetamines cause coronary vasospasm and hypertensive crises
## Monitoring Strategies
Baseline ECG and echocardiography are essential before cardiotoxic chemotherapy. Serial left ventricular ejection fraction (LVEF) monitoring by echocardiography or MUGA scan is standard during anthracycline therapy. Cardiac biomarkers (troponin I, BNP/NT-proBNP) can detect subclinical injury before LVEF decline.
## Cardioprotective Approaches
Dexrazoxane chelates iron and reduces anthracycline free radical generation. Liposomal doxorubicin formulations reduce cardiac exposure. Beta-blockers and ACE inhibitors may attenuate chemotherapy-induced cardiomyopathy. Exercise during cancer treatment shows emerging cardioprotective benefit.
## Key Takeaways
- Anthracycline cardiotoxicity is dose-dependent and often irreversible
- hERG channel blockade underlies most drug-induced QT prolongation
- Checkpoint inhibitor myocarditis is rare but has high mortality
- Serial LVEF and cardiac biomarker monitoring detect early injury
- Dexrazoxane, liposomal formulations, and cardioprotective medications reduce risk