Chemotherapy as Second Hit in Desmoplakin Cardiomyopathy

Cancer therapy-related cardiac dysfunction is traditionally considered an acquired cardiomyopathy; however, genetic susceptibility may predispose patients to disproportionate myocardial injury, supporting a second-hit model.

A 37-year-old woman with breast cancer and no cardiovascular history developed left ventricular dysfunction during anthracycline chemotherapy, with further deterioration after anti-human epidermal growth factor receptor 2 therapy. Cardiovascular magnetic resonance demonstrated biventricular dysfunction, ventricular dilatation, and ring-like subepicardial late gadolinium enhancement, atypical for isolated cardiotoxicity. Genetic testing revealed a pathogenic loss-of-function Desmoplakin variant, establishing DSP-related cardiomyopathy. Anti-human epidermal growth factor receptor 2 therapy was discontinued, heart failure therapy optimized, and an implantable cardioverter-defibrillator implanted for primary prevention.

This case shows how chemotherapy may unmask latent genetic cardiomyopathy, emphasizing the diagnostic value of tissue characterization and genetic testing when ventricular dysfunction is unexpected.

Severe ventricular dysfunction during cancer therapy should prompt genetic evaluation, with cardiovascular magnetic resonance and genetic testing playing a key role in guiding diagnosis and risk stratification.