Dexrazoxane protects against doxorubicin-induced cardiotoxicity in susceptible human living myocardial slices: A proof-of-concept study

Abstract

BACKGROUND AND PURPOSE: The increasing number of cancer survivors has caused growing concern over chemotherapy-induced cardiotoxicity. This study aimed to investigate a novel human model of cardiotoxicity and explore cardioprotection. EXPERIMENTAL APPROACH: Living myocardial slices (LMS) were obtained from explanted end-stage heart failure hearts, then exposed to doxorubicin (Dox) to investigate cardiotoxic effects and to dexrazoxane (Dex) to explore cardioprotection. We assessed contractile function and glucose consumption, followed by evaluation of calcium transients, structural integrity and transcriptomic changes. Additionally, electrocardiogram (ECG) alterations were analysed in patients treated with anthracyclines to corroborate the cardiotoxicity findings from LMS. KEY RESULTS: We observed distinct functional responses to Dox, with LMS derived from some patients exhibiting high susceptibility to Dox-induced cardiotoxicity. LMS from susceptible patients displayed reduced contractile function and excitability, myofibre dyssynchrony, structural damage and decreased metabolic activity. Dex pretreatment partially mitigated these effects, preserving contractile function and preventing structural damage. Consistent with ex vivo findings, patients treated with anthracyclines exhibited acute and chronic alterations in T-, P- and R-wave morphology of the ECG, confirming variable susceptibility at the clinical level. CONCLUSIONS AND IMPLICATIONS: We highlight the value of human LMS in studying Dox-induced cardiotoxicity and the cardioprotective potential of Dex, even when sourced from end-stage heart failure patients. Susceptible patients harboured cardiomyopathy-associated genetic mutations, suggesting that genetic screening including cardiomyopathy-associated genes, prior to anthracycline treatment, could enable improved patient risk stratification. We demonstrate the potential utility of ECG changes for early detection of subclinical cardiotoxicity.