Mitigation of Anthracycline Cardiotoxicity & Cardiovascular Risk Profiling of Cancer Patients

Abstract

Anthracyclines remain one of the most widely used classes of cancer chemotherapy with proven efficacy across a wide range of malignancies. Despite clear anti-tumour efficacy in both adults and children, anthracyclines are attributed with high rates of ‘cardiotoxicity’. Anthracycline-induced cardiotoxicity (AIC) is frequently undiagnosed and subsequently presents as symptomatic cardiac failure, conveying a poor prognosis. Therefore, when considering cancer patients, many of whom already have a higher baseline risk of cardiovascular disease compared with the general population, AIC threatens to limit long-term cancer patient survival. Various drug infusion rates, newer formulations, and more recently Angiotensin Converting Enzyme inhibitors (ACEi) have been administered to prevent late-onset cardiotoxicities, whilst maximising anthracycline efficacy. Despite ACEi being well studied in cardiovascular medicine, their mechanism(s) for the treatment and prevention of AIC remains unknown. The study objective was to investigate the relationship between AIC and angiotensin signalling mechanisms, in both preclinical and clinical studies. Exposure of the AC10 human ventricular cardiomyocyte cell line to clinically relevant concentrations of doxorubicin in vitro showed a significant concentration- and time-independent induction of angiotensin II receptor type 1 (AT1R) gene expression. This supports previous observations that doxorubicin induces cellular hypertrophy in AC10 cells, an effect mitigated by exposure to angiotensin receptor blocking therapeutics. Regarding clinical effects, the study also demonstrates a relationship between anthracycline-induced cardiotoxicity and genotype of ACE, presence of cellular hypertrophy and fibrosis in cardiac tissue of patients treated with doxorubicin, and baseline blood pressure and subsequent development of AIC. These findings are significant in offering a new paradigm for the mechanism of AIC and protective strategies for its identification and mitigation. This research therefore supports interference with angiotensin signalling as a putative clinical strategy, supporting the transition towards preventative strategies for cardiotoxicity, advocating a proactive approach to cardiovascular risk assessment, and minimising risks through primary prevention.