Abstract
AIMS: Anthracyclines are key components of various chemotherapy regimens, but their clinical utility is limited by severe cardiotoxic side effects. Previous studies have suggested that anthracycline-induced cardiotoxicity (AIC) may be driven by alterations in myocardial lipid metabolism. This study aimed to systematically explore the cardiac lipidomic landscape of AIC with regard to potential pathomechanisms and novel therapeutic targets. METHODS AND RESULTS: Mass spectrometry-based untargeted lipidomics were performed on myocardial biopsies from 13 patients with AIC (age 53 ± 31 years, 54% female, left ventricular ejection fraction 19 ± 4%) and 15 age- and sex-matched controls. Lipidomic profiles were also compared with 15 patients with other heart failure aetiologies (matched for sex and age). A total of 627 individual lipid species from 22 different lipid classes were analysed. AIC was associated with a lower proportion of polyunsaturated fatty acids towards more monounsaturated and saturated sidechains as well as significant alterations in the proportion of odd-chain fatty acids. Pathway analyses indicated a higher precursor conversion into lysolipids in AIC. This accumulation of lysolipid species was not observed in other heart failure aetiologies and may represent a specific finding in AIC. CONCLUSION: Anthracycline-induced cardiotoxicity leads to distinct alterations of the myocardial lipidome. Increased levels of myocardial lysolipids were identified as a novel lipidomic trait in AIC, which appears to be distinct from other causes of heart failure. Further research studying pharmacological interventions in lysolipid metabolism for prevention and therapy of AIC is warranted.