Age- and sex-specific modulation of human cardiac electrophysiology by doxorubicin.

Acute doxorubicin (DOX)-induced cardiotoxicity leads to electrophysiological changes, including QT prolongation, reduced QRS voltages and T-wave abnormalities. We previously demonstrated in mice that the effects of DOX on cardiac electrophysiology are sex dependent. Determine sex- and age-specific cardiotoxic effects of DOX on human cardiac electrophysiology and whether targeting p38 MAPKs could be cardioprotective in human hearts. Human cardiac slices were cultured for 24 h with DOX (0-50 µM). Slices were optically mapped to measure action potential duration (APD₈₀) and transverse conduction velocity (CVT). Tissues were preserved for RNA sequencing. In separate slices p38 MAPK inhibitors SB203580 or compound 62 were applied alongside DOX. DOX induced dose-dependent APD₈₀ prolongation in young female and old hearts of both sexes. Phase 3 APD₈₀ prolongation was associated with increased CACNA1C expression in young females. DOX also slowed CVT in young males and females, as well as in old males, despite increased SCN5A gene expression in young hearts of both sexes and increased GJA1 in young females. Furthermore inhibiting p38α/β MAPKs with SB203580 did not prevent DOX-induced APD₈₀ prolongation and CVT slowing, whereas pan-p38 MAPK inhibitor, compound 62, attenuated these effects in male and female hearts, suggesting a role for p38γ and/or p38δ MAPKs in mediating DOX cardiotoxicity in human hearts. Acute DOX-induced electrophysiological cardiotoxicity is sex- and age dependent. This study introduces novel patient-specific diagnostic markers for detecting acute DOX-induced cardiotoxicity. Additionally targeting p38γ and p38δ MAPKs in human hearts could offer a new cardioprotective therapy during DOX chemotherapy. KEY POINTS: Acute markers of doxorubicin-induced cardiotoxicity (DIC) vary between males and females, as well as between young and old hearts. In younger hearts action potential duration (APD) prolongation is more commonly seen in females, whereas in older hearts sex differences are less noticeable. Inhibiting p38γ and p38δ MAPKs could serve as a promising cardioprotective therapy to prevent DIC.