Sex‐specific repolarization heterogeneity in mouse left ventricle: Optical mapping combined with mathematical modeling predict the contribution of specific ionic currents

Ventricular repolarization shows notable sex‐specificity, with female sex being associated with longer QT‐intervals in electrocardiography irrespective of the species studied. From a clinical point of view, women are at a greater risk for drug‐induced torsade de pointes and symptomatic long‐QT syndrome. Here, we present an optical mapping (OM) approach to reveal sex‐specific action potential (AP) heterogeneity in a slice preparation of mouse hearts. Left ventricular epicardial repolarization in female versus male mice shows longer and, interindividually, more variable AP duration (APD), yielding a less prominent transmural APD gradient. By combining OM with mathematical modeling, we suggest a significant role of I(Kto,f) and I(Kur) in AP broadening in females. Other transmembrane currents, including I(NaL), only marginally affect basal APD. As in many cardiac pathophysiologies, increasing [Ca(2+)](i) poses a risk for arrhythmia, the response of AP morphology to enhanced activation of L‐type calcium channels (LTCC) was assessed in a sex‐selective manner. Both APD and its variation increased significantly more in female versus male mice after pharmacological LTCC activation, which we hypothesize to be due to sex‐specific I(NaL) expression based on mathematical modeling. Altogether, we demonstrate a more delayed repolarization of LV epicardium, a leveled LV transmural APD gradient, and a more pronounced epicardial APD response to Ca(2+) influx in females versus males. Mathematical modeling quantifies the relative contributions of selected ionic currents to sex‐specific AP morphology under normal and pathophysiological conditions.