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.