Sex Differences in the Function of Cardiac Sodium-Calcium Exchanger in Physiological and Pathophysiological Settings: Implications for Cardiac Arrhythmias

In the past decades, it has become increasingly clear that women and men significantly differ in the epidemiology, pathophysiology and outcome of cardiovascular diseases that also include certain cardiac electrophysiological aspects leading to different disease phenotypes and disparate outcomes of pharmacological interventions. These dissimilarities stem from numerous differences in ion channel expression, kinetics and regulation. One of the first observations of sex-related differences was the longer QT-interval in women measured on the ECG. Sex hormones can influence the electrophysiological parameters on the genomic level altering gene expression. In this regard, the reduced expression of various ion channels carrying repolarizing currents, including Ito, IK1, IKr, IKs and IK,ATP, have been described in women. Sex hormones can also change ion channel functions by non-genomic effects, including the modulation of specific signalling pathways (such as eNOS). Furthermore, direct effects of sex hormones on ion channels were also described. For example, 17β-oestradiol directly reduced IKr, while testosterone increased IKr and progesterone enhanced IKs. In addition to repolarizing ion currents, sex hormones can influence a large number of transmembrane ion channels and exchangers in various ways, therefore, in this chapter, the sex-related differences regarding an important component of intracellular Ca2+ handling, the Na+/Ca2+ exchanger are discussed.