Sex‐deparities in cardiac electrophysiology: L‐type Ca²⁺ current and the Na⁺–Ca²⁺ exchanger go hand in hand

Sex disparities in electrocardiogram variables and arrhythmia susceptibility exist, notably in Brugada syndrome and Long QT syndrome (LQTS) (Pham & Rosen, 2002; James et al. 2006). Animal studies highlight the role of differences in ion current densities in the sex-related distinction in cardiac electrophysiology. In various species, ventricular myocytes of females have a larger depolarizing L-type Ca2+ current (ICa,L), but smaller repolarizing K+ currents than those of males (Pham & Rosen, 2002; James et al. 2006). Recent evidence based on ion channel and transporter subunit expression (Gaborit et al. 2010) and a patch clamp study (Verkerk et al. 2005) indicates that similar differences may also underlie sex disparities in human cardiac electrophysiology. While various studies highlight the role of ion currents in sex-related distinction in cardiac electrophysiology, the role of pumps and/or exchangers, such as the Na+/Ca2+ exchanger (NCX), are less intensively studied. For many years, the accepted concept has been that, for the maintenance of Ca2+ homeostasis in cardiac myocytes, influx of Ca2+ through ICa,L equals Ca2+ efflux through NCX (Blaustein & Lederer, 1999). Thus, the larger ICa,L in myocytes of females has been assumed to be accompanied by a larger NCX. However, a sex difference in NCX magnitude in cardiac myocytes is debated (see Chen et al. and primary references cited therein). An article by Chen and colleagues (2011) in a recent issue of The Journal of Physiology re-examines the question of whether NCX is involved in sex disparities in cardiac electrophysiology of adult rabbits. In this article, the emphasis is on regional variation, because previous studies have reported rather complex sex-based differences in various ionic currents across the ventricular wall (Xiao et al. 2006) and from base to apex (Sims et al. 2008). In adult rabbits, the group of Salama reported a larger ICa,L in female myocytes isolated from the base, but not the apex, of the heart (Sims et al. 2008). As one might expect and in accordance with the concept that Ca2+ that goes into the cell must also come out of it, Chen et al. (2011) found that myocytes isolated from the base of the heart of female rabbits have more expression of NCX1 protein and a larger NCX current (INCX) than those from male rabbits. No differences in INCX were observed between myocytes isolated from the apex of female and male rabbits. Thus, the study of Chen et al. demonstrates regional sex differences in INCX. Sex hormones largely account for the sex disparities in cardiac electrophysiology (Mendelsohn & Karas, 1999). Sex hormones exert non-genomic effects (functional properties) and genomic effects (protein synthesis) on membrane proteins, including ion channels and exchangers. Chen et al. found that INCX decreased in the absence, but increased in the presence of 17β-oestradiol during a 3 day culturing period. The 17β-oestradiol-induced INCX increase was blunted by an oestrogen receptor antagonist, inhibition of transcription, and translocation. Taken together, these results suggest that the NCX exchanger was modulated by a genomic mechanism. Of interest, the genomic modulation of NCX was only observed in myocytes isolated from the heart base of female rabbits, while it was unaltered in myocytes isolated from the heart apex of female rabbits, and myocytes from male rabbits (isolated either from base or apex). The absence of 17β-oestradiol effects in male myocytes may be due to the fact that male myocytes lack modulation of the progesterone receptor in response to 17β-oestradiol (Kararigas et al. 2010). Chen et al. (2011) do not explore the pathophysiological basis of the intriguing finding of this regional genomic modulation of INCX. A possible mechanism that is discussed is that oestrogen receptors have various subtypes, which may have various distributions in the heart. Further studies are required to identify the molecular basis of the regional differences in INCX magnitude in female hearts. In their study, Chen et al. (2011) further found that only myocytes from the heart base of female rabbits have the propensity to develop early afterdepolarizations (EADs) in response to dofetilide. EADs are involved in ‘torsade de pointes’ (TdP) arrhythmias, which are more frequently found in women than men (James et al. 2006). Chen et al. found that this increased vulnerability to dofetilide-induced EADs was mediated by genomic mechanisms. They also demonstrated that a low dose of KB-R7943, an inhibitor of the reverse mode of NCX, abolished the dofetilide-induced EADs. This agrees with recent findings that NCX inhibition in intact rabbit heart models of LQTS types 2 and 3 is effective in preventing TdP (Milberg et al. 2008). Thus, besides ICa,L (Sims et al. 2008), NCX is also critical for the increased incidence of TdP arrhythmias in females. Whether the large INCX in myocytes from the heart base of female rabbits is due to a larger ICa,L or vice versa is a matter of debate. Chen et al. (2011) propose that increased Ca2+ influx via ICa,L should be balanced by increased efflux. However, recently two adaptations of excitation–contraction coupling to the absence of NCX in transgenic mice were identified (Pott et al. 2007): (1) a reduction of ICa,L and (2) a shortening of the action potential. Both mechanisms contribute to Ca2+ homeostasis by reducing Ca2+ influx. These findings demonstrate that ICa,L and the action potential can remodel in response to NCX changes. The study of Chen et al. (2011) does not address the question whether changes in NCX are cause or effect. Nevertheless, it provides further demonstration that NCX and ICa,L go hand in hand. H.L.T. is supported by the Netherlands Organization for Scientific Research (NWO, grant ZonMW Vici 918.86.616).