Sex and regional differences in rabbit right ventricular L‐type calcium current levels and mathematical modelling of arrhythmia vulnerability

Abstract

What is the central question of this study? Regional variations of ventricular L-type calcium current (I ) amplitude may underlie the increased arrhythmia risk in adult females. Current amplitude variations have been described for the left ventricle but not for the right ventricle. What is the main finding and its importance? Adult female rabbit right ventricular base myocytes exhibit elevated I compared with female apex or male myocytes. Oestrogen upregulated I in cultured female myocytes. Mathematical simulations modelling long QT syndrome type 2 demonstrated that elevated I prolonged action potentials and induced early after-depolarizations. Thus, ventricular arrhythmias in adult females may be associated with an oestrogen-induced upregulation of I . Previous studies have shown that adult rabbit left ventricular myocytes exhibit sex and regional differences in L-type calcium current (I ) levels that contribute to increased female susceptibility to arrhythmogenic early after-depolarizations (EADs). We used patch-clamp recordings from isolated adult male and female rabbit right ventricular myocytes to determine apex-base differences in I density and used mathematical modelling to examine the contribution of I to EAD formation. Current density measured at 0 mV in female base myocytes was 67% higher than in male base myocytes and 55% higher than in female apex myocytes. No differences were observed between male and female apex myocytes, between male apex and base myocytes, or in the voltage dependences of I activation or inactivation. The role of oestrogen was investigated using cultured adult female right ventricular base myocytes. After 2 days, 17β-estradiol (1 nm) produced a 65% increase in I density compared with untreated control myocytes, suggesting an oestrogen-induced upregulation of I . Action potential simulations using a modified Luo-Rudy cardiomyocyte model showed that increased I density, at the level observed in female base myocytes, resulted in longer duration action potentials, and when combined with a 50% reduction of the rapidly inactivating delayed rectifier potassium current conductance to model long QT syndrome type 2, the action potential was accompanied by one or more EADs. Thus, we found higher levels of I in adult female right ventricle base myocytes and the upregulation of this current by oestrogen. Simulations of long QT syndrome type 2 showed that elevated I contributed to genesis of EADs.

GPER mediates estrogen cardioprotection against epinephrine-induced stress

“…In addition, our results also demonstrated that estrogen did not affect the contraction of female rats ventricular cardiomyocytes under normal conditions. This finding conformed with recent findings by Kalik et al They also found that I Ca-L of cardiomyocytes was unchanged by estrogen (Kalik et al 2017). Ullrich et al and Yang et al reported earlier that estrogen altered I Ca-L (Ullrich et al 2007, Yang et al 2012.…”

Three-Week-Old Rabbit Ventricular Cardiomyocytes as a Novel System to Study Cardiac Excitation and EC Coupling

“…Nevertheless, the functional calcium channels are robust and stable during 48 h of culturing (Moshal et al, 2019), and they are not affected by overexpression of GFP. Our values of I Ca,L (−7 to −9 pA/pF) in 3wRbCMs are comparable to previously reported maximal I Ca,L in the range from −4 to −6 pA/pF found in adult (13 weeks old) rabbit cardiac ventricular myocytes (Kalik et al, 2017) and I Ca,L of −7.5 pA/pF found in human ventricular myocytes (Jost et al, 2013). Of note, the persistence of I Ca and small changes in I to in cultured cells likely underlie the lack of prolongation of APD50 in cultured cells as compared to freshly dissociated myocytes (Supplementary Figure 10).…”

Estrogen and calcium handling proteins: new discoveries and mechanisms in cardiovascular diseases

“…In our recent study, we found that estrogen supplementation significantly increased I CaL , Ca v 1.2␣ mRNA, and protein levels in OVX mice cardiomyocytes compared with male and sham female cardiomyocytes (69). Elsewhere, estrogen increased I CaL and prolonged the plateau period of action potential, leading to a longer QT interval, an effect that increased the risk of LQT2 arrhythmia phenotype (19,27,53,84,94,115,144,145). Additionally, dysregulation of human ether-a-go-go-related gene (hERG)-encoded potassium channels has been linked to the prolongation of QT interval (110).…”