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

NEW FINDINGS: What is the central question of this study? Regional variations of ventricular L-type calcium current (ICa-L ) 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 ICa-L compared with female apex or male myocytes. Oestrogen upregulated ICa-L in cultured female myocytes. Mathematical simulations modelling long QT syndrome type 2 demonstrated that elevated ICa-L prolonged action potentials and induced early after-depolarizations. Thus, ventricular arrhythmias in adult females may be associated with an oestrogen-induced upregulation of ICa-L . Previous studies have shown that adult rabbit left ventricular myocytes exhibit sex and regional differences in L-type calcium current (ICa-L ) 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 ICa-L density and used mathematical modelling to examine the contribution of ICa-L 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 ICa-L 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 ICa-L density compared with untreated control myocytes, suggesting an oestrogen-induced upregulation of ICa-L . Action potential simulations using a modified Luo-Rudy cardiomyocyte model showed that increased ICa-L 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 ICa-L 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 ICa-L contributed to genesis of EADs.