Sex and regional differences in rabbit right ventricular l-type calcium current levels and mathematical modeling of arrhythmia vulnerability

Abstract

Previous studies have shown that adult rabbit left ventricular myocytes exhibit sex and regional differences in L-type calcium current (I_Ca-L) levels that contribute to increased susceptibility to arrhythmogenic early afterdepolarizations (EADs). We used patch clamp recordings from isolated adult male and female rabbit right ventricular myocytes to determine apex-base differences in I_Ca-L density, and mathematical modeling to examine I_Ca-L contribution to EAD formation. Current density measured at 0 mV in female base myocytes was 67% higher than male base myocytes and 55% higher than female apex myocytes. No differences were observed between male and female apex myocytes, male apex and base myocytes, or in the voltage dependences of I_Ca-L activation or inactivation. The role of estrogen was investigated using cultured adult female right ventricular base myocytes. After 2 days, 17β-estradiol (1 nm) produced a 65% increase in I_Ca-L density compared to untreated controls, suggesting an estrogen-induced up-regulation of I_Ca-L. Action potential (AP) simulations using a modified Luo-Rudy cardiomyocyte model found that increased I_Ca-L density, at the level observed in female base myocytes, resulted in longer duration APs, and when combined with a 50% reduction of the rapidly inactivating delayed rectifier potassium current conductance to model Long QT Syndrome Type 2 (LQT2), the AP was accompanied by one or more EADs. Thus we found higher levels of I_Ca-L in adult female right ventricle base myocytes and the upregulation of this current by estrogen. Simulations of LQT2 found that elevated I_Ca-L contributed to EAD genesis.

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