Sex and Regional Differences in L-type Calcium Current Distribution in Adult Rabbit Right Ventricle: Influence Action Potential Duration and the Propensity for Cardiac Arrhythmia

Abstract

Long QT syndrome (LQTS) is a form of heart disease that is known to affect 1 in 10,000 individuals (Vincent 2002). Individuals who suffer from congenital or acquired forms of LQTS are at an increased risk to develop deadly arrhythmias. Women are known to have longer rate corrected QT intervals (QTc) and action potential durations (APDs) than men, resulting in an increased risk for arrhythmia. Previous studies have indicated that this is primarily due to sex differences in the levels of the delayed and inward rectifier potassium currents, IKr and IKs, which regulate cardiac repolarization. However, recent data suggesting a role for calcium currents has lead us to re-examine the factors are responsible for sensitivity to arrhythmia generation. The L-type calcium current (ICa-L) is a significant contributor to the magnitude and duration of the cardiac action potential. Recently, several reports have linked sex differences in ICa-L to gender-associated arrhythmia vulnerability. In the present study, differences in the apex to base distribution of ICa-L in adult male and female right ventricles were assessed by the patch clamp technique and a modified Luo-Rudy action potential model. Female base myocytes exhibited a 84.6% higher ICa-L density than male base myocytes, but apex myocytes from males and females showed similar ICa-L densities. Within the female right ventricle, base myocytes had a 56.5% higher current density than did apex myocytes. No differences were found between male base and apex myocytes. The increased current density observed in female base myocytes was not associated with alterations of ICa-L activation or deactivation voltage characteristics. Cardiac action potential modeling indicated that increased ICa-L could contribute to arrhythmia development. The data thus support the hypothesis that higher L-type calcium current densities may contribute to the propensity for arrhythmias in some individuals.