Sex, Age, and Regional Differences in L-Type Calcium Current Are Important Determinants of Arrhythmia Phenotype in Rabbit Hearts With Drug-Induced Long QT Type 2

Abstract

In congenital and acquired long QT type 2, women are more vulnerable than men to Torsade de Pointes. In prepubertal rabbits (and children), the arrhythmia phenotype is reversed; however, females still have longer action potential durations than males. Thus, sex differences in K + channels and action potential durations alone cannot account for sex-dependent arrhythmia phenotypes. The L-type calcium current ( I Ca,L ) is another determinant of action potential duration, Ca 2+ overload, early afterdepolarizations (EADs), and Torsade de Pointes. Therefore, sex, age, and regional differences in I Ca,L density and in EAD susceptibility were analyzed in epicardial left ventricular myocytes isolated from the apex and base of prepubertal and adult rabbit hearts. In prepubertal rabbits, peak I Ca,L at the base was 22% higher in males than females (6.4±0.5 versus 5.0±0.2 pA/pF; P <0.03) and higher than at the apex (6.4±0.5 versus 5.0±0.3 pA/pF; P <0.02). Sex differences were reversed in adults: I Ca,L at the base was 32% higher in females than males (9.5±0.7 versus 6.4±0.6 pA/pF; P <0.002) and 28% higher than the apex (9.5±0.7 versus 6.9±0.5 pA/pF; P <0.01). Apex–base differences in I Ca,L were not significant in adult male and prepubertal female hearts. Western blot analysis showed that Ca v 1.2α levels varied with sex, maturity, and apex–base, with differences similar to variations in I Ca,L ; optical mapping revealed that the earliest EADs fired at the base. Single myocyte experiments and Luo–Rudy simulations concur that I Ca,L elevation promotes EADs and is an important determinant of long QT type 2 arrhythmia phenotype, most likely by reducing repolarization reserve and by enhancing Ca 2+ overload and the propensity for I Ca,L reactivation.