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)1.2alpha 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.