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

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,I-L) is another determinant of action potential duration, Ca2+ overload, early afterdepolarizations (EADs), and Torsade de Pointes. Therefore, sex, age, and regional differences in I-Ca,I-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,I-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,I-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,I-L were not significant in adult male and prepubertal female hearts. Western blot analysis showed that Ca(v)1.2 alpha levels varied with sex, maturity, and apex-base, with differences similar to variations in I-Ca,I-L; optical mapping revealed that the earliest EADs fired at the base. Single myocyte experiments and Luo-Rudy simulations concur that I-Ca,I-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 Ca2+ overload and the propensity for I-Ca,I-L reactivation.