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

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 ϩ 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 2ϩ 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 (6.4Ϯ0.5 versus 5.0Ϯ0.2 pA/pF; PϽ0.03) and higher than at the apex (6.4Ϯ0.5 versus 5.0Ϯ0.3 pA/pF; PϽ0.02). Sex differences were reversed in adults: I Ca,L at the base was 32% higher in females than males (9.5Ϯ0.7 versus 6.4Ϯ0.6 pA/pF; PϽ0.002) and 28% higher than the apex (9.5Ϯ0.7 versus 6.9Ϯ0.5 pA/pF; PϽ0.01). Apex-base differences in I Ca,L were not significant in adult male and prepubertal female hearts. Western blot analysis showed that Ca v 1.2␣ 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 2ϩ overload and the propensity for I Ca,L reactivation. (Circ Res. 2008;102:e86 -e100.)

Bradycardia alters Ca2+dynamics enhancing dispersion of repolarization and arrhythmia risk

“…We previously reported that female rabbit hearts express higher protein levels of Cav1.2␣ and NCX1 and have significantly higher current densities of I Ca,L and I NCX (25-30%) at the base compared with the apex. The greater Ca 2ϩ influx via I Ca,L and reverse mode I NCX lead to greater SR Ca 2ϩ overload and a greater propensity to EADs in female myocytes isolated from the base compared with those isolated from the apex, endocardium or isolated from male hearts (17,52,65).…”

Drug-Induced Arrhythmia

“…37,38 L-type calcium current density has also been found to be an important predictor of arrhythmia susceptibility, likely related to its effects on intracellular calcium overload and early afterdepolarizations. 39 Spatial heterogeneity or dispersion of repolarization across the ventricular wall (transmural dispersion of repolarization) is among the strongest preclinical predictors of the potential of a drug to cause TdP. 38 This heterogeneity of repolarization relates to the differing properties of the epicardial, midmyocardial (M cells), and endocardial cells and to the heightened susceptibility of M cells to the action potential-prolonging effects of drugs that selectively block I Kr ( Figure 3).…”

The L-type Ca2+ Channel as a Potential Mediator of Pathology During Alterations in Cellular Redox State

“…EADs are depolarisations of the membrane potential that occur predominantly during phase 2 or 3 of the cardiac action potential and can degenerate to polymorphic ventricular tachycardia [54,55]. Generation of EADs requires an inward current that is large enough to increase total inward membrane current.…”