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

• Published in: Circulation research Vol. 102; no. 9; pp. e86 - e100
• Main Authors: Sims, Carl, Reisenweber, Steven, Viswanathan, Prakash C, Choi, Bum-Rak, Walker, William H, Salama, Guy
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 09.05.2008
• Subjects: Action Potentials; Age Factors; Animals; Calcium Channels, L-Type - genetics; Calcium Channels, L-Type - metabolism; Computer Simulation; Female; Heart Ventricles - metabolism; Ion Channel Gating; Long QT Syndrome - chemically induced; Long QT Syndrome - etiology; Long QT Syndrome - metabolism; Long QT Syndrome - physiopathology; Male; Models, Cardiovascular; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Patch-Clamp Techniques; Pericardium - metabolism; Phenotype; Potassium Channel Blockers - toxicity; Pyrrolidines - toxicity; Rabbits; Research Design; Risk Factors; RNA, Messenger - metabolism; Sex Factors; Sodium-Calcium Exchanger - metabolism; Time Factors; Torsades de Pointes - chemically induced; Torsades de Pointes - etiology; Torsades de Pointes - metabolism; Torsades de Pointes - physiopathology
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.108.173740

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 (ICa,L) is another determinant of action potential duration, Ca overload, early afterdepolarizations (EADs), and Torsade de Pointes. Therefore, sex, age, and regional differences in ICa,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 ICa,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 adultsICa,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 ICa,L were not significant in adult male and prepubertal female hearts. Western blot analysis showed that Cav1.2α levels varied with sex, maturity, and apex–base, with differences similar to variations in ICa,L; optical mapping revealed that the earliest EADs fired at the base. Single myocyte experiments and Luo–Rudy simulations concur that ICa,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 overload and the propensity for ICa,L reactivation.