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(Circulation Research. 2008;102:e86.)
© 2008 American Heart Association, Inc.

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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

Carl Sims, Steven Reisenweber, Prakash C. Viswanathan, Bum-Rak Choi, William H. Walker, Guy Salama

From the Department of Cell Biology and Physiology, University of Pittsburgh, School of Medicine, Pittsburgh, Pa. Present address for C.S.: Department of Biological Sciences, Youngstown State University, Ohio. Present address for B.-R.C.: Cardiovascular Research Center, Rhode Island Hospital & Brown Medical School, Providence.

Correspondence to Guy Salama, PhD, University of Pittsburgh, School of Medicine, Department of Cell Biology and Physiology, S312 Biomedical Science Tower, 3500 Terrace St, Pittsburgh, PA 15261. E-mail gsalama{at}pitt.edu

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, Ca²⁺ 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_v1.2 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 Ca²⁺ overload and the propensity for I_Ca,L reactivation.

Key Words: cardiac voltage-gated calcium current • I_Ca,L, sex differences • QT interval • ion channel expression • Torsade de Pointes

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