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Sex-based transmural differences in cardiac repolarization and ionic-current properties in canine left ventricles

¹Departments of Pharmacology and Therapeutics and ²Physiology, McGill University; and ³Department of Medicine and Research Center, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada

Submitted 7 December 2005 ; accepted in final form 20 February 2006

The female sex is associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. This study examined the hypothesis that sex differences in repolarization may be associated with differential transmural ion-current distribution. Whole cell patch-clamp and current-clamp were used to study ionic currents and action potentials (APs) in isolated canine left ventricular cells from epicardium, midmyocardium, and endocardium. No sex differences in AP duration (APD) were found in cells from epicardium versus endocardium. In midmyocardium, APD was significantly longer in female dogs (e.g., at 1 Hz, female vs. male: 288 ± 21 vs. 237 ± 8 ms; P < 0.05), resulting in greater transmural APD heterogeneity in females. No sex differences in inward rectifier K⁺ current (I_K1) were observed. Transient outward K⁺ current (I_to) densities in epicardium and midmyocardium also showed no sex differences. In endocardium, female dogs had significantly smaller I_to (e.g., at +30 mV, female vs. male: 2.5 ± 0.2 vs. 3.5 ± 0.3 pA/pF; P < 0.05). Rapid delayed-rectifier K⁺ current (I_Kr) density and activation voltage-dependence showed no sex differences. Female dogs had significantly larger slow delayed-rectifier K⁺ current (I_Ks) in epicardium and endocardium (e.g., at +40 mV; tail densities, female vs. male; epicardium: 1.3 ± 0.1 vs. 0.8 ± 0.1 pA/pF; P < 0.001; endocardium: 1.2 ± 0.1 vs. 0.7 ± 0.1 pA/pF; P < 0.05), but there were no sex differences in midmyocardial I_Ks. Female dogs had larger L-type Ca²⁺ current (I_Ca,L) densities in all layers than male dogs (e.g., at –20 mV, female vs. male, epicardium: –4.2 ± 0.4 vs. –3.2 ± 0.2 pA/pF; midmyocardium: –4.5 ± 0.5 vs. –3.3 ± 0.3 pA/pF; endocarium: –4.5 ± 0.4 vs. –3.2 ± 0.3 pA/pF; P < 0.05 for each). We conclude that there are sex-based transmural differences in ionic currents that may underlie sex differences in transmural cardiac repolarization.

sex difference; transmural dispersion of repolarization; ion channels; action potential

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