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1 Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
2 Medicine, University of Montreal, Montreal, Quebec, Canada; Research Center, Montreal Heart Institute, Montreal, Quebec, Canada
3 Physiology, McGill University, Montreal, Quebec, Canada
4 Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; Medicine, University of Montreal, Montreal, Quebec, Canada; Research Center, Montreal Heart Institute, Montreal, Quebec, Canada
* To whom correspondence should be addressed. E-mail: stanley.nattel{at}icm-mhi.org.
Female gender is associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. This study examined the hypothesis that gender 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 gender 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 gender differences in IK1 were observed. Ito densities in epicardium and midmyocardium also showed no gender differences. In endocardium, female dogs had significantly smaller Ito (e.g. at +30 mV, female vs. male: 2.5±0.2 vs. 3.5±0.3 pA/pF; P<0.05). IKr density and activation voltage-dependence showed no gender differences. Female dogs had significantly larger IKs 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 gender differences in midmyocardial IKs. Female dogs had larger ICa,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 gender-based transmural differences in ionic currents which may underlie gender differences in transmural cardiac repolarization.
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