Larger dispersion of INa in female dog ventricle as a mechanism for gender-specific incidence of cardiac arrhythmias.
OBJECTIVE
Women have a higher incidence of long QT-related arrhythmias, whereas men exhibit a higher incidence of Brugada syndrome (BrS). The cardiac sodium current (I(Na)) is associated with arrhythmias in BrS and long QT-syndrome (LQTS) and conduction disease. Although a great deal of work has been performed to explain how heterogeneous distribution of repolarizing currents triggers arrhythmias, the transmural distribution of I(Na) within the cardiac ventricle and its contribution to generate the arrhythmogenic substrate remain unknown. We undertook to determine whether I(Na) was heterogeneously distributed within the ventricular wall of canine heart, an animal model close to humans.


RESULTS
Using patch-clamp and molecular biology techniques, we tested whether gender differences exist in the ventricular distribution and amplitude of I(Na) in the canine heart model. Our results show that the I(Na) amplitude is smaller in the female epicardial and endocardial layers of the left ventricle, but similar to male in the mid-myocardium. Exposure of female cardiomyocytes to testosterone increased the amplitude of I(Na) to levels similar to male in epicardium, but had no effects in mid-myocardial and endocardial cells. Castrated male dogs displayed I(Na) amplitudes similar to what was found in female hearts.


CONCLUSIONS
The larger dispersion of I(Na) amplitude within the female cardiac ventricle may contribute to the higher risk of arrhythmias in females. Testosterone modulates this dispersion. By decreasing the transmural dispersion of I(Na), testosterone may exert a protective effect against LQTS-related arrhythmias in males.
Barajas-Martinez
Hector
H
Department of Physiology and Biophysics, Faculty of Medicine, University of Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, Quebec, Canada.
Haufe
Volker
V
Chamberland
Caroline
C
Roy
Marie-Josée Blais
MJ
Fecteau
Marie Hélène
MH
Cordeiro
Jonathan M
JM
Dumaine
Robert
R
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000453:epidemiology* / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D022062:Electrophysiologic Techniques, Cardiac; D004699:Endocardium / Q000166:cytology / Q000378:metabolism; D005260:Female; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010496:Pericardium / Q000166:cytology / Q000378:metabolism; D012307:Risk Factors; D012727:Sex Characteristics; D015222:Sodium Channels / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology
D015222:Sodium Channels; D013739:Testosterone