Cardiovascular Research Advance Access first published online on September 18, 2008
This version [Corrected Proof] published online on October 16, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn255
Larger dispersion of INa in female dog ventricle as a mechanism for gender-specific incidence of cardiac arrhythmias
1 Department of Physiology and Biophysics, Faculty of Medicine, University of Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, Quebec, Canada J1H 5N4
2 Masonic Medical Research Laboratory, Utica, NY, USA
* Corresponding author. Tel: +1 819 820 6868, ext 12556; +1 819 820 6887. E-mail address: robert.dumaine{at}usherbrooke.ca
Aims: Women have a higher incidence of long QT-related arrhythmias, whereas men exhibit a higher incidence of Brugada syndrome (BrS). The cardiac sodium current (INa) 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 INa within the cardiac ventricle and its contribution to generate the arrhythmogenic substrate remain unknown. We undertook to determine whether INa was heterogeneously distributed within the ventricular wall of canine heart, an animal model close to humans.
Methods and results: Using patch-clamp and molecular biology techniques, we tested whether gender differences exist in the ventricular distribution and amplitude of INa in the canine heart model. Our results show that the INa 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 INa to levels similar to male in epicardium, but had no effects in mid-myocardial and endocardial cells. Castrated male dogs displayed INa amplitudes similar to what was found in female hearts.
Conclusion: The larger dispersion of INa 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 INa, testosterone may exert a protective effect against LQTS-related arrhythmias in males.
KEYWORDS Sodium current; Female; Male; Testosterone
Time for primary review: 23 days
These authors contributed equally to this work.