Larger dispersion of I_Na in female dog ventricle as a mechanism for gender-specific incidence of cardiac arrhythmias

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.

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.

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.