Background: Sex is a major determinant of the incidence and clinical presentation in arrhythmia syndromes such as male predominance in Brugada syndrome (BrS). We generated a novel SCN5A-G1408R/+ knock-in mouse model mimicking key features of human BrS regarding male predominance and susceptibility to ventricular tachycardias. So far, there are limited data on the molecular mechanisms of androgens on cardiac arrhythmogenicity.

Methods and Results: Sex-dependent analysis showed that 81% (25/31 animals) of male G1408R/+ and only 14% (2/14 animals) of their female littermates developed flecainide-induced polymorphic ventricular tachycardias (VT). To determine a potential antiarrhythmic effect of different antiandrogenic treatments and its influence on transcriptional alteration of cardiac ion channel genes, male G1408R/+ mice were either chronically treated with the AR blocker flutamide or orchiectomized. Male G1408R/+ mice, previously 100% inducible for VT underwent androgen deprivation (flutamide for 4 weeks vs. orchiectomy). The arrhythmogenic phenotype was rescued in both groups of antiandrogenic therapy. VT incidence in the flutamide group was reduced to 12% (1/8), while VT in the orchiectomy group declined to 33% (2/6). At baseline, (untreated) male G1408R/+ mice exhibit reduced cardiac expression of Na_V1.5 protein compared to male wild type (wt), particularly in right ventricular myocardium. Chronic treatment with flutamide resulted in increased Na_V1.5 expression in male G1408R/+ mice to levels similar to male wt. Interestingly, orchiectomized G1408R/+ mice revealed an even higher level of Na_V1.5 protein compared to wt, with levels particularly abundant at the right ventricle of male wt.

Conclusions: We observed a significant anti-arrhythmic effect induced by androgen deprivation in the novel G1408R/+ mouse model mimicking human BrS. Of note, our data indicate that inhibition of the AR-dependent pathway importantly drives the anti-arrhythmic effect, potentially by increasing right ventricular Na_V1.5 membrane expression.