BS-452757-4 ANTI-ARRHYTHMIC EFFECTS OF ANDROGEN DEPRIVATION THERAPIES IN A SCN5A LOSS-OF-FUNCTION MOUSE MODEL

Sex is a major determinant of the incidence and clinical presentation in arrhythmia syndromes such as Brugada syndrome (BrS). We generated novel SCN5A-G1408R/+ knock-in mouse model mimicking key features human BrS regarding male predominance susceptibility to ventricular tachycardias. This study aimed explore effect molecular mechanisms androgen deprivation on cardiac arrhythmogenicity BrS. Animals were studied using surface ECG with without flecainide challenge (10 mg/kg body weight), telemetric recordings, molecular, biochemical well histological analyses. To antiandrogenic treatments rhythmogenic state its influence transcriptional alterations ion channel genes, G1408R/+ mice either chronically treated receptor (AR) blocker flutamide by subcutaneously implanted osmotic pumps or orchiectomized. Sex-dependent analysis showed that 81% (25/31 animals) only 14% (2/14 their female littermates developed flecainide-induced polymorphic tachycardias (VT). Only mice, previously 100% inducible for VT underwent (flutamide 4 weeks vs. orchiectomy). The arrhythmogenic phenotype was rescued both groups therapy. group reduced 13% (2/16), while orchiectomy declined 33% (3/9). At baseline, (untreated) exhibited expression NaV1.5 protein compared wild type (wt) particularly right myocardium. Treatment resulted increased levels similar wt mice. Interestingly, orchiectomized revealed even higher which abundant free wall. observed significant anti-arrhythmic induced Our data indicate potentially driven increasing membrane result anti-androgenic treatment.