Ionic and Cellular Basis for the Predominance of the Brugada Syndrome Phenotype in Males

Abstract

Background-The Brugada syndrome displays an autosomal dominant mode of transmission with low penetrance. Despite equal genetic transmission of the disease, the clinical phenotype is 8 to 10 times more prevalent in males than in females. The basis for this intriguing sex-related distinction is unknown. The present study tests the hypothesis that the disparity in expression of the Brugada phenotype is a result of a more prominent I to -mediated action potential notch in the right ventricular (RV) epicardium of males versus females. Methods and Results-We studied epicardial tissue slices, arterially perfused wedge preparations, and dissociated epicardial myocytes isolated from male and female canine hearts. RV epicardium action potential phase 1 amplitude was 64.8Ϯ2.0% of that of phase 2 in males compared with 73.8Ϯ4.4% in females (PϽ0.05) at a cycle length of 2000 ms. I to density was 26% smaller and time constant for inactivation 17% smaller at ϩ40 mV in female versus male RV epicardial cells (PϽ0.05). The other functional characteristics of I to , including the voltage dependence of inactivation and time course of reactivation, were no different between the sexes. Pinacidil caused loss of action potential dome in male, but not female, RV epicardial tissue slices. Terfenadine (5 mol/L) induced phase 2 reentry in 6 of 7 male but only 2 of 7 female arterially perfused wedge preparations. Two of 6 male and 1 of 2 female preparations developed polymorphic ventricular tachycardia/ventricular fibrillation. Conclusions-Our results suggest that the predominance of the Brugada phenotype in males is a result of the presence of a more prominent I to in males versus females.

Brugada syndrome and ischemia-induced ST-segment elevation. Similarities and differences

“…The phenomenon, however, is observed rarely and only in RV wedge preparations displaying prominent I to -mediated notch. In this regard, we observed important differences in the magnitude of I to -mediated spike and dome morphology in the RV Epi between females and males [25] (more prominent in the latter) as well as among breeds (unpublished observation).…”

Sex‐Dependent Phenotypic Variability of an SCN5A Mutation: Brugada Syndrome and Sick Sinus Syndrome

“…Both males and females equally inherit the responsive gene. Di Diego et al studied epicardial myocytes isolated from male and female canine hearts and reported that the predominance of the Brugada phenotype in males is a result of the presence of a more prominent Ito in males versus females 9. Shimizu et al reported that a higher testosterone level associated with a lower body mass index and body fat percentage plays a significant role in male predominance in BS 10.…”

Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome

“…8,17,18 Studies suggest sex-related differences in I to contribute to the 8-to 10-fold greater prevalence of the Brugada phenotype in males compared with females. 19 The smaller I to in females was in large part due to a more rapid decay of the current. A more prominent transient outward current (I to ) underlies the larger action potential notch and greater sensitivity of right ventricular epicardium of males to sodium channel block.…”