Brugada Syndrome and Pregnancy: Delving Into the Role of Sex Hormones in Ion Channelopathies

Abstract

Since its initial description in 1992 as a clinical syndrome involving a specific electrocardiogram (ECG) pattern and an increased susceptibility for ventricular arrhythmias and sudden cardiac death (SCD), the Brugada syndrome (BrS) has prompted much research activity aimed at defining the clinical, genetic, and molecular aspects of the disease. Major advances in genetics have allowed the identification of mutations linked to the syndrome in more than 10 different genes thus far. Recognized mutations disturb the expression and/or function of different cardiac ion channels that participate in the cardiac action potential, so the syndrome is now included among the so-called channelopathies. The common functional consequence of these mutations, confirmed by experimental models, is thought to be a heterogeneous imbalance between positive outward and inward currents during early phases of repolarization, which can explain both the ST-segment elevation in the ECG and the susceptibility to ventricular arrhythmias through a phase-2 reentry mechanism. However, important questions concerning the mechanisms and/or clinical manifestations of the BrS remain unanswered. For example, only around 20% to 30% of patients have a positive genetic test, indicating that the disease-causing mutation or mechanism remains unknown for most of them. Also intriguing is the broad phenotypic expression of the syndrome even for a given mutation, which may range from the absence of symptoms or ECG manifestation to the occurrence of SCD at an early age. This latter observation supports the concept that particularities in intrinsic susceptibility and/or the effect of certain modulators (genetic, molecular, or external) might play a role in the final phenotype of patients with BrS. In line with this last concept, the difference in clinical expression between men and women with BrS is a wellestablished observation for which there is no full mechanistic understanding yet. All the main series of BrS concur in reporting a higher symptom and event rate among men than among women with the syndrome. The ECG expression is also more pronounced