Sex-related differences in incidence, phenotype and risk of sudden cardiac death in inherited arrhythmia syndromes

Abstract

Inherited Arrhythmia Syndromes (IAS) including long QT and Brugada Syndrome, are characterized by life-threatening arrhythmias in the absence of apparent structural heart disease and are caused by pathogenic variants in genes encoding cardiac ion channels or associated proteins. Studies of large pedigrees of families affected by IAS have demonstrated incomplete penetrance and variable expressivity. Biological sex is one of several factors that have been recognized to modulate disease severity in IAS. There is a growing body of evidence linking sex hormones to the susceptibility to arrhythmias, yet, many sex-specific disease aspects remain underrecognized as female sex and women with IAS are underinvestigated and findings from male-predominant cohorts are often generalized to both sexes with minimal to no consideration of relevant sex-associated differences in prevalence, disease manifestations and outcome. In this review, we highlight current knowledge of sex-related biological differences in normal cardiac electrophysiology and sex-associated factors that influence IAS phenotypes.

Keywords: Brugada syndrome; catecholaminergic polymorphic ventricular tachycardia; estrogen; long QT syndrome; precision medicine; progesterone; short QT syndrome; testosterone.

Figure 1

Sex hormones and their influence on cardiac electrophysiology. (A) Variation in female hormone levels during the menstrual cycle. (B) Variation in female sex hormones and electrical parameters during pregnancy and the postpartum period. (C) The increase of female sex hormones until adolescence. (D) The variation of female and male sex hormones with age. (E) The influence of various hormones on cardiac electrical currents and action potential duration.