Role of sexual hormones in Arrhythmogenic Cardiomyopathy

Arrhythmogenic Cardiomyopathy (AC) is a genetic primary cardiac disease at risk of sudden death (SD) mainly in the young and athletes. AC has a prevalence of 1:2000 in the population and its clinical phenotype is characterized by ventricular arrhythmias, typically triggered by physical or emotional stresses. The disease genotype includes, in 50% of genetically diagnosed cases, mutations in genes encoding desmosomal proteins, which possess multiple biological roles and are expressed by several cardiac and extra-cardiac cell types. The typical structural features of AC hearts are progressive cardiomyocyte (CM) death, inflammation, and fibro/fatty replacement of the myocardium, which lead to the morpho-functional abnormalities, and generate a pro-arrhythmogenic substrate. Despite the genetics and morphological features of AC are well known, the AC pathogenesis is still obscure and mechanism-driven therapies, efficient in preventing disease progression, are not available. In addition, the disease has large phenotypic variation, incomplete penetrance, and both age-related progression and arrhythmias are the result of complex interactions between genetic, acquired and environmental factors, thus making the clinical diagnosis of AC and SD prevention challenging tasks. The correlation between arrhythmic events and acute exercise or emotions, and their inducibility by adrenergic agonists, leave little doubt on the association between the Sympathetic Nervous System (SNS) and arrhythmia triggering. Recently, in the laboratory where I conduced my thesis work, it has been demonstrated that cardiac and extra-cardiac sympathetic neurons (SNs) express desmosomal proteins and, as such, they are disease mutation carriers, supporting the notion whereby SNs may be affected in AC and contribute to disease pathogenesis. This concept is in line with the results of radionuclide imaging, revealing that human AC hearts display regional increase in sympathetic stimulation of the ventricular myocardium and reduced noradrenaline (NE) reuptake, resulting in focal areas of aberrant beta-adrenoceptor (beta-AR) stimulation. In addition, we recently identified the sympathetic neurotransmitter, Neuropeptide Y (NPY), as a factor triggering the adipogenic differentiation of cardiac mesenchymal stromal cells, which have been identified as source of the adipose tissue in AC human hearts. Clinical observation supports that gender plays an important role in disease pathogenesis. In fact, despite a similar prevalence of mutation carriers in both genders, the disease expression is usually more severe in men, with a higher prevalence of male than female patients, who experienced AC consequences. Furthermore, male sex is an independent predictor of lifetime arrhythmic events which also occur at an earlier age, as compared to females, leading to the common tenet of ‘AC as a disease of males’. Recently, it has been demonstrated that, independently from the desmosomal mutations, male patients developing major adverse cardiac events, have significantly increased serum testosterone levels, compared to those of patients with a favourable outcome. Interestingly, testosterone is a mediator of cell growth and, through the Wnt/β-catenin pathway, is a key regulator of adipogenesis and lipogenesis. In addition, testosterone directly affects SN activity, as it “increases the muscle sympathetic nerve activity in humans” and rescues “from the castration-induced decrease in the noradrenergic innervation of rat vas deferens”. In terms of arrhythmogenesis, although testosterone has been suggested to generally decrease arrhythmic vulnerability through its effects on the QT interval of the electrocardiogram, males are at greater risk of arrhythmic SD in both genetic and acquired cardiomyopathies, leaving uncertainty on the role of male sexual hormones in the presence of a specific arrhythmogenic background.