The Hidden Fragility in the Heart of the Athletes: A Review of Genetic Biomarkers

Abstract

Sudden cardiac death (SCD) is a devastating event which can also affect people in apparent good health, such as young athletes. It is known that intense and continuous exercise along with a genetic background that predisposes a person to the risk of fatal arrhythmias is a trigger for SCD. Therefore, knowledge of the athlete's genetic conditions underlying the onset of SCD must be extended, in order to develop new effective prevention and/or therapeutic strategies. Arrhythmic features occur across a broad spectrum of cardiac diseases, sometimes presenting with overlapping phenotypes. The genetic basis of arrhythmogenic disorders has been greatly highlighted in the last 30 years, and has shown marked heterogeneity. The advent of next-generation sequencing has constantly updated our understanding of the genetic basis of arrhythmogenic diseases and is laying the foundation for precision medicine. With the exception of a few clinical cases involving a single athlete showing a highly suspected phenotype for the presence of a heart disease, there are few studies to date that analysed the applicability of genetic testing on cohorts of athletes. This evidence shows that genetic testing can contribute to the diagnosis of up to 13% of athletes; however, the presence of clinical markers is essential. This review aims to provide a reference collection on current knowledge of the genetic basis of sudden cardiac death in athletes and to review updated evidence on the effectiveness of genetic testing in early identification of athletes at risk for SCD.

Keywords: athletes; cardiomyopathies; channelopathies; genetic test; next generation sequencing; preventive medicine; sudden cardiac death.

Figure 1

Cartoon of the cardiomyocyte components involved in the molecular mechanisms associated with sudden cardiac death (SCD). The figure illustrates the main ion channels (Kyr7.1, HERG, Cav1.2, Nav1.5, Ryr2) linked to channelopathies (long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT)); sarcomere proteins associated to hypertrophic cardiomyopathy (HCM); proteins participating in the organization of desmosomes and adherents junctions, linked to arrhythmogenic cardiomyopathy (ACM); the cytoplasmic, mitochondrial, sarcoplasmic reticulum proteins and the proteins of the dystroglycan complex that are associated with the development of dilated cardiomyopathy (DCM).