Cardiogenetics 2020; volume 10:8860 Sudden cardiac death in young vent many disorders, including cardiovas- athletes: Literature review of cular risk factors, obesity, depression, anxi- Correspondence: Giulia Frisso and Cristina ety, musculoskeletal problems and stress.1-3 Mazzaccara, Department of Molecular molecular basis Numerous epidemiological studies have Medicine and Medical Biotechnology/ shown an association between moderate CEINGE- Advanced Biotechnologies, Via Pansini 5, 80131 Naples, Italy. Cristina Mazzaccara,1,2 Bruno Mirra,1,2 aerobic exercise and decreased risk of coro- 1,2 4-6 Tel.: +39.081.7462405; +39.081.7462422 - Ferdinando Barretta, nary heart disease, reduced risk of ven- Fax: +39.081.7462404. Barbara Lombardo,1,2 Olga Scudiero,1,2 tricular fibrillation in patients affected by a E-mail: [email protected]; 7,8 Giulia Frisso1,2 first myocardial infarction, as well as a [email protected] reduction of overall death and cardiovascu- 1Department of Molecular Medicine and lar mortality in cardiac patients subjected to Key words: Sudden cardiac death; cardiomy- Medical Biotechnology, University of 9,10 opathy; genetic testing; athletes. 2 adequate training programs. Furthermore Naples Federico II; CEINGE Advanced the use of biochemical and haematological Biotechnologies, Naples, Italy Contributions: GF, CM, BM; wrote the manu- tests to evaluate risk factors in athlete is of script and approved the final version; FB, BL, relevance and interest at the amateur, com- OS; involved in literature data collection. All 11 petitive and elite level. authors critically reviewed the manuscript. However, for a small number of indi- Abstract viduals physical exercise can increase the Funding: the authors declare that no sources of risk of sudden cardiac death (SCD).12,13 In funding were used in the preparation of this Intense athletic training and competi- particular, vigorous activity can transiently review. tion can rarely result in sudden cardiac increase the risk of SCD in asymptomatic death (SCD). Despite the introduction of Conflict of interest: the authors declare no young athletes carrying genetic mutations pre-participation cardiovascular screening, conflict of interests. predisposing to arrhythmic diseases.14,15 especially among young competitive ath- Sudden cardiac death is the most fre- letes, sport-related SCD remains a debated Received for publication: 31 January 2020. quent medical cause of sudden death in ath- Revision received: 24 March 2020. issue among medical personnel, sports com- only letes. Estimates vary widely based on the Accepted for publication: 27 March 2020. munities and laypersons alike, and gener- analyzed population, sports-associated SCD ates significant media attention. The most represents about 6% of the overall SCD bur- This work is licensed under a Creative frequent cause of SCD is a hidden inherited Commons Attribution NonCommercial 4.0 den.16,17 In Europe and North America the cardiomyopathy, the athletes may not even License (CC BY-NC 4.0). incidence of SCD is 2 athletes of use100,000 be aware of. Predictive medicine, by per year.18 In the Veneto region of Northern © searching the presence of pathogenic alter- Copyright: the Author(s), 2020 Italy, where >110,000 athletes were evaluat- ations in cardiac genes, may be an integra- Licensee PAGEPress, Italy ed over a 21-year follow-up period, the inci- Cardiogenetics 2020; 10:8860 tive tool, besides the conventional ones dence of SCD was 2.6/100,000 person- doi:10.4081/cardiogenetics.2020.8860 used in cardiology (mainly electro and years in male athletes and 1.1/100,000 per- echocardiogram), to reach a definitive diag- son-years in their female counterparts.13 nosis in athletes showing signs/symptoms, The incidence varied by sex, the risk of even borderline, of inherited cardiomyopa- relevant role for the early identification of SCD being higher in men than in women.15 thy/channelopathy, and in athletes present- molecular alterations that can be causative Some athlete subgroups, specifically 21 ing family history of SCD and/or of heredi- or con-causative of SCD in athletes. It is African Americans, male basketball and tary cardiac disease. In this review, we important to identify the specific DNA football players, appear to be at higher risk revised the molecular basis of the major car- defect associated with a clinically manifest in the United States, whereas male soccer diac diseases associated to sudden cardiac heart disease in an athlete, and, above all, to players had a higher incidence of SCD than death and the clinical molecular biology recognize the possible individual predispo- other athletes in Europe.18,19 This observa- approach that can be used to perform risk sition to develop a latent heart disease, tion suggests that individuals participating assessment at DNA level of sudden cardiac before the disease can manifest itself with in sports of high dynamic and low isometric death, contributing to the early implementa-Non-commercial the fatal event of SCD. intensity are at higher risk of death. tion of adequate therapy. Alterations can In this review we will discuss genetic Few studies report prevalence of sports- occur in ion channel genes, in genes encod- causes of sudden cardiac death in athletes, related sudden death in the general popula- ing desmosomal and junctional proteins, with particular emphasis on challenges in tion. Of note, paper of Marijon et al. sarcomeric and Z-disc proteins, proteins for molecular diagnostics of inherited cardiac showed that only 6% of sports-related sud- the cytoskeleton and the nuclear envelope. disease, like channelopathy and cardiomy- den death in the general population occur in The advent of next generation sequencing opathy. young competitive athletes, the remaining (NGS) technology has provided the means involving amateur athletes.20 to search for mutations in all these genes, at Though SCD is rare, its occurrence in the same time. Therefore, this molecular athletes who are often young and presum- approach should be the preferred methodol- ably healthy has a large emotional and Cardiac diseases in young athletes ogy for the aforementioned purpose. social impact on the surrounding communi- Cardiac diseases associated with SCD ty. Therefore, considerable effort has been differ in young vs older athletes, the SCD made to better understand the causes of cause being elusive even after autopsy in SCD in athletes and to discover optimal young subjects. Guidelines of the European Introduction strategies for prevention. Society of Cardiology (ESC) encouraged Regular physical activity is a powerful To this aim, the clinical molecular biol- molecular autopsy22 in addition to the stan- tool for improving health and helps to pre- ogy laboratory has acquired an increasingly dard autopsy, as it may allow the post- [Cardiogenetics 2020; 10:8860] [page 1] Review mortem diagnosis of cardiac chan- Inherited cardiomyopathies are char- nelopathies, which explain 15–25% of sud- acterized by both allelic heterogeneity, Cardiac channelopathies den arrhythmic deaths. The most common which occurs when mutations within the Cardiac channelopathies are rare inher- causes of sport-related SCD in adolescents same gene can produce different pheno- ited primary electrical disorders, without and young adults are inherited cardiomy- types, and genetic heterogeneity, occur- evidence of structural cardiomyopathy, 18,23-31 opathies, a clinically heterogeneous ring when mutations within different resulting from dysfunction of cardiac ion group of heart muscle disorders, character- genes produce the same phenotype. channels. This alteration impairs cardiac ized by the presence of abnormal myocar- For example, SCN5A gene mutations action potential or intracellular calcium dial structure and/or function, in the are associated with distinct chan- handling and results in electrical instabili- absence of ischemic heart disease or abnor- nelopathies, such as long QT syndrome, ty,50 leading to life-threatening cardiac 32 mal loading conditions. Brugada syndrome, and also to HCM or arrhythmias, including ventricular tachycar- 51 Arrhythmogenic cardiomyopathy DCM. Instead, DCM may be caused by dia or fibrillation (VT/VF) predisposing to (ACM) has been reported to account for mutations in sarcomeric, cytoskeletal, gap SCD. Channelopathies are usually transmit- approximately 25% in Italy, whereas it junction and even ion channel genes. ted as an autosomal dominant trait and accounts for only 6% of cases in the Variable penetrance and incomplete show variable clinical penetrance and 13,25,33,34 USA. By contrast, hypertrophic car- expression are common in all cardiomy- expressivity. The main clinical features diomyopathy (HCM) is one of the leading opathies, even among related subjects include syncope and SCD; however, most 52,53 causes of SCD among athletes in the USA, sharing the same pathogenic allele, and patients remain asymptomatic throughout where it has been reported to accounting for may reflect the action of modifier genes, life and symptoms may be triggered by more than 30% of fatal cases,9,22,28 while in epigenetic changes, environmental fac- physical activity (light, moderate and European studies HCM is reported to cause tors, or other factors such as age, gender, heavy), sexual activity, emotions and sleep. less than 10% of SCDs.29 These divergences ethnicity or physical activity. To establish Early diagnosis of genetic carriers is war- are attributable to the heterogeneity of rela- the diagnosis of inherited