Incremental value of genetic testing for diagnosis of heart conditions in athletes

This editorial refers to ‘Yield and clinical significance of genetic screening in elite and amateur athletes’, by G. Limongelli et al., pp. 1081–1090. The continuing, vigorous debate regarding the best approach for pre-participation screening is undeniable evidence of how important the issue is for athletes, healthcare providers and the general public. The overall goal of this endeavour is to identify pre-existing cardiac abnormalities that increase risk of sudden cardiac arrest (SCA) based on warning symptoms, family history, and cost-effective clinical evaluation. However, the recommendations from healthcare organizations and societies are not always consistent, which is reflected in the diverse practices adopted by different sporting associations.1 For example, for competitive athletes, the European Society of Cardiology (ESC) recommends personal history, physical examination, and a resting 12-lead electrocardiogram (ECG) at a minimum,2 while the American Heart Association/American College of Cardiology (AHA/ACC) do not recommend the 12-lead ECG for mass screening based on sensitivity, specificity, and cost-effectiveness criteria.3 The International Olympic Committee recommends the ESC approach but the Fédération Internationale de Football Association (FIFA) mandates echocardiography in addition to the ESC recommendations.1 As of now, there is no evidence that inclusion of genetic testing as an initial component of pre-participation screening is useful and has never been recommended. In the current issue of the EJPC, Limongelli et al.4 report their findings from a combination of pre-participation screening, advanced clinical evaluation, and genetic testing in a small group of athletes. A total of 5892 consecutive elite and amateur athletes underwent pre-participation screening and 61 (1%) were found to have one or more clinical markers for suspected inherited cardiac disease. An unspecified number of these 61 athletes underwent additional clinical evaluation with one or more out of four tests: 24/48 h ECG monitoring, cardiac magnetic resonance imaging, signal average ECG, and flecainide challenge. All 61 athletes underwent genetic testing, the nature and extent of which varied significantly depending on the time period of evaluation. A definitive (clinical or genetic) diagnosis was made in 14 athletes (23%). This was attributed to clinical evaluation in 6 (10%) and genetic testing in 8 (13%). There was no overlap between the two groups, i.e. all eight athletes diagnosed with disease-causing mutations did not have any evidence of a heart disease phenotype based on the clinical evaluations that were performed. These findings are of interest, but before discussing any potential implications, it is important to understand the limitations of this study. The protocol for pre-participation screening used by Limongelli and co-workers is unique to this study, which poses challenges for comparability with other studies. They used family and personal history, standard 12-lead ECG, echocardiography, and exercise stress test. The latter two tests are not recommended as standard practice by ESC or ACC/AHA and were not included in the largest Italian pre-participation screening study.5 Based on their description of the methodology, it is not clear whether a physical examination was a uniform component of pre-participation screening for all athletes, a standard requirement in most guidelines. No components of the physical exam were included among the clinical markers that indicated a positive pre-screening result. The tests used for additional clinical evaluation were applied non-uniformly, based on results of screening in individual athletes. This retrospective analysis was conducted from data obtained over 10 years, during which time period there was significant variation in nature and extent of genetic testing such that this evaluation was also non-uniform. Finally, compared with existing studies, the sample size of athletes who qualified for additional clinical and genetic evaluation is relatively small. The main finding of the study from Limongelli et al. is that in a subgroup of athletes identified through pre-participation screening, genetic testing provided definitive diagnoses of inherited cardiac conditions beyond the yield of additional clinical testing. Since all genetic tests were performed after pre-participation screening, it is important to recognize that these findings relate specifically to genetic ‘testing’, and not genetic ‘screening’ in athletes identified as being at potentially high risk for heritable cardiac disease. Compared with a recent study based exclusively on pre-participation screening with abnormal T-waves on ECG, the yield of genetic testing in this study was higher (13% compared with 2.5%).6 Also, contrary to expectations none of the athletes with clinical phenotypes identified had disease-related mutations on genetic testing. Since we are not provided with details of which athletes with positive genetic tests had a positive family history, we do not have a good explanation for either finding; and cannot exclude the possibility of chance observations occurring in a relatively small sample. This approach used by Limongelli et al. is consistent with the overall strategy employed for seeking a definitive diagnosis in young individuals at high risk for inherited arrhythmias even if they are not athletes (Figure 1).7 In a sizeable proportion of young individuals deemed to be at high risk by screening (77% in the current study), a definitive diagnosis cannot be made. This group includes both individuals who have had a false-positive screening result as well as others that potentially have a concealed phenotype not yet associated with a known disease-causing genetic variation. Current and future approaches to sudden cardiac arrest prevention in the young. Modified with permission from Aro et al.7 The inclusion of both elite and amateur athletes is a strength of this study, since the incidence rates of SCA associated with sports activity are similar in competitive and non-competitive athletes.8 No matter what the level or standard of athletic activity, risk of SCA is mostly increased due to a pre-existing condition, not by the sport itself. We are learning that there may be rare exceptions where the cardiac condition can potentially be worsened by ongoing sporting activity (Arrhythmogenic right ventricular cardiomyopathy).1 Therefore, the primary target of pre-participation screening is identification of pre-existing cardiac disease. It is also important to recognize that in the context of overall SCA in the young, a minority of these events are associated with sports activity. In a recent population-based study conducted in a single large US community over a 12-year period, sports-related SCAs accounted for 39% of SCAs in patients aged ≤18 years, 13% of SCAs in patients aged 19–25, and 7% of SCAs in patients aged 25–34.9 It is also likely that acquired (as opposed to inherited) cardiovascular disease may play a larger role than was previously recognized. The latter study also reported an unexpectedly high overall prevalence of classical cardiovascular risk factors including obesity, diabetes mellitus, hypertension, hyperlipidaemia, and smoking; with ≥1 risk factors in 58% of young SCA cases.9 While inherited conditions such as cardiomyopathies and cardiac ion-channel disorders are identified more commonly in the young, it is increasingly important to also screen for, and modify, risk factors of acquired cardiovascular conditions that can cause SCA (Figure 1). Since the overall prevalence of hypertension as a risk factor is high and on the rise in the young, adolescent athletes should also be screened and treated.10 In the event that target organ damage is present, competitive sports may need to be restricted. However, competitive athletes with well-controlled hypertension, no target organ damage and without additional risk factors, can resume any form of sporting activity. In conclusion, the debate regarding the optimal approach to pre-participation screening of athletes is likely to continue. Approaches are likely to differ based on regional adoption of the scientific evidence as well as cost and other considerations. The report by Limongelli et al. suggests that genetic testing improves diagnostic yield beyond the clinical evaluation in athletes that are potentially at increased risk of SCA following pre-participation screening. While their study has potential limitations, this work should stimulate further investigation in larger numbers of young subjects. Genetic testing currently does not have a role in the initial pre-participation screening of athletes, but knowledge is a moving target. Whole-genome sequencing, genomic analysis, and phenotype–genotype correlations continue to gather momentum and we should remain open to considering new approaches in the future. Funded by National Institutes of Health, National Heart Lung and Blood Institute grants R01HL126938, R01HL145675, and R01HL147358 to S.S.C. S.S.C. holds the Pauline and Harold Price Chair in Cardiac Electrophysiology at Cedars-Sinai, Los Angeles. Conflict of interest: None declared. The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Preventive Cardiology or of the European Society of Cardiology.