T-wave inversion in young athletes: Should we check their bones or their identity card? The quest for precision medicine

Young athletes deserve special care in all aspects of sports and, in particular, in the prevention of the potential deleterious consequences. Cardiovascular sudden death, although extremely rare, should be carefully addressed in pre-participation screening programmes, keeping in mind the special features of young athletes. Athletes training for competitive sports are encouraged, under current guidelines, to undergo a review of clinical history and a physical examination, but the role of the electrocardiogram (ECG) in the pre-participation cardiovascular screening protocol is still a topic of passionate debate.1 The central arguments concern accuracy, cost-effectiveness and the need for more robust evidence supporting improved outcomes based on ECG screening.1 Randomised clinical trials would certainly clarify whether ECG screening improves clinical outcomes, but ethical, legal and logistic issues present important challenges. Alternatively, well-designed observational studies with a long follow-up could partially address this issue. In recent years, researchers have improved the accuracy of ECG interpretation and, arguably, the cost-effectiveness of ECG screening. Early electrocardiographic criteria of the European Society of Cardiology had low specificity, which led to an unacceptably high number of false positives and rather low efficiency when added to pre-participation screening programmes. In the quest to optimise cost-effectiveness, efforts to standardise ECG interpretation have produced notable success.2 T-wave inversion (TWI) in precordial leads (V1–V4) has drawn the most attention because of common misdiagnoses and variable interpretation even among sports medicine physicians and cardiologists. The usefulness of a diagnostic or screening test depends on its ability to precisely differentiate patients from healthy individuals. At least in part, its accuracy relies on the ratio of positive tests in affected (patients) and non-affected (healthy) individuals. In other words, if a test is similarly positive in healthy and diseased individuals, it is useless; if positive only in diseased, but not in healthy individuals, the test is extremely useful. In the specific case of the ECG during pre-participation screening, however, the presence of TWI is relevant both in patients with cardiomyopathies and in healthy individuals. On the one hand, right TWI (V1–V3) is a common finding in several cardiomyopathies. TWI is a hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), seemingly due to right ventricle (RV) microstructural changes and dilation and to dislocation of the left ventricle (LV).3 Myocarditis and other cardiomyopathies may also present with precordial TWI. Ischaemic heart disease accounts for most cardiovascular conditions presenting with TWI in individuals older than 35 years. Although right TWI may be detected in patients with hypertrophic cardiomyopathy, it is commonly accompanied by lateral and inferior lead TWI and a variety of ECG abnormalities.1 On the other hand, the presence of TWI in otherwise healthy individuals should also be considered. TWI is more frequent in healthy athletes than in non-athletes, likely because of a right-shift deviation of the cardiac axis.4 TWI in precordial leads is common in black athletes and non-athletes, independent of sex. Aging modulates normal T-wave morphology and modifies the ratio of benign to pathological TWI, further complicating this scenario (Figure 1). The prevalence of physiological T-wave inversion (TWI) decreases with age, but a large variability exists depeding on the maturity stage. This should be considered when evaluating young atlhetes with TWI. The evolution of TWI during the growth years is particularly challenging. At birth, T-waves are upright, but become negative within the first few days of life and remain so until puberty. Indeed, TWI in right precordial leads (V1–V3) is so common in children younger than nine years5 that it confers little or no adverse prognosis. On the other hand, TWI in adult individuals, especially athletes, should always be carefully considered – but what about isolated right TWI in athletes between 9–18 years old? Some researchers have suggested that negative T-waves in athletes older than 16 years are rare and potentially associated with an underlying cardiomyopathy.6 Indeed, this is reflected in current ECG interpretation guidelines, that recommend further exploration of right TWI only if appearing in athletes older than 16 years.2 In contrast, TWI after 14 years of age is recognised as a major criterion for ARVC in the current diagnostic guidelines.7 In the present issue of the European Journal of Preventive Cardiology, an international collaboration of renowned researchers sheds light on how TWI should be interpreted in young athletes.8 In 732 Arab and black athletes aged 11–18 years who underwent pre-participation screening including echocardiography, the presence of TWI in right precordial leads was recorded. The biological age of each young athlete was estimated from left-hand wrist radiological imaging. In order to test the age-criterion performance in exploring TWI, current guidelines were applied twice: first using the standard chronological (16-year-old) criterion to flag those individuals requiring further exploration and then a threshold based on radiological (i.e. biological) age estimation. In their population, the biological threshold outperformed chronological aging in the categorization of ‘physiological’ and ‘pathological’ TWI. These conclusions are remarkable for several reasons. First, while the association between pubertal development and regression of precordial juvenile TWI had been previously reported, the present work demonstrates a driving role of ‘biological’ over ‘chronological’ age for pre-participation screening purposes. Second, current recommendations claim that the ‘16-year-old threshold’ is applicable to all athletes, independent of race and sex. The age of sexual maturation differs by race.9 If maturity underlies T-wave reversion, should not maturity be used to guide TWI interpretation? Third, if the biological age for both Arab and black young athletes is older than their chronological age, as reported by McClean and collaborators,8 one wonders whether this reflects the competitive advantage enjoyed by the most physically mature athletes over their ‘biologically younger’ chronological peers. The results suggest that biological age assessment could, potentially, be used to better stratify individuals at the extremes of normality (e.g. elite athletes). Although these findings based on a scientifically attractive approach represent a step forward in our understanding of the ECG of the young athlete, some limitations should not be disregarded. The present conclusions were obtained with a single major outcome, leaving a large degree of uncertainty. Follow-up of these athletes would be desirable to uncover potential misdiagnosis. Hormonal changes and maturation occur earlier in women than men: could similar conclusions be applied to female athletes? And, finally, how could we use these data? Overall, McClean and collaborators have opened a door to improve the predictive power and accuracy of current ECG criteria, particularly in children.8 Nevertheless, applicability in clinical practice still needs to be established. Chronological age is easily assessed in most individuals but the maturity stage (i.e. biological age) requires additional work-up. Tanner stage is easily assessed, but is subject to ethical and child-protection considerations. As in the present study, radiology imaging may provide a more accurate and objective assessment than Tanner staging but requires an additional test involving ionising radiation exposure. So when should maturation status/biological age be determined? It seems reasonable to limit additional tests to those children in whom T-wave abnormalities have been detected. In these flagged individuals who need to undergo a second test, should we go for X-ray to ascertain biological age or echocardiography to rule out structural heart disease? In our opinion, both tests provide complementary information that should be integrated into pre-participation cardiovascular evaluation. According to the Precision Medicine Initiative, precision medicine is ‘an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person'.10 A single normality criterion may not be valid for everybody. This path is already being followed to refine ECG interpretation in athletes. In black athletes, TWI preceded by J-point and convex ST elevation may be considered physiological.11 Even within this population, the prevalence of physiological TWI depends on geographical origins.12 The prevalence of cardiomyopathies in certain regions might modify ECG predictive values and, potentially, ECG cost-effectiveness. In this regard, large geographical variability has been reported for ARVC, one of the major cardiac conditions accounting for right TWI.13 An accurate age assessment could further refine ECG interpretation. As McClean and collaborators suggest, looking at bones may better discriminate the significance of TWI in young individuals than checking an identity card for their chronological age.8 The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article. The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work has been partially funded by European Union (grant agreement No 633196 (CATCH ME)), AGAUR (Agència de Gestió d’Ajuts Universitaris i de Recerca, 2017SGR1548) and Instituto de Salud Carlos III (PI16/00703; PI16/00435).