T-wave inversions in athletes: frequency and prognostic significance. A systematic review and meta-analysis

T-wave inversions in athletes: frequency and prognostic significance. 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A systematic review and meta-analysis Javier Sanmartin, Joan Cartanya-Bonvehi, Helen Valenzuela, Lidia Carballeira, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8638655/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Aim: T-wave inversions (TWI) are a challenging finding in athletes' electrocardiograms. This study aimed to determine the frequency and prognosis of TWI in athletes. Methods: A systematic review and meta-analysis were conducted following PRISMA guidelines and registered in PROSPERO (CRD42023494038). Data sources were PubMed, Scopus, and Web of Science. We included original research articles reporting on the prevalence or underlying substrates of TWI and providing data on athletes participating in any type of sports, sex, or race. Risk of bias was evaluated using the Joanna Briggs Institute Critical Appraisal Tool for Cross-Sectional Studies. Fixed or random-effects models were used depending on heterogeneity. Sensitivity and subgroup analyses (sex, age, ethnicity, diagnostic criteria) were predefined. Results: Of 4,509 articles identified, 115 were selected (258,954 individuals). Substantial heterogeneity was observed among the study results. The global TWI prevalence in athletes > 16 years according to the Seattle criteria was 6% (4%, 1%, and 1% in anterior, inferior, and lateral leads, respectively). Prevalence was higher in Black athletes. TWI was more frequent in athletes than non-athletes (Prevalence ratio=1.49; 95% Confidence Interval: 1.13–1.97). Cardiomyopathy diagnosis among athletes with TWI showed high variability, but in most studies, prevalence was <1%. Acute cardiovascular event incidence was 0 in 16 of 19 studies with clinical follow-up. Conclusions: TWI is more frequent in athletes than non-athletes but remains low overall. While it may reflect physiological exercise related ventricular remodelling, thorough evaluation is essential to exclude structural heart disease. Cardiovascular event incidence in athletes with TWI is very low. T wave inversion repolarization prevalence sudden death athletes cardiomyopathies Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 KEY POINTS The prevalence of TWI in athletes is 6% (Seattle criteria), and is more common in Black athletes. TWI are more frequent in athletes than in the general population (Prevalence ratio: 1.49; 95% confidence interval: 1.13–1.97). The prevalence of structural cardiac disease among athletes with TWI varies across studies (10% in 6 studies). The incidence of clinical cardiovascular events in athletes with TWI is very rare. INTRODUCTION Sudden cardiac death (SCD) is a rare but striking event in young athletes, most often associated with underlying structural heart diseases or cardiac channelopathies ( 1 ). These events have a great impact due to their occurrence in individuals who are otherwise perceived as healthy. As a preventive strategy, pre-participation cardiovascular screening is recommended to detect potentially life-threatening cardiac abnormalities in athletes ( 2 ), although this practice remains controversial ( 3 ). The electrocardiogram (ECG) is among the primary tests used in this initial screening ( 4 ). It is cost-effective, widely accessible, and valuable for detecting both structural and electrical cardiac alterations, though its routine use is still debated ( 5 – 7 ). Interpreting the ECG of athletes is particularly challenging because physiological cardiac adaptations may closely mimic pathological findings ( 5 ). These adaptations include increased ventricular mass, enlarged chamber dimensions, greater wall thickness, as well as autonomic changes related to increased vagal tone or reduced sympathetic activity ( 7 ). Several criteria have been developed to interpret the ECG of athletes, including those from the European Society of Cardiology (ESC) ( 8 ), the Seattle ( 9 ), and more recently the International criteria ( 10 ). T-wave inversion (TWI) is a repolarization abnormality observed more frequently in athletes than in the general population ( 11 ). However, the presence of TWI is considered an abnormal ECG finding, with the exception of ST elevation followed by TWI in V1-V4 in black athletes and TWI in V1-V3 in athletes < 16 years old ( 10 ). TWI poses a diagnostic challenge, as it can reflect either benign ventricular remodelling associated with intense training or an early manifestation of cardiomyopathies that predispose athletes to SCD ( 12 – 14 ). To aid in distinguishing physiological from pathological TWI, various ECG parameters have been proposed ( 5 , 15 ), such as J-point elevation, ST-segment morphology, the anatomical location of TWI, and the depth of inversion. The aims of this systematic review were: i) to determine the prevalence of TWI in athletes and whether it is higher than in the general population; ii) to identify structural heart diseases associated with TWI; and iii) to evaluate its prognostic significance in this population. MATERIALS AND METHODS 2.1.-Design of the study A systematic review and meta-analysis were conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0 ( 16 ), and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ( 17 ). The protocol was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42023494038. A specific protocol was prepared, and no amendments were made to the information provided at registration or within the protocol. 2.2.-PICOS format of the research questions Three research questions were developed using the Population, Intervention, Comparator, Outcome, and Study Design (PICOS) framework (Supplementary Table 1) and are summarized as follows: Question 1: a. What is the prevalence of TWI in athletes?; b. Is the prevalence of TWI higher in athletes compared to non-athletes? Question 2: Is TWI in athletes associated with underlying structural cardiac disease? Question 3: Does the presence of TWI in athletes confer an increased risk of cardiovascular events or SCD? 2.3.-Search strategy A systematic literature search was conducted in three electronic databases: PubMed, Scopus, and Web of Science. Studies published from the inception of each database up to September 2023 were considered for inclusion. An updated search was performed in PubMed to capture additional studies published between September 2023 and June 2025. The search strategy was structured around two main conceptual domains, with terms mapped to relevant Medical Subject Headings (MeSH): Repolarization abnormalities: “Repolarization,” “T-wave,” “ST segment,” “Abnormal ECG,” “Abnormal EKG,” “Electrocardiographic abnormalities,” “Electrocardiographic patterns,” “Electrocardiographical abnormalities,” and “Electrocardiographical patterns” (MeSH term: Electrocardiography, Ambulatory ). Athlete population: “Athletes,” “Sport,” and “Athlete’s heart” (MeSH terms: Athletes , Sport , Cardiomegaly, Exercise-Induced ). Within each conceptual group, search terms were combined using the Boolean operator “OR”, and the two conceptual groups were linked using “AND” to construct the final search strategy. 2.4.-Eligibility criteria and study selection Eligibility criteria included: (i) original research articles reporting on the prevalence or underlying substrates of TWI; (ii) studies providing data specifically on athletes, with or without comparisons to non-athlete populations; (iii) inclusion of male and/or female participants; (iv) inclusion of participants of any race, with particular attention to Black and Caucasian populations; (v) participation in any type of sport, at any level; and (vi) no age restrictions. Studies were also included if they reported diagnostic procedures used to rule out structural cardiomyopathies or provided follow-up data on athletes with TWI to assess the risk of cardiovascular events. Exclusion criteria encompassed studies focusing on arrhythmias, prolonged or shortened QT intervals, other channelopathies, atrioventricular conduction abnormalities, ventricular hypertrophy, or those solely dedicated to morphological assessments (e.g., echocardiography, cardiac magnetic resonance imaging) of the athlete’s heart. Study selection followed a three-step screening process: ( 1 ) title screening, ( 2 ) abstract screening, and ( 3 ) full-text review of potentially eligible articles. In those studies, analysing the same set of athletes in more than one publication, the study with the largest sample size or the longest follow-up was selected. Two independent reviewers (JS and RE) assessed each study. Discrepancies were resolved through discussion and consensus with a third reviewer (JC-B). Additionally, reference lists of all included studies were screened to identify any relevant articles not retrieved through the initial search strategy. 2.5.-Variables of interest, data extraction From each included study, two authors independently extracted the following variables of interest: first author; year of publication; country; study design; sample size; participant characteristics (sex, race, age range, and details of sports participation); prevalence of TWI in athletes and, if applicable, in control groups; TWI location (anterior, inferior, or lateral); criteria used to define TWI (e.g., ESC, Seattle, International, or other); data on associated structural cardiac abnormalities; follow-up duration; and incidence of cardiovascular outcomes during follow-up. In the event of discrepancies between the two reviewers (JS and RE), a third reviewer (JC-B) was consulted to reach consensus. TWI was defined according to one of the following accepted criteria: (i) the 2010 ESC guidelines define TWI as a negative T wave ≥ 2 mm in ≥ 2 contiguous leads, excluding leads DIII and aVR ( 8 ); (ii) the Seattle and International criteria define TWI as a negative T wave ≥ 1 mm in 2 contiguous leads, excluding leads aVR, DIII and V1 ( 9 , 10 ). The location of TWI was classified based on the affected electrocardiographic leads as follows: (i) anterior (V2–V4); (ii) inferior (DII–aVF); and, (iii) lateral (V5–V6 and/or DI–aVL). Studies presenting results on the inferolateral leads were classified as on the inferior leads. In athletes ≤ 16 years, the presence of TWI in V2 or V2-V3 was considered juvenile TWI pattern and was analysed independently. 2.6.-Risk of bias assessment To assess the risk of bias in the studies included in the meta-analysis, we used the Joanna Briggs Institute (JBI) Critical Appraisal Tool for Analytical Cross-Sectional Studies ( 18 ). This tool evaluates key methodological domains, including: the clarity of inclusion criteria; the definition of the study setting and participant recruitment; the validity and reliability of exposure and outcome measurements; the identification and management of potential confounding factors; and the appropriateness of the statistical analyses employed. Each domain was rated as adequate, not adequate, unclear, or not applicable (for non-analytical, descriptive studies). A global index was assigned: adequate when all the domains were adequate, unclear when at least one domain was unclear and the rest were adequate, and non-adequate when at least one domain was not adequate. 2.7.-Statistical analysis A meta-analysis was conducted, for studies that did not report a 95% confidence interval (CI), the standard error (SE) of the prevalence was calculated using the following formula: $$\:\sqrt{\raisebox{1ex}{$p\left(1-p\right)$}\!\left/\:\!\raisebox{-1ex}{$n$}\right.}$$ where: p = prevalence n = sample size In studies reporting the prevalence of TWI in both athletes and control groups, the SE of the difference in prevalence between the two groups was calculated using the following formula: $$\:\sqrt{\frac{p1(1-p1)}{n1}+\frac{p2(1-p2)}{n2}}$$ where: p1 = prevalence in athletes n1 = sample size of athletes p2 = prevalence in controls n2 = sample size of controls In studies evaluating the incidence of cardiovascular events during follow-up, annualized incidence rates were calculated to standardize differences in follow-up duration across studies. Specifically, the cumulative incidence was divided by the mean or median follow-up time reported in each study, to estimate annual incidence rates per 1,000 athletes. Homogeneity statistics were used to assess the degree of unexplained variability in effect estimates across studies, commonly referred to as between-study heterogeneity. The I² statistic was employed to quantify this heterogeneity. The I² statistic estimates the proportion of total variation due to true heterogeneity rather than sampling error. If heterogeneity was low (I² 50% was interpreted as evidence of substantial heterogeneity. In such cases, a random-effects model was applied, and a meta-regression analysis was performed to identify potential variables explaining the heterogeneity. Potential publication bias was explored using funnel plots and the Egger's regression asymmetry test with a significant threshold set at p 16 years), sex, ethnicity and TWI diagnostic criteria applied. For studies reporting TWI prevalence in athletes aged ≤ 18 years, these data were included in the ≤ 16 years age stratum. 2.8.-Equity, diversity, inclusion statement and data availability The collection and analysis of the data were stratified by sex and ethnicity. The author team is balanced by gender, and one of the co-authors is a medical student who contributed to this work as part of his master’s thesis. Data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review are available upon request to the corresponding author. RESULTS 3.1.-Literature search The initial literature search identified 5,963 potentially relevant articles, of which 1,454 turned out to be duplicates. After applying the selection criteria and adding 10 articles obtained through other sources, 107 articles were retained for analysis. Additionally, 8 articles were also included after the additional search to June 2025 was performed, resulting in a final total of 115 studies included in the analysis (Fig. 1 ). 3.2.-Prevalence of TWI in athletes (Question 1-a) To address this question, 110 articles comprising a total of 258,954 individuals were included in the analysis. Of these, 58 were performed in Europe ( 4 , 13 , 14 , 19 , 20 – 43 , 44 – 73 ), 24 in the United States ( 12 , 74 – 96 ) and 28 in other countries ( 15 , 97 – 123 ). Regarding sex distribution, 32 studies included only men, 6 only women, 66 both men and women, and 6 did not report sex distribution. Concerning ethnicity, 28 studies included only Caucasians, 4 only Black individuals, 6 other ethnic groups, 47 mixed ethnicities, and 25 did not clearly state ethnicity. The main characteristics of the studies are summarized in Supplementary Table 2. 3.2.1.-Prevalence of TWI in athletes > 16 years Forty-two studies used the Seattle criteria ( 12 , 31 , 34 , 44 , 47 , 48 , 50 , 52 , 53 , 56 – 58 , 60 , 62 , 65 , 66 , 68 , 73 , 79 , 83 , 84 , 86 – 89 , 91 – 95 , 104 , 107 , 110 , 113 , 114 , 116 – 118 , 120 – 123 ) and 32 studies applied the ESC criteria ( 4 , 13 , 14 , 25 , 26 , 29 – 31 , 35 , 36 , 38 – 42 , 44 , 45 , 49 , 66 , 68 , 69 , 75 – 77 , 80 , 83 , 101 – 103 , 105 , 108 , 110 , 112 ). The heterogeneity between studies was very high, in most metanalyses the I 2 was > 80%, therefore, the random effects model was selected. The overall prevalence of TWI in athletes > 16 years according to the Seattle criteria was 6% (95% Confidence Interval -CI-: 4–7%). Prevalence by anatomical location was 4% (95%CI: 2–5%), 1% (95%CI: 1–2%) and 1% (95%CI: 0–1%) in the anterior, inferior and lateral leads, respectively (Fig. 2 ). Funnel plots are presented in Supplementary Fig. 1, Egger’s test for funnel plot asymmetry suggested the presence of publication bias or substantial heterogeneity among studies (p-value < 0.05). When the ESC criteria were applied, the overall prevalence of TWI was slightly lower, at 5% (Supplementary Fig. 2). Prevalence by anatomical location was 4%, 1% and 0% in the anterior, inferior and lateral leads, respectively (Supplementary Fig. 2). When considering the Seattle criteria, the prevalence of TWI was higher among Black athletes than in Caucasian athletes, both overall (15% vs 4%) (Fig. 3 ), and across all leads (Supplementary Figs. 3–4). Similar findings were observed when other diagnostic criteria were used. When applying the Seattle criteria and stratifying the analysis by sex, women showed a higher overall prevalence compared to men (8% vs. 6%) (Fig. 4 ). This higher prevalence was observed in the anterior leads but not in the inferior or lateral leads (Supplementary Figs. 5–6). This higher prevalence was not observed when using the ESC criteria. Moreover, in the meta-regression analysis when considered sex, region, black ethnicity, and age of the athletes, sex was not a variable that explained the heterogeneity between studies (Supplementary Table 3). The meta-regression showed that the higher the percentage of Black athletes and the higher the age of the athletes included in the studies, the higher the prevalence of TWI (Fig. 5 ). 3.2.2.-Prevalence of TWI in athletes ≤ 16 years To analyse the prevalence of TWI in young athletes (≤ 16 years/18 years), 29 studies were included ( 15 , 23 , 27 , 28 , 32 , 33 , 37 , 43 , 45 , 46 , 51 , 52 , 54 – 56 , 61 , 63 , 64 , 66 – 72 , 85 , 90 , 96 , 99 ). Of these, 19 studies reported the prevalence of juvenile TWI (V1-V3), which was 6%. Additionally, 17 studies provided data on TWI in other specific locations ( 23 , 28 , 32 , 33 , 37 , 43 , 45 , 46 , 54 , 61 , 64 , 67 , 70 – 72 , 85 , 90 ) showing prevalences of 2% in the extended anterior leads, 1% in the inferior leads, and 0% in the lateral leads (Supplementary Fig. 6). 3.2.3.-Prevalence of TWI in athletes vs non-athletes (Question 1-b) For this analysis, the diagnostic criteria for TWI used in each study (Seattle, ESC, or other) were considered. A total of 14 studies were included in this analysis ( 13 , 21 – 23 , 27 , 28 , 31 , 34 , 37 , 42 , 53 , 54 , 70 , 102 ). The presence of TWI in any lead was more frequent in athletes compared to non-athletes, with a PR of 1.49 (95% CI: 1.13–1.97) (Fig. 6 -A). Specifically, TWI in the inferior leads was more prevalent among athletes (PR = 1.70; 95% CI: 1.23–2.35). However, the differences in TWI prevalence in the anterior and lateral leads were not statistically significant (Fig. 6 ). A sensitivity analysis excluding studies in which the prevalence of TWI was 0% in either athletes or non-athletes yielded consistent results (data not shown). 3.2.4.-Risk of bias assessment question 1 The qualitative assessment of risk of bias is presented in Supplementary Table 4. Most concerns were identified in the first two domains, which relate to the definition of the sample selection criteria and the study setting. Among the included studies, 53 were judged adequate, 31 showed some uncertainty, and 26 were considered inadequate. 3.3.-Relationship between TWI with structural cardiac diseases in athletes (Question 2) Thirty-five studies assessed the presence of structural cardiomyopathies and included at least 30 athletes with TWI (Table 1 ). In 20 of these studies ( 13 , 28 , 31 , 34 , 37 , 42 , 44 , 46 , 50 , 53 , 57 , 61 , 66 , 67 , 75 , 78 , 83 , 87 , 103 ), the prevalence of structural cardiac disease among athletes with TWI was < 1%. Nine studies ( 4 , 15 , 32 , 41 , 64 , 101 , 121 , 122 ) reported a prevalence between 1% and 10%, while six studies ( 14 , 26 , 72 , 124 – 126 ) reported a prevalence exceeding 10%. The most frequently identified structural cardiomyopathies were hypertrophic cardiomyopathy, arrhythmogenic ventricular cardiomyopathy, and dilated cardiomyopathy. Notably, TWI in the lateral leads was most frequently associated with a confirmed diagnosis of cardiomyopathy. 3.4.-Relationship between TWI with a higher risk of cardiovascular events or sudden cardiac death (Question 3) In studies with long-term follow-up of athletes with TWI, two distinct outcomes were identified: i) the delayed diagnosis of a structural heart disease in athletes who initially presented no detectable pathology, and ii) the occurrence of major adverse cardiovascular events, including SCD, syncope, or ventricular arrhythmias. Thirteen studies evaluated the incidence of newly diagnosed structural heart disease (Table 2 -A). The annual incidence rate ranged from 0 to 54.9 cases per 1,000 athletes: six studies reported no new diagnoses during the follow-up ( 59 , 67 , 70 , 121 , 123 , 125 ), five studies reported an incidence between 0.1 and 10 cases per 1,000 athletes per year ( 26 , 31 , 50 , 61 , 127 ), and two studies reported an incidence of 33.3 and 54.9 cases per 1,000 athletes per year ( 14 , 128 ). Consistent with previous findings, the most commonly diagnosed conditions were hypertrophic cardiomyopathy, arrhythmogenic ventricular cardiomyopathy, and dilated cardiomyopathy. These new diagnoses were most frequently related to the presence of TWI in the lateral leads. Twenty-one studies analysed the incidence of major cardiovascular events among athletes with TWI (Table 2 -B). The reported annual incidence rate ranged from 0 to 83.33 events per 1,000 athletes per year. Seventeen studies reported no events during the follow-up ( 14 , 24 , 31 , 37 , 38 , 50 , 59 , 61 , 67 , 70 , 83 , 107 , 121 , 123 , 125 , 127 , 128 ), while four studies reported incidence rates of 1.37 ( 26 ), 2.24 ( 64 ), 32.97 ( 14 ), and 83.33 ( 35 ) events per 1,000 athletes per year. DISCUSSION In this systematic review, the prevalence of TWI in athletes ranged from 5% to 6%, depending on the diagnostic criteria applied. TWI most frequently involved the anterior leads and was more common in Black athletes. Its prevalence was higher in athletes than in non-athletes. A minority of athletes with TWI were diagnosed with an underlying structural cardiomyopathy, with the likelihood of such a diagnosis increasing when TWI affected the lateral leads. In most studies, the prognosis of TWI in athletes was favourable, with a very low incidence of cardiovascular events reported during follow-up. 4.1.-Prevalence of TWI in athletes In this study we report that the prevalence of TWI is 49% higher in athletes than in non-athletes. However, TWI is considered an abnormal ECG finding, with certain exceptions, such as in Black athletes and in athletes younger than 16 years, when TWI affects the anterior leads ( 10 ). The results of our metanalysis indicate that the prevalence of TWI in athletes is 5–6%, depending on the diagnostic criteria applied, and it predominantly affects the anterior leads. There is considerable heterogeneity among studies, with some reporting a prevalence of 0%, while others report prevalences exceeding 20%. While some of this heterogeneity may be explained by differences in the diagnostic criteria considered, the results of our meta-regression indicated that the ethnicity, region, and age of the athletes explained 40% of the heterogeneity among studies. Other factors that could also contribute are inconsistent definition of “athlete” -affecting the volume and intensity of training-, differences in participant selection criteria across studies, and variability in the level of expertise in ECG interpretation in athletes. The higher prevalence of TWI among athletes of Black ethnicity has been attributed to a combination of genetic, endocrine, and haemodynamic factors ( 66 ). Furthermore, Black individuals tend to have increased myocardial wall thickness and greater left ventricular mass compared to White individuals ( 31 , 37 ), and this increased ventricular mass has been associated with a higher prevalence of TWI ( 28 , 31 , 110 , 128 ). Interestingly, the geographical origin of athletes has also been recently related to the frequency of repolarization abnormalities, which are significantly more common among West (6.4%) and Middle African (8.5%) athletes than among those from East (1.5%) and North Africans (< 1%) ( 110 ). Several studies have reported a positive correlation between the intensity of training, the duration of participation in high-performance programmes, or the level of physical fitness, and the prevalence of TWI ( 47 , 56 , 60 , 105 , 112 ). In addition, inter-observer variability and differences in expertise in the interpretation of athletes’ ECG may introduce bias in the assessment of TWI ( 129 ). To address this issue, various initiatives, such as in-person and online training courses ( 130 ), have been implemented to enhance medical education and proficiency in ECG interpretation in the context of athletic population. The mechanisms underlying the presence of TWI in athletes are diverse and include: i) ventricular remodelling. For instance, the papillary muscle/left ventricular mass ratio > = 3.5%, the apical displacement of the papillary muscle, or both have been related to the presence of lateral TWI ( 125 ). Moreover, lateral displacement of the right ventricle or the cardiac apex toward the left axilla has been also associated with progressive TWI in the anterior leads ( 82 , 131 ); ii) structural variants, some authors have associated anterior TWI with the presence of false tendons in the left ventricle ( 49 ); iii) neuroanatomical changes, such as increased vagal tone ( 7 ), which activates the acetylcholine-controlled potassium channel (I K−ACh ), reducing the action potential gradient between the epicardium and endocardium. This change may affect the vectorcardiogram of repolarisation and contribute to the appearance of TWI ( 132 ); iv) myocardial ischaemia. Cardiac repolarisation initiates in the epicardium and terminates in the endocardium, reflected in a positive T wave due to the shorter duration of the action potential in the epicardium relative to the endocardium ( 12 ). In ischemic conditions, reduced endocardial repolarisation time can diminish this gradient, potentially inverting the repolarisation vector and resulting in TWI ( 12 ). The presence of anterior TWI is more frequently observed in athletes under the age of 16 ( 15 , 61 ). This finding has been associated with the right ventricular dominance during early adolescence ( 15 , 28 , 32 , 55 , 61 , 70 ). After the age of 16, anterior TWI generally tends to regress. 4.2.-TWI and structural cardiomyopathy at the diagnosis or the follow-up The presence of TWI requires ruling out several cardiac pathologies associated with SCD, including hypertrophic cardiomyopathy, arrhythmogenic ventricular cardiomyopathy, dilated cardiomyopathy, myocarditis, atherosclerotic coronary artery disease, long QT syndrome, and Brugada syndrome ( 102 ). Additionally, other conditions include electrolyte imbalances (such as potassium or magnesium deficiencies), certain drugs, and congenital cardiac defects ( 1 ). In our review, we selected 35 studies comprising ≥ 30 athletes with TWI in which the presence of structural cardiomyopathies was specifically evaluated. In 20 of these studies, the reported prevalence of cardiomyopathy was below 1%, whereas six studies reported prevalences exceeding 10% ( 14 , 26 , 72 , 124 – 126 ). The higher prevalence observed in these latter studies may be attributable to deeper TWI ( 14 , 26 ), predominance in the lateral leads ( 26 , 72 , 125 ) and the use of cardiac magnetic resonance ( 14 , 124 – 126 ), which has greater sensitivity than echocardiography for detecting structural cardiac abnormalities ( 14 , 133 ). The limited sample sizes may also have contributed to the heterogeneity across studies. When analysing by location, TWI in the lateral leads is most suggestive of underlying structural heart disease ( 61 ), most commonly hypertrophic cardiomyopathy, particularly when the inversion is ≥ 2mm and accompanied by ST segment depression ( 31 , 35 , 37 , 46 , 56 , 85 , 102 , 121 , 133 ). Furthermore, normalization of TWI during exercise testing has been reported as a favourable prognostic indicator ( 26 , 134 ). However, Zorzi et al. ( 135 ) have shown that patients with overt arrhythmogenic ventricular cardiomyopathy may also exhibit normalization of T-waves during exercise, thereby questioning the prognostic value of this finding. An additional important consideration is that the absence of detectable structural abnormalities at the time of the exploration does not exclude the possibility of future development of cardiomyopathy. TWI may represent an early phenotypic expression manifestation of an underlying condition that precedes structural abnormalities detectable via imaging by several years ( 14 , 31 , 35 , 48 , 102 ). In this review, while half of the studies with follow-up data (6 out of 12) did not report any new cardiac diagnosis, the remainder reported incidence rates of newly diagnosed cardiomyopathies ranging from 1 to 7 per 1,000 athletes per year. One study reported an incidence of 54.9 new diagnoses per 1,000 athletes per year (5 new cases in 91 athletes followed up for 1 year). This study employed a standardised follow-up protocol, including routine cardiac magnetic resonance, underscoring the relevance of comprehensive evaluation for ruling out structural cardiomyopathies. Indeed, recent guidelines recommend the use of CMR in the diagnosis process of these pathologies ( 136 ). 4.3.-TWI and clinical cardiovascular events The incidence of clinical cardiovascular events in athletes with TWI is very rare. Only one study reported a high incidence (83.3 events per 1,000 athletes per year), but this finding was based on a small sample of six athletes with TWI followed over two years, during which a single case of SCD occurred ( 35 ). The clinical relevance of TWI should also be contextualised with the family (SCD) and personal history (syncope) of the athlete. 4.4.-Strengths and limitations This represents the most comprehensive systematic review to date aimed at determining the prevalence of TWI in athletes and its prognostic significance. However, several limitations affecting comparability across studies must be acknowledged: i) the criteria used to define the presence of TWI vary among studies; ii) participant inclusion criteria differ widely, particularly in terms of age, ethnicity, sex, training intensity, and type of sport, …); iii) there is considerable variability in the diagnostic modalities employed to identify underlying cardiomyopathies. CONCLUSIONS TWI is more common in athletes than in non-athletes, although its overall prevalence remains low, there is substantial heterogeneity across studies. It is observed more frequently in individuals of Black ethnicity. While TWI may represent an adaptive response to sport-induced ventricular remodelling, it can also be indicative of underlying structural heart disease. Accurate identification and thorough evaluation, particularly through advanced imaging modalities such as magnetic resonance imaging, are essential for appropriate clinical management. Overall, the clinical prognosis of athletes with TWI is favourable, with a very low incidence of cardiovascular events. Abbreviations CI: Confidence Interval ECG: Electrocardiogram ESC: European Society of Cardiology JBI: Joanna Briggs Institute MeSH: Medical Subject Headings PICOS: Population, Intervention, Comparator, Outcome, and Study Design PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses SCD: Sudden Cardiac Death SE: Standard Error TWI: T-wave inversion Declarations - Ethics approval and consent to participate: Not applicable. - Consent for publication: All the authors have approved the final version of the manuscript and have consent for publication. -Availability of data and material: Data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review are available upon request to the corresponding author. -Competing interests: The authors declare no competing financial interests. -Funding: This research was partially funded by CIBERCV (Instituto de Salud Carlos III) -Authors' contributions: Substantial contributions to the conception or design of the work: JC-B, RE Acquisition: JS, JC-B, RE Analysis: JS, RE Interpretation of data for the work: JS, JC-B, HV, LC, SM, AB, RE Drafting the work: JS, RE Reviewing it critically for important intellectual content: JC-B, HV, LC, SM, AB Final approval of the version to be published: JS, JC-B, HV, LC, SM, AB, RE Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: JS, JC-B, HV, LC, SM, AB, RE -Acknowledgements: Not applicable. 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Card Electrophysiol Clin. 2024;16:35–49. Riding NR, Drezner JA. Performance of the BMJ learning training modules for ECG interpretation in athletes. Heart. 2018;104:2051–7. Claessen G, Brosnan M, La Gerche A, Heidbuchel H. Signs of RV overload on the athlete’s ECG. J Electrocardiol. 2015;48:399–406. Tomson TT, Arora R. Modulation of Cardiac Potassium Current by Neural Tone and Ischemia. Card Electrophysiol Clin. 2016;8:349–60. Thiagarajan N, Ho WHH, Lim DYZ, Loo WTW, Shen G, Sundar V, et al. Yield of Cardiac Magnetic Resonance Imaging in a Preparticipation Cohort of Young Asian Males with T Wave Inversion. Circulation. 2022;146:1802–4. Serra-Grima R, Estorch M, Carrió I, Subirana M, Bernà L, Prat T. Marked ventricular repolarization abnormalities in highly trained athletes’ electrocardiograms: Clinical and prognostic implications. J Am Coll Cardiol. 2000;36:1310–6. Zorzi A, Elmaghawry M, Rigato I, Cardoso Bianchini F, Crespi Ponta G, Michieli P, et al. Exercise-induced normalization of right precordial negative T waves in arrhythmogenic right ventricular cardiomyopathy. Am J Cardiol. 2013;112:411–5. Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44:3503–626. Tables Tables are available in the Supplementary Files section. Supplementary Files PRISMA2020checklist.docx Supplementarymaterial.docx SupplementaryTable2.xlsx Tables.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 01 Apr, 2026 Reviewers invited by journal 26 Feb, 2026 Editor assigned by journal 21 Jan, 2026 First submitted to journal 20 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8638655","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":597312826,"identity":"7cc8a8da-f136-49b0-8e97-e0a8776402cb","order_by":0,"name":"Javier Sanmartin","email":"","orcid":"","institution":"Faculty of Medicine, University of Vic-Central University of Catalonia","correspondingAuthor":false,"prefix":"","firstName":"Javier","middleName":"","lastName":"Sanmartin","suffix":""},{"id":597312827,"identity":"02c6347b-1083-4bf4-ba2e-c5f99b88caee","order_by":1,"name":"Joan Cartanya-Bonvehi","email":"","orcid":"","institution":"Faculty of Medicine, University of Vic-Central University of Catalonia","correspondingAuthor":false,"prefix":"","firstName":"Joan","middleName":"","lastName":"Cartanya-Bonvehi","suffix":""},{"id":597312828,"identity":"9fc20075-a681-4fcc-842e-cb6106df38a5","order_by":2,"name":"Helen Valenzuela","email":"","orcid":"","institution":"Faculty of Medicine, University of Vic-Central University of Catalonia","correspondingAuthor":false,"prefix":"","firstName":"Helen","middleName":"","lastName":"Valenzuela","suffix":""},{"id":597312829,"identity":"1797c120-0607-4e4c-8737-d62f24aa53c2","order_by":3,"name":"Lidia Carballeira","email":"","orcid":"","institution":"Faculty of Medicine, University of Vic-Central University of Catalonia","correspondingAuthor":false,"prefix":"","firstName":"Lidia","middleName":"","lastName":"Carballeira","suffix":""},{"id":597312830,"identity":"e1858572-d33a-49d3-ba29-1ec6bd797469","order_by":4,"name":"Silvia Montserrat","email":"","orcid":"","institution":"Faculty of Medicine, University of Vic-Central University of Catalonia","correspondingAuthor":false,"prefix":"","firstName":"Silvia","middleName":"","lastName":"Montserrat","suffix":""},{"id":597312831,"identity":"734c0bb5-195b-469a-9636-12b63367f069","order_by":5,"name":"Adrian Baranchuk","email":"","orcid":"","institution":"Division of Cardiology, Kingston Health Science Center, Queen's University. Kingston, Ontario","correspondingAuthor":false,"prefix":"","firstName":"Adrian","middleName":"","lastName":"Baranchuk","suffix":""},{"id":597312832,"identity":"1fcc261a-1d0e-4085-9b32-fe8e11bfd263","order_by":6,"name":"Roberto Elosua","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYFAC5gYQKQfjJhChhRGsxRhdiwFBLYkNRGsxb29sfPizzS59e3v7wwc/99jl6baffcBcUPEHpxaZMwebjXnbknPnnDljbNjzLLnY7Ey6AfOMM7htkZBIbJNmbGPOnSGRwybBc+BA4rYDaQzMvG14tMg/bJP82VafLiH//PnPPyAt558BtfzDZwtjmwRv2+EECQkGM2awLTdAtjTg0cKT2GzMc+644QyeHGNpmQPJQC3PGA7zHDPGrYX98MGHP8qq5SXYjz/8+OaAHdBhaYyPeWrkcGrBDg6QqH4UjIJRMApGARoAAFA5VCpSyvk9AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-8235-0095","institution":"Hospital del Mar Research Institute","correspondingAuthor":true,"prefix":"","firstName":"Roberto","middleName":"","lastName":"Elosua","suffix":""}],"badges":[],"createdAt":"2026-01-19 11:01:38","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8638655/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8638655/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103769814,"identity":"5a23d05a-7a33-4edd-ba52-448fc79d4876","added_by":"auto","created_at":"2026-03-02 16:52:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":206353,"visible":true,"origin":"","legend":"\u003cp\u003ePreferred Reporting Items for Systematic Reviews and Metanalyses (PRISMA) flow diagram.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8638655/v1/56912f463b1abe6b2ddb5822.png"},{"id":103769815,"identity":"13ff071f-f5e9-4e58-ad60-bf7ca285dc60","added_by":"auto","created_at":"2026-03-02 16:52:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":888018,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots displaying the pooled prevalence of T wave inversion (TWI) in competitive athletes aged \u0026gt;16 years, based on lead distribution and following the Seattle criteria for ECG interpretation: A) Overall TWI prevalence across all leads; B) Anterior TWI (leads V2-V4); C) Inferior TWI (leads II, aVF); D) Lateral TWI (leads I, aVL, V5-V6).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8638655/v1/b1b70f14a18e9035348bbf86.png"},{"id":103769823,"identity":"1fef4908-94bc-48e5-9288-43321653af68","added_by":"auto","created_at":"2026-03-02 16:52:55","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":394866,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots showing the prevalence of T wave inversion (TWI) in male and female competitive athletes aged \u0026gt;16 years, using the ESC criteria for ECG interpretation. A) Male athletes. B) Female athletes.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8638655/v1/6a1e3859037dc10168a3121e.png"},{"id":103769822,"identity":"e123af91-6f40-48ef-93ac-1fad8801bd05","added_by":"auto","created_at":"2026-03-02 16:52:55","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":465155,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots showing the prevalence of T wave inversion (TWI) in Caucasian and Black competitive athletes aged \u0026gt;16 years, using the ESC criteria for ECG interpretation: A) Caucasian athletes; B) Black athletes.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8638655/v1/9932eefaa83d95a40d4b99aa.png"},{"id":105751769,"identity":"369482bd-25b2-4bf9-b74f-2f96814c25dd","added_by":"auto","created_at":"2026-03-30 15:43:01","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":389059,"visible":true,"origin":"","legend":"\u003cp\u003eBubble plots showing the results of the meta-regression results: A) relation between the percentage of Black athletes included in the study and the prevalence of TWI; B) relation between the mean age of athletes included in the study and the prevalence of TWI.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-8638655/v1/8ff9082250897ff14b4f2b08.png"},{"id":104400493,"identity":"59d8d428-47bf-4aba-a3b3-c14080754d24","added_by":"auto","created_at":"2026-03-11 12:10:07","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1436991,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots showing the prevalence ratio (PR) of T wave inversion (TWI) in competitive athletes versus non-athletes, aged \u0026gt;16 years, based on lead distribution and following the\u003cstrong\u003e \u003c/strong\u003eSeattle criteria for ECG interpretation: A) All leads combined; B) Anterior leads (V2-V4); C) Inferior leads (II, aVF); D) Lateral leads (I, aVL, V5-V6).\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-8638655/v1/c1ef25db0a36056c48cdffe4.png"},{"id":105752476,"identity":"71a545e3-97ab-4d26-a468-eb88f8a40af6","added_by":"auto","created_at":"2026-03-30 16:00:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4693520,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8638655/v1/f4b97c7f-546d-4258-8809-13d264fe1b31.pdf"},{"id":103769818,"identity":"b8aa06b6-85ae-4ca9-ba42-063fbba9b113","added_by":"auto","created_at":"2026-03-02 16:52:55","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":277648,"visible":true,"origin":"","legend":"","description":"","filename":"PRISMA2020checklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-8638655/v1/63430f809f8386936433bf0c.docx"},{"id":103769821,"identity":"d03566ee-8c2e-49ad-a6be-9f8ab93f5d15","added_by":"auto","created_at":"2026-03-02 16:52:55","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":2688008,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-8638655/v1/7aabeda27fa78db8ec84ebe0.docx"},{"id":104400055,"identity":"fba5a60b-27b3-4935-8efc-33b2ec784780","added_by":"auto","created_at":"2026-03-11 12:08:42","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":59987,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8638655/v1/7b63d6b4f3c7aa92cdd7f67a.xlsx"},{"id":103769816,"identity":"b643d220-17ac-464a-ad6c-52f501bd0644","added_by":"auto","created_at":"2026-03-02 16:52:55","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":29847,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8638655/v1/a990ce20aabb01c1a013a10e.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eT-wave inversions in athletes: frequency and prognostic significance. A systematic review and meta-analysis\u003c/p\u003e","fulltext":[{"header":"KEY POINTS","content":"\u003cp\u003eThe prevalence of TWI in athletes is 6% (Seattle criteria), and is more common in Black athletes.\u003c/p\u003e \u003cp\u003eTWI are more frequent in athletes than in the general population (Prevalence ratio: 1.49; 95% confidence interval: 1.13\u0026ndash;1.97).\u003c/p\u003e \u003cp\u003eThe prevalence of structural cardiac disease among athletes with TWI varies across studies (\u0026lt;\u0026thinsp;1% in 19 studies; 1\u0026ndash;10% in 8 studies; \u0026gt;10% in 6 studies).\u003c/p\u003e \u003cp\u003eThe incidence of clinical cardiovascular events in athletes with TWI is very rare.\u003c/p\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003eSudden cardiac death (SCD) is a rare but striking event in young athletes, most often associated with underlying structural heart diseases or cardiac channelopathies (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). These events have a great impact due to their occurrence in individuals who are otherwise perceived as healthy. As a preventive strategy, pre-participation cardiovascular screening is recommended to detect potentially life-threatening cardiac abnormalities in athletes (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), although this practice remains controversial (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe electrocardiogram (ECG) is among the primary tests used in this initial screening (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). It is cost-effective, widely accessible, and valuable for detecting both structural and electrical cardiac alterations, though its routine use is still debated (\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Interpreting the ECG of athletes is particularly challenging because physiological cardiac adaptations may closely mimic pathological findings (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). These adaptations include increased ventricular mass, enlarged chamber dimensions, greater wall thickness, as well as autonomic changes related to increased vagal tone or reduced sympathetic activity (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Several criteria have been developed to interpret the ECG of athletes, including those from the European Society of Cardiology (ESC) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), the Seattle (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), and more recently the International criteria (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eT-wave inversion (TWI) is a repolarization abnormality observed more frequently in athletes than in the general population (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). However, the presence of TWI is considered an abnormal ECG finding, with the exception of ST elevation followed by TWI in V1-V4 in black athletes and TWI in V1-V3 in athletes\u0026thinsp;\u0026lt;\u0026thinsp;16 years old (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). TWI poses a diagnostic challenge, as it can reflect either benign ventricular remodelling associated with intense training or an early manifestation of cardiomyopathies that predispose athletes to SCD (\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). To aid in distinguishing physiological from pathological TWI, various ECG parameters have been proposed (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), such as J-point elevation, ST-segment morphology, the anatomical location of TWI, and the depth of inversion.\u003c/p\u003e \u003cp\u003eThe aims of this systematic review were: i) to determine the prevalence of TWI in athletes and whether it is higher than in the general population; ii) to identify structural heart diseases associated with TWI; and iii) to evaluate its prognostic significance in this population.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.1.-Design of the study\u003c/h2\u003e \u003cp\u003eA systematic review and meta-analysis were conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0 (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The protocol was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42023494038. A specific protocol was prepared, and no amendments were made to the information provided at registration or within the protocol.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.2.-PICOS format of the research questions\u003c/h2\u003e \u003cp\u003eThree research questions were developed using the Population, Intervention, Comparator, Outcome, and Study Design (PICOS) framework (Supplementary Table\u0026nbsp;1) and are summarized as follows:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eQuestion 1: a. What is the prevalence of TWI in athletes?; b. Is the prevalence of TWI higher in athletes compared to non-athletes?\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eQuestion 2: Is TWI in athletes associated with underlying structural cardiac disease?\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eQuestion 3: Does the presence of TWI in athletes confer an increased risk of cardiovascular events or SCD?\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.3.-Search strategy\u003c/h2\u003e \u003cp\u003eA systematic literature search was conducted in three electronic databases: PubMed, Scopus, and Web of Science. Studies published from the inception of each database up to September 2023 were considered for inclusion. An updated search was performed in PubMed to capture additional studies published between September 2023 and June 2025. The search strategy was structured around two main conceptual domains, with terms mapped to relevant Medical Subject Headings (MeSH):\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eRepolarization abnormalities: \u0026ldquo;Repolarization,\u0026rdquo; \u0026ldquo;T-wave,\u0026rdquo; \u0026ldquo;ST segment,\u0026rdquo; \u0026ldquo;Abnormal ECG,\u0026rdquo; \u0026ldquo;Abnormal EKG,\u0026rdquo; \u0026ldquo;Electrocardiographic abnormalities,\u0026rdquo; \u0026ldquo;Electrocardiographic patterns,\u0026rdquo; \u0026ldquo;Electrocardiographical abnormalities,\u0026rdquo; and \u0026ldquo;Electrocardiographical patterns\u0026rdquo; (MeSH term: \u003cem\u003eElectrocardiography, Ambulatory\u003c/em\u003e).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAthlete population: \u0026ldquo;Athletes,\u0026rdquo; \u0026ldquo;Sport,\u0026rdquo; and \u0026ldquo;Athlete\u0026rsquo;s heart\u0026rdquo; (MeSH terms: \u003cem\u003eAthletes\u003c/em\u003e, \u003cem\u003eSport\u003c/em\u003e, \u003cem\u003eCardiomegaly, Exercise-Induced\u003c/em\u003e).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eWithin each conceptual group, search terms were combined using the Boolean operator \u0026ldquo;OR\u0026rdquo;, and the two conceptual groups were linked using \u0026ldquo;AND\u0026rdquo; to construct the final search strategy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.4.-Eligibility criteria and study selection\u003c/h2\u003e \u003cp\u003eEligibility criteria included: (i) original research articles reporting on the prevalence or underlying substrates of TWI; (ii) studies providing data specifically on athletes, with or without comparisons to non-athlete populations; (iii) inclusion of male and/or female participants; (iv) inclusion of participants of any race, with particular attention to Black and Caucasian populations; (v) participation in any type of sport, at any level; and (vi) no age restrictions. Studies were also included if they reported diagnostic procedures used to rule out structural cardiomyopathies or provided follow-up data on athletes with TWI to assess the risk of cardiovascular events.\u003c/p\u003e \u003cp\u003eExclusion criteria encompassed studies focusing on arrhythmias, prolonged or shortened QT intervals, other channelopathies, atrioventricular conduction abnormalities, ventricular hypertrophy, or those solely dedicated to morphological assessments (e.g., echocardiography, cardiac magnetic resonance imaging) of the athlete\u0026rsquo;s heart.\u003c/p\u003e \u003cp\u003eStudy selection followed a three-step screening process: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) title screening, (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) abstract screening, and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) full-text review of potentially eligible articles. In those studies, analysing the same set of athletes in more than one publication, the study with the largest sample size or the longest follow-up was selected. Two independent reviewers (JS and RE) assessed each study. Discrepancies were resolved through discussion and consensus with a third reviewer (JC-B).\u003c/p\u003e \u003cp\u003eAdditionally, reference lists of all included studies were screened to identify any relevant articles not retrieved through the initial search strategy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.5.-Variables of interest, data extraction\u003c/h2\u003e \u003cp\u003eFrom each included study, two authors independently extracted the following variables of interest: first author; year of publication; country; study design; sample size; participant characteristics (sex, race, age range, and details of sports participation); prevalence of TWI in athletes and, if applicable, in control groups; TWI location (anterior, inferior, or lateral); criteria used to define TWI (e.g., ESC, Seattle, International, or other); data on associated structural cardiac abnormalities; follow-up duration; and incidence of cardiovascular outcomes during follow-up. In the event of discrepancies between the two reviewers (JS and RE), a third reviewer (JC-B) was consulted to reach consensus.\u003c/p\u003e \u003cp\u003eTWI was defined according to one of the following accepted criteria: (i) the 2010 ESC guidelines define TWI as a negative T wave\u0026thinsp;\u0026ge;\u0026thinsp;2 mm in \u0026ge;\u0026thinsp;2 contiguous leads, excluding leads DIII and aVR (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e); (ii) the Seattle and International criteria define TWI as a negative T wave\u0026thinsp;\u0026ge;\u0026thinsp;1 mm in 2 contiguous leads, excluding leads aVR, DIII and V1 (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The location of TWI was classified based on the affected electrocardiographic leads as follows: (i) anterior (V2\u0026ndash;V4); (ii) inferior (DII\u0026ndash;aVF); and, (iii) lateral (V5\u0026ndash;V6 and/or DI\u0026ndash;aVL). Studies presenting results on the inferolateral leads were classified as on the inferior leads. In athletes\u0026thinsp;\u0026le;\u0026thinsp;16 years, the presence of TWI in V2 or V2-V3 was considered juvenile TWI pattern and was analysed independently.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e2.6.-Risk of bias assessment\u003c/h2\u003e \u003cp\u003eTo assess the risk of bias in the studies included in the meta-analysis, we used the Joanna Briggs Institute (JBI) Critical Appraisal Tool for Analytical Cross-Sectional Studies (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). This tool evaluates key methodological domains, including: the clarity of inclusion criteria; the definition of the study setting and participant recruitment; the validity and reliability of exposure and outcome measurements; the identification and management of potential confounding factors; and the appropriateness of the statistical analyses employed. Each domain was rated as adequate, not adequate, unclear, or not applicable (for non-analytical, descriptive studies). A global index was assigned: adequate when all the domains were adequate, unclear when at least one domain was unclear and the rest were adequate, and non-adequate when at least one domain was not adequate.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e2.7.-Statistical analysis\u003c/h2\u003e \u003cp\u003eA meta-analysis was conducted, for studies that did not report a 95% confidence interval (CI), the standard error (SE) of the prevalence was calculated using the following formula:\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$\\:\\sqrt{\\raisebox{1ex}{$p\\left(1-p\\right)$}\\!\\left/\\:\\!\\raisebox{-1ex}{$n$}\\right.}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003ewhere: p\u0026thinsp;=\u0026thinsp;prevalence\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;sample size\u003c/p\u003e \u003cp\u003eIn studies reporting the prevalence of TWI in both athletes and control groups, the SE of the difference in prevalence between the two groups was calculated using the following formula:\u003cdiv id=\"Equb\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equb\" name=\"EquationSource\"\u003e\n$$\\:\\sqrt{\\frac{p1(1-p1)}{n1}+\\frac{p2(1-p2)}{n2}}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003ewhere: p1\u0026thinsp;=\u0026thinsp;prevalence in athletes\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003en1\u0026thinsp;=\u0026thinsp;sample size of athletes\u003c/p\u003e \u003cp\u003ep2\u0026thinsp;=\u0026thinsp;prevalence in controls\u003c/p\u003e \u003cp\u003en2\u0026thinsp;=\u0026thinsp;sample size of controls\u003c/p\u003e \u003cp\u003eIn studies evaluating the incidence of cardiovascular events during follow-up, annualized incidence rates were calculated to standardize differences in follow-up duration across studies. Specifically, the cumulative incidence was divided by the mean or median follow-up time reported in each study, to estimate annual incidence rates per 1,000 athletes.\u003c/p\u003e \u003cp\u003eHomogeneity statistics were used to assess the degree of unexplained variability in effect estimates across studies, commonly referred to as between-study heterogeneity. The I\u0026sup2; statistic was employed to quantify this heterogeneity. The I\u0026sup2; statistic estimates the proportion of total variation due to true heterogeneity rather than sampling error. If heterogeneity was low (I\u0026sup2; \u0026lt; 50%), a fixed-effects model was used. An I\u0026sup2; value\u0026thinsp;\u0026gt;\u0026thinsp;50% was interpreted as evidence of substantial heterogeneity. In such cases, a random-effects model was applied, and a meta-regression analysis was performed to identify potential variables explaining the heterogeneity.\u003c/p\u003e \u003cp\u003ePotential publication bias was explored using funnel plots and the Egger's regression asymmetry test with a significant threshold set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003cp\u003eThe meta-analyses were conducted using RStudio and the R package 'meta'. The prevalence of TWI was stratified by age (\u0026le;\u0026thinsp;16 years and \u0026gt;\u0026thinsp;16 years), sex, ethnicity and TWI diagnostic criteria applied. For studies reporting TWI prevalence in athletes aged\u0026thinsp;\u0026le;\u0026thinsp;18 years, these data were included in the \u0026le;\u0026thinsp;16 years age stratum.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e2.8.-Equity, diversity, inclusion statement and data availability\u003c/h2\u003e \u003cp\u003eThe collection and analysis of the data were stratified by sex and ethnicity. The author team is balanced by gender, and one of the co-authors is a medical student who contributed to this work as part of his master\u0026rsquo;s thesis. Data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review are available upon request to the corresponding author.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.1.-Literature search\u003c/h2\u003e \u003cp\u003eThe initial literature search identified 5,963 potentially relevant articles, of which 1,454 turned out to be duplicates. After applying the selection criteria and adding 10 articles obtained through other sources, 107 articles were retained for analysis. Additionally, 8 articles were also included after the additional search to June 2025 was performed, resulting in a final total of 115 studies included in the analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.2.-Prevalence of TWI in athletes (Question 1-a)\u003c/h2\u003e \u003cp\u003eTo address this question, 110 articles comprising a total of 258,954 individuals were included in the analysis. Of these, 58 were performed in Europe (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39 CR40 CR41 CR42\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan additionalcitationids=\"CR45 CR46 CR47 CR48 CR49 CR50 CR51 CR52 CR53 CR54 CR55 CR56 CR57 CR58 CR59 CR60 CR61 CR62 CR63 CR64 CR65 CR66 CR67 CR68 CR69 CR70 CR71 CR72\" citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e), 24 in the United States (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR75 CR76 CR77 CR78 CR79 CR80 CR81 CR82 CR83 CR84 CR85 CR86 CR87 CR88 CR89 CR90 CR91 CR92 CR93 CR94 CR95\" citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e) and 28 in other countries (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan additionalcitationids=\"CR98 CR99 CR100 CR101 CR102 CR103 CR104 CR105 CR106 CR107 CR108 CR109 CR110 CR111 CR112 CR113 CR114 CR115 CR116 CR117 CR118 CR119 CR120 CR121 CR122\" citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR123\" class=\"CitationRef\"\u003e123\u003c/span\u003e). Regarding sex distribution, 32 studies included only men, 6 only women, 66 both men and women, and 6 did not report sex distribution. Concerning ethnicity, 28 studies included only Caucasians, 4 only Black individuals, 6 other ethnic groups, 47 mixed ethnicities, and 25 did not clearly state ethnicity. The main characteristics of the studies are summarized in Supplementary Table\u0026nbsp;2.\u003c/p\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003e3.2.1.-Prevalence of TWI in athletes\u0026thinsp;\u0026gt;\u0026thinsp;16 years\u003c/h2\u003e \u003cp\u003eForty-two studies used the Seattle criteria (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan additionalcitationids=\"CR57\" citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e, \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e, \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e, \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e, \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e, \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e, \u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e, \u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e, \u003cspan additionalcitationids=\"CR87 CR88\" citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e, \u003cspan additionalcitationids=\"CR92 CR93 CR94\" citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e, \u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e, \u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e, \u003cspan citationid=\"CR110\" class=\"CitationRef\"\u003e110\u003c/span\u003e, \u003cspan citationid=\"CR113\" class=\"CitationRef\"\u003e113\u003c/span\u003e, \u003cspan citationid=\"CR114\" class=\"CitationRef\"\u003e114\u003c/span\u003e, \u003cspan additionalcitationids=\"CR117\" citationid=\"CR116\" class=\"CitationRef\"\u003e116\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR118\" class=\"CitationRef\"\u003e118\u003c/span\u003e, \u003cspan additionalcitationids=\"CR121 CR122\" citationid=\"CR120\" class=\"CitationRef\"\u003e120\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR123\" class=\"CitationRef\"\u003e123\u003c/span\u003e) and 32 studies applied the ESC criteria (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan additionalcitationids=\"CR39 CR40 CR41\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e, \u003cspan additionalcitationids=\"CR76\" citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e, \u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e, \u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e, \u003cspan additionalcitationids=\"CR102\" citationid=\"CR101\" class=\"CitationRef\"\u003e101\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e, \u003cspan citationid=\"CR105\" class=\"CitationRef\"\u003e105\u003c/span\u003e, \u003cspan citationid=\"CR108\" class=\"CitationRef\"\u003e108\u003c/span\u003e, \u003cspan citationid=\"CR110\" class=\"CitationRef\"\u003e110\u003c/span\u003e, \u003cspan citationid=\"CR112\" class=\"CitationRef\"\u003e112\u003c/span\u003e). The heterogeneity between studies was very high, in most metanalyses the I\u003csup\u003e2\u003c/sup\u003e was \u0026gt;\u0026thinsp;80%, therefore, the random effects model was selected.\u003c/p\u003e \u003cp\u003eThe overall prevalence of TWI in athletes\u0026thinsp;\u0026gt;\u0026thinsp;16 years according to the Seattle criteria was 6% (95% Confidence Interval -CI-: 4\u0026ndash;7%). Prevalence by anatomical location was 4% (95%CI: 2\u0026ndash;5%), 1% (95%CI: 1\u0026ndash;2%) and 1% (95%CI: 0\u0026ndash;1%) in the anterior, inferior and lateral leads, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Funnel plots are presented in Supplementary Fig.\u0026nbsp;1, Egger\u0026rsquo;s test for funnel plot asymmetry suggested the presence of publication bias or substantial heterogeneity among studies (p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05). When the ESC criteria were applied, the overall prevalence of TWI was slightly lower, at 5% (Supplementary Fig.\u0026nbsp;2). Prevalence by anatomical location was 4%, 1% and 0% in the anterior, inferior and lateral leads, respectively (Supplementary Fig.\u0026nbsp;2).\u003c/p\u003e \u003cp\u003eWhen considering the Seattle criteria, the prevalence of TWI was higher among Black athletes than in Caucasian athletes, both overall (15% vs 4%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), and across all leads (Supplementary Figs.\u0026nbsp;3\u0026ndash;4). Similar findings were observed when other diagnostic criteria were used.\u003c/p\u003e \u003cp\u003eWhen applying the Seattle criteria and stratifying the analysis by sex, women showed a higher overall prevalence compared to men (8% vs. 6%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). This higher prevalence was observed in the anterior leads but not in the inferior or lateral leads (Supplementary Figs.\u0026nbsp;5\u0026ndash;6). This higher prevalence was not observed when using the ESC criteria. Moreover, in the meta-regression analysis when considered sex, region, black ethnicity, and age of the athletes, sex was not a variable that explained the heterogeneity between studies (Supplementary Table\u0026nbsp;3). The meta-regression showed that the higher the percentage of Black athletes and the higher the age of the athletes included in the studies, the higher the prevalence of TWI (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003e3.2.2.-Prevalence of TWI in athletes\u0026thinsp;\u0026le;\u0026thinsp;16 years\u003c/h2\u003e \u003cp\u003eTo analyse the prevalence of TWI in young athletes (\u0026le;\u0026thinsp;16 years/18 years), 29 studies were included (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan additionalcitationids=\"CR55\" citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e, \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e, \u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e, \u003cspan additionalcitationids=\"CR67 CR68 CR69 CR70 CR71\" citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e, \u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e, \u003cspan citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e, \u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003e). Of these, 19 studies reported the prevalence of juvenile TWI (V1-V3), which was 6%. Additionally, 17 studies provided data on TWI in other specific locations (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e, \u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan additionalcitationids=\"CR71\" citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e, \u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e) showing prevalences of 2% in the extended anterior leads, 1% in the inferior leads, and 0% in the lateral leads (Supplementary Fig.\u0026nbsp;6).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e \u003ch2\u003e3.2.3.-Prevalence of TWI in athletes vs non-athletes (Question 1-b)\u003c/h2\u003e \u003cp\u003eFor this analysis, the diagnostic criteria for TWI used in each study (Seattle, ESC, or other) were considered. A total of 14 studies were included in this analysis (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e, \u003cspan citationid=\"CR102\" class=\"CitationRef\"\u003e102\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe presence of TWI in any lead was more frequent in athletes compared to non-athletes, with a PR of 1.49 (95% CI: 1.13\u0026ndash;1.97) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e-A). Specifically, TWI in the inferior leads was more prevalent among athletes (PR\u0026thinsp;=\u0026thinsp;1.70; 95% CI: 1.23\u0026ndash;2.35). However, the differences in TWI prevalence in the anterior and lateral leads were not statistically significant (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). A sensitivity analysis excluding studies in which the prevalence of TWI was 0% in either athletes or non-athletes yielded consistent results (data not shown).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section3\"\u003e \u003ch2\u003e3.2.4.-Risk of bias assessment question 1\u003c/h2\u003e \u003cp\u003eThe qualitative assessment of risk of bias is presented in Supplementary Table\u0026nbsp;4. Most concerns were identified in the first two domains, which relate to the definition of the sample selection criteria and the study setting. Among the included studies, 53 were judged adequate, 31 showed some uncertainty, and 26 were considered inadequate.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003e3.3.-Relationship between TWI with structural cardiac diseases in athletes (Question 2)\u003c/h2\u003e \u003cp\u003eThirty-five studies assessed the presence of structural cardiomyopathies and included at least 30 athletes with TWI (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In 20 of these studies (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e, \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e, \u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e, \u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e, \u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e, \u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e), the prevalence of structural cardiac disease among athletes with TWI was \u0026lt;\u0026thinsp;1%. Nine studies (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e, \u003cspan citationid=\"CR101\" class=\"CitationRef\"\u003e101\u003c/span\u003e, \u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e, \u003cspan citationid=\"CR122\" class=\"CitationRef\"\u003e122\u003c/span\u003e) reported a prevalence between 1% and 10%, while six studies (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan additionalcitationids=\"CR125\" citationid=\"CR124\" class=\"CitationRef\"\u003e124\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR126\" class=\"CitationRef\"\u003e126\u003c/span\u003e) reported a prevalence exceeding 10%. The most frequently identified structural cardiomyopathies were hypertrophic cardiomyopathy, arrhythmogenic ventricular cardiomyopathy, and dilated cardiomyopathy. Notably, TWI in the lateral leads was most frequently associated with a confirmed diagnosis of cardiomyopathy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003e3.4.-Relationship between TWI with a higher risk of cardiovascular events or sudden cardiac death (Question 3)\u003c/h2\u003e \u003cp\u003eIn studies with long-term follow-up of athletes with TWI, two distinct outcomes were identified: i) the delayed diagnosis of a structural heart disease in athletes who initially presented no detectable pathology, and ii) the occurrence of major adverse cardiovascular events, including SCD, syncope, or ventricular arrhythmias.\u003c/p\u003e \u003cp\u003eThirteen studies evaluated the incidence of newly diagnosed structural heart disease (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e-A). The annual incidence rate ranged from 0 to 54.9 cases per 1,000 athletes: six studies reported no new diagnoses during the follow-up (\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e, \u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e, \u003cspan citationid=\"CR123\" class=\"CitationRef\"\u003e123\u003c/span\u003e, \u003cspan citationid=\"CR125\" class=\"CitationRef\"\u003e125\u003c/span\u003e), five studies reported an incidence between 0.1 and 10 cases per 1,000 athletes per year (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e, \u003cspan citationid=\"CR127\" class=\"CitationRef\"\u003e127\u003c/span\u003e), and two studies reported an incidence of 33.3 and 54.9 cases per 1,000 athletes per year (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR128\" class=\"CitationRef\"\u003e128\u003c/span\u003e). Consistent with previous findings, the most commonly diagnosed conditions were hypertrophic cardiomyopathy, arrhythmogenic ventricular cardiomyopathy, and dilated cardiomyopathy. These new diagnoses were most frequently related to the presence of TWI in the lateral leads.\u003c/p\u003e \u003cp\u003eTwenty-one studies analysed the incidence of major cardiovascular events among athletes with TWI (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e-B). The reported annual incidence rate ranged from 0 to 83.33 events per 1,000 athletes per year. Seventeen studies reported no events during the follow-up (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e, \u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e, \u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e, \u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e, \u003cspan citationid=\"CR123\" class=\"CitationRef\"\u003e123\u003c/span\u003e, \u003cspan citationid=\"CR125\" class=\"CitationRef\"\u003e125\u003c/span\u003e, \u003cspan citationid=\"CR127\" class=\"CitationRef\"\u003e127\u003c/span\u003e, \u003cspan citationid=\"CR128\" class=\"CitationRef\"\u003e128\u003c/span\u003e), while four studies reported incidence rates of 1.37 (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), 2.24 (\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e), 32.97 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), and 83.33 (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e) events per 1,000 athletes per year.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this systematic review, the prevalence of TWI in athletes ranged from 5% to 6%, depending on the diagnostic criteria applied. TWI most frequently involved the anterior leads and was more common in Black athletes. Its prevalence was higher in athletes than in non-athletes. A minority of athletes with TWI were diagnosed with an underlying structural cardiomyopathy, with the likelihood of such a diagnosis increasing when TWI affected the lateral leads. In most studies, the prognosis of TWI in athletes was favourable, with a very low incidence of cardiovascular events reported during follow-up.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section2\"\u003e \u003ch2\u003e4.1.-Prevalence of TWI in athletes\u003c/h2\u003e \u003cp\u003eIn this study we report that the prevalence of TWI is 49% higher in athletes than in non-athletes. However, TWI is considered an abnormal ECG finding, with certain exceptions, such as in Black athletes and in athletes younger than 16 years, when TWI affects the anterior leads (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The results of our metanalysis indicate that the prevalence of TWI in athletes is 5\u0026ndash;6%, depending on the diagnostic criteria applied, and it predominantly affects the anterior leads. There is considerable heterogeneity among studies, with some reporting a prevalence of 0%, while others report prevalences exceeding 20%. While some of this heterogeneity may be explained by differences in the diagnostic criteria considered, the results of our meta-regression indicated that the ethnicity, region, and age of the athletes explained 40% of the heterogeneity among studies. Other factors that could also contribute are inconsistent definition of \u0026ldquo;athlete\u0026rdquo; -affecting the volume and intensity of training-, differences in participant selection criteria across studies, and variability in the level of expertise in ECG interpretation in athletes.\u003c/p\u003e \u003cp\u003eThe higher prevalence of TWI among athletes of Black ethnicity has been attributed to a combination of genetic, endocrine, and haemodynamic factors (\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e). Furthermore, Black individuals tend to have increased myocardial wall thickness and greater left ventricular mass compared to White individuals (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e), and this increased ventricular mass has been associated with a higher prevalence of TWI (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR110\" class=\"CitationRef\"\u003e110\u003c/span\u003e, \u003cspan citationid=\"CR128\" class=\"CitationRef\"\u003e128\u003c/span\u003e). Interestingly, the geographical origin of athletes has also been recently related to the frequency of repolarization abnormalities, which are significantly more common among West (6.4%) and Middle African (8.5%) athletes than among those from East (1.5%) and North Africans (\u0026lt;\u0026thinsp;1%) (\u003cspan citationid=\"CR110\" class=\"CitationRef\"\u003e110\u003c/span\u003e). Several studies have reported a positive correlation between the intensity of training, the duration of participation in high-performance programmes, or the level of physical fitness, and the prevalence of TWI (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e, \u003cspan citationid=\"CR105\" class=\"CitationRef\"\u003e105\u003c/span\u003e, \u003cspan citationid=\"CR112\" class=\"CitationRef\"\u003e112\u003c/span\u003e). In addition, inter-observer variability and differences in expertise in the interpretation of athletes\u0026rsquo; ECG may introduce bias in the assessment of TWI (\u003cspan citationid=\"CR129\" class=\"CitationRef\"\u003e129\u003c/span\u003e). To address this issue, various initiatives, such as in-person and online training courses (\u003cspan citationid=\"CR130\" class=\"CitationRef\"\u003e130\u003c/span\u003e), have been implemented to enhance medical education and proficiency in ECG interpretation in the context of athletic population.\u003c/p\u003e \u003cp\u003eThe mechanisms underlying the presence of TWI in athletes are diverse and include: i) ventricular remodelling. For instance, the papillary muscle/left ventricular mass ratio\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;3.5%, the apical displacement of the papillary muscle, or both have been related to the presence of lateral TWI (\u003cspan citationid=\"CR125\" class=\"CitationRef\"\u003e125\u003c/span\u003e). Moreover, lateral displacement of the right ventricle or the cardiac apex toward the left axilla has been also associated with progressive TWI in the anterior leads (\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e, \u003cspan citationid=\"CR131\" class=\"CitationRef\"\u003e131\u003c/span\u003e); ii) structural variants, some authors have associated anterior TWI with the presence of false tendons in the left ventricle (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e); iii) neuroanatomical changes, such as increased vagal tone (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), which activates the acetylcholine-controlled potassium channel (I\u003csub\u003eK\u0026minus;ACh\u003c/sub\u003e), reducing the action potential gradient between the epicardium and endocardium. This change may affect the vectorcardiogram of repolarisation and contribute to the appearance of TWI (\u003cspan citationid=\"CR132\" class=\"CitationRef\"\u003e132\u003c/span\u003e); iv) myocardial ischaemia. Cardiac repolarisation initiates in the epicardium and terminates in the endocardium, reflected in a positive T wave due to the shorter duration of the action potential in the epicardium relative to the endocardium (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In ischemic conditions, reduced endocardial repolarisation time can diminish this gradient, potentially inverting the repolarisation vector and resulting in TWI (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe presence of anterior TWI is more frequently observed in athletes under the age of 16 (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e). This finding has been associated with the right ventricular dominance during early adolescence (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e, \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e). After the age of 16, anterior TWI generally tends to regress.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003e4.2.-TWI and structural cardiomyopathy at the diagnosis or the follow-up\u003c/h2\u003e \u003cp\u003eThe presence of TWI requires ruling out several cardiac pathologies associated with SCD, including hypertrophic cardiomyopathy, arrhythmogenic ventricular cardiomyopathy, dilated cardiomyopathy, myocarditis, atherosclerotic coronary artery disease, long QT syndrome, and Brugada syndrome (\u003cspan citationid=\"CR102\" class=\"CitationRef\"\u003e102\u003c/span\u003e). Additionally, other conditions include electrolyte imbalances (such as potassium or magnesium deficiencies), certain drugs, and congenital cardiac defects (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn our review, we selected 35 studies comprising\u0026thinsp;\u0026ge;\u0026thinsp;30 athletes with TWI in which the presence of structural cardiomyopathies was specifically evaluated. In 20 of these studies, the reported prevalence of cardiomyopathy was below 1%, whereas six studies reported prevalences exceeding 10% (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan additionalcitationids=\"CR125\" citationid=\"CR124\" class=\"CitationRef\"\u003e124\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR126\" class=\"CitationRef\"\u003e126\u003c/span\u003e). The higher prevalence observed in these latter studies may be attributable to deeper TWI (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), predominance in the lateral leads (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan citationid=\"CR125\" class=\"CitationRef\"\u003e125\u003c/span\u003e) and the use of cardiac magnetic resonance (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR125\" citationid=\"CR124\" class=\"CitationRef\"\u003e124\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR126\" class=\"CitationRef\"\u003e126\u003c/span\u003e), which has greater sensitivity than echocardiography for detecting structural cardiac abnormalities (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR133\" class=\"CitationRef\"\u003e133\u003c/span\u003e). The limited sample sizes may also have contributed to the heterogeneity across studies.\u003c/p\u003e \u003cp\u003eWhen analysing by location, TWI in the lateral leads is most suggestive of underlying structural heart disease (\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e), most commonly hypertrophic cardiomyopathy, particularly when the inversion is \u0026ge;\u0026thinsp;2mm and accompanied by ST segment depression (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e, \u003cspan citationid=\"CR102\" class=\"CitationRef\"\u003e102\u003c/span\u003e, \u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e, \u003cspan citationid=\"CR133\" class=\"CitationRef\"\u003e133\u003c/span\u003e). Furthermore, normalization of TWI during exercise testing has been reported as a favourable prognostic indicator (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR134\" class=\"CitationRef\"\u003e134\u003c/span\u003e). However, Zorzi et al. (\u003cspan citationid=\"CR135\" class=\"CitationRef\"\u003e135\u003c/span\u003e) have shown that patients with overt arrhythmogenic ventricular cardiomyopathy may also exhibit normalization of T-waves during exercise, thereby questioning the prognostic value of this finding.\u003c/p\u003e \u003cp\u003eAn additional important consideration is that the absence of detectable structural abnormalities at the time of the exploration does not exclude the possibility of future development of cardiomyopathy. TWI may represent an early phenotypic expression manifestation of an underlying condition that precedes structural abnormalities detectable via imaging by several years (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR102\" class=\"CitationRef\"\u003e102\u003c/span\u003e). In this review, while half of the studies with follow-up data (6 out of 12) did not report any new cardiac diagnosis, the remainder reported incidence rates of newly diagnosed cardiomyopathies ranging from 1 to 7 per 1,000 athletes per year. One study reported an incidence of 54.9 new diagnoses per 1,000 athletes per year (5 new cases in 91 athletes followed up for 1 year). This study employed a standardised follow-up protocol, including routine cardiac magnetic resonance, underscoring the relevance of comprehensive evaluation for ruling out structural cardiomyopathies. Indeed, recent guidelines recommend the use of CMR in the diagnosis process of these pathologies (\u003cspan citationid=\"CR136\" class=\"CitationRef\"\u003e136\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec25\" class=\"Section2\"\u003e \u003ch2\u003e4.3.-TWI and clinical cardiovascular events\u003c/h2\u003e \u003cp\u003eThe incidence of clinical cardiovascular events in athletes with TWI is very rare. Only one study reported a high incidence (83.3 events per 1,000 athletes per year), but this finding was based on a small sample of six athletes with TWI followed over two years, during which a single case of SCD occurred (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). The clinical relevance of TWI should also be contextualised with the family (SCD) and personal history (syncope) of the athlete.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section2\"\u003e \u003ch2\u003e4.4.-Strengths and limitations\u003c/h2\u003e \u003cp\u003eThis represents the most comprehensive systematic review to date aimed at determining the prevalence of TWI in athletes and its prognostic significance. However, several limitations affecting comparability across studies must be acknowledged: i) the criteria used to define the presence of TWI vary among studies; ii) participant inclusion criteria differ widely, particularly in terms of age, ethnicity, sex, training intensity, and type of sport, \u0026hellip;); iii) there is considerable variability in the diagnostic modalities employed to identify underlying cardiomyopathies.\u003c/p\u003e \u003c/div\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eTWI is more common in athletes than in non-athletes, although its overall prevalence remains low, there is substantial heterogeneity across studies. It is observed more frequently in individuals of Black ethnicity. While TWI may represent an adaptive response to sport-induced ventricular remodelling, it can also be indicative of underlying structural heart disease. Accurate identification and thorough evaluation, particularly through advanced imaging modalities such as magnetic resonance imaging, are essential for appropriate clinical management. Overall, the clinical prognosis of athletes with TWI is favourable, with a very low incidence of cardiovascular events.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCI: Confidence Interval\u003c/p\u003e \u003cp\u003eECG: Electrocardiogram\u003c/p\u003e \u003cp\u003eESC: European Society of Cardiology\u003c/p\u003e \u003cp\u003eJBI: Joanna Briggs Institute\u003c/p\u003e \u003cp\u003eMeSH: Medical Subject Headings\u003c/p\u003e \u003cp\u003ePICOS: Population, Intervention, Comparator, Outcome, and Study Design\u003c/p\u003e \u003cp\u003ePRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses\u003c/p\u003e \u003cp\u003eSCD: Sudden Cardiac Death\u003c/p\u003e \u003cp\u003eSE: Standard Error\u003c/p\u003e \u003cp\u003eTWI: T-wave inversion\u003c/p\u003e \u003cp\u003e"},{"header":"Declarations","content":"\u003cp\u003e- Ethics approval and consent to participate: Not applicable.\u003c/p\u003e\n\u003cp\u003e- Consent for publication: All the authors have approved the final version of the manuscript and have consent for publication.\u003c/p\u003e\n\u003cp\u003e-Availability of data and material: Data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review are available upon request to the corresponding author.\u003c/p\u003e\n\u003cp\u003e-Competing interests: The authors declare no competing financial interests.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;-Funding: This research was partially funded by CIBERCV (Instituto de Salud Carlos III)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e-Authors\u0026apos; contributions:\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eSubstantial contributions to the conception or design of the work: JC-B, RE\u003c/li\u003e\n \u003cli\u003eAcquisition: JS, JC-B, RE\u003c/li\u003e\n \u003cli\u003eAnalysis: JS, RE\u003c/li\u003e\n \u003cli\u003eInterpretation of data for the work:\u0026nbsp;JS, JC-B, HV, LC, SM, AB, RE\u003c/li\u003e\n \u003cli\u003eDrafting the work: JS, RE\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eReviewing it critically for important intellectual content:\u0026nbsp;JC-B, HV, LC, SM, AB\u003c/li\u003e\n \u003cli\u003eFinal approval of the version to be published:\u0026nbsp;JS, JC-B, HV, LC, SM, AB, RE\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAgreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved:\u0026nbsp;JS, JC-B, HV, LC, SM, AB, RE\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e-Acknowledgements: Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eD\u0026rsquo;Ascenzi F, Valentini F, Pistoresi S, Frascaro F, Piu P, Cavigli L, et al. 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Eur Heart J. 2023;44:3503\u0026ndash;626.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"sports-medicine-open","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"smoa","sideBox":"Learn more about [Sports Medicine-Open](http://sportsmedicine-open.springeropen.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/smoa/default.aspx","title":"Sports Medicine-Open","twitterHandle":"@SpringerOpen","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"T wave inversion, repolarization, prevalence, sudden death, athletes, cardiomyopathies","lastPublishedDoi":"10.21203/rs.3.rs-8638655/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8638655/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eAim:\u003c/strong\u003e T-wave inversions (TWI) are a challenging finding in athletes' electrocardiograms. This study aimed to determine the frequency and prognosis of TWI in athletes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e A systematic review and meta-analysis were conducted following PRISMA guidelines and registered in PROSPERO (CRD42023494038). Data sources were PubMed, Scopus, and Web of Science. We included original research articles reporting on the prevalence or underlying substrates of TWI and providing data on athletes participating in any type of sports, sex, or race. Risk of bias was evaluated using the Joanna Briggs Institute Critical Appraisal Tool for Cross-Sectional Studies. Fixed or random-effects models were used depending on heterogeneity. Sensitivity and subgroup analyses (sex, age, ethnicity, diagnostic criteria) were predefined.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eOf 4,509 articles identified, 115 were selected (258,954 individuals). Substantial heterogeneity was observed among the study results. The global TWI prevalence in athletes \u0026gt; 16 years according to the Seattle criteria was 6% (4%, 1%, and 1% in anterior, inferior, and lateral leads, respectively). Prevalence was higher in Black athletes. TWI was more frequent in athletes than non-athletes (Prevalence ratio=1.49; 95% Confidence Interval: 1.13–1.97). Cardiomyopathy diagnosis among athletes with TWI showed high variability, but in most studies, prevalence was \u0026lt;1%. Acute cardiovascular event incidence was 0 in 16 of 19 studies with clinical follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e TWI is more frequent in athletes than non-athletes but remains low overall. While it may reflect physiological exercise related ventricular remodelling, thorough evaluation is essential to exclude structural heart disease. Cardiovascular event incidence in athletes with TWI is very low.\u003c/p\u003e","manuscriptTitle":"T-wave inversions in athletes: frequency and prognostic significance. 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