Aims Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden death in young athletes, and substantial interest persists in strategies for timely identification. We assessed the diagnostic efficacy of Italian pre-participation screening programme with 12-lead ECG (in addition to history and physical examination) for identification of HCM.
Methods and results Four thousand four hundred and fifty members of the Italian national teams, initially judged eligible for competition as a result of systematic pre-participation screening across Italy, subsequently underwent clinical and echocardiographic examination at the Institute of Sports Medicine and Science (Rome) to assess the presence of previously undetected HCM. None of the 4450 athletes showed clinical evidence of HCM. Other cardiac abnormalities were detected in only 12 athletes, including myocarditis (n=4), mitral valve prolapse (n=3), Marfan's syndrome (n=2), aortic regurgitation with bicuspid valve (n=2), and arrhythmogenic right ventricular cardiomyopathy (n=1). In addition, echocardiography identified four athletes with borderline left ventricular wall thickness (i.e. 13 mm) in the ‘grey zone’ of overlap between HCM and athlete's heart. In two of these athletes, subsequent genetic analysis or clinical changes over an average 8-year follow-up resulted, respectively, in a definitive or possible diagnosis of HCM.
Conclusion The Italian national pre-participation screening programme including 12-lead ECG appears to be efficient in identifying young athletes with HCM, leading to their timely disqualification from competitive sports. These data also suggest that routine echocardiography is not an obligatory component of broad-based screening programmes designed to identify young athletes with HCM.
Sudden and unexpected deaths in young competitive athletes are uncommon but highly visible events, which consistently raise concern and ethical issues in both the lay public and medical community.1,2 Hypertrophic cardiomyopathy (HCM) has been repeatedly reported as a leading cause of the athletic field deaths and is responsible for more than one-third of all such sudden deaths in the USA2–5 However, the frequency of sudden death in young athletes due to HCM appears to be much lower in Italy.6,7
It has been hypothesized that this paradox is the consequence of the timely identification of young individuals with HCM by national pre-participation screening, a unique programme implemented by law in Italy over the last 25 years, which routinely includes the 12-lead ECG, in addition to history and physical examination.8 Therefore, we undertook the present analysis to determine whether the Italian pre-participation screening programme is responsible for the timely identification and disqualification of young athletes with HCM and, consequently, the low prevalence of athletic field deaths due to this disease.
Italian pre-participation screening programme
Systematic pre-participation screening of competitive athletes constitutes an Italian medical programme established by legislation in 1982 and implemented for the last 25 years.8 All citizens participating in organized and competitive sports are required to undergo preventive general medical and cardiovascular evaluation, which routinely includes 12-lead ECG, in addition to personal and family history and physical examination (with measurement of blood pressure). Physicians primarily responsible for pre-participation screening in Italy are licensed specialists in sport medicine, who attend a full-time post-graduate residency programme for 4 years.8
Pre-participation screening evaluations are usually performed in sports clinics and private offices, which are present in virtually all major communities of more than 10 000 population. An estimated population of over 3 million competitive athletes are evaluated annually throughout Italy within this pre-participation screening programme to exclude cardiovascular disease. Athletes judged to be free of cardiovascular disease (or other limiting conditions) obtain a certification of eligibility for competitive sports. In contrast, athletes in whom a suspicion for cardiovascular disease is raised are referred to major clinical centres for the purpose of diagnosis and assessment of eligibility for competitive sports.
In accord with the provision of the Italian National Olympic Committee, those athletes cleared at national pre-participation screening who are considered elite on the basis of their best results may become members of the Italian national teams. Of these elite athletes, about 500 per year are selected, based on their best performances, for referral to the Institute of Sports Medicine and Science in Rome for a medical and physiological evaluation before their participation in national or international events, with a protocol which routinely includes echocardiography.8
During the 9-year period (1990–1998), 4485 elite athletes had been referred consecutively to the Institute of Sport Medicine and Science. Each was regarded as an elite athlete and considered a candidate for national and international competition as a member of the Italian teams on the basis of their past athletic performance. These 4485 athletes had been previously examined within the national pre-participation screening programme in satellite centres throughout Italy, cleared medically, and judged eligible for sport competition. In each, the diagnosis of HCM (or other cardiac disease) had been considered to be excluded, based on history, physical examination, and 12-lead ECG. It was our objective at our institution in Rome to confirm the absence (or verify the presence) of HCM in these athletes by echocardiographic study.
The 4485 athletes were considered eligible for inclusion in our study population and agree to participate in the present investigation. Of these, however, 35 had technically unsatisfactory echocardiograms and were excluded from the present analysis. Therefore, our final study population comprised 4450 athletes.
All athletes were white Italians (with exception of three black Africans), aged 24±6 years (range 9–56), predominantly male (3293 or 74%), with body surface area of 1.2–2.7 m2 (mean 1.9±0.3). Athletes participated in 38 different sports disciplines, most commonly soccer or rowing/canoeing (10% each), gymnastics (7%), tennis (5%), basketball or track and field (4% each), and cycling or alpine skiing (3% each). All had been engaged in intensive training schedule for ≥2 consecutive years (median 7); 1200 (27%) had achieved an international level of recognition, with the remaining 3250 (73%) competing at national level. Selected data from 957 men and 450 women athletes included in this study have been presented as part of prior analyses.9,10
Evaluation at Institute of Sports Medicine and Science
The 4450 athletes were evaluated in our institution from 2 to 8 months (mean 5) after the most recent pre-participation screening examination. Each subject underwent two-dimensional and Doppler echocardiography. In case diagnosis and/or risk stratification could not be resolved definitively by echocardiography, other testing was performed, including cardiac magnetic resonance (n=5), coronary angiography (n=2), myocardial biopsy (n=2), electrophysiological study with programmed ventricular stimulation (n=2), and genetic testing (n=1).
Clinical diagnosis of HCM was based on the echocardiographic evidence of a hypertrophied (wall thickness ≥13 mm), non-dilated left ventricle in the absence of another cardiac or systemic disease that could itself cause hypertrophy of the magnitude present in that patient.5 Differential diagnosis between HCM and physiological left ventricular (LV) hypertrophy (i.e. athlete's heart) was based on morphological and clinical criteria, as previously reported.11
Structural cardiac disease (including HCM) was clinically suspected when certain ECG abnormalities were present, most commonly increased R-wave (i.e. >15 mm in standard lead I and/or >12 mm in aVL and/or >18 mm in precordial leads V5 and V6), depressed ST-segment and/or deep inverted T-waves in precordial and/or peripheral leads, deep (>2 mm) Q-waves in more than two leads, prolonged P-wave duration of 0.12 s in standard leads I or II and inverted P-wave with terminal negativity of >1 mm and ≥0.04 s in duration in lead V1, consistent with left atrial enlargement.12
Cardiac magnetic resonance was performed with a 1.5 T dedicated scanner (Sonata Siemens Medical System) with a torso phased array coil for cardiac imaging. The protocol of CMR study was previously reported.13
Genetic testing for HCM was performed by direct DNA sequencing of the entire coding sequences of the genes more commonly implicated as disease-causing (i.e. MYH7, MYBPC3, TNNT2, TNNI3, TMPI). Analysis was performed by PCR amplification of gene segments; both strands of the segments were then sequenced to identify specific DNA variants. This process analysed the entire coding region of each of the genes examined, including the exon–intron splice junctions encompassing 106 exons.14
Athletes with structural cardiac abnormalities were managed according to the Italian guidelines for competitive sports eligibility,15 closely resembling Bethesda Conference No. 36 and recommendations of the European Society of Cardiology.16,17 Athletes with cardiac disease judged to convey a disproportionate risk for sudden death or disease progression were permanently disqualified from competitive sports. Athletes identified with myocarditis were temporarily withdrawn from training and competition (usually for 6–12 months) according to the current guidelines,16,17 pending complete regression of abnormal findings demonstrable on serial clinical, echocardiographic, and ECG studies. Clinical status was re-assessed in each of these athletes during the last 2 years, either by a re-examination at the Institute of Sport Medicine and Science in Rome or by a telephone interview.
In 4397 of the 4450 athletes (98.8%), the clinical diagnosis of HCM was excluded by echocardiography, based on normal LV wall thicknesses (7–12 mm, mean 9.4±1.2), in the absence of systolic anterior motion (SAM) of the mitral valve and LV outflow obstruction5 (Figure 1).
Flow chart showing the study design and results of echocardiography (and other diagnostic testing) in a large cohort of 4450 competitive athletes previously cleared at the Italian national pre-participation screening programme. CV, cardiovascular; LVH, LV hypertrophy.
Athletes with physiological LV hypertrophy
A subset of 41 athletes showed LV hypertrophy, including 37 (0.8%, all males) with increased LV wall thicknesses (13–15 mm), associated with distinct cavity enlargement (end-diastolic transverse dimension, 55–65 mm); each had also normal LV systolic function (ejection fraction >50%) and diastolic filling pattern, without SAM and LV outflow obstruction.
ECGs were abnormal in 28 (75%) of these athletes, including 21 with increased R and/or S-wave precordial lead voltages (Sokoloff–Lyon index ≥30 mm), seven with deep narrow Q-waves (≥2 mm), six with T-wave inversion, two with abnormal R-wave progression in precordial leads, and in one with left atrial enlargement.
These athletes were engaged predominantly in rowing/canoeing (n=21) and road cycling (n=9) and had achieved an international level of competition. Each was judged to have an expression of physiological LV hypertrophy and cardiac remodelling consistent with athlete's heart.9,11,18 (Figure 1).
Athletes with LV hypertrophy in the grey zone
At initial evaluation, the remaining four athletes (0.1%; three males) had ventricular septal thickness of 13 mm, associated with non-dilated LV cavity (end-diastolic dimension 49–52 mm); each also had normal LV systolic function and diastolic filling pattern, in the absence of SAM or LV outflow obstruction (Table 1).
Demographic, morphological, and clinical findings in four grey zone athletes at initial and most recent evaluation
Max. LV thickness (mm)
Cardiac myosin-binding protein C mutation (E542Q)
Myocardial bridge on distal LAD; NVST
F, female; LA, left atrium; LAD, left anterior descending coronary artery; LVDD, LV diastolic cavity dimension; max, maximum; M, male; NSVT, non-sustained ventricular tachycardia.
ECGs were abnormal in three of these four athletes, showing increased R and/or S-wave lead voltages and T-wave inversion in precordial leads in three and deep narrow Q-waves in one. These athletes were engaged in swimming (n=2), cycling (n=1), and rowing (n=1). Each was considered to be in the overlapping grey zone of LV hypertrophy, consistent with both athlete's heart and non-obstructive HCM.11 (Figure 1).
These four grey zone athletes had serial echocardiographic studies performed over the ensuing 8–12 years. After 8 years of observation (at the age of 28), an international level swimmer (no. 1 in Table 1) showed changes in cardiac dimensions (represented by increase in maximum LV wall thickness from 13 to 15 mm, with reduction of cavity size from 50 to 47 mm). Cardiac magnetic resonance imaging showed asymmetric thickening of anterior ventricular septum (18 mm). Small areas of post-gadolinium delayed hyperenhancement were present in the anterior septum, consistent with fibrosis. LV myocardial biopsy showed cardiac muscle cell disarray and increased interstitial fibrosis. A molecular diagnosis of HCM was established by laboratory detection of a cardiac myosin-binding protein C mutation (E542Q).
After 9-year follow-up (at age 29), second of these athletes (no. 2 in Table 1) developed symptomatic episodes of rapid (220 bpm) non-sustained ventricular tachycardia with exercise; a new evidence of mild SAM was observed at echocardiography and a myocardial bridge of the distal left anterior descending coronary artery was identified by coronary arteriography. These findings, in addition to borderline LV wall thickness of 13 mm, were regarded as consistent with a possible diagnosis of HCM.5,19
These two athletes with definite or possible HCM (nos 1 and 2 in Table 1) were withdrawn from training and competition in accordance with the Italian guidelines, closely resembling European and US recommendations.16,17 The remaining two athletes (nos 3 and 4) were regarded as probably having non-pathological cardiac conditions, based on the absence of changes in clinical profile and cardiac morphology over 8 and 12 years, respectively; no restriction was imposed on their athletic training.
Other cardiac abnormalities
Other structural abnormalities were identified by echocardiography (or additional diagnostic testing) in 12 of the 4450 athletes, most commonly myocarditis (n=4) and mitral valve prolapse (n=3) (Figure 2). Athletes with the Marfan syndrome and arrhythmogenic right ventricular cardiomyopathy (ARVC) were permanently disqualified from competitive sports.16,17 Athletes with myocarditis were temporarily withdrawn from regular training and competition (usually 6–12 months16,17) with serial clinical and echocardiographic assessments until complete regression of abnormal clinical findings. Over a 6±3-year (range 1–12) follow-up period subsequent to their initial disqualification, none of the 12 athletes with cardiac abnormalities found at our institute experienced symptoms or adverse cardiac events.
Cardiovascular diseases unsuspected by national pre-participation screening, but identified for the first time by echocardiography (and other testing) at the Institute of Sports Medicine and Science. MVP, mitral valve prolapse.
Sudden death in young athletes is a highly visible event, which continues to generate substantial interest and debate in the lay and medical communities,1,2 particularly with regard to the feasibility and efficacy of large population pre-participation screening,20–23 and criteria for selective withdrawal from competition of individuals at risk.16,17 Several investigations have clarified the spectrum of pathological conditions responsible for athletic field deaths, with HCM the most common in the USA and responsible for about one-third of all such events occurring during sport participation.2–5
In contrast, the number of athletic field deaths due to HCM in Italy is negligible,6,7 despite a prevalence of the disease in the general population apparently similar to that in other countries.24–28 This apparent paradox is believed to be consequence of the national pre-participation screening programme, introduced by law and implemented in Italy for more than 25 years.8 To establish evidence for this hypothesis, the present investigation was designed, in which a large cohort of about 4500 young competitive athletes who received medical clearance for sports participation at national pre-participation screening were subsequently re-evaluated with echocardiography at the Institute of Sport Medicine and Science in Rome.
On the basis of the known prevalence of the HCM phenotype identified by echocardiographic surveys in large diverse population studies (i.e. 0.1–0.2%),24–27 we assumed that five to 10 athletes would have been identified with HCM in our large cohort, if previous national pre-participation screening had been ineffective in detecting this disease. However, our study showed that despite careful and expert clinical and echocardiographic investigation, no unequivocal cases of HCM were recognized among the substantial number of athletes cleared at national pre-participation screening. Therefore, we conclude that the 12-lead ECG, as a routine element in the Italian national screening programme (in addition to history and physical examination), is effective in leading to the diagnosis of HCM, which may ultimately result in the prudent disqualification of athletes from competition according to the current consensus guidelines.15–17
Therefore, our findings also infer that echocardiography is not absolutely necessary as a routine diagnostic test for the detection (or suspicion) of HCM in a broad-based population screening programme. However, we also recognize that echocardiography did identify in this cohort a variety of cardiovascular diseases, which were not reliably predicted by ECG alone, including most commonly mitral valve prolapse and myocarditis, Marfan' syndrome, and ARVC.
Of particular note are the four athletes initially considered to represent the overlapping grey zone between HCM and physiological LV hypertrophy of the athlete's heart.11 These athletes were cleared at pre-participation screening, with ECG abnormalities that were judged to be innocent expressions of the athlete's heart,12 consistent with their level of athletic training and not an indicator, per se, for disqualification based on European consensus guidelines.16,17 However, after serial echocardiographic testing and long-term observation over an average 8-year period, we were eventually able to make an unequivocal diagnosis of HCM in one of these athletes, by genetic testing, a methodology not available when this individual was initially evaluated. Another athlete had only equivocal findings supporting the diagnosis of HCM most recently,5 whereas two others did not develop morphological and clinical features of this disease over the long follow-up period.
Clinical diagnosis of HCM may be difficult in young people, given that LV remodelling typically evolves over time and hypertrophy may be delayed even into adulthood.29,30 Indeed, this could explain the diagnostic scenario in our young athletes, in whom the clinical and phenotypic expressions of HCM were preceded over long periods of time by only ECG alterations.29–31 Although genetic testing could have resolved diagnosis earlier in such athletes, substantial obstacles nevertheless persist for translating DNA-based laboratory methods into routine clinical practice.30 Therefore, diagnosis of HCM was possible only after prolonged periods of observation. For these reasons, athletes in the borderline grey zone between athlete's heart and HCM,11 although not necessarily disqualified from competition, nevertheless deserve continued clinical surveillance.
It is important to emphasize that the present study design was confined to those athletes who were previously judged to be free of cardiovascular disease at the national pre-participation screening assessment. We do not have access to data describing those athletes suspected to have (or documented with) cardiac abnormalities as a result of the screening programme (i.e. the positive test results). Therefore, in this study, we are not able to resolve issues related to true-positive and false-positive screening for HCM.
In conclusion, the present cohort study provides a measure of clarity to several issues surrounding the complex strategy of screening large populations of young competitive athletes for HCM. From our data, based on a large population of about 4500 trained athletes, it appears that the national pre-participation screening programme implemented in Italy with 12-lead ECG (in addition to history and physical examination) is effective in identifying HCM, thereby leading to the disqualification of these athletes from competitive sports. Our findings also suggest that routine echocardiography is not an absolutely necessary component of such large-scale screening programmes designed to recognize HCM in young athletes.
. Cardiac disease in young trained athletes: insights into methods for distinguishing athlete's heart from structural heart disease, with particular emphasis on hypertrophic cardiomyopathy. Circulation 1995;91:1596-1601.
. Recommendations for competitive sports participation in athletes with cardiovascular disease. A consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology, and the Working Group of Myocardial and Pericardial diseases of the European Society of Cardiology. Eur Heart J 2005;26:1422-1445.
. Cardiovascular preparticipation screening of competitive athletes. A statement for health professionals for the Sudden Death Committee (Clinical Cardiology) and Congenital Cardiac Defects Committee (Cardiovascular Disease in the Young) American Heart Association Circulation 1996.94:850-856.
. Does sport activity enhance the risk of sudden death in adolescents and young adults? J Am Coll Cardiol 2003;42:1959-1963.
. Cardiovascular pre-participation screening of young competitive athletes for prevention of sudden death: proposal for a common European protocol. Consensus Statement of the Study Group of Sport Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005;26:516-524.
. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA study. Coronary Artery Risk Development in (Young) Adults. Circulation 1995;92:785-789.