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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 67, NO. 18, 2016 ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2016.02.062 Etiology of Sudden Death in Sports Insights From a United Kingdom Regional Registry Gherardo Finocchiaro, MD,a Michael Papadakis, MBBS, MD,a Jan-Lukas Robertus, MD,b Harshil Dhutia, MBBS,a Alexandros Klavdios Steriotis, MD, PHD,a Maite Tome, MD, PHD,a Greg Mellor, MBCHB,a Ahmed Merghani, MBBS,a Aneil Malhotra, MBBCHIR,a Elijah Behr, MBBS, MD,a Sanjay Sharma, MBCHB, MD,a Mary N. Sheppard, MBBCH, BAO, MDb ABSTRACT BACKGROUND Accurate knowledge of causes of sudden cardiac death (SCD) in athletes and its precipitating factors is necessary to establish preventative strategies. OBJECTIVES This study investigated causes of SCD and their association with intensive physical activity in a large cohort of athletes. METHODS Between 1994 and 2014, 357 consecutive cases of athletes who died suddenly (mean 29 11 years of age, 92% males, 76% Caucasian, 69% competitive) were referred to our cardiac pathology center. All subjects underwent detailed post-mortem evaluation, including histological analysis by an expert cardiac pathologist. Clinical information was obtained from referring coroners. RESULTS Sudden arrhythmic death syndrome (SADS) was the most prevalent cause of death (n ¼ 149 [42%]). Myocardial disease was detected in 40% of cases, including idiopathic left ventricular hypertrophy (LVH) and/or fibrosis (n ¼ 59, 16%); arrhythmogenic right ventricular cardiomyopathy (ARVC) (13%); and hypertrophic cardiomyopathy (HCM) (6%). Coronary artery anomalies occurred in 5% of cases. SADS and coronary artery anomalies affected predominantly young athletes (# 35 years of age), whereas myocardial disease was more common in older individuals. SCD during intense exertion occurred in 61% of cases; ARVC and left ventricular fibrosis most strongly predicted SCD during exertion. CONCLUSIONS Conditions predisposing to SCD in sports demonstrate a significant age predilection. The strong association of ARVC and left ventricular fibrosis with exercise-induced SCD reinforces the need for early detection and abstinence from intense exercise. However, almost 40% of athletes die at rest, highlighting the need for complementary preventive strategies. (J Am Coll Cardiol 2016;67:2108–15) © 2016 by the American College of Cardiology Foundation. S udden cardiac death (SCD) is a tragic event that post-mortem examination performed by an experi- occasionally affects apparently healthy indi- enced cardiac pathologist. A recent study comparing viduals (1), including young (#35 years of the interpretation of autopsy findings between a age) athletes (2–5). A spectrum of cardiac diseases is referring pathologist and a specialist cardiac patholo- implicated in SCD, with variable prevalence depend- gist demonstrated a 40% disparity with respect to ing on the age and other demographics of the actual cause of death (7). cohort (6). Many reports regarding the causes of Knowledge of precise causes and precipitating SCD in athletes are limited by the lack of a detailed factors of SCD may influence national strategies to Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster. From the aCardiovascular Sciences Research Centre, St. George’s, University of London, London, United Kingdom; and the b Cardiovascular Pathology Department, St. George’s, University of London, London, United Kingdom. Dr. Behr has received research funds from Biotronik and St. Jude Medical; and fellowship support from McColl’s Retail Group. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Sharma and Sheppard are joint senior authors. Manuscript received December 11, 2015; revised manuscript received February 12, 2016, accepted February 26, 2016. Finocchiaro et al. JACC VOL. 67, NO. 18, 2016 MAY 10, 2016:2108–15 2109 Sudden Death in Athletes prevent such events, including pre-participation conducted in all cases in accordance with the ABBREVIATIONS screening methods and widespread availability of usual investigation of sudden and unex- AND ACRONYMS automated pected participation external defibrillators screening with (AEDs). Pre- deaths in the United Kingdom. electrocardiography Comprehensive macroscopic examination of (ECG) is useful for detecting quiescent inherited car- the whole heart and histological analysis diac diseases, particularly inherited cardiomyopa- were performed in accordance with guide- thies, and ion-channelopathies but has limited value lines on “Autopsy practice for sudden death AED = automatic external defibrillator ARVC = arrhythmogenic right ventricular cardiomyopathy CAD = coronary artery disease in detecting athletes with coronary artery disease with likely cardiac pathology” of the Royal (CAD). AEDs appear to be more effective in the College of Pathologists (10) and the Associa- cardiomyopathy termination of arrhythmias in athletes with CAD or tion for European Cardiovascular Pathology LV = left ventricular coronary artery anomalies than in athletes with car- (11). All cardiac structures were systemati- LVH = left ventricular diomyopathy (8,9). cally examined. Heart weight was recorded in hypertrophy grams, and ventricular wall thickness and SADS = sudden arrhythmic SEE PAGE 2116 The objective of this study was to investigate the HCM = hypertrophic internal cavity dimensions were measured at death syndrome mid-ventricular level, excluding the papillary SCD = sudden cardiac death causes and circumstances of SCD in a large cohort of muscles and fat. A minimum of 10 blocks of tissue athletes, as determined by post-mortem examination were taken for histological analysis as reported pre- performed by an expert cardiac pathologist. METHODS The Cardiac Risk in the Young (CRY) center for cardiac pathology is located at St. George’s University of London. The center is led by an expert cardiac pathologist (M.N.S.) and receives over 400 whole hearts from cases of SCD across the United Kingdom annually. General pathologists are likely to refer to the CRY center when the clinical history is suggestive of inherited cardiac disease, especially when the viously (6,7). Sections of myocardium were fixed in formalin, embedded in paraffin, and stained with hematoxylin and eosin and with elastic Van Gieson stain to highlight myocardial fibrosis. Criteria for defining specific cardiac pathologies have been previously described (6,12) and are summarized in Table 1. Sudden arrhythmic death syndrome (SADS) was a diagnosis of exclusion, defined as a structurally normal heart with no evident abnormality on macroscopic and histological evaluation and a negative result for toxicology screening (13–15). death affects a young or athletic individual or when CLINICAL INFORMATION. The referring coroner and the cause of death is uncertain after the initial pathologist were asked to complete a questionnaire autopsy. regarding the demographics of the deceased, medical STUDY POPULATION. We retrospectively reviewed history, family history, cardiac symptoms, nature and cases from a database of 3,684 cases of SCD referred level of physical activity, and exact circumstances of to the CRY center for cardiac pathology between 1994 death. Data were derived from a number of sources and 2014. SCD was defined as death occurring within including: interviews with the family of the deceased, 12 h of apparent wellbeing. We retrieved a sub- potential witnesses to the SCD, and reports from the group of 357 cases (9.7%) of individuals who had deceased’s family physician. Data were collected engaged in regular sport activities, defined as >3 h of prospectively and stored in an electronic database. organized physical training per week. The majority STATISTICAL (84%) of referrals occurred between 2004 and 2014. performed using PASW version 18.0 software (PASW, ANALYSIS. Statistical analysis was Competitive athletes were defined as those who were Inc., Chicago, Illinois). Results are mean SD for involved in organized sports requiring participation continuous variables or numbers of cases and per- in regular, formal competition. Circumstances of centages for categorical variables. Comparison of death were subdivided broadly into death occurring groups was performed using Student t test for during exercise and death during rest or sleep. continuous variables with correction for unequal POST-MORTEM EXAMINATION. All SCD cases under- variance when necessary and chi-square test or Fisher went a full post-mortem evaluation by the local exact test, as appropriate for categorical variables. pathologist. Following the exclusion of extra-cardiac Univariate and multivariate logistic regression ana- causes, the heart was sent to our center after writ- lyses were used to determine the factors associated ten consent of the coroner and the family of the with death during exertion. Age, sex, and variables deceased. The local pathologist also performed an that were univariately correlated with the dependent initial cardiac autopsy before referring the heart in variable were selected and entered into the forward 58% of cases. A thorough toxicology screen was stepwise multiple regression model. 2110 Finocchiaro et al. JACC VOL. 67, NO. 18, 2016 MAY 10, 2016:2108–15 Sudden Death in Athletes T A B L E 1 Pathological Macroscopic and Microscopic Criteria Defining Main Underlying Diseases Pathology participating in regular training and competition in team (n ¼ 155 [43%]) or individual (n ¼ 90 [26%]) sports. The rest of the cohort (n ¼ 112 [31%]) consisted of Macroscopic Criteria Microscopic Criteria Left ventricular wall thickness >15 mm circumferentially or focally and/or heart weight >500 g*† Myocyte hypertrophy, myocyte disarray (>20% of myocardial disarray in at least 2 tissue blocks of 4 cm2), and interstitial fibrosis Idiopathic left ventricular hypertrophy Left ventricular wall thickness >15 mm and heart weight >500 g* Myocyte hypertrophy with or without fibrosis in the absence of myocyte disarray rugby (n ¼ 19 [5%]), tennis (n ¼ 6 [2%]), golf (n ¼ 6 [2%]), Idiopathic left ventricular fibrosis Normal heart weight and wall thickness with/without scarring macroscopically Fibrosis (>20% in at least 2 tissue blocks of 4 cm2) with no myocyte disarray (n ¼ 288 [81%]). Of the 69 symptomatic athletes (29%), Arrhythmogenic right ventricular cardiomyopathy Right or left ventricular thinning, fatty replacement, fibrosis on the epicardial surface or outer wall Fat and fibrosis (>20% in at least 2 tissue blocks of 4 cm2) in the wall of the right and/or left ventricle, particularly in outer wall, with degenerative changes in the myocytes Hypertrophic cardiomyopathy Myocarditis Normal or dilated ventricles Anomalous coronary artery Coronary atherosclerosis Dilated cardiomyopathy Mitral valve prolapse Bicuspid aortic valve Inflammation (>20% in at least 2 tissue blocks of 4 cm2) with myocyte necrosis Anomalous origin of the coronary artery, coronary artery atresia, stenosis Fibrosis/acute/chronic infarction in the left ventricle Atherosclerosis with estimated luminal narrowing >75% Acute or chronic infarction in the left ventricle Increase in heart weight (>500 g in males, >400 g in females) with dilated left ventricle (>4 cm) and thin wall (<10 mm). Absence of coronary artery disease. Diffuse interstitial and replacement fibrosis (>20% in at least 2 tissue blocks of 4 cm2) in the left ventricle with degenerative changes in the myocytes Prolapse of mitral valve above the atrioventricular junction with ballooning between chordae in one or both leaflets Myxoid degeneration with expansion in spongiosa of leaflets and destruction of fibrosa layer Normal running (n ¼ 92 [25%]; 40 participating in half-marathons and marathons), football (n ¼ 91 [25%]), cycling (n ¼ 30 [8%]), gymnastics (n ¼ 30 [8%]), swimming (n ¼ 22 [6%]), weightlifting (n ¼ 20 [6%]), boxing (n ¼ 5 [1%]), and other sports (n ¼ 36 [10%]). The majority of the athletes were asymptomatic 27 (8%) had palpitations, 20 (6%) had chest pain, 18 (5%) had syncope, and 4 (1%) reported decreased exercise tolerance. Five patients experienced palpitations due to paroxysmal atrial fibrillation, including 1 in the context of Wolff-Parkinson-White syndrome. One athlete received a diagnosis of myocarditis 4 years before death, and 1 athlete was hospitalized 4 months prior to death for suspected myocarditis. There was a family history of premature sudden death (defined as death of a first-degree relative <50 years of age) in 28 cases (8%). The main comorbidities were asthma (n ¼ 28%, 8%), epilepsy (n ¼ 5, 1%), and treated arterial hypertension (n ¼ 4, 1%). CAUSES. The main causes of death are shown in the Central Illustration. A normal post-mortem indicative of SADS was the most common finding and accounted for 149 deaths (42%). Myocardial disease was present in 130 cases (35%). Among these cases, idiopathic left ventricular hypertrophy (LVH) and/or fibrosis accounted for 59 deaths (16%), followed by arrhythmogenic right ventricular cardiomyopathy (ARVC) (n ¼ 48 [13%]), and hypertrophic cardiomyopathy (HCM) (n ¼ 23 [6%]). The majority of individuals with ARVC also demonstrated LV involvement, with 17 Fusion of 2 aortic cusps, with or without presence of a raphe often with significant valve stenosis Morphologically normal heart recreational athletes. Sporting disciplines included cases (35%) exhibiting fibrofatty infiltration of the LV and 41 cases (85%) showing evidence of left ventricNormal *Heart weight >400 g in women. †In this cohort, heart weight was normal in 39% of HCM cases. In a small proportion of cases, HCM was diagnosed on the basis of the presence of myocyte hypertrophy, myocardial disarray, and fibrosis on microscopy, despite normal heart weight and wall thickness on macroscopic evaluation. ular (LV) fibrosis. Coronary artery pathology occurred in 7% of cases, with coronary artery anomalies accounting for the majority of the cases. CAUSES OF DEATH BY AGE AND SEX. The prevalence of specific cardiac pathologies varied with age (Central Illustration). SADS was most common in younger cases RESULTS and showed a reduced trend with increasing age (Figure 1). A structurally normal heart was reported in CLINICAL CHARACTERISTICS. The mean age at death 56% of children and adolescents (<18 years), 44% of of the 357 athletes was 29 11 years (range: 7 to young adults (18 to 35 years of age), and 26% of older 67 years; median: 27 years), with a large male pre- individuals (>35 years of age; p <0.001 comparing <18 dominance (n ¼ 330, 92%). The average body mass in- and >35 years of age; p ¼ 0.004 comparing 18 to 35 dex and body surface area were 25 5 kg/m 2 and 2.2 years of age and those >35 years of age). Coronary ar- 0.4 m 2, respectively. A significant proportion of in- tery anomalies were also more prevalent in younger dividuals were competitive athletes (n ¼ 245 [69%]), individuals, accounting for 11% of deaths in children Finocchiaro et al. JACC VOL. 67, NO. 18, 2016 MAY 10, 2016:2108–15 Sudden Death in Athletes CENTRAL ILLUSTRATION Sudden Death in Athletes: Causes of Sudden Cardiac Death Finocchiaro, G. et al. J Am Coll Cardiol. 2016;67(18):2108–15. Sudden death is shown in the overall population (A), in subjects <18 years of age (B), subjects 18 to 35 years of age (C), and subjects >35 years of age (D). In the overall population, the subgroup classified as “Other” (n ¼ 43) comprised: mitral valve abnormalities/prolapse; n ¼ 7, myocardial infarction with normal coronaries; n ¼ 4, bicuspid aortic valve; n ¼ 3, aortic dissection; n ¼ 3, cocaine/steroid use; n ¼ 2, cardiac sarcoidosis; n ¼ 1, atrium septal defect (ASD). In the remaining 23 cases, the cause of death could not be attributed to a single disease entity or condition and the post-mortem findings were considered of uncertain significance. LVH ¼ left ventricle hypertrophy; RV ¼ right ventricle. and adolescents compared to only 2% in adults >35 Mean heart weight was 421 110 g. Seventy hearts years of age. In contrast, diseases of the myocardium (20%) exhibited an absolute value of >500 g. Of these, were the majority were diagnosed with idiopathic LVH more common in older athletes (Central Illustration). Idiopathic LVH and/or fibrosis was pre- with or without fibrosis (n ¼ 30 [42%]), followed by sent in 10% of individuals <18 years of age and in 26% HCM (n ¼ 13 [19%]), and ARVC (n ¼ 12 [17%]) of those >35 years of age (p ¼ 0.01). ARVC was detected (Figure 1). in only 4% of individuals <18 years of age and in 18% of those >35 years of age (p ¼ 0.009). There were only 27 females in our cohort. The majority (55%) showed a normal heart at post-mortem 2111 2112 Finocchiaro et al. JACC VOL. 67, NO. 18, 2016 MAY 10, 2016:2108–15 Sudden Death in Athletes F I G U R E 1 Heart Weight Distribution in the Overall Cohort 140 Idiopathic LVH/fibrosis 120 Hypertrophic cardiomyopathy 13% 2% 4% Arrhythmogenic RV cardiomyopathy Coronary artery anomaly 1% 42% Coronary atheroma Dilated cardiomyopathy 100 Other 17% 80 19% n 60 n=70 (20%) 40 20 0 100 200 300 400 500 600 Heart Weight 700 800 900 1000 Histogram shows distribution of heart weights in the overall cohort. Individuals with a heart weight $500 g are represented in red columns. Pie chart presents the cause of death in individuals with a heart weight $500 g (n ¼ 70). RV ¼ right ventricle. examination. Idiopathic fibrosis accounted for 11% of and those of athletes who died at rest were similar, deaths, ARVC for 7%, and HCM for 4% of the other and only a minority of subjects (8%) had a family deaths. None of the female athletes showed idio- history of sudden death. Patients who died at rest pathic LVH. were more likely to demonstrate a normal heart at CIRCUMSTANCES OF DEATH. The majority of ath- post-mortem examination (Table 2). Conversely, ath- letes died during exertion (n ¼ 219 [61%]), including a letes who died during exertion were more likely to small proportion of individuals (n ¼ 14 [4%]) who have ARVC (20% vs. 3%, respectively; p < 0.001), LV died during altercation. Of the 138 subjects who died fibrosis (39% vs. 22%, respectively; p < 0.001), and at rest, 47 (34%) died during sleep. The age and sex coronary artery anomalies (7% vs. 1%, respectively; distributions of athletes who died during exertion p ¼ 0.01). Multivariate analysis identified ARVC (hazard ratio [HR]: 6.01; 95% confidence interval [CI]: 1.97 to 18.32; T A B L E 2 Characteristics of the Population According to p ¼ 0.001) as the strongest independent predictor of Circumstances of Death SCD during exercise, followed by LV fibrosis (HR: 2.11; Total (N ¼ 357) Died on Exertion (n ¼ 219) Died at Rest (n ¼ 138) Age, yrs 29 11 29 12 29 11 0.944 Males 326 (92) 201 (92) 125 (91) 0.673 Family history of SD p Value 95% CI: 1.15 to 3.88; p ¼ 0.01) (Table 3). DISCUSSION 28 (8) 17 (8) 11 (8) 0.911 This study reports on a large number of young 421 110 413 107 434 115 0.086 LV fibrosis 85 (39) 30 (22) <0.001 athletes dying suddenly in the United Kingdom for 115 (32) SADS 149 (42) 75 (34) 74 (54) <0.001 Heart weight, g HCM 23 (6) 13 (6) 10 (7) 0.237 ARVC 48 (13) 44 (20) 4 (3) <0.001 ILVH and/or fibrosis 59 (16) 34 (15) 25 (18) Coronary artery anomaly 18 (5) 16 (7) Coronary artery atheroma 8 (2) 6 (3) whom all post-mortem examinations were conducted by a cardiac pathologist with expertise in conditions predisposing to SCD. In comparison to a smaller study 0.548 published by our group (6), the large sample size of 2 (1) 0.01 almost 70% competitive athletes allowed for a greater 2 (1) 0.521 degree of certainty relating to the impact of specific Values are mean SD or n (%). ARVC ¼ arrhythmogenic right ventricular cardiomyopathy; HCM ¼ hypertrophic cardiomyopathy; ILVH ¼ idiopathic left ventricular hypertrophy; LV ¼ left ventricular; SADS ¼ sudden arrhythmic death syndrome; SD ¼ sudden death. pathologies associated with SCD during intensive exercise. CAUSES OF SCD IN ATHLETES. In agreement with our earlier study (6) and with studies in U.S. Finocchiaro et al. JACC VOL. 67, NO. 18, 2016 MAY 10, 2016:2108–15 Sudden Death in Athletes collegiate athletes (16) and young military personnel (17), a normal heart indicative of a diagnosis of SADS T A B L E 3 Multivariate Analysis of Death During Exercise Univariate Analysis was present in a significant proportion of athletes. A p Value Male 1.29 (0.58–2.81) 0.534 0.946 structurally normal heart accounted for 42% of the overall cohort in this study, compared to the 23% we reported previously (6). Although the high prevalence Multivariate Analysis Hazard Ratio (95% CI) Hazard Ratio (95% CI) Age at death 0.99 (0.98–1.12) of SADS in our cohort may be partly explained by a Caucasian ethnicity 1.09 (0.43–2.72) 0.85 referral bias, its high prevalence in U.S. cohorts (31% Family history of SD 0.96 (0.43–2.12) 0.93 in collegiate athletes and 41% in young military Competitive athlete 1.13 (0.71–1.8) 0.59 personnel) underscores the importance of inherited LV fibrosis 2.43 (1.48–4.01) <0.001 primary arrhythmia syndromes as a major cause of Heart weight* 0.96 (0.95–0.97) 0.001 SCD in athletes (16,17). ARVC 8.36 (2.93–23.84) <0.001 6.01 (1.97–18.32) Myocardial disease accounted for 40% of cases. Idiopathic LVH and/or fibrosis and ARVC were the Coronary artery anomaly 5.32 (1.20–23.51) 2.11 (1.15–3.88) 0.008 SADS 0.44 (0.29–0.68) 0.002 HCM 0.80 (0.34–1.88) 0.613 predominant diagnoses. The significance of idiopathic LVH is uncertain. The entity may be an innocent bystander, but the possibility of pathological *For every 10 g increase. CI ¼ confidence interval; other abbreviations as in Table 3. LVH as a variant of HCM, cannot be excluded, particularly in the presence of LV fibrosis (12). Idiopathic LVH may also be a trigger for arrhythmia in intense exercise may be a causal factor. Studies individuals with underlying primary arrhythmia have previously reported raised serum concentration syndrome. In a recent study by our group, familial of biomarkers of myocyte injury following endurance evaluation of victims of SCD with autopsy findings events, consistent with idiopathic LVH, identified primary fibrosis on cardiac magnetic resonance and a higher arrhythmia syndromes in 6 of 13 (46%) families and burden of atrial and ventricular arrhythmias in vet- probable HCM in only 1 family (12). In such circum- eran endurance athletes (20–22). More than 80% of stances, a false diagnosis of HCM has potentially athletes died suddenly without warning symptoms, significant implications for surviving relatives who underscoring the possible limitations of cardiac may be subjected to targeted screening for cardio- screening based only on medical history and physical myopathy rather than the extensive evaluation, examination (23). including pharmacological provocation tests, to detect primary arrhythmia syndromes (18). In this study, HCM contributed to only 6% of deaths. That is in contrast to the established perception that HCM is the commonest cause of SCD in athletes (4,19). This may partly reflect the stringent diagnostic criteria applied by our group, which requires the presence of >20% of myocardial disarray in at least 2 tissue blocks of 4 cm 2 (14). In contrast, nonspecialist pathologists may attribute exerciseinduced adaptations such as LVH to HCM (7) without conducting a detailed histological analysis of the heart. This probability highlights the importance that post-mortem examinations in athletes should be performed by pathologists with a high level of experience in conditions predisposing to SCD. We cannot disregard the possibility of selection bias, as an increased prevalence of myocardial EFFECT OF AGE. In agreement with previous studies (6,24), SADS exhibited a significant age predilection. SADS accounted for more than one-half of all deaths in children and adolescents, but for only 26% of deaths in individuals older than 35 years of age. In contrast, myocardial disease was more prevalent with advancing age. ARVC, a condition commonly associated with SCD in young athletes, was rarely detected in children and adolescents (4%) but accounted 18% of deaths in individuals >35 years. Our results are consistent with a large autopsy study in 200 cases of ARVC (25), where the average age of death was at 33 years and almost 40% of deaths occurred after age 35. Interestingly, ARVC was associated with an increased heart weight in 25% of cases. general pathologists may be less inclined to refer RELATIONSHIP BETWEEN SUDDEN CARDIAC DEATH diseases such as HCM to our center if they are confi- AND EXERCISE. As reported previously (4,26), we dent about the diagnosis. demonstrated that SCD in athletes occurs more An important minority (8%) showed idiopathic frequently during exercise. The strongest predictor fibrosis. Possible explanations include healed myo- for SCD during exertion was ARVC. Athletes with carditis or incomplete expression of cardiomyopathy. ARVC were 6 times more likely to die on exertion However, it is also possible that long-standing compared to those with other cardiac pathologies p Value 0.01 0.001 2113 2114 Finocchiaro et al. JACC VOL. 67, NO. 18, 2016 MAY 10, 2016:2108–15 Sudden Death in Athletes (92% experienced SCD on the athletic field). LV athletes is a rare event, the large number of fibrosis of post-mortem examinations performed in our unit in exercise-induced SCD. Coronary artery anomalies this cohort suggests that the results are a genuine were a rare cause of SCD, but the majority of deaths representation of the type and frequency of cardiac occurred during exertion. Although HCM is consid- diseases implicated in SCD in young athletes. was also an independent predictor ered the leading cause of exercise induced SCD in It is possible that subtle or incomplete expressions athletes, deaths from HCM in our cohort did not show of cardiomyopathy may have been misclassified as any predilection for exercise. Our results, however, SADS; however, considering our thorough laboratory should be interpreted with caution given the rela- protocol, it is highly unlikely that such cases tively low numbers of HCM-related deaths in this accounted for a significant proportion of deaths study. In agreement with current published reports, attributed to SADS. SADS accounted for the majority of deaths at rest Our study does not include data relating to survi- (54%) compared to a third of deaths (34%) during vors of sudden cardiac arrest. As such, it is possible exertion. that the results are biased toward lethal causes of CLINICAL IMPLICATIONS. Given that almost 40% of athletes died outside the context of exercise, including 13% during sleep, it is highly unlikely that the provision of AEDs in public venues would have prevented these deaths. Many of the SCDs during sudden cardiac arrest such as cardiomyopathies and primary arrhythmia syndromes, whereas diseases more amenable to survival following cardiac arrest are under-represented (8,9). CONCLUSIONS rest were related to SADS and possibly to primary arrhythmia syndromes that are often detectable Conditions predisposing to SCD in sport demonstrate with individuals. significant age predilection. SADS accounts for most of Pre-participation screening may therefore be useful in the deaths in the very young, whereas cardiomyopa- this scenario. With ARVC, ECG may be abnormal in thies predominate with increasing age. Although the 55% ECG-based majority of athletes die during exertion, almost 40% pre-participation screening might be effective at die at rest, highlighting the need for complementary detecting athletes with the condition. Immediate preventative strategies in addition to provision of availability potentially AED. The strong association of ARVC with exercise- life-saving for cases that are not detected during induced SCD reinforces the need for competitive pre-participation screening. Finally, LV fibrosis is sport restriction in athletes with the condition. increasingly recognized in athletes but is not consid- Finally, the high prevalence of idiopathic LVH or ered in isolation as a reason for exercise restriction. fibrosis underscores the need for further research in This study suggests that LV fibrosis is a trigger for the field in order to delineate their significance. an to ECG 75% of of in asymptomatic cases an AED (27–29), could and be exercise induced fatal arrhythmias in some athletes and warrants longitudinal assessment of asymptom- REPRINT REQUESTS AND CORRESPONDENCE: Dr. atic athletes with isolated LV fibrosis (30). Sanjay Sharma, Cardiovascular Sciences, St. George’s STUDY LIMITATIONS. The CRY Centre for Cardiac Pathology at St George’s University of London is more likely to receive hearts from subjects where the clinical history is suggestive of an inherited cardiac disease. Local pathologists are more likely to refer challenging cases, such as athletes with ambiguous autopsy findings or athletes for whom an obvious cause of death cannot be established. These facts introduce a potential referral bias; pathologies such as coronary artery atherosclerosis and HCM may be under-represented in this cohort. Similarly, the prevalence of less well-defined entities such as idiopathic LVH and a morphologically normal heart may be overestimated. Nevertheless, we receive a high volume of unexpected SCD referrals (>400 per year); 58% are in individuals <35 years of age at death, including athletes. Considering that SCD in young University of London, Cranmer Terrace, London SW17 0RE, United Kingdom. E-mail: [email protected]. PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: Causes of sudden death in athletes vary with age. SADS is prevalent in children and adolescents, whereas cardiomyopathies are the most common cause in adults. ARVC is strongly associated with sudden death during exertion. TRANSLATIONAL OUTLOOK: Further studies are needed to better understanding the causes and circumstances of sudden death to facilitate development of preventive strategies. Finocchiaro et al. JACC VOL. 67, NO. 18, 2016 MAY 10, 2016:2108–15 Sudden Death in Athletes REFERENCES 1. Meyer L, Stubbs B, Fahrenbruch C, et al. Incidence, causes, and survival trends from cardiovascular-related sudden cardiac arrest in children and young adults 0 to 35 years of age: a 30-year review. Circulation 2012;126:1363–72. 2. Sharma S, Merghani A, Gati S. Cardiac screening of young athletes prior to participation in sports: difficulties in detecting the fatally flawed among the fabulously fit. JAMA Intern Med 2015;175:125–7. 3. Corrado D, Basso C, Rizzoli G, Schiavon M, Thiene G. Does sports activity enhance the risk of sudden death in adolescents and young adults? J Am Coll Cardiol 2003;42:1959–63. 4. 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