Sudden cardiac death (SCD) in athletes is always shocking, tragic, and stirs controversy regarding screening for pre-existing cardiovascular pathology. Could these deaths be prevented? What type of screening is required? To answer these questions, a better understanding of the causes of SCD in athletes is required. Traditionally, in the United States, hypertrophic cardiomyopathy (HCM) has been reported as the leading cardiovascular cause of death in athletes.¹ However, more recent research and research from other countries has questioned whether sudden arrhythmic death syndrome (SADS) (death with a structurally and histologically normal heart, presumed to be electrical disease) may represent a larger proportion of deaths than previously thought. In addition, as autopsies are refined, there is an increasing proportion of hearts which show left ventricular hypertrophy (LVH) with or without myocardial fibrosis that do not meet the definition of HCM, prompting the question whether acquired LVH could be pathologic in some cases or whether this is an early expression of cardiomyopathy. Further, it seems death from cardiomyopathy may be more frequent in certain sports or races. A more nuanced look at the causes of SCD may offer new insights.

The cause of SCD is highly dependent on age, with electrical and structural disease more prevalent in populations <25 years of age and coronary artery disease (CAD) more common in athletes over the age of 35. In fact, CAD represents <10% of deaths in high school and college athletes and >85% of sport-related death in older athletes.^1-4 Cardiovascular screening for congenital cardiac pathology versus acquired CAD should be examined separately; therefore, this discussion will focus on athletes aged 14-35.

While the cause of death may be related to age, the determination of cause is often dependent on the expertise and resources available at post-mortem examination. In the United States, a 2009 National Academy of Sciences Blue Ribbon Report concluded "coroners and medical examiner offices are struggling with inadequate resources, poor scientific training and substandard facilities and technology."⁵ The charge of most coroners and medical examiners is to determine under what circumstances a death has occurred: "natural," homicide or suicide. An exact medical cause of death, while important to the family for both peace of mind and for screening of surviving relatives, is not a priority and has possibly contributed to misperceptions.

It is against this backdrop that HCM was initially reported as the leading cause of SCD in US athletes based on a large registry. However, the determination of HCM was established primarily based on local autopsies, and the registry was based out of a HCM center utilizing passive surveillance for case identification. This report suggested up to 36% of SCD cases were due to HCM although the athletes with suspected cardiovascular events but no precise diagnosis of death (i.e., possible SADS) were dropped from the pool, thereby increasing the proportion of cases attributed to HCM. If the cardiac cases with unknown causes were included, HCM instead accounted for 24% of deaths in the cohort.¹

In contrast, a study of unselected NCAA athletes reported a much larger proportion of SCD attributed to SADS with strictly defined HCM accounting for only 8% of deaths. Interestingly, if LVH with fibrosis or cardiomyopathies not meeting the definition of HCM were included, this number increased to 24% of deaths.² Although this study had less risk of selection bias, it also relied on local post-mortem examinations of variable quality.

In the United Kingdom a referral center for cardiac pathology examines a large proportion of sudden deaths in athletes and reported 44% of the deaths in 18-35-year-old athletes were due to SADS.⁶ HCM accounted for only 8% of deaths with LVH with fibrosis accounting for another 14% of deaths. While this study provided a uniform and high quality post-mortem examination, only cases of sudden death referred from local coroners were reviewed at this center.⁶ This may have led to a skewed sample with more obvious causes of death such as HCM not being referred.

A study on the etiology of SCD with standardized, quality autopsies, an unselected population and active surveillance in active duty military personnel ages 18-35, often seen as comparable to athletes due to the regular, vigorous training required, provides additional insight. This study reported death due to SADS in 41% of cases, HCM in 13%, with another 8% of deaths due to left ventricular cardiomyopathies; a similar distribution to that seen in the United Kingdom.⁷

Indeed, a meta-analysis which included 34 studies on the cause of SCD in athletes showed HCM responsible for 10.3% of deaths and SADS represented 26.7%.⁸ This correlates to conditions which are found at screening. In a meta-analysis of over 47,000 athletes that reviewed conditions identified at screening, there were 160 conditions associated with SCD discovered: 42% Wolff-Parkinson-White (WPW); 11% Long QT Syndrome (LQTS); and 11% HCM, equating to a prevalence of WPW of 1 in 700 athletes and 1 in 4,200 for LQTS and HCM.⁹ While the prevalence of WPW and LQTS is consistent with published studies, the lower prevalence of HCM in the screened population may reflect pathology that has not yet manifested, as many of the studies included youth and high school athletes, or that HCM athletes were selected out because of the physical demands of the sport. Given the high prevalence of WPW reported compared to other conditions associated with SADS, and given molecular autopsy identifies channelopathies in SADS only 35% of the time,¹⁰ one could question if WPW is responsible for a larger proportion of SADS than previously appreciated. Because WPW is common and treatable, aggressive and earlier identification could be warranted if this were the case and this possibility should be explored with further research.

Finally, emerging research would suggest that the causes of SCD may be variable among different athlete groups. In studies of high risk groups such African Americans and male basketball players, it appears that left ventricular pathology is more frequent than in other athletes.^2,3 This is important as HCM readily exhibits ECG abnormalities in 90% of cases and ECG changes may precede structural changes and further supports a targeted approach to screening.¹¹

In the end, it seems there are several important takeaways. First, HCM may not cause SCD as commonly as previously thought; however, HCM and other left ventricular pathology remain an important cause of SCD, especially in high risk groups. Whether the left ventricular pathology is congenital or acquired and the role of exercise in both are intriguing questions. Second, WPW is prevalent in the athletic population, easily identified and often treatable, and questions arise if this is a more common cause of SCD than previously appreciated. Finally, it is indisputable that standardized high quality autopsies in combination with genetic testing and expert interpretation can further our understanding of the causes of SCD in young athletes and inform prevention strategies. Continued collaborative efforts to increase the understanding of both the incidence and etiology of SCD should be pursued.

References

1. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980-2006. Circulation 2009;119:1085-92.
2. Harom K, Asif IM, Maleszewski JJ, et al. Incidence, cause, and comparative frequency of sudden cardiac death in national collegiate athletic association athletes: a decade in review. Circulation 2015;132:10-9.
3. Harmon KG, Asif IM, Maleszewski JJ, et al. Incidence and etiology of sudden cardiac arrest and death in high school athletes in the United States. Mayo Clin Proc 2016;91:1493-1502.
4. Marijon E, Tafflet M, Celermajer DS, et al. Sports-related sudden death in the general population. Circulation 2011;124:672-81.
5. Committee on Identifying the Needs of the Forensic Science Community. Strengthening Forensic Science in the United States: A Path Forward. Washington, DC: The National Academies Press; 2009.
6. Finocchiaro G, Papadakis M, Robertus JL, et al. Etiology of sudden death in sports: insights from a United Kingdom regional registry. J Am Coll Cardiol 2016;67:2108-15.
7. Eckhart RE, Shry EA, Burke AP, et al. Sudden death in young adults: an autopsy-based series of a population undergoing active surveillance. J Am Coll Cardiol 2011;58:1254-61.
8. Ullal AJ, Abdelfattah RS, Ashley EA, Froelicher VF. Hypertrophic cardiomyopathy as a cause of sudden cardiac death in the young: a meta-analysis. Am J Med 2016;129:486-96.
9. Harmon KG, Zigman M, Drezner JA. The effectiveness of screening history, physical exam, and ECG to detect potentially lethal cardiac disorders in athletes: a systematic review/meta-analysis. J Electriocardiol 2015;48:329-38.
10. Tester DJ, Medeiros-Domingo A, Will ML, Haglund CM, Ackerman MJ. Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsy-negative sudden unexplained death referred for postmortem genetic testing. Mayo Clin Proc 2012;87:524-39.
11. Drezner JA, O'Connor FG, Harmon KG, et al. AMSSM position statement on cardiovascular preparticipation screening in athletes: current evidence, knowledge gaps, recommendations and future directions. Br J Sports Med 2017;51:153-67.

Keywords: Athletes, Hypertrophy, Left Ventricular, Cause of Death, Basketball, Coronary Artery Disease, Channelopathies, Death, Sudden, Cardiac, Cardiomyopathy, Hypertrophic, Referral and Consultation, Genetic Testing, Registries, Electrocardiography, Long QT Syndrome, Cohort Studies

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