Epidemiology and aetiology of sudden cardiac death in athletes

Sudden cardiac death (SCD) is a devastating and tragic occurrence that may affect individuals of all ages. It is defined as an unexpected death occurring within one hour of the onset of symptoms, if witnessed, or within 24 hours of last being seen alive and well, if unwitnessed. Athletes are considered to be the healthiest of all the population, and exercise is known to reduce the risk of atherosclerotic coronary artery disease. However, both amateur and highly trained athletes do die suddenly and unexpectedly, and this gets widespread media attention as it is so shocking and unexpected. This brings SCD, its frequency and causes into the spotlight. This review focuses on the epidemiology and aetiology of SCD in athletes from a pathological perspective.

Epidemiology

The incidence of sudden cardiac death (SCD) in athletes varies widely between studies, ranging between 0.24 and 6.8 per 100,000 person-years.^1,2 This is partially explained by the differences in the populations studied, differences in the definition of an athlete, and the inclusion of sudden cardiac arrest into studies.

Age has been shown to be an important determinant of risk, with a nationwide Danish study showing that those aged 12 to 35 years were at a lower risk (0.43 to 2.95 per 100,000 person-years) compared with those aged 36 to 49 years (0.47 to 6.64 per 100,000 person-years).³ Interestingly, this study also showed that the risk of SCD is higher in the general population at 10.7 per 100,000 person-years, highlighting that most SCD in the young occurs in non-athletes.

It is well recognised that SCD occurs at a higher frequency in males, with a ratio of around 2:1 when compared with females.⁴ In athletes this is further exaggerated, with a similar study reporting a ratio of over 12:1.⁵ When female athletes are compared with males they are more likely to die at rest, as opposed to during exertion.⁶

In the US, black athletes have a higher risk of SCD than white athletes, with a reported incidence of 5.65 per 100,000 person-years compared with 3.02 per 100,000 person-years, respectively.⁷ Similarly, in a prospective cohort of elite adolescent soccer players in the UK, the risk of SCD was approximately seven times higher in black (25 per 100,000 person-years) compared with white (3.86 per 100,000 person-years) athletes.¹

Type of sport has also been shown to have an effect, with ice hockey (4.25 per 100,000 person-years), basketball (2.51 per 100,000 person-years) and American football (1.21 per 100,000 person-years) having the greatest risks of SCD.⁸ In a UK cohort of 357 SCDs occurring in athletes, the most common sports disciplines were running (25%), football (25%), cycling (8%) and gymnastics (8%).⁵

Aetiology

SCD in athletes is caused by a wide variety of cardiac disease. While ischaemic heart disease (IHD) is common in older athletes, in younger athletes, genetic conditions, such as cardiomyopathy and channelopathy, are more common. It is important to eliminate causes such as hyperthermia, as this is one of the most common causes of sudden death in athletes. This is defined by a body temperature of over 40 °C.⁹ Hypothermia, with a body temperature of less than 32 °C, may also cause cardiac arrest, particularly in athletes exercising in cold weather or water.¹⁰ Both these conditions are usually identified by the first responders to cardiac arrest.

Role of the autopsy

Autopsy is the gold standard for identifying the cause of death.¹¹ SCD is often the first manifestation of disease, and autopsy is the only opportunity to establish an accurate cause of death in the athlete. It is concerning that, in a recent worldwide International Federation of Association Football (FIFA) report into sudden death in young footballers, only 20% had an autopsy.¹² A European survey has highlighted that up to 40% of SCD in those under 50 years did not have an autopsy.¹³ A full autopsy with detailed pathological examination of the heart should be undertaken in all young SCD to establish an accurate cause of death because of the implications of a diagnosis of a hereditary cardiac condition for blood relatives.¹⁴ Also, not all sudden deaths are due to cardiac causes, with 20–40% being unnatural or non-cardiac in origin after autopsy.^15,16

The UK Royal College of Pathologists, and the Association for European Cardiovascular Pathology have published recommended guidelines for autopsy investigation of SCD cases.^13,17,18 The Association for European Cardiovascular Pathology has also recently issued guidelines for diagnosis of genetic cardiomyopathies at autopsy.¹⁹ Blood for toxicology is essential,²⁰ and fresh blood/spleen should routinely be saved for genetic testing, if deemed necessary, and the examinations may also include biochemistry and microbiology in selected cases.¹⁷

We know from previous studies that expert cardiac pathology evaluation is essential, as this significantly improves the post-mortem diagnostic accuracy.^14,21 A UK study found that the initial diagnosis of cause of SCD, made by the referring pathologist, was altered after expert evaluation in 41% of cases.¹⁴ For arrhythmogenic cardiomyopathy, only two out of 20 were confirmed by the expert cardiac pathologist.¹⁴

Sudden arrhythmic death syndrome

Sudden arrhythmic death syndrome (SADS) is the term used in the post-mortem setting to describe an individual who has died suddenly and unexpectedly, where no cause of death is found at autopsy or on toxicology, and detailed histology of the heart shows it to be morphologically normal. This is the so-called negative autopsy. This is the most common cause of SCD in European athletes, and accounts for between 20% and 40% in this population.^5,22 When this diagnosis is made, the family must be screened for underlying channelopathies, a group of disorders affecting the ion channels of the heart, which include long-QT syndrome (LQTS), short-QT syndrome, Brugada and catecholaminergic polymorphic ventricular tachycardia (CPVT), conduction disease and idiopathic ventricular fibrillation. The main role of the autopsy is to establish that the heart is normal, and that minor abnormalities or mild coronary artery disease are not erroneously considered the cause of death.²¹ Toxicology should always be done in all cases, as we have shown that it can be positive in 10% of potential SADS cases.²⁰

Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is cardiologically defined as a left ventricular wall thickness of 15 mm or more in any myocardial segment that is not explained solely by loading conditions. The disease is estimated to have a prevalence of one in 500 in the general population.²³ HCM is reported to cause between 2% and 36% of SCD in athletes,^5,16,24 and is reported as the most common cause of SCD in athletes in the US, making up 36%.¹⁶ Contrastingly, in the UK, HCM causes 6% of SCDs.⁵ Most HCM patients die suddenly at rest, rather than on exertion.^25,26 The differences in the proportion of SCD caused by HCM in all these studies may be explained by how the diagnosis is made.⁴ At autopsy, on macroscopic examination there is frequently increased heart weight with asymmetric left ventricular hypertrophy²⁷ (figure 1A) and normal coronary arteries. It is important to state that the heart can appear normal in 30% of cases, so pathologists need to be aware that histology should be taken on all normal hearts in individuals with SCD.²⁵

The diagnosis is made histologically with the detection of widespread myocyte disarray in the left ventricle (figure 1B). Pathologists need to be strict in their definition of myocyte disarray and guidelines should be carefully followed.¹⁹ There is a genetic cause in up to 70% of cases. Once the diagnosis is made, then the pathologist informs the medical examiner and coroner who will inform the family that they need cardiological screening in view of the SCD. Sudden death is the first presentation with the diagnosis made at autopsy in 79% of cases in our HCM series, emphasising the role of the autopsy and pathologist.^25,28

Arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is a mainly inherited cardiac disease characterised by progressive replacement of the myocardium by fibrofatty tissue, with a subepicardial distribution in both ventricles. This can lead to cardiac arrhythmia, ventricular dysfunction, and SCD.²⁹ ACM has an estimated prevalence of one in 1,000 to one in 5,000,^30,31 and the genes underlying arrhythmogenic right ventricular cardiomyopathy (ARVC) mainly encode proteins of the cardiac desmosome.³² Originally denoted as ARVC, it is now recognised to affect both ventricles, with a recent study showing left ventricular (LV) involvement in 87% of cases.²⁹ ACM is emerging as one of the most common causes of death in athletes, ranging from 4% to 22% in SCD studies.^5,16,33 SCD with ACM is frequently associated with exertion. At autopsy, the diagnosis is made based upon both the macroscopic and microscopic findings in the heart. Macroscopically, there can be fat and fibrous tissue in a subepicardial distribution in both ventricles in the absence of significant coronary artery disease (figure 2A). Again, as in HCM, the heart can look macroscopically normal. Microscopically, fibrous tissue and fat replace the myocardium (figure 2B).²⁹ There are mimics of ACM, such as cardiac sarcoid,³⁴ so again, histology is essential in all cases for correct diagnosis.

Dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is cardiologically defined by the presence of LV dilatation and contractile dysfunction not explained by coronary artery disease or abnormal loading conditions.³⁵ There are several genes that are causative of DCM, which encode structural components of the sarcomere and desmosome. Some are associated with a higher risk of SCD, such as FLNC, DES, DSP, PLN, LMNA, TMEM43 or RMB20.²³ Other causes include myocarditis, exposure to drugs, toxins or allergens, endocrine or autoimmune disease. DCM is a rarer cause of SCD in athletes, occurring in just 1–3%.^5,7,16 Classically, on pathological examination, the heart shows enlargement, increased weight, dilation of the left ventricle with wall thinning and mural thrombi in atria and ventricles with dilated valve annulus (figure 3A). Histology usually shows interstitial and replacement fibrosis, but this may be absent (figure 3B).

Idiopathic left ventricular hypertrophy

Idiopathic left ventricular hypertrophy (ILVH) is an emerging entity that accounts for 16–17% of SCD in athletes, and in more recent studies, is the predominant cardiomyopathy.^5,22 It is defined by an increased heart weight in the absence of significant coronary artery disease, valvular disease, other cardiomyopathy, hypertension, obesity, alcohol misuse and diabetes. It is histologically distinct from HCM by the absence of myocyte disarray on histology.⁴ A recent study on decedents with ILVH, utilising post-mortem genetic testing and comprehensive screening of direct blood relatives, found that there were no variants associated with HCM and no evidence of HCM in relatives. This suggests that ILVH is an entity that is distinct from HCM.³⁶ Further evaluation of families and genetic testing will clarify this entity and its causes.

Idiopathic left ventricular fibrosis

Left ventricular fibrosis is usually explained by coronary artery disease, toxic causes such as alcohol, or cardiomyopathy. In a small proportion it remains unexplained and does not reach the criteria for a diagnosis of dilated, arrhythmogenic or hypertrophic cardiomyopathy. These are labelled as idiopathic left ventricular fibrosis (ILVF), which is another emerging entity. In studies where it is diagnosed, it accounts for up to 8% of SCD in athletes.⁵ Recent studies of decedents with ILVF have shown that variants associated with cardiomyopathy, but also channelopathy, may be found in these individuals,^37,38 replicating what has been found on cardiological screening of blood relatives.²¹

Ischaemic heart disease

Ischaemic heart disease (IHD) is the world’s biggest killer and, despite exercise being protective against coronary artery atheroma, it is still a well-recognised cause of SCD in mainly older athletes. A nationwide Danish study of individuals aged 12–49 years reported that IHD was the most common cause of SCD, accounting for 43%.³ In younger individuals, such as US athletes at collegiate level with an average age of 19 years, IHD accounts for a much lower proportion of SCD (6%),²² and in our study, 2% in a mainly younger cohort.⁵ We have reported on premature atheroma in younger patients, the youngest being 11 years old.³⁹ Findings at post-mortem include significant atheromatous narrowing of the coronary arteries, atheromatous plaque rupture and thrombosis, acute infarction of the myocardium and myocardial fibrosis. Blood relatives should be screened for familial hypercholesterolaemia when IHD occurs in young athletes.

Myocarditis

Myocarditis is histologically defined as an inflammatory infiltrate associated with myocyte necrosis not caused by ischaemia.⁴⁰ The process is generally diffuse with widespread involvement of the myocardium in both left and right ventricles. Originally thought to be induced by viruses, bacteria, protozoa and fungi, as well as a variety of toxic substances and drugs and systemic immune-mediated diseases, it is now recognised that a myocarditis picture may be seen in inherited cardiomyopathy.⁴¹ Myocarditis is reported to be the cause of 2–7% of SCD in athletes.^3,5,22 At autopsy, the heart may appear normal macroscopically or have dilated ventricles with colour variegation of the myocardium. Histologically, there must be myocyte necrosis with an associated inflammatory infiltrate, which can be subcategorised as lymphohistiocytic (56%), neutrophilic (17%), eosinophilic (16%), toxic (7%) or giant cell (4%) (figure 4).⁴²

Coronary artery anomalies

Anomalous coronary arteries are a rare cause of SCD in athletes, accounting for 3–9%, and frequently occurring with exertion and first presenting at post-mortem.^3,5,22 The left or right coronary artery arises in the wrong sinus (figure 5). The course is considered to be malignant when it passes within the aortic wall and between the pulmonary trunk and the aorta, which can cause compression of the proximal coronary artery resulting in ischaemia and SCD.⁴³

Mitral valve prolapse

Mitral valve prolapse (MVP) has been reported as the cause of SCD in 2% of athletes.^5,22 The condition affects both males and females equally. In a cohort of 120 cases of MVP identified following SCD, 11 (9%) died associated with exertion.⁴⁴ Both valve leaflets show ballooning, thickening, elongation and annular disjunction at autopsy, with or without ventricular scarring (figure 6).

Commotio cordis

This is a rare cause of SCD in athletes, generally occurring in younger individuals because of the pliability of the chest wall.⁴⁵ It is due to the impact of an object, usually a baseball or football, into the chest over the left intercostal space with immediate collapse and death. It is believed to occur in a vulnerable time in the cardiac cycle leading to cardiac arrest.⁴⁶ The heart is normal at post-mortem, but there may be evidence of impact on the skin. The diagnosis is reliant on the circumstances of being hit in the chest shortly prior to SCD.⁴⁵

Contusio cordis

Contusio cordis is a similar entity to commotio cordis, but is distinguished as the blow to the chest results in structural cardiac injury.⁴⁷ There may simply be contusion of myocardial muscle, but there can be more severe injuries, such as rupture of a cardiac chamber, or disruption of a heart valve. Contusion may cause ventricular arrhythmia or conduction abnormalities resulting in SCD. Ventricular rupture can be rapidly fatal, and tamponade may occur. When rupture is through the septum, this leads to shunting with right ventricular hypertrophy, heart failure and death.

Conclusion

The incidence of SCD in athletes varies widely between studies, ranging between 0.24 and 6.8 per 100,000 person-years. It has diverse causes and is potentially heritable in over 75% of cases. Autopsy and thorough histopathological cardiac evaluation are essential to determine the causes of SCD.

Key messages

• The incidence of sudden cardiac death (SCD) in athletes is between 0.24 and 6.8 per 100,000 person-years
• SCD in athletes has diverse aetiology and is caused by potentially heritable cardiac conditions in over 75%
• SCD is frequently the first presentation of cardiac disease in athletes
• Autopsy and thorough histopathological cardiac evaluation are essential to determine the causes of SCD

Conflicts of interest

None declared.

Funding

Cardiac Risk in the Young (CRY) fund the cardiovascular pathology laboratories. JW is funded by the National Institute for Health and Care Research.

Patient consent

Example images are provided from a large anonymised dataset.

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