Coronary atherosclerosis in middle‐aged athletes: Current insights, burning questions, and future perspectives

Abstract Regular exercise training is considered healthy as it reduces the risk of cardiovascular events and mortality. Nevertheless, athletes are not immune to the development of cardiovascular diseases and recent studies reported a higher prevalence of coronary artery calcifications and atherosclerotic plaques in athletes compared to less active controls. These observations have raised many questions among sport scientists, sports cardiologists, amateur athletes, and the general population. For example, Are athletes (not) immune for coronary atherosclerosis? How to assess coronary atherosclerosis in athletes? What about chalk (calcified plaque) and cheese (mixed plaque)? Does exercise intensity play a role? Are there sport‐related differences? Are there sex differences? Can sports medical evaluation detect coronary atherosclerosis? Do athletes get worried? Should athletes get worried? How should athletes with coronary atherosclerosis be managed? The goal of this review is to discuss the latest scientific insights and to answer these important questions. Furthermore, we will explore potential clinical implications and point out directions for further research.


| INTRODUCTION
"If we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health" Hippocrates, 460-377 BC It has been known for more than 2000 years that habitual physical activity and regular exercise training importantly contribute to a healthy lifestyle. Sufficient physical activity and exercise are associated with remarkable reductions in cardiovascular events [1][2][3][4][5] and increased longevity. 6 Only 15 minutes of physical activity per day is associated with a 14% reduction in all-cause mortality. 4 In contrast, insufficient physical activity is responsible for a population attributable fraction of 12% for cardiovascular disease (CVD) mortality. 7 As such, exercise is one of the most effective measures to reduce the risk of CVD in general, and coronary heart diseases in particular as ≥44% of CVD deaths are attributable to atherosclerotic coronary heart disease. Exercise-induced CVD risk reductions do, therefore, translate to large health benefits as CVDs are the primary cause of death worldwide, accounting for ±18 million deaths per year (±31% of total mortality). 7 The common dogma is that more exercise yields greater health benefits. However, recent studies reported intriguing findings on the effects of long-term high-volume high-intensity exercise training on the prevalence and severity of atherosclerotic coronary heart disease among amateur athletes. [8][9][10] A higher prevalence of coronary artery calcifications (CACs) and atherosclerotic plaques has been found in athletes vs controls, with a higher CAC and plaque prevalence in the most active vs least active athletes. These findings have raised many questions among healthcare professionals, sports scientists, and athletes. The goal of the present review is to discuss the latest insights from this field of research and to provide evidence-based answers to these eminent questions.

| ARE ATHLETES (NOT) IMMUNE TO CORONARY ATHEROSCLEROSIS?
The development and progression of CVD is importantly dependent on lifestyle factors, including physical activity and nutrition. 7 It has been suggested that atherosclerosis is typically a disease of modern society, as physical inactivity and atherogenic diets are common nowadays. However, when researchers made computed tomography (CT) scans of mummies from ancient Egypt, 20 out of 44 mummies (45%) had atherosclerosis at an estimated age of 45 ± 9 years. 11 Of those mummies, two had definite coronary atherosclerosis, the earliest documentation of coronary atherosclerosis.
A postmortem pathology study from 1960 investigated coronary atherosclerosis in men aged 30 to 60 years who died suddenly from accidents, homicide, or suicide. 12 Study participants were classified as sedentary (eg, accountant, bank clerk, and chauffeur) or physically active (eg, construction worker, gardener, and plumber) based on their occupation history. Surprisingly, a similar degree of coronary atherosclerosis was found among the sedentary and physically active group, suggesting that development of coronary atherosclerosis was not associated with habitual physical activity. 12 In 1977, Bassler described a case series of runners who had died. 13 Interestingly, autopsy reports revealed that none of the marathon runners died of atherosclerotic coronary artery disease, suggesting that marathon runners could be immune for coronary atherosclerosis as they avoided tobacco smoking and unhealthy diets and covered great distances on foot. 13 Unfortunately, a 1979 case series of four marathon runners reported autopsy-proven coronary atherosclerosis, which rejected the Bassler's hypothesis that long-distance runners are protected from the development of coronary heart disease. 14 In conclusion, the development of atherosclerosis is importantly dependent on lifestyle factors such as insufficient physical activity and an atherogenic diet, but athletes are not immune to atherosclerosis.

| HOW TO ASSESS CORONARY ATHEROSCLEROSIS IN ATHLETES?
Although older studies relied on autopsy to determine the presence and severity of coronary atherosclerosis, the development of imaging techniques changed the availability of methods to assess coronary heart disease characteristics. Nowadays, coronary atherosclerosis is typically measured non-invasively using a CT scan. This can be done with or without a contrast agent. A non-contrast CT scan allows quantification of CAC by calculating a CAC score (CACS). 15 The Agatston CACS is calculated by multiplying the area of each calcification by 1, 2, 3, or 4 depending on the density of the area, and summing up the scores for all slices. The density score is based on the highest Hounsfield units (HU) of the area, with a density score of 1 for HU 130 to 199, 2 for 200 to 299, 3 for 300 to 399, and 4 for ≥400 HU. 16 CAC scoring only includes areas with a density ≥130 HU and ≥1 mm 2 .
The CACS is related to the coronary atherosclerotic burden and a strong predictor for future CVD. 17 In a study of 4425 patients followed up for 3 years, the probability of major adverse cardiac events was estimated for CACS categories. Patients without CAC (a CACS of 0) had a major adverse cardiac event rate of 2.1%. The rate of cardiac events was 12.9% for those with CACS >0 to 100, 16.3% for those with CACS >100 to 400, and 33.8% for those with CACS >400, indicating the strong prognostic value of CAC. 18 As such, CACS are widely used to assess atherosclerotic burden and future cardiovascular risk in an easy, non-invasive way. Interestingly, although the CACS itself is a multiplication of CAC area and density, a distinction can be made between the CV risk associated with increases in the area and density of CAC regions. Higher CAC area (or volume) is associated with a higher CVD risk, whereas a higher CAC density is associated with a lower risk of CVD. 19 Using a contrast-enhanced coronary CT scan (coronary CT angiography, CCTA), the lumen of the coronary arteries can also be imaged and plaque characteristics can be determined. This allows for determination of plaque morphology and divide plaques into calcified, non-calcified, and mixed (both calcified and non-calcified parts) plaques. 20 The differentiation of plaques based on their morphology into calcified, non-calcified, and mixed plaques importantly impacts the associated CV risk. 18 For example, in the previously mentioned study of 4425 patients, calcified plaques were associated with a 3-year major adverse cardiac event risk of 5.5%, whereas this was 22.7% for non-calcified plaques and 37.7% for mixed plaques. 18 As CAC scoring only includes plaques with an area of density ≥130 HU and ≥1 mm 2 , plaque components below that threshold are not included in the CACS. This means that noncalcified or only minimally calcified, mixed plaque ("cheese") can only be detected using a contrast-enhanced CT. Moreover, CCTA also allows for assessment of high-risk plaque features such as the napkin-ring sign, positive remodeling, low-attenuation (<30 HU) plaque, and spotty calcification, which are also associated with worse prognosis. 21 CT scanning uses radiation to construct images and tremendous efforts have been made over the last decades to reduce the radiation dose associated with CT scanning. A routine CCTA examination can now be performed at 2 to 4 mSv, while newer technologies even allow CCTA acquisitions at <1 mSv. 22 CAC scoring also requires ±1 mSv of radiation, but recent efforts suggest CAC scoring can be improved and done at lower doses requiring ±0.2 to 0.3 mSv of radiation. 23 Although the associated radiation dose is not high, it is not negligible and thus performing CAC scoring or CCTA should clearly be of value to the individual.

| DO CORONARY ATHEROSCLEROSIS CHARACTERISTICS DIFFER BETWEEN ATHLETES AND CONTROLS?
Although several studies demonstrated that athletes are not immune to coronary atherosclerosis, it was generally assumed that coronary atherosclerosis would be less prevalent in athletes compared to the general population. In 2008, Möhlenkamp et al studied 108 male marathon runners and compared them to 864 age-matched and 216 age-and risk factormatched control subjects from the Heinz-Nixdorf Recall study. 10 They found that the German marathon runners had similar CACS compared to age-matched controls, but higher CACS compared to the controls matched for both age and risk factors (Table 1). These findings were surprising and suggested more coronary atherosclerosis in athletes vs controls. Criticists raised the possibility that the inclusion criteria may have caused bias. Participants older than 50 years with ≥5 marathon completion in the previous 3 years were recruited for the study. Hence, marathoners might have relatively recently adopted an active lifestyle, which improved their risk factors whereas their CACS reflected their prior exposure to higher risk factors. Nevertheless, Merghani et al confirmed findings from the German study and reported that male British athletes had higher CACS than control subjects (median CACS of 86 vs 3, P = .02), but only in those with prevalent CAC 9 (Table 1) 1.6-6.6) compared with the least active athletes (<1000 MET-min/wk, 43%). 8 However, CACS did not differ between the athletes with prevalent CAC in their study. DeFina et al studied 21 758 generally healthy American men and divided them based on their physical activity level into individuals performing <1500, 1500 to 2999, and ≥ 3000 MET-min/wk. 24 The most active individuals were more likely to have a CACS >100 (OR adjusted : 1.11; 95% CI: 1.03-1.20) compared with individuals performing less physical activity. Collectively, these findings indicate that athletes are more likely to have high CACS than controls.
Aengevaeren et al and Merghani et al also performed a contrastenhanced CT scan following CAC scoring. Prevalence of atherosclerotic plaques was higher in male athletes compared to controls (44% vs 22%) 9 and in the most active athletes (77%; OR adjusted : 3.3; 95% CI: 1.6-7.1) compared to the least active athletes (56%). 8 However, plaque morphology differed significantly across groups. Athletes demonstrated predominantly calcified plaques (73%) instead of mixed plaques (23%), whereas controls had fewer calcified plaques (31%, P = .0006) and predominantly mixed plaques (62%, P = .0002). 9 Similarly, the most active athletes had less often atherosclerotic plaques of a mixed morphology (48%; ORadjusted: 0.35; 95% CI: 0.15-0.85) compared with the least active athletes (69%). The most active athletes also had more often only calcified plaques compared to the least active athletes (38% vs 16%; OR adjusted : 3.57; 95% CI: 1.28-9.97). These findings indicate a more benign plaque composition in athletes vs controls, as calcified plaques are associated with a lower cardiovascular risk than mixed plaques. 18 The comparison of atherosclerosis induced health risks between athletes and the general population is therefore inappropriate, as "chalk" (ie, low-risk calcified plaques) has different risk estimates compared to cheese (ie, higher risk non-calcified/mixed plaques). These observations emphasize that personalized medicine is needed in the treatment of coronary atherosclerosis.
T A B L E 1 Coronary atherosclerosis characteristics across studies comparing athletes and controls Möhlenkamp (2008) 10 Merghani (2017) 9 Aengevaeren (2017)  in female participants, whereas this association was present for men. 24 Although limited evidence is available, current data suggest that the association between exercise and coronary atherosclerosis is weaker in female athletes compared to their male counterparts, which may be mediated by estrogen.

| CAN SPORTS MEDICAL EVALUATION DETECT CORONARY ATHEROSCLEROSIS?
A sports medical evaluation typically includes taking a medical history, patients. 33 Patients were asked: "On a scale of 0 to 10, how much do you exercise (0-none, 10-always)?" This question was then categorized as "no exercise" (score of 0 or 1), "low exercise" (score of 2-5), "moderately active" (score of 6-8), and "highly active" (score of 9 and 10 potential myocardial ischemia. These should not necessarily lead to coronary interventions, as there is currently no evidence that a stent will increase life expectancy in an asymptomatic athlete, but could provide maximal heart rate guidelines and guide training schedules and additional medical therapy in individuals with ischemia. Also, in certain cases, invasive coronary angiography with fractional flow reserve measurements can be considered based on the anatomical information from CCTA. Figure 3 provides a basic schematic summary of these considerations.

Recommendations from the European Sports Cardiology
Section for participation in leisure time or competitive sports for athletes-patients with coronary artery disease provide guidance for participation in sports for athletes with asymptomatic coronary atherosclerosis. 42 In short, athletes should be assessed for inducible ischemia and coronary risk factors. Exercise testing, potentially followed by stress imaging tests, to assess functional ischemia is