Undetected coronary artery disease in apparently healthy athletes

The heart attack recently suffered by the Spanish professional goalkeeper Iker Casillas, aged 37 years,1 has sparked intense debate among health professionals and the general population. Notably, only 2 days earlier, the 46-year-old Spanish cyclist Fernando Civera died from cardiac arrest during the second stage of the cycling race ‘Titan Desert’ 2019.2 However, these two recent cases are just the tip of the iceberg. In a study by Landry et al.,3 the incidence of sudden cardiac arrest was assessed in competitive and non-competitive athletes occurring from 2009 to 2014 in individuals aged 12 to 45 years during participation in a sport; there were finally 74 sudden cardiac arrests produced (16 during competitive sports and 58 during non-competitive sports).3 Another two recent deaths during sports participation have also been reported.4 One of them, a 21-year-old cyclist, Gijs Verdick, suffered a double cardiac arrest during a 5-day stage race. The other, Daan Myngheer, a 22-year-old cyclist, suffered an out of competition myocardial infarction while he was participating in a 2-day (three stage) race (Criterium International, France). Sudden cardiac death (SCD) in professional soccer players has also been investigated among players of the major European competitions from January 2000 to June 2017.5 In that study, 59 cases of SCD due to cardiovascular events were found (all men; mean age at death 25 ± 5 years). Many other elite athletes have experienced SCD, including Davide Astori (Italian national football team player, who died before a match at 31 years of age), Michael Goolaerts (professional cyclist, who died during the 2018 Paris–Roubaix at 23 years), Eduardo Gory Guerrero (former World Wrestling Federation champion, who died in his sleep at 38 years) or Fabricio Paulino de Melo (National Basketball Association player, who also suffered a heart attack during his sleep at 26 years). Thus questions are currently arising such as: How could this happen in relatively young healthy men? What was wrong? Could these cardiac events have been prevented? What happens now? We should first underscore that the characteristics and circumstances of the recent Spanish cases are quite different. First and foremost, Casillas is a professional football player while Civera was an amateur recreational cyclist. The incidence of sudden cardiac arrest in competitive athletes does not actually mirror the real risk of cardiovascular complications in non-competitive exercisers.3 It is now well known that coronary atherosclerosis, i.e. coronary artery disease (CAD), is the leading cause of exercise-related cardiac events in athletes aged 35 years or older. The risk factors associated with CAD are numerous and include obesity, hypertension, diabetes, physical inactivity, smoking, hypercholesterolemia, psychological and emotional stress, genetic predisposition (family history of heart disease), age, sex and race. Besides these, a plethora of novel, still not well appreciated biochemical risk factors are starting to emerge, such as lipoprotein(a), a major carrier of oxidised phospholipids, homocysteine, C-reactive protein, small and dense low-density lipoprotein cholesterol particles, fibrinogen and myeloperoxidase, among others. Many risk factors may be minimised, controlled, treated, or even eliminated through appropriate lifestyle and behaviour modifications, while little can be done for others. Is it hence possible to develop coronary heart disease without presenting with risk factors? Definitely yes, this is possible, albeit relatively infrequent. Pre-participation cardiac screening (medical history and physical examination, electrocardiogram, echocardiogram, exercise stress test) is the most effective strategy to prevent acute cardiovascular events in young people.6,7 However, strenuous efforts may increase the risk of adverse cardiac events in apparently healthy athletic individuals aged 35–40 years or older, as subclinical CAD (i.e. the presence of atherosclerotic plaques in asymptomatic subjects) is commonplace in this population.8,9 Laddu and co-workers evaluated the prevalence of coronary artery calcification after 25 years of physical activity.10 The authors followed up with 3175 participants over 25 years, and concluded that the most active population has a higher probability of developing coronary subclinical atherosclerosis by middle age. In addition, two separate investigations have recently identified the presence of CAD in 42–53% of veteran marathon runners and endurance cyclists, respectively.11,12 It is important to emphasise that the tendency for plaque was calcified rather than mixed, and hence more benign. Unfortunately, pre-participation screening/examination has severe limitations in terms of identifying subclinical coronary atherosclerosis. Strategies other than pre-participation cardiac screening have been shown to be potentially effective for unmasking many CAD cases at an early stage. Imaging techniques such as ultrasound of carotids, infrarenal abdominal aorta and iliofemoral arteries, positron emission tomography (a marker of calcification activity), computed tomography (CT) for coronary artery calcium scoring, contrast-enhanced CT angiography and cardiac magnetic resonance can detect CAD and accurately characterise the overall coronary atherosclerotic burden in athletes considered to be at higher risk.8,13,14 Among these, coronary artery calcium scoring and contrast-enhanced CT angiography probably may be regarded as valuable approaches for pre-participation screening, with a high diagnostic capacity to detect CAD.13 Interestingly, there is recent evidence that the discretionary use of imaging techniques (e.g. electrocardiogram and echocardiogram) may be cost-effective for identifying a subset of athletes more vulnerable to SCD.15 In addition, investigations aimed at identifying novel biological variables such as genetic, transcriptomic and/or epigenetic biomarkers are underway, and the potential usefulness of genetic screening to assess disease risk in asymptomatic persons has been already emphasised.16 Transcriptomic and epigenetic biomarkers are also revolutionising precision medicine,17 thus allowing the elucidation of critical pathways, while the role of traditional biomarkers such as cardiac troponin will also probably be reaffirmed in this setting.18 Classic cardiac screening protocols are insufficient to prevent acute cardiovascular events in athletes older than 35 years. The case of Iker Casillas has made this clear. There is an urgent need for new imaging techniques and/or targeted biomarkers to boost the sensitivity of identifying and preventing CAD in these older athletes. Although so far we have insufficient evidence to support the introduction of the aforementioned techniques and methods in pre-participation screening of asymptomatic athletes aged 35 years or older, cardiac imaging should be considered in certain high-level professional athletes as well as in endurance athletes so that appropriate management strategies can be implemented. With regard to the issue of whether athletes diagnosed with CAD or experiencing a cardiac event should return to competition, reliable guidelines have been published to assist clinicians in managing these individuals according to their CAD risk profile.19 In brief, an athlete-patient who has suffered myocardial infarction but has undergone complete revascularisation without residual ischaemia is encouraged to return to gradual exercise as soon as possible, starting with low-intensity and short-duration efforts. Exercise duration and intensity can then be gradually increased until the athlete is able to exercise without limitations while always remaining vigilant for the appearance of new symptoms. The duration of this process depends on the extent of myocardial damage and remodelling, which will need to be assessed after 3 months. Although the athlete-patient completes a cardiac rehabilitation programme, not all such programmes are really suitable because goals are typically undersized for trained athletes. However, more intense training and competition should only be considered after a gradual steady increase in the training workload. Finally, a minimum of 3 months after a percutaneous coronary intervention is recommended before the athlete returns to competitive sport. Contact sports should be avoided while the athlete-patient is under antiplatelet or anticoagulant therapy, because of an obvious risk of traumatic bleeding. Periodic cardiac assessment, at least on a yearly basis, is then advisable. An aggressive statin therapy for at least 2 years after a primary event is also recommended to foster atherosclerotic plaque remission and lower the overall risk of recurrence. Athletes willing to return to competition are warned to wait at least this long before recommencing full training and competition.20 The athlete must weigh the risks of disease with the importance of exercise and competition for mental health and psychological wellbeing, also considering the possible economic aspects (for professional athletes) and overall lifestyle. The return to high-intensity activity after suffering a myocardial infarction causes anxiety and overwhelming feelings for both athlete and physician. Thus, physician–athlete dialogue to decide on the return to competition is also of paramount importance. All these factors, along with the overall risk profile provided by the physician, should help in the design of customised appropriate exercise prescription for all athletes with CAD. Fabian Sanchis-Gomar is supported by a postdoctoral contract granted by Subprograma Atracció de Talent – Contractes Postdoctorals de la Universitat de València. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: H. Pareja-Galeano is supported by internal funding by Universidad Europea (#2019/UEM01).