Article Text

Download PDFPDF

Management of mature athletes with cardiovascular conditions
  1. Andrew D’Silva,
  2. Sanjay Sharma
  1. Clinical Cardiology and Academic Group, St George’s University of London,, London, UK
  1. Correspondence to Professor Sanjay Sharma, Cardiology Clinical and Academic Group, St George’s, University of London, Cranmer Terrace, London, SW17 0RE; sasharma{at}sgul.ac.uk

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Learning objectives

  • To appreciate the benefits of exercise training and safety issues in exercise and sport.

  • To recognise the risk factors and mechanisms of sudden cardiac death during and after strenuous exercise with specific population challenges.

  • To understand the contraindications to exercise/sporting competition and the recommendations for professional and recreational sport participation.

Introduction

Exercise is a potent therapy for the prevention1–4 and rehabilitation5 of cardiovascular disease, including the management of risk factors for atherosclerotic cardiovascular disease.6 It is important to recognise, however, that an ‘exercise paradox’ exists where vigorous physical activity transiently elevates the risk of sudden cardiac death (SCD) (figure 1). The risk is greatest in individuals who are not accustomed to regular exercise and undertake high intensity physical activity with little or no systematic training.7–9 

Figure 1

Exercise paradox. AF, atrial fibrillation; SCD, sudden cardiac death. Data taken from Nocon et al,1 Warburton et al,6 Marijon et al,17 Moore et al,2 McTiernan et al 3 and Hamer et al.4

In a previous review in the journal, we outlined the management of young competitive athletes with cardiovascular conditions.10 This population has been the main focus of attention for preparticipation screening,11 12 as the early detection of inherited cardiomyopathies and arrhythmic syndromes has the potential to prevent decades of lost life. Though widely debated,13 the methods of screening in this population are generally acceptable, and particularly the inclusion of an ECG is effective in detecting the majority of potentially fatal cardiac conditions relevant to this population.14 15

SCDs among young competitive athletes, however, account for just over 6% of all exercise-related SCDs.16 A far greater burden falls to non-elite, older athletes over 35 years of age, where the cause is overwhelmingly due to coronary artery disease (CAD) attributing to over 80% of deaths17–19 (figure 2).

Figure 2

Variation in sudden cardiac death incidence and causes across different age groups. RV, right ventricular; VT, ventricular tachycardia. Reproduced with permission from La Gerche et al.19

In this article, we define mature competitive athletes as individuals, above 35 years of age, who compete in events with an emphasis on excellence and undertake regular systematic training. Notably, the population at risk is predominantly composed of mature recreational athletes who, by comparison, undertake a variety of informal recreational sports, which may be vigorous in nature, though without stipulation on achieving excellence or undertaking regular training. Evidence is sparse on this latter group, who require no regulation or organisational affiliation and therefore provide little opportunity for systematic examination through professional surveillance.

While preparticipation screening in young competitive athletes is adopted by many countries and international sporting organisations,11 12 20 the recommendations for mature athletes draw even greater controversy, not least because of the lack of evidence demonstrating that ischaemic heart disease (IHD) detection algorithms translate to a reduction in exercise-related SCD. As increasing physical activity is heavily promoted in society for the substantial health benefits and there is an increasing population of middle-aged individuals who participate in mass endurance events, the issue is highly relevant and deserving of attention. Many aspects of the previous review10 also hold relevance to an older population of athletes. This article will focus specifically on the cardiovascular conditions of greater relevance to mature athletes.

Hypertension

Hypertension is the most common cardiovascular condition in the general population and affects almost a third of the population aged over 40 years. The precise prevalence of hypertension in mature athletes is unknown but may not be too dissimilar compared with the general population. Influencing factors include age, sex and sporting discipline and intensity of sport. Performance-enhancing agents, such as anabolic steroids and frequent reliance on non-steroidal anti-inflammatory agents, should also be considered as a potential cause of hypertension in athletes.

Static (resistance or isometric) exercise is associated with elevations in blood pressure (BP), whereas predominantly dynamic forms of exercise are associated with falls in BP persisting for up to 24 hours after exercise. Athletes achieving elevations of systolic BP >200 mmHg may be predisposed to hypertension despite normal BP values at rest and should be evaluated comprehensively with 24-hour ambulatory BP monitoring.21

Control of hypertension is of paramount importance in the prevention of IHD, stroke and heart failure. Though hypertension is not implicated as a direct cause of SCD in athletes, it is associated with an increased risk of complex ventricular arrhythmias and therefore appropriate emphasis should be placed on the correct diagnosis, assessment of target end organ damage and optimal BP control, using principles advocated in the general population with hypertension.22

Sports may have an impact on the choice of antihypertensive agents. In competitive athletes, beta-blockers and diuretics may be considered as doping agents for some sports, particularly those where an advantage can be gained through weight loss or control of tremor.23 In addition, neither agent is ideal for endurance athletes, as beta-blockers frequently impair exercise performance and diuretics may cause dangerous electrolyte and fluid disturbances. Calcium channel blockers, ACE inhibitors and angiotensin II receptor blockers are better choices for hypertensive endurance athletes.23

Arrhythmia

Bradyarrhythmias

Sinus bradycardia is common in the majority of well-trained athletes,24 25 though the exact underlying mechanism remains unclear. Classical theories implicate enhancement of parasympathetic tone through increased vagal stimulation.26 Meanwhile, modern animal studies suggest that a reduction in the I f (funny) current could be responsible for bradycardia through intrinsic sinus node changes, specifically, downregulating ion-channels associated with potassium/sodium hyperpolarisation.27–29

First-degree atrioventricular (AV) block is a common training-related ECG finding resulting from delayed conduction in the AV node.14 Endurance athletes also demonstrate a higher prevalence of type 1 second-degree AV block,30 31 and periods of low atrial or junctional escape rhythms, at rates of 40–60 bpm, are also normal phenomena. Occasionally, marked sinus bradycardia (<40 bpm) at rest or sinus pauses >3 s can be found in asymptomatic, well-trained endurance athletes.32 Such findings are usually benign, more evident at rest, particularly during sleep and do not require intervention in asymptomatic individuals.

These bradyarrhythmias are usually eliminated with exercise, providing a useful diagnostic tool. The presence of symptoms such as lightheadedness, presyncope, syncope or exertional fatigue may require long periods of ambulatory monitoring for symptom–rhythm correlation and detection of pathology.

Higher degree AV blocks, including type 2 second-degree AV block (Mobitz type II) and complete heart block, are very uncommon and require comprehensive investigation for underlying pathology including structural heart disease, infectious and infiltrative causes (particularly Lyme disease and sarcoidosis respectively in those aged under 55 years).33 34 Pacemaker implantation is indicated where the pathological substrate is not reversible. A diagnosis of cardiac sarcoidosis requires consideration of SCD risk, including the decision to implant a cardioverter defibrillator (ICD).35 Cardiac MRI may provide valuable tissue characterisation, with the detection of inflammation, oedema and scar in addition to information provided by echocardiography. Care must be taken not to mistake second-degree 2:1 AV block with Wenckebach physiology from true Mobitz type II AV block with 2:1 conduction.36 This can usually be achieved by exercise ECG testing though electrophysiological study may be required in exceptional cases.37

Interventricular conduction delay

Incomplete right bundle branch block (RBBB) is common and does not require further investigation in asymptomatic athletes.14 Complete RBBB is rarer occurring in up to 3% and may be associated with a non-pathological increase in right ventricular chamber size,38 resulting from athletic training. International recommendations for ECG interpretation recognise isolated RBBB as a potentially normal variant, though in some cases RBBB may arise from pathological processes causing right ventricular pressure or volume overload.39

Left bundle branch block (LBBB) is usually a marker of underlying cardiac pathology. Detailed investigation is indicated for structural heart disease and IHD. Syncope or presyncope may be potentially attributable to higher degrees of AV block, where ambulatory monitoring and electrophysiological study may be useful. Athletes with abnormal AV conduction, characterised by an HV interval >90 ms or a His-Purkinje block, should be considered for a cardiac pacemaker, whereas those with structurally normal hearts and normal electrophysiological study may participate in all competitive activities.37 Asymptomatic, rate-dependent LBBB is frequently benign in the presence of a structurally normal heart; however, its induction at low heart rates may be a subtle indicator of disease and worthy of comprehensive evaluation.37 A schema for evaluating athletes with bradycardia and/or conduction delays is outlined in figure 3.

Figure 3

Investigation of athletes with bradycardia and/or conduction delays. AVB, atrioventricular block; CAD, coronary artery disease; cLBBB, complete left bundle branch block; CMR, cardiac magnetic resonance scan; cRBBB, complete right bundle branch block; EP, electrophysiological study.

Athletes with permanent pacemakers and ICDs

Athletes with permanent pacemakers and ICDs may participate in sports where the underlying heart condition does not preclude participation.23 37 Athletes who are pacing dependent and those with ICDs should avoid engaging in collision sports and sports involving projectiles that can cause damage to the device. For athletes with pacemakers who are not pacing dependent, it is prudent to wear protective equipment if engaging in contact sports, although such practice is not recommended.37 Pacemaker programming should aim to ensure appropriate rate adaptation during exercise and if persistent sinus rhythm is present, this may be used for tracking. During follow-up, exercise testing and 24-hour Holter monitoring may assist in optimising programming for improved pacing rate responsiveness in some athletes. Athletes with ICDs may be considered for participation in sports with higher peak static and dynamic components than class IA if free from ventricular arrhythmia requiring device therapy for 3 months. Such athletes require careful counselling regarding the potential risk of inappropriate shocks and device-related trauma.40

Tachyarrhythmias

Endurance athletes experience a fivefold increased risk of atrial fibrillation (AF).41 The total accumulated lifetime physical activity appears to be the critical factor determining AF development. Most studies suggest that athletes developing exercise-induced AF have been engaged in more than 10 years of regular exercise training.42–46 In one study >2000 hours of lifetime vigorous exercise was associated with an odds ratio of 4 for the presence of AF.46 Another study demonstrated that those who exercised more intensively and achieved faster race times were at higher risk of AF over a 9-year follow-up period than slower athletes.47 In the wider population, a U-shaped relationship is thought to exist between physical activity and AF incidence,46 48 where engagement in low-to-moderate physical activity reduces the risk of AF from a sedentary baseline but increasing doses, to the levels and intensity described above, may elevate risk. Presumably, modest physical activity is valuable in offsetting conventional risk factors for AF such as hypertension, obesity and IHD; however, mechanisms underpinning the development of exercise-induced AF in endurance athletes remain incompletely understood. Atrial structural remodelling, resulting in dilatation and fibrosis, has been proposed as a potential maladaptive response to vigorous exercise contributing to AF development. Convincing arguments have also been made for enhanced parasympathetic tone potentially being responsible through shortening the atrial refractory period, facilitating re-entry formation and subsequent establishment of AF.49 In reality, the pathophysiology of exercise-induced AF is likely to be multifactorial and may involve individual susceptibility factors that are yet to be discovered.50

Mature recreational athletes who develop AF without a substantial background of cumulative exercise should be evaluated for the conventional causes of AF, such as hypertension, IHD, valvular heart disease, alcohol abuse and thyrotoxicosis. The management of AF and ventricular arrhythmia were outlined in detail in the previous review.10

Ischaemic heart disease

Atherosclerotic CAD is a potentially fatal condition facing athletes over 35 years of age.18 Sedentary individuals, however, who have the most to gain from regular physical activity are paradoxically at greater risk of exercise-associated cardiac arrest and myocardial infarction (MI) with vigorous exercise.7 8 51 A striking 9:1 male predominance is seen in SCD among competitive athletes52 and this increases to 20:1 among individuals engaged in recreational exercise,16 with large registries reporting proportions of 93%53–95%16 of SCDs occurring in men. Potential explanations for this sex discrepancy in SCDs include a relatively lower participation rate and engagement at lower intensity levels among women, although hormonal influences cannot be disregarded.

The most common mode of SCD during sporting activity is an abrupt ventricular tachyarrhythmia.17 It is notable that many deaths in marathons occur in the final quartile of the event,52 54 suggesting that an electrolyte and/or metabolic component may contribute to risk. Limited postmortem studies support acute coronary plaque rupture pathology in sudden deaths occurring during emotional stress or strenuous activity.55 It is possible that demand ischaemia, variation in sympathetic activity, vascular reactivity and increase in platelet aggregation during exertion also play a role in precipitating acute coronary events and ventricular arrhythmia.

Athletes with known CAD, having suffered an acute coronary syndrome (ACS) or anginal chest pain are at increased risk of MI associated with vigorous physical exertion.56 For this reason, current recommendations from both the European Society of Cardiology (ESC)23 and the American Heart Association/American College of Cardiology (AHA/ACC)57 advocate risk stratification for recurrent events, inducible ischaemia and arrhythmia. A high probability of exercise-induced cardiac events is indicated by the presence of any of the following: symptoms of ischaemia, reduced exercise capacity, left ventricular ejection fraction <50%, haemodynamically significant coronary stenosis, exercise-induced ischaemia or complex ventricular tachyarrhythmia. Athletes with any of these features should be advised to limit themselves to sports with low dynamic and low-to-moderate static demands, once symptoms have stabilised and at least 3 months after an acute MI or coronary revascularisation procedure.

Of paramount importance is compliance with optimised secondary prevention medical therapy to treat underlying, established CAD and reduce the risk of future events. Two particular medications are of worthy of mention as they can result in a reduction in athletic performance. Beta-blockers confer significant benefit in patients with reduced left ventricular ejection fraction post-ACS and should be continued indefinitely at tolerated target doses despite adverse effects on athletic performance. The issue is more contentious in patients with normal left ventricular function. Though current recommendations advocate continued treatment post-MI,58–60 in asymptomatic, fully revascularised, low-risk patients, strong arguments can be made to individualise treatment on the basis of symptoms and tolerability.61–63

Effective statin therapy achieving targeted lipid lowering is critically important in cardiovascular secondary prevention. Unfortunately, athletes and physically active individuals experience myalgia more commonly with statins.64 65 The importance of lifelong compliance must be impressed on the athlete, as return to exercise is not an adequate substitute for evidence-based therapy.

Athletes may have concealed CAD, where they are asymptomatic though demonstrate unequivocal ischaemia during provocative testing coupled with angiographic evidence of haemodynamically significant coronary artery stenosis. Such individuals should be risk stratified in same way as symptomatic patients.

Finally, athletes with proven CAD who do not have haemodynamically significant coronary stenosis (<50% luminal narrowing), inducible ischaemia or complex ventricular arrhythmias on provocative testing may undertake all competitive activities, provided resting left ventricular ejection fraction is >50% and there is adherence to medical therapy.57 These recommendations also apply to athletes with coronary revascularisation and are summarised in figure 4. The most recent AHA/ACC recommendations adopt a much more liberal position to competitive exercise with underlying CAD and depart significantly from previous consensus documents, which confined them to competition in disciplines with low dynamic and low/moderate static components under previous Bethesda US guidelines.66 The new leniency is despite CAD being responsible for 80% of SCDs in mature athletes17 18 with no contemporary evidence to support the safety of sports participation in this group. Communication with athletes with proven CAD should include explanation of these uncertainties, including that CAD may progress despite appropriate treatment, that acute cardiac events can occur at sites of only mild coronary stenoses and that fatal arrhythmias may still arise from demand ischaemia during exercise.

Figure 4

Diagnosis and management algorithm for athletes with cardiovascular conditions including which patients benefit from referral to tertiary level specialist centres. AV, atrioventricular; BP, blood pressure; CAD, coronary artery disease; EP, electrophysiological study; ICD, implantable cardioverter defibrillator; LBBB, left bundle branch block; LV EF, left ventricular ejection fraction; MI, myocardial infarction; RBBB, right bundle branch block. Reference to classes of sports, relating to dynamic and static components, pertains to the Mitchell classification published in the previous review.10

Prevention of SCD in mature athletes

Given that the overwhelming majority of SCD affecting mature athletes are attributable to CAD, recommendations regarding preparticipation evaluation of mature athletes seem logical and prudent. Such recommendations have been developed by the AHA67 and European Association of Cardiovascular Prevention and Rehabilitation (EACPR).68 Unfortunately, neither approach has been tested prospectively or shown to be effective in reducing exercise-related cardiovascular events. Common elements to these recommendations include an initial self-assessment questionnaire, aiming to identify known cardiovascular disease, risk factors or symptoms. Following this, a physician’s detailed cardiovascular evaluation is recommended for those with positive self-assessment, aiming to highlight those who might benefit from maximal exercise testing to detect underlying CAD.

The main differences provided by the EACPR recommendations are in distinguishing whether an individual is sedentary or active before undertaking an increase in physical activity and the level of intensity of the intended activity. These additions recognise that both factors contribute to SCD risk.7–9 16 Figure 5 summarises the EACPR recommendations in two management algorithms.69

Figure 5

European Association of Cardiovascular Prevention and Rehabilitation preparticipation cardiovascular evaluation protocol for asymptomatic sedentary adult/senior individuals (A) and active adult/senior individuals (B). Hx, history; Phys.exam., physical examination. Reproduced with permission from Corrado et al.69

Given the size of the population concerned and the lack of resources to support organised systematic screening programmes for mature athletes, such a stratified approach beginning with self-assessment allows a large proportion of healthy individuals to be granted eligibility for sports participation without unnecessary obstacles to increasing physical activity in the general population.68 A physician-led cardiovascular evaluation includes history, physical examination, estimation of 10 year cardiovascular risk using a validated scoring system70 71 and a resting ECG.

The value of maximal exercise testing for asymptomatic athletes at high cardiovascular risk in order to prevent SCD is more debatable. ECG exercise testing has established prognostic value,72–74 widespread availability and relatively low cost. Inducible ischaemia and complex ventricular arrhythmias can be assessed simultaneously in a maximally tolerated, graded manner providing valuable additional information regarding exercise capacity and fitness. A number of limitations to ECG exercise testing are worthy of mention. The predictive value of ECG stress testing for exercise-related cardiovascular events in asymptomatic, middle-aged men is low,75 with 18% sensitivity and 92% specificity,72 largely owing to low disease prevalence in a relatively healthy population. False-positive exercise tests are also a considerable problem, particularly for older athletes76 and women,77 78 and generate additional diagnostic testing with associated cost and anxiety. Diagnostic ischaemic ECG changes develop at an advanced stage of the ischaemia cascade and indicate the presence of haemodynamically significant coronary stenosis. Plaque rupture resulting in arrhythmic SCD, however, can occur in coronary lesions with only mild-to-moderate stenosis,79 escaping detection. Negative functional tests may therefore be falsely reassuring, and in some cases neither the treadmill nor pharmacological stress agent in the imaging laboratory is able to adequately reproduce the haemodyamic and metabolic stresses associated with athletic competition and resultant demand ischaemia. Finally, endurance athletes tend to have supranormal coronary perfusion reserve80; endurance training significantly improves endothelial function,81 and higher intensity exercise stimulates coronary artery collateral growth.82 These phenomena may account for atypical presentations of CAD in endurance athletes, who may experience only breathlessness or reduced exercise performance, rather than classical anginal symptoms. In such cases, a negative exercise test is not reassuring, and it is our practice to proceed to CT coronary angiography (CTCA), based on a wealth of anecdotal experience of athletes with reduced performance and normal exercise tests but with severe CAD at coronary angiography.

Future directions in the management of mature athletes

Given that vulnerable, mild-to-moderate coronary stenoses may be a substrate for exercise-associated cardiac events, in the context of haemodynamic, adrenergic and metabolic stress, this raises the possibility that coronary artery calcium scoring (CACS) and/or CTCA may be effective screening tools in mature athletes. CACS and CTCA have proven predictive value for MI and SCD over clinical risk stratification.83 84 In a recent study of 318 asymptomatic male athletes aged over 45 years, CT identified occult CAD in 19%, where exercise ECG testing was negative during a high work load.85 Other studies suggest that CACS improves prediction of MI or death due to CAD only in intermediate-risk patients (Framingham Risk Score 10%–20%)86 but adds no predictive power for those with low risk (Framingham Risk Score <10%) as assessed by traditional cardiovascular disease risk factors.86–88 There are, in addition, implications of cost-effectiveness, radiation exposure, potential contrast reactions and incidental findings associated with CACS/CTCA. Moreover, studies in mature athletes suggest that endurance exercise may be associated with a greater burden in coronary calcification.85 89 Whether this translates to hard clinical end points, such as ACS events or SCD, is yet to be determined. Two recent publications suggest that plaque morphology in mature athletes is more frequently of a stable, calcified type.90 91 In contrast, relatively sedentary individuals with similarly low Framingham scores show a greater proportions of mixed morphology and soft plaques that are more vulnerable to rupture.91

A study of 102 male runners over 50 years of age, demonstrated a positive association between higher coronary artery calcium scores and late gadolinium enhancement (LGE) on cardiac MRI, which was seen in 12%. Interestingly, the LGE distribution was consistent with myocardial scarring resulting from IHD in only 42%. The majority demonstrated LGE in a non-ischaemic, midmyocardial, patchy distribution, raising the possibility that these findings may arise through distinct underlying mechanisms. The prevalence of LGE in athletes was not statistically different from that seen in controls and therefore these findings should be interpreted with caution.89

The aforementioned studies, however, enrolled relatively small cohorts and are therefore vulnerable to confounding factors and underpowered to address long-term clinical outcomes. The studies also found that those athletes demonstrating LGE had greater accumulated years of exercise exposure.92–94 Our own experience suggests that focal fibrosis in the region of the right ventricular insertion points is present in over 40% of mature and younger endurance athletes and may be adaptive rather than maladaptive. Large, prospective trials in mature athletes, with long endurance exercise exposure, are required to determine the cause and clinical significance of coronary calcification and ventricular fibrosis identified in mature athletes.

Conclusion

Mature athletes commonly experience structural and electrical cardiac remodelling consistent with the ‘athlete’s heart’.

Greater habitual physical activity is a public health imperative, crucial in curbing rapidly growing epidemics, particularly type 2 diabetes and obesity. Vigorous exercise, however, can also transiently elevate the acute risk of SCD in predisposed individuals. IHD is responsible for the majority of deaths among mature athletes, and men possess a ninefold greater risk than women. Detection of underlying CAD in individuals who increase their physical activity level is highly desirable as a potential strategy to reduce SCDs; however, effective preparticipation screening protocols have not yet been proven in mature athletes. Current recommendations advocate selective ECG stress testing; however, this approach and alternatives suffer important limitations. The evidence base for mature athletes is sparse, and research in this area to inform clinical practice is desperately needed. Key priorities in future research should include evaluating optimal strategies to reduce exercise-associated cardiac events in mature athletes and to establish whether high volume accumulated exercise exposure has clinically important sequelae. Athletes with hypertension and hypercholesterolaemia may experience troublesome adverse effects on treatment and therefore medications should be personalised depending on choices available and according to patient risk/benefit profile.

Key messages

  • Exercise is overwhelmingly beneficial for cardiovascular health, though vigorous intensity activity transiently elevates the risk of sudden cardiac death (SCD) for a small number of individuals with underlying cardiac conditions.

  • Bradycardia and conduction blocks are common in athletes, but high degree atrioventricular blocks are associated with pathology and require intervention.

  • Atherosclerotic coronary artery disease is the principle cause of SCD in the mature athlete, and men are significantly more susceptible than women.

  • Uncertainty remains over the best strategy to prevent SCD in mature athletes, and further research is needed.

CME credits for Education in Heart

Education in Heart articles are accredited for CME by various providers. To answer the accompanying multiple choice questions (MCQs) and obtain your credits, click on the ‘Take the Test’ link on the online version of the article. The MCQs are hosted on BMJ Learning. All users must complete a one-time registration on BMJ Learning and subsequently log in on every visit using their username and password to access modules and their CME record. Accreditation is only valid for 2 years from the date of publication. Printable CME certificates are available to users that achieve the minimum pass mark.

References

  1. 1.
  2. 2.
  3. 3.
  4. 4.
  5. 5.
  6. 6.
  7. 7.
  8. 8.
  9. 9.
  10. 10.
  11. 11.
  12. 12.
  13. 13.
  14. 14.
  15. 15.
  16. *16.
  17. 17.
  18. 18.
  19. 19.
  20. 20.
  21. 21.
  22. 22.
  23. *23.
  24. 24.
  25. 25.
  26. 26.
  27. 27.
  28. 28.
  29. 29.
  30. 30.
  31. 31.
  32. 32.
  33. 33.
  34. 34.
  35. 35.
  36. 36.
  37. 37.
  38. 38.
  39. *39.
  40. 40.
  41. 41.
  42. 42.
  43. 43.
  44. 44.
  45. 45.
  46. 46.
  47. 47.
  48. 48.
  49. 49.
  50. 50.
  51. 51.
  52. *52.
  53. 53.
  54. 54.
  55. 55.
  56. 56.
  57. *57.
  58. 58.
  59. 59.
  60. 60.
  61. 61.
  62. 62.
  63. 63.
  64. 64.
  65. 65.
  66. 66.
  67. 67.
  68. 68.
  69. 69.
  70. 70.
  71. 71.
  72. 72.
  73. 73.
  74. 74.
  75. 75.
  76. 76.
  77. 77.
  78. 78.
  79. 79.
  80. 80.
  81. 81.
  82. 82.
  83. 83.
  84. 84.
  85. 85.
  86. 86.
  87. 87.
  88. 88.
  89. 89.
  90. 90.
  91. *91.
  92. 92.
  93. 93.
  94. 94.

Footnotes

  • Contributors AD wrote the article. SS edited the article and provided critical review, also contributed original material to the final manuscript.

  • Competing interests AD was supported by a research grant from the charitable organization Cardiac Risk in the Young (CRY), which supports cardiovascular screening of young individuals. SS has been co-applicant on previous grants with CRY.

  • Provenance and peer review Commissioned; externally peer reviewed.

  • Author note References marked with a * are key references for this paper.

  • Correction notice The corresponding authors address has been updated since this paper was first published online.