Myocarditis in athletes
Myocarditis: incidence and importance for sports cardiology
Acute and subacute myocarditis and perimyocarditis are the cause of sudden cardiac death in 5–25% of athletes [1–4]. The disease is not uncommon and accounts for up to 10% of autopsies in the general population [5,6].
In general, viral infections are responsible for the majority of cases of myocarditis, inducing inflammation of the myocardium with infiltration of inflammatory cells into muscle fibres and interstitium, causing oedema, muscle fibre membrane defects, and eventually apoptosis. All this creates an electrically unstable condition, which favours the development of atrial and ventricular tachyarrhythmias or conduction defects. When the extent of damage to the myocardial fibres is substantial, the process eventually evolves in dilatation and impairment of left ventricular function.
In contrast, pericarditis is primarily limited to the pericardium and pericardial sac; it does not affect the myocardial fibres, but rather induces pericardial inflammation with subsequent effusion. If both the myocardium and pericardium are affected, the disease state is termed perimyocarditis.
Clinically myocarditis and perimyocarditis may present in acute or chronic form, ranging from a pauci-symptomatic presentation to a clinical manifestation of severe heart failure. When dilated myopathy is detected, virus-induced cardiomyopathy is often a clinically derived diagnosis of exclusion, when other causes have been excluded.
Pathogens of myocarditis are mainly cardiotropic viruses, such as adenoviruses, enteroviruses (Coxsackie virus B3, hepatitis C or human immunodeficiency virus), parvovirus B19, or human herpes virus 6 . Therefore, a myocardial manifestation of virus infection in athletes and active leisure-time sportsmen may be suspected particularly during or after an upper respiratory tract infection or gastroenteritis  or in those with lowered immune response. The proportion of individuals experiencing myocardial involvement during viral infection is estimated to be approximately 5%, but the majority of them will remain subclinical. As exercise may reduce immunological competence, particularly when performed with strenuous intensity and prolonged duration, it is possible that a locally confined and transient infection may spread, causing more severe disease states.
Other, less common, causes of myocarditis are :
(1) bacterial (Mycobacteria, streptococcal species, Mycoplasma pneumoniae, Treponema pallidum);
(2) fungal (Aspergillus, Candida, Coccidiodes, Cryptococcus, Histoplasma);
(3) protozoal (Trypanosoma cruzi), parasitic (schistosomiasis, Larva migrans);
(4) toxic (anthracyclines, cocaine, interleukin-2);
(5) medication (sulfonamides, cephalosporins, diuretics, digoxin, tricyclic antidepressants, dobutamine);
(6) immunological (Churg–Strauss syndrome, inflammatory bowel disease, giant cell myocarditis, diabetes mellitus, sarcoidosis, systemic lupus erythematosus, thyrotoxicosis, Takayasu’s arteritis, Wegener’s granulomatosis).
Pathophysiology and phases of inflammation
Myocarditis follows a heterogeneous pattern of pathophysiology from viral infection to myocardial inflammation and apoptosis. The interplay between the myocardial microbial-induced agents and the different components of the patient’s immune system determines the histological and clinical phenotype [7,9].
Viruses enter the body via the upper respiratory tract, bronchial tree, or gastrointestinal tract, where they may either penetrate the circulation and affect the heart directly or reside into the reticuloendothelial system (e.g. endothelial cells or bone marrow) as an extra-cardiac reservoir, maintaining the potential to infect myocardial fibres at any time later in life [6,8].
Viruses have a distinct pattern of infection. Enteroviruses such as Coxsackieviruses primarily infect myocytes inducing lytic processes, whereas erythroviruses such as parvovirus B19 only infect endothelial cells within the myocardium, thereby inducing apoptosis by endothelial dysfunction and secondary inflammation7.
This acute phase of myocardial infection is followed by a phase of chronic inflammation with autoreactive immunopathogenesis. This may develop via a persistent viral infection, but is also found independently. This phase is of clinical importance as it determines mid- to long-term myocardial damage with clinical signs of impaired cardiac systolic function and arrhythmias .
Special aspects in athletes
Athletes are more exposed to microbes than the general population. There may be an increased risk of infection in certain sports such as orienteering (exposure to ticks and borreliosis) or contact sports with higher potential of droplet infection (e.g. boxing). Furthermore, elite athletes gather in large groups for training in extreme environments (e.g. skiers in Chile, cross-country skiers in Lapland), which further increases the likelihood of infection, and there is also the possibility of impaired immune competence, for example at higher altitudes during mountain training.
Additionally, elite athletes come from all over the world and sport events are organized globally, so that these athletes are all prone to potential infection by microbes during training and competition. These include bacterial infections such as tuberculosis, which is ubiquitous but is more common in third world countries, Chagas disease, which is primarily present in South America, and schistosomiasis (bilharziosis), which is present in Japan, China, Africa, Arabia, South America, and the Caribbean.
Athletes may also be taking medication, such as tricyclic antidepressants, or drugs, such as cocaine. Therefore it is crucial to take a thorough medical history, focusing particularly on travel schedules in the preceding months, in order to make a diagnosis. Thus physicians assessing athletes with cardiac problems should be familiar with characteristic signs and symptoms of diseases including those not commonly present in Europe.
A summary of viral myocarditis is given in Box 184.108.40.206.
Exercise and myocarditis
Clinical data linking strenuous prolonged exercise to manifestation of myocarditis and deterioration in health have not been assessed in humans, but clinical experience clearly shows this relationship. Mild forms of myocarditis or perimyocarditis are more likely to be involved, because of their relatively high prevalence in athletes.
Animal studies indicate that a reduction of immune competence induced by exercise increases mortality in a murine model of Coxsackie virus B3 myocarditis [10,11]. In addition, it has been clearly shown that strenuous exercise may impair immunological competence, increasing the risk of upper respiratory tract infection  and possibly myocardial involvement. This is exaggerated in extreme environmental conditions.
Athletes are different from sedentary individuals with respect to their perception of clinical symptoms (see Box 220.127.116.11). As they have been exercising for decades and know their body extremely well at rest as well as its reaction during exercise and recovery, the perception of a mild general decline of exercise capacity or muscular strength, although expressed vaguely, can well be one of the early signs of myocardial involvement in myocarditis. These symptoms often represent a subacute state that will not be diagnosed immediately as myocarditis, as several clinical parameters, including ECG and echocardiography, may be unremarkable. In these cases athletes present with higher heart rates at rest and during comparable exercise intensities, experience muscle soreness, and reduced general ‘drive’. In these conditions diagnosis of mild forms of perimyocarditis or myocarditis is difficult, particularly as symptoms include only reduced exercise performance and body discomfort, sometimes accompanied by mild depressive symptoms, which are also characteristic of an ‘overtraining syndrome’ whose cause is still unresolved but also includes viral pathogens. In all these cases myocarditis should be suspected and be at the top of a clinical work-up list for athletes.
Typical symptoms that are more straightforward for supporting the diagnosis of myocarditis are chest pain, particularly when lying on the left side in pericardial involvement, and palpitations caused by atrial as well as ventricular arrhythmias. Atrial fibrillation in young athletes is generally rare, but definitely requires a myocardial work-up, including CMR for excluding perimyocarditis (see Case 1 in Box 18.104.22.168 and Fig. 22.214.171.124). Episodes of atrial fibrillation are almost always self-limiting, lasting for only minutes, but remain indicative of perimyocarditis involving the area of the left atrium. Although the incidence of atrial fibrillation in older endurance athletes is greater and is not usually caused by acute viral myocarditis, the diagnosis of myocarditis has to be excluded. The diagnosis is clear when pericardial effusion is present in echocardiography.
New onset of ventricular arrhythmias at rest or during exercise in athletes should suggest a work-up for acute myocarditis. As athletes are very sensitive to their bodies, these ectopic beats are perceived as palpitations and will often lead to direct presentation to a physician for clinical work-up. Ventricular arrhythmias seem to be more or less independent of exercise. Interestingly, it is often observed that, in comparison with the resting state, the number of ventricular arrhythmias decreases rather than increases during exercise. This is usually different from coronary ischaemia where the number of arrhythmias increases during exercise. Because of a low resting heart rate, often <50bpm in endurance athletes, these ventricular ectopic beats may cause light-headedness, dizziness, or even presyncope.
On routine examination in pre-participation screening, athletes without major symptoms at rest or during exercise will be diagnosed by echocardiography, revealing a reduced left ventricular ejection fraction which is usually mild, but can sometimes be as low as 40%. Also, a pericardial effusion is easily diagnosed in a routine check-up by echocardiography. The effusion is usually small, but sometimes extends up to 1cm or more. In almost all cases a sound clinical work-up will not yield a specific viral antigen. Most of these athletes present in a subacute state of undetected myocarditis. Pericardial effusion will commonly resolve within a month, but can persist for several months in some cases.
Analyses for the diagnosis of myocarditis, including evidence for inflammation, cardiac biomarkers, and virus serology, are the same for both athletes and sedentary individuals, and include troponin I and CK-MB. However, cardiac markers such as CK, troponin I/T, and myoglobin may be physiologically elevated in athletes after an intensive training session or strenuous competition . In addition, only approximately 25% of myocarditis cases reveal elevated troponin levels [14,15]. Virus serology is often inconclusive, and is not generally recommended as serology and endomyocardial biopsy (EMB) overlap in only 10% of the cases.
Characteristic ECG abnormalities in myocarditis are tachycardia, atrial fibrillation, AV block, low voltage as in pericardial effusion, ST elevation in leads from different regions (lateral, inferior, posterior, anterior), T-wave inversions, and ventricular ectopy.
Atrial fibrillation or atrial ectopic beats, pericardial effusion, and ST elevation are more characteristic of pericarditis, whereas conduction abnormalities or ventricular ectopy are more often seen in myocarditis. ECG abnormalities may be present in combination and then often represent perimyocarditis (see Case 2 in Box 126.96.36.199 and Fig. 188.8.131.52).
Echocardiography is mandatory and is a key diagnostic tool in the clinical work-up for myocarditis. Left ventricular ejection fraction and global or local impairment of LV function may be reduced in myocarditis. Regional as well as global impairment is observed. Sometimes a patchy pattern can be seen, mostly in the septal region, but a normal texture does not exclude acute or subacute myocarditis. A slight thickening of the myocardial wall associated with diastolic impairment may also be present. In an elite endurance athlete it is difficult to differentiate an LV dilatation as found in myocarditis from a physiological athlete’s heart when previous examinations are not available for comparison.
In addition, a close evaluation of all four valves is mandatory to exclude bacterial endocarditis. A pericardial effusion will lead to the diagnosis of pericarditis. Stress-echocardiography will not yield additional information.
Exercise testing is not a core diagnostic tool for assessing myocarditis. It rarely adds any diagnostic results beyond resting ECG. During the acute phase ergometry should not be performed, and in the subacute phase exertion should be limited to submaximal intensities. In subacute or healed myocarditis reduced frequency of ventricular ectopic beats is often observed during exercise.
Twenty-four hour Holter monitoring
Monitoring of arrhythmias is an important diagnostic tool in myocarditis and pericarditis during the acute phase and for follow-up. It should be included in the diagnostic work-up performed every six weeks during the first three months.
Cardiac magnetic resonance
CMR is the gold standard for assessing myocarditis because of its ability to assess myocardial oedema and scarring. Nevertheless it cannot replace myocardial biopsy for differentiating between different forms of myocarditis (e.g. giant cell myocarditis and others).
In myocarditis the most important CMR sequences are T2-weighted images for assessing myocardial oedema and late gadolinium enhancement (LGE) for assessing scarring (see Case 1 in Box 184.108.40.206). LGE reveals a typical sub-epicardial or patchy pattern distributed within the myocardium. LGE is usually localized within the lateral wall (see Case 1 in Box 220.127.116.11).
Ninety per cent of patients with acute myocarditis have a positive LGE . Persistence of positive LGE is clinically valuable as it is the best predictor of death in patients with viral myocarditis  (see Box 18.104.22.168). It reveals a hazard ratio of 8.4 for all-cause mortality and 12.8 for cardiac mortality, findings which are independent of clinical symptoms. The sensitivity of LGE is approximately 50–60% [15,17]. When morphology and myocardial function are added to LGE, the sensitivity for myocarditis is 84% . This is superior to functional parameters such as ejection fraction, enlargement of the left ventricle, or New York Heart Association (NYHA) class (HR 1.0–2.2. for cardiac mortality) . The presence of LGE places a patient, irrespective of disease entity, at higher risk for sudden cardiac death (SCD). Occurrence of SCD in patients without LGE is very unlikely, even in the presence of impaired LV function .
Data from Grun S, Schumm J, Greulich S et al. Long-term follow-up of biopsy-proven viral myocarditis: predictors of mortality and incomplete recovery. Journal of the American College of Cardiology, Volume 59, pp. 1604–1615. Copyright © 2012 Elsevier.
EMB is the definitive test to confirm myocarditis. However, the indication remains limited and should be carried out in experienced centres, where it can be performed with a low rate of complications. In young individuals with significantly impaired myocardial function and new-onset heart failure it should be performed as soon as possible. CMR may help with guidance to the EMB site. EMB should not be performed in athletes with evidence of pericarditis in CMR without involvement of the myocardium (see Box 22.214.171.124).
Therapy of myocarditis focuses on the treatment of heart failure following the ‘unloading heart’ principle when function is impaired . Therefore exercise should be strictly avoided. In addition, medication is aimed at blocking neuro-hormonal activation. Anti-inflammatory treatment with non-steroidal anti-inflammatory drugs (NSAIDs) should be limited to patients with pericardial involvement and symptoms only. The lowest dose required to relieve symptoms should be followed. Colchicine has shown positive effects in both chronic and as acute forms. Immunosuppressive treatment by prednisolone or azathioprine, immunoglobulins, immuno-adsorption, or anti-viral treatment is still being evaluated in research settings. If there is evidence of giant cell myocarditis, this should be treated with prednisolone and azathioprine.
As a myocardial manifestation of adenovirus and enterovirus infection may be suspected particularly during or after upper respiratory tract infection or gastroenteritis, athletes should be more cautious when they experience symptoms of coughing, sore throat, running nose, or diarrhoea. These viruses are not only cardiotropic, but may also cause peripheral muscle soreness and joint pain often accompanied by a general body tiredness. If this is present or even accompanied by sub-febrile temperatures, the athlete should completely refrain from any strenuous physical activity, as this may further impair immunological response and capacity by increasing the potential for systemic viral circulation and myocardial infection. In addition to this pathological mechanism of immunosuppression by exercise, other mechanisms include increased transition of viruses from the respiratory system to the circulation and impairment of the integrity of the gastro-intestinal tract.
Therefore athletes with a viral infection should be particularly cautious and refrain completely from exercise during the acute phase. The two key components that limit any intentional exercise are systemic tiredness and an increase in body temperature (which may only be slight). Exercise can be started again when these general symptoms of a cold have resolved. It is a generally accepted that a period of at least 3–5 days without symptoms should elapse before starting exercise of moderate intensity. In more severe cases this should be extended to 7–10 days. This strict regime can be modified when mild symptoms, such as those in a mild case of influenza, are present.
Exercise recommendation in myocarditis
In acute severe myocarditis, which has led to admission to hospital and even caused a reduction of left ventricular ejection fraction, exercise is strictly forbidden during the acute phase. The rest period depends on the severity and course of the disease. Therefore resumption of exercise strongly depends on clinical presentation, such as impairment of LV ejection fraction, arrhythmias, conduction ECG abnormalities, or pericardial effusion. In these cases exercise should not be started until six months after recovery [2,18].
Most athletes experience only mild forms of myocarditis, which do not require admission to hospital. However, intentional strenuous endurance exercise is strictly forbidden even in these mild forms. In addition, resistance exercise must not be performed until all symptoms have completely resolved.
Exercise can be increased slowly during the recovery phase. If all the pathologies have resolved, moderate exercise of short duration (e.g. 5–10min) can be performed more times daily. Recovery phases are also very important, and training days should be followed by resting or recovery days. Initial training intensity is strictly submaximal, with lactate levels below 2.0mmol/l or lower than VT1 in spiro-ergometry. Duration can be continuously increased. This should be the primary target before increasing the intensity of exercise.
Eligibility for competitive sports
The official guidelines of the European Association of Preventive Cardiology (EAPC), formerly EACPR, and the Scientific Statement of the American Heart Association  recommend that athletes with a diagnosis of myocarditis should be excluded from both competitive and amateur leisure-time sports activity for six months. This covers the whole spectrum of disease when the myocardium is involved, as best documented by CMR.
After this period all athletes should be re-evaluated prior to resuming competitive sports. During this phase clinically stable patients can perform daily activities such as cycling to work, walking, and similar activities. Intensity should clearly be limited to low-moderate physical activity. This intensity is best prescribed in the form of a maximal heart rate assessed in a sub-maximal exercise test (aerobic exercise capacity).
If the myocardium is unaffected and the disease is limited to the pericardium, as in pericarditis, athletes should also be excluded from competitive and amateur sports activities. The exclusion period is shorter than for myocarditis, and exclusion for competitive sports is recommended to be at least three months. If pericarditis leads to constrictive disease, then exercise is limited per se and treatment options should be evaluated.
If symptoms (overall reduced physical exercise capacity or more severe signs such as arrhythmias, impaired ejection fraction, or prolonged signs of myocardial involvement on CMR such as oedema) continue beyond these three or six months, then this period will have to be extended. A work-up for athletes is shown in Fig. 126.96.36.199.
It is of particular importance to specify activities regarding mode, duration, intensity, and frequency for elite athletes, as they have a different perception of ‘low activity’ than normal or sedentary patients. In some the advice of ‘low activity’ is perceived as ‘cycling or running for an hour every day’. In addition, golf may be a form of exercise that is perceived by the physician from his or her experience as of low to moderate cardiopulmonary intensity. However, it must be realized that in elite sports even golf poses a cardiopulmonary strain, and training consists of additional types of exercise, such resistance exercise, on a daily basis. Therefore recommendations for elite athletes to return to participation in competitive sport should be prescribed cautiously (see Box 188.8.131.52).
Data from Maron BJ et al. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 3: Hypertrophic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy and Other Cardiomyopathies, and Myocarditis: A Scientific Statement From the American Heart Association and American College of Cardiology. Circulation, Volume 132, pp.273–80. Copyright © 2015 American Heart Association.
Data from Pelliccia A, Corrado D, Bjornstad HH, Panhuyzen-Goedkoop N, Urhausen A, Carre F, Anastasakis A, Vanhees L, Arbustini E, Priori S. Recommendations for participation in competitive sport and leisure-time physical activity in individuals with cardiomyopathies, myocarditis and pericarditis. Eur J Cardiovasc Prev Rehabil 2006;13:876–85.
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