Journal of Cardiovascular Translational Research https://doi.org/10.1007/s12265-020-09996-1

REVIEW ARTICLE

Myocarditis in the Athlete: Arrhythmogenic Substrates, Clinical Manifestations, Management, and Eligibility Decisions

Riccardo Vio1 & Alessandro Zorzi1 & Domenico Corrado1

Received: 3 October 2019 /Accepted: 24 March 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract is as an important cause of sudden cardiac death (SCD) among athletes. The incidence of SCD ascribed to myocarditis did not change after the introduction of pre-participation screening in Italy, due to the transient nature of the disease and problems in the differential diagnosis with the athlete’s heart. The arrhythmic burden and the underlying mechanisms differ between the acute and chronic setting, depending on the relative impact of acute versus post-inflammatory myocardial fibrosis. In the acute phase, ventricular vary from isolated ventricular ectopic beats to complex tachy- cardias that can lead to SCD. Atrioventricular blocks are typical of specific forms of myocarditis, and supraventricular arrhyth- mias may be observed in case of atrial inflammation. Athletes with acute myocarditis should be temporarily restricted from physical exercise, until complete recovery. However, ventricular may also occur in the chronic phase in the context of post-inflammatory myocardial scar.

Keywords Myocarditis . Athletes . Sport . Ventricular ARVC Arrhythmogenic right ventricular tachycardia . Ventricular . . . Sudden death

Introduction

Abbreviations Myocarditis is an inflammatory disease of the heart muscle AM Acute myocarditis most often caused by infectious agents (infective myocar- SCD Sudden cardiac death ditis), autoimmune conditions, or pharmacological and en- EMB Endomyocardial biopsy vironmental toxins (non-infective myocarditis) [1]. LGE Late gadolinium enhancement Infective myocarditis due to viral agents (coxsackievirus, CMR Cardiac magnetic resonance adenovirus, parvovirus, and herpes virus) is fairly the most AV Atrioventricular common form of the disease and is usually characterized LV Left ventricular by a benign prognosis [2]. The majority of patients with AF Atrial fibrillation acute myocarditis (AM) have a mild and transient cardiac VF involvement, most often mimicking the clinical features of VT acute coronary syndromes, and a favorable clinical course ICD Implantable cardioverter defibrillator with a complete clinical recovery; acute and sudden cardiac death (SCD) are less common clinical pre- Associate Editor Domingo A. Pascual-Figal oversaw the review of this sentations [1, 3, 4]. Post-inflammatory myocardial article sequelae are not so rare and consist of repair subepicardial-midmural myocardial fibrosis which occurs * Domenico Corrado [email protected] as a result of the healing process of a previous acute myo- cardial lesion [5]. There is growing evidence that non- 1 Department of Cardiac, Thoracic, Vascular Sciences and Public ischemic myocardial scar, either post-myocarditis or due Health, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy to other myocardial diseases, may act as a substrate of J. of Cardiovasc. Trans. Res. life-threatening ventricular arrhythmias and arrhythmic Challenges in the Diagnosis of Acute Myocarditis , mostly in young people and athletes [6]. in the Athlete The present article reviews the etiology, pathogenesis, clin- ical manifestations, risk stratification, and management of Definitive diagnosis of AM relies on histologic demonstration myocarditis occurring in the athlete, with particular reference of myocardial inflammatory infiltrates and myocyte degener- to the different arrhythmogenic substrates and mechanisms ation and death on endomyocardial biopsy (EMB). However, acting in the acute and chronic disease settings. the use of EMB is uncommon in the routine clinical practice and according to current guidelines the invasive approach for histologic examination of myocardial samples is reserved to Myocarditis in the Athletes selected clinical scenarios that do not include most common benign and self-limiting presentation [26]. In the absence of Although definite evidence is lacking, athletes may be EMB confirmation, the clinical diagnosis of myocarditis is at higher risk of developing myocarditis than the gener- strongly suspected or highly probable in the presence of ≥ 2 al population. Sports activity can influence the suscep- criteria including compatible clinical symptoms, electrocar- tibility to infections, depending on the intensity and du- diographic abnormalities, elevation of myocardiocytolysis ration of the physical exercise. While moderate physical markers, evidence of non-ischemic morphofunctional ventric- activity may improve immunological defenses [7–9], in- ular abnormalities, and increased T2 signal for myocardial tense and prolonged training and competition lower the /regional late gadolinium enhancement (LGE) at cardi- immunity by reducing salivary secretory immunoglobu- ac magnetic resonance (CMR) [1]. lin A, lactoferrin, and lysozyme and altering the T cell Personal and family history, physical examination, and 12- response, all mechanisms that may increase the vulner- lead ECG are crucial in the initial evaluation of athletes with ability of athletes to viral infections [7, 8, 10–14]. Non- suspected myocarditis. Symptoms, such as chest , dys- infective myocarditis, i.e., immune-mediated and toxic pnea, and fatigue, possibly start after a respiratory or gastro- myocarditis, may also be favored. intestinal infection. Sports activity may also worsen the pathobiological At the electrocardiogram, repolarization abnormalities are course of AM [15–18]. Murine models of myocarditis by the most common alterations in AM, being detected in 40% of coxsackievirus B3 showed a striking augment in the viru- patients; ST segment elevation (typically concave and diffuse lence of the pathogen agents when the animals were forced without reciprocal changes) is more frequent than ST segment to swim [15]. The acceleration of coxsackie B3 myocardi- depression (6% vs 2%), and negative T waves (36%) are ob- tis course induced by exercise was also reported by Kiel served mainly in lateral leads [27]. These ECG changes are et al., who observed that exercise increased both the extent typically transient in AM [28], and even when present, their of myocardial cell necrosis and overall mortality [16]. significance might be uncertain since athletes frequently show Worsening of the myocardial pathological damage can oc- repolarization abnormalities (i.e., early repolarization) [29]. cur not only in viral myocarditis but also in autoimmune The most notable ECG feature of early repolarization is ST myocarditis as demonstrated by the increase of both hu- segment elevation, which may vary on morphology, location, moral and cellular immunities against the heart muscle in anddegree;Twaveinversioncanalsobeobservedparticular- mice exercised by treadmill [19]. ly in black athletes but confined to leads V1-V4 [30]. Myocarditis has been traditionally regarded as cause of Pathologic Q waves are reported in 13% of patients with life-threatening ventricular arrhythmias and SCD in the AM [27], whereas they are rare in athletes [31]. PR segment athletes. The incidence of SCD due to AM in the athlete depression and low voltages can reveal the existence of peri- ranges from 2 to 12% of all fatalities [20–24]. Data from cardial inflammation and effusion and tend to disappear the registry of juvenile SCD of the Veneto region of Italy throughout the healing process. Other ECG changes include showed that the mortality did not significantly change atrioventricular (AV) and bundle branch blocks. before and after the implementation of systematic pre- Electrocardiographic differential diagnosis between AM and participation screening in Italy (from 0.3/100.000 to athlete’s heart is summarized in Table 1. 0.15/100.000, p =0.42)[25]. Failure to identify athletes Biomarkers indicative of myocardial injury are usually el- with myocarditis by pre-participation screening reflects evated in myocarditis; however, the majority of healthy ath- the acute and unpredictable nature of the inflammatory letes after prolonged exercise show values of cardiac troponin process, which often is clinically silent and may lead to above the 99th percentile [32]. electrical ventricular instability and cardiac arrest in oth- Echocardiography may solve the dilemma, identifying erwise asymptomatic individuals. Furthermore, highly signs of the disease such as global left ventricular (LV) en- trained athletes tend to underestimate or hide symptoms largement and dysfunction, localized wall motion abnormali- to avoid limitations to competitive sports eligibility. ties, and relaxation alterations suggestive of the presence of J. of Cardiovasc. Trans. Res.

Table 1 Electrocardiographic differential diagnosis between acute myocarditis and athlete’sheart

Acute myocarditis Athlete’sheart

Repolarization abnormalities - ST segment elevation Diffuse Localized (usually in the anterior leads) or diffuse - ST segment depression Possible Absent - inversion Mainly in lateral or inferior leads Confined to V1-V4 in Afro-Caribbean athletes Q waves Pathological (amplitude ≥ 25% of the ensuing R wave Non-pathological (≥ 4 mm in depth but < 25% of and/or ≥ 0.04 s in duration) the ensuing R wave and < 0.04 s in duration) Voltages of the QRS Low High PR segment depression Possible Absent AV block Any degree First-degree or second-degree type 1 Left or right bundle branch block Incomplete right bundle branch block

inflammatory lesions [33, 34]. Modest bradyarrhythmia), syncope, or SCD [37–40]. Table 2 reports and increased reflectivity of the pericardial leaflets may be the prevalence of various arrhythmias in AM. observed. Of note, both patients with myocarditis and athletes may show mild depression of the LV ejection fraction at rest, but in healthy athletes, wall motion abnormalities are always Supraventricular Arrhythmias absent. Moreover, exercise echocardiography can exacerbate regional wall motion abnormalities and further reduce the is a common finding in AM as a result of the ejection fraction in patients with myocarditis while systolic and heart failure. Adrenergic stimula- function typically normalizes in healthy athletes during exer- tion occurring in atrial inflammation is involved in the onset of cise [35]. atrial tachyarrhythmias [3]. In fact, the inflammatory process CMR imaging has emerged and progressively gained im- of AM often extends to the atria; atrial myocarditis in the portance as a non-invasive modality for the diagnosis of AM absence of ventricular involvement has also been reported by identifying regions with myocardial edema (T2-weighted [41–44]. sequences) and providing information on myocardial damage/ Since either local or systemic inflammation is associated necrosis by the technique of LGE. Specific imaging criteria with induction and maintenance of atrial fibrillation (AF) (“Lake Louis” criteria) can be used to confirm the diagnosis of in the general population [45, 46], it is not surprising that AM based on demonstration of epicardial and/or this represents a common complication in myo- midmyocardial edema, hyperemia, and myocardial fibrosis/ carditis, with a reported prevalence of 2.5–14% [27, 39, LGE [36]. Edema and LGE are usually absent in athletes, 47]. The postulated mechanism is that the inflammatory although the former is rarely seen after exercise and the latter process causes an increased automaticity of the atrial myo- can be the sign of a previous silent myocarditis or of an un- cardium resulting in the occurrence of atrial ectopic beats, derlying cardiomyopathy (see below) [6, 35]. which may trigger AF [48]. In patients with Wolff- Parkinson-White syndrome who died suddenly, Basso Arrhythmias in Acute Myocarditis et al. demonstrated the presence of inflammatory infiltrates in the atrial myocardium close to the accessory pathway, a The mechanisms involved in the pathogenesis of myocarditis finding which substantiates a cause-effect relationship be- are not fully understood and still remain an open field of tween atrial myocarditis and rapid pre-exited AF research. The majority of the studies focused on viral and degenerated into ventricular fibrillation (VF) [49]. autoimmune myocarditis, postulating a three-phase process Inflammatory-mediated increase of ectopic activity arising from acute injury to chronic [1]. from the pulmonary vein, which is a well-recognized trig- Acute injury leads to cardiac damage, exposure of intracellular gerofAF[48, 50–52], may also induce focal atrial tachy- antigens, and activation of the innate immune system. cardia and in patients with dual AV node pathways or ac- Inflammatory infiltrates and dying myocytes predispose to cessory pathways, paroxysmal supraventricular tachycar- the development of tachyarrhythmias, either supraventricular dia [53]. Atrial inflammation leading to myocyte necrosis or ventricular [5]. and fibrotic changes creates a structural myocardial sub- It has been reported that in up to 24% of cases, the first strate which worsens the electrical atrial instability and clinical manifestation consists of arrhythmias (either tachy- or favors the arrhythmia permanence [54]. J. of Cardiovasc. Trans. Res.

Table 2 Prevalence of arrhythmias in patients with acute myocarditis

Arrhythmia Prevalence (%) Studies

Sustained supraventricular tachycardia 0.8 Anderson (2014)a Atrial fibrillation/ 2.5–14 Imazio (2008) Anzini (2013) Ukena (2011) Non-sustained ventricular tachycardia 28 Anzini (2013) Sustained ventricular tachycardia or ventricular fibrillation/flutter 7.3–9.7 Anzini (2013) Anderson (2014)a AV blocks (any degree) 10 Caforio (2007) a Pediatric population

Atrioventricular Blocks Several mechanisms have been proposed to explain the onset of ventricular arrhythmias in AM. First, myocarditis AV block is traditionally associated with myocarditis, being may cause myocardial similar to coronary artery reported in 10% of biopsy-proven AM patients [37]. While disease. Ischemic mechanisms include mural thrombi, coro- first-degree AV block is frequently encountered, advanced AV nary artery embolization, and arteritis [64]. In addition, vaso- block is uncommon and observed in specific variants of myo- active and catecholamines produced during the acute carditis, such as myocarditis, sarcoidosis, and bac- phase of viral infection can cause coronary artery spasm [65]. terial or protozoal AM. Another mechanism contributing to the arrhythmic pheno- Giant cell myocarditis is a rare and rapidly progressive type of AM is myocardial edema (Fig. 2): local inflammation, inflammatory heart disease usually characterized by an omi- release, and cell death constitute the basis for its nous prognosis [55]. In a recent series of patients diagnosed formation, resulting in some cases in LV tumefaction (i.e., with giant cell myocarditis, distal AV conduction block was inflammatory pseudo-hypertrophy) [33, 36]. A recent study reported in 28% of cases [56]. demonstrated that the electrocardiographic expression of High-degree AV block is typically observed in cardiac sar- transmural edema consists is the inversion of the T waves in coidosis (i.e., idiopathic granulomatous myocarditis), which is the ECG leads exploring the affected LV wall, and interest- also complicated by ventricular tachycardia (VT) or VF and ingly such ECG abnormalities normalized completely during SCD which may represent the first clinical manifestation of follow-up, underscoring its transient and acute nature (Fig. 3) the disease [57–59]. Autopsy studies reported the presence of [28]. There is experimental evidence that acute inflammation myocardial in 20–30% of patients, with a patchy can modify the electrophysiological properties of the myocar- fashion distribution, although some regions are preferred in- dium through multiple mechanisms, favoring ventricular ar- cluding the interventricular septum and atria, potentially jus- rhythmias [62–66]. tifying the conduction defects [60]. Finally, AM has been associated with clinical deterioration Myocardial inflammation by bacterial and protozoal infec- of pre-existing cardiac diseases, such as hypertrophic cardio- tion typically causes bradyarrhythmia. In this regard, Lyme myopathy [66]. Arrhythmogenic right ventricular cardiomy- and diphtheria myocarditis are both bacterial infection charac- opathy (ARVC) patients suffering arrhythmic storms fre- teristically associated with various degree of AVblock (Fig. 1) quently displays sign of acute inflammation at CMR or [61, 62]; is a protozoal infection caused by EMB (so-called hot-phase), although the inflammatory mech- Trypanosoma cruzi, which can present clinically as AM with anism (viral versus immune-mediated) remains to be right bundle branch block or left anterior fascicular block po- established [67–69]. tentially leading to complete [63].

Ventricular Arrhythmias Arrhythmias in the Chronic Phase

Ventricular arrhythmias vary from simple isolated ventricular Three arrhythmic mechanisms may explain the occurrence of ectopic beats to complex and life-threatening . life-threatening ventricular arrhythmias in patients after an Anzini et al. documented the presence of non-sustained VT episode of AM: 1) recurrent myocarditis or persistent myocar- in 28% of AM patients, whereas sustained VT or VF repre- dial inflammation; 2) residual LV dysfunction and 3) post- sented the first clinical manifestation in 7% of patients [39]. inflammatory myocardial scar. J. of Cardiovasc. Trans. Res.

Fig. 1 Serial electrocardiograms and CMR imaging of a young athlete and inflammatory “pseudo-hypertrophy” (b). One week after the myocar- with acute Lyme myocarditis, presenting with cardiogenic shock and ditis onset, the ECG demonstrated the restoration of normal AV conduc- third-degree AV block. A 19-year-old male football player was admitted tion (c). The CMR before discharge showed consistent reduction of myo- for cardiogenic shock. The ECG at admission showed complete AVblock cardial edema and reduction of the ventricular wall thickness (d). Lab (a). The CMR performed in the acute phase revealed circumferential tests conducted during hospitalization confirmed the infection from edema with the highest signal intensity in the interventricular septum Borrelia burgdorferi

Fig. 2 Coronary angiography and CMR imaging of patient with biopsy proven acute myocarditis who suffered out-of-hospital car- diac arrest. Out-of-hospital cardi- ac arrest occurred in a 41-year-old male with biopsy-proven AM. Coronary angiography showed normal right (a) and left (b)cor- onary arteries. CMR showing myocardial edema (two cham- bers, long axis view; T2-weighted sequences) (c) and transmural LGE (two chambers, long axis view; T1-weighted inversion re- covery post-contrast sequences) (d) affecting the mid-apical infe- rior LV wall. Modified and reproduced with permission from [90] J. of Cardiovasc. Trans. Res.

Fig. 3 Cardiac magnetic resonance findings in a representative patient sequences (b). Semiquantitive analysis by CMR42, Circle with inferior T wave inversion. ECG at the time of CMR showing the Cardiovascular Imaging Inc. software showing the transmural arrange- presence of negative T waves in inferior leads (a). Long-axis three-cham- ment of myocardial edema (c). Modified and reproduced with permission ber view showing infero-lateral myocardial edema in T2-weighted from [28]

The healing process of AM can cause a myocardial scar The role of myocardial fibrosis as a source of ventricular that can act as a substrate for life-threatening ventricular arrhythmias was demonstrated by an outcome study on 405 tachyarrhythmias even in subjects with a normal LV function. patients with clinically suspected myocarditis. During a mean Post-inflammatory fibrosis typically shows a “band” pattern follow-up of 4.4 years, major arrhythmic events occurred only and involves the subepicardial/midmyocardial layers of the in patients with evidence of LV myocardial LGE/scar at CMR infero-lateral LV wall [36]. Such lesion can be evidenced [85]. “in vivo” by gadolinium enhanced CMR sequences, while it Myocardial scar with a subepicardial/midmyocardial (i.e., is usually undetectable by echocardiography because fibrosis non-ischemic) distribution has been increasingly reported as a involves a small myocardial area and is confined to outer wall myocardial substrate for life-threatening ventricular arrhyth- layers without reaching the subendocardium, which is the part mias and cardiac arrest mostly in young people and athletes of the LV wall that most contributes to myocardial contractil- (Fig. 4)[6, 86–88]. A previous study reported that, during a ity [70]. The resting ECG is often unremarkable and this ex- mean 3-year follow-up, 6 (22%) athletes with ventricular ar- plains why the affected athlete is missed at pre-participation rhythmias and a non-ischemic LV scar experienced major ar- screening and its prevalence among middle-aged athletes en- rhythmic events such as appropriate implantable cardioverter gaged in long-term endurance sports activities is low (17/613, defibrillator (ICD) shock, sustained VT and SCD compared 2.8%) (Table 3)[71–84]. with none of control athletes with ventricular arrhythmias in J. of Cardiovasc. Trans. Res.

Table 3 Prevalence and pattern of distribution of LGE in athletes

Authors, year of No. Mean Males Inclusion criteria %LGE LGE pattern in athletes publication age (%) (years)

Mohlenkamp 102 57 100 Marathon runners (≥ 5 marathons in the last 3 years), age 12 (4 5: subendocardial 2008 > 50 years old con- 7: midmyocardial spot Breuckmann trols) 2009 Mousavi 2009 14 33 57 Marathon runners, moderately trained 0 O’Hanlon et al. 17 34 100 Marathon runners, mean 7 h training/week 0 2010 Oomah et al. 15 32 47 Half marathon runners, non-elite 0 2011 Wilson et al. 12 57 100 Endurance elite, various sports, > 50 years old 50 (0 4: junctional 2011 con- 1: subendocardial trols) 1: subepicardial/midmyocardial stria La Gerche et al. 40 37 90 Endurance, > 10 h/training, high performance 13 1: Junctional 2012 4: spots in the septum Erz et al. 2013 95 35 77 Endurance, > 7 h/week for > 2 years 2.1 1: inferior wall spot Mangold 2013 1: lateral wall spot Franzen et al. 40 41 100 Triathlon running, > 5 h/week for > 2 years 0 2013 Bohm et al. 33 47 100 Endurance, > 10 h/week for > 10 years 3 (0 1: subepicardial/midmyocardial stria 2016 con- trols) Sanchis-Gomar 10 40–70 ? long-term sports activity 20 2: subepicardial/midmyocardial stria et al. 2016 Merghani et al. 152 54 70 > 40 years of age, ran ≥ 10 miles or cycled ≥ 30 miles per 16 (11) 7: subendocardial ≥ ≥ 2017 week for 10 years, and competed in 10 endurance 8: subepicardial/midmyocardial stria events Tahir et al. 2018 83 43 65 Triathlon, > 10 h/week for > 3 years 11 (0 5: subepicardial/midmyocardial stria con- 1: transmural trols) 1: subendocardial 2: junctional

LGE late gadolinium enhancement the absence of LV scar. In 5 of 6 athletes the event occurred symptoms and the arrhythmogenic potential inherent to the during effort [6]. myocardial fibrosis. Although isolated LV LGE with subepicardial/ The available data indicate that in the presence of positive midmyocardial distribution is traditionally interpreted as the family history, symptoms, or ventricular arrhythmias, espe- consequence of a previous viral myocarditis, there is increas- cially if worsened by exercise, athletes with an isolated non- ing evidence that it may reflect a segmental inherited cardio- ischemic LV scar should prudentially refrain from practicing myopathy, namely, a left-dominant ARVC (Fig. 5). This sports activity with high cardiovascular demand. ARVC variant is characterized by fibrofatty myocardial re- placement of the LV and predisposes to life-threatening ven- Eligibility to Sports Activity tricular arrhythmias similarly to the classic right-ventricular dominant counterpart. Other genetically determined cardiac Athletes with proven myocarditis should be temporarily re- diseases may be associated with non-ischemic LV scars unre- stricted from exercise programs including competitive and lated to previous AM [85]. Hence, in the absence of an overt leisure-time sports activity [5]. Past European and American clinical history of a previous AM, the finding of a non- consensus documents recommended a minimum of 6 months ischemic LV scar in an asymptomatic athlete deserves proper of inactivity from the onset of the disease [86, 87]. This time clinical attention and cannot be simply dismissed as a sign of a period has been shortened to 3 months in more recent recom- healed remote inflammatory process. Particularly, affected mendations, but it can be extended to 6 months according to athletes should be accurately evaluated for family history, the clinical severity and duration of the illness, LV function, J. of Cardiovasc. Trans. Res.

Fig. 4 Representative case of an athlete who suffered sustained ventricular tachycardia secondary to post-inflammatory myocardial fibrosis. A 42-year-old martial art player presented with frequent and coupled premature ventricu- lar beats with right bundle branch block/superior axis morphology during exercise testing (a). The athlete experienced sustained VT during follow-up (b). Post- contrast sequences on contrast- enhanced CMR, 4-chamber view (c), and short-axis view (d)re- vealed a subepicardial/ midmyocardial “stria” of LGE involving the antero-lateral, later- al, and infero-lateral LV wall consistent with post- inflammatory myocardial fibro- sis. Modified and reproduced with permission from [6]

and extent of the inflammatory process on CMR [88, 89]. This tachyarrhythmias are excluded. Clinical follow-up every interval has been considered sufficient to ensure clinical and 6 months, particularly within the first 2 years, is recommended biological resolution of the disease. However, clinical reas- [88]. If the evaluation indicates the persistence of active myo- sessment is indicated before resuming competition, including carditis or the development of pro-arrhythmic scars, the ath- 12-lead ECG, echocardiography, exercise testing, 24-h Holter lete should be considered not eligible to competitive sports. monitoring, and blood sample. The athlete is allowed to restart With regard to non-ischemic LV myocardial fibrosis evi- training and competition if serum biomarkers and LV function denced by CMR, the recent ESC recommendations clearly normalize and major ventricular or supraventricular state that athletes with LGE and frequent or complex

Fig. 5 Contrast-enhanced CMR findings of an asymptomatic 23- year-old female carrying a desmoplakin-gene mutation. Four-chamber (a) and short axis (b) views showing LGE mostly involving the subepicardial layer of the postero-lateral LV wall at mid-basal level (white arrows), in the absence of other morpho- functional ventricular abnormali- ties. The electrocardiogram and echocardiogram of this patient were normal. Modified and reproduced with permission from [91] J. of Cardiovasc. Trans. Res. ventricular arrhythmias should refrain from competitive sports death in competitive athletes. Circulation Arrhythmia and [88]. Athletes with persistent LGE and no LV dysfunction or Electrophysiology, 9, e004229. 7. Brolinson, P., & Elliott, D. (2007). Exercise and the immune sys- frequent/repetitive arrhythmias can resume physical activity, tem. Clinical Journal of Sport Medicine, 26(3), 311–319. but a strict clinical surveillance is recommended, as they may 8. Nieman, D. C. (1999). 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