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Myocardial Fibrosis in Athletes

Published:October 06, 2016DOI:https://doi.org/10.1016/j.mayocp.2016.07.012

      Abstract

      Myocardial fibrosis (MF) is a common phenomenon in the late stages of diverse cardiac diseases and is a predictive factor for sudden cardiac death. Myocardial fibrosis detected by magnetic resonance imaging has also been reported in athletes. Regular exercise improves cardiovascular health, but there may be a limit of benefit in the exercise dose-response relationship. Intense exercise training could induce pathologic cardiac remodeling, ultimately leading to MF, but the clinical implications of MF in athletes are unknown. For this comprehensive review, we performed a systematic search of the PubMed and MEDLINE databases up to June 2016. Key Medical Subject Headings terms and keywords pertaining to MF and exercise (training) were included. Articles were included if they represented primary MF data in athletes. We identified 65 athletes with MF from 19 case studies/series and 14 athletic population studies. Myocardial fibrosis in athletes was predominantly identified in the intraventricular septum and where the right ventricle joins the septum. Although the underlying mechanisms are unknown, we summarize the evidence for genetic predisposition, silent myocarditis, pulmonary artery pressure overload, and prolonged exercise-induced repetitive micro-injury as contributors to the development of MF in athletes. We also discuss the clinical implications and potential treatment strategies of MF in athletes.

      Abbreviations and Acronyms:

      CAD (coronary artery disease), CMR (cardiac magnetic resonance imaging), ECG (electrocardiogram), LAD (left anterior descending), LGE (late gadolinium enhancement), LV (left ventricle), MF (myocardial fibrosis), RV (right ventricle)
      Article Highlights
      • Habitual physical activity is known to reduce the risk of future cardiovascular morbidity and mortality. Several studies exploring the relationship between physical activity and cardiovascular health have reported a curvilinear association. However, emerging evidence suggests that cardiac maladaptations may occur in a few endurance athletes who perform exercise at the upper end of the physical activity continuum. Among other observations (ie, enhanced coronary artery calcification, cardiac dysfunction, cardiac biomarker release, and arrhythmias), evidence of myocardial fibrosis (MF) has been reported in case reports and athletic population studies.
      • Typically, MF is observed in cardiac patients and is a predictive factor for adverse cardiac outcome, such as sudden cardiac death. Whether the development of MF in athletes is related to their exercise training and competition regimens or is secondary to (subclinical) cardiovascular disease is key because this provides essential insight into the underlying mechanisms.
      • Characterization of the phenotype of MF is important to allow early identification of athletes at risk. Furthermore, the pattern, location, and quantification of MF may importantly drive the choice of specific treatment strategies and lifestyle advice.
      Cardiac remodeling is a common adaptation in trained athletes that consists of increased left ventricular (LV) and right ventricular (RV) dimensions and atrial cavity size and is associated with normal systolic and diastolic function.
      • Pluim B.M.
      • Zwinderman A.H.
      • van der Laarse A.
      • van der Wall E.E.
      The athlete's heart: a meta-analysis of cardiac structure and function.
      • Utomi V.
      • Oxborough D.
      • Whyte G.P.
      • et al.
      Systematic review and meta-analysis of training mode, imaging modality and body size influences on the morphology and function of the male athlete's heart.
      The increase in cardiac dimensions typical of an athlete’s heart facilitates an increase in stroke volume and cardiac output during exercise.
      • Eijsvogels T.M.
      • Fernandez A.B.
      • Thompson P.D.
      Are there deleterious cardiac effects of acute and chronic endurance exercise?.
      It is generally accepted that exercise benefits cardiovascular health,
      • Eijsvogels T.M.
      • Molossi S.
      • Lee D.C.
      • Emery M.S.
      • Thompson P.D.
      Exercise at the extremes: the amount of exercise to reduce cardiovascular events.
      but myocardial fibrosis (MF) has been detected in endurance athletes by cardiac magnetic resonance imaging (CMR) using late gadolinium enhancement (LGE).
      • Wilson M.
      • O'Hanlon R.
      • Prasad S.
      • et al.
      Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes.
      • La Gerche A.
      • Burns A.T.
      • Mooney D.J.
      • et al.
      Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes.
      • Breuckmann F.
      • Möhlenkamp S.
      • Nassenstein K.
      • et al.
      Myocardial late gadolinium enhancement: prevalence, pattern, and prognostic relevance in marathon runners.
      • Mordi I.
      • Carrick D.
      • Bezerra H.
      • Tzemos N.
      T1 and T2 mapping for early diagnosis of dilated non-ischaemic cardiomyopathy in middle-aged patients and differentiation from normal physiological adaptation.
      • Karlstedt E.
      • Chelvanathan A.
      • Da Silva M.
      • et al.
      The impact of repeated marathon running on cardiovascular function in the aging population.
      • Erz G.
      • Mangold S.
      • Franzen E.
      • et al.
      Correlation between ECG abnormalities and cardiac parameters in highly trained asymptomatic male endurance athletes: evaluation using cardiac magnetic resonance imaging.
      • Mangold S.
      • Kramer U.
      • Franzen E.
      • et al.
      Detection of cardiovascular disease in elite athletes using cardiac magnetic resonance imaging.
      Myocardial fibrosis is defined by a significant increase in the collagen volume of myocardial tissue. It is a complex process that involves all components of the myocardial tissue and can be triggered by tissue injury from myocardial ischemia (hypoxia), inflammation, and hypertensive overload.
      • Zannad F.
      • Radauceanu A.
      Effect of MR blockade on collagen formation and cardiovascular disease with a specific emphasis on heart failure.
      Fibrosis generally occurs with cardiac remodeling secondary to diseases such as heart failure, hypertension, and valvular dysfunction.
      • Hill J.A.
      • Olson E.N.
      Cardiac plasticity.
      Myocardial fibrosis leads to increased myocardial stiffness,
      • Sugihara N.
      • Genda A.
      • Shimizu M.
      • et al.
      Diastolic dysfunction and its relation to myocardial fibrosis in essential hypertension.
      which increases LV end-diastolic and left atrial pressures. In animal models and patient studies, MF is also associated with reduced ventricular systolic function.
      • Iles L.
      • Pfluger H.
      • Phrommintikul A.
      • et al.
      Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping.
      Patients with MF have a higher incidence of ventricular arrhythmias
      • Diez J.
      Mechanisms of cardiac fibrosis in hypertension.
      • McLenachan J.M.
      • Dargie H.J.
      Ventricular arrhythmias in hypertensive left ventricular hypertrophy: relationship to coronary artery disease, left ventricular dysfunction, and myocardial fibrosis.
      and more adverse cardiac outcomes.
      • Kwong R.Y.
      • Sattar H.
      • Wu H.
      • et al.
      Incidence and prognostic implication of unrecognized myocardial scar characterized by cardiac magnetic resonance in diabetic patients without clinical evidence of myocardial infarction.
      Not all endurance athletes demonstrate MF,
      • Mousavi N.
      • Czarnecki A.
      • Kumar K.
      • et al.
      Relation of biomarkers and cardiac magnetic resonance imaging after marathon running.
      • Hanssen H.
      • Keithahn A.
      • Hertel G.
      • et al.
      Magnetic resonance imaging of myocardial injury and ventricular torsion after marathon running.
      • Trivax J.E.
      • Franklin B.A.
      • Goldstein J.A.
      • et al.
      Acute cardiac effects of marathon running.
      • Gaudreault V.
      • Tizon-Marcos H.
      • Poirier P.
      • et al.
      Transient myocardial tissue and function changes during a marathon in less fit marathon runners.
      • O'Hanlon R.
      • Wilson M.
      • Wage R.
      • et al.
      Troponin release following endurance exercise: is inflammation the cause? a cardiovascular magnetic resonance study.
      making the relationship between lifelong endurance exercise and the development of MF unclear. Furthermore, the clinical implications of MF in athletes are unknown. This systematic review summarizes the available data on the prevalence of MF in physically active individuals to identify predictors and the potential mechanism(s) of MF development and its clinical implications.

      Methods

      MF Assessment

      Myocardial fibrosis can be determined by microscopic examination of tissue samples or by CMR. Myocardial tissue is obtained in vivo by transvenous endomyocardial biopsy of the RV. Fibrillar collagen can then be quantified under polarized light after Picrosirius red
      • Lattouf R.
      • Younes R.
      • Lutomski D.
      • et al.
      Picrosirius red staining: a useful tool to appraise collagen networks in normal and pathological tissues.
      or Masson trichrome
      • Roberts W.C.
      • Siegel R.J.
      • McManus B.M.
      Idiopathic dilated cardiomyopathy: analysis of 152 necropsy patients.
      staining. Using CMR to assess LGE, a sign of MF, is preferred for assessment of focal MF because it is readily available, is noninvasive, and has the capacity to assess all the cardiac chambers. Alternatively, CMR-based contrast-enhanced T1 mapping can be used to assess diffuse MF.
      • Mewton N.
      • Liu C.Y.
      • Croisille P.
      • Bluemke D.
      • Lima J.A.
      Assessment of myocardial fibrosis with cardiovascular magnetic resonance.
      • Bull S.
      • White S.K.
      • Piechnik S.K.
      • et al.
      Human non-contrast T1 values and correlation with histology in diffuse fibrosis.

      Search Strategy

      We performed a systematic search of peer-reviewed studies that examined MF in athletes using cardiac biopsy or CMR. The literature was searched using the PubMed and MEDLINE databases up to June 1, 2016. Key Medical Subject Headings terms and keywords were included pertaining to MF (delayed [gadolinium] enhancement, pathological late gadolinium enhancement, myocardial late gadolinium enhancement, abnormal late gadolinium enhancement, fibrosis, myocardium, myocardial fibrosis, papillary muscles/pathology, ventricular dysplasia, and ventricular torsion) and exercise training (exercise, athletes, sports, sport, motor activity, marathon, triathlon, bicycling, swimming, physical endurance, marathon running, sports medicine, and exercise-induced).

      Selection of Studies

      The selection process consisted of review of the titles, abstracts, and full texts of articles by two authors (F.R.S. and T.M.H.E.), who later met to reach mutual consensus. The inclusion criteria were (1) fibrosis established by validated techniques and (2) a study population consisting of athletes, defined as “individuals who are proficient in sports, have routinely performed exercise training for an extended period of time and participate in sporting events.” The only exclusion criteria was underlying (genetic) cardiovascular disease, such as hypertrophic cardiomyopathy or arrhythmogenic RV cardiomyopathy.

      Results

      The systematic search yielded 33 studies: 19 case reports/series using biopsy (n=17) and CMR (n=2) to determine MF and 14 studies in athletic populations using CMR to determine MF (Figure 1).
      Figure thumbnail gr1
      Figure 1Flowchart of the search strategy to determine the prevalence of myocardial fibrosis (MF) in athletes. The following Medical Subject Headings keywords were used in the literature search: delayed enhancement, pathological late gadolinium enhancement, myocardial late gadolinium enhancement, abnormal late gadolinium enhancement, fibrosis, myocardium, myocardial fibrosis, papillary muscles/pathology, ventricular dysplasia, ventricular torsion, exercise, athletes, sports, sport, motor activity, marathon, triathlon, bicycling, swimming, physical endurance, marathon running, sports medicine, and exercise-induced.

      MF Reported in Case Studies/Series

      Case reports/series included 35 athletes (Table 1) participating in a wide range of sports: orienteering,
      • Larsson E.
      • Wesslen L.
      • Lindquist O.
      • et al.
      Sudden unexpected cardiac deaths among young Swedish orienteers: morphological changes in hearts and other organs.
      powerlifting,
      • Lakhan S.E.
      • Harle L.
      Cardiac fibrosis in the elderly, normotensive athlete: case report and review of the literature.
      basketball,
      • Schnell F.
      • Claessen G.
      • La Gerche A.
      • et al.
      Subepicardial delayed gadolinium enhancement in asymptomatic athletes: let sleeping dogs lie?.
      volleyball,
      • Zeppilli P.
      • Santini C.
      • Palmieri V.
      • Vannicelli R.
      • Giordano A.
      • Frustaci A.
      Role of myocarditis in athletes with minor arrhythmias and/or echocardiographic abnormalities.
      waterskiing,
      • Zeppilli P.
      • Santini C.
      • Palmieri V.
      • Vannicelli R.
      • Giordano A.
      • Frustaci A.
      Role of myocarditis in athletes with minor arrhythmias and/or echocardiographic abnormalities.
      soccer,
      • Thiene G.
      • Pennelli N.
      • Rossi L.
      Cardiac conduction system abnormalities as a possible cause of sudden death in young athletes.
      • Zeppilli P.
      • Santini C.
      • Palmieri V.
      • Vannicelli R.
      • Giordano A.
      • Frustaci A.
      Role of myocarditis in athletes with minor arrhythmias and/or echocardiographic abnormalities.
      • Lesauskaite V.
      • Valanciute A.
      Causes of sudden cardiac death in young athletes: the role of hypoperfusion.
      • Ottaviani G.
      • Lavezzi A.M.
      • Matturri L.
      Sudden unexpected death in young athletes.
      • Pressler A.
      • Schmid A.
      • Freiberger V.
      • Scherr J.
      • Uder M.
      • Halle M.
      Myocarditis, myocardial fibrosis and eligibility for competitive sports.
      (marathon) running,
      • Bharati S.
      • Dreifus L.S.
      • Chopskie E.
      • Lev M.
      Conduction system in a trained jogger with sudden death.
      • Rowe W.J.
      A world record marathon runner with silent ischemia without coronary atherosclerosis.
      • Lesauskaite V.
      • Valanciute A.
      Causes of sudden cardiac death in young athletes: the role of hypoperfusion.
      • Whyte G.
      • Sheppard M.
      • George K.
      • et al.
      Post-mortem evidence of idiopathic left ventricular hypertrophy and idiopathic interstitial myocardial fibrosis: is exercise the cause.
      • Bhella P.S.
      • Kelly J.P.
      • Peshock R.
      • Levine B.D.
      Delayed enhancement of the intraventricular septum following an extraordinary endurance exercise.
      cycling,
      • Poussel M.
      • Djaballah K.
      • Laroppe J.
      • Brembilla-Perrot B.
      • Marie P.Y.
      • Chenuel B.
      Left ventricle fibrosis associated with nonsustained ventricular tachycardia in an elite athlete: is exercise responsible? a case report.
      • Schnell F.
      • Claessen G.
      • La Gerche A.
      • et al.
      Subepicardial delayed gadolinium enhancement in asymptomatic athletes: let sleeping dogs lie?.
      and triathlon.
      • Harper R.W.
      • Mottram P.M.
      Exercise-induced right ventricular dysplasia/cardiomyopathy: an emerging condition distinct from arrhythmogenic right ventricular dysplasia/cardiomyopathy.
      To our knowledge, the first report of MF in athletes was published in 1983 and described MF in a soccer player.
      • Thiene G.
      • Pennelli N.
      • Rossi L.
      Cardiac conduction system abnormalities as a possible cause of sudden death in young athletes.
      Athletes ranged in age from 13 to 73 years at MF diagnosis, and 76% of the population was male. Although the sex and age of 6 athletes was not reported,
      • Heidbüchel H.
      • Hoogsteen J.
      • Fagard R.
      • et al.
      High prevalence of right ventricular involvement in endurance athletes with ventricular arrhythmias: role of an electrophysiologic study in risk stratification.
      • La Gerche A.
      • Robberecht C.
      • Kuiperi C.
      • et al.
      Lower than expected desmosomal gene mutation prevalence in endurance athletes with complex ventricular arrhythmias of right ventricular origin.
      most athletes with MF were young (20 of 35 were aged ≤30 years). In 12 athletes (34%), the biopsies were performed postmortem.
      Table 1Characteristics of Case Series and Reports of Myocardial Fibrosis (MF) in Athletes
      Reference, yearType of athleteYears of exercise/hours of sport per week/number of marathonsAge (y)SexDescription of MFMode of diagnosis
      Thiene et al,
      • Thiene G.
      • Pennelli N.
      • Rossi L.
      Cardiac conduction system abnormalities as a possible cause of sudden death in young athletes.
      1983
      Soccer player (n=1)Not specified24MalePatchy fibrosis, scattered myofibrillar degeneration with contraction bands, and initial polymorphonuclear neutrophil infiltrationBiopsy (postmortem)
      Bharati et al,
      • Bharati S.
      • Dreifus L.S.
      • Chopskie E.
      • Lev M.
      Conduction system in a trained jogger with sudden death.
      1988
      Runner (n=1)Trained on a regular basis47MaleMyocardial disarray, fibrosis, fatty infiltration, mononuclear cell infiltration of the left-sided bundle of His, and fibrosis of the right bundle branch; patchy fibrosis of the left side of the septumBiopsy (postmortem)
      Rowe,
      • Rowe W.J.
      A world record marathon runner with silent ischemia without coronary atherosclerosis.
      1991
      Marathon runner (n=1)Completed 524 marathons, most in <4 h

      Also cross-country ski and canoe races, triathlons, and ultramarathons
      62MaleFocal fibrosis of the LV papillary muscles consistent with remote ischemiaBiopsy (post-mortem)
      Zeppilli et al,
      • Zeppilli P.
      • Santini C.
      • Palmieri V.
      • Vannicelli R.
      • Giordano A.
      • Frustaci A.
      Role of myocarditis in athletes with minor arrhythmias and/or echocardiographic abnormalities.
      1994
      Basketball player (n=1)

      Soccer players (n=2)

      Volleyball player (n=1)

      Water-skier (n=1)
      Not specified17-2360% maleFibrosis prevailing in the RV with occasional focus of cellular necrosis (basketball player)

      Focal nonspecific fibrosis (soccer player)

      Diffuse, nonspecific fibrosis (soccer player)

      Myocarditis with fibrosis largely prevailing in the RV (volleyball player)

      Mild focal increase of the interstitial fibrous tissue, suggesting active myocarditis (water-skier)
      Biopsy (minor arrhythmias or echocardiographic abnormalities)
      Kindermann et al,
      • Kindermann W.
      • Janzen I.
      • Urhausen A.
      • Schieffer H.J.
      Heart enlargement in an athlete: a diagnostic challenge.
      1998
      Endurance athlete (n=1)Weekly 10 h of endurance training, including 50 km of running and 1-2 h of mountain biking32MaleFocal fibrosisBiopsy (drop of performance)
      Larsson et al,
      • Larsson E.
      • Wesslen L.
      • Lindquist O.
      • et al.
      Sudden unexpected cardiac deaths among young Swedish orienteers: morphological changes in hearts and other organs.
      1999
      Orienteers (n=2)One participant was ranked in the national elite class27, 28100% maleMyocarditis healed, fibrosis, hypertrophy Hypertrophy, fibrosisBiopsy (postmortem)
      Lesauskaite and Valanciute,
      • Lesauskaite V.
      • Valanciute A.
      Causes of sudden cardiac death in young athletes: the role of hypoperfusion.
      1998
      Runner (n=1)

      Soccer player (n=1)
      Rated officially as a first-class runner; middle and long distances

      Not specified
      22

      20
      100% maleScar tissue (foci of connective and granulation tissue) in the posterior wall of the LV and interventricular septum

      Foci of connective tissue in the LV and interventricular septum
      Biopsy (postmortem)
      Heidbüchel et al,
      • Heidbüchel H.
      • Hoogsteen J.
      • Fagard R.
      • et al.
      High prevalence of right ventricular involvement in endurance athletes with ventricular arrhythmias: role of an electrophysiologic study in risk stratification.
      2003
      Endurance athletes (n=3)≥3 x 2 h/wk for ≥5 yNot specifiedNot specifiedFibrosis (with fat in 1 patient)Biopsy (ventricular arrhythmias)
      Murty et al,
      • Murty O.P.
      • Mun K.S.
      • Hussin H.
      Silent bony calcification of coronaries in an adolescent: an unusual case.
      2008
      Not specified (n=1)Not specified16MaleThere were wide swaths of MF consistent with areas of old healed infarction, as well as areas of recent infarction; other areas in the heart showed myocardial fatty infiltration, fibrosis, and marked myofibrillary disarrayBiopsy (postmortem)
      Ottaviani et al,
      • Ottaviani G.
      • Lavezzi A.M.
      • Matturri L.
      Sudden unexpected death in young athletes.
      2008
      Soccer player (n=1)Not specified13MaleThe lateral wall of the LV presented an area of MF, characterized by replacement of the necrotic fibers by dense collagenous scarringBiopsy (postmortem)
      Lakhan and Harle,
      • Lakhan S.E.
      • Harle L.
      Cardiac fibrosis in the elderly, normotensive athlete: case report and review of the literature.
      2008
      Powerlifter (n=1)Participated regularly in aerobic activity and traveled frequently73FemaleWidespread interstitial MF in the RV and LV, mostly prevalent in the endomyocardium and affecting 25% of the myocardiumBiopsy (postmortem)
      Whyte et al,
      • Whyte G.
      • Sheppard M.
      • George K.
      • et al.
      Post-mortem evidence of idiopathic left ventricular hypertrophy and idiopathic interstitial myocardial fibrosis: is exercise the cause.
      2009
      Marathon runner (n=1)Running for 20 y, completed multiple marathons, personal best 2 h and 30 min57MaleFibrosis throughout both chambers, predominating in the LV; widespread replacement fibrosis in the lateral and posterior ventricular walls, and interstitial fibrosis in the inner layer of the myocardiumBiopsy (postmortem)
      Harper and Mottram,
      • Harper R.W.
      • Mottram P.M.
      Exercise-induced right ventricular dysplasia/cardiomyopathy: an emerging condition distinct from arrhythmogenic right ventricular dysplasia/cardiomyopathy.
      2009
      Triathlete (n=1)Averaged 10-15 events per year

      Former world champion
      32FemalePatchy interstitial fibrosis in the RVBiopsy (exercise-induced recurrent ventricular tachycardia)
      La Gerche et al,
      • La Gerche A.
      • Robberecht C.
      • Kuiperi C.
      • et al.
      Lower than expected desmosomal gene mutation prevalence in endurance athletes with complex ventricular arrhythmias of right ventricular origin.
      2010
      Endurance athletes (n=3)≥3 h/wk of sport with a moderate to intense dynamic component, competitively or recreationally for ≥5 yNot specifiedNot specifiedSeptal fibrosisBiopsy (RV arrhythmias)
      Bhella et al,
      • Bhella P.S.
      • Kelly J.P.
      • Peshock R.
      • Levine B.D.
      Delayed enhancement of the intraventricular septum following an extraordinary endurance exercise.
      2010
      Runner (n=1)After running 1460 km and ascending >2600 m the run was ended; in support of the event, after a 3-d rest, the individual cycled an additional 1580 km in 9 d ascending another 1190 m46MaleAt the inferior insertion of the RV and in the interventricular septum that may represent subtle inflammation secondary to a combined exercise and altitude effectCMR
      Sivridis et al,
      • Sivridis E.
      • Pavlidis P.
      • Stamos C.
      • Giatromanolaki A.
      Sudden death after myocardial infarction in a high-school athlete.
      2010
      Competitive high school athlete (n=1)Not specified14FemaleExtensive areas of interstitial fibrosis involving the posterior LV wall, the interventricular septum, and the papillary musclesBiopsy (postmortem)
      Pressler et al,
      • Pressler A.
      • Schmid A.
      • Freiberger V.
      • Scherr J.
      • Uder M.
      • Halle M.
      Myocarditis, myocardial fibrosis and eligibility for competitive sports.
      2011
      Soccer player (n=1)Professional soccer player18MaleEpimyocardial LGE in the lateral and parts of the apical and posterior wallsBiopsy (return-to-field examination after severe myocarditis)
      Poussel et al,
      • Poussel M.
      • Djaballah K.
      • Laroppe J.
      • Brembilla-Perrot B.
      • Marie P.Y.
      • Chenuel B.
      Left ventricle fibrosis associated with nonsustained ventricular tachycardia in an elite athlete: is exercise responsible? a case report.
      2012
      Cyclist (n=1)23,000 km per year for 14 y30MaleFocal fibrosis of the LV and intracardiac dimensions consistent with physiologic remodelingBiopsy (palpitations)
      Schnell et al,
      • Schnell F.
      • Claessen G.
      • La Gerche A.
      • et al.
      Subepicardial delayed gadolinium enhancement in asymptomatic athletes: let sleeping dogs lie?.
      2016
      Cyclists (n=5)

      Football player (n=1)

      Basketball player (n=1)
      ≥6 h/wk for ≥5 y19-3286% maleLGE predominantly in the lateral wall; mean ± SD size of 20.3±7.7 g

      Subepicardial (cyclist, football player, basketball player)

      Transmural patches (cyclist)

      Intramural patches (cyclists)

      Likely to reflect chronic scarring
      CMR (pathologic T-wave inversions on ECG (n=4) or ventricular arrhythmias (n=3)
      CMR = cardiac magnetic resonance imaging; ECG = electrocardiogram; LGE = late gadolinium enhancement; LV = left ventricle; RV = right ventricle.

      MF Reported in Athletic Populations

      The existence of MF was also assessed by CMR in athletic populations (Table 2). A total of 509 endurance exercise athletes were examined; 7 studies confirmed the presence of MF in athletes, and 7 studies did not. Overall, 89% of the population was male, and MF was reported in 30 of the 509 athletes (5.9%). Interestingly, lifetime exercise exposure (1-100 completed marathons) and age (26-72 years) varied substantially across participants, but most reports occurred in long-term endurance athletes.
      Table 2Prevalence and Patterns of Myocardial Fibrosis (MF) in Athletic Populations Using CMR
      CAD = coronary artery disease; CMR = cardiac magnetic resonance imaging; LAD = left anterior descending; LGE = late gadolinium enhancement; LV = left ventricle; RV = right ventricle.
      Studies are arranged from highest to lowest MF prevalence.
      Reference, yearStudy populationExercise exposureAge (y), mean ± SDSexPrevalence of MF (%)Pattern/location of MF
      Wilson et al,
      • Wilson M.
      • O'Hanlon R.
      • Prasad S.
      • et al.
      Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes.
      2011
      Lifelong veteran endurance athletes (n=12)

      Veteran sedentary controls (n=20)

      Young endurance athletes (n=17)
      Mean ± SD of 43±6 y of competitive exercise training

      No exercise training

      Mean ± SD of 18±7 y of competitive exercise training
      57±6

      60±5

      31±5
      100% male50

      0

      0
      1. Septal and lateral wall

      2. Epicardial lateral wall

      3. Basal and mid insertion point

      4. Inferior insertion point mid and apical

      5. Insertion point inferior mid/apical

      6. Inferior insertion point
      La Gerche et al,
      • La Gerche A.
      • Burns A.T.
      • Mooney D.J.
      • et al.
      Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes.
      2012
      Marathon runners (n=7)

      Endurance triathletes (n=11)

      Alpine cyclists (n=9)

      Ultra-triathletes (n=13)
      >10 h of intense training per week

      Finished in the first 25% of the field in a recent endurance event
      37±890% male12.8Interventricular septum, frequently in the vicinity of the RV attachment
      Breuckmann et al,
      • Breuckmann F.
      • Möhlenkamp S.
      • Nassenstein K.
      • et al.
      Myocardial late gadolinium enhancement: prevalence, pattern, and prognostic relevance in marathon runners.
      2009
      Marathon runners (n=102)

      Sedentary controls (n=102)
      ≥5 marathons in ≤3 y

      No exercise training
      57±6100% maleAthletes, 12

      Controls, 4
      Athletes: 42% involving the subendocardial layer and partial transmural spreading; 58% atypical patchy to streaky subepicardial to midmyocardial hyperenhancement, which may represent interstitial fibrosis or myocardial fiber disarray for various potential reasons

      Controls: 50% CAD pattern; 50% non-CAD pattern
      Mordi et al,
      • Mordi I.
      • Carrick D.
      • Bezerra H.
      • Tzemos N.
      T1 and T2 mapping for early diagnosis of dilated non-ischaemic cardiomyopathy in middle-aged patients and differentiation from normal physiological adaptation.
      2016
      Aerobic exercise (n=21), predominantly running>6 h/wk of intensive aerobic exercise at amateur level46±11100% male9.5Small amounts of LGE at RV insertion points
      Karlstedt et al,
      • Karlstedt E.
      • Chelvanathan A.
      • Da Silva M.
      • et al.
      The impact of repeated marathon running on cardiovascular function in the aging population.
      2012
      Marathon runners (n=25)Mean ± SD of 47±7 miles/wk

      ≥3 marathons in the past 2 y
      55±484% male8Anterior wall of the LV myocardium in subendocardial distribution before running the marathon, with concomitant evidence of obstructive LAD artery disease
      Erz et al,
      • Erz G.
      • Mangold S.
      • Franzen E.
      • et al.
      Correlation between ECG abnormalities and cardiac parameters in highly trained asymptomatic male endurance athletes: evaluation using cardiac magnetic resonance imaging.
      2013
      Runners (n=23)

      Triathletes (n=16)

      Cyclists (n=5)

      Speed skater (n=1)
      7 h/wk for ≥2 y40±9100% male2.2Posterolateral wall of the LV, indicative of nonischemic scarring; most likely due to former myocarditis
      Mangold et al,
      • Mangold S.
      • Kramer U.
      • Franzen E.
      • et al.
      Detection of cardiovascular disease in elite athletes using cardiac magnetic resonance imaging.
      2013
      Long-distance runners (n=39)

      Cyclists (n=8)

      Triathletes (n=34)

      Handball players (n=13)

      Speed skater (n=1)
      Mean ± SD of 13.1±4.2 h/wk for ≥2 y35±1177% male2.1 (2 cyclists)Spot-shaped pattern consistent with a nonischemic, postinflammation

      Disseminated and intramural myocardial hyperenhancement
      Mousavi et al,
      • Mousavi N.
      • Czarnecki A.
      • Kumar K.
      • et al.
      Relation of biomarkers and cardiac magnetic resonance imaging after marathon running.
      2009
      Moderately trained marathon runners (n=10)

      Highly trained marathon runners (n=4)
      Mean ± SD of 26±8 miles/wk

      Mean ± SD of 53±12 miles/wk
      33±657% male0Not applicable
      Hanssen et al,
      • Hanssen H.
      • Keithahn A.
      • Hertel G.
      • et al.
      Magnetic resonance imaging of myocardial injury and ventricular torsion after marathon running.
      2011
      Marathon runners (n=28)Mean ± SD training mileage of 43±17 km/wk in the 10 wk before the marathon; median ± SD finish time was 245±55 min41±5100% male0Not applicable
      Trivax et al,
      • Trivax J.E.
      • Franklin B.A.
      • Goldstein J.A.
      • et al.
      Acute cardiac effects of marathon running.
      2010
      Marathon runners (n=25)Previous 6 mo: mean ± SD of 30.2±11.4 miles/wk

      Past 5 y: mean ± SD of 17.0±11.8 miles/wk
      39±952% female0Not applicable
      Gaudreault et al,
      • Gaudreault V.
      • Tizon-Marcos H.
      • Poirier P.
      • et al.
      Transient myocardial tissue and function changes during a marathon in less fit marathon runners.
      2013
      Marathon runners (n=20)Mean ± SD of 8.1±2.3 h/wk

      Mean ± SD of 9±8 marathons in a mean ± SD of 14±5 y
      45±870% male0Not applicable
      O’Hanlon et al,
      • O'Hanlon R.
      • Wilson M.
      • Wage R.
      • et al.
      Troponin release following endurance exercise: is inflammation the cause? a cardiovascular magnetic resonance study.
      2010
      Marathon runners (n=17)7 h/wk34±7100% male0Not applicable
      Heidbüchel et al,
      • Heidbüchel H.
      • Hoogsteen J.
      • Fagard R.
      • et al.
      High prevalence of right ventricular involvement in endurance athletes with ventricular arrhythmias: role of an electrophysiologic study in risk stratification.
      2003
      Endurance athletes (n=28)≥3 × 2 h/wk for ≥5 yNot specifiedNot specified0Not applicable
      Scharhag et al,
      • Scharhag J.
      • Urhausen A.
      • Schneider G.
      • et al.
      Reproducibility and clinical significance of exercise-induced increases in cardiac troponins and N-terminal pro brain natriuretic peptide in endurance athletes.
      2006
      Mountain bike marathon cyclists (n=15)

      Marathon runners (n=5)
      Training history in endurance exercise of a mean ± SD of 7±3 y and trained a mean ± SD of 9±4 h/wk36±7100% male0Not applicable
      a CAD = coronary artery disease; CMR = cardiac magnetic resonance imaging; LAD = left anterior descending; LGE = late gadolinium enhancement; LV = left ventricle; RV = right ventricle.
      b Studies are arranged from highest to lowest MF prevalence.

      Patterns, Location, and Quantification of MF

      The pattern of MF in athletes determined by microscopic examination varies (Table 1), and this likely represents different causes. Fourteen of the 35 athletes with MF (40%) included in the case reports/series demonstrated a nonspecific LGE pattern, and the remaining athletes demonstrated an ischemic (n=7, 20%), myocarditic (n=7, 20%), or hypertrophic (n=1, 3%) MF pattern; the pattern was not specified in 6 athletes (17%) (Figure 2).
      Figure thumbnail gr2
      Figure 2The prevalence of the pattern of myocardial fibrosis (MF) found in athletes in case reports/series and athletic population studies.
      Findings from the CMR studies confirm the variation in MF patterns (Table 2). Most athletes with MF (12 of 30, 40%) show a nonspecific LGE pattern.
      • Wilson M.
      • O'Hanlon R.
      • Prasad S.
      • et al.
      Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes.
      • Breuckmann F.
      • Möhlenkamp S.
      • Nassenstein K.
      • et al.
      Myocardial late gadolinium enhancement: prevalence, pattern, and prognostic relevance in marathon runners.
      • Mangold S.
      • Kramer U.
      • Franzen E.
      • et al.
      Detection of cardiovascular disease in elite athletes using cardiac magnetic resonance imaging.
      A subendocardial pattern, typically seen after ischemic myocardial injury because the subendocardium is the region most vulnerable to reduced coronary blood flow, was observed in 8 of 30 athletes with MF (27%).
      • Wilson M.
      • O'Hanlon R.
      • Prasad S.
      • et al.
      Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes.
      • Breuckmann F.
      • Möhlenkamp S.
      • Nassenstein K.
      • et al.
      Myocardial late gadolinium enhancement: prevalence, pattern, and prognostic relevance in marathon runners.
      • Karlstedt E.
      • Chelvanathan A.
      • Da Silva M.
      • et al.
      The impact of repeated marathon running on cardiovascular function in the aging population.
      There are also several reports of probable scarring from myocarditis (n=3, 10%) and mechanical overload (n=7, 23%) (Figure 2).
      • Wilson M.
      • O'Hanlon R.
      • Prasad S.
      • et al.
      Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes.
      • Mordi I.
      • Carrick D.
      • Bezerra H.
      • Tzemos N.
      T1 and T2 mapping for early diagnosis of dilated non-ischaemic cardiomyopathy in middle-aged patients and differentiation from normal physiological adaptation.
      • Erz G.
      • Mangold S.
      • Franzen E.
      • et al.
      Correlation between ECG abnormalities and cardiac parameters in highly trained asymptomatic male endurance athletes: evaluation using cardiac magnetic resonance imaging.
      • Mangold S.
      • Kramer U.
      • Franzen E.
      • et al.
      Detection of cardiovascular disease in elite athletes using cardiac magnetic resonance imaging.
      The location of MF determined by biopsy (case studies/series) and CMR-LGE (athletic population studies) varies substantially (Figure 3). La Gerche et al
      • La Gerche A.
      • Burns A.T.
      • Mooney D.J.
      • et al.
      Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes.
      reported that MF was confined to the interventricular septum, frequently where the RV attaches to the septum (the hinge points). Overall, a significant proportion of MF in athletes is found in the septum (19 of 65, 29%)
      • Wilson M.
      • O'Hanlon R.
      • Prasad S.
      • et al.
      Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes.
      • La Gerche A.
      • Burns A.T.
      • Mooney D.J.
      • et al.
      Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes.
      • Lesauskaite V.
      • Valanciute A.
      Causes of sudden cardiac death in young athletes: the role of hypoperfusion.
      • La Gerche A.
      • Robberecht C.
      • Kuiperi C.
      • et al.
      Lower than expected desmosomal gene mutation prevalence in endurance athletes with complex ventricular arrhythmias of right ventricular origin.
      • Bhella P.S.
      • Kelly J.P.
      • Peshock R.
      • Levine B.D.
      Delayed enhancement of the intraventricular septum following an extraordinary endurance exercise.
      • Sivridis E.
      • Pavlidis P.
      • Stamos C.
      • Giatromanolaki A.
      Sudden death after myocardial infarction in a high-school athlete.
      and RV insertion points (12 of 65, 19%).
      • Wilson M.
      • O'Hanlon R.
      • Prasad S.
      • et al.
      Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes.
      • La Gerche A.
      • Burns A.T.
      • Mooney D.J.
      • et al.
      Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes.
      • Mordi I.
      • Carrick D.
      • Bezerra H.
      • Tzemos N.
      T1 and T2 mapping for early diagnosis of dilated non-ischaemic cardiomyopathy in middle-aged patients and differentiation from normal physiological adaptation.
      • Bhella P.S.
      • Kelly J.P.
      • Peshock R.
      • Levine B.D.
      Delayed enhancement of the intraventricular septum following an extraordinary endurance exercise.
      Some have speculated that the distention of the RV during endurance exercise due to an acute increase in RV work with exercise may be responsible for this interventricular scar pattern.
      • La Gerche A.
      • Burns A.T.
      • Mooney D.J.
      • et al.
      Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes.
      Figure thumbnail gr3
      Figure 3The frequency of the location of myocardial fibrosis (MF) reported in case studies/series and athletic population studies. In 10 athletes (5 in case series
      • Bharati S.
      • Dreifus L.S.
      • Chopskie E.
      • Lev M.
      Conduction system in a trained jogger with sudden death.
      • Lesauskaite V.
      • Valanciute A.
      Causes of sudden cardiac death in young athletes: the role of hypoperfusion.
      • Whyte G.
      • Sheppard M.
      • George K.
      • et al.
      Post-mortem evidence of idiopathic left ventricular hypertrophy and idiopathic interstitial myocardial fibrosis: is exercise the cause.
      • Sivridis E.
      • Pavlidis P.
      • Stamos C.
      • Giatromanolaki A.
      Sudden death after myocardial infarction in a high-school athlete.
      and 5 in an athletic population study
      • La Gerche A.
      • Burns A.T.
      • Mooney D.J.
      • et al.
      Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes.
      ), MF was present at multiple locations of the heart. LV = left ventricle; RV = right ventricle.
      The quantification of MF is poorly reported: only 3 case reports and 1 CMR study describe the extent of fibrosis. The volume of the scar in a biopsy taken from a runner confirmed that MF was present in 2.9% of the LV and 3.5% of the interventricular septum.
      • Lesauskaite V.
      • Valanciute A.
      Causes of sudden cardiac death in young athletes: the role of hypoperfusion.
      In another case it was reported that approximately 25% of the myocardium was involved in some kind of MF.
      • Lakhan S.E.
      • Harle L.
      Cardiac fibrosis in the elderly, normotensive athlete: case report and review of the literature.
      Breuckmann et al
      • Breuckmann F.
      • Möhlenkamp S.
      • Nassenstein K.
      • et al.
      Myocardial late gadolinium enhancement: prevalence, pattern, and prognostic relevance in marathon runners.
      reinforced the heterogeneity of the percentage of LGE-positive myocardium (range, 0.5%-17.8%) in German marathon runners. Also, these authors found that the median percentage of MF was comparable between runners with a subendocardial LGE pattern (0.9%), runners with a nonspecific pattern (1.2%), and physically inactive controls (2.2%). Last, the mean ± SD volume of the LGE region in the study by Schnell et al
      • Schnell F.
      • Claessen G.
      • La Gerche A.
      • et al.
      Subepicardial delayed gadolinium enhancement in asymptomatic athletes: let sleeping dogs lie?.
      was 20.3±7.7 g, which was the equivalent of 12%±4.8% of the LV mass.

      Discussion

      The present review reveals that the phenotype of MF in athletes demonstrates large variance in patterns, location, and quantification. Nonetheless, a nonspecific LGE pattern, location in the RV or septum, and representing 1% to 3% of the myocardium seem to be the most common descriptors used for MF typically found in athletes by magnetic resonance imaging. The phenotype of MF in athletes differs from that in the general population, and this difference may provide insight into the underlying mechanisms and clinical prognosis of MF in assumingly healthy athletes.

      MF in Athletes vs Controls

      The prevalence of MF varied from 0% to 50% in often small-scale athlete populations. Only 2 studies compared MF prevalence between athletes and age- and sex-matched physically inactive controls.
      • Wilson M.
      • O'Hanlon R.
      • Prasad S.
      • et al.
      Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes.
      • Breuckmann F.
      • Möhlenkamp S.
      • Nassenstein K.
      • et al.
      Myocardial late gadolinium enhancement: prevalence, pattern, and prognostic relevance in marathon runners.
      Breuckmann et al
      • Breuckmann F.
      • Möhlenkamp S.
      • Nassenstein K.
      • et al.
      Myocardial late gadolinium enhancement: prevalence, pattern, and prognostic relevance in marathon runners.
      found that MF was more prevalent in athletes (n=102) than in controls (n=102) (12% vs 4%; P=.077). Wilson et al
      • Wilson M.
      • O'Hanlon R.
      • Prasad S.
      • et al.
      Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes.
      observed MF in 6 of 12 lifelong veteran endurance athletes but not in any of 20 sedentary peers. Although both studies reported a higher prevalence of MF in athletes vs physically inactive controls, the presence of MF in these control groups was lower compared with recent observations in the general population. In a large American cohort study of nonathletes (mean ± SD age, 68±9 years), MF was found in 146 of 1840 participants (7.9%).
      • Turkbey E.B.
      • Nacif M.S.
      • Guo M.
      • et al.
      Prevalence and correlates of myocardial scar in a US cohort.
      Population studies from Iceland (n=936)
      • Schelbert E.B.
      • Cao J.J.
      • Sigurdsson S.
      • et al.
      Prevalence and prognosis of unrecognized myocardial infarction determined by cardiac magnetic resonance in older adults.
      and Sweden (n=248)
      • Barbier C.E.
      • Bjerner T.
      • Johansson L.
      • Lind L.
      • Ahlstrom H.
      Myocardial scars more frequent than expected: magnetic resonance imaging detects potential risk group.
      report an even higher prevalence of unknown MF (17.0% and 19.8%, respectively). These findings highlight the need for additional high-quality studies comparing the prevalence and extent of MF in large populations of physically active and inactive individuals. Future studies should consider the amount and intensity of exercise training, as well as the lifelong exercise exposure, to test the hypothesis that MF prevalence differs between athletes and the general population.

      Focal vs Diffuse MF

      The CMR studies assessing MF in athletes included predominantly LGE measurements. Although CMR-LGE is a validated technique to assess quantification of focal MF, it does not provide information about the presence of diffuse MF. This may lead to underestimating the true prevalence of MF in athletes and may limit the generalizability of these findings. Nevertheless, 2 recent studies used T1 and T2 mapping to assess (diffuse) MF in athletes.
      • Mordi I.
      • Carrick D.
      • Bezerra H.
      • Tzemos N.
      T1 and T2 mapping for early diagnosis of dilated non-ischaemic cardiomyopathy in middle-aged patients and differentiation from normal physiological adaptation.
      • Gormeli C.A.
      • Gormeli G.
      • Yagmur J.
      • et al.
      Assessment of myocardial changes in athletes with native T1 mapping and cardiac functional evaluation using 3 T MRI.
      In a Scottish study, no difference in native T1, T2 relaxation time and extracellular volume was observed between athletes (n=21, ≥6 h/wk of exercise training) and controls (n=21).
      • Mordi I.
      • Carrick D.
      • Bezerra H.
      • Tzemos N.
      T1 and T2 mapping for early diagnosis of dilated non-ischaemic cardiomyopathy in middle-aged patients and differentiation from normal physiological adaptation.
      In contrast, significantly higher native T1 values of the LV and interventricular septum were found in Turkish athletes (≥6 h/wk intense exercise training) compared with age- and sex-matched controls (<3 h/wk moderate exercise). Moreover, athletes reporting at least 5 years of exercise training had higher T1 values, indicating more diffuse fibrosis compared with athletes exercising for less than 5 years (P<.05).
      • Gormeli C.A.
      • Gormeli G.
      • Yagmur J.
      • et al.
      Assessment of myocardial changes in athletes with native T1 mapping and cardiac functional evaluation using 3 T MRI.
      These findings suggest a higher prevalence of diffuse MF in Turkish athletes vs controls. Apart from the age difference between Scottish (mean ± SD age, 46±11 years) and Turkish (mean ± SD age, 25±3 years) athletes, there is no clear explanation for the conflicting outcomes. We, therefore, recommend that future studies include measurements of T1 relaxation times before and after contrast administration to determine the myocardial extracellular volume fraction and to quantify diffuse MF in addition to LGE-based assessment of focal MF. Also, the use of free-breathing, motion-corrected, averaged LGE CMR measurements may improve image quality of the RV.
      • Piehler K.M.
      • Wong T.C.
      • Puntil K.S.
      • et al.
      Free-breathing, motion-corrected late gadolinium enhancement is robust and extends risk stratification to vulnerable patients.
      Use of these novel imaging techniques should further improve our understanding of the development, progression, and clinical interpretation of MF in athletes.

      Factors Associated With MF

      Several studies identified factors that are associated with the presence of MF in athletes. La Gerche et al
      • La Gerche A.
      • Burns A.T.
      • Mooney D.J.
      • et al.
      Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes.
      reported that athletes with LGE had participated in endurance exercise longer (mean ± SD, 20±16 years) than athletes without MF (mean ± SD, 8±6 years; P=.043). Similarly, Wilson et al
      • Wilson M.
      • O'Hanlon R.
      • Prasad S.
      • et al.
      Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes.
      reported that LGE was related to the years of training (P<.001) and the number of completed competitive marathons (P<.001) or ultra-endurance marathons (>50 miles) (P=.007). Möhlenkamp et al
      • Möhlenkamp S.
      • Lehmann N.
      • Breuckmann F.
      • et al.
      Running: the risk of coronary events: prevalence and prognostic relevance of coronary atherosclerosis in marathon runners.
      reported an association between the number of completed marathons and LGE (P=.02). Evidence from case reports/series confirms that athletes diagnosed as having MF demonstrate high doses of exercise for many years (Table 1). For example, an athlete trained 10 h/wk, including 50 km of running and 1 to 2 hours of mountain biking,
      • Kindermann W.
      • Janzen I.
      • Urhausen A.
      • Schieffer H.J.
      Heart enlargement in an athlete: a diagnostic challenge.
      while another athlete cycled an average of 23,000 km/y for 14 years.
      • Poussel M.
      • Djaballah K.
      • Laroppe J.
      • Brembilla-Perrot B.
      • Marie P.Y.
      • Chenuel B.
      Left ventricle fibrosis associated with nonsustained ventricular tachycardia in an elite athlete: is exercise responsible? a case report.
      These studies and case reports suggest a dose-response relationship between lifetime exercise exposure and MF development. Indeed, Wilson et al
      • Wilson M.
      • O'Hanlon R.
      • Prasad S.
      • et al.
      Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes.
      found that the prevalence of MF was the highest (50%) in veteran endurance athletes (mean ± SD age, 57±6 years) who had been involved in lifelong competitive training for a mean ± SD of 43±6 years. Studies including predominantly younger participants or less-trained individuals generally fail to find MF.
      • Mousavi N.
      • Czarnecki A.
      • Kumar K.
      • et al.
      Relation of biomarkers and cardiac magnetic resonance imaging after marathon running.
      • Hanssen H.
      • Keithahn A.
      • Hertel G.
      • et al.
      Magnetic resonance imaging of myocardial injury and ventricular torsion after marathon running.
      • Trivax J.E.
      • Franklin B.A.
      • Goldstein J.A.
      • et al.
      Acute cardiac effects of marathon running.
      • Gaudreault V.
      • Tizon-Marcos H.
      • Poirier P.
      • et al.
      Transient myocardial tissue and function changes during a marathon in less fit marathon runners.
      • O'Hanlon R.
      • Wilson M.
      • Wage R.
      • et al.
      Troponin release following endurance exercise: is inflammation the cause? a cardiovascular magnetic resonance study.

      Potential Mechanisms of MF Development

      Evidence of MF in athletic populations is exclusively based on observational studies, which do not provide insight into potential underlying mechanisms. However, we summarize the available evidence for 4 different pathways based on patient characteristics, location and patterns of MF, and identified predictors.

      Genetic Predisposition

      Ten case reports describe the presence of MF in 28 young athletes (≤30 years old). Their young age raises the question whether genetic predisposition contributes to MF development. Hypertrophic cardiomyopathy is the most common genetic heart disease
      • Olivotto I.
      • Girolami F.
      • Nistri S.
      • et al.
      The many faces of hypertrophic cardiomyopathy: from developmental biology to clinical practice.
      and is associated with a high prevalence of MF.
      • Rubinshtein R.
      • Glockner J.F.
      • Ommen S.R.
      • et al.
      Characteristics and clinical significance of late gadolinium enhancement by contrast-enhanced magnetic resonance imaging in patients with hypertrophic cardiomyopathy.
      In hypertrophic cardiomyopathy, LGE varies from very limited to large, confluent, infarct-like patches occupying significant proportions of the LV,
      • Olivotto I.
      • Maron M.S.
      • Autore C.
      • et al.
      Assessment and significance of left ventricular mass by cardiovascular magnetic resonance in hypertrophic cardiomyopathy.
      and it localizes preferentially to the most hypertrophied regions of the ventricle.
      • Olivotto I.
      • Girolami F.
      • Nistri S.
      • et al.
      The many faces of hypertrophic cardiomyopathy: from developmental biology to clinical practice.
      Furthermore, hypertrophic cardiomyopathy is a frequent cause of sudden cardiac death in young competitive athletes.
      • Maron B.J.
      • Shirani J.
      • Poliac L.C.
      • Mathenge R.
      • Roberts W.C.
      • Mueller F.O.
      Sudden death in young competitive athletes: clinical, demographic, and pathological profiles.
      Mutations in genes coding for sarcomere proteins, Z-disk or calcium-handling proteins, are responsible for the phenotype of hypertrophic cardiomyopathy.
      • Marian A.J.
      Genetic determinants of cardiac hypertrophy.
      However, variability can be so striking in individuals with the same genetic defect that little, if any, relationship can be established between mutations and phenotype, clinical course, and patient outcome. Similarly, genetic factors may contribute to the variability of MF presentations in athletes.

      Silent Myocarditis

      The results of 5 biopsy studies and 3 CMR-LGE studies suggest that myocarditis is responsible for LGE and that this is probably true in some (n=10) but not all (n=65) athletes. Late gadolinium enhancement has high specificity for the detection of injury in myocarditis but variable sensitivity to detect active or chronic inflammation.
      • Friedrich M.G.
      • Sechtem U.
      • Schulz-Menger J.
      • et al.
      Cardiovascular magnetic resonance in myocarditis: a JACC White Paper.
      This might be due to limited areas of necrotic myocytes that cannot be visualized because of limited pixel size in CMR images compared with larger regions of scarring in ischemic necrosis. Myocarditis is defined as inflammatory cellular infiltrate, whereas associated myocyte necrosis may be present on stained heart tissue sections.
      • Aretz H.T.
      • Billingham M.E.
      • Edwards W.D.
      • et al.
      Myocarditis: a histopathologic definition and classification.
      Myocarditis usually results from infections with viruses such as coxsackievirus B3, adenoviruses, and parvovirus B19 but may also result from other pathogens, such as the protozoan Trypanosoma cruzi (Chagas disease), toxic or hypersensitivity drug reactions (anticonvulsants, antibiotics, and antipsychotics), giant cell myocarditis, or sarcoidosis.
      • Cooper Jr., L.T.
      Myocarditis.
      Several animal studies found that exercise itself may cause myocarditis and lead to the development of MF.
      • Benito B.
      • Gay-Jordi G.
      • Serrano-Mollar A.
      • et al.
      Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training.
      • Aschar-Sobbi R.
      • Izaddoustdar F.
      • Korogyi A.S.
      • et al.
      Increased atrial arrhythmia susceptibility induced by intense endurance exercise in mice requires TNFalpha.
      • Chen Y.
      • Serfass R.C.
      • Mackey-Bojack S.M.
      • Kelly K.L.
      • Titus J.L.
      • Apple F.S.
      Cardiac troponin T alterations in myocardium and serum of rats after stressful, prolonged intense exercise.
      In a rat model of exercise training, MF disappeared after cessation of the exercise.
      • Benito B.
      • Gay-Jordi G.
      • Serrano-Mollar A.
      • et al.
      Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training.
      We are unaware of evidence that exercise can produce myocarditis in humans.
      Many patients with myocarditis have minimal or no symptoms.
      • McCarthy III, R.E.
      • Boehmer J.P.
      • Hruban R.H.
      • et al.
      Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis.
      Despite this, the infection may cause ventricular dilatation or fibrosis.
      • Kallwellis-Opara A.
      • Dorner A.
      • Poller W.C.
      • et al.
      Autoimmunological features in inflammatory cardiomyopathy.
      A mouse model found that physical activity during a “silent” myocarditis may exaggerate damage to the heart.
      • Cabinian A.E.
      • Kiel R.J.
      • Smith F.
      • Ho K.L.
      • Khatib R.
      • Reyes M.P.
      Modification of exercise-aggravated coxsackievirus B3 murine myocarditis by T lymphocyte suppression in an inbred model.
      Mice were infected with coxsackievirus to induce myocarditis and then were divided into 4 groups: group 1 received immunosuppression with daily doses of cyclosporine and an antithymocyte monoclonal antibody, group 2 performed daily swimming exericise, group 3 received both interventions, and group 4 served as controls. After 21 days, mortality rates were highest in the exercise-only group (group 2).
      • Cabinian A.E.
      • Kiel R.J.
      • Smith F.
      • Ho K.L.
      • Khatib R.
      • Reyes M.P.
      Modification of exercise-aggravated coxsackievirus B3 murine myocarditis by T lymphocyte suppression in an inbred model.
      Hence, it is possible that continued exercise training accelerates myocardial damage and MF during a silent myocarditis.

      Pulmonary Artery Pressure Overload

      The volume of LGE is typically small and confined to the septum or RV insertion points in 48% of athletes diagnosed as having MF by magnetic resonance imaging LGE. This may result from local mechanical stress due to prolonged exercise. Interestingly, MF in this cardiac location is also observed in patients with pulmonary arterial hypertension.
      • Blyth K.G.
      • Groenning B.A.
      • Martin T.N.
      • et al.
      Contrast enhanced-cardiovascular magnetic resonance imaging in patients with pulmonary hypertension.
      • McCann G.P.
      • Beek A.M.
      • Vonk-Noordegraaf A.
      • van Rossum A.C.
      Delayed contrast-enhanced magnetic resonance imaging in pulmonary arterial hypertension.
      Late gadolinium enhancement was present at a similar anatomical location in adults whose RV was forced to produce systemic pressures after atrial redirection surgery for transposition of the great vessels.
      • Babu-Narayan S.V.
      • Goktekin O.
      • Moon J.C.
      • et al.
      Late gadolinium enhancement cardiovascular magnetic resonance of the systemic right ventricle in adults with previous atrial redirection surgery for transposition of the great arteries.
      Focal LGE has been reported at the superior and inferior insertion points of the RV and LV in 36% and 89% of these patients, respectively.
      • Babu-Narayan S.V.
      • Goktekin O.
      • Moon J.C.
      • et al.
      Late gadolinium enhancement cardiovascular magnetic resonance of the systemic right ventricle in adults with previous atrial redirection surgery for transposition of the great arteries.
      Exercise produces a greater relative increase in pulmonic than aortic systolic pressure, resulting in an increase in wall stress of 125% vs 4% for the RV and LV, respectively.
      • La Gerche A.
      • Heidbuchel H.
      • Burns A.T.
      • et al.
      Disproportionate exercise load and remodeling of the athlete's right ventricle.
      The thinner wall of the RV may facilitate the progression from increased wall stress to cardiomyocyte damage more than in the LV. Although echocardiography studies show that acute exercise-induced changes in RV structure and function fully recover within days,
      • La Gerche A.
      • Burns A.T.
      • Mooney D.J.
      • et al.
      Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes.
      chronic structural changes from repetitive prolonged exercise are possible. Therefore, MF in athletes may result from long-term endurance exercise training and competition and the associated repetitive exercise-induced elevations in pulmonary artery pressures.

      Repetitive Microdamage

      Cardiac troponin I and T are the standard biomarkers used to serologically identify myocardial damage. Many studies have reported increases in cardiac troponin levels after prolonged exercise.
      • Shave R.
      • Baggish A.
      • George K.
      • et al.
      Exercise-induced cardiac troponin elevation: evidence, mechanisms, and implications.
      Elevated troponin levels were found in 100% of Boston Marathon participants
      • Eijsvogels T.M.
      • Januzzi J.L.
      • Taylor B.A.
      • et al.
      Impact of statin use on exercise-induced cardiac troponin elevations.
      and are directly related to exercise intensity.
      • Eijsvogels T.M.
      • Hoogerwerf M.D.
      • Oudegeest-Sander M.H.
      • Hopman M.T.
      • Thijssen D.H.
      The impact of exercise intensity on cardiac troponin I release.
      Exercise-induced troponin elevations are hypothesized to be benign and to represent reversible cardiomyocyte membrane damage,
      • Eijsvogels T.M.
      • Fernandez A.B.
      • Thompson P.D.
      Are there deleterious cardiac effects of acute and chronic endurance exercise?.
      but they may represent microdamage to cardiomyocytes. Accordingly, repetitive exposure to high-intensity endurance exercise–induced cardiac microdamage, evidenced by minor troponin level elevations, could lead to MF development after lifelong exercise training, as observed in veteran athletes.
      • Wilson M.
      • O'Hanlon R.
      • Prasad S.
      • et al.
      Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes.

      Clinical Implications of MF

      The presence of MF is an important risk factor for adverse cardiac outcomes in clinical populations.
      • Kwong R.Y.
      • Sattar H.
      • Wu H.
      • et al.
      Incidence and prognostic implication of unrecognized myocardial scar characterized by cardiac magnetic resonance in diabetic patients without clinical evidence of myocardial infarction.
      • Assomull R.G.
      • Prasad S.K.
      • Lyne J.
      • et al.
      Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy.
      • Bello D.
      • Shah D.J.
      • Farah G.M.
      • et al.
      Gadolinium cardiovascular magnetic resonance predicts reversible myocardial dysfunction and remodeling in patients with heart failure undergoing beta-blocker therapy.
      • Kwon D.H.
      • Halley C.M.
      • Popovic Z.B.
      • et al.
      Gender differences in survival in patients with severe left ventricular dysfunction despite similar extent of myocardial scar measured on cardiac magnetic resonance.
      • Kwong R.Y.
      • Chan A.K.
      • Brown K.A.
      • et al.
      Impact of unrecognized myocardial scar detected by cardiac magnetic resonance imaging on event-free survival in patients presenting with signs or symptoms of coronary artery disease.
      However, the impact of MF on cardiovascular health has not been carefully studied in athletes. Three of 12 German marathon runners with LGE (25%) required revascularization during a mean ± SD of 21±3 months of follow-up compared with 1 of 90 runners (1%) without LGE (P<.001).
      • Breuckmann F.
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      • Nassenstein K.
      • et al.
      Myocardial late gadolinium enhancement: prevalence, pattern, and prognostic relevance in marathon runners.
      Half of the runners with MF, however, had an LGE pattern suggestive of ischemic myocardial injury. The increased risk of MF on adverse outcomes persisted during a mean ± SD of 74±12 months of follow-up.
      • Möhlenkamp S.
      • Leineweber K.
      • Lehmann N.
      • et al.
      Coronary atherosclerosis burden, but not transient troponin elevation, predicts long-term outcome in recreational marathon runners.
      Runners with coronary events had a higher prevalence of LGE (57%) compared with peers without coronary events (8%; P=.003), despite comparable mean ± SD 10-year Framingham Risk Scores (7.9%±2.3% vs 7.0%±3.7%).
      • Möhlenkamp S.
      • Leineweber K.
      • Lehmann N.
      • et al.
      Coronary atherosclerosis burden, but not transient troponin elevation, predicts long-term outcome in recreational marathon runners.
      The presence of LGE in this cohort was also associated with higher coronary artery calcification scores (median Agatston coronary artery calcium scores, 192 vs 26; P=.0046),
      • Möhlenkamp S.
      • Lehmann N.
      • Breuckmann F.
      • et al.
      Running: the risk of coronary events: prevalence and prognostic relevance of coronary atherosclerosis in marathon runners.
      demonstrating that the increased incidence of cardiovascular events in some runners with LGE is due to atherosclerosis and previous infarction. Other studies in other patients do not support atherosclerosis and previous infarction as the cause of the LGE. Although the German findings suggest a worse prognosis in athletes with MF, it must be emphasized that these data are derived from a single cohort. Nevertheless, athletes with LGE patterns consistent with coronary artery disease and previous infarction or those with evidence of active myocardial inflammation should be pharmacologically treated to reduce their risk of an acute cardiac event and to treat their myocarditis, respectively.
      The prognostic significance of nonspecific MF patterns seen in athletes is unknown. There is no evidence that athletes with this pattern should be restricted from exercise. Additional clinical testing should be recommended based on the individual’s symptoms and clinical profile. Myocardial fibrosis detected by LGE in cardiac studies of asymptomatic athletes performed for other nonclinical reasons should be treated as an incidental finding and not pursued.
      The impact of lifelong exercise training on cardiovascular health is under debate.
      • Eijsvogels T.M.
      • Fernandez A.B.
      • Thompson P.D.
      Are there deleterious cardiac effects of acute and chronic endurance exercise?.
      • O'Keefe J.H.
      • Franklin B.
      • Lavie C.J.
      Exercising for health and longevity vs peak performance: different regimens for different goals.
      Although some studies report a U-shaped association between exercise volume and cardiovascular risk,
      • Armstrong M.E.
      • Green J.
      • Reeves G.K.
      • Beral V.
      • Cairns B.J.
      Million Women Study Collaborators
      Frequent physical activity may not reduce vascular disease risk as much as moderate activity: large prospective study of women in the United Kingdom.
      • Schnohr P.
      • O'Keefe J.H.
      • Marott J.L.
      • Lange P.
      • Jensen G.B.
      Dose of jogging and long-term mortality: the Copenhagen City Heart Study.
      most available evidence suggests a curvilinear relationship, with greater health benefits at larger exercise doses.
      • Arem H.
      • Moore S.C.
      • Patel A.
      • et al.
      Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship.
      • Lee D.C.
      • Pate R.R.
      • Lavie C.J.
      • Sui X.
      • Church T.S.
      • Blair S.N.
      Leisure-time running reduces all-cause and cardiovascular mortality risk.
      • Maessen M.F.
      • Verbeek A.L.
      • Bakker E.A.
      • Thompson P.D.
      • Hopman M.T.
      • Eijsvogels T.M.
      Lifelong exercise patterns and cardiovascular health.
      Furthermore, there is substantial evidence that longevity benefits are most prominent in the most active individuals (ie, elite athletes).
      • Farahmand B.Y.
      • Ahlbom A.
      • Ekblom O.
      • et al.
      Mortality amongst participants in Vasaloppet: a classical long-distance ski race in Sweden.
      Nevertheless, data from CMR athletic population studies suggest that some long-term endurance athletes develop MF.

      Conclusion

      Myocardial fibrosis has been reported in some lifelong endurance athletes. The pattern of LGE is heterogeneous, which may represent different causation and could contribute to the difference in MF locations between case studies/series and athletic population studies. In a few of these athletes, CMR-detected LGE is consistent with coronary artery disease and previous infarction and seems to be associated with increased risk of cardiovascular events. Other middle-aged and older athletes demonstrate LGE largely confined to the interventricular septum, often near the hinge points between the RV and the septum. This pattern seems more common in long-term endurance athletes and may represent the effect of repetitive myocardial microtrauma or repetitive dilatation of the RV with exercise. Athletes with underlying cardiovascular disease should receive pharmacological treatment to reduce the risk of secondary events. The significance of nonspecific MF is largely unknown, and future studies investigating the functional and clinical consequences of MF in athletes are warranted.

      Supplemental Online Material

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