Non-Ischemic Myocardial Fibrosis in Athletes

Quick Takes

  • Prolonged, high-intensity exercise may cause cardiac fibrosis even in the absence of predisposition to cardiac disease.
  • The prognostic significance of myocardial fibrosis in an otherwise healthy athlete remains controversial.
  • Findings of focal LGE at the right ventricular hinge points in asymptomatic athletes is of uncertain clinical significance.

Myocardial fibrosis or scar is characterized by the accumulation of collagen in the extracellular matrix as a result of myocardial damage from a range of pathologies. The patterns of fibrosis can be broadly classified as reactive or replacement fibrosis.1 Reactive fibrosis is characterized by the synthesis of collagen by myocytes in response to cardiac stress from aging, pressure or volume overload, reactive oxygen species, or the renin-angiotensin aldosterone system and beta-adrenergic system. In replacement fibrosis, myocytes damaged by ischemia or viral infection are replaced by collagen. Reactive fibrosis may progress to replacement fibrosis.1 Replacement fibrosis can be localized as in myocardial infarction or can be more diffuse following systemic conditions such as viral myocarditis.

Myocardial fibrosis reduces ventricular compliance, the downstream effects of which include heart failure with preserved or reduced ejection fraction, atrial enlargement, atrial fibrillation, and ventricular arrhythmias. Replacement myocardial fibrosis can be easily identified using magnetic resonance imaging (MRI) after the injection of gadolinium-based contrast agents (late gadolinium enhancement [LGE]). The presence of myocardial LGE is an emerging risk factor for future cardiac events and mortality in multiple pathologic states in the non-athletic population.2 Reactive fibrosis, on the other hand, is a more diffuse process and may not be easily detected using LGE. Recent developments in nonparametric cardiac MRI techniques such as T1 mapping (myocardial T1 and extracellular volume [ECV] measurements) allow for identification and quantification of diffuse reactive fibrosis. T1 relaxation time varies in relation to the composition of the myocardium and rises with any increase in fibrotic tissue. T1 maps can depict even relatively small variations of T1 within the heart to highlight tissue pathology. T1 mapping performed before and after the injection of a contrast agent allows measurement of ECV, which quantifies the relative expansion of extracellular matrix as a result of diffuse reactive fibrosis.3

Emerging data in athletes suggest that prolonged, high-intensity exercise may also cause cardiac damage and fibrosis even in the absence of predisposition to cardiac disease.4 One animal study looking at rats that were forced to run for 16 weeks (equivalent to 10 years of endurance exercise training in humans) demonstrated the development of eccentric cardiac hypertrophy, myocardial fibrosis and inducible ventricular tachycardia in 42% of the rats. Interestingly, the fibrotic changes were reversed after an 8-week exercise cessation.5 Not all studies, however, support this hypothesis.6,7 Athletes with LGE tend to be older than athletes without LGE. The prevalence of LGE also increases with years of competitive exercise training and the number of completed endurance events.8

In general, asymptomatic endurance athletes with a normal ECG may display two non-ischemic LGE patterns: (a) mid-myocardial LGE at the right ventricular (RV) insertion points (points in the interventricular septum where right and left ventricle muscles connect, also called "hinge points") and (b) subepicardial or mid-myocardial LGE in the inferolateral segments or less commonly in the interventricular septum or elsewhere.3 Inferior RV insertion point fibrosis is the most commonly observed pattern in athletes irrespective of age. Its prevalence has been reported in up to 20 to 30% of athletes and has been associated with combined training load and training intensity.8 These data may reflect the effects of pressure and/or volume overload present in the RV during intensive exercise, which causes tension in the insertion points and may lead to micro injuries visible as spots of LGE in that location.9 Those locations are thought to be watershed areas of the coronary circulation. A similar LGE pattern has been demonstrated in findings seen in congenital heart disease patients with volume and pressure overload of the RV, some patients with hypertrophic cardiomyopathy, and also in seemingly healthy, elderly individuals. These associations are considered benign in these settings.3 The other pattern of LGE seen in endurance athletes is epicardial or mid-myocardial involving the inferolateral wall and less commonly the ventricular septum. This pattern is less often observed compared to the hinge point LGE. As fibrosis of the lateral wall of the myocardium is a characteristic finding in acute and healed myocarditis, it is plausible that this pattern might actually represent evidence of prior silent myocarditis in otherwise asymptomatic athletes.3

It is well-established that non-RV insertion point LGE in cardiomyopathies predicts outcomes. Myocarditis is usually self-limiting and small residual scars are generally considered benign and do not require further cardiovascular testing. Such small focal areas of mid-myocardial fibrosis have also been found in almost 4% of the general population.10 Minor non-ischemic fibrosis observed in a large community-based population of older adults was not shown to influence prognosis when adjusted for cardiovascular risk factors.11 Only if the areas of fibrosis are larger or form striae, especially in the anteroseptal myocardium, is there increased risk of life-threatening ventricular arrhythmias and sudden death.12-15 Athletes that have larger areas of post-myocarditis LGE are likely to be symptomatic and have electrocardiogram (ECG) and echocardiographic abnormalities.12-14 In a study of 251 competitive athletes with apparently idiopathic ventricular arrhythmia (VA) who underwent cardiac MRI, mid-myocardial or subepicardial LGE stria occurred in 11% of athletes and was associated with higher prevalence of  exercise-induced VA as well as more complex arrhythmic phenotypes (multiple morphologies).16 In another study comparing 288 competitive athletes and 144 sedentary controls, the prevalence of VA in athletes was low and similar to that of sedentary individuals and unrelated to the type and intensity of sports activity.17 In a small subset of athletes with exercise-induced or complex VA who underwent CMR, LGE was only detected in three athletes in a non-ischemic pattern.17

It remains unclear what proportion of asymptomatic athletes have large areas of post-myocarditis LGE. Most recently, COVID-19-related myocardial injury in asymptomatic or mildly symptomatic athletes has been of great concern. An observational report of 26 COVID-19 positive collegiate athletes revealed LGE in 46% with four (15%) meeting updated Lake Louise Criteria for acute myocardial inflammation.18 The high rate of LGE reported was similar to the 38% seen in another study of 93 healthy triathletes.19 However, it is important to note the lack of case controls in these recent observational studies in addition to the inability to determine whether the observed LGE findings represent high risk features. A larger study of 59 COVID-19-positive collegiate athletes, which included a comparison with 60 athletic and 27 healthy control groups, found two (3%) asymptomatic COVID-19 positive athletes meeting criteria for myocarditis.20 Focal LGE isolated to the RV insertion points was present in 22% of COVID-19-positive athletes compared with the same LGE pattern in 24% of athletic controls. Importantly, this did not meet criteria for myocardial inflammation and the clinical significance remains uncertain.

Whether the presence of myocardial fibrosis in an otherwise healthy athlete portends a bad prognosis or risk of adverse events remains a subject of much debate. Not all endurance athletes have evidence of myocardial fibrosis, making the relationship between lifelong endurance exercise and the development of myocardial fibrosis and its clinical and prognostic implications unknown. This remodeling may reflect sequelae of other cardiac conditions. To determine whether myocardial fibrosis is predictive of adverse clinical outcomes in otherwise asymptomatic athletes, longitudinal studies are needed to comprehensively analyze the presence and patterns of LGE, factors predisposing asymptomatic athletes to the development of myocardial fibrosis, and the relationship of myocardial fibrosis to intensity of exercise and years of athletic training.

References

  1. Mewton N, Liu CY, Croisille P, Bluemke D, Lima JAC. Assessment of myocardial fibrosis with cardiovascular magnetic resonance. J Am Coll Cardiol 2011;57:891–903.
  2. Milano AD, Faggian G, Dodonov M, et al. Prognostic value of myocardial fibrosis in patients with severe aortic valve stenosis. J Thoracic Cardiovasc Surg 2012;144:830–37.
  3. Małek ŁA, Bucciarelli-Ducci C. Myocardial fibrosis in athletes—current perspective. Clin Cardiol 2020;43:882-88.
  4. La Gerche A, Burns AT, Mooney DJ, et al. Exercise-induced right ventricular dysfunction and structural remodeling in endurance athletes. Eur Heart J 2012;33:998-1006.
  5. Benito B, Gay-Jordi G, Serrano-Mollar A, et al. Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training. Circulation 2011;123:13-22.
  6. Hanssen H, Keithahn A, Hertel G, et al. Magnetic resonance imaging of myocardial injury and ventricular torsion after marathon running. Clin Sci (Lond) 2011;120:143–52.
  7. O'Hanlon R, Wilson M, Wage R, et al. Troponin release following endurance exercise: is inflammation the cause? A cardiovascular magnetic resonance study. J Cardiovasc Magn Res 2010;12:38.
  8. Wilson M, O'Hanlon R, Prasad S, et al. Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes. J Appl Physiol 2011;110:1622–26.
  9. Małek ŁA, Barczuk‐Falęcka M, Werys K, et al. Cardiovascular magnetic resonance with parametric mapping in long‐term ultra‐marathon runners. Eur J Radiol 2019;17:89‐94.
  10. Turkbey EB, Nacif MS, Guo M, et al. Prevalence and correlates of myocardial scar in a US cohort. JAMA 2015;314:1945-54.
  11. Shanbhag SM, Greve AM, Aspelund T, et al. Prevalence and prognosis of ischaemic and non-ischaemic myocardial fibrosis in older adults. Eur Heart J 2019;40:529-38.
  12. Zorzi A, Perazzolo Marra M, Rigato I, et al. Nonischemic left ventricular scar as a substrate of life-threatening ventricular arrhythmias and sudden cardiac death in competitive athletes. Circ Arrhythmia Electrophysiol 2016;9:e004229.
  13. Schnell F, Claessen G, La Gerche A, et al. Subepicardial delayed gadolinium enhancement in asymptomatic athletes: let sleeping dogs lie? Br J Sports Med 2016;50:111-17.
  14. Cipriani A, Zorzi A, Sarto P, et al. Predictive value of exercise testing in athletes with ventricular ectopy evaluated by cardiac magnetic resonance. Heart Rhythm 2019;16:239-48.
  15. Aquaro GD, Perfetti M, Camastra G, et al. Cardiac MR with late gadolinium enhancement in acute myocarditis with preserved systolic function: ITAMY study. J Am Coll Cardiol 2017;70:1977-87.
  16. Crescenzi C, Zorzi A, Vessella T, et al. Predictors of left ventricular scar using cardiac magnetic resonance in athletes with apparently idiopathic ventricular arrhythmias. J Am Heart Assoc 2021;10:e018206.
  17. Zorzi A, De Lazzari M, Mastella G, et al. Ventricular arrhythmias in young competitive athletes: prevalence, determinants, and underlying substrate. J Am Heart Assoc 2018;7:e009171.
  18. Rajpal S, Tong MS, Borchers J, et al. Cardiovascular magnetic resonance findings in competitive athletes recovering from COVID-19 infection. JAMA Cardiol 2021;6:116-18.
  19. Domenech-Ximenos B, Sanz-de la Garza M, Prat-González S, et al. Prevalence and pattern of cardiovascular magnetic resonance late gadolinium enhancement in highly trained endurance athletes. J Cardiovasc Magn Reson 2020;22:62.
  20. Clark DE, Parikh A, Dendy JM, et al. COVID-19 myocardial pathology evaluation in athletes with cardiac magnetic resonance (COMPETE CMR). Circulation 2021;143:609-12.

Clinical Topics: Arrhythmias and Clinical EP, Congenital Heart Disease and Pediatric Cardiology, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Sports and Exercise Cardiology, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Imaging, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Acute Heart Failure, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Exercise, Sports and Exercise and Congenital Heart Disease and Pediatric Cardiology, Sports and Exercise and Imaging

Keywords: Sports, Athletes, Contrast Media, Cicatrix, Myocarditis, Reactive Oxygen Species, Gadolinium, Heart Ventricles, Ventricular Septum, Atrial Fibrillation, Prevalence, Stroke Volume, Renin-Angiotensin System, Factor XI, COVID-19, Cardiovascular Diseases, Risk Factors, Cardiomyopathies, Heart Failure, Myocardium, Cardiomyopathy, Hypertrophic, Myocardial Infarction, Magnetic Resonance Imaging, Electrocardiography, Cardiomegaly, Tachycardia, Ventricular, Heart Defects, Congenital, Coronary Circulation, Exercise, Ischemia, Muscle Cells, Extracellular Matrix, Phenotype, Echocardiography, Inflammation, Adrenergic Agents


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