key: cord-0798122-qbcdhrj3 authors: Symanski, John D.; Tso, Jason V.; Phelan, Dermot M.; Kim, Jonathan H. title: Myocarditis in the Athlete: a focus on COVID-19 sequelae date: 2022-02-17 journal: Clin Sports Med DOI: 10.1016/j.csm.2022.02.007 sha: 912e586a5b51385f6e504d2fc8c361c0b603f12a doc_id: 798122 cord_uid: qbcdhrj3 Myocarditis is a leading cause of sudden death in athletes. Early data demonstrating increased prevalence of cardiac injury in hospitalized patients with COVID-19 raised concerns for athletes recovered from COVID-19 and the possibility of underlying myocarditis. However, subsequent large registries have provided reassuring data affirming low prevalence of myocarditis in athletes convalesced from COVID-19. While the clinical significance of sub-clinical myocarditis detected by cardiac MRI remains uncertain, clinical outcomes have not demonstrated an increase in acute cardiac events in athletes throughout the pandemic. Future directions include defining mechanisms underlying ‘long-haul’ COVID-19 and the potential impact of new viral variants. Myocarditis is an inflammatory disease of the myocardium with wide-ranging clinical presentations from mild self-limited cardiac symptoms to the presence of cardiac dysfunction and possible fulminant heart failure. 1 Myocarditis is frequently due to acute viral infection and has become a focus of concern during the coronavirus disease 2019 (COVID- 19) pandemic. [1] [2] [3] Among competitive athletes and highly active individuals, exercise during active viral myocarditis may exacerbate myocardial inflammation with precipitation of malignant ventricular arrhythmias. Indeed, myocarditis is a leading cause of sudden cardiac death (SCD) in athletes. [4] [5] [6] [7] In consideration of return-to-play (RTP) for competitive athletes diagnosed with myocarditis, consensus guidelines exist that emphasize temporal abstinence from exercise training coupled J o u r n a l P r e -p r o o f with complete resolution of myocardial inflammation, normalization of cardiac function and absence of ventricular arrhythmias with exertion. 8, 9 In the general population, infection with SARS-CoV-2 may lead to severe cardiac sequalae, especially in older individuals with significant underlying co-morbidities. [10] [11] [12] [13] Recognition of the high prevalence of clinically relevant cardiac injury among hospitalized patients with COVID-19 which was documented to be associated with poor outcomes led to significant apprehension in the care of competitive athletes. Whether athletes with asymptomatic or mild-COVID-19 infection might harbor myocarditis and remain at high risk for adverse cardiac events after recovery was of particular concern. [13] [14] [15] Since the early stages of the pandemic, considerable data have been acquired to provide sports medicine practitioners with updated prevalence estimates of cardiac injury in competitive athletes convalesced from COVID-19. [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] In this review, we detail the pathophysiology and clinical evaluation of athletes diagnosed with clinical myocarditis. We will also discuss key developments focused on athletes infected by COVID-19. We aim to provide an evidence-based rationale in the care of athletes and highly active individuals for sports medicine and cardiology practitioners in the context of myocarditis and COVID-19 related cardiac injury. Viruses are the most common pathogens known to cause myocarditis. Endomyocardial biopsy samples have revealed adenovirus, enteroviruses (Coxsackie type B [CVB3] and cytomegalovirus), parvovirus B-19 (B19V), and human herpesvirus 6 (HHV6) to be most frequent, with variations in prevalence by geographic regions. [1] [2] [3] Bacterial, fungal, and protozoal infections, drug-induced hypersensitivity eosinophilic reactions, and other autoimmune J o u r n a l P r e -p r o o f conditions represent less frequent causes of myocarditis. [1] [2] [3] 27 With infection, usually from the upper respiratory system or gastrointestinal tract, viral myocarditis is thought to progress over three phases: (1) an acute phase typically lasting 3-7 days during which the virus gains entry to myocardial and vascular endothelial cells via viral-specific mechanisms or receptors followed by viral replication and subsequent myocyte necrosis; (2) a subacute phase of approximately 1-3 months with host immune cells and cytokine activation causing further cardiac damage and potential impairments in cardiac function. While most myocarditis cases will resolve spontaneously, a minority will progress to (3), a chronic phase (chronic myocarditis or chronic inflammatory cardiomyopathy) characterized by myocyte abnormalities (variations in cell diameter), focal or diffuse fibrosis, and inflammatory cell infiltrates, which appear to be mediated through autoimmune processes rather than persistent viral-mediated injury. 2, 27 Myocarditis has been implicated in 3-10% of cases of SCD in young athletes. [4] [5] [6] [7] Athletes may be particularly vulnerable to myocarditis given the repetitive physical exhaustion associated with exercise training as well as the ancillary stresses that accompany competitive sports participation. 6, 28 Prolonged intense physical exertion such as marathon running and training may lead to impaired immune responses and increased susceptibility to infection for 3-72 hours. 29 Additionally, in murine models, forced exercise following coxsackievirus infection increases viral titers and the cytotoxic T-cell response, leading to increased myocardial necrosis and mortality. 30, 31 The clinical presentation of myocarditis can be variable. Fulminant myocarditis often presents with acute, severe heart failure symptoms (dyspnea, chest pain) and potentially J o u r n a l P r e -p r o o f catastrophic malignant arrhythmias, heart block 7 , or cardiogenic shock. 32 In more typical cases of myocarditis, clinical symptoms are generally less severe, but may still manifest angina, dyspnea, palpitations, or syncope. In some cases, specific complaints may be absent or attributed to the initial systemic symptoms of seasonal viral infections. Athletes may be more attuned to minor physiologic disturbances and complain of non-specific symptoms such as fatigue, myalgias, or exercise intolerance. 28 Highlighting the variability in symptomatic myocarditis presentation, a recent analysis of 97 myocarditis-related sudden death cases in young individuals (mean age 19.3 ± 6.2 years) determined that only 47% reported symptoms prior to death. 7 These data should be interpreted cautiously, however, as retrospective evaluation of symptoms in autopsy-based studies may be unreliable. With the emergence of the COVID-19 pandemic, initial reports detailed an alarmingly high prevalence of myocardial injury in hospitalized patients. [11] [12] [13] [14] [15] These observational reports indicated biomarker evidence of cardiac injury was common among hospitalized patients with COVID-19 and that those with cardiac injury were at particularly high risk of mortality. 11, 12 Importantly, patients included in these studies had severe illness (reason for hospitalization), were older, and displayed a high incidence of comorbid conditions. [11] [12] [13] [14] [15] Nevertheless, this high rate of cardiac involvement suggested a possible SARS-CoV-2 tropism for cardiac cells and raised concerns for individuals experiencing asymptomatic or mild COVID-19 infection. 33, 34 Entry of the virus via the ACE-2 receptor in respiratory and cardiac tissue was purported as a potential underlying mechanism leading to the high prevalence of observed cardiac injury. 35 However, subsequent autopsy-based studies have noted absence of lymphocytic predominant J o u r n a l P r e -p r o o f myonecrosis 36, 37 and classic histologic evidence of myocarditis associated with COVID-19 infection. 36 Given these data, mechanisms underlying COVID-19-related cardiac injury appear multi-factorial and caution is required in the clinical interpretation of patients diagnosed with COVID-19 myocarditis. Clinical diagnosis of myocarditis in athletes can be extremely challenging (see Figures 1 and 2). 7, 28, 38 As the compilation of COVID-19 data in athletes has evolved over time, differentiating clinically relevant cardiac injury and presumed myocarditis from sub-clinical injury of unclear clinical significance remains a critically important issue. Given early concerns taken from observational data in hospitalized patients with COVID-19, 10-15 prior expert consensus recommendations advised a post-infection screening evaluation in athletes, beginning with a focused medical history and examination, no earlier than 10 days after COVID-19 test positivity. 39 Inclusion of so-called 'triad' testing (ECG, troponin, and echocardiography) was also recommended as the cornerstone of the RTP evaluation. However, as clinical outcomes of athletes convalesced from COVID-19 and prevalence of cardiac injury in this population were reported, it became clearer that: 1) most competitive athletes experienced either asymptomatic or mild COVID-19 symptoms, 2) prevalence of cardiac injury was low in this population, and 3) those diagnosed with clinical myocarditis usually report cardiopulmonary symptoms consistent with myocarditis. 40 As such, it must be emphasized that COVID-myocarditis in the athlete remains a clinical diagnosis associated with high pre-test probability of disease. As with other causes of myocarditis, presenting symptoms in individuals with cardiac involvement due to COVID-19 may include chest pain, dyspnea, palpitations, and syncope. For J o u r n a l P r e -p r o o f athletes who have RTP, a decline in the athlete's peak performance, prolonged dyspnea, or persistence of an elevated heart rate during recovery from exercise might herald the existence of myocardial inflammation and may require ongoing clinical investigation to exclude the presence of cardiac injury if there is sufficient clinical suspicion. The highly fit and competitive athlete may be less inclined to acknowledge symptoms due to concern of being withheld from training and competition or loss of team standing/position. Therefore, it is imperative for coaches, trainers, and team physicians to encourage athletes to remain attentive and be forthright with suggestive symptoms. The 12-lead ECG may provide invaluable clues in patients with myocarditis, though this test is limited by poor sensitivity (47%) and specificity. [41] [42] [43] Suggestive features may include subtle increases in resting heart rate, PR and QRS interval durations, premature ventricular contraction (PVC) burden, or reduction of QRS amplitude ( Table 1) . More striking abnormalities include new bundle branch blocks or fractionated QRS (>120 msec), sinus arrest, high-grade AV block, complex ventricular ectopy, and ST-segment changes mimicking acute myocardial infarction. The incidence of abnormal ECG findings varies by study population, severity of symptoms, and extent and distribution of myocardial inflammation. In a contemporary series of 443 mostly young (median age 34 years) and highly symptomatic patients with acute myocarditis from the Lombardy region of Italy, ST-segment elevation was the most common ECG finding (57.5%) with other ST-segment abnormalities noted in an additional 23.5%. 44 Harris et al. 7 suggested that among lethal cases of myocarditis, inflammatory J o u r n a l P r e -p r o o f involvement of the conduction system is relatively common (38%) and may result in sudden death from heart block. By contrast, ECG abnormalities appear infrequently among athletes with myocarditis following COVID-19 infection. In the two largest series of athletes evaluated after COVID-19 infection, ECG changes were uncommon, even among those with cardiac magnetic resonance imaging (CMRI) findings of myocarditis. 23, 26 The Big 10 COVID-19 Registry (N=1597 athletes) identified 37 individuals with clinical or subclinical myocarditis utilizing CMRI. 23 Overall, 4 of 9 athletes (44%) with clinical symptoms of myocarditis (chest pain, dyspnea, and palpitations) and just 1 of 28 (14%) without cardiac symptoms exhibited abnormal ECG findings. The Outcomes Registry for Cardiac Conditions in Athletes (ORCCA) identified 21 cases with myocardial or pericardial involvement by CMRI from screening of 3018 post-COVID athletes with mostly mild or moderate symptoms. ECG abnormalities were rare (4/21 or 19%) with Twave inversion in V5-6 observed in just one case. 26 As many athletes exhibit ST-segment or Twave alterations, which can simulate pathologic findings, adherence to standardized interpretation guidelines for athletes and direct comparison with previously obtained ECG tracings is crucial. 45 In the clinical assessment of myocarditis, high-sensitivity troponin is the preferred biomarker (alternatively early generation troponin or CK-MB assays) to assess myocyte necrosis Clinics Care Point:  Abnormal ECG findings occur infrequently among athletes following COVID- 19 infection, even when MRI features suggestive of acute myocarditis are present. J o u r n a l P r e -p r o o f along with C-reactive protein (CRP). 41, 44 The differential complete blood count may show eosinophilia in the presence of eosinophilic myocarditis. 46 Peripheral blood serologic and virologic tests are frequently unrevealing, except with suspected Lyme disease or HIV. 41 Antinuclear antibody testing may be appropriate in patients with known or suspected history of autoimmune disorders. 47 When considering biomarker interpretation in athletes diagnosed with COVID-19, it is important to consider the training history as recent physical activity may precipitate troponin release ( Table 1) . 48 It has been recommended that high-sensitivity troponin assessment not be performed within ~24-48 hours of exercise. 40 Recently, a novel circulating micro-RNA produced by cardiac myosin-specific type 17 helper lymphocytes (T17) has been identified in mice and humans with myocarditis. J o u r n a l P r e -p r o o f mild regional hypokinesis (particularly in the inferior and inferolateral segments), and abnormalities of tissue-Doppler and regional strain imaging may be recognized. 2, 50, 51 Right ventricular (RV) dysfunction may also be evident, especially in those with severe pulmonary injury. 28 Pericardial effusions have been observed with varying frequencies. In the early phases of myocarditis, LV dimensions are generally normal; even when the EF is reduced. LV dilation often implies chronicity, with the caveat that the athlete's type of exercise training (particularly endurance modalities) and corollary cardiovascular adaptations may affect chamber dimensions ( Table 1) . Recognition of LV dysfunction should also continue to prompt the clinician to consider potential effects of performance enhancing (anabolic steroid, amphetamines) and LGE images. 60 In this first iteration, abnormal findings in 2 of the three elements diagnosed acute myocarditis with a 74% sensitivity and 86% specificity. 61 The addition of novel parametric (T1 and T2) mapping techniques has been shown to improve the diagnostic accuracy of CMRI for acute myocarditis. The 2018 Updated Lake Louise Criteria include T2-mapping for edema and native T1-mapping and extracellular volume (ECV) for inflammatory injury. 55 One study examining the updated criteria reported enhanced sensitivity (87.5%) while preserving high specificity (96.2%) for diagnosis of acute myocarditis. 62 At present, there have been eleven separate reports, primarily small observational case series, detailing CMRI findings in athletes following COVID-19 infection ( Table 2) . These studies vary in terms of subject age, sex, race, ethnicity, geographic distribution, sporting discipline, and symptomatology and detailed correlations of ECG, biomarker, and echocardiographic findings have been inconsistent. Indications for CMRI, either clinically directed or universally mandated, and timing relative to symptom onset or COVID-19 positivity have also been non-uniform. Further, scanner type (1.5 vs. 3 T), imaging protocols/sequences, and the experience of the interpreter have not been standardized. Finally, while prior studies incorporated the updated Lake Louise criteria, absence of case-control comparative groups of non-infected athletes and non-athletes represent a critical omission in most of these studies. Additional limitations are present in careful review of these studies. First, there is stark discrepancy in the observed frequency of CMRI-defined myocarditis with rates ranging between 0 to 17%. [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] In the Big Ten COVID-19 Registry (N=1,597 athletes), among the 13 participating institutions, incidence rates for myocarditis varied by site from 0 to 7.6%. 23 A second limitation J o u r n a l P r e -p r o o f of CMRI studies in athletes has been the lack of standardized CMRI interpretation by a core laboratory to validate abnormal findings. As such, given the expertise required for CMRI interpretation, interpreter bias is a clear, critical limitation. For example, while Brito et al. 21 observed a high prevalence of pericardial enhancement and associated effusions in 39.5% (N=19) of a cohort of convalesced COVID-19 athletes (N=48), in no other CMR-based athletic study has this degree of presumed pericarditis been replicated. Fibrosis confirmed by LGE is often observed in myocarditis ( Table 2 ). Yet, whether LGE reported in prior COVID-19 convalesced athlete case series data represents recent COVID-19 injury is unknown in the absence of comparative baseline CMRI data. Prior investigators appropriately excluded focal septal RV insertion site fibrosis as an indicator of COVID-19 injury given the increasing recognition of this finding as a likely benign marker in athletes, particularly masters-level endurance athletes. 63, 64 A recent report demonstrated focal non-ischemic fibrosis in 17% of asymptomatic triathletes, which appeared to correlate with exercise-induced hypertension and competition history. 63 Another study identified focal LGE in 37.6% of healthy endurance athletes vs. 2.8% in healthy control subjects (p<0.001), with a typical pattern in the RV insertion points. 64 In each of these studies, athletes with LGE also tended to exhibit higher ECV in remote, non-fibrotic myocardium assessed with T1-mapping. The significance of "subclinical" myocarditis detailed with CMR-based screening remains uncertain. Present short-term cardiac outcomes are reassuring after RTP in competitive athletes and, to-date, no sports-related cardiac events clearly linked to COVID-19 have been confirmed in any athlete included in published registry data. 23 . 23 In addition to evidence suggesting CMRI-based screening does not improve athlete health outcomes, we must also acknowledge the legitimate concerns of costs in implementing widespread CMRI screening, limited scanner availability, and inappropriate health care resource allocation as separate reasons why CMRI screening for all athletes convalesced from COVID-19 is not practical. Future unfortunate and tragic athlete SCD cases will undoubtedly still occur, just as prior to the COVID-19 pandemic. This emphasizes the importance of careful adjudication of follow-up data from U.S. and multi-national registries, avoidance of overreaching correlation with potential prior COVID-19 infection, and continued vigilance with emergency preparedness to prevent such tragic events. As exercise may augment pathogen virulence in other acute viral infections, it is prudent to assume this may also be the case with SARS-CoV2. 29 refined RTP strategies to be tailored to symptom severity, with more severe symptoms warranting a longer period of rest and more extensive cardiac risk-stratification. 40, 66 Clinics Care Point:  Cardiac MRI is recommended for athletes with clinically suspected acute myocarditis including those with chest pain, elevated high-sensitivity troponin levels, and abnormal ECG changes in the absence of obstructive or anomalous coronary arteries. Imaging should typically be performed within 2-3 weeks of symptom onset and/or abnormal biomarker or ECG findings with interpretation by experienced imaging specialists. An important unaddressed clinical issue is whether athletes with a remote history of COVID-19 and have fully recovered should undergo cardiovascular risk assessment. This also applies to those found to have a positive COVID-19 antibody test without any history of prior clinical symptoms. Currently, definitive outcomes data to address this issue are lacking. However, there are currently no data to suggest that athletes with prior COVID-19 infection are suffering from increased rates of sudden cardiac death or incident heart failure. [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] J o u r n a l P r e -p r o o f Case 1. A 34-year-old former professional rugby player and recreational cyclist, presenting with cardiac arrest. Two week earlier, he suffered a witnessed spell during sleep with erratic breathing, loss of bladder continence, and transient unresponsiveness. He woke shortly before arrival of emergency responders and felt otherwise normal. Initial evaluation including 12-lead ECG (A), head CT and EEG, high sensitivity troponin, trans-thoracic echocardiography, and coronary CT angiography (not shown) were unremarkable. The patient was discharged with an event monitor and maintained his exercise routine without symptom limitation. Two days after cycling 80 miles, he suffered a ventricular fibrillation arrest captured on the event monitor (B); again, recognized by erratic breathing during sleep. Following successful resuscitation, he experienced transient LV dysfunction requiring circulatory support with V-A ECMO. Ventricular function normalized by hospital day 2 and the patient was weaned from cardiopulmonary support. Serial COVID-19 testing was negative. Cardiac MRI one week after admission revealed normal cardiac chamber dimensions, LV wall thickness, and bi-ventricular function (EF 65%). Delayed gadolinium enhancement images (C) revealed a mid-myocardial stripe of LGE (arrows) involving the mid and distal septum, basal and apical lateral walls (quantitative scar burden 8%). Parametric mapping demonstrated diffusely elevated native T1 (D, E) and T2 values. Clinical history and MRI features were most consistent with myocarditis. He reported no chest discomfort or shortness of breath. High sensitivity troponin was elevated a 5,452 ng/L and COVID-19 testing was positive. Echocardiography revealed normal left ventricular chamber and wall thickness with low-normal LV systolic function (EF 53%). No regional wall motion abnormalities were evident and global longitudinal strain normal at -17.3%. RV size and function were normal, and a trivial posterior pericardial effusion was noted. Troponin levels normalized within two weeks. Cardiac MRI performed three weeks after presentation revealed a mildly dilated LV chamber with normal wall thickness and an LVEF of 67%. Sub-epicardial LGE was present in the basal to apical inferior and apical lateral segments with a scar size of 14%. Native T1 values were mildly elevated along the lateral segments and normal in all other regions. T2 values were normal. Management of acute myocarditis and chronic inflammatory cardiomyopathy Diagnosis and management of myocarditis in children. A scientific statement from the American Heart Association Incidence, cause, and comparative frequency of sudden cardiac death in national collegiate athletic association athletes Aetiology and incidence of sudden cardiac arrest and death in young competitive athletes in the USA: a 4-year prospective study Sudden deaths in young competitive athletes Sudden unexpected death due to myocarditis in young people, including athletes Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: task force 3: hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and other cardiomyopathies, and myocarditis Recommendations for participation in competitive and leisure time sport in athletes with cardiomyopathies, myocarditis, and J o u r n a l P r e -p r o o f pericarditis: position statement of the sport cardiology section of the European Association of Preventive Cardiology (EAPC) COVID-19 and cardiovascular disease Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19) Coronavirus historical perspective, disease mechanisms, and clinical outcomes Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19) Cardiac involvement in patients recovered from COVID-2019 identified using magnetic resonance imaging Cardiovascular magnetic resonance findings in competitive athletes recovering from COVID-19 infection Evaluation for myocarditis in competitive student athletes recovering from coronavirus disease 2019 with cardiac magnetic resonance imaging Cardiac involvement in consecutive elite athletes recovered from Covid-19: A magnetic resonance study COVID-10 myocardial pathology evaluation in athletes with cardiac magnetic resonance (COMPETE CMR) Prevalence of inflammatory heart disease among professional athletes with prior COVID-19 infection who received systematic return-toplay cardiac screening High Prevalence of pericardial involvement in college student athletes recovering from COVID-19 Cardiovascular evaluation after COVID-19 Results of an algorithm-guided screening Prevalence of clinical and subclinical myocarditis in competitive athletes with recent SARS-CoV-2 infection: results from the big ten COVID-19 cardiac registry Cardiac magnetic resonance findings in patients recovered from COVID-19. Initial experience in elite athletes Findings form cardiovascular evaluation of national collegiate athletic association division I collegiate student-athletes after asymptomatic or mildly symptomatic SARS-CoV-2 infection Outcomes registry for cardiac conditions in athletes investigators. SARS-CoV-2 cardiac involvement in young competitive athletes Update on myocarditis Myocarditis in athletes: a clinical perspective Marathon training and immune function Coxsackie-virus B3 myocarditis in C3H/HeJ mice: description of an inbred model and the effect of exercise on virulence Augmentation of the virulence of murine coxsackie-virus B-3 myocardiomyopathy by exercise Recognition and initial management of fulminant myocarditis Potential effects of coronaviruses on the cardiovascular system: a review Coronavirus Disease 2019 (COVID-19) and the heart-is heart failure the next chapter Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19 Pathological evidence for SARS-CoV-2 as a cause of myocarditis: JACC review topic of the week Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study Myocarditis in athletes is a challenge A game plan for the resumption of sport and exercise after coronavirus disease 2019 (COVID-19) Infection Screening of potential cardiac involvement in competitive athletes recovering from COVID-19. An expert consensus statement Current state of knowledge on etiology, diagnosis, management, and therapy of myocarditis: A position statement of the european society of cardiology working group on myocardial and pericardial disease Prognositic electrocardiographic parameters in patients with suspected myocarditis Electrocardiography of myocarditis revisited: Clinical and prognostic ssignificance of electrocardiographic changes Clinical presentation and outcome in a contemporary cohort of patients with acute myocarditis: Multicenter Lombardy fegistry International recommendations for electrocardiographic interpretation in athletes Eosinophic myocarditis: characteristics, treatment, and outcomes Immune-mediated and autoimmune myocarditis: clinical presentation, diagnosis, and management Exercise-induced cardiac troponin elevation. Evidence, mechanisms, and implications A novel circulating microRNA for the detection of acute myocarditis Fulminant versus acute nonfulminant myocarditis in patients with left ventricular systolic dysfunction Speckle tracking echocardiography in acute myocarditis Prominent left ventricular trabeculations in competitive athletes: A proposal for risk stratification and management The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology: endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations Systematic review of patients presenting with suspected myocardial infarction and non-obstructive coronary arteries Prognostic value of cardiac magnetic resonance tissue characterization in risk stratifying patients with suspected myocarditis Cardiac magnetic resonance working group of the Italian Society of Cardiology. Cardiac MR with late gadolinium enhancement in acute myocarditis with preserved systolic function: ITAMY study Late gadolinium enhancement and the risk for ventricular arrhythmias or sudden death in dilated cardiomyopathy: systematic review and metaanalysis Cardiovascular magnetic resonance in myocarditis: a JACC white paper Diagnostic performance of extracellular volume, native T1, and T2 mapping versus Lake Louise criteria by cardiac magnetic resonance for detection of acute J o u r n a l P r e -p r o o f myocarditis: a meta-analysis Comparison of the original and the 2018 Lake Louise criteria for diagnosis of acute myocarditis: results of a validation cohort Myocardial fibrosis in competitive triathletes detected by contrast-enhanced CMR correlates with exercise-induced hypertension and competition history Prevalence and pattern of cardiovascular magnetic resonance late gadolinium enhancement in highly trained endurance athletes Diagnosis, treatment, and outcome of giant-cell myocarditis in the era of combined immunosuppression Management and outcomes of cardiac sarcoidosis: a 20-year experience in two tertiary care centres ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology solution set oversight committee Symptoms  None  Chest pain, abnormal shortness of breath beyond normal exercise-induced symptoms, palpitations, pre-syncope or syncope, decrement in performance.  Changes related to high vagal tone (such as bradycardia, early repolarization, first degree heart block or Mobitz type I AV block) or athletic remodeling (LVH, atrial enlargement) Any pathologic changes compared to prior study  Frequent or multiform premature ventricular beats or arrhythmias  ST and T-wave changes  Left bundle branch block  Advanced AV block Biomarkers  Troponin and BNP/NT-Pro BNP may be mildly elevated immediately after strenuous exercise but return to normal quickly (<48 hours) Persistent (>48 hours) or more than mild elevation in cardiac biomarkers.  Elevation in C-reactive protein, erythrocyte sedimentation rate, and leukocytosis.  Symmetric dilation of all four cardiac chambers without regional wall motion abnormalities.  Symmetric eccentric LV hypertrophy  Normal or low-normal EF with normal diastolic function  Normal augmentation of biventricular function with exercise (≥10% with exercise)  Normal/low-normal global longitudinal strain, better than -16%.  Prominent LV apical trabeculations with normal LVEF and wall thickness  Disproportionate LV or RV enlargement  Asymmetric wall thickening (>2mm between contiguous segments  Any segmental wall motion abnormalities.  Abnormal EF (<50% LVEF, <44% RVEF) particularly if associated with low tissue Doppler/abnormal diastolic function  Failure to augment biventricular function with exercise  Abnormal global longitudinal strain, worse than -16%  >Trivial pericardial effusion  Morpho-functional changes outlined in the echocardiographic section above.  LGE is absent with possible exception of right ventricular insertion point LGE  Parametric maps are normal  Morpho-functional changes outlined in the echocardiographic section above.  LGE in a mid-or sub-epicardial distribution  >Trivial pericardial effusion with prominent pericardial enhancement  Abnormal T1 or T2 mapping J o u r n a l P r e -p r o o f