Approach

The evaluation of patients with suspected myocarditis begins with a complete history and physical examination. If myocarditis is still suspected, then further work-up with a 12-lead ECG, chest x-ray, laboratory evaluation of cardiac biomarkers, and two-dimensional echo should be performed.[16][21]​​​​​[57]​ Recommendations on which patients should undergo endomyocardial biopsy (EMB) vary and local guidelines should be consulted.[5][58][59][60][61]​​​​​​​​ Contrast-enhanced cardiac magnetic resonance imaging (MRI) has been shown to assist in the diagnosis of myocarditis by providing detailed tissue characterisation.[16][21]​​​​​[57][62]​​​​ ​​Positron emission tomography-computed tomography (PET-CT), especially 18F-fluorodeoxyglucose (FDG) PET-CT, can also be of value.[21]

The approach may be modified for children with suspected myocarditis. The 2021 American Heart Association (AHA) statement on paediatric myocarditis lays out a new paradigm for myocarditis based on diagnostic strata and also provides guidance on approach.[15] Cardiac MRI is the preferred diagnostic modality in children because it is non-invasive, but EMB retains specific indications.[15] 

The American College of Cardiology describes the spectrum of myocarditis in 4 stages, mirroring the adult heart failure paradigm: stage A (at risk), stage B (asymptomatic with structural heart disease), stage C (symptomatic myocarditis), and stage D (advanced/refractory myocarditis).[56] Although this classification is based on adult studies, the ACC suggests that the approach can be adapted for paediatric populations. See Criteria.

History

Patients presenting with myocarditis are usually aged <50 years. A history of viral prodrome 2-3 weeks prior to the onset of myocarditis is commonly present. Symptoms may include chest pain, dyspnoea, orthopnoea, syncope, fatigue, and palpitations.[16]

In children, a viral prodrome will be the most common history, followed by history suggestive of arrhythmias or syncope.[15] The common symptoms include fever, fatigue, respiratory symptoms, abdominal pain, emesis, and lethargy.[15]

The patient's medical history may be significant for autoimmune disease such as collagen-vascular diseases as well as inflammatory bowel disease, diabetes mellitus, sarcoidosis, thyrotoxicosis, granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), or Loeffler's syndrome. In addition, a history of travel to endemic areas where causative organisms are found may suggest a specific infectious aetiology.

A thorough drug history along with other possible exposures to toxic substances or cocaine should be obtained to exclude any drug or toxic aetiologies. These include anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), fluoropyrimidines (e.g., fluorouracil, capecitabine), immunotherapies (e.g., ipilimumab, tremelimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, and trastuzumab), arsenic, zidovudine, carbon monoxide, ethanol, interleukin-2, cocaine, amphetamine, smallpox or mpox vaccine, SARS-CoV-2 (COVID-19) mRNA vaccine (may occur with other types of COVID-19 vaccines), catecholamines (e.g., adrenaline, noradrenaline, dopamine), cyclophosphamide, heavy metals (copper, iron, lead), radiation, antibiotics (penicillins, cephalosporins, sulfonamides), amphotericin B, thiazide diuretics, anticonvulsants (carbamazepine, phenytoin, phenobarbital), digoxin, lithium, amitriptyline, clozapine, snake venom, bee venom, black widow spider venom, scorpion venom, and wasp venom.[30][31][32][52][53][54]​​​​

Physical examination

A thorough examination for both the cardiorespiratory findings and other general findings that may point to possible aetiology should be performed. Findings can include rales, elevated neck veins, S3 gallop, S3 and S4 summation gallop, pericardial friction rub, peripheral hypoperfusion, sinus tachycardia, atrial and ventricular arrhythmias, hypotension, altered sensorium, hepatomegaly, and lymphadenopathy. Resting tachycardia is an especially important sign in adolescents where the symptoms can be masked significantly in both acute and chronic myocarditis.

12-lead ECG

A 12-lead ECG should be ordered immediately on presentation in anyone with chest pain or cardiac symptoms.[15][16]​​ In myocarditis it most commonly displays non-specific ST-segment and T-wave abnormalities; however, ST-segment elevation and depression frequently occur. Children can present with atrial and ventricular arrhythmias and such a presentation can be a marker of poor outcomes.[63] A component of pericarditis is common in children and can be evident as non-specific ST-segment changes in all of the precordial leads.

Laboratory evaluation

Cardiac biomarkers should be ordered immediately in any patient with suspected myocarditis. Creatine kinase and creatine kinase-MB levels are often mildly elevated. Troponin (I or T) levels have shown to be a more reliable indicator of myocardial damage, including in children.[15][16]​ However, it should be noted that some patients with myocarditis do not have elevated high-sensitivity cardiac troponin levels.[56]

Serum B-type natriuretic peptide may be helpful in distinguishing primary cardiac from primary pulmonary aetiologies of dyspnoea when the physical examination and initial work-up is unclear or non-specific. In myocarditis it is elevated in response to ventricular distention such as occurs in congestive heart failure.[59]

Chest x-ray (CXR)

Should be ordered in all patients with suspected myocarditis.[64] As a first-line investigation, CXR helps rule out pulmonary oedema and provides an initial assessment of cardiac silhouette and pulmonary vasculature.[16] In the context of acute heart failure due to myocarditis, CXR may reveal pulmonary congestion. Cardiomegaly can suggest associated myopericarditis with pericardial effusion or chronic myocarditis evolving into dilated cardiomyopathy.

Two-dimensional echocardiogram

This should be ordered in every patient suspected of having myocarditis.[15][16][57]​​ Myocarditis can cause global and regional left ventricular motion abnormalities, systolic and diastolic dysfunction, and dilatation.[Figure caption and citation for the preceding image starts]: Apical 4-chamber transthoracic echocardiogram in a patient with myocarditis. The right ventricle is dilated with hypokinesis. Triscupid regurgitation is present with a reduced continuous wave Doppler gradient indicating right ventricular failureFrom: Rasmussen TB, Dalager S, Andersen NH, et al. BMJ Case Reports 2009; doi:10.1136/bcr.09.2008.0997 [Citation ends].com.bmj.content.model.Caption@229cdff9[Figure caption and citation for the preceding image starts]: Apical 4-chamber echocardiogram in a patient presenting with myocarditis showing a slightly dilated left ventricle with spontaneous ultrasonic contrast indicating severely impaired left ventricular systolic functionFrom: Rasmussen TB, Dalager S, Andersen NH, et al. BMJ Case Reports 2009; doi:10.1136/bcr.09.2008.0997 [Citation ends].com.bmj.content.model.Caption@4f253c2​ Special attention should be paid to evaluation for clots which can change therapies and risk profile. Development of intracardiac thrombosis can occur due to a prothrombotic, proinflammatory state as well as stagnant blood in the dysfunctional heart.[65]

Endomyocardial biopsy (EMB)

The potential risks and benefits of EMB should always be carefully assessed, particularly during the acute presentation, as the risk of arrhythmia or ventricular perforation is highest at this time. Recommendations on which patients should undergo EMB vary and local guidelines should be consulted.[5][58][59][60]​​​​[61][66]​​​​[67]​​​​

The ACC recommends EMB in adults with suspected:[56]

  • Asymptomatic (stage B) myocarditis in the setting of immune checkpoint inhibitor therapy

  • Symptomatic (stage C) myocarditis with left ventricular dysfunction, symptomatic heart failure, arrhythmia, peripheral eosinophilia, or when the diagnosis is uncertain and cardiac MRI cannot be obtained

  • Most patients with advanced (stage D) myocarditis

The ACC recommends against EMB for low-risk adults with stage C myocarditis (i.e., symptomatic myocarditis with normal left ventricular ejection fraction, haemodynamic and electrical stability, and no or minimal late gadolinium enhancement) and adults with stage B myocarditis that is not due to immune checkpoint inhibitor therapy.[56]

A statement on dilated cardiomyopathies from the AHA recommends biopsy for adults 'with clinically suspected unexplained acute myocarditis who require inotropic support or mechanical circulatory support and those with Mobitz type 2 second-degree or higher heart block, sustained or symptomatic ventricular tachycardia, or failure to respond to guideline-based medical management within 1-2 weeks'.[58] The 2022 AHA/ACC/Heart Failure Society of America (HFSA) adult heart failure (HF) guidelines state 'Endomyocardial biopsy may be advantageous in patients with heart failure in which a histological diagnosis, such as myocarditis, may influence treatment decisions'.​[59]​ A joint statement from Heart Failure Association of European Society of Cardiology (ESC), HFSA, and Japanese HF Society recommends EMB 'in patients with fulminant/acute myocarditis presenting with cardiogenic shock or acute HF and left ventricular (LV) dysfunction, with or without malignant ventricular arrhythmias and/or conduction abnormalities'. They also recommend considering EMB in 'haemodynamically stable patients with clinical symptoms and diagnostic criteria (electrocardiographic abnormalities, elevated troponin levels, and imaging findings) suggestive of myocarditis, in the absence of significant coronary artery disease'.[61]

[Figure caption and citation for the preceding image starts]: Histological findings in a patient with giant cell myocarditis. A: severe myocardial necrosis and fibrotic replacement of the cardiomyocytes with granulation tissue and fibrosis is present in a section from the anterolateral left ventricular wall; B: a sharp demarcating border between vital and necrotic myocardium is seen, confirmed by additional immunohistochemical staining for myoglobin; C: at the inflammatory border, cells consisting of prominent multi-nucleated giant cells, macrophages, lymphocytes, and eosinophilic granulocytes are seen in close proximity to vital myocardium; D: immunohistochemical staining for complement 4d is positive in all vessels, suggestive of complement cascade activationFrom: Rasmussen TB, Dalager S, Andersen NH, et al. BMJ Case Reports 2009; doi:10.1136/bcr.09.2008.0997 [Citation ends].com.bmj.content.model.Caption@1a336052

Additionally, the biopsies can be used for viral polymerase chain reaction (PCR) testing to diagnose viral myocarditis with specificity, and to analyse immune-mediated injury and potentially inflammatory markers at a molecular level.[68]

In children, cardiac MRI has replaced traditional EMB as the preferred diagnostic modality because it is non-invasive.[15] However, EMB retains specific indications, particularly in confirming diagnoses such as lymphocytic myocarditis, hypersensitivity myocarditis, and giant cell myocarditis, where histopathological evaluation directly informs clinical management. Immunohistochemistry has greatly increased the ability to assess for inflammatory cells.[15][Figure caption and citation for the preceding image starts]: Histological findings in a patient with giant cell myocarditis. A: severe myocardial necrosis and fibrotic replacement of the cardiomyocytes with granulation tissue and fibrosis is present in a section from the anterolateral left ventricular wall; B: a sharp demarcating border between vital and necrotic myocardium is seen, confirmed by additional immunohistochemical staining for myoglobin; C: at the inflammatory border, cells consisting of prominent multi-nucleated giant cells, macrophages, lymphocytes, and eosinophilic granulocytes are seen in close proximity to vital myocardium; D: immunohistochemical staining for complement 4d is positive in all vessels, suggestive of complement cascade activationFrom: Rasmussen TB, Dalager S, Andersen NH, et al. BMJ Case Reports 2009; doi:10.1136/bcr.09.2008.0997 [Citation ends].com.bmj.content.model.Caption@3785fe75

Cardiac MRI

Cardiac MRI is as an important tool in the assessment of suspected myocarditis, particularly when trying to distinguish acute myocarditis from acute MI.[16][57][62] In some cases, findings from cardiac MRI can also be useful in determining the aetiology of myocarditis.[69]​​

Lake Louise consensus criteria were updated in 2018 to propose that presence of both T2 and T1 findings provide strong evidence for myocardial inflammation.[70]

In children, the primary purpose of cardiac MRI is to identify myocardial injury, and to differentiate acute myocarditis from non-inflammatory cardiomyopathies.[15]

Other tests

  • Coronary angiography: this should be performed when the presenting symptoms and findings are indistinguishable from the acute coronary syndromes.

  • FDG PET-CT: helps diagnose myocarditis by providing metabolic information of inflammation as increased FDG uptake. FDG PET-CT is useful in chronic myocarditis, where cardiac magnetic resonance does not have the same accuracy as in acute myocarditis.[71] FDG PET-CT is also a valuable diagnostic tool for cardiac sarcoidosis and can facilitate differentiation from giant cell myocarditis.[72] In cardiac sarcoidosis presenting with myocarditis, FDG PET-CT typically reveals tracer uptake in the lungs, lymph nodes, and myocardial tissue. In addition, FDG PET-CT can help detect myocarditis in the context of systemic autoimmune diseases, where abnormal tracer accumulation may be seen in the myocardium as well as other involved organs, such as the aortic wall in certain forms of vasculitis.[67]

  • MRI-guided EMB: this is a promising new technology that seems to significantly increase the sensitivity of EMB in the diagnosis of myocarditis.[73] This is still in the developmental phase and requires validation in larger studies.

  • Genetic testing: genetic predisposition is increasingly recognised as a risk factor for myocarditis.[55] The ACC recommends genetic counselling and testing for all consenting patients, followed by cascade screening of family members if a pathogenic variant is identified to facilitate early detection, surveillance, and management of at-risk relatives.[56]

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