Laboratory Studies
Laboratory studies in the workup of myocarditis may include the following:
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Basic metabolic panel
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Complete blood cell (CBC) count with differential: Leukocytosis (may demonstrate eosinophilia)
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Elevated erythrocyte sedimentation rate (and other acute phase reactants, such as C-reactive protein)
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Rheumatologic screening: To rule out systemic inflammatory diseases
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Cardiac enzymes and natriuretic peptide: Elevated creatine kinase or cardiac troponins (In fulminant myocarditis, an elevated serum cardiac troponin [cTn] is almost always present, but the absence of its elevation does not rule out myocarditis. [20] )
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Serum viral antibody titers: For viral myocarditis
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Liver function tests (LFTs)
The hallmark of coronavirus disease 2019 (COVID-19)-related myocarditis is elevated troponin levels (36% of patients). [12]
Cardiac enzymes
Elevated cardiac enzymes are an indicator for cardiac myonecrosis. Cardiac troponin (troponin I or T), in particular, is elevated in at least 50% of patients with biopsy-proven myocarditis. Cardiac enzymes may also help to identify patients with resolution of viral myocarditis.
The test has 89% specificity and 34% sensitivity and increases more frequently than creatine kinase MB subunits (elevated in only 5.7% of patients with biopsy-proven myocarditis). However, these studies have been performed using standard clinical assays, and the sensitivity of newer-generation high-sensitivity cardiac troponin assays in diagnosing myocarditis may differ.
Viral antibody titers
Common viral antibody titers available for clinical evaluation include coxsackievirus group B, human immunodeficiency virus (HIV), cytomegalovirus, Ebstein-Barr virus, hepatitis virus family, and influenza viruses. Titers increase 4-fold or more, with a gradual fall during convalescence (nonspecific); hence, serial testing is required.
Antibody titer testing is rarely indicated in the diagnosis of viral myocarditis or any dilated cardiomyopathies, owing to its low specificity and the delayed rising of viral titers, which would have no impact on therapeutic decisions.
Viral genome
The presence of viral genome in endomyocardial biopsy samples is considered the criterion standard for viral persistence. However, the test lacks specificity, because the presence of viral genome can also be present in healthy controls. The most common viral genomes found include those of parvovirus and herpes simplex.
Histologic findings
Biopsy specimens from endomyocardial biopsy (EMB) should reveal the simultaneous findings of lymphocyte infiltration and myocyte necrosis.
Echocardiography
Echocardiography is performed to exclude other causes of heart failure (eg, amyloidosis or valvular or congenital causes) and to evaluate the degree of cardiac dysfunction (usually diffuse hypokinesis and diastolic dysfunction). It also may allow gross localization of the extent of inflammation (ie, wall motion abnormalities, wall thickening, pericardial effusion). In addition, echocardiography may distinguish between fulminant and acute myocarditis by identifying near-normal left ventricular diastolic dimensions and increased septal thickness in fulminant myocarditis (versus increased left ventricular diastolic dimensions and normal septal thickness in acute myocarditis), with marked improvement in systolic function in time.
Scintigraphy
Antimyosin scintigraphy (using antimyosin antibody injections) can identify myocardial inflammation with high sensitivity (91-100%) and negative predictive power (93-100%) but has low specificity (31-44%) and low positive predictive power (28-33%). In contrast, gallium scanning is used to reflect severe myocardial cellular infiltration and has a good negative predictive value, although specificity is low. Positron emission tomography (PET) scanning has been used in selected cases (eg, sarcoidosis) to assess the degree and location of inflammation.
In cases of suspected fulminant myocarditis, there should be a low threshold for coronary angiographic assessment. [20]
Additional Imaging Techniques
Cardiac angiography is often indicated to rule out coronary ischemia as a cause of new-onset heart failure, especially when clinical presentation mimics acute myocardial infarction. It usually shows high filling pressures and reduced cardiac outputs.
Gadolinium-enhanced magnetic resonance imaging (MRI) is used for assessment of the extent of inflammation and cellular edema, although it is still nonspecific. Delayed-enhanced MRI has also been used to quantify the amount of scarring that occurred following acute myocarditis. [35]
Monney et al suggested that cardiac magnetic resonance (CMR) scanning may be useful in patients with suspected acute coronary syndrome who are found not to have coronary artery disease. Despite preserved systolic function, a significant proportion of these patients were subsequently diagnosed with acute myocarditis on the basis of the CMR scan findings. [36]
Radunski et al evaluated the accuracy of T2, T1, and extracellular volume (ECV) quantification as novel quantitative tissue markers in comparison with standard "Lake-Louise" cardiac magnetic resonance (CMR) criteria to diagnose myocarditis. At 1.5-T, CMR was performed in 104 patients with myocarditis and 21 control subjects. Patients with myocarditis underwent CMR 2 weeks (interquartile range: 1 to 7 weeks) after presentation with new-onset heart failure or acute chest pain. The diagnostic accuracies of conventional CMR were 70% for T2w CMR, 59% for EGE, and 67% for LGE. The diagnostic accuracies of mapping techniques were 63% for myocardial T2, 69% for native myocardial T1, and 76% for global myocardial ECV. The diagnostic accuracy of CMR was significantly increased to 90% by a stepwise approach, using the presence of LGE and myocardial ECV ≥27% as diagnostic criteria, compared with 79% for the Lake-Louise criteria. ECV quantification with LGE imaging significantly improved the diagnostic accuracy of CMR, compared to standard Lake-Louise criteria. [37]
Bohnen et al tested the performance of novel quantitative T1 and T2 mapping cardiovascular magnetic resonance (CMR) techniques to identify active myocarditis in patients with recent-onset heart failure. The study population consisted of 31 consecutive patients with recent-onset heart failure, reduced left ventricular function, and clinically suspected myocarditis who underwent endomyocardial biopsy and CMR at 1.5 Tesla. Endomyocardial biopsy revealed active myocarditis in 16 of 31 patients. Patients with active myocarditis showed no significant differences from patients without active myocarditis in clinical characteristics, standard Lake-Louise CMR parameters, global myocardial T1, or extracellular volume fraction. However, median global myocardial T2 was significantly higher in patients with active myocarditis compared to patients without active myocarditis. A cutoff value for global myocardial T2 of ≥60 ms yielded a sensitivity, specificity, accuracy, negative and positive predictive value of 94% (70%-100%), 60% (32%-84%), 77% (60%-89%), 90% (56%-100%), and 71% (48%-89%) for active myocarditis, respectively. For assessing the activity of myocarditis in patients with recent-onset heart failure and reduced left ventricular function, T2 mapping seems to be superior to standard CMR parameters, global myocardial T1, and extracellular volume fraction values. [38]
Endomyocardial Biopsy
Endomyocardial biopsy (EMB) is the criterion standard for the diagnosis of myocarditis, including the following conditions [9] :
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Adenoviral or enteroviral myocarditis
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Human herpesvirus 6 myocarditis
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Hypersensitivity myocarditis
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Eosinophilic cell myocarditis
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Checkpoint inhibitor-related myocarditis
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Giant cell myocarditis
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Idiopathic granulomatous myocarditis (cardiac sarcoidosis)
However, endomyocardial biopsy has limited sensitivity and specificity, as inflammation can be diffuse or focal. However, the use of routine EMB in establishing the diagnosis of myocarditis rarely is helpful clinically, because histologic diagnosis seldom has an impact on therapeutic strategies, unless giant cell myocarditis is suspected. [2, 3]
Nonetheless, the Heart Failure Society of America 2010 comprehensive heart failure practice guideline recommends considering endomyocardial biopsy for patients with acute deterioration of heart function of unknown origin that is not responding to medical treatment. [4]
The risk of adverse events in endomyocardial biopsy approaches 6%, including complications in 2.7% of patients on sheath insertion and 3.3% on the biopsy procedure; there is also a 0.5% probability of perforation. [3]
Because of sampling technique, sensitivity may increase with multiple biopsies (50% for 1 biopsy, 90% for 7 biopsies). The standard is to obtain at least 4 or 5 biopsies, although false-negative rates still may be as high as 55%.
False-positive rates are also high, owing to small numbers of normally occurring lymphocytes in the myocardium and the difficulty in distinguishing between lymphocytes and other cells (such as eosinophils in hypersensitive/eosinophilic myocarditis). Moreover, wide interobserver variability in histologic interpretations is also a factor.
Noncaseating granulomas for sarcoid myocarditis are found in only 5% of cases by biopsies and in as many as 27% in autopsy series.
Persistent viral messenger ribonucleic acid (mRNA), which can be found in only 25-50% of patients with biopsy-proven acute myocarditis, often confers a poor prognosis. Epidemiologic results from the European Study on the Epidemiology and Treatment of Cardiac Inflammatory Disease (ESETCID) database found that only 11.8% of patients with suspected acute or chronic myocarditis and reduced ejection fractions had detectable viral genomes in biopsy samples. [39]
Electrocardiogram
Electrocardiograms are often nonspecific (eg, sinus tachycardia, nonspecific ST- or T-wave changes). Occasionally, heart block (atrioventricular block or intraventricular conduction delay), ventricular arrhythmia, or injury patterns, with ST- or T-wave changes mimicking myocardial ischemia or pericarditis (pseudoinfarction pattern), may indicate poorer prognosis.
In fulminant myocarditis, low QRS voltage may be present owing to myocardial edema, and it is common to see a nonvascular distribution of ST segment elevations (however, do not delay angiographic evaluation of the coronary anatomy). [20] There may also be concomitant evidence of pericarditis with PR segment depression. It is unusual for evidence of left ventricular hypertrophy to be present. [20]
Arrhythmia is common in Chagas heart disease. The following may be seen: right bundle-branch block with or without bifascicular block (50%), complete heart block (7-8%), atrial fibrillation (7-10%), and ventricular arrhythmia (39%).
Staging
The Dallas classification (1987) and the World Health Organization (WHO) Marburg classification (1996) are commonly used based on the patterns in the following histologic characteristics [6] :
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Cell types: Lymphocytic, eosinophilic, neutrophilic, giant cell, granulomatous, or mixed
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Amount: None (grade 0), mild (grade 1), moderate (grade 2), or severe (grade 3)
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Distribution: Focal (outside vessel lumen), confluent, diffuse, or reparative (in fibrotic areas)
The Dallas classification on initial biopsy is as follows:
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Myocarditis: Myocardial necrosis, degeneration, or both, in the absence of significant coronary artery disease with adjacent inflammatory infiltrate with or without fibrosis
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Borderline myocarditis: Inflammatory infiltrate too sparse or myocyte damage not apparent
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No myocarditis
The Dallas classification on subsequent biopsy is as follows:
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Ongoing (persistent) myocarditis with or without fibrosis
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Resolving (healing) myocarditis with or without fibrosis
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Resolved (healed) myocarditis with or without fibrosis
WHO Marburg criteria (1996) defines myocarditis as a minimum of 14 infiltrating leukocytes/mm2, preferably T cells (CD45RO), with as many as 4 macrophages possibly included. [39]
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Myocarditis. Hematoxylin and eosin staining. Low power. This image shows numerous lymphocytes with associated myocyte damage. Photo courtesy of Dr Donald Weilbaecher.
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Myocarditis. Hematoxylin and eosin staining. High power. Toxoplasmosis (numerous purple granular-like structures within a myocyte) is demonstrated.
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Myocarditis. Hematoxylin and eosin staining. High power. Lymphocytes, histiocytes, and a multinucleated giant cell representing sarcoidosis (a diagnosis of exclusion) is shown.
