What is the appropriate diagnostic workup to determine the etiology of myocarditis?

Diagnostic Workup for Myocarditis Etiology

The diagnostic workup for myocarditis should begin with cardiac magnetic resonance imaging (CMR) as the primary noninvasive tool, combined with troponin measurement and ECG, reserving endomyocardial biopsy for cases requiring histologic confirmation of specific etiologies or when patients fail to respond to initial management. 1, 2

Initial Clinical Assessment

Key Clinical Features to Identify

• Chest pain characteristics: Diffuse, pressure-like chest pain mimicking acute coronary syndrome suggests myocarditis, whereas sharp, pleuritic, positional pain points toward pericardial involvement 2
• Heart failure manifestations: Dyspnea, fatigue, reduced exercise tolerance, orthopnea, and peripheral edema indicate myocardial involvement 2
• Arrhythmia symptoms: Palpitations, syncope, or presyncope may indicate myocarditis with arrhythmic complications 3
• Recent viral illness: Preceding respiratory or gastrointestinal symptoms suggest infectious etiology 4
• Medication history: Recent initiation of immune checkpoint inhibitors, chemotherapy agents, or other cardiotoxic drugs 1, 4
• Autoimmune disease history: Presence of systemic lupus erythematosus, sarcoidosis, or other autoimmune conditions 5

Laboratory Evaluation

Essential Biomarkers

• Troponin elevation: Indicates myocardial injury and helps differentiate myocarditis from isolated pericarditis; normal troponin essentially excludes significant myocardial involvement 2
• C-reactive protein (CRP): Elevated in both myocarditis and pericarditis, useful for monitoring treatment response rather than diagnosis 2
• Complete blood count: May reveal eosinophilia (eosinophilic myocarditis) or leukocytosis 5
• Viral serologies and PCR: Blood samples (5-10 mL in EDTA or citrate) should be collected at the time of diagnosis for molecular testing of viral genomes, particularly when endomyocardial biopsy is planned 6

Etiology-Specific Testing

• Thyroid function tests: Hyperthyroidism can cause autoimmune myocarditis 1
• HIV testing: Chronic HIV infection shows high rates of subclinical myocardial inflammation 1
• Chagas serology: In endemic areas or patients with travel history 1
• Autoantibodies: Antimicrosomal and antithyroglobulin antibodies for thyroid-related myocarditis; ANA, anti-dsDNA for lupus 1

Electrocardiographic Findings

• Atypical ECG changes, focal ST-segment alterations, arrhythmias, or atrioventricular block are more frequent in myocarditis and help establish the diagnosis 2
• Diffuse ST-segment elevation may occur but is less specific 3

Cardiovascular Magnetic Resonance Imaging (Primary Diagnostic Tool)

Updated Lake Louise Criteria (2018)

CMR provides strong evidence for myocardial inflammation when demonstrating the combination of myocardial edema with markers of inflammatory myocardial injury. 1

Required Findings for High Specificity

• At least one T2-based criterion (indicating edema):

  • Global or regional increase of myocardial T2 relaxation time, OR
  • Increased signal intensity in T2-weighted CMR images 1

• PLUS at least one T1-based criterion (indicating injury):

  • Increased myocardial T1 mapping
  • Increased extracellular volume (ECV)
  • Late gadolinium enhancement (LGE), typically sub-epicardial or mid-wall pattern, especially in lateral/inferolateral walls 1, 2

CMR Pattern Recognition for Specific Etiologies

• Sarcoidosis: Native T1 mapping is the best discriminator; offers incremental value when LGE and left ventricular systolic function are normal 1
• Chagas disease: LGE present in 69-78% of patients, correlates with clinical severity 1
• HIV-related myocarditis: LGE in 82%, primarily sub-epicardial pattern; elevated native T1, ECV, and T2 ratios 1
• Checkpoint inhibitor myocarditis: CMR should be included in diagnostic workup 1

Important Caveat

Having only one positive marker (T2-based OR T1-based) may still support myocarditis diagnosis in an appropriate clinical scenario, albeit with less specificity 1

Echocardiography

• Initial assessment tool: Evaluate for new focal or diffuse wall-motion abnormalities and reduced ejection fraction 2
• Pericardial effusion assessment: Presence suggests myopericarditis overlap 2
• Exclude alternate diagnoses: Rule out valvular disease, regional wall motion abnormalities suggesting coronary disease 3

Endomyocardial Biopsy (Selective Use)

Indications for Biopsy

• Fulminant myocarditis with hemodynamic compromise requiring mechanical circulatory support 3, 4
• Suspected giant cell myocarditis or eosinophilic myocarditis where immunosuppression may be beneficial 5, 6
• Suspected cardiac sarcoidosis requiring confirmation for immunosuppressive therapy 1
• Non-responders to initial management even at later stages 3
• When specific histologic diagnosis will change management 7, 3

Optimal Biopsy Technique

• At least 3-4 fragments, each 1-2 mm in size 6
• One specimen: Fixed in 10% buffered formalin for light microscopy and histological examination 6
• One specimen: Snap-frozen in liquid nitrogen and stored at -80°C for molecular testing (PCR for viral genomes) 6
• Additional sampling recommended in suspected focal myocardial lesions 6

Histological Criteria

• >14 leukocytes/mm² with >7 T lymphocytes/mm² establishes diagnosis of myocarditis 6
• Immunohistochemistry combined with histology increases sensitivity compared to Dallas criteria alone 6
• Molecular testing: PCR or nested-PCR for viral genome detection; must be accompanied by parallel blood sample investigation 6

Diagnostic Algorithm

1. Measure troponin and perform ECG: Elevated troponin with atypical ECG changes suggests myocarditis 2, 3

2. Perform transthoracic echocardiography: Assess for new LV dysfunction and exclude alternate diagnoses 2, 3

3. Obtain CMR with updated Lake Louise Criteria:

   • Myocardial LGE (sub-epicardial or mid-wall) with elevated T2 mapping confirms myocarditis 1, 2
   • Pericardial enhancement without myocardial LGE indicates isolated pericarditis 2

4. Collect blood samples for viral PCR and etiology-specific testing at time of diagnosis 6

5. Consider endomyocardial biopsy when:

   • Fulminant presentation with hemodynamic instability 3, 4
   • Suspected giant cell or eosinophilic myocarditis 5, 6
   • No response to initial management 3
   • Specific histologic diagnosis will alter therapy 7, 3

Genetic Testing Considerations

• Consider genetic testing in cases with:
  • Recurrent myocarditis 8
  • Family history of cardiomyopathy 5
  • Persistent LV dysfunction despite resolution of inflammation 3
  • Atypical presentation or disease course 5

Common Pitfalls to Avoid

• Do not rely on troponin alone: Normal troponin excludes significant myocardial involvement, but elevated troponin requires imaging to confirm myocarditis versus other causes 2
• Do not perform routine endomyocardial biopsy: CMR now enables definitive noninvasive diagnosis in most cases; biopsy is reserved for specific indications 1, 8, 7
• Do not skip blood viral PCR: When endomyocardial biopsy is performed, parallel blood testing is essential to interpret positive myocardial viral PCR results 6
• Do not delay CMR: Optimal sensitivity for detecting myocardial inflammation is limited to a few weeks from presentation 1