What is the recommended evaluation and treatment approach for a patient with suspected myocarditis, considering their demographic and medical history, including any history of viral infections, autoimmune disorders, or exposure to toxins?

Evaluation for Myocarditis

All patients with suspected myocarditis require immediate 12-lead ECG, cardiac troponin measurement, and transthoracic echocardiography, followed by cardiac MRI in hemodynamically stable patients to confirm diagnosis before discharge. 1

Initial Clinical Assessment

Diagnostic Criteria for Clinical Suspicion

Myocarditis should be clinically suspected when ≥1 clinical symptom (chest pain, dyspnea, palpitations, syncope) AND ≥1 diagnostic abnormality from different categories are present after excluding coronary artery disease with ≥50% stenosis. 1 Approximately 82-95% of adult patients present with chest pain, 19-49% with dyspnea, and 5-7% with syncope. 2

Immediate Exclusion of Life-Threatening Alternatives

• Rule out acute coronary syndrome first in patients with cardiovascular risk factors or established coronary artery disease, as troponin elevation is non-specific. 3
• Exclude pulmonary embolism, pneumonitis, or pulmonary edema with chest imaging in patients with dyspnea. 3
• Consider stress-induced (Takotsubo) cardiomyopathy in the differential diagnosis. 3

Mandatory Initial Diagnostic Tests

12-Lead Electrocardiogram

Look for specific patterns that suggest myocarditis: 1

• QRS width >120 ms (suggests extensive myocardial involvement)
• PR-segment depression with diffuse ST-elevation (indicates associated pericarditis)
• Low voltage with thickened LV walls on echo (suggests myocardial edema)
• AV block (first through third degree), bundle branch block, or sinus arrest 3
• New Q waves, T-wave inversion, or intraventricular conduction delays 3

Critical pitfall: ECG may be normal in up to 10% of myocarditis cases, so normal ECG does not exclude the diagnosis. 1

Cardiac Biomarkers

Obtain cardiac troponin I or T immediately as the primary marker of myocardial injury. 3, 1 Biopsy-proven acute and viral myocarditis is associated with significantly elevated high-sensitivity troponin T concentrations. 4 Additional markers include: 3

• Creatine kinase (CK and CK-MB)
• Erythrocyte sedimentation rate (ESR)
• C-reactive protein (CRP)
• NT-proBNP or BNP (for prognostic stratification)

Important caveat: Troponin can be normal in subacute or chronic presentations, so normal troponin does not definitively rule out myocarditis. 1 However, myocarditis can be effectively ruled out only if ALL of the following are absent: no cardiac symptoms, normal troponin, normal ECG, and normal echocardiography. 1

Transthoracic Echocardiography

Perform immediately to assess: 1

• Regional or global wall motion abnormalities
• Left or right ventricular systolic/diastolic dysfunction
• Increased wall thickness (suggests myocardial edema)
• Pericardial effusion
• Intracavitary thrombi

Echocardiography helps exclude alternative diagnoses such as valvular disease, congenital heart disease, or other cardiomyopathies. 3 However, echocardiography has lower sensitivity than cardiac MRI and cannot detect subepicardial or mid-myocardial patterns typical of myocarditis. 5

Advanced Diagnostic Imaging: Cardiac MRI

Indications and Timing

Cardiac MRI should be performed in all hemodynamically stable patients with suspected myocarditis, ideally >10 days from symptom onset and before hospital discharge. 1, 5 The European Society of Cardiology gives cardiac MRI a Class I indication for myocarditis assessment. 1, 5

Updated Lake Louise Criteria (2018)

Diagnosis requires BOTH ≥1 T2-based criterion (myocardial edema) AND ≥1 T1-based criterion (myocardial injury/fibrosis) for high-specificity diagnosis. 1, 5 This combination increases specificity for acute myocardial inflammation. 1

Prognostic Value of Cardiac MRI

The presence and extent of late gadolinium enhancement (LGE) is the strongest independent predictor of sudden cardiac death, cardiac mortality, and all-cause mortality in myocarditis patients. 5 Specific patterns include:

• Epicardial or mid-wall delayed gadolinium enhancement (characteristic of myocarditis, distinguishes from ischemic disease which shows endocardial pattern) 3, 5
• Extensive LGE involving multiple segments (identifies patients at significantly elevated risk for ventricular arrhythmias and sudden cardiac death) 5
• Myocardial edema without fibrosis (indicates good recovery potential) 5

Critical Risks of Omitting Pre-Discharge Cardiac MRI

• Patients may be lost to follow-up before obtaining this critical test, leaving them at unquantified risk for sudden death. 5
• Early arrhythmic events may occur in the interval between discharge and delayed outpatient CMR in patients with extensive but undetected LGE. 5
• Guideline-directed medical therapy cannot be optimally titrated without knowing the extent of ventricular dysfunction and inflammation. 5

Endomyocardial Biopsy Indications

Class I Indications (Must Perform)

Endomyocardial biopsy is mandatory in the following scenarios: 3, 1

• Acute fulminant myocarditis with hemodynamic compromise requiring inotropic support or mechanical circulatory support
• New-onset heart failure with dilated ventricle AND new ventricular arrhythmias or heart block
• Refractory sustained ventricular tachyarrhythmias despite optimal medical management
• Hemodynamically compromising sustained ventricular arrhythmias or aborted cardiac arrest
• Suspected giant cell myocarditis or cardiac sarcoidosis (requires histologic confirmation for immunosuppression decisions)

Diagnostic Yield Optimization

Pre-procedural cardiac MRI localization of inflammatory changes reduces sampling errors and improves diagnostic yield. 1 Endomyocardial biopsy provides definitive histopathologic confirmation through direct tissue analysis, immunohistochemical evaluation, and viral genome detection. 1

When Biopsy Can Be Deferred

If cardiac MRI is diagnostic (meets Lake Louise Criteria) and the patient is hemodynamically stable without life-threatening arrhythmias, endomyocardial biopsy may not be required for clinical management. 1 However, if diagnosis remains uncertain after cardiac MRI or if CMR is contraindicated/non-diagnostic, endomyocardial biopsy should be performed. 3

Alternative Advanced Imaging When Cardiac MRI Unavailable

If cardiac MRI is not available, contraindicated, or non-diagnostic, cardiac PET-CT is recommended to evaluate for myocardial inflammation using: 3

• [18F]2-fluoro-2-deoxy-D-glucose (18F-FDG)-PET-CT, or preferentially
• Gallium-68-DOTATOC-PET-CT

Cardiac PET has shown good agreement with cardiac MRI criteria of inflammation. 3

Immediate Management During Diagnostic Workup

Hospital Admission Criteria

All suspected cases of myocarditis should be admitted to level 2 or 3 care with continuous ECG monitoring and resuscitation facilities. 3 Specific high-risk features requiring mandatory admission include: 1

• Ventricular arrhythmias or heart block (high risk of sudden cardiac death)
• Progressive wall motion abnormalities with deteriorating LV function
• Persistent or fluctuating troponin concentrations
• Widening QRS complex
• Frequent non-sustained ventricular arrhythmias

Interrupt Causative Agents

• Permanently discontinue immune checkpoint inhibitors if immune-related myocarditis is confirmed. 3
• Avoid NSAIDs absolutely due to increased inflammation and mortality risk. 3, 6

Clinical Phenotyping for Risk Stratification

Acute Fulminant Myocarditis

Characterized by refractory malignant ventricular tachyarrhythmias with severe acute heart failure, with adverse short-term prognosis and early death from multisystem failure. 1 These patients have approximately 28% rate of mortality or heart transplant at 60 days and require inotropic agents or mechanical circulatory support. 2

Uncomplicated Myocarditis

Approximately 75% of patients admitted with myocarditis have an uncomplicated course with mortality rate of approximately 0%. 2 However, these patients still require 3-6 months of complete exercise abstinence. 3, 6

Complicated Myocarditis

Acute myocarditis complicated by acute heart failure or ventricular arrhythmias is associated with 12% rate of either in-hospital mortality or need for heart transplant. 2

Special Considerations

Immune Checkpoint Inhibitor-Related Myocarditis

Normal cardiac enzymes cannot always rule out myocarditis in patients on immune checkpoint inhibitor therapy, as these patients can have life-threatening myocarditis with associated myasthenia gravis or myositis. 1 Baseline evaluation before initiating ICI therapy should include troponin, BNP/NT-proBNP, total CK, fasting lipid profile, and ECG. 3

Viral Serology and Laboratory Tests

Routine viral serology testing is not very specific and serum markers of inflammation are not very sensitive. 3 However, detection of myocardial viral genome on endomyocardial biopsy is associated with significantly higher troponin concentrations. 4

Follow-Up Surveillance

NT-proBNP in the highest quartile (>4,225 ng/ml) is predictive for cardiac death or heart transplantation during follow-up. 4 Repeat cardiac MRI at 3-6 months is recommended to assess recovery and confirm resolution of inflammation. 5