What is the pathophysiology of myocarditis and how should it be managed?

Myocarditis: Pathophysiology and Management

Pathophysiology

Myocarditis results from myocardial infection and/or autoimmunity causing active inflammatory destruction of myocytes, with a wide spectrum of infectious agents and toxic/hypersensitivity reactions as potential triggers. 1

Etiologic Agents and Mechanisms

• Viral pathogens are the most common infectious causes, including enteroviruses (Coxsackie B), adenoviruses, parvovirus B19, and human herpes virus type 6 1
• Non-viral infectious agents include bacteria, chlamydia, rickettsia, fungi, and protozoans 1
• HIV-related myocarditis occurs through multiple mechanisms: viral glycoprotein 120-induced cardiotoxicity with cellular apoptosis, opportunistic infections, autoimmune responses, drug-related cardiac toxicity, and nutritional deficiencies 1
• Autoimmune mechanisms involve exposure of cryptic antigens, molecular mimicry, deficient thymic training/Treg induction, and HLA/gender predisposition 2

Immunopathogenic Process

• Innate immune response involves monocytes/macrophages, neutrophils, and eosinophils playing both priming and final effector roles 2
• Adaptive T cell responses show anti-paradigmatic features: Th17 response is dispensable for acute myocarditis but drives progression to dilated cardiomyopathy 2
• Humoral response, previously considered a bystander, is important in late-stage hemodynamic complications 2
• Stromal cells like fibroblasts participate through specific cytokine production 2
• Chronic progression involves viral persistence merging with autoimmune processes leading to chronic inflammation, tissue remodeling, and ultimately dilated cardiomyopathy 3

Histopathologic Definition

• Microscopic diagnosis requires inflammatory cells together with necrotic myocytes 1
• WHO definition specifies inflammatory disease of the myocardium diagnosed by established histological, immunological, and immunohistochemical criteria 1
• Inflammatory cardiomyopathy refers to myocarditis associated with cardiac dysfunction 1

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Clinical Presentation and Risk Stratification

Two Distinct Clinical Settings

Acute myocarditis presents in two critical patterns that determine management approach and prognosis: 1

1. Acute fulminant myocarditis with refractory malignant ventricular tachyarrhythmias in severe acute heart failure, with adverse short-term prognosis and early death from multisystem failure 1
2. Long-term evolution to inflammatory cardiomyopathy with LV dysfunction and high risk of sudden cardiac death similar to dilated cardiomyopathy 1

Warning Signs of Deterioration

• Progressive wall motion abnormalities with deteriorating LV function on echocardiography 1
• Persistent or fluctuating cardiac troponin concentrations 1
• Widening of the QRS complex and frequent non-sustained ventricular arrhythmias may precede sustained life-threatening arrhythmia 1

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Diagnostic Approach

Initial Essential Testing

When myocarditis is suspected, initial testing must include 12-lead ECG, transthoracic echocardiogram, and assessment of biomarkers (troponins), erythrocyte sedimentation rate, and C-reactive protein. 1

• Cardiology consultation is recommended for rising troponin and/or ECG or echocardiographic abnormalities concerning for myocarditis 1
• ECG findings may show QRS >120 ms, PR segment depression, or diffuse ST elevation 4, 5

Advanced Diagnostic Modalities

• Cardiac MRI is a sensitive, non-invasive test for confirmation of acute myocarditis and should be performed in hemodynamically stable patients with suspected myocarditis 1
• Endomyocardial biopsy remains the gold standard for definite diagnosis and should be performed especially in patients with life-threatening disease course 1, 6
• CMR for risk stratification: Persistent myocardial inflammatory infiltrates by immunohistological evidence and/or abnormal localized fibrosis may be considered as an additional indicator of increased risk of sudden cardiac death 1

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Management Strategy

Acute Phase Management

Hospitalization is recommended for patients with definite myocarditis, ideally at an advanced heart failure center; fulminant myocarditis requires centers with expertise in advanced heart failure, mechanical circulatory support, and advanced therapies. 1

Supportive Medical Therapy

• Guideline-directed medical therapy with neurohormonal blockade using ACE inhibitors and beta-blockers is recommended 1, 6
• Heart failure management with diuretics as clinically indicated in patients with reduced ejection fraction 6, 5
• Exercise restriction during the acute phase to reduce myocardial oxygen demand and prevent worsening inflammation 6, 5

Arrhythmia Management

• Prolonged ECG monitoring and hospital admission are mandatory for patients with ventricular arrhythmias or heart block 1, 4
• Temporary pacemaker insertion is recommended for symptomatic heart block or symptomatic sinus node dysfunction 1, 6, 5
• Antiarrhythmic therapy (amiodarone) for symptomatic non-sustained or sustained ventricular tachycardia during acute myocarditis 6, 5
• Avoid ICD implantation during the acute phase, as many arrhythmias resolve with recovery 6, 5
• Delayed ICD implantation may be considered in patients who survive the acute phase but have persistent life-threatening ventricular arrhythmias, provided survival >1 year with good functional status is expected 6
• Earlier ICD consideration for giant cell myocarditis or sarcoidosis with hemodynamically compromising sustained ventricular arrhythmias or aborted cardiac arrest, due to adverse prognosis 1

Immunosuppressive Therapy: Critical Decision Points

When Immunosuppression IS Indicated

• Giant cell myocarditis requires aggressive multidrug immunosuppression, as this rapidly fatal condition shows improved survival with immunotherapy 6
• Cardiac sarcoidosis should receive corticosteroids as first-line therapy, with alternative immunosuppressive agents for steroid-intolerant patients or those who worsen despite corticosteroids 6
• COVID-19 myocarditis with pneumonia (ongoing need for supplemental oxygen) should be treated with corticosteroids 1
• Hemodynamic compromise or MIS-A: Intravenous corticosteroids may be considered in suspected or confirmed COVID-19 myocarditis 1
• Fulminant myocarditis: Empiric corticosteroids may be considered with biopsy evidence of severe myocardial infiltrates, balanced against infection risk 1

When Immunosuppression IS NOT Indicated

The Myocarditis Treatment Trial definitively showed no beneficial effect of prednisone with either azathioprine or cyclosporine in patients with biopsy-proven lymphocytic myocarditis, representing the typical viral myocarditis pattern. 6

Pericardial Involvement

• NSAIDs, colchicine, and/or prednisone are reasonable for suspected pericardial involvement 1

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Special Considerations

Lyme Disease and Diphtheria

• Heart block is frequently associated with Lyme's disease and diphtheria myocarditis, which can trigger ventricular tachyarrhythmias 1

Post-Myocarditis Dysautonomia

• Viral infections causing myocarditis can trigger acute or chronic dysautonomia due to autonomic nervous system dysfunction 4, 5
• POTS diagnosis: Heart rate increase >30 beats/minute over supine baseline after 5-10 minutes of standing, with symptoms including palpitations, dizziness, weakness, and blurred vision 4, 5
• Beta-blockers may be useful for controlling tachycardia but should be used with caution in patients with orthostatic hypotension 4
• Gradual exercise therapy is crucial for recovery, but standard vertical activity may worsen symptoms 4

Return to Athletic Activity

Athletes with acute myocarditis should undergo resting echocardiogram, 24-hour Holter monitoring, and exercise ECG at least 3-6 months after initial illness before returning to competitive sports. 4

• Criteria for return to play: Normal left ventricular systolic function, normalized serum markers of myocardial injury and inflammation, and absence of clinically relevant arrhythmias on Holter monitoring and exercise ECG 4
• Minimum 3-month exercise abstinence in the absence of spontaneous/inducible cardiac arrhythmias on ECG monitoring and exercise stress testing 1

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Prognosis and Long-Term Follow-Up

• Most cases of myocarditis are self-limited with complete recovery, as cardiac dysfunction is usually completely reversible 6
• Fulminant myocarditis with progressive heart failure is relatively rare but carries high acute mortality 6
• Risk of dilated cardiomyopathy: 21% of patients develop this condition in long-term follow-up studies 4
• Guideline-directed medical therapy for heart failure should be continued after discharge as appropriate 1

Common Pitfalls to Avoid

• Do not implant ICD during acute phase when arrhythmias may be transient and reversible 6, 5
• Do not use immunosuppression for typical lymphocytic (viral) myocarditis based on the negative Myocarditis Treatment Trial 6
• Do not allow premature return to exercise before complete resolution of inflammation and normalization of cardiac function 1, 4
• Do not miss specific etiologies (giant cell, sarcoidosis, Lyme, diphtheria) that require targeted therapy 1, 6