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Myocarditis - Basic to Advanced Clinical Overview

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1. Definition

• Goldman-Cecil Medicine, p. 511
• Robbins & Kumar Basic Pathology, p. 375

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2. Epidemiology

• Incidence and prevalence are hard to estimate due to variable presentation (often subclinical)
• Population estimates: 1 in 100,000 to 1 in 10,000
• Postmortem studies: myocarditis found in up to 12% of young victims of sudden cardiac death
• More common in young adults and males
• May also be the inflammatory phase of arrhythmogenic cardiomyopathy

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3. Etiology - Causes (Complete Classification)

A. Infectious Causes

B. Immune-Mediated Causes

• Autoantigens: SLE, polymyositis/dermatomyositis, systemic sclerosis, EGPA
• Alloantigens: Heart transplant rejection
• Allergen (drug hypersensitivity): Penicillin, sulfonamides, methyldopa, tetracycline, thiazides, tricyclic antidepressants

C. Toxic Causes

• Drugs: Anthracyclines, cocaine, amphetamines, cyclophosphamide, 5-FU, trastuzumab, checkpoint inhibitors (increasingly recognized), clozapine
• Physical agents: Electric shock, radiation, hyperpyrexia
• Heavy metals: Copper, iron, lead
• Others: Arsenic, snake bite, scorpion venom, carbon monoxide

D. Special Cases

• mRNA COVID-19 vaccine myocarditis: Rare, especially in male adolescents/young adults after the 2nd dose, usually within 1 week - most recover uneventfully
• Giant cell myocarditis (GCM): Rare, fulminant, aggressive - requires early immunosuppression
• Eosinophilic myocarditis: Drug hypersensitivity or hypereosinophilic syndrome
• Goldman-Cecil Medicine, Table 47-3, p. 510-511
• Robbins & Kumar Basic Pathology, p. 375

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4. Pathogenesis

Phase 1 - Direct Viral Invasion (Days 1-4)

Phase 2 - Innate Immune Activation (Days 4-14)

Phase 3 - Adaptive Immune Response / Autoimmunity (Weeks onwards)

• Activation of CD4+ T lymphocytes promotes clonal expansion of B lymphocytes
• Circulating anti-heart antibodies are produced (against myosin heavy chain, adenine nucleotide translocator, beta-1 adrenoceptors, contractile and mitochondrial proteins)
• Molecular mimicry: Viral antigens cross-react with myocardial proteins
• This autoimmune response leads to long-term ventricular remodeling and extracellular matrix changes

Why Some Progress to Dilated Cardiomyopathy (DCM)?

1. Immunopathogenic hypothesis - Abnormal immune response "smolders" into subacute/chronic phase
2. Viral persistence - Virus persists in myocardium and drives ongoing inflammation
3. Combined mechanisms - Both viral persistence + autoimmunity + possible genetic susceptibility

• Goldman-Cecil Medicine, p. 511
• Fuster & Hurst's The Heart 15e, p. (ch. 55)

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5. Histopathology (Morphology)

Dallas Criteria (1986) - Still Referenced

Microscopic Appearance (Viral)

• Myocardium: edema, interstitial inflammatory infiltrates, myocyte injury
• Diffuse lymphocytic infiltrate is most common
• In acute phase: heart appears normal or dilated, may be flabby and mottled with pale/hemorrhagic areas
• Mural thrombi may be present

Giant Cell Myocarditis (Special)

• Multinucleated giant cells + eosinophils + lymphocytes
• Indicates aggressive disease with poor prognosis

Eosinophilic (Hypersensitivity) Myocarditis

• Eosinophil-rich infiltrate
• Often drug-related; typically mild but rarely causes CHF or sudden death
• Robbins & Kumar Basic Pathology, p. 375
• Goldman-Cecil Medicine, p. 511

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6. Clinical Presentations

A. Asymptomatic / Subclinical

• Most common form
• Manifests only as transient ECG abnormalities (nonspecific ST-T changes)
• Discovered incidentally

B. Myopericarditis (Chest Pain Syndrome)

• Prodrome: Fever, myalgia, coryza, gastroenteritis (viral illness 1-2 weeks prior)
• Chest pain - sharp, pleuritic, mimics ACS (but coronaries are normal!)
• Mildly elevated troponin
• Usually good prognosis if LV function preserved
• ~15% may develop recurrent myopericarditis

C. New-Onset Heart Failure / Dilated Cardiomyopathy

• Exertional dyspnea, fatigue, orthopnea, PND
• Signs of LV failure
• Most common presentation requiring hospitalization

D. Acute/Fulminant Myocarditis

• Cardiogenic shock with acute cardiovascular collapse
• Rapid hemodynamic compromise
• May require mechanical circulatory support
• Paradoxically, can have better long-term prognosis than subacute forms if patient survives the acute phase

E. Arrhythmia Presentation

• Palpitations, syncope, sudden cardiac death (sometimes the first presentation)
• PVCs, NSVT, accelerated idioventricular rhythm, polymorphic VT
• In lymphocytic myocarditis: PVCs often originate from inferior LV (RBBB + superior axis morphology)
• AV block (especially in Lyme disease - self-limited, may need temporary pacing)
• Ventricular arrhythmias persist even after apparent healing due to residual scar (late gadolinium enhancement substrate)

F. Autoimmune Rheumatic Disease Associated

• SLE: Most common symptom = exertional dyspnea; ECG shows sinus tachycardia, ST-T changes; troponin I may rise markedly
• Polymyositis/Dermatomyositis, SSc, EGPA: Also recognized associations
• May be initial feature of underlying rheumatic disease
• Goldman-Cecil Medicine, p. 512
• Grainger & Allison Diagnostic Radiology, p. 330-331
• Braunwald's Heart Disease, ch. 55

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7. Diagnosis

Step 1: History & Physical

• Recent viral illness + new cardiac symptoms = high suspicion
• Physical exam: tachycardia, S3 gallop, signs of heart failure, friction rub (if pericarditis)

Step 2: Laboratory Tests

Step 3: ECG

• Most common: sinus tachycardia
• Nonspecific ST-T wave changes
• Pathologic Q waves
• Low QRS voltages
• AV block (Lyme)
• SVT / VT / PVCs

Step 4: Echocardiography

• Impaired LV or RV systolic function (with or without dilation)
• Regional wall motion abnormalities
• LV thrombus
• Diastolic impairment
• Pericardial effusion

Step 5: Cardiac MRI (CMR) - Key Non-Invasive Tool

1. T2-weighted imaging - myocardial edema (T2 signal ratio >2.0)
2. Early gadolinium enhancement (EGE) - hyperemia/capillary leak (global EGE ratio >4.0)
3. Late gadolinium enhancement (LGE) - necrosis/fibrosis

A negative LGE does NOT exclude myocarditis - early enhancement (EGE) should be assessed when macroscopic necrosis is absent.

• Coronary microvascular dysfunction (adenosine stress first-pass perfusion)
• Myocardial fibrosis for arrhythmic risk stratification

Step 6: Endomyocardial Biopsy (EMB) - Gold Standard

• Requiring inotropic support
• Mobitz type 2° or higher heart block
• Sustained or symptomatic VT
• Failure to respond to guideline-directed medical therapy (GDMT) within 1-2 weeks
• Features suggesting systemic disease (amyloidosis, sarcoidosis, hemochromatosis)

• Conventional H&E + Dallas criteria
• Immunohistochemistry - subtypes of infiltrating lymphocytes, abnormal cellular adhesion molecule expression
• PCR/RT-PCR on extracted RNA/DNA - for viral genome detection
• Immunofluorescence - immune complex deposition (in SLE)
• Goldman-Cecil Medicine, p. 512
• Grainger & Allison Diagnostic Radiology, p. 331
• Braunwald's Heart Disease, Figure 55.7

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8. Special Subtypes

Giant Cell Myocarditis (GCM)

• Rare, idiopathic, often associated with autoimmune diseases and thymoma
• Fulminant course - high mortality without treatment
• Histology: multinucleated giant cells, diffuse inflammation with eosinophils
• Requires combined immunosuppression (cyclosporine + steroids ± azathioprine)
• May need transplantation; disease can recur in transplanted heart

Chagas Disease (Trypanosoma cruzi)

• Most common infective myocarditis worldwide (~6 million infected in Latin America)
• ~300,000 infected in USA (immigration)
• Acute phase: Sometimes causes severe myocarditis, 10% die; often unrecognized
• Chronic phase (10-20 years later): Progressive CHF, RBBB + left anterior hemiblock, PVCs, apical aneurysm, VT, sudden death
• VT mechanism: scar-related reentry from inferolateral LV (RBBB + right axis morphology)

Lyme Myocarditis

• Occurs in ~5% of Lyme disease patients
• Primarily manifests as self-limited conduction system disease (AV block)
• Frequently requires temporary pacemaker

Immune Checkpoint Inhibitor (ICI) Myocarditis

• Increasingly recognized with cancer immunotherapy (PD-1/PD-L1/CTLA-4 inhibitors)
• Fulminant presentation common; high mortality (~40-50%)
• Requires immediate immunosuppression with high-dose corticosteroids + stopping ICI

COVID-19 / Post-mRNA Vaccine Myocarditis

• Vaccine: predominantly males <30 years, after 2nd dose, within 7 days
• Most resolve uneventfully with conservative management
• SARS-CoV-2 infection itself also causes lymphocytic myocarditis

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9. Management

A. General Supportive Care (All Patients)

1. Bed rest - restrict strenuous physical activity for at least 3-6 months (competitive sports contraindicated)
2. Heart failure guideline-directed medical therapy (GDMT):
   • ACE inhibitor / ARB - for LV dysfunction
   • Beta-blockers - for HF with reduced EF
   • Diuretics - for volume overload / congestion
   • MRA (spironolactone/eplerenone) - if EF <35%
3. NSAIDs - useful for pericarditic chest pain; colchicine as adjunct
   • Note: NSAIDs may worsen myocarditis in experimental models - use cautiously in pure myocarditis
4. Anticoagulation - if LV thrombus, AF, or severe LV dysfunction (EF <30%)

B. Hemodynamic Support (Fulminant)

• Vasopressors/inotropes - norepinephrine, dobutamine
• Intra-aortic balloon pump (IABP)
• Ventricular assist devices (VADs) - temporary (Impella, TandemHeart, ECMO)
• Permanent VAD as bridge to recovery or transplantation

C. Immunosuppressive Therapy

D. Antiviral Therapy

• No proven benefit currently for viral myocarditis in clinical trials
• Theoretical basis: if viral persistence drives inflammation, antivirals could help
• HIV myocarditis: highly active antiretroviral therapy (HAART)

E. Arrhythmia Management

• PVCs/NSVT: beta-blockers; antiarrhythmic drugs if needed
• AV block: temporary pacing (Lyme resolves spontaneously)
• ICD: Consider for:
  • Sustained VT + depressed LV function
  • LGE on CMR (arrhythmic risk marker)
  • Inducible VT on EP testing
• Catheter ablation for recurrent VT: Challenging due to varied scar locations; recurrence rates >50%

F. Cardiac Transplantation

• Last resort for refractory end-stage heart failure
• Note: GCM can recur in the transplanted heart

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10. Prognosis

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11. Summary Flow - Diagnostic Approach

Young patient + chest pain / HF / arrhythmia / prodromal viral illness
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ECG + Troponin + Echo
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Exclude ACS (coronary angiography if needed - normal coronaries in myocarditis)
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Cardiac MRI (Lake Louise Criteria)
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If hemodynamically unstable / no GDMT response / high-grade AV block / VT
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Endomyocardial Biopsy → Dallas criteria + Immunohistochemistry + PCR
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Subtype-directed treatment

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Sources

• Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine (Braunwald's)
• Goldman-Cecil Medicine International Edition (Goldman-Cecil)
• Robbins & Kumar Basic Pathology 10e (Robbins)
• Grainger & Allison's Diagnostic Radiology
• Fuster & Hurst's The Heart, 15th Edition
• Firestein & Kelley's Textbook of Rheumatology