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Myocarditis

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1. Definition

• Fuster and Hurst's The Heart, 15th ed.
• Goldman-Cecil Medicine, International Edition

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2. Epidemiology

• Fuster and Hurst's The Heart, 15th ed.
• Goldman-Cecil Medicine

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3. Etiology

Infectious

• Enteroviruses: Coxsackievirus A and B (historically dominant)
• Adenovirus, parvovirus B19, human herpesvirus 6 (HHV-6, increasingly detected)
• Epstein-Barr virus, cytomegalovirus (CMV), influenza A/B
• HIV (lymphocytic myocarditis, strong predictor of poor prognosis)
• SARS-CoV-2, hepatitis C, poliovirus, measles, mumps, rubella, rabies, RSV, dengue, yellow fever

• Corynebacterium diphtheriae, Staphylococcus, Streptococcus, Mycoplasma pneumoniae, Neisseria meningitidis/gonorrhoeae, Salmonella, Brucella, Haemophilus influenzae, Mycobacterium, Vibrio cholerae

• Borrelia burgdorferi (Lyme disease), Treponema pallidum, Leptospira

• Trypanosoma cruzi (Chagas disease) - endemic in rural South/Central America; ~6 million infected worldwide, ~300,000 in the US
• Toxoplasma gondii (especially immunocompromised)

• Trichinella spiralis (most common helminthic cause with cardiac involvement)
• Echinococcus granulosus, Taenia solium

• Coxiella burnetii, Rickettsia rickettsii, Rickettsia tsutsugamushi

• Aspergillus, Candida, Cryptococcus, Histoplasma, Coccidioides, Blastomyces, Actinomyces

Immune-Mediated / Autoimmune

Toxic

• Drugs/chemotherapy: anthracyclines, cyclophosphamide, 5-fluorouracil, trastuzumab, interferon, interleukin-2, clozapine
• Immune checkpoint inhibitors: ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab (can cause fulminant myocarditis)
• Recreational drugs: cocaine, amphetamines, heroin, ethanol
• Physical agents: electric shock, radiation, hyperpyrexia
• Heavy metals: copper, iron, lead
• Venoms: snake bite, scorpion, wasp/spider stings
• Others: arsenic, carbon monoxide, phosphorus
• Goldman-Cecil Medicine, Table 47-3
• Fuster and Hurst's The Heart, Table 20-2

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4. Pathogenesis

Phase 1 - Direct Myocardial Injury (Days 0-3)

Phase 2 - Immune-Mediated Injury (Days 4-14)

Phase 3 - Chronic/Dilated Phase (Weeks to Years)

• Ongoing autoimmune injury leads to progressive myocyte loss and replacement fibrosis
• Viral persistence in some patients maintains the inflammatory stimulus
• Results in dilated cardiomyopathy (DCM) with LV dysfunction, arrhythmias, and heart failure
• In Chagas disease, chronic immune-mediated myocarditis (with low parasite burden persisting in tissue) develops 10-20 years after acute infection

Special Mechanisms

• Giant cell myocarditis: T-cell-mediated giant cell formation with extensive myocyte necrosis
• Eosinophilic myocarditis: eosinophil degranulation releases major basic protein and eosinophil cationic protein, directly toxic to myocytes
• Checkpoint inhibitor myocarditis: immune checkpoint blockade results in unregulated T-cell activation against cardiac antigens
• Hypersensitivity myocarditis: Type IV hypersensitivity reaction, often drug-triggered, associated with eosinophilic infiltrate
• Robbins & Kumar Basic Pathology
• Goldman-Cecil Medicine
• Fuster and Hurst's The Heart

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5. Histopathology

Dallas Criteria (1986, still the reference standard)

Note: Dallas criteria have low sensitivity (10-20% diagnostic yield) due to patchy involvement and sampling error. Modern practice supplements with immunohistochemistry and PCR.

Gross Pathology

• Heart may appear normal or dilated
• In advanced/acute stages: myocardium is flabby, mottled with pale and hemorrhagic areas
• Mural thrombi may be present

Microscopic Features by Type

• Edema, interstitial inflammatory infiltrates, myocyte injury
• Diffuse lymphocytic infiltrate (most common pattern)
• Often patchy - may not be sampled on endomyocardial biopsy (EMB)
• Resolves without sequelae or heals by fibrosis

• Interstitial and perivascular infiltrates with lymphocytes, macrophages, and a high proportion of eosinophils

• Multinucleated giant cells + extensive myocyte necrosis
• Mixed infiltrate: T lymphocytes, eosinophils, macrophages
• No granuloma formation (distinguishing from sarcoidosis)
• Fulminant course, poor prognosis

• Non-caseating granulomas with Langhans giant cells
• Involving myocardium, conduction system

• Intracellular T. cruzi amastigotes within myocytes
• Inflammatory infiltrate: lymphocytes, macrophages, eosinophils
• Chronic phase: fibrosis, ventricular aneurysm (especially posterolateral LV)

• Small focal fibrinoid necrosis with lymphocyte/plasma cell infiltration
• Immune complex deposition around myocyte bundles
• Granular immunofluorescent staining with complement deposition
• Robbins & Kumar Basic Pathology, p. 375
• Goldman-Cecil Medicine

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6. Clinical Features

A. Acute Chest Pain Syndrome (most common)

• Mimics acute coronary syndrome (ACS)
• Sharp or pressure-like chest pain, often pleuritic
• Usually preceded by a viral prodrome (1-4 weeks prior): fever, myalgias, upper respiratory illness, gastroenteritis
• Elevated troponin, ECG changes
• Normal coronary arteries on angiography

B. New-Onset Heart Failure

• Exertional dyspnea, fatigue, palpitations
• Signs of LV dysfunction: orthopnea, PND, peripheral edema
• Global or regional wall motion abnormalities on echo

C. Arrhythmic Presentation

• Palpitations, presyncope, syncope, or sudden cardiac death
• Ventricular tachycardia/fibrillation, AV block, multifocal PVCs

Fulminant Myocarditis

• Severe hemodynamic collapse requiring inotropic/mechanical support
• Paradoxically better long-term prognosis if patient survives acute phase
• Early warning signs: sinus tachycardia, narrow pulse pressure, cool/mottled extremities, elevated lactate

Symptoms and Signs Summary

• Fuster and Hurst's The Heart, 15th ed.
• Grainger & Allison's Diagnostic Radiology
• Goldman-Cecil Medicine

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7. Diagnosis

Laboratory Investigations

• Cardiac troponin I/T: elevated (key biomarker; degree of elevation does not predict severity)
• CK-MB: elevated
• BNP/NT-proBNP: elevated if heart failure present
• ESR, CRP: elevated (non-specific inflammation)
• CBC: leukocytosis; eosinophilia in hypersensitivity/eosinophilic myocarditis
• Viral serology: rising antibody titers for specific viruses
• ANA, anti-dsDNA, ENA panel, RF, myositis immunoblot: if autoimmune etiology suspected
• Complement (C3/C4): consumed in SLE
• Blood cultures: if bacterial etiology suspected
• Borrelia serology: if Lyme disease suspected

Electrocardiogram (ECG)

• Non-specific ST-T changes (most common)
• Diffuse ST elevation (if myopericarditis)
• Sinus tachycardia
• New LBBB or RBBB
• PR prolongation, AV block (1st, 2nd, or 3rd degree)
• PVCs, non-sustained or sustained VT
• QTc prolongation

Echocardiography

• Global or regional wall motion abnormalities (may mimic STEMI)
• LV dilation, reduced ejection fraction
• Diastolic dysfunction
• Pericardial effusion (myopericarditis)
• Mural thrombus

Cardiac MRI (CMR) - Key Non-invasive Diagnostic Tool

Key imaging distinction: In myocarditis, LGE is subepicardial (often lateral or inferior wall). In MI, LGE is subendocardial or transmural in a coronary distribution. In Takotsubo, LGE is typically absent.

Chest X-Ray

• May be normal
• Cardiomegaly in dilated/fulminant cases
• Pulmonary congestion if heart failure present

Coronary Angiography

• Performed to exclude obstructive CAD when presentation mimics ACS
• Normal coronaries in myocarditis

Endomyocardial Biopsy (EMB)

1. New-onset heart failure (<2 weeks) with hemodynamic compromise (fulminant myocarditis)
2. New-onset heart failure (2 weeks - 3 months) with dilated LV, new ventricular arrhythmias, Mobitz II/complete AV block, or failure to respond to standard therapy within 1-2 weeks
3. Suspicion of giant cell myocarditis (rapid-onset VT or progressive HF in a young patient)

• Patchy disease leads to sampling error
• Dallas criteria sensitivity: 10-20% in some series
• Modern approach: supplement with immunohistochemistry (CD3, CD20, CD68 T-cell/macrophage markers) and PCR-based viral genome detection (DNA/RNA extraction from biopsy)
• Goldman-Cecil Medicine
• Grainger & Allison's Diagnostic Radiology
• Fuster and Hurst's The Heart

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8. Management

General Principles

1. Identify and remove the trigger (discontinue offending drug, treat underlying infection)
2. Supportive care first in all patients
3. NSAIDs are contraindicated (harmful in animal models of myocarditis; unlike pericarditis)
4. Physical activity restriction: athletes should abstain from competitive sports for at least 3-6 months following acute myocarditis

A. Supportive / Heart Failure Management

B. Hemodynamic Support (Fulminant Myocarditis)

• Inotropic agents: dobutamine, levosimendan
• Vasopressors: noradrenaline preferred over dopamine (fewer arrhythmias)
• Intra-aortic balloon pump (IABP)
• Ventricular assist devices (VAD)
• Extracorporeal membrane oxygenation (ECMO): shown to be effective as a bridge to recovery or transplantation in fulminant myocarditis
• Cardiac transplantation: for refractory, end-stage cases

C. Immunosuppressive Therapy

Evidence note: A key RCT (Myocarditis Treatment Trial, n=111) found no mortality benefit of prednisolone + cyclosporine or azathioprine in biopsy-proven myocarditis overall. A separate RCT showed LVEF improvement with immunosuppression in patients with HLA expression on EMB, but no mortality difference at 2 years. - Goldman-Cecil Medicine

D. Specific Treatments

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9. Prognosis

Predictors of Poor Prognosis

• Initial biventricular failure
• Sustained ventricular arrhythmias
• Low cardiac output at presentation
• LVEF <50% at presentation
• Syncope
• Failure to recover LV function within 6 months

Prognosis by Subtype

• Fuster and Hurst's The Heart, 15th ed.

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10. Complications

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11. Differential Diagnosis

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Key Sources

• Fuster and Hurst's The Heart, 15th Edition (Chapter 20)
• Goldman-Cecil Medicine, International Edition (Chapter 47)
• Robbins & Kumar Basic Pathology (p. 375)
• Grainger & Allison's Diagnostic Radiology
• Braunwald's Heart Disease, A Textbook of Cardiovascular Medicine