myocarditis

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Myocarditis

Definition

Myocarditis is an inflammatory process involving the myocardium, defined histologically by the presence of myocyte injury (degeneration or necrosis) and an inflammatory infiltrate not due to ischemia. It encompasses a diverse group of clinical entities in which infectious agents and/or inflammatory processes target the myocardium. The clinical spectrum ranges from asymptomatic ECG abnormalities to hemodynamic collapse and sudden death.

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

Epidemiology

Prevalence estimates range from 1 in 100,000 to 1 in 10,000
Postmortem studies report myocarditis in up to 12% of young victims of sudden cardiac death
Some degree of myocarditis is detected in nearly 10% of routine autopsies but is often clinically unrecognized
Up to 5% of patients with acute viral illness may exhibit a form of myocarditis
Linked to the development of dilated cardiomyopathy (DCM) in up to 16% of adult cases and 46% in children
Rosen's Emergency Medicine, p. 1119
Goldman-Cecil Medicine, p. 511

Etiology

Causes span the full microbial spectrum plus immune-mediated and toxic insults:

Infectious

Category	Key Organisms
Viral (most common in the West)	Coxsackievirus A & B, enteroviruses, parvovirus B19, HHV-6, adenovirus, HIV, CMV, influenza, SARS-CoV-2, EBV, hepatitis C
Protozoal	Trypanosoma cruzi (Chagas - most common worldwide), Toxoplasma gondii
Bacterial	Borrelia burgdorferi (Lyme), Corynebacterium diphtheriae, Mycoplasma pneumoniae, Salmonella, Neisseria spp.
Spirochetal	Treponema pallidum, Borrelia, Leptospira
Fungal	Aspergillus, Candida, Cryptococcus
Parasitic	Trichinella spiralis (most common helminthic cardiac disease), Echinococcus
Rickettsial	Coxiella burnetii, Rickettsia rickettsii

Immune-mediated

Systemic lupus erythematosus, systemic sclerosis, polymyositis/dermatomyositis
Sarcoidosis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
Giant cell myocarditis, Kawasaki disease, heart transplant rejection
Hypersensitivity reactions (penicillin, sulfonamides, methyldopa, tricyclic antidepressants, thiazide diuretics)
Immune checkpoint inhibitor therapy

Toxic

Anthracyclines, cocaine, amphetamines, cyclophosphamide
Heavy metals (copper, iron, lead), arsenic, carbon monoxide
Physical agents: radiation, electric shock, hyperpyrexia

Vaccine-related

mRNA COVID-19 vaccines: rare cases, predominantly in male adolescents and young adults, most often after the second dose, usually within 1 week. Most recover uneventfully. Estimated excess incidence ~1-10 per million persons after mRNA vaccines.
Goldman-Cecil Medicine, pp. 511-512
Robbins Basic Pathology, p. 375
Rosen's Emergency Medicine, p. 1119

Pathogenesis

Viral myocarditis is best understood and follows three phases:

Acute (cytotoxic) phase: Direct viral invasion with cytotoxicity, focal necrosis
Subacute phase: Increase in humoral factors leading to autoimmune injury. The host antiviral immune response that initially limits viral damage, when prolonged, causes inflammatory damage. Viruses can trigger an immune reaction that cross-reacts with myocardial proteins such as myosin heavy chain (molecular mimicry)
Chronic phase: Diffuse myocardial fibrosis and cardiac dysfunction, potentially leading to DCM

A breakdown of T-cell tolerance can produce chronic inflammation. Anti-beta-myosin antibodies are found in higher concentrations in patients with myocarditis and DCM compared to controls, supporting a predominantly autoimmune mechanism in idiopathic DCM following myocarditis.

For non-viral causes: Trypanosoma cruzi causes 10% mortality in the acute phase; survivors may enter a chronic immune-mediated phase with CHF and arrhythmias 10-20 years later (20-30% of patients with chronic Chagas disease develop cardiac disease).

Rosen's Emergency Medicine, p. 1119
Robbins Basic Pathology, pp. 374-375

Morphology / Histopathology

Gross: In acute myocarditis, the heart may appear normal or dilated. In advanced stages the myocardium is typically flabby and mottled with pale and hemorrhagic areas. Mural thrombi may be present.

Microscopy:

Viral myocarditis: Edema, interstitial inflammatory infiltrates (predominantly lymphocytic), and myocyte injury. Inflammatory involvement is often patchy.
Hypersensitivity myocarditis: Interstitial and perivascular infiltrates composed of lymphocytes, macrophages, and a high proportion of eosinophils
SLE myocarditis: Small focal areas of fibrinoid necrosis with lymphocyte and plasma cell infiltration; immune complex deposition around myocyte bundles; granular complement staining on immunofluorescence

If the patient survives the acute phase, lesions may resolve without significant sequelae or heal by fibrosis (substrate for future arrhythmia via scar-related reentry).

Myocardial biopsy in myocarditis showing dense lymphocytic infiltrate between myocardial fibers

Endomyocardial biopsy specimen showing viral myocarditis. Note the dense lymphocytic infiltrate infiltrating between myocardial fibers. - Rosen's Emergency Medicine

The Dallas criteria remain the historical standard for biopsy diagnosis - requiring the combination of leukocyte infiltration and necrosis. Four histologic patterns are recognized:

Active myocarditis - myocyte degeneration/necrosis + definite cellular infiltrate ± fibrosis
Borderline myocarditis - cellular infiltrate without myocyte injury
Persistent myocarditis - continued infiltration
Healed myocarditis - scarring without active infiltrate

Molecular analysis (DNA/RNA extraction + PCR) of biopsy specimens substantially refines diagnosis.

Robbins Basic Pathology, p. 375
Goldman-Cecil Medicine, p. 511
Grainger & Allison's Diagnostic Radiology, p. 331

Clinical Features

The presentation is highly variable:

Prodrome: Flu-like symptoms - fever, fatigue, myalgias, vomiting, diarrhea (reflecting the preceding viral illness)

Common presentations in adults:

Dyspnea, chest pain (can mimic ACS), palpitations
New-onset heart failure or unexplained arrhythmias in an otherwise healthy patient

Presentation in children:

Dyspnea is most common
Infants may present with a fulminant syndrome: fever, cyanosis, respiratory distress, tachycardia, cardiac failure

Red flags for poor outcome:

Severe dyspnea, heart failure, hemodynamic instability at presentation
Ventricular dysrhythmias

Giant cell myocarditis - a particularly severe variant (10-20% of biopsy-positive cases): rapid onset of chest pain, fever, and hemodynamic compromise, often with ventricular tachycardia or AV block.

Rosen's Emergency Medicine, p. 1119
Goldman-Cecil Medicine, p. 512

Diagnostic Testing

ECG

Sinus tachycardia (most common)
Widened QRS, low voltages, prolonged QT interval
ST/T-wave changes (nonspecific)
AV block or complete heart block (especially Lyme myocarditis)
AMI pattern - may extend beyond distribution of a single coronary artery
Supraventricular or ventricular tachycardias; PVCs often originating from the inferior LV (RBBB superior axis morphology in lymphocytic myocarditis)

Biomarkers

Troponin I/T: May be elevated; a negative serial troponin does not exclude the diagnosis
ESR, CRP, WBC: Of no independent diagnostic value
In SLE myocarditis: raised ESR, increased anti-dsDNA titers, complement consumption

Echocardiography

Reduced LV ejection fraction, global hypokinesis
Regional wall motion abnormalities not following coronary artery anatomy
Possible pericardial effusion
May be relatively unremarkable in mild cases

Cardiac MRI (modality of choice for non-invasive diagnosis)

The Lake Louise Criteria use a combination of:

T2-weighted sequences (STIR): Myocardial edema - subepicardial or mid-wall hyperintensity
Early gadolinium enhancement: Inflammatory hyperemia
Late gadolinium enhancement (LGE): Subepicardial non-ischemic distribution, most frequently in the lateral and/or inferior wall

Key CMR points:

LGE in myocarditis is subepicardial, distinguishing it from STEMI (subendocardial/transmural LGE) and takotsubo (typically absent LGE)
A negative LGE study does NOT exclude acute myocarditis - early enhancement imaging is needed to detect inflammatory hyperemia without macroscopic necrosis
Septal, mid-wall, and patchy LGE distribution is associated with increased risk of sudden death

Cardiac MRI in acute myocarditis: A) T2-weighted STIR image showing subepicardial hyperintensity (arrow) in the inferior wall. B) Late gadolinium enhancement image showing contrast uptake in a non-ischemic pattern (arrow). Coronary angiography was negative.

Cardiac MRI in acute myocarditis. (A) T2-weighted STIR short-axis image shows subepicardial hyperintensity (arrow) in the inferior wall. (B) Late gadolinium enhancement in corresponding plane shows non-ischemic contrast uptake (arrow). The patient presented with chest pain and mildly elevated cardiac enzymes; emergency coronary angiography was negative. - Grainger & Allison's Diagnostic Radiology

Coronary Angiography

Indicated when the presentation mimics ACS to exclude obstructive coronary artery disease
Typically shows normal arteries in myocarditis

Endomyocardial Biopsy

Histologic gold standard, but has variable sensitivity due to sampling error (patchy inflammation)
Sensitivity can be increased by MRI-guided targeting of abnormal regions
Indications: Suspected giant cell myocarditis (young person with rapidly progressive heart failure + ventricular tachyarrhythmias or AV block), or when the diagnosis would change management
Not routinely used due to invasive nature and variable sensitivity
Grainger & Allison's Diagnostic Radiology, pp. 330-332
Rosen's Emergency Medicine, p. 1120
Goldman-Cecil Medicine, p. 511

Management

Acute Supportive Care

Activity restriction (complete rest; avoid strenuous exertion during active inflammation)
Afterload reduction and diuresis
Standard heart failure therapy: ACE inhibitors, diuretics, beta-blockers, anticoagulants (per heart failure guidelines)
Rhythm management for arrhythmias

Fulminant Myocarditis

Inotropic support
Mechanical circulatory support (ventricular assist devices)
ECMO (extracorporeal membrane oxygenation)
Cardiac transplantation for refractory cases

Immunosuppression

The role is uncertain in viral lymphocytic myocarditis:

A landmark RCT of 111 adults with biopsy-proven myocarditis showed no difference in mortality or LV function improvement with prednisolone + cyclosporine or azathioprine vs placebo
A subsequent trial using MHC expression on biopsy to select patients showed improved LVEF with prednisolone + azathioprine, but no mortality benefit at 2-year follow-up

Immunosuppression is indicated for:

Giant cell myocarditis (benefits established)
Eosinophilic myocarditis
Cardiac sarcoidosis
Biopsy-proven, infection-negative immune-mediated myocarditis refractory to conventional heart failure therapy
SLE-related myocarditis, polymyositis/dermatomyositis-related myocarditis
Goldman-Cecil Medicine, pp. 512-513
Rosen's Emergency Medicine, p. 1120
Braunwald's Heart Disease, p. 565

Prognosis and Complications

Most patients with acute viral myocarditis recover without sequelae
Residual myocardial fibrosis (detectable as LGE on CMR) can serve as a persistent substrate for scar-related reentrant VT and sudden cardiac death
Progression to dilated cardiomyopathy occurs in a significant subset (up to 16% of adults, 46% of children)
Long-term prognosis in children correlates with severity of initial presentation
Chagas disease: 20-30% of patients develop cardiac disease with CHF, aneurysms, and VT over decades; sudden death may be the first manifestation
Giant cell myocarditis has the worst prognosis among the histologic subtypes
Braunwald's Heart Disease, p. 565
Rosen's Emergency Medicine, p. 1120

Special Situations

SARS-CoV-2 / COVID-19

Myocarditis is a rare complication with an apparent excess incidence of ~40 extra events per million persons. The risk from infection appears to exceed the risk from mRNA vaccination. Vaccine-associated myocarditis risk is highest under age 40 and more pronounced after the second mRNA dose.

Lyme Myocarditis

Occurs in ~5% of patients with Lyme disease. Manifests primarily as self-limited conduction system disease - classically high-degree AV block, frequently requiring temporary pacemaker insertion. Managed with antibiotics.

Peripartum Myocarditis

Autoimmune in nature; myocarditis may be an initial feature of rheumatic diseases requiring consideration in the differential of unexplained heart failure.

Sources:

Robbins & Kumar Basic Pathology, 10e
Goldman-Cecil Medicine, International Edition
Braunwald's Heart Disease, 12e
Rosen's Emergency Medicine, 10e
Grainger & Allison's Diagnostic Radiology, 7e
Braunwald's Heart Disease (Rheumatic Disease chapter)

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