Myocarditis - Harrison's Principles of Internal Medicine (22nd Ed., 2025)

Harrison's, Chapter 268 - Pages 2054-2062

DEFINITION

• Complete resolution
• Relapsing course
• Progression to chronic dilated cardiomyopathy (DCM)

MODELS OF INFECTIOUS MYOCARDITIS

Three Phases (from Coxsackie B / enterovirus murine models)

• Viral entry may be enhanced by genetic variants of the coxsackie/adenovirus receptor
• Enteroviral protease A degrades dystrophin (a myocyte structural protein) and induces apoptosis, interferes with autophagy
• Direct myocardial invasion proven for: enteroviruses, HIV, dengue virus
• Many common viruses do NOT inflict cardiac damage directly; early injury comes from cytokine storm and nonspecific immune responses
• Early immunosuppression in animal models worsened cardiac injury (by increasing viral replication)

• Recognition of common antigenic patterns triggers macrophage activation and T- and B-cell expansion
• This phase without direct viral injury = "virally triggered" myocarditis (e.g., adenovirus, influenza, COVID-19)
• Molecular mimicry between viral and cardiac antigens may drive autoreactive T-cell injury with NO ongoing viral infection
• Emerging concept: viral "hijacking" of cellular machinery to produce extracellular vesicles containing viral RNA, which gain protected entry into other cells

• Demonstrated in enterovirus animal models
• Rarely due to enteroviruses in adults; limited data on whether viral myocarditis in humans commonly leads to chronic DCM

ACUTE MYOCARDITIS

Epidemiology & Clinical Profile

• Increasingly recognized due to high-sensitivity troponin and cardiac MRI
• Most often caused by active infection (viral)
• Also caused by non-infectious inflammation: sarcoidosis, giant cell myocarditis, eosinophilic myocarditis, systemic autoimmune diseases, immunotherapies (e.g., checkpoint inhibitors)

Causes of Infectious Myocarditis

• Enteroviruses (coxsackievirus B was the classic historical cause; now less common in adults)
• Adenovirus
• Parvovirus B19 - now recognized as common; tends to infect endothelial cells more than myocytes
• COVID-19 (SARS-CoV-2) - particularly after mRNA vaccination (vaccine-associated myocarditis, predominantly in young males)
• Influenza, HIV, CMV, EBV, HHV-6, dengue, hepatitis C

• Major cause of myocarditis worldwide (endemic in Latin America)
• Acute Chagas myocarditis occurs at time of infection, often mild/subclinical
• Chronic Chagas cardiomyopathy is the major disease burden - develops decades after initial infection; involves fibrosis, conduction system damage, and DCM

• Bacterial (rare): Borrelia burgdorferi (Lyme disease) - causes AV block; Corynebacterium diphtheriae - toxin-mediated; Clostridium species
• Rickettsial, fungal, parasitic (Toxoplasma, Trichinella) in immunocompromised hosts

CHRONIC MYOCARDITIS

Chronic Active Myocarditis

• Persistently elevated inflammatory markers and ongoing histologic inflammation
• Often progresses to DCM
• May require prolonged immunosuppression

Specific Entities

• Rare but highly aggressive
• Histology: multinucleated giant cells with extensive myocyte necrosis, eosinophilic infiltrate
• Rapid progression to cardiogenic shock and death without treatment
• Treat with: combined immunosuppression (cyclosporine + corticosteroids + azathioprine)
• High rate of relapse; some patients require mechanical circulatory support or heart transplantation

• Cardiac sarcoidosis causes granulomatous inflammation of the myocardium
• Manifests as: heart block, ventricular arrhythmias, DCM
• Diagnosis: PET scan (FDG uptake) + cardiac MRI (late gadolinium enhancement)
• Treatment: corticosteroids (first line); ICD for arrhythmia risk

• Associated with: drug hypersensitivity reactions, parasitic infections, hypereosinophilic syndrome
• Histology: eosinophilic infiltration
• Treatment: remove offending drug; corticosteroids

NONINFECTIVE INFLAMMATORY MYOCARDITIS

Immune Checkpoint Inhibitor (ICI) Myocarditis

• ICIs (anti-PD-1, anti-PD-L1, anti-CTLA-4) used in cancer immunotherapy cause myocarditis in ~1-2% of patients
• Fulminant presentation common; highest mortality among ICI toxicities (~25-50%)
• Mechanism: unchecked T-cell activation against cardiac self-antigens
• Often presents with: chest pain, dyspnea, arrhythmias, rapidly deteriorating LV function
• Management:
  • Stop the ICI immediately
  • High-dose corticosteroids (methylprednisolone 1 g/day IV)
  • For refractory cases: mycophenolate mofetil, IVIG, plasmapheresis, abatacept, anti-thymocyte globulin

Vaccine-Associated Myocarditis (mRNA COVID-19 vaccines)

• Predominantly in young males (12-29 years) after 2nd dose
• Usually mild and self-limiting
• Mechanism: likely immune-mediated (molecular mimicry or excess immune activation)
• Most cases resolve with NSAIDs and rest

Autoimmune Disease-Associated

• Systemic lupus erythematosus (SLE), rheumatoid arthritis, polymyositis/dermatomyositis, systemic sclerosis
• Myocarditis is often subclinical but can be identified on cardiac MRI

CLINICAL PRESENTATION

Symptoms

• Chest pain - often pleuritic or positional (pericarditis co-existing = myopericarditis)
• Dyspnea - from LV dysfunction
• Palpitations - arrhythmias common
• Fatigue
• Preceded (1-4 weeks earlier) by flu-like illness or viral prodrome in many cases

Signs

• Tachycardia (often disproportionate)
• S3 gallop, mitral regurgitation murmur (from LV dilation)
• Signs of heart failure: elevated JVP, peripheral edema, pulmonary crackles
• Cardiogenic shock in fulminant cases: hypotension, cold extremities, altered mental status

Spectrum of Severity

1. Mild: subclinical troponin rise, normal/near-normal EF, incidental finding
2. Moderate: symptomatic heart failure, reduced EF, arrhythmias
3. Fulminant myocarditis: acute cardiogenic shock, often with preserved LV volume (biopsy shows diffuse inflammation); paradoxically has better long-term prognosis than acute non-fulminant forms if patient survives the acute phase

DIAGNOSIS

Biomarkers

• Troponin I or T: elevated (hallmark); high-sensitivity assays have increased detection of mild cases
• CRP, ESR: elevated in active inflammation
• BNP/NT-proBNP: elevated with LV dysfunction/failure
• CK-MB: can be elevated but less specific

ECG

• ST segment changes: diffuse ST elevation (often concave/"saddle-shaped" if pericarditis coexists) OR ST depression
• Bundle branch block, QRS prolongation
• AV block (especially in Lyme or sarcoid myocarditis)
• Non-specific T-wave inversions
• Ventricular arrhythmias (PVCs, VT)
• Note: ECG can be entirely normal

Echocardiography

• Global LV dysfunction (wall motion abnormalities, reduced EF) - more common than regional
• LV dilation in subacute/chronic cases
• In fulminant myocarditis: small, non-dilated LV with diffuse hypokinesis and preserved or thickened walls (due to myocardial edema) - distinguishes it from DCM
• Pericardial effusion (if myopericarditis)

Cardiac MRI (CMR) - Gold Standard Non-Invasive Test

• T2 mapping / T2-weighted imaging: myocardial edema (increased T2 signal)
• T1 mapping: diffuse myocardial injury
• Late Gadolinium Enhancement (LGE): fibrosis/necrosis - characteristically subepicardial or mid-myocardial distribution (vs. subendocardial in MI)

Endomyocardial Biopsy (EMB)

• Dallas Criteria (histopathological):
  • Active myocarditis: inflammatory infiltrate + myocyte necrosis/degeneration not from ischemia
  • Borderline myocarditis: infiltrate without necrosis
• Limitations: sampling error (patchy disease), low sensitivity (~50%), procedural risk
• Indications in Harrison's:
  • New-onset heart failure not responding to standard therapy
  • Fulminant myocarditis with hemodynamic compromise
  • Suspected giant cell myocarditis (urgent - changes management critically)
  • Suspected cardiac sarcoidosis
  • Arrhythmias unresponsive to therapy
• Additional studies on biopsy: immunohistochemistry (CD3, CD68 for T cells/macrophages), PCR for viral genome, electron microscopy

TREATMENT

General / Supportive

• Physical activity restriction: all patients with acute myocarditis should avoid competitive sports and vigorous exercise for 3-6 months (or until resolution confirmed on CMR/echo)
• Standard heart failure therapy:
  • ACE inhibitors/ARBs - for LV dysfunction
  • Beta-blockers - for LV dysfunction and arrhythmias
  • Mineralocorticoid receptor antagonists - if EF <35%
  • SGLT2 inhibitors - as part of contemporary HFrEF therapy
  • Diuretics for congestion

Antiviral Therapy

• No proven benefit of antivirals in most viral myocarditis
• Exception: HIV myocarditis - antiretroviral therapy improves cardiac function
• Exception: CMV myocarditis in immunocompromised - ganciclovir/valganciclovir

Immunosuppression

• NOT routinely recommended in acute viral myocarditis (no benefit in trials; may worsen viral myocarditis by enhancing viral replication)
• Specific indications where immunosuppression IS used:
  • Giant cell myocarditis: cyclosporine + steroids + azathioprine
  • Cardiac sarcoidosis: corticosteroids
  • Eosinophilic myocarditis: steroids + remove offending agent
  • ICI myocarditis: high-dose methylprednisolone
  • Autoimmune myocarditis (SLE, etc.): treat the underlying disease

Fulminant Myocarditis / Cardiogenic Shock

• Hemodynamic support with mechanical circulatory support (MCS):
  • Intra-aortic balloon pump (IABP)
  • Impella device
  • Extracorporeal membrane oxygenation (ECMO) - especially in refractory cases
• EMB recommended to identify giant cell myocarditis (which requires urgent immunosuppression)
• Temporary pacing for AV block
• Bridge to recovery or heart transplantation

Heart Transplantation

• For refractory giant cell myocarditis or end-stage cardiomyopathy secondary to myocarditis
• Note: GCM can recur in the transplanted heart

Arrhythmia Management

• VT/VF: amiodarone acutely; ICD if persistent arrhythmia or EF <35% after recovery period
• Complete AV block: temporary transvenous pacing; permanent pacemaker if no recovery (e.g., Lyme myocarditis - often resolves with antibiotics)

ACUTE FULMINANT MYOCARDITIS (from Harrison's Ch. 270 - Cardiogenic Shock)

• Can mimic acute MI with ST abnormalities or bundle branch block + marked troponin elevation
• Accounts for a small proportion of cardiogenic shock cases
• Key distinguishing features from acute MI cardiogenic shock:
  • Younger patients
  • Absence of typical ischemic chest pain
  • Global LV dysfunction (not regional as in MI)
  • No coronary obstruction on angiography
• Management = same as for CS from acute MI minus revascularization
• EMB recommended to identify giant cell myocarditis
• Refractory CS managed with mechanical circulatory support

INFLAMMATORY MYOCARDITIS (Cross-reference summary)

• Inflammatory cardiomyopathy (virus-negative, inflammation-positive on biopsy) may respond to immunosuppression (TIMIC trial, ETiMD trial showed benefit of prednisone + azathioprine in virus-negative inflammatory cardiomyopathy)
• Virus-positive inflammatory cardiomyopathy does NOT benefit from immunosuppression

KEY FACTS TO REMEMBER (High-Yield for Exams)