Myocarditis

• Direct viral/pathogen injury: Viruses (particularly enterovirus, adenovirus, parvovirus B19, coronavirus, and influenza) and other pathogens directly invade cardiomyocytes via cellular receptors (e.g., coxsackievirus-adenovirus receptor [CAR], angiotensin-converting enzyme 2 [ACE2]). Viral replication leads to cardiomyocyte lysis through viral protease-mediated damage and induction of apoptosis via viral glycoproteins.

• Innate immune activation and myocardial inflammation: Pattern recognition receptors (toll-like receptors [TLRs], retinoic acid-inducible gene I [RIG-I]) recognize viral pathogen-associated molecular patterns, triggering release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and chemokines. Infiltrating macrophages, dendritic cells, and innate lymphoid cells amplify the inflammatory cascade through production of reactive oxygen species (ROS) and further cytokine release. This robust innate response, while initially protective, causes collateral myocardial damage and impaired contractility.

• Adaptive immunity and tissue remodeling: CD8+ cytotoxic T lymphocytes and CD4+ helper T cells recognize viral antigens and further damage infected cardiomyocytes. In some cases, molecular mimicry—whereby viral epitopes cross-react with cardiac myosin, tropomyosin, and other contractile proteins—perpetuates autoimmune injury independent of active viral replication. The chronic inflammatory phase leads to myocardial fibrosis, collagen deposition, and ventricular remodeling through activation of cardiac fibroblasts and increased TGF-β signaling. This remodeling process may progress to dilated cardiomyopathy with systolic dysfunction.

• Cardiac dysfunction mechanisms: Inflammatory cytokines impair myocardial contractility through nitric oxide-mediated effects on excitation-contraction coupling and calcium handling. Increased myocardial stiffness results from edema, inflammation, and fibrosis. Myocardial necrosis and apoptosis reduce viable contractile tissue. Conduction abnormalities arise from inflammation of the conduction system, manifesting as arrhythmias. Increased left ventricular wall stress triggers compensatory neurohormonal activation (RAAS, sympathetic nervous system), which provides short-term hemodynamic support but promotes long-term adverse remodeling.

• Viral: Enterovirus (especially coxsackievirus B and echovirus) and adenovirus are historically most common in developed countries; parvovirus B19 is increasingly recognized; coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has emerged as a major etiology; influenza and respiratory syncytial virus (RSV); human immunodeficiency virus (HIV) and hepatitis C virus (HCV) in appropriate populations; cytomegalovirus (CMV) in immunocompromised hosts.

• Bacterial: Streptococcus pyogenes, Staphylococcus aureus (including MRSA), Corynebacterium diphtheriae (toxin-mediated), Neisseria meningitidis, Borrelia burgdorferi (Lyme disease), Mycobacterium tuberculosis.

• Parasitic: Trypanosoma cruzi (Chagas disease—leading cause in Central and South America), Plasmodium species (malaria), Echinococcus, Toxoplasma gondii in immunocompromised patients.

• Fungal: Aspergillus, Candida, Cryptococcus, Coccidioides immitis, Histoplasma capsulatum.

Non-infectious causes

• Toxins and drugs: Chemotherapy agents (anthracyclines such as doxorubicin, 5-fluorouracil, tyrosine kinase inhibitors, immune checkpoint inhibitors); alcohol (particularly with poor nutrition); cocaine and amphetamines; antimicrobials (antiretrovirals, anticonvulsants, antibiotics like fluoroquinolones); heavy metals (arsenic, lead).

• Immune-mediated: Systemic lupus erythematosus (SLE), rheumatoid arthritis, systemic sclerosis, polymyositis/dermatomyositis, giant cell arteritis, Takayasu arteritis, granulomatosis with polyangiitis (GPA).

• Hypersensitivity reactions: Drug allergy (penicillins, NSAIDs, sulfonamides, anticonvulsants), serum sickness.

• Other: Sarcoidosis (cardiac involvement in <5% of sarcoidosis patients but significant when present), peripartum cardiomyopathy, radiation therapy, inflammatory bowel disease, celiac disease.

Risk factors for severe disease

• Extremes of age (very young children, elderly).
• Immunocompromised state (HIV/AIDS, post-transplant, chemotherapy).
• Fulminant presentation at diagnosis.
• Genetic polymorphisms in TLR and cytokine genes.
• Delayed presentation or diagnosis.

• Cardinal symptoms: Chest pain (pleuritic, substernal, often myopericardial), dyspnea (from pulmonary edema or reduced cardiac output), palpitations, syncope or presyncope (arrhythmia-related), and constitutional symptoms (fever, myalgias, fatigue) typically following a prodromal viral illness by days to weeks.

• Severe/fulminant presentations (10–15% of cases): Acute onset of cardiogenic shock, hemoptysis, severe dyspnea, altered mental status from hypoperfusion, rapid progression over hours to days.

• Physical examination findings:
• Tachycardia and tachypnea reflecting reduced cardiac output and pulmonary congestion.
• New or worsening heart murmur (mitral regurgitation from papillary muscle dysfunction or from dilated left ventricle).
• Elevated jugular venous pressure (JVP) indicating right ventricular involvement or biventricular failure.
• Hepatomegaly and peripheral edema from systemic venous congestion.
• Gallop rhythm (S3 and/or S4) from impaired relaxation or forceful atrial contraction into a stiff ventricle.
• Pulmonary crackles from pulmonary edema.
• Cool extremities, delayed capillary refill in cardiogenic shock.
• Pulsus alternans (beat-to-beat variation in pulse amplitude) indicating severe ventricular dysfunction.

• Arrhythmia presentations: Palpitations, syncope, aborted sudden cardiac death; fulminant myocarditis frequently manifests with ventricular arrhythmias and hemodynamic collapse.

• Atypical/subclinical presentations: Asymptomatic or mild exertional dyspnea in mild cases; incidental cardiomegaly on imaging; arrhythmia discovered on routine screening in athletes.

Laboratory findings

• Elevated cardiac biomarkers: Troponin I or T (most sensitive and specific; elevation indicates myocardial necrosis; peak within 3–7 days); myoglobin (earlier but less specific); creatine kinase-MB (CK-MB); B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) elevation correlates with ventricular dysfunction and adverse prognosis.

• Inflammatory markers: Elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR); elevated white blood cell count with left shift.

• Viral serology and PCR: Acute and convalescent serologies for common viruses; reverse transcription PCR (RT-PCR) from respiratory or stool specimens (limited sensitivity); blood PCR increasingly used for parvovirus B19, adenovirus, enterovirus, and coronavirus.

Electrocardiography (ECG)

• Nonspecific findings (most common): Diffuse ST-segment elevation or PR depression (mimicking acute pericarditis); T-wave inversions; prolonged QT interval.
• Conduction abnormalities: AV block, intraventricular conduction delay, bundle branch block.
• Arrhythmias: Ventricular ectopy, ventricular tachycardia, atrial fibrillation.
• Pattern: Often more diffuse than acute coronary syndrome (not confined to single vascular territory); may demonstrate the "myopericarditis" pattern when pericardial involvement coexists.

Echocardiography

• Ventricular dysfunction: Global hypokinesis with reduced left ventricular ejection fraction (LVEF); regional wall motion abnormalities (though myocarditis classically shows global rather than coronary-distribution pattern).
• Chamber dilation: Left and/or right ventricular enlargement.
• Wall thickness: Myocardial edema may cause increased wall thickness in acute phase.
• Pericardial effusion: Present in up to 60% of myocarditis cases.
• Functional mitral regurgitation from papillary muscle dysfunction or LV dilation.
• Severity assessment: Degree of systolic dysfunction and hemodynamics guides management intensity.

Cardiac magnetic resonance imaging (CMR) — gold standard for diagnosis

• Lake Louise Criteria for myocarditis diagnosis require ≥2 of 3 criteria:

1. 1.Regional or global myocardial signal intensity increase on T2-weighted imaging or elevated myocardial T2 relaxation time (indicates myocardial edema, highly sensitive for acute inflammation).
2. 2.Increased early gadolinium enhancement (EGE) ratio (myocardial-to-skeletal muscle ratio >4, reflects capillary permeability and inflammation).
3. 3.Late gadolinium enhancement (LGE) in a non-ischemic distribution pattern, typically subepicardial or midwall (indicates myocardial fibrosis/scar, present in chronic or resolving myocarditis).

• Additional findings: Pericardial enhancement and effusion.
• Sensitivity and specificity: CMR has ~70–80% sensitivity and >85% specificity for myocarditis; advantage over biopsy is non-invasive assessment of the entire myocardium.

Endomyocardial biopsy (EMB)

• Histopathology (Dallas criteria, largely replaced by clinical assessment):
• Acute myocarditis: Inflammatory infiltrate (predominantly lymphocytes, some macrophages) ± associated myocyte necrosis.
• Chronic myocarditis: Fibrosis, inflammatory infiltrate, myocyte degeneration.

• Current role: Reserved for specific indications: fulminant myocarditis (to guide immunosuppression), suspected myocarditis with hemodynamic compromise not responding to standard therapy, diagnostic uncertainty, or suspected infiltrative disease (sarcoidosis, giant cell myocarditis). Immunohistochemistry and viral PCR on biopsy specimens can identify viral persistence and guide antiviral therapy in select cases.

Cardiac catheterization

• Useful to exclude acute coronary syndrome when presentation mimics ACS (elevated troponin, chest pain, ECG changes); reveals normal coronary arteries in myocarditis (unless coincidental coronary disease).
• May show elevated filling pressures (elevated pulmonary artery occlusion pressure, elevated right atrial pressure) in heart failure.
• Useful in fulminant cases to assess hemodynamics and guide initiation of mechanical circulatory support.

Diagnostic approach summary

1. 1.Clinical suspicion from presenting syndrome (chest pain/dyspnea after viral prodrome, young patient with acute heart failure).
2. 2.ECG and troponin for initial assessment; elevated troponin + compatible ECG + clinical context.
3. 3.Echocardiography to assess ventricular function, exclude other structural disease, assess for pericardial effusion.
4. 4.CMR if diagnosis remains uncertain or if prognostic information needed; recommended in most suspected cases.
5. 5.Viral testing (serology, PCR) when diagnosis suspected and to guide infectious disease aspects.
6. 6.EMB for fulminant cases or when diagnosis unclear and will change management.

General supportive measures

• Activity restriction: Complete bed rest initially in symptomatic cases; gradual return to activity over weeks to months based on clinical and functional recovery; avoid strenuous exertion and competitive sports until recovery confirmed (persistent LV dysfunction or arrhythmia risk).
• Hemodynamic monitoring: Continuous telemetry in hospitalized patients for arrhythmia detection; consider ICU admission for hemodynamically unstable cases.
• Fluid management: Fluid restriction and diuretics (furosemide, bumetanide) for pulmonary edema and elevated filling pressures; cautious approach to avoid excessive diuresis that may worsen cardiac output in some cases.

Pharmacological therapy for heart failure/reduced systolic function

• Angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin II receptor blockers (ARBs): Enalapril, lisinopril, or losartan; first-line agents that reduce afterload, inhibit neurohormonal activation, and promote favorable remodeling. Initiate at low dose and titrate as tolerated.

• Beta-blockers: Metoprolol, carvedilol, or bisoprolol; reduce sympathetic drive, lower heart rate and blood pressure, improve diastolic function. Critical caveat: In acute fulminant myocarditis with hemodynamic instability, beta-blockers must be withheld or used with extreme caution until hemodynamic stabilization achieved; premature use can precipitate cardiogenic shock.

• Aldosterone antagonists (spironolactone, eplerenone): Consider in persistent systolic dysfunction for neurohormonal blockade.

• Inotropic support for cardiogenic shock: Dobutamine (β-1-adrenergic agonist increasing contractility and causing vasodilation) or milrinone (phosphodiesterase-3 inhibitor with inotropic and vasodilatory effects); preferred over catecholamines in fulminant myocarditis. Levosimendan (not available in US) is inodilator with potentially favorable hemodynamics.

• Vasopressor support if hypotension refractory to inotropes: Norepinephrine preferred over pure vasoconstrictors.

Mechanical circulatory support

• Indicated in fulminant myocarditis with cardiogenic shock refractory to medical therapy: Extracorporeal membrane oxygenation (ECMO), intra-aortic balloon pump (IABP), or left ventricular assist device (LVAD) as bridge to recovery or transplantation. ECMO provides both cardiac and respiratory support and is preferred in rapidly deteriorating

Acute emergencies

• Cardiogenic shock (fulminant myocarditis): diffuse myocardial edema and cytokine-mediated depression of excitation–contraction coupling collapse stroke volume over hours. Signaled by narrow pulse pressure, cool mottled extremities, rising lactate, oliguria, and a small hyperdynamic-appearing but severely hypokinetic thickened LV on echo. Requires ICU care and early consideration of temporary mechanical circulatory support (ECMO), as outlined in the AHA scientific statement on recognition and management of fulminant myocarditis.
• Ventricular fibrillation / pulseless VT: inflammatory scar and edema create re-entrant circuits and triggered activity. Immediate defibrillation per AHA ACLS; these are the shockable rhythms and the leading mechanism of sudden death in myocarditis.
• High-grade or complete AV block: inflammation of the AV node and His–Purkinje system. Bradycardia with syncope demands transcutaneous/transvenous pacing. Disproportionate conduction disease should raise suspicion for Lyme carditis, cardiac sarcoidosis, giant cell myocarditis, or diphtheritic myocarditis; Lyme block typically resolves with IV ceftriaxone (IDSA/AAN/ACR Lyme guideline) without a permanent device.
• Cardiac tamponade in myopericarditis: enlarging effusion produces pulsus paradoxus, JVD, and echocardiographic RA/RV diastolic collapse — pericardiocentesis is emergent.
• LV mural thrombus with systemic embolism: stasis within an akinetic, dilated ventricle; suspect with new focal neurologic deficit or limb ischemia.

Chronic sequelae

• Dilated cardiomyopathy with chronic HFrEF: fibrotic remodeling after the inflammatory phase. Manage with all four guideline-directed classes per the 2022 AHA/ACC/HFSA heart failure guideline — ARNI (or ACEI/ARB), beta blocker, MRA, and SGLT2 inhibitor.
• Persistent late gadolinium enhancement on CMR: a fibrotic arrhythmic substrate and the strongest imaging predictor of later ventricular arrhythmia and death.

Treatment-related harms

• Beta blockade during decompensation: negative inotropy can precipitate shock; withhold until hemodynamically stable.
• Over-diuresis: an edematous, stiff ventricle is preload-dependent — hypotension and prerenal AKI follow.
• Corticosteroids/immunosuppression: infection, hyperglycemia; not routine for uncomplicated viral lymphocytic myocarditis.
• Mechanical support: bleeding, hemolysis, limb ischemia, stroke.

• The classic stem: a young, previously healthy patient with a recent flu-like or GI prodrome who develops chest pain, dyspnea, and an elevated troponin — with normal coronary arteries on angiography. Troponin elevation without obstructive CAD in a young patient is myocarditis until proven otherwise.
• Best next step after ECG, troponin, and echocardiography: cardiac MRI applying the Lake Louise criteria. Reserve endomyocardial biopsy for fulminant disease, hemodynamic deterioration despite therapy, or suspicion of giant cell myocarditis or cardiac sarcoidosis — situations where histology changes management.
• The association examiners love: Coxsackievirus B (enterovirus) as the archetypal cause; parvovirus B19 and human herpesvirus 6 on modern biopsy PCR; Trypanosoma cruzi for a Latin American immigrant with megaesophagus/megacolon, RBBB with left anterior fascicular block, and an apical aneurysm.
• Giant cell myocarditis: multinucleated giant cells without granulomas, rapidly progressive heart failure with refractory ventricular tachycardia and heart block in a middle-aged adult; requires biopsy, combined immunosuppression, and early transplant/MCS referral. Contrast with cardiac sarcoidosis, which shows non-caseating granulomas.
• Eosinophilic (hypersensitivity) myocarditis: rash, fever, peripheral eosinophilia days to weeks after a new drug — stop the culprit drug and give corticosteroids. Immune checkpoint inhibitor myocarditis often co-occurs with myositis/myasthenia and is treated with high-dose corticosteroids and permanent drug discontinuation (ASCO immune-related adverse event guideline).
• Distractor to avoid: reflexively starting a beta blocker in a hypotensive, acutely decompensated patient — it can precipitate cardiogenic shock. Stabilize first, then layer on the four HFrEF classes (ARNI/ACEI/ARB, beta blocker, MRA, SGLT2 inhibitor) per the 2022 AHA/ACC/HFSA guideline.
• Second distractor: calling diffuse ST elevation a STEMI. Myocarditis/myopericarditis produces diffuse ST elevation with PR depression crossing coronary territories; a new LBBB is likewise not a stand-alone STEMI criterion (apply Sgarbossa criteria).
• Sports: myocarditis is a leading cause of sudden cardiac death in young athletes; AHA/ACC eligibility recommendations advise abstaining from competitive sport for several months with reassessment of function, biomarkers, and rhythm before return.