Myocarditis

Myocarditis is inflammation of the myocardium and is most commonly caused by a viral infection (e.g., parvovirus B19, coxsackievirus infection) but can also occur in patients with acute rheumatic fever or autoimmune diseases (e.g., systemic lupus erythematosus, vasculitis). Myocarditis most commonly occurs in infants, adolescents 15–18 years of age, and young adults. Patients may be asymptomatic or present with new-onset chest pain, arrhythmias, and/or new-onset heart failure. Fulminant myocarditis is a rare and life-threatening manifestation of severe myocardial inflammation characterized by hemodynamic instability and/or electrical instability (e.g., ventricular arrhythmia, high-grade atrioventricular block). Initial diagnostic studies involve 12-lead ECG, inflammatory markers, cardiac biomarkers, and transthoracic echocardiography (TTE). A definitive diagnostic study (i.e., cardiac MRI and/or endomyocardial biopsy) should be performed if myocarditis cannot be confirmed on initial diagnostic workup or to determine the underlying cause. Management involves inpatient care with ongoing monitoring, symptomatic treatment (e.g., for heart failure), and treatment of the underlying cause. Transfer to a facility with advanced cardiac care capacity may be necessary. Patients with fulminant myocarditis may also require circulatory support (e.g., inotropic agents, mechanical circulatory support) and/or arrhythmia management (e.g., temporary pacing). Most adults with viral myocarditis make a full recovery, but there is a small risk of progression to dilated cardiomyopathy. Affected children are at risk for ongoing heart failure, transplantation, and death.

The exact incidence is unknown.

• 1–5% of viral infections are estimated to have cardiac involvement.
• Often occurs in young patients (average age ∼ 40 years)
• In ∼ 10% of sudden deaths in young adults, myocarditis is diagnosed in the post-mortem examination. ^[1]

Epidemiological data refers to the US, unless otherwise specified.

Infectious ^[2][3]

• Viral
  • Most commonly implicated: enterovirus (e.g., coxsackie B1-B5 virus), parvovirus B19, human herpesvirus 6, adenovirus, HCV, HIV
  • Other viruses: EBV, CMV, echovirus, influenza A H1N1, SARS-CoV-2
• Bacterial
  • Acute rheumatic fever due to group A β‑hemolytic streptococcus
  • Corynebacterium diphtheriae (diphtheria)
  • Borrelia burgdorferi (Lyme disease)
  • Mycobacterium tuberculosis
  • Mycoplasma pneumoniae
• Fungal
  • Candida spp.
  • Aspergillus spp.
• Parasitic
  • Protozoan: Toxoplasma gondii, Trypanosoma cruzi (Chagas disease, which is common in South America)
  • Helminthic: Trichinella spp., Echinococcus spp.

Myocarditis is a rare complication of mRNA vaccination (e.g., COVID-19 vaccination); however, the incidence of myocarditis is higher following SARS-CoV-2 infection than after COVID-19 vaccination. ^[4][5]

Noninfectious ^[2][6]

• Connective tissue diseases; (e.g., systemic lupus erythematosus, sarcoidosis, dermatomyositis, polymyositis)
• Vasculitis (e.g., Kawasaki disease)
• Toxic myocarditis
  • Toxic substances (e.g., carbon monoxide, black widow venom)
  • Medications (e.g., sulfonamides; , immune checkpoint inhibitors), chemotherapy (e.g., anthracycline, doxorubicin)
  • Alcohol, cocaine
  • Radiation therapy
• Genetic variants associated with myocarditis (e.g., DSP variants) ^[2]
• Thymoma
• Vaccines (e.g., smallpox, SARS-CoV-2)

Patients with myocarditis typically have no ASCVD risk factors.

• Myocarditis is often asymptomatic.
• Development of symptoms may be acute (e.g., in fulminant myocarditis) or chronic.
• Features of upper respiratory or gastrointestinal viral infection (e.g., flu-like symptoms, fever, vomiting; ) may have been present in the preceding 1–2 weeks. ^[2]

Classic features of symptomatic myocarditis ^[2]

• Chest pain
  • Clinical features of acute coronary syndrome
  • Possible clinical features of pericarditis (e.g., pleuritic chest pain, pericardial friction rub)
• Clinical features of acute heart failure
  • Dyspnea, exercise intolerance, fatigue, S3 gallop
  • Clinical features of dilated cardiomyopathy (e.g., systolic murmur)
• Symptoms of cardiac arrhythmias
  • Palpitations, syncope, or presyncope
  • Arrhythmias include sinus tachycardia (often disproportionately high relative to body temperature), ventricular extrasystoles, and heart block with bradyarrhythmia.

Clinical manifestations of myocarditis are heterogeneous and nonspecific, ranging from asymptomatic myocarditis to fulminant myocarditis.

High-risk features include symptomatic heart failure, ventricular arrhythmias, and/or heart block.

Features of fulminant myocarditis ^[2]

Classic features of myocarditis, plus either of the following requiring intervention:

• Hemodynamic instability (e.g., cardiogenic shock)
• Electrical instability (e.g., Mobitz type II, ventricular tachycardia)

Suspect myocarditis in patients with classic clinical features and risk factors (e.g., recent infection, young age, no ASCVD risk factors).

Approach ^[2]

• Admit to hospital.
  • Consult specialists (e.g., cardiology, critical care) early.
  • Transfer urgently to an advanced heart failure center if fulminant myocarditis or high-risk features are present. ^[2]
• Order initial diagnostics.
  • 12-lead ECG
  • Laboratory studies (e.g., high-sensitivity troponin)
  • TTE
  • Coronary angiography if indicated to rule out differential diagnoses of chest pain.
• Obtain a definitive diagnostic study (i.e., cardiac MRI and/or endomyocardial biopsy) if myocarditis cannot be confirmed on initial diagnostic workup or to determine the underlying cause. ^[2]
• Consider additional studies to determine the underlying cause (e.g., HIV testing, diagnostics for Lyme disease).

Maintain a high index of suspicion for myocarditis in young adults and in patients with a relevant history (e.g., exposure to cardiotoxic agents or a recent viral infection). ^[2]

Arrange urgent transfer to an advanced heart failure center for patients with fulminant myocarditis or high-risk features. ^[2]

Diagnostic confirmation of symptomatic myocarditis ^[2]

• ≥ 1 of the following:
  • Chest pain
  • Heart failure and/or cardiogenic shock
  • Arrhythmias
• AND ≥ 1 of the following:
  • Elevated high-sensitivity troponin with supportive evidence (e.g., echocardiography findings consistent with myocarditis)
  • Endomyocardial biopsy findings consistent with myocarditis
  • Cardiac MRI findings consistent with myocarditis

Initial diagnostic workup

12-lead ECG ^[2][7]

ECG findings in myocarditis are often abnormal but nonspecific. ^[2]

• Sinus tachycardia
• Arrhythmias
  • Frequent atrial or ventricular premature beats
  • Supraventricular arrhythmia, e.g., atrial fibrillation
  • Ventricular arrhythmia, e.g., ventricular fibrillation
• Conduction abnormalities, e.g., AV block, bundle branch block
• Repolarization abnormalities
  • Nonspecific ST-segment changes
  • Diffuse, concave ST elevations
  • T-wave changes, e.g., T-wave inversion
• Low QRS voltage due to pericardial effusion or myocardial edema
• Abnormal Q waves

Laboratory studies ^[2][8]

Obtain routine studies for all patients. Additional studies to determine the underlying cause should be guided by clinical suspicion.

• Routine studies
  • ↑ Cardiac biomarkers
    • High-sensitivity troponin ^[2]
    • CK, CK-MB
    • BNP, NT-proBNP
  • ↑ ESR, ↑ CRP
  • CBC: leukocytosis (eosinophilia)
• Additional studies ^[7][9]
  • For infectious causes, e.g.:
    • Blood cultures in patients with fever
    • HIV testing
    • Viral hepatitis panel
    • Diagnostics for Lyme disease
  • For noninfectious causes, e.g.:
    • ANAs for suspected connective tissue diseases
    • Screening for toxic substances for suspected toxic myocarditis

Initial imaging ^[2]

• Transthoracic echocardiography
  • Obtain for all patients with suspected myocarditis. ^[2]
  • Supportive findings
    • Global or regional wall motion abnormality (systolic or diastolic)
    • Reduced ejection fraction
    • Ventricular dilation
    • Increased wall thickness
    • Pericardial effusion
    • Complications (e.g., endocavitary thrombus)
  • May also reveal alternative noninflammatory causes of acute heart failure (e.g., valvular dysfunction)
• Coronary angiography (invasive or CT)
  • Consider in all patients to exclude differential diagnoses (e.g., coronary artery disease, spontaneous coronary artery dissection). ^[2]
  • Alternative: Cardiac MRI with stress perfusion study can be used to rule out significant ischemic heart disease. ^[2]
• X-ray and/or CT chest
  • Commonly ordered to evaluate chest pain
  • Chest x-ray is often performed as an initial test in patients with suspected fulminant myocarditis. ^[9]
  • Findings are nonspecific (e.g., cardiac enlargement, pulmonary edema, pleural effusions).
• Advanced imaging
  • May be considered by specialists in specific situations (e.g., in patients with arrhythmias)
  • Options include resting FDG PET-CT scan, PET-MRI, and SPECT.

Definitive diagnostic studies ^[2]

Obtain a definitive diagnostic study (i.e., cardiac MRI and/or endomyocardial biopsy) if myocarditis cannot be confirmed on initial diagnostic workup or to determine the underlying cause.

Cardiac MRI ^[2]

• Used for stable patients
• Can be used to confirm myocarditis but cannot determine the underlying cause
• Used to identify sites for endomyocardial biopsy
• Findings
  • Functional and structural abnormalities similar to TTE findings
  • Myocardial edema, capillary hyperemia
  • Pericardial effusion or inflammation
  • Diffuse, late gadolinium enhancement

Proceed directly to endomyocardial biopsy for patients with suspected fulminant myocarditis and patients who do not responded to standard care for arrhythmia and/or congestive heart failure within 1–2 weeks. ^[9]

Endomyocardial biopsy ^[2]

Endomyocardial biopsy can be used to establish the underlying cause of myocarditis and guide treatment (e.g., antiviral therapy, systemic immunomodulators).

• Indications
  • Fulminant myocarditis
  • Symptomatic myocarditis with:
    • Impaired left ventricular function or symptomatic heart failure
    • Arrhythmias (e.g., high-degree atrioventricular block, ventricular arrhythmias)
    • Peripheral eosinophilia
  • Patients with asymptomatic myocarditis receiving immune checkpoint inhibitors
• Procedure: cardiac catheterization with ≥ 3 samples collected ^[9]
• Findings ^[2]
  • Histopathology
    • Myocyte necrosis (may be focal)
    • Inflammatory cell infiltrate (e.g., lymphocytic)
  • Immunohistochemistry (e.g., presence of CD3⁺T cells) increases sensitivity.
  • Viral PCR: possible detection of viral DNA or RNA (e.g., parvovirus B19, HSV) ^[7][10]

In addition to confirming the diagnosis of myocarditis, endomyocardial biopsy can be used to identify the underlying cause. ^[2]

• See “Differential diagnosis of chest pain.”
• Pericarditis
• Acute coronary syndrome (e.g., myocardial infarction)
• Arrhythmia-induced cardiomyopathy
• Cardiac amyloidosis

The differential diagnoses listed here are not exhaustive.

For hemodynamically unstable patients, see “Management of fulminant myocarditis.”

Approach ^[2]

• Admit for inpatient management (e.g., continuous cardiac monitoring).
• Consult relevant specialist teams (e.g., cardiology, rheumatology).
• Urgently transfer to an advanced heart failure center if high-risk features are present (e.g., hemodynamic instability, life-threatening arrhythmias, symptomatic heart failure).
• Start symptomatic treatment as needed.
• Treat the underlying cause.

Symptomatic treatment ^[2][11]

• Pain management
  • Consider NSAIDs and colchicine or patients with pericardial-type chest pain without heart failure or shock.
  • See “Treatment of pericarditis” for dosages.
• Management of acute heart failure
• Management of arrhythmias
  • Life-threatening arrhythmias can occur at any stage but often resolve after several weeks.
    • Temporary measures may be necessary (e.g., temporary pacemaker, wearable cardioverter-defibrillator).
    • Consider indications for a permanent cardiac implantable electronic device only after resolution of the acute phase.
  • See “Management of tachycardia” and “Management of bradycardia” for details.

Use NSAIDs with caution as they can increase sodium retention, exacerbate renal hypoperfusion, and may increase mortality in patients with myocarditis. ^[1][9]

Immediately consult cardiology for patients with fulminant myocarditis. Maintain a low threshold for starting treatment of refractory acute heart failure (e.g., with mechanical circulatory support). See also “Management of fulminant myocarditis.” ^[9]

Treatment of the underlying cause ^[1][11]

• Consider under specialist guidance and tailor to the patient.
• Review and consider stopping medications that can cause toxic myocarditis. ^[9][12]
• Treatment may include:
  • Systemic immunomodulators (e.g., for giant cell myocarditis, cardiac sarcoidosis): glucocorticoids (e.g., methylprednisolone), calcineurin inhibitors, IV immunoglobulin
  • Antiviral therapy
  • Antibiotic therapy (e.g., for Lyme carditis)

All treatment should be guided by a specialist.

Management of fulminant myocarditis ^[2][9]

Fulminant myocarditis is a rare and life-threatening manifestation of severe myocardial inflammation.

• Follow the ABCDE approach.
• Urgently transfer to an advanced heart failure center with a specialist myocarditis team.
• Admit to a cardiac or intensive care unit for management of cardiogenic shock (e.g., inotropic agents) or arrhythmia management (e.g., temporary pacing, wearable cardioverter-defibrillator).
• Obtain markers of end-organ damage.
  • ABG or VBG, lactate
  • LFTs
  • BMP
• Specific treatment depends on the cause and may include high-dose glucocorticoids.
• Consider consultation for durable interventions (e.g., permanent pacemaker, durable left ventricular assist device, heart transplantation) if there is no response to treatment.

Long-term management ^[2]

• Recommend avoiding aerobic activity for 3–6 months after diagnosis. ^[2]
• Follow-up at regular intervals; visits should include:
  • Clinical assessment
  • ECG
  • TTE
• Recommend genetic testing of first-degree relatives for patients with a causative genetic variant.

• Progression to dilated cardiomyopathy (∼ 15% of cases)
• Heart failure or sudden cardiac death; : probably due to ventricular tachycardia or fibrillation (common in adults < 40 years old)
• Acute and/or persistent arrhythmias
• Atrioventricular block
• Intracardiac thrombi formation, which can result in systemic embolization
• Concurrent pericarditis (perimyocarditis) that may lead to cardiac tamponade (associated with large pericardial effusions)

References:^[2]

We list the most important complications. The selection is not exhaustive.

• Most adults make a full recovery; however, progression to dilated cardiomyopathy may occur.
• Markers of poor prognosis ^[2]
  • Poor ventricular function, left bundle-branch block, reduced ejection fraction
  • Persistence of the virus in the myocardium
  • Persistent, chronic myocarditis ^[12]
• For prognosis in children, see “Myocarditis in children.”

Myocarditis in children

Epidemiology

• ♂ > ♀ ^[4]
• Incidence: 1–2 per 100,000 people per year ^[4][8]
• Most common in children < 4 years of age and adolescents 15–18 years of age ^[4]

Etiology ^[13]

• Similar to etiology of myocarditis in adults, including vaccine-associated myocarditis
• Additionally in children:
  • Multisystem inflammatory syndrome in children (MIS-C myocarditis)
  • Kawasaki disease

Myocarditis is a rare complication of COVID-19 vaccination in adolescents; however, the incidence of myocarditis is higher following SARS-CoV-2 infection than vaccination. ^[4][5]

Clinical features

• Similar to clinical features of myocarditis in adults ^[4][8][13]
• Preceding viral illness occurs in most affected children. ^[8][13]
• Gastrointestinal symptoms (e.g., vomiting, abdominal pain) are more common in children than in adults. ^[4]
• Initial presentation may be cardiac arrest. ^[13]

Diagnosis ^[4][8][13]

Diagnosis in children is similar to adult diagnostics of myocarditis, with the following considerations:

• There are no diagnostic criteria for children. ^[13]
• ECG changes are less common in MIS-C myocarditis than with other etiologies. ^[4]
• Avoid studies that pose higher risk to children than adults.
  • Cardiac MRI typically preferred over endomyocardial biopsy ^[2][4]
  • Minimize exposure to ionizing radiation (e.g., nuclear studies). ^[13]

Management ^[4][8][13]

Evidence to guide treatment in children is lacking. Management in children is similar to adult management of myocarditis, with the following considerations:

• Transfer patients to a facility with capacity for advanced pediatric cardiovascular care. ^[13]
• Systemic immunomodulators (e.g., glucocorticoids, intravenous immunoglobulin) are commonly used, but there is limited evidence for their effectiveness. ^[8][13]

Rapid hemodynamic deterioration can occur, particularly in patients with arrhythmias and/or borderline hypotension. ^[13]

Prognosis

• Heart failure: 27% ^[14]
• Transplantation: 4% ^[15]
• Mortality: ∼ 7% ^[14][16]
• Patients with vaccine-associated myocarditis typically recover fully. ^[4][17]