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Feb.15.2022

Myocarditis

Synopsis

Key Points

  • Myocarditis is inflammation of the myocardium, which typically manifests as chest pain, heart failure and/or arrhythmias; may be mild and self-limited or fulminant, with severe left ventricular dysfunction and need for hemodynamic support
  • Most commonly related to viral infection but can result from bacterial, fungal, or parasitic infection; cardiotoxins; hypersensitivity reactions to drugs; and systemic autoimmune disorders
  • Classic presentation of acute, nonfulminant myocarditis occurs within 1 to 4 weeks after onset of a viral syndrome; symptoms are nonspecific (eg, fatigue, decreased exercise tolerance, palpitations, pseudo-ischemic chest pain at rest) r1
  • Occurs across the age spectrum, but young adults are most commonly affected. Older patients may present with de novo heart failure, whereas infants and children may have a less specific presentation, with fever, lethargy, and poor feeding
  • In contrast to acute myocarditis, fulminant myocarditis presents with rapid onset of heart failure, progressing to cardiogenic shock within 1 or 2 days. Sudden cardiac death may occur r1r2
  • Initial diagnostic evaluation includes ECG (typically abnormal findings with a variety of ST-T wave changes and sometimes evidence of conduction abnormalities); chest radiograph; echocardiogram; and results of basic laboratory testing, including levels of cardiac troponin (typically elevated), brain natriuretic peptide (elevated if heart failure is present), and inflammatory biomarkers (nonspecific but often elevated) r1
  • Cardiac MRI can support the diagnosis and may obviate need for endomyocardial biopsy, especially if a combination of T-1– and T-2–based myocarditis markers are present on imaging r1r3r4
  • Treatment is primarily supportive, with appropriate management of heart failure, cardiogenic shock, and arrhythmias according to established clinical practice guidelines. Patients with fulminant myocarditis and cardiogenic shock usually require mechanical circulatory support with extracorporeal membrane oxygenation or a ventricular assist device, and cardiac transplant may be required
  • Specific, evidence-supported treatments directed against myocardial inflammation are lacking; however, high-dose IV immunoglobulin is commonly administered to children with myocarditis and may be considered for adults with myocarditis and refractory heart failure. Giant cell myocarditis and myocarditis associated with systemic autoimmune disease may respond to combination immunosuppressive therapies r5r6r7
  • Prognosis varies by disease presentation, histologic subtype, and age. Acute, nonfulminant myocarditis often resolves spontaneously without significant sequelae but may relapse or become chronic and progress to dilated cardiomyopathy, whereas fulminant myocarditis often has a good prognosis with full recovery if aggressively managed at onset, especially in children r8r9

Urgent Action

  • Admit hemodynamically stable, asymptomatic or mildly symptomatic patients suspected of having myocarditis and initiate clinical monitoring until a definitive diagnosis is reached. Condition may progress quickly to cardiopulmonary emergency, even in the setting of initially preserved systolic function r1
  • Admit hemodynamically unstable patients and patients with other severe presentation (eg, chest pain suggesting acute coronary syndrome, arrhythmia, heart failure) to ICU with hemodynamic monitoring, cardiac catheterization, and endomyocardial biopsy capability r1
  • Patients with fulminant myocarditis should be managed by physicians with expertise in critical care in a facility in which ventricular assist devices and extracorporeal membrane oxygenation are available to provide a bridge to transplant or to recovery r1

Pitfalls

  • Athletes with myocarditis may still be at risk for arrhythmia and sudden death despite resolution of acute myocardial inflammation and must be carefully evaluated before return to athletic activities r10

Terminology

Clinical Clarification

  • Myocarditis is inflammation of the myocardium, which typically manifests as chest pain, heart failure, and/or arrhythmias; may be mild and self limited or fulminant with severe left ventricular dysfunction and need for hemodynamic support r11
  • Most commonly related to viral infection but may be a result of bacterial, fungal, or parasitic infection; or cardiotoxins, drugs, and systemic autoimmune disorders
  • Clinical diagnosis of myocarditis may be established by noninvasive clinical criteria; definitive diagnostic confirmation has classically been established by endomyocardial biopsy

Classification

  • By symptom onset and disease phase r1
    • Acute (nonfulminant) myocarditis
      • Onset is less distinct than fulminant myocarditis r12
      • Symptoms are less severe and treatment with inotropes and vasopressors is typically not necessary
    • Fulminant myocarditis (about 10% of cases) r12
      • Abrupt new-onset unexplained class IV heart failure symptoms (identified as developing acutely over 1-2 days) with normal-sized or dilated left ventricle and hemodynamic compromise r1r13
      • Refractory sustained arrhythmias are common
      • Symptoms require treatment with inotropes or vasopressors or mechanical circulatory support
      • More common in children than adults r8
    • Chronic myocarditis r14
      • Characterized by cardiac repair and remodeling
      • Chronic inflammation and fibrosis may occur, leading to dilated cardiomyopathy and irreversible systolic and diastolic dysfunction d1
  • By type of myocardial inflammatory cell infiltrate (may also have distinct clinical presentations) r1
    • Common
      • Lymphocytic myocarditis r1
        • Typically presents as acute or fulminant myocarditis
        • Resolves spontaneously or may progress to chronic myocarditis and ultimately to dilated cardiomyopathy d1
    • Rare
      • Giant cell myocarditis r15
        • Most cases are in young, healthy people; a few cases are associated with systemic autoimmune disease
        • Presentation is aggressive but more subtle than fulminant myocarditis
        • Can deteriorate very quickly into cardiogenic shock and multiorgan failure; short survival time with standard therapy
        • However, relatively favorable outcome at 12 months when patients are treated with high-dose multiagent immunosuppressive therapy r16
      • Eosinophilic myocarditis r17
        • Several distinct associations, with presentations ranging from minimally symptomatic to fulminant
          • Idiopathic (large proportion of cases)
          • Allergic eosinophilic: caused by hypersensitivity reaction to a foreign antigen, typically a drug
          • Associated with immune-related disorders: eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome), hypereosinophilic syndrome
          • Associated with infections
          • Associated with pregnancy or cancer (very rare)

Diagnosis

Clinical Presentation

History

  • Antecedent infection is common but may have been unrecognized by the patient
    • Nearly any virus (and less commonly, a wide variety of other pathogens) may cause myocarditis; symptoms vary widely and may include fever, headache, respiratory symptoms, and/or rash c1c2c3c4
  • Recent use of new drug associated with myocarditis or recent vaccine administration (especially tetanus) may suggest hypersensitivity as the mechanism of myocardial inflammation
  • The patient may have a known autoimmune or inflammatory disease associated with myocarditis, or suggestive symptoms may be present (eg, rash, joint pain or swelling, preexisting respiratory symptoms, ocular symptoms suggesting uveitis) c5c6
  • Presentation varies greatly and ranges from mild chest pain and palpitations to cardiogenic shock and ventricular arrhythmia with sudden death
    • Classic presentation is acute, nonfulminant syndrome occurring within 1 to 4 weeks after onset of a viral syndrome r1
      • Symptoms may be nonspecific
        • Fatigue; decreased exercise tolerance c7
        • Dyspnea with exertion c8
        • Palpitations c9
        • Chest pain at rest c10
        • Unexplained syncope c11
      • May present with de novo congestive heart failure, especially in middle-aged or older adults c12
    • Fulminant myocarditis presents with rapid onset of heart failure, progressing to cardiogenic shock
      • When associated with prodromal viral infection, usually occurs within 2 weeks of infection r15
      • Severe heart failure symptoms develop abruptly over 1 to 2 days r1
      • May present with sustained arrhythmias c13
  • Presentation in children varies with age
    • Newborns and infants are typically more severely affected than older children and adults and are more likely to present with circulatory shock and acute dilated cardiomyopathy r18c14c15d1
    • Less severe, nonspecific presentations include fussiness, lethargy, fever, poor feeding and feeding difficulties, vomiting, and difficulty breathing c16c17c18c19
    • Children older than 2 years may have chest pain, abdominal pain, myalgias, cough, and lethargy r8c20c21c22

Physical examination

  • Patients with acute, nonfulminant myocarditis present with a range of manifestations; patients may appear well with normal findings on physical examination or may have physical signs of myocarditis
    • Rapid or irregular pulse, or both c23c24
    • In infants, tachypnea and diaphoresis during feeding with poor weight gain c25c26c27
    • In children, tachycardia, tachypnea, and abnormal respiratory examination results are most common when myocarditis is the ultimate diagnosis; fever may be present c28c29
    • If congestive heart failure develops, expected findings may include:
      • Elevated jugular venous pressure c30
      • Rales and wheezes c31c32
      • S₃ gallop c33
      • Hepatomegaly c34
      • Peripheral edema c35
  • Expected findings with development of fulminant myocarditis:
    • Cardiopulmonary examination reflects heart failure and pulmonary edema c36c37
    • New cardiac murmur (mitral or tricuspid regurgitation) may appear c38
    • Altered mental status, tachycardia, hypotension, and evidence of poor distal perfusion with cardiogenic shock c39c40

Causes and Risk Factors

Causes

  • Myocardial inflammation resulting from a wide range of inciting events
    • Viral infection is the most common antecedent event; cases without other identified cause are usually considered to be secondary to undocumented viral infection c41
      • Mechanism is an immune response leading to organ dysfunction
      • Common viral causes include adenoviruses, enteroviruses (especially coxsackievirus), parvoviruses (especially B19V), influenza viruses, measles virus, and human herpesvirus 6 c42c43c44c45c46c47c48
      • Less common viral infections include cytomegalovirus, HSV, hepatitis C virus, HIV, and Epstein-Barr virus c49c50c51c52
      • Has been associated with COVID-19 and COVID-19 vaccines. The frequency and prognostic impact of COVID-19–mediated myocarditis is uncertain r19
    • Other infectious agents
      • Bacterial infection as a cause is less common than viral infection
        • Staphylococcus, Streptococcus, Pneumococcus, Meningococcus, Gonococcus, Salmonella, Brucella, and Nocardia species; Corynebacterium diphtheriae, Haemophilus influenzae, Mycobacterium tuberculosis, and Mycoplasma pneumoniaec53c54c55c56c57c58c59c60c61
        • Spirochetal infections, especially Borrelia burgdorferi (Lyme carditis) and Leptospira species c62c63
        • Rickettsial infections, including Rickettsia rickettsii, Rickettsia tsutsugamushi, and Coxiella burnetiic64c65c66
      • Fungal infection
        • Aspergillus, Actinomyces, Blastomyces, Candida, Coccidioides, Cryptococcus, Histoplasma, Mucormycoses, and Sporothrix c67c68c69c70c71c72c73c74
      • Parasitic infection (associated with eosinophilic myocarditis)
        • Trypanosoma cruzi, Toxoplasma gondii, Trichinella spiralis, Echinococcus granulosus, and Taenia solium c75c76c77c78c79
        • Entamoeba and Leishmania species c80c81
    • Exposure to myocardial toxins
      • Chemotherapeutic agents (eg, anthracyclines, cyclophosphamide) c82
      • Stimulants such as amphetamines (excluding amphetamine salts used to treat attention-deficit/hyperactivity disorder) and cocaine c83c84
      • Catecholamine excess related to pheochromocytoma c85
      • Heavy metals c86
      • Physical agents, such as radiation and electric shock
    • Hypersensitivity states
      • Drug-induced
        • Associated with use of antiseizure agents (primarily carbamazepine) and antipsychotics (primarily clozapine) as well as a number of antibiotics c87c88
          • Most cases of myocarditis develop early in the course of drug use; when related to clozapine use, manifestations may occur up to 2 years after initiation of drug therapy r8
          • Amongst antibiotics, minocycline and β-lactam antibiotics are most frequently associated c89
        • Associated with the use of immune checkpoint inhibitors (treatment with anti-PD1, anti-CTLA4, or both) for cancer therapy
          • Most cases occur early in therapy, after 1 or 2 doses r20
      • Vaccine-induced; noted after tetanus and smallpox vaccines in case reports c90c91
    • Myocardial inflammation may occur as a component of many systemic autoimmune, inflammatory, and other systemic disease states
      • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) c92
      • Granulomatosis with polyangiitis (Wegener granulomatosis) c93d2
      • Hypereosinophilic syndrome c94
      • Systemic lupus erythematosus c95d3
      • Scleroderma c96
      • Polymyositis c97d4
      • Sarcoidosis c98d5
      • Behçet disease c99d6
      • Rheumatoid arthritis c100d7
      • Kawasaki disease c101d8
      • Inflammatory bowel disease c102d8
      • Myasthenia gravis c103d9
      • Type 1 diabetes mellitus c104d10
      • Thyrotoxicosis c105d11
      • Malignancy c106

Risk factors and/or associations

Age
  • Most frequent in young adults; however, may affect people of all ages c107c108c109c110c111
  • In children, there is a bimodal distribution by age: infancy and mid-teenage years c112c113c114
  • Fulminant myocarditis of unknown origin is more common in children and neonates
Sex
  • Men more frequently have myocarditis diagnosis and have a worse prognosis than women c115c116
Other risk factors/associations
  • Genetic (familial) association with dilated cardiomyopathy or myocarditis (based on current diagnostic criteria)

Diagnostic Procedures

Primary diagnostic tools

  • Suspect myocarditis based on clinical presentation after exclusion of alternate causes for presenting manifestations
    • Most common presentation patterns include chest pain, arrhythmia, heart failure, or all 3
    • Other conditions with similar patterns of presentation include angiographically significant coronary artery disease, valvular heart disease, congenital heart disease, and hypertensive cardiomyopathy
  • First line evaluation for patients who present with clinically suspected myocarditis
    • The following initial evaluation is recommended for all patients: r1
      • 12-lead ECG; consider Holter monitor r1c117c118
      • Chest radiograph c119
      • Transthoracic echocardiogram r1c120
      • Inflammatory biomarkers (ie, erythrocyte sedimentation rate and C-reactive protein; WBC count) r1c121c122c123
      • Cardiac troponin level r1c124
    • The following tests may be recommended in consultation with cardiologist based on individual clinical presentation:
      • Cardiac MRI r1c125
      • Focused laboratory evaluation r1
        • Brain natriuretic peptide or NT-proBNP (N-terminal-proBNP) when heart failure is suspected but uncertain r1c126
        • Routine viral serologies are not recommended; however, serologies to identify suspected hepatitis C virus infection, suspected rickettsial infection, Lyme disease in endemic areas, and HIV in high-risk patients are recommended r1c127c128c129
        • Testing for associated systemic disease if suggested by presentation (eg, autoimmune disorder such as systemic lupus erythematosus) c130
  • Clinical diagnosis of myocarditis can be made with the following clinical criteria: r1
    • 1 or more compatible clinical presentations, and
    • 1 or more additional diagnostic criteria (ie, a newly abnormal compatible ECG or Holter monitor result, elevated cardiac troponin level, functional or structural abnormality on cardiac imaging, or specific pattern on cardiac MRI)
    • If asymptomatic (ie, compatible clinical presentation is absent), must meet 2 diagnostic criteria from different categories (ECG, laboratory, imaging)
  • Guidelines differ regarding some aspects of second-tier evaluation for patients with clinical myocarditis, particularly indications for confirmatory endomyocardial biopsy
    • European guidelines recommend that all patients who fulfill the criteria for clinically suspected myocarditis also undergo the following evaluations: r1
      • Coronary angiography (to exclude ischemic heart disease) c131
        • Important when clinical presentation is compatible with acute coronary syndrome
      • Endomyocardial biopsy for definitive diagnosis c132
        • Considered the gold standard for diagnosis and, in some cases, can identify underlying cause
    • American College of Cardiology/American Heart Association guidelines accept more selective use of endomyocardial biopsy than European guidelines r3r5r21
      • Noninvasive diagnostic criteria can be used to diagnose suspected or probable acute myocarditis when diagnosis is suspected and endomyocardial biopsy is infeasible or not clearly indicated r3
      • Biopsy is strongly recommended (Class I recommendation) only for patients with severe presentation in the following scenarios: r5
        • Patients with new-onset heart failure of less than 2 weeks' duration associated with a normal-sized or dilated left ventricle and hemodynamic compromise
        • New-onset heart failure of 2 weeks' to 3 months' duration associated with a dilated left ventricle and new ventricular arrhythmias, second- or third-degree heart block, or failure to respond to usual care within 1 to 2 weeks
    • American College of Cardiology Foundation/American Heart Association heart failure guidelines recommend endomyocardial biopsy when seeking a specific diagnosis will likely influence therapy r21
      • Biopsy is suggested for most patients with presentation consistent with giant cell myocarditis, eosinophilic myocarditis, and myocarditis associated with a systemic autoimmune/inflammatory condition (eg, systemic lupus erythematosus, cardiac sarcoid) because immunosuppressive therapy may be beneficial r22

Laboratory

  • Laboratory studies are indicated for all patients with suspected myocarditis to support diagnosis r1
    • Markers of inflammation and infection
      • Erythrocyte sedimentation rate, C-reactive protein levels, or both r1c133c134
        • May be elevated with myocarditis
        • Nonspecific, often elevated with acute pericarditis as well
      • WBC count r23c135
        • Eosinophilia suggests possibility of underlying hypersensitivity reaction (eg, to a drug) or another type of eosinophilic myocarditis; however, peripheral eosinophilia is absent in 25% of patients with eosinophilic myocarditis r17
    • Troponin levels r1c136
      • Troponin I and troponin T may be elevated in adults and children with acute myocarditis r8c137c138
    • Brain natriuretic peptide or NT-proBNP (N-terminal-proBNP) levels r1c139
      • Often elevated
      • Can help to distinguish respiratory symptoms of cardiac (versus pulmonary) origin, if elevated

Imaging

  • Chest radiograph c140
    • Appearance may be normal or show cardiomegaly and pulmonary vascular congestion if heart failure is present
  • Cardiovascular MRI c141
    • Indicated for clinically stable patients to support diagnosis of myocarditis r1r4
    • Requires breath-holding sequences; infants and young children (and those who are severely ill) require intubation and mechanical ventilation
    • Can support but not definitively exclude diagnosis; may not detect less severe forms of disease r9
    • Best for identifying acute, active inflammation and less well established for identifying chronic myocarditis r1
      • Highest sensitivity exists for diagnosis of acute inflammation if performed within 2 weeks of symptom onset r18
    • Utility is limited in patients with frequent ventricular and atrial arrhythmias r24
    • Use Lake Louise criteria; consensus-based recommendation for modification of original criteria is availabler4r1
      • Strong evidence with increased specificity for myocardial inflammation exists when study shows both myocardial edema and other markers of inflammatory myocardial injury
      • Findings consistent with myocardial inflammation include: r4
        • Myocardial edema
        • Markers of inflammatory myocardial injury
          • T1-based criteria include:
            • Increased myocardial T1 relaxation time
            • Increased extracellular volume
            • Late gadolinium enhancement
              • Late gadolinium enhancement correlates with a greater risk of assist device implantation, transplant, or death in both childrenr25 and adults r4
          • T2-based criteria include:
            • Global or regional increase of myocardial T2 relaxation time
            • Increased signal intensity in T2-weighted images
          • Note that presence of positive T1- and T2-based markers increases specificity for diagnosing acute myocardial inflammation; however, having only 1 marker may still support a diagnosis of acute myocardial inflammation but with less specificity r4
      • Supportive evidence includes presence of left ventricle dysfunction or pericardial effusion r4
    • Indications for repeating cardiovascular MRI in 1 to 2 weeks include: r1
      • Failure to meet full criteria
      • No criteria met in patient presenting with very recent onset of symptoms with strong clinical suspicion for myocarditis

Functional testing

  • 12-lead ECG r1c142
    • Indicated for all patients with clinically suspected myocarditis r1
    • Neither specific nor sensitive for myocarditis r1
    • Findings typically abnormal r1
    • Most common findings in acute phase of clinical myocarditis are nonspecific and include: r18
      • Sinus tachycardia with low-voltage QRS complexes
      • T-wave changes (T-wave inversion)
    • Other findings may include:
      • ST-T segment elevation is typically concave and diffuse without reciprocal changes r1
      • ST segment depression may occur r1
      • New Q waves r4
      • Reduced R wave height r1
      • PR depression may resemble findings associated with acute myocardial infarction or pericarditis
    • Conduction delays and arrhythmias are common, occurring in more than half of patients r8r9
      • Conduction delays may include first- to third-degree atrioventricular block, bundle branch block, intraventricular conduction delay (wide QRS) r1
      • Arrhythmias may include frequent premature ventricular contractions, supraventricular tachycardia, sinus arrest, atrial fibrillation, ventricular tachycardia or fibrillation, and asystole r1
      • Atrioventricular conduction delay in the context of mild left ventricular dilation suggests Lyme carditis (often associated with complete heart block), cardiac sarcoidosis, or giant cell myocarditis r1r26
      • Myocarditis due to Trypanosoma cruzi may be associated with complete heart block
    • Negative predictors for survival include QRS prolongation, northwest axis deviation, and new left bundle branch block r1
  • Holter monitor c143
    • Consider if there are symptoms or ECG signs of arrhythmia
      • Tachyarrhythmias are often nonsustained and typically do not cause hemodynamic compromise except in fulminant disease r8
      • Reported ventricular arrhythmia occurrence is more frequent in myocarditis due to HIV, Borrelia burgdorferi in Lyme disease, Corynebacterium diphtheriae, Trypanosoma cruzi, giant cell myocarditis, and cardiac sarcoid r22
      • Conversely, ventricular arrhythmias are rare in myocarditis associated with systemic lupus erythematosus and other systemic autoimmune diseases r22
  • Transthoracic echocardiogram r1c144
    • Indicated for all patients with clinically suspected myocarditis as a useful measurement tool of cardiac chamber sizes, wall thickness, and systolic and diastolic function r1
      • Although it is not diagnostic of myocarditis, it can assess for other causes of heart failure
    • Findings vary and may include:
      • Regional wall motion abnormalities
      • Diastolic dysfunction with preserved ejection fraction
      • Global ventricular dysfunction
      • Ventricular thrombi (up to 25% of patients) r8
      • Pericardial effusion
    • Marked left ventricular dilation and normal wall thickness is often noted in patients with acute myocarditis
    • Nondilated, thickened, and hypocontractile left ventricle is often noted in patients with fulminant myocarditis
      • Right ventricular dysfunction is uncommon; however, when present, it is a strong predictor of the need for heart transplant r8

Procedures

Endomyocardial biopsy c145
General explanation
  • Tissue samples are taken from right or left ventricle for light microscopy, viral polymerase chain reaction, and immunohistochemistry r1
  • Performed via cardiac catheterization
  • At least 3 samples are obtained to decrease sampling error r1
  • Peripheral blood sample is obtained at time of biopsy to exclude systemic viral infection r1
Indication
  • Gold standard for diagnostic confirmation; however, procedure is no longer routine in most patients when clinical diagnosis is clear and results are not anticipated to alter management r1
Complications
  • Low complication rate (less than 1%) if performed by experienced team r1
    • Major complications are rare and include cardiac rupture, cardiac tamponade, and complete atrioventricular block r22r27
    • Minor complications include pericardial effusion, conduction abnormalities, and arrhythmias r27
    • Complications are more frequent in pediatric patients, with an increased risk of ventricular perforation r18r28
Interpretation of results
  • May characterize underlying cause and type of inflammation (eg, giant cell, eosinophilic, sarcoidosis), which will then help guide specific therapy (eg, immunosuppression, antimicrobials) r1
  • Techniques to determine underlying cause include histology, immunohistochemistry, and viral genome analysis r1r9
  • Definitive diagnosis is established by histologic and immunohistochemical criteria (WHO/International Society and Federation of Cardiology Task Force) r1
    • Histologic criteria
      • Inflammatory infiltrates in the myocardium
      • Nonischemic necrosis
      • Myocyte degeneration
    • Immunohistochemical criteria
      • 14 leukocytes/mm² or higher, including up to 4 monocytes/mm²
      • 7 CD3-positive T-lymphocytes/mm² or higher
  • Sampling error may lead to false-negative results r22

Other diagnostic tools

  • Clinical diagnostic criteria
    • Classically, diagnosis has been considered definitive only with histologic and immunohistochemical evidence from endomyocardial biopsy
    • The European Society of Cardiology Working Group on Myocardial and Pericardial Diseases noninvasive diagnostic criteria for clinically suspected myocarditis include: r1
      • At least 1 clinical presentation with at least 1 of the specific diagnostic criteria, or at least 2 specific diagnostic criteria from different categories if patient is asymptomatic
        • Clinical presentations
          • Acute chest pain, either pericarditic or pseudo-ischemic
          • New onset of or worsening dyspnea at rest or during exercise and/or fatigue, with or without other signs of heart failure
          • Palpitation or unexplained arrhythmia symptoms
          • Syncope
          • Aborted sudden cardiac death
          • Unexplained cardiogenic shock
        • Specific diagnostic criteria
          • Category 1: newly abnormal ECG finding or Holter/stress test features or both, with any of the following:
            • Atrioventricular block (first-, second-, or third-degree) or bundle branch block
            • ST-T wave changes (ST elevation or non-ST elevation, T-wave inversion)
            • Reduced R wave height
            • Abnormal Q waves
            • Intraventricular conduction delay
            • Sinus arrest
            • Low voltage, frequent premature beats
            • Ventricular tachycardia, ventricular fibrillation, or asystole
            • Supraventricular tachycardia
            • Atrial fibrillation
          • Category 2: elevated troponin T or troponin I levels (indicating myocardial cytolysis)
          • Category 3: functional and structural abnormalities on cardiac imaging
            • Regional wall motion or global systolic or diastolic function abnormality; may be accompanied by:
              • Ventricular dilation
              • Increased wall thickness
              • Pericardial effusion
              • Endocavitary thrombi
          • Category 4: edema or classical myocarditis pattern on late gadolinium enhancement on cardiac MRI

Differential Diagnosis

Most common

  • Newborns, infants, and younger children r18
    • Critical coarctation of the aorta r29c146
      • Congenital narrowing of the proximal thoracic aorta (typically as stenosis in the juxtaductal position), hypoplasia of the transverse aortic arch, or stenosis of the abdominal aorta c147
      • Heart failure results during ductal closure when coarctation is significantly stenotic owing to acute development of left ventricular outflow obstruction; manifestations closely resemble those of myocarditis
      • Decreased femoral arterial pulse volume compared with right brachial artery, raised upper limb blood pressures compared with lower limb, and differential cyanosis raise concern of coarctation of the aorta
      • Response to prostaglandin infusion is consistent with a ductal-dependent congenital heart lesion
      • Differentiate and diagnose with transthoracic echocardiography
    • Anomalous origin of the left coronary artery from pulmonary artery r30c148
      • Congenital abnormality in which the left coronary artery arises from the pulmonary artery rather than the aorta
      • Manifestations often develop with decrease in pulmonary arterial resistance in the first few weeks of life, presenting with symptoms and signs of congestive heart failure similar to myocarditis
      • Diagnoses are difficult to differentiate on clinical grounds alone; ancillary studies (eg, echocardiogram) are often required to aid in differentiation
      • Differentiate with echocardiography and identification of anomalous origin of the coronary artery; angiography is the gold standard for diagnostic confirmation
    • Sepsis r31c149d12
      • Presents similarly in neonates and infants, with nonspecific manifestations such as tachypnea, respiratory distress, tachycardia, poor perfusion, lethargy, fussiness, and poor feeding; cardiac and other organ dysfunction may develop
      • Sepsis may be more likely to result in temperature instability and abnormally high or low WBC indices than myocarditis; however, depending on underlying cause, fever may be a manifestation of myocarditis
      • Diagnoses are difficult to differentiate on clinical grounds alone; ancillary studies (eg, echocardiogram, cultures) are often required to aid in differentiation
      • Diagnose sepsis with blood cultures and clinical course (eg, response to empiric antibiotics)
    • Hypoglycemia r32c150
      • Presents similarly in neonates and infants, with nonspecific manifestations such as tachypnea, tachycardia, lethargy, fussiness, and poor feeding
      • Diagnoses are difficult to differentiate on clinical grounds alone; ancillary studies (eg, serum glucose) are required to aid in differentiation
      • Diagnose hypoglycemia by serum glucose level
      • Plasma glucose level defining hypoglycemia is not rigorously agreed on in the first 72 hours of life; levels below about 45 mg/dL are generally considered abnormal, r33especially when accompanied by symptoms of hypoglycemia; by 72 hours of life, normal glucose levels reach 60 to 100 mg/dL
  • Older children and adults r18
    • Pericarditis r34c151d13
      • Acute or chronic inflammation of the pericardium, most commonly caused by a virus
        • Other causes include nonviral infections, autoimmune diseases, uremia, previous myocardial infarction, cardiac surgery, malignancies, radiation, medications, and trauma
      • Presentation may be similar to myocarditis with difficulty breathing, chest pain, and diminished cardiac output secondary to pericardial effusion and tamponade r1
      • Characteristic chest pain associated with pericarditis may help differentiate conditions; chest pain exacerbated by cough, inspiration, and supine positioning that improves with leaning forward suggests pericarditis r35
      • Presence of a pericardial friction rub is pathognomonic for pericarditis but not universally appreciable on examination; presence of pulsus paradoxus suggests tamponade or constrictive pericarditis; Beck triad (ie, hypotension, increased jugular venous pressure, muffled heart sounds) suggests tamponade physiology r35
      • Acute pericarditis may be diagnosed with 2 of 4 manifestations: chest pain, pericardial friction rub, characteristic ECG findings (diffuse ST elevation and PR depression), and pericardial effusion on echocardiogram
      • Cardiac MRI may be required to differentiate the 2 conditions if diagnosis remains uncertain
    • Cardiomyopathy r36r37c152d1
      • Heterogeneous group of myocardial disorders, typically characterized by either ventricular hypertrophy or dilation
      • Potential causes of cardiomyopathy are diverse and include hypertensive, genetic (familial), inflammatory, metabolic, endocrine, toxic, and infiltrative processes
      • Presentation reflects underlying pathology; dilated cardiomyopathy typically presents as heart failure or reduced cardiac output, whereas hypertrophic cardiomyopathy may present with chest pain, syncope, arrhythmias, or sudden death
      • ECG findings are often abnormal and may vary depending on cause; typical findings include left ventricular hypertrophy, various left atrial abnormalities, possibly pathologic Q waves, and arrhythmia (eg, atrial fibrillation)
      • Differentiate by clinical presentation and cardiac evaluation beginning with ECG and echocardiography; confirmation of underlying cause involves a focused secondary evaluation guided by clinical presentation
    • Acute coronary syndromes c153d14
      • Group of clinical symptoms associated with acute myocardial ischemia, including unstable angina and myocardial infarction (ST-elevation myocardial infarction and non-ST-segment elevation myocardial infarction), usually resulting from coronary artery disease r38
      • Presenting patterns in patients with angina that mimic myocarditis include chest pain, dyspnea, syncope, and fatigue r1r38
      • ECG findings (eg, ST-segment elevation or depression, T-wave inversion, Q waves) may be similar between conditions; findings in patients with myocarditis may be diffuse or reflect coronary or noncoronary distribution pattern r2
      • Cardiac troponin levels may be elevated in both conditions
      • Differentiate by clinical presentation, clinical course, and ancillary test findings, including echocardiogram; cardiac MRI; and radionucleotide testing, coronary angiography, or both, depending on individual presentation r39
      • Diagnostic confirmation of myocardial infarction usually involves a combination of factors, including consistent clinical presentation, ECG findings, supportive biomarker profile, and imaging studies r40
    • Endocarditis r41c154d15
      • Infectious or noninfectious (eg, lupus, malignancy) development of cardiac vegetations usually involving cardiac valves d3
      • May present similarly with congestive heart failure; fever may be present
      • In contrast to patients with myocarditis, there may be evidence of major (arterial) embolization of vegetations as well as other classic stigmata of endocarditis, such as Janeway lesions, conjunctival hemorrhage, Osler nodes, or Roth spots. Murmur is suggestive of endocarditis
      • Differentiate by clinical presentation and ancillary testing; cardiac imaging with echocardiogram differentiates conditions
      • Diagnosis of endocarditis is based on Duke criteria; blood cultures remain critical to diagnosis of infectious endocarditis

Treatment

Goals

  • Stabilize and support adequate hemodynamics r1
  • Manage causative infection or condition when possible r1

Disposition

Admission criteria

Admit hemodynamically stable, asymptomatic, or mildly symptomatic patients suspected of having myocarditis and initiate clinical monitoring until a definitive diagnosis is established r1

  • Condition may progress quickly to cardiopulmonary emergency even if systolic function is initially preserved
Criteria for ICU admission
  • Admit hemodynamically unstable patients and patients with other severe presentation (eg, chest pain that suggests acute coronary syndrome, arrhythmia, heart failure) to an ICU with hemodynamic monitoring, cardiac catheterization, and endomyocardial biopsy capability r1

Recommendations for specialist referral

  • Consult cardiologist for all patients with myocarditis for further diagnostic and treatment recommendations
  • Patients with fulminant myocarditis should be managed by a cardiologist and team of other physicians with expertise in critical care in a facility with ventricular assist device and extracorporeal membrane oxygenation capability r1
  • Consider consultation with an infectious disease specialist in patients with suspected underlying infectious cause for diagnostic and treatment recommendations
  • Consult a rheumatologist to direct appropriate immunosuppressive therapy for patients with underlying systemic autoimmune and inflammatory disease processes

Treatment Options

Treat patients symptomatically based on standard therapeutic approaches for the primary presentation (ie, heart failure, arrhythmia) r24

  • Treatment of heart failure is guided by the patient's hemodynamic stability
    • Hemodynamically unstable patients
      • Admit patients to an ICU capable of respiratory and mechanical cardiopulmonary support for management of heart failure r1
      • Manage according to current clinical practice guidelines for heart failure and cardiogenic shock r11r21r42r43r44
      • Consider extracorporeal membrane oxygenation or ventricular-assist devices for acute or fulminant cases with cardiogenic shock and severe ventricular dysfunction r1
      • Consider cardiac transplant if pharmacologic support and mechanical assistance are unsuccessful in stabilizing the patient r1
        • Cardiac transplant is generally not recommended for patients in the acute phase of the disease, as recovery is possible; however, transplant may be considered if the patient cannot otherwise be stabilized
    • Hemodynamically stable patients r1
      • Treat patients with standard therapy for heart failure, including diuretics, ACE inhibitor, or angiotensin-receptor blockade, and β-adrenergic blockade r1r21r42
      • Consider aldosterone antagonists for patients with persistent heart failure unresponsive to other treatments r21r42
  • Manage arrhythmias (which range from conduction delays to life-threatening ventricular tachycardia or ventricular fibrillation) according to current clinical practice guidelines; therapies may include antiarrhythmic drugs and device therapies r1r45r46r47r48
    • No evidence to support cause-based strategy for arrhythmia treatment r22
    • Temporary pacing may be needed for complete atrioventricular block r1
    • Indications for cardiac defibrillator device
      • For patients with ventricular tachycardia or ventricular fibrillation, consider bridging the period to recovery using a wearable cardiac defibrillator r1
      • For patients who have experienced cardiac arrest caused by ventricular fibrillation or after symptomatic ventricular tachycardia, an implantable cardiac defibrillator device may be necessary r9
      • Consider placement of an implantable device in patients who have giant cell myocarditis with ventricular fibrillation or hemodynamically unstable ventricular tachycardia if meaningful survival longer than 1 year is expected r48

Specific therapies may be indicated in certain situations

  • Viral myocarditis
    • IV immunoglobulin
      • Use is controversial because data are limited and inconclusive r6r7
      • Some experts administer IV immunoglobulin to children with acute myocarditis; consult a pediatric cardiologist for guidance
    • Antiviral therapies
      • Use of such therapies is not routine in either children or adults
      • Data are limited and additional research is needed
      • When the viral pathogen is known or strongly suspected, antiviral drugs with known efficacy against that pathogen are appropriate
        • Ganciclovir has been used successfully to treat severe cytomegalovirus myocarditis r49
        • Oseltamivir is typically given for presumed or confirmed concurrent  influenza infection r50
    • Glucocorticoids
      • Data are limited and additional research is needed
      • May improve left ventricular ejection fraction in patients with viral myocarditis based on small trials of poor methodologic quality; mortality reduction has not been consistently proved r51
  • Other infectious causes of myocarditis r1
    • Appropriate pathogen-directed therapies to eradicate underlying infection are indicated although there may be little direct effect on the myocardium
  • Giant cell myocarditis
    • Immunosuppression
      • Data suggest that patients with biopsy-confirmed giant cell myocarditis benefit from therapy with immunosuppressive agents, alone and in combination r1r52
      • Combined immunosuppression (regimen of 2-4 drugs, which included cyclosporine) resulted in 69% transplant-free survival at 1 year, 58% at 2 years, and 52% at 5 years, although malignant ventricular rhythms recurred or persisted in most of these patients r53
      • Rule out active infection using polymerase chain reaction on endomyocardial biopsy samples before beginning immunosuppression therapy r1
  • Myocarditis with known eosinophilic histology and myocarditis associated with known systemic autoimmune or inflammatory condition
    • Identification of an underlying condition is relevant to treatment selection
      • Myocarditis associated with extracardiac autoimmune disease (eg, systemic lupus erythematosus, eosinophilic granulomatosis, polyangiitis) or inflammatory disease (eg, cardiac sarcoid) with no evidence of viral infection r1r54
        • Must have a negative viral polymerase chain reaction result on biopsy specimen before treatment
        • Glucocorticoids with or without an immunosuppressive agent are the cornerstone of treatment
        • Consider a tailored immunosuppression/immunomodulation regimen, depending on the phase of the disease and underlying autoimmune or immune-mediated condition r55
      • Parasitic infection: appropriate antiparasitic agent

Drug therapy

  • IV immunoglobulin c155
    • Consider for viral myocarditis in children (often given routinely despite lack of convincing evidence of efficacy) r1
      • Immune Globulin (Human) Solution for injection; Neonates: 2 g/kg IV as a single dose.
      • Immune Globulin (Human) Solution for injection; Infants, Children, and Adolescents: 2 g/kg IV as a single dose.

Nondrug and supportive care

Discontinue any drug implicated as a possible cause of hypersensitivity myocarditis

Instruct all patients to restrict physical activity throughout the acute phase of illness r1c156

  • Regardless of age, sex, and left ventricular function, athletes with myocarditis (probable or confirmed) should not participate in competitive or leisure sports until: r10
    • Resolution of all symptoms, and:
    • Results of retesting are normal (resting echocardiogram, 24-hour Holter monitoring, and an exercise ECG) performed no less than 3 to 6 months after the initial illness, and: r10
    • European guidelines recommend that the nonparticipation period should be 6 months from onset of illness r1
  • Nonathletes should also restrict physical activity for at least 6 months r1r10
  • Reassess the patient after resolution of clinical presentation before releasing them to resume competitive sports r1
Procedures
Mechanical circulatory support c157
General explanation r56
  • Provides cardiopulmonary support when the heart can no longer provide adequate physiologic support. Used as a bridge to recovery or a bridge to cardiac transplant
    • Extracorporeal membrane oxygenation c158
      • Can be either venovenous (provides oxygenation alone) or venoarterial (for oxygenation and circulatory support); venoarterial circuit (often femoral vein to femoral artery) is used for fulminant myocarditis
      • Venoarterial circuit includes a continuous-flow centrifugal pump and a membrane oxygenator for gas exchange
      • A venous cannula drains deoxygenated blood into the membrane oxygenator for gas exchange, and oxygenated blood is subsequently infused back into the patient through an arterial cannula
    • Ventricular assist device: left (most common), right, or biventricular c159
      • Mechanical pump is positioned surgically or percutaneously, depending on device
      • Many device configurations are available. One such left ventricular assist device involves percutaneous placement (via the femoral artery) at apex of left ventricle with blood inflow from the left ventricle and arterial return pumped to the ascending aorta
      • For durable, portable units, a battery pack and small control unit are worn externally, connected to the pump through a lead into a skin port
Indication
  • Fulminant myocarditis with cardiogenic shock
Complications
  • Bleeding
  • Infection
  • Pump thrombosis
  • Device malfunction
  • Stroke
Implantable cardioverter defibrillator
General explanation r57
  • Insertion of single- or dual-chamber leads to detect and respond to ventricular arrhythmias
  • Device may be either entirely subcutaneous or transvenous
  • Delivers high-voltage cardioversion or defibrillation shocks to treat ventricular fibrillation and tiered therapyto treat ventricular tachycardia
  • Defibrillation shocks are synchronized to the intracardiac electrogram, so cardioversion and defibrillation are essentially equivalent when delivered by these devices
Indication
  • Patients with myocarditis after cardiac arrest caused by ventricular fibrillation or after symptomatic ventricular tachycardia r9
Complications
  • Lead-related complications, including malfunction or displacement r58
  • Inappropriate shocks r45
  • Psychological sequelae have been associated with use
  • Rare complications include subclavian stenosis, thrombus, hemorrhage, and hematoma r59
Cardiac pacing r60c160
General explanation
  • Transvenous endocardial pacing r57
    • Insertion of small, distal tip electrode for pacing and sensing via internal or external jugular, subclavian, brachial, or femoral route. Pacemakers use a separate lead for each chamber paced
Indication
  • Temporary pacemaker insertion is indicated for patients with myocarditis and third-degree atrioventricular block r1
Complications
  • Procedure-related complications include hematoma, thrombophlebitis/phlebitis, lead dislodgement, infection, pneumothorax or hemothorax, myocardial perforation, and air embolism
  • Device malfunction (failure to sense, failure to capture)

Monitoring

  • Follow all patients who have had myocarditis long-term using clinical assessment, ECG, and echocardiography r1
  • Monitoring regarding sports participation
    • Time between initial assessment and reassessment before returning to sports depends on disease severity
      • Screen patients every 6 months during follow-up before they participate in sports r1
      • Evaluate patients with a resting echocardiogram, 24-hour Holter monitoring, and exercise ECG before returning to competitive sports r10
        • Athletes must meet the following criteria before they resume training and competitive sports: r10
          • Ventricular function within normal range
          • Normal levels of serum markers of myocardial injury, inflammation, and heart failure
          • Absence of arrhythmias on Holter monitor and exercise ECG findings
        • There is no definitive recommendation regarding whether late gadolinium enhancement on cardiac MRI should be resolved before returning to sports

Complications and Prognosis

Complications

  • Dilated cardiomyopathy c161d1
    • Clinical diagnosis characterized by dilation and impaired contraction of the left or both ventricles that is not explained by abnormal loading conditions or coronary artery disease r1
    • Myocarditis progresses to dilated cardiomyopathy in about 20% of patients r61r62
      • In children, may develop up to 12 years after initial diagnosis r8
      • Many patients (25%-35%) who progress to dilated cardiomyopathy have detectable viral genome on endomyocardial biopsy r2
  • Arrhythmia c162
    • Acute-phase arrhythmias are usually self-limiting when properly managed but can be refractory and fatal in fulminant myocarditis r22
    • More commonly reported with giant cell myocarditis and with HIV myocarditis (as compared with myocarditis related to more common infections) r22
    • Factors that may be associated with increased arrhythmic risk include sinus bradycardia, prolonged QRS duration, wall-motion abnormalities and systolic dysfunction, persistent or fluctuating cardiac troponin levels, late gadolinium enhancement on cardiac MRI, and frequent nonsustained ventricular arrhythmias r22
    • Implantable cardioverter defibrillator placement is usually deferred to allow time for spontaneous resolution of myocarditis, but earlier placement may be warranted in giant cell myocarditis
  • Sudden cardiac death r2c163
    • May occur without antecedent symptoms or macroscopic cardiac abnormalities r10
    • In the acute phase, physical exertion is associated with increased risk r22
    • Registry autopsy data on trained high school and college athletes in the United States identify myocarditis as an underlying condition in a small percentage of sudden deaths r63
  • Valvular insufficiency related to papillary muscle rupture has been reported

Prognosis

  • Patients may have full or partial recovery; relapse may occur years after the first episode r1
  • Prognosis is variable and determined by disease class, histology, clinical presentation, and patient age
    • Disease class
      • Acute myocarditis r1
        • Approximately 50% of cases resolve within 2 to 4 weeks r1
          • Prognosis is excellent in patients with acute lymphocytic myocarditis (most common histologic type of acute myocarditis), mild symptoms, and preserved left ventricular ejection fraction; most patients improve spontaneously without sequela r8
          • Children with acute myocarditis are expected to have a good prognosis and high chance for recovery of left ventricular function r26
        • About 25% of cases progress to persistent cardiac dysfunction r1
        • 12% to 25% of cases deteriorate acutely; result is death or end-stage dilated cardiomyopathy requiring heart transplant r1
          • Biventricular dysfunction at presentation is a major predictor of death or need for transplant r1
          • Acute myocarditis has been shown to cause sudden death in up to 12% of cases r8
      • Fulminant myocarditis r1
        • Patients with hemodynamic compromise at presentation have excellent long-term prognosis if aggressive therapy is initiated early in the fulminant phase r9
        • Patients with fulminant disease are more likely to recover left ventricular function than those with acute, nonfulminant myocarditis r8
        • Sickest patients at presentation have best recovery odds, especially in younger patients who are treated with mechanical circulatory support r13r64
    • Histology
      • Giant cell myocarditis has a poorer survival rate than other histopathologic types of myocarditis r1
        • Patients often require heart transplant although it may be prevented by early treatment with combination immunosuppressive therapy r53
          • In a review of 32 patients, transplant-free survival with immunosuppressive therapy was 69% at 1 year, 58% at 2 years, and 52% at 5 years
          • Sustained ventricular tachyarrhythmias during follow-up were common
        • Median survival of less than 6 months for both adults and children without transplant r8
        • Recurs in up to 25% of patients after heart transplant r8
    • Clinical presentation (in patients with acute lymphocytic myocarditis)
      • Increased likelihood of cardiac death or need for transplant is associated with the following: r8
        • Syncope
        • Right ventricular systolic dysfunction at presentation
        • Elevated pulmonary artery pressure
        • Advanced New York Heart Association functional class
      • Increased risk for death is associated with the following: r8
        • Prolonged QRS duration of 120 milliseconds r9
        • Immunohistologic signs of inflammation (eg, CD3 or CD68)
      • Poor long-term prognosis is predicted by the presence of any of the following signs: r24
        • Acute hemodynamic instability
        • Presentation with heart failure and left ventricular ejection fraction less than 45% r8
        • Intraventricular conduction abnormalities
        • Extensive structural derangement of the ventricular myocardium with left ventricular remodeling and dysfunction
    • Prognosis in children
      • Histologic resolution is noted in about 73% of patients at 6 months and 96% at 1 year from presentation r8

Screening and Prevention

Screening c164

Prevention

  • There is currently no prevention strategy for myocarditis with the exception of ensuring current vaccination status, as this ensures protection against some potentially causative viral infections r8c165
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