INTRODUCTION — Myocarditis is an inflammatory disease of cardiac muscle that is caused by a variety of infectious and noninfectious conditions (table 1) [1]. It can be an acute, subacute, or chronic disorder, and may present with focal or diffuse involvement of the myocardium. Myocarditis can be produced by a variety of infectious and noninfectious causes [1]. In addition, many inherited cardiomyopathies (eg, Fabry disease and arrhythmogenic right ventricular [RV] cardiomyopathy) may present with features of acute or chronic myocarditis [2].
The clinical manifestations and diagnosis of myocarditis will be reviewed here. The etiology, pathogenesis, treatment, and prognosis of this disorder are discussed separately. (See "Myocarditis: Causes and pathogenesis" and "Treatment and prognosis of myocarditis in adults".)
Myocardial injury (including clinically suspected myocarditis) in patients with coronavirus disease 2019 (COVID-19) is discussed separately. (See "COVID-19: Evaluation and management of cardiac disease in adults".)
DEFINITIONS — Myocarditis is an inflammatory disease of the myocardium. Inflammatory cardiomyopathy is defined as myocarditis accompanied by cardiac dysfunction [3]. Inflammatory cardiomyopathy can lead to dilated cardiomyopathy or be associated with other cardiomyopathies. (See "Definition and classification of the cardiomyopathies".)
EPIDEMIOLOGY — The frequency of myocarditis has not been well defined, as the clinical presentation is variable and there is no sensitive and specific noninvasive diagnostic test that can confirm the diagnosis.
In the 2019 Global Burden of Disease report, the rate of myocarditis was 6.1 per 100,000 (95% uncertainty interval [UI] 4.2-8.7 per 100,000) in men and 4.4 per 100,000 (95% UI 3.0-6.3 per 100,000) in women between 35 and 39 years [4]:
●Myocarditis-related mortality rate in this age bracket was 0.2 per 100,000 (95% UI 0.2-0.3 per 100,000) in men compared with 0.1 per 100,000 (95% UI 0.1-0.2 per 100,000) in women. Myocarditis resulted in death in 1 in 72 men (585 deaths per 42,200 incident cases) and 1 in 87 women (324 deaths per 28,100 incident cases) in this age bracket who were diagnosed in 2019 [4].
●Marked regional variations in age-standardized disability-adjusted life years (DALYs) were observed. These ranged from 0-11 DALYs per 100,000 in most European countries and Canada to more than 54 per 100,000 in certain Asian, Eastern European, and South American countries.
The sensitivity of endomyocardial biopsy using conventional histology (Dallas criteria) for myocarditis may be as low as 10 to 35 percent due to variability in interpretation and sampling error, but application of immunohistochemistry and viral polymerase chain reaction (PCR) have yielded higher sensitivity [5-10]. (See 'Endomyocardial biopsy' below and "Myocarditis: Causes and pathogenesis".)
Many cases of myocarditis likely go undetected because they are subclinical or present with nonspecific signs. For example, the rate of troponin rise after smallpox vaccination is 1:200, yet the rate of clinically suspected myocarditis has been reported to be approximately 1:5500 [11,12]. Subtle cardiac symptoms and signs may be overshadowed by systemic manifestations of the underlying infection or disease process. In the early stages of viral myocarditis, for example, the patient may have fever, myalgias, and muscle tenderness. The muscle symptoms are attributable to myositis induced by a myotropic virus such as coxsackievirus A. In the United States Myocarditis Treatment Trial, 89 percent of subjects reported a syndrome consistent with a viral prodrome [13].
In contrast, in a study of 443 patients admitted to hospitals with suspected acute myocarditis, 118 (26.6 percent) had either left ventricular ejection fraction (LVEF) <50 percent, sustained ventricular arrhythmias, or a low cardiac output syndrome. Patients who presented with these complications had worse long-term outcomes, as discussed separately [14]. (See "Treatment and prognosis of myocarditis in adults", section on 'Clinical predictors'.)
CLINICAL MANIFESTATIONS
Variable presentation — The clinical manifestations of myocarditis are highly variable, ranging from subclinical disease to fatigue, chest pain, heart failure (HF), cardiogenic shock, arrhythmias, and sudden death (table 2) [14-16]. There is no population-based epidemiologic study that has defined presenting symptoms of acute or subacute/chronic myocarditis; this is due in part to the absence of a safe and sensitive noninvasive diagnostic test that can confirm the diagnosis.
The variability in presentation reflects the variability in histological disease severity, etiology, and disease stage at presentation. Myocardial inflammation may be focal or diffuse, involving any or all cardiac chambers. Severe, diffuse myocarditis can result in acute dilated cardiomyopathy. The histological features of chronic myocarditis are usually more subtle, and include altered human leukocyte antigen and adhesion molecule expression, and inflammatory cell infiltrates that are apparent only on cell-specific immunostains (ie, CD3 for T lymphocytes and CD68 for macrophages) [17,18].
Classification — Acute myocarditis has been defined as a condition with symptoms of HF developing over three months or less, while chronic myocarditis has been defined as developing over greater than three months [19].
A clinicopathologic classification of inflammatory cardiomyopathy utilizing both histologic and clinical features may aid diagnosis, management, and prognostication in patients with HF due to myocarditis. One group proposed the following classification, though not all experts agree with such distinct clinicopathologic forms [20] (see 'Histology' below): acute forms (fulminant myocarditis and acute myocarditis), and chronic forms (chronic active myocarditis, and chronic persistent myocarditis), which intersect with the clinical profiles as described below. (See 'Profiles of acute myocarditis' below and 'Profiles of subacute/chronic myocarditis' below.)
Profiles of acute myocarditis — Among patients with myocarditis who present with acute symptoms and signs of cardiovascular disease, presentation varies; key clinical profiles were described in the 2013 European Society of Cardiology (ESC) position statement on myocarditis [1]:
●Acute coronary syndrome-like with acute chest pain in the absence of angiographic evidence of coronary artery disease (CAD):
•Acute chest pain frequently starts within one to four weeks after a respiratory or gastrointestinal infection and is frequently associated with severe and recurrent symptoms.
•ST/T wave changes include ST segment elevation or depression and T wave inversions.
•Global or regional LV and/or RV dysfunction (on echocardiography or cardiovascular magnetic resonance [CMR]) may or may not be detected.
•Troponin T or I may or may not be elevated. The time course of troponin elevation may be similar to that with acute myocardial infarction (MI) or may be prolonged and sustained over several weeks or months.
●New onset or worsening HF in the absence of CAD and known causes of HF:
•New onset or progressive HF over two weeks to three months with symptoms including dyspnea, peripheral edema, chest discomfort, and fatigue.
•Impaired LV and/or RV systolic function; the LV and/or RV may or may not be dilated and wall thicknesses may or may not be increased, as assessed by echocardiography or CMR. Some patients with ventricular dysfunction may progress to dilated cardiomyopathy. (See "Treatment and prognosis of myocarditis in adults", section on 'Variable disease course'.)
•Symptoms may start after a respiratory or gastrointestinal infection or in the peripartum period. (See "Peripartum cardiomyopathy: Etiology, clinical manifestations, and diagnosis", section on 'Myocarditis'.)
•The electrocardiogram (ECG) may show non-specific changes, bundle branch block, atrioventricular (AV) block, or ventricular arrhythmias.
●Life-threatening condition in the absence of CAD and known causes of HF with one or more of the following:
•Life-threatening arrhythmias and aborted sudden death.
•Cardiogenic shock – This presentation, known as fulminant myocarditis, may occur around two weeks after a distinct viral prodrome [21]. Patients have severe cardiovascular compromise and may require mechanical circulatory support. Multiple foci of active lymphocytic myocarditis are common, and ventricular systolic dysfunction often normalized in patients surviving the acute illness [22]. Fulminant myocarditis is identified clinically based upon presenting symptoms and signs; cardiac imaging is not diagnostic since echocardiographic features of fulminant myocarditis overlap those seen in other types of acute myocarditis, as discussed below. (See 'Echocardiography' below and "Treatment and prognosis of myocarditis in adults", section on 'Fulminant myocarditis'.)
•Severely impaired LV function.
Patients with acute myocarditis with associated pericarditis may present with positional or pleuritic chest pain and pericardial effusion, as discussed separately. (See "Myopericarditis".)
Profiles of subacute/chronic myocarditis — Some patients with myocarditis present with an indistinct onset of illness (ie, developing over more than three months), which has been described as subacute or chronic myocarditis.
●Chronic active myocarditis has been described as presenting with frequent clinical and histologic relapses, development of ventricular systolic dysfunction associated with chronic inflammatory changes, and mild to moderate fibrosis on endomyocardial biopsy.
●Chronic persistent myocarditis, which was also described as presenting with a less distinct onset of illness, was characterized by a persistent histologic infiltrate, often with foci of myocyte necrosis, and no ventricular systolic dysfunction despite persistent chest pain or palpitation.
SYMPTOMS AND SIGNS
Nonspecific characteristics — A number of clinical features of myocarditis are nonspecific, such as myalgias and a history of recent upper respiratory infection. Age at onset varies but is typically between 20 to 50 years [23]. Some patients have evidence of systemic viral or other infections (bacterial, rickettsial, fungal, or parasitic) or have a rash (and eosinophilia) following administration of a new drug or vaccine, but many do not. As an example, a history of recent upper respiratory infection or enteritis was present in 36 percent of patients in a series of patients with biopsy-proven myocarditis [24]. Since many cardiotropic viruses, including coxsackie A, are also myotropic, the concurrent presence of muscle aching and particularly muscle tenderness in this setting may increase suspicion of myocarditis. One presentation is an acute viral infection (eg, exanthematous disease in children and adults due to parvovirus B19) accompanied by tachycardia out of proportion to fever. (See "Clinical manifestations and diagnosis of parvovirus B19 infection".)
Cardiac manifestations
Heart failure — Many symptomatic cases of postviral or lymphocytic myocarditis present with a syndrome of HF and dilated cardiomyopathy. In a large review of 1230 cases of initially unexplained cardiomyopathy in the United States, 9 percent were thought to be due to myocarditis [25]. A similar prevalence (10 percent) was noted in the Myocarditis Treatment Trial in which endomyocardial biopsy was performed in over 2200 patients with unexplained HF of less than two years duration [13].
In many patients who develop HF, fatigue and decreased exercise capacity are the initial manifestations. However, rapidly evolving diffuse severe myocarditis can result in acute myocardial failure and cardiogenic shock. Signs of RV failure include increased jugular venous pressure, hepatomegaly, and peripheral edema. Patients with predominant LV involvement present with symptoms of pulmonary congestion including dyspnea, orthopnea, pulmonary rales, and, in severe cases, acute pulmonary edema. (See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults".)
Chest pain — Chest pain in patients with myocarditis may reflect associated pericarditis. Myocarditis can mimic myocardial ischemia and/or infarction both symptomatically and on the ECG, particularly in younger patients [6,26-29]. Elevated troponin in the setting of pericarditis is often due to epicardial inflammation and termed "myopericarditis." HF and sudden death are rare in this condition, but recurrent myocarditis occurs in approximately 11 percent [30]. (See "Myopericarditis".)
As an example, in one study of 45 patients presenting with suspected acute coronary syndrome with a normal coronary angiogram, 35 (78 percent) had a diffuse or focal myocarditis on myocardial imaging [27]. Complete recovery of LV function occurred at six months in 81 percent of these patients. Focal wall motion abnormalities associated with myocarditis may be due to localized inflammation or ischemia caused by coronary spasm [31]. (See 'Differential diagnosis' below.)
Sudden cardiac death — Myocarditis may present with unexpected sudden death [32-34]. In an autopsy series of patients under age 40 who presented with sudden death in the absence of known heart disease, myocarditis was responsible for 22 percent of cases under age 30 and 11 percent in older subjects [32]. In another autopsy study of sudden death occurring in competitive athletes, myocarditis was present in 6 percent of cardiovascular deaths [35]. In a series of autopsies in military recruits, myocarditis accounted for 20 percent of deaths due to identifiable structural cardiac abnormalities [34]. (See "Pathophysiology and etiology of sudden cardiac arrest".)
Arrhythmias — A number of arrhythmias may be seen in patients with myocarditis. Sinus tachycardia is more frequent than serious atrial or ventricular arrhythmias, while palpitations secondary to premature atrial complex (PAC; also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat) or, more often, ventricular extrasystoles are common. Bradyarrhythmia and syncope due to new-onset unexplained heart block may also occur both in infectious (eg, Lyme disease) and in immune-mediated forms of myocarditis (eg, sarcoidosis, giant cell myocarditis). (See "Clinical manifestations of Lyme disease in adults", section on 'Carditis' and "Clinical manifestations and diagnosis of cardiac sarcoidosis".)
Physical examination — There are no specific physical examination findings for myocarditis.
In patients with HF, the physical examination may reveal signs of fluid overload (including elevated jugular venous pressure and edema), as well as other evidence of cardiac dysfunction (eg, a third heart sound). If left or RV dilation is severe, auscultation may reveal murmurs of functional mitral or tricuspid regurgitation. (See "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Physical examination' and "Auscultation of heart sounds", section on 'Third (S3) and fourth (S4) heart sounds' and "Auscultation of cardiac murmurs in adults", section on 'Holosystolic murmurs'.)
A pericardial friction rub and/or effusion may be detected in some patients with myocarditis and associated pericarditis (myopericarditis). (See "Myopericarditis".)
Initial testing — Initial testing generally includes ECG, cardiac biomarkers, and chest radiography. Routine laboratory studies of blood reveal only nonspecific abnormalities, such as elevated acute phase reactants (c-reactive protein [CRP]) in patients with acute myocarditis, although peripheral eosinophilia is found in most patients with eosinophilic myocarditis. Measurement of brain natriuretic peptide (BNP) or N-terminal-proBNP (NT-proBNP) is recommended if HF is suspected but the diagnosis is uncertain; these are the most sensitive initial tests for HF. (See "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Initial testing' and "Natriuretic peptide measurement in heart failure".)
Acute phase reactants — A CRP level is commonly checked in patients with suspected myocarditis. Patients with acute myocarditis commonly have elevated acute phase reactants, but this finding is nonspecific. As an example, in a study of 386 patients with acute myocarditis and preserved LVEF, 99 percent of patients had an elevated erythrocyte sedimentation rate (ESR) and/or c-reactive protein (CRP) level [36]. However, levels of these acute phase reactants were similar in patients with and without adverse cardiac events during follow-up (median of 4.3 years). Data are lacking on the prevalence of elevations in ESR and CRP in patients with chronic myocarditis. Given the many conditions associated with elevations in acute phase reactants, this finding is of limited utility in diagnosing myocarditis. (See "Acute phase reactants".)
Complete blood count with differential — A complete blood count with differential may reveal a high eosinophil count in patients with eosinophilic myocarditis. A systematic review including 179 patients hospitalized with histologically proven eosinophilic myocarditis reported peripheral eosinophilia in 75.9 percent [37]. In this study, peripheral eosinophilia was frequently found among patients with hypersensitivity (63.5 percent) but higher rates of eosinophilia were found in patients with the other types of eosinophilic myocarditis (idiopathic, eosinophilic granulomatosis with polyangitis, hypereosinophilic syndrome, and others).
Cardiac biomarkers — Serum cardiac troponin levels are commonly elevated in patients with myocarditis, particularly those with short duration of symptoms (ie, less than one month) [36,38]. Serum troponin levels are obtained to aid in diagnosis of myocarditis, as recommended by the American Heart Association (AHA) scientific statement for specific dilated cardiomyopathies and the European Society of Cardiology (ESC) position statement on the management of acute myocarditis, but absence of troponin elevation does not exclude myocarditis [1,39]. Persistent elevations in cardiac enzymes suggest ongoing necrosis. (See "Troponin testing: Clinical use".)
Electrocardiogram — An ECG is not required to diagnose myocarditis but is generally obtained to exclude alternate causes of cardiac symptoms such as ischemia, to evaluate for arrhythmias, and to identify features (eg, high grade AV block) that may suggest certain causes of myocarditis. The ECG in patients with myocarditis may be normal or show nonspecific abnormalities. Findings may include nonspecific ST changes, single atrial or ventricular ectopic beats, complex ventricular arrhythmias (couplets or nonsustained ventricular tachycardia), or, rarely, atrial tachycardia or atrial fibrillation. High grade AV block is uncommon in lymphocytic myocarditis, but common in Lyme disease, cardiac sarcoidosis, and idiopathic giant cell myocarditis. (See "Lyme carditis", section on 'Atrioventricular conduction abnormalities' and "Treatment and prognosis of myocarditis in adults" and "Treatment and prognosis of myocarditis in adults", section on 'Giant cell myocarditis'.)
The ECG in some patients with myocarditis is similar to the ECG pattern of acute isolated pericarditis (which is suggestive of myopericarditis) or acute MI [6,26-29,40]. Like acute MI, myocarditis may be associated with regional ST elevations and Q waves. Myocarditis should be suspected in young patients who present with a possible MI but have a normal coronary angiogram. In one study of 45 such patients, 35 (78 percent) had a diffuse or focal myocarditis on myocardial imaging [27]. Complete recovery of LV function occurred at six months in 81 percent. (See "Electrocardiogram in the diagnosis of myocardial ischemia and infarction".)
The presence of Q waves or left bundle branch block was associated with higher rates of death or transplantation in some [41] but not in all studies [24,42].
Chest radiograph — The heart size on chest radiograph varies from normal to enlarged with or without pulmonary vascular congestion and pleural effusions. In some cases, biventricular cardiomegaly is associated with the absence of pulmonary congestion such as in those with right RV and/or moderate or severe tricuspid regurgitation. However, chest radiography has limited sensitivity for identification of cardiomegaly or for diagnosis of HF. (See "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Chest radiograph'.)
BNP or NT-proBNP — BNP or NT-proBNP level should be measured if HF is suspected but the diagnosis is uncertain; these are the most sensitive initial tests for HF. (See "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Initial testing' and "Natriuretic peptide measurement in heart failure".)
DIAGNOSIS — There are two clinical issues relevant to the diagnosis of myocarditis: when it should be suspected and how the diagnosis is confirmed.
When to suspect myocarditis — Myocarditis should be suspected in patients with or without cardiac signs and symptoms (table 2), who have a rise in cardiac biomarkers (eg, troponin), ECG changes suggestive of acute myocardial injury, arrhythmia, or global or regional abnormalities of LV systolic function, particularly if the clinical findings are new and unexplained [43]. The clinical presentation of myocarditis is highly variable and myocarditis can mimic other noninflammatory cardiac disorders. Therefore, a high level of clinical suspicion is needed.
Clinical suspicion for myocarditis should be high in a patient who presents with clinical signs and symptoms of an acute MI, particularly if the patient lacks cardiovascular risk factors or the coronary angiogram is normal [6,26-29,43]. In this setting myocarditis should be distinguished from stress (takotsubo) cardiomyopathy. (See 'Differential diagnosis' below.)
Myocarditis rarely occurs after vaccine administration (eg, COVID-19 mRNA vaccine, vaccinia virus inoculation, tetanus toxoid inoculation). (See "COVID-19: Vaccines", section on 'Myocarditis' and "Myocarditis: Causes and pathogenesis", section on 'Vaccine-related' and "Myopericarditis", section on 'Vaccinia-associated myopericarditis'.)
Pericarditis (infectious or idiopathic) with accompanying cardiac biomarker elevation is suggestive of myopericarditis. (See "Acute pericarditis: Clinical presentation and diagnosis", section on 'Clinical features' and "Myopericarditis".)
Approach to diagnosis of myocarditis — The diagnostic evaluation of patients with suspected myocarditis should include the following components:
●History and physical examination to evaluate for symptoms and signs of myocarditis and HF (table 2) and assess possible causes. (See 'Clinical manifestations' above and 'Physical examination' above.)
●Initial laboratory testing including an ECG, c-reactive protein, serum troponin levels, and generally a chest radiograph. Natriuretic peptide measurement is indicated if the diagnosis of HF is uncertain. Routine acute and convalescent viral serology testing is not helpful [44] and is not recommended. (See 'Initial testing' above.)
●Cardiac imaging:
•An echocardiogram is performed in all patients with suspected myocarditis to evaluate regional and global ventricular function, valvular function, and other potential causes of cardiac dysfunction.
•Coronary angiography is indicated in selected patients with clinical presentation indistinguishable from an acute coronary syndrome, lifestyle-limiting coronary disease despite medical therapy, or high-risk features for ischemic heart disease on noninvasive testing. (See 'Cardiac catheterization' below.)
•CMR imaging is indicated in patients with suspected myocarditis with elevated troponin level and/or ventricular dysfunction without a clear cause such as ischemic heart disease. CMR often provides supportive evidence of myocarditis when endomyocardial biopsy (EMB) is not performed for whatever reason. (See 'Cardiac imaging' below.)
●In selected patients with suspected myocarditis who exhibit signs of worsening hemodynamic compromise despite guideline-based medical management, cardiac catheterization may aid determination of hemodynamic status. (See 'Cardiac catheterization' below.)
●An EMB is performed as clinically indicated. The decision of whether to proceed with EMB should be based upon the likelihood that EMB will significantly impact patient management [45]. (See 'Indications for EMB' below.)
How to diagnose myocarditis — A diagnosis of myocarditis is definitively established in patients who have diagnostic findings on EMB. The World Health Organization/International Society and Federation of Cardiology (WHO/ISFC) definition specifies diagnosis by established histological (Dallas criteria), immunological, and immunohistochemical criteria [3]. (See 'EMB diagnostic criteria for myocarditis' below.)
For patients who do not undergo EMB or have nondiagnostic findings on EMB, a definitive diagnosis cannot be established, but a diagnosis of clinically suspected myocarditis may be made if diagnostic criteria are met.
Definitive diagnosis of myocarditis — A definitive diagnosis of myocarditis is based upon identification of diagnostic findings on EMB, including histology (Dallas criteria) as well as immunohistochemical stains. This approach is supported by the WHO classification and definition of cardiomyopathies as well as later expert scientific statements [1,3,46,47], although many patients with suspected myocarditis are not considered candidates for EMB. When EMB findings are diagnostic, myocarditis is diagnosed even in the setting of concurrent heart disease, such as CAD. (See 'EMB diagnostic criteria for myocarditis' below.)
Diagnosis of clinically suspected myocarditis — A combination of clinical presentation and noninvasive diagnostic findings including typical CMR abnormalities may be used to make a diagnosis of "clinically suspected" myocarditis. While histology remains the gold standard for establishing the diagnosis of myocarditis, low-risk patients may be diagnosed with "clinically suspected myocarditis" on the basis of a compatible clinical presentation. However, the accuracy of this approach is limited, since clinical features at presentation in myocarditis are polymorphic and there is no sign, symptom, or constellation of clinical features that is diagnostic of acute or subacute/chronic myocarditis.
●When to apply criteria for clinically suspected myocarditis – Criteria for clinically suspected myocarditis may be applied in the following settings:
•To help identify patients who may be candidates for EMB. The 2013 European Society of Cardiology (ESC) position statement recommended consideration of selective coronary angiography and EMB in all patients with clinically suspected myocarditis. However, we reserve EMB for the subset of these patients with the indications for EMB as described below. (See 'Indications for EMB' below.)
•To provide a clinical diagnosis for patients who do not have one indication for EMB or who have undergone EMB with nondiagnostic results. In this setting, a diagnosis of "clinically suspected myocarditis" is generally not sufficient to serve as a basis for immunosuppressive therapy but may be helpful to guide other aspects of management (eg, exercise recommendations).
●Criteria for clinically suspected myocarditis – We agree with the 2013 ESC position statement criteria for "clinically suspected" myocarditis, which require that a patient have at least one of the following clinical presentations of myocarditis and at least one diagnostic criteria; if the patient is asymptomatic at least two diagnostic criteria are required [1]. A diagnosis of clinically suspected myocarditis also generally requires the absence of other clinical conditions that could explain the clinical findings such as cardiovascular disease (eg, angiographically significant CAD [coronary stenosis ≥50 percent], valve disease, or congenital heart disease), or an extra-cardiac condition (eg, hyperthyroidism). While it is possible to make a diagnosis of "clinically suspected" myocarditis in a patient with a concomitant condition such as CAD, clinical findings must be carefully reviewed to determine whether findings can be explained by a single disease process or whether the patient likely has at least two separate conditions. Clinical suspicion is higher with greater numbers of fulfilled criteria unrelated to other conditions [1].
•Clinical presentations:
-Acute chest pain (pericarditis or pseudo-ischemic).
-New-onset (days up to three months) or worsening of dyspnea at rest or exercise, and/or fatigue, with or without left and/or right HF signs.
-Palpitation, and/or unexplained arrhythmia symptoms and/or syncope, and/or aborted sudden cardiac death.
-Unexplained cardiogenic shock.
•Diagnostic criteria:
-ECG/Holter stress test features – New 12-lead ECG and/or Holter and/or stress testing abnormalities with any of the following: first to third degree AV block or bundle branch block, ST/T wave change (ST elevation or T wave inversion), sinus arrest, ventricular tachycardia or fibrillation, asystole, atrial fibrillation, significantly reduced R wave height, intraventricular conduction delay (widened QRS complex), abnormal Q waves, low voltage, frequent premature beats, or supraventricular tachycardia.
-Elevated troponin T or troponin I.
-Functional and structural abnormalities on cardiac imaging (echocardiogram, angiogram, or CMR) – New, otherwise unexplained abnormality of LV and/or RV function (regional wall motion abnormality or global systolic or diastolic dysfunction); such abnormality may occur with or without one or more of the following: ventricular dilatation, increased ventricular wall thickness, pericardial effusion or intracavitary thrombus.
-Tissue characterization by CMR – The presence of updated Lake Louse criteria suggests myocarditis. (See 'Cardiovascular magnetic resonance' below.)
•The following ancillary features support the clinical suspicion of myocarditis:
-Fever ≥38.0°C at presentation or during the preceding 30 days with or without associated symptoms (eg, chills, headache, myalgias, malaise, decreased appetite, nausea, vomiting, or diarrhea).
-Prior clinical suspected or definite myocarditis.
-Exposure to toxic agents.
-Extra-cardiac autoimmune disease.
Of note, these above criteria for clinically-suspected myocarditis are not applicable for patients who meet criteria for more specific conditions, such as cardiac sarcoidosis, which is discussed separately. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'How to diagnose cardiac sarcoidosis'.)
Cardiac imaging
Echocardiography — The echocardiogram is the key method of detecting impaired ventricular function in suspected myocarditis, even when subclinical [48,49]. Findings include LV dilation, changes in LV geometry (eg, development of a more spheroid shape), and wall motion abnormalities. The systolic dysfunction is generally global, but may be regional or segmental. An abnormal tissue Doppler signal may provide additional evidence of myocarditis, although data are limited [50].
Mild impairment in myocardial contractility may be evident only when the study is performed at rest rather than during exercise. However, exercise-induced wall motion abnormalities may also be seen; they are usually due to microvascular dysfunction.
The echocardiogram can also detect coexistent pericardial involvement, silent intracardiac thrombi (movie 1), and functional mitral or tricuspid regurgitation.
Fulminant and acute myocarditis are both associated with LV dilation and systolic dysfunction. The extent of LV dysfunction and dilation does not necessarily distinguish the two. Patients with fulminant myocarditis typically have near-normal LV diastolic dimensions and mildly increased interventricular septal thickness, while those with acute myocarditis have normal or increased LV diastolic dimensions and normal or increased septal thickness [51]. Patients with fulminant myocarditis who survive the acute illness frequently have dramatic improvement in systolic function within several months, while recovery of systolic function is less common in patients with acute myocarditis [24,51]. A spherical-shaped ventricle commonly seen in acute myocarditis tends to remodel to a more normal elliptical shape over several months [52]. (See 'Definitions' above.)
Three-dimensional echocardiography may provide more accurate and objective noninvasive EF measurements than standard two-dimensional echocardiography but requires adequate acoustic windows.
Cardiovascular magnetic resonance — CMR imaging enables detection of various features of myocarditis, including evidence of inflammatory hyperemia and edema, LGE suggestive of myocyte necrosis and scar (image 1) [53-55], changes in ventricular size and geometry, regional and global wall motion abnormalities (including quantification of LVEF), and identification of accompanying pericardial effusion [55]. CMR findings can suggest a diagnosis of myocarditis, although sensitivity is variable and time-dependent and CMR findings are non-specific. (See "Clinical utility of cardiovascular magnetic resonance imaging" and "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Acute myocarditis'.)
The role of CMR in assessing prognosis of myocarditis is discussed separately. (See "Treatment and prognosis of myocarditis in adults", section on 'Predictors of outcome'.)
Updated Lake Louise criteria — An expert consensus paper proposed the following updated Lake Louise Criteria for CMR diagnosis of myocarditis for patients with clinically suspected myocarditis [56]. The updated Lake Louise criteria were developed to incorporate T1 and T2 mapping and to enhance specificity compared to criteria requiring only a T1-based or a T2-based marker for myocarditis.
●Main criteria - CMR findings are deemed suggestive of myocarditis if both T2-based imaging and T1-based imaging criteria are present:
•T2-based imaging with one or more of the following signs of myocardial edema (with T2 values compared with published or locally established normal values):
-Regional (an area of at least 10 contiguous pixels) high T2 signal intensity (SI)
-Global T2 SI ratio ≥2.0 in T2-weighted (T2W) CMR images
-Regional or global increase of myocardial T2 relaxation time
•T1-based imaging with either or both of the following findings:
-Regional or global increase in native myocardial T1 relaxation time or extracellular volume (ECV). (When late gadolinium [LGE] imaging is also performed, the region of elevated T1 should extend beyond the area of LGE).
-Areas with high SI in a nonischemic distribution pattern in LGE images (ie, typically involving the subepicardium or midwall with infrequent involvement of subendocardium [36,57]; findings are often multifocal). The LGE pattern for myocarditis generally differs from that seen with ischemic cardiomyopathy (which typically involves the endocardium with variable extension into the midmyocardium and epicardium).
LGE images are typically obtained about 10 minutes after intravenous gadolinium contrast injection using inversion recovery-prepared gadolinium-enhanced T1-weighted pulse sequences. (See "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Late gadolinium enhancement'.)
If the clinical suspicion of myocarditis is high, neither or only one of the above criteria are present, and the initial CMR study was performed soon after the onset of symptoms, the CMR study should be repeated one to two weeks after the initial CMR study [55].
●Supportive criteria - The updated Lake Lousie criteria also include “supportive criteria” that are not sufficient to support a diagnosis of myocarditis but are commonly identified in patients with myocarditis:
•Pericardial findings:
-Pericardial effusion in cine CMR images.
-High signal intensity of the pericardium consistent with pericardial inflammation with LGE, or with T1 or T2 mapping.
•LV wall motion abnormality in cine CMR images – Evidence of focal and/or global LV systolic function in cine CMR images.
Comparison of methods — Among individual CMR markers for myocarditis, meta-analyses have found that native T1 mapping offers the highest median diagnostic accuracy, but there is great heterogeneity in diagnostic performance among studies for each CMR marker and for various combinations of markers [56,58,59]. A meta-analysis identified the following median estimated area-under-the-curve values and total ranges [56]:
●Individual markers: T1 mapping 89 (71-99), LGE 83 (53-96), T2 mapping 80 (73-86), T2W imaging 73 (58-100), extracellular volume 74 (59-82), and early gadolinium enhancement (EGE) 73 (62-93).
●Combinations: Original Lake Louse criteria (2 of 3; T2W imaging, EGE, and LGE) 84 (57-90, based on 8 studies), T2W plus LGE 76 (71-89, 3 studies), T2 mapping plus LGE 90 (83-97, 2 studies), T2W plus T1 mapping 84 (73-95, 2 studies), and T1 mapping plus LGE 96 (82-97, 5 studies).
The available evidence suggests that native T1 mapping has the highest diagnostic accuracy among clinically available CMR markers. However, a consensus is lacking on the optimum threshold T1 for diagnosis of myocarditis since absolute T1 values depend upon the CMR sequence and the algorithm for T1 calculation [60]. Thus, T1 mapping is generally used with site-specific reference values benchmarked against published values. Also, T1 mapping detects alterations associated with both acute and chronic myocarditis, so it is not specific for acute myocarditis [55].
Cardiac catheterization — Although generally not required, coronary angiography is indicated in selected patients with clinical presentation indistinguishable from an acute coronary syndrome, lifestyle-limiting coronary disease despite medical therapy, or high-risk features for ischemic heart disease on noninvasive testing. (See "Overview of the acute management of ST-elevation myocardial infarction" and "Non-ST-elevation acute coronary syndromes: Revascularization" and "Chronic coronary syndrome: Overview of care", section on 'Identifying patients for angiography and revascularization'.)
In selected patients with myocarditis who exhibit signs of worsening hemodynamic compromise despite guideline-based medical management, cardiac catheterization may be helpful in characterizing and managing their hemodynamic status. (See "Pulmonary artery catheterization: Indications, contraindications, and complications in adults", section on 'Indications'.)
Radionuclide ventriculography — Since ventricular function is generally assessed by echocardiography and CMR is generally considered the clinical gold standard for assessment of LV volumes and LVEF, radionuclide ventriculography is usually not needed. However, radionuclide studies can be useful when transthoracic echocardiographic images are suboptimal and transesophageal echocardiography and CMR are unavailable. There may be less variability in the EF measurement obtained with serial radionuclide ventriculography as compared with measurement by two-dimensional echocardiography because its analysis is less operator-dependent. (See "Tests to evaluate left ventricular systolic function".)
Other tests — Positron emission tomography using fluorine-18 labeled deoxyglucose (FDG-PET) imaging of viral myocarditis has been reported but data are limited [61]. FDG-PET imaging is primarily used to diagnose suspected cardiac sarcoidosis, as discussed separately. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'Diagnosis'.)
Serum autoantibodies to various cardiac and muscle-specific autoantigens have been detected in patients with myocarditis and dilated cardiomyopathy, but a specific reliable test for cardiac autoantibodies is not yet widely available for clinical use [1].
Endomyocardial biopsy
Indications for EMB — Once other causes of HF (such as ischemic heart disease, critical valvular lesions, and restrictive and hypertrophic cardiomyopathies) have been excluded, the need for an EMB should be based upon the likelihood that the results will change management [45]. This will depend upon the time course, severity, and characteristics of the presentation as addressed in the 2007 American Heart Association/American College of Cardiology Foundation/European Society of Cardiology (AHA/ACCF/ESC) scientific statement on EMB (table 3) [19] (see "Endomyocardial biopsy").
EMB is recommended in the following settings:
●For patients with unexplained fulminant HF (new onset HF of less than two weeks duration associated with hemodynamic compromise)
●Unexplained new onset HF of two weeks to three months duration associated with a dilated LV and new ventricular arrhythmias, Mobitz type II second-degree AV block, third-degree AV block, or failure to respond to usual care within one to two weeks.
EMB is suggested in the following settings (when other evaluation is inconclusive):
●HF of >3 months duration associated with dilated LV and new ventricular arrhythmias, second or third degree AV block, or failure to respond to usual care within one or two weeks
●HF associated with dilated cardiomyopathy associated with suspected allergic reaction and/or eosinophilia.
●Other specific clinical settings when other evaluation is inconclusive and diagnosis may impact treatment or prognosis, as discussed separately. (See "Endomyocardial biopsy", section on 'EMB suggested in selected cases'.)
Most patients presenting with subacute to chronic HF in whom a diagnosis of idiopathic dilated cardiomyopathy is made should first be managed with appropriate therapy for HF (see "Overview of the management of heart failure with reduced ejection fraction in adults"). Most of these patients will respond to medical therapy alone and do not require EMB.
Analysis of the EMB is also helpful in identifying the etiopathogenetic form of myocarditis, as discussed below. Additional information obtained by other laboratory testing (including appropriate serum tests for autoimmune disease, serum protein electrophoresis and fat aspirates for amyloidosis, and ferritin levels for hemochromatosis) also guide the decision to proceed to EMB. (See 'Identifying the cause of myocarditis' below.)
EMB diagnostic criteria for myocarditis — For patients with an indication for EMB, a definitive diagnosis of myocarditis is established based upon EMB, including histologic (Dallas criteria) as well as immunohistochemical criteria. In patients with definite myocarditis, viral genomes may or may not be detected by molecular techniques (mainly polymerase chain reaction [PCR]). The WHO/ISFC definition of myocarditis includes histological (Dallas) criteria as well as immunological and immunohistochemical criteria [3]. This approach was endorsed in subsequent scientific statements [1,46,47].
Histology — Histologic examination of EMB in myocarditis reveals cellular infiltrates, which are usually histiocytic and mononuclear with or without associated myocyte damage. Specific histological forms of myocarditis include eosinophilic, granulomatous, and giant cell myocarditis. The infiltrates are of varying severity and are often associated with myocyte necrosis and disorganization of the myocardial cytoskeleton (picture 1A-B). With subacute and chronic myocarditis, interstitial fibrosis may replace myocytes, and myofiber hypertrophy may also be seen (picture 2). Criteria for the histological diagnosis of myocarditis include the Dallas criteria that rely on standard histological stains, and several others that use immunohistologic criteria.
Histopathologic diagnosis of a specific cause of myocarditis is occasionally possible in patients with toxoplasmosis, Chagas disease, Lyme carditis, cytomegalovirus myocarditis, and trichinellosis. Electron microscopic examination is occasionally useful to exclude anthracycline toxicity, but other forms of anthracycline-related myocardial dysfunction have entirely non-specific findings in the myocardium. (See "Endomyocardial biopsy", section on 'Indications'.)
Dallas criteria — The Dallas criteria were developed by a panel of cardiac pathologists as a working standard for the United States Myocarditis Treatment Trial; these criteria are now used by most investigators to define the disease [62]:
●Active myocarditis is defined as "an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of the ischemic damage associated with coronary artery disease." The infiltrates are usually mononuclear, but may be neutrophilic, or occasionally, eosinophilic (picture 1A-B).
●"Borderline myocarditis" is the term used when the inflammatory infiltrate is too sparse or myocyte injury is not demonstrated.
There are, however, concerns about the diagnostic accuracy of the Dallas criteria for the diagnosis of myocarditis [5,63,64]. In one report of 38 cases, using autopsy as the gold standard, the sensitivity and specificity of EMB were approximately 60 and 80 percent, respectively [64]. A lower sensitivity of 35 percent has been noted when a clinical and functional gold standard is used [63].
The low sensitivity of the Dallas criteria is likely in part due to the focal and transient nature of the inflammatory infiltrates [8,64]. In the above autopsy study of 38 cases, RV biopsy was positive in 63 percent of patients, and LV biopsy was positive in 55 percent of patients, but only 17 to 20 percent of individual biopsy specimens were positive [64]. In a report comparing CMR and histology, the most common site of focal involvement was the epicardial surface of the LV free wall, while most EMBs are obtained from the RV side of the interventricular septum [8]. Active myocarditis was found in 19 of 21 patients with EMB directed by CMR imaging and was infrequent in regions not identified by CMR imaging. However, the clinical applicability of this method is uncertain given the risk of LV free wall biopsy.
Another problem with the Dallas criteria is that even expert pathologists often disagree on the interpretation of myocardial biopsy material [5]. For example, in the Myocarditis Treatment Trial, the diagnosis was confirmed by the expert panel in only 64 percent of cases [13].
An additional limitation of the Dallas criteria is that viral genome may be present in the myocardium without sufficient histologic changes to meet the Dallas criteria, as discussed below. (See 'PCR and immunohistochemistry' below.)
PCR and immunohistochemistry — Detection of viral genome by PCR may be used to identify specific viral pathogens, although the clinical value of viral genome detection remains uncertain, especially in the absence of histologic criteria for myocarditis. We agree with the 2013 ESC position statement, which defined "immunohistochemical criteria" for myocarditis to include an abnormal inflammatory infiltrate defined as ≥14 leukocytes/mm2, including up to 4 monocytes/mm2 with the presence of CD3-positive T-lymphocytes ≥7 cells/mm2 [1]. The sensitivity of alternate immunohistochemical criteria has been reported [17].
Case series from the 1990s suggested that enteroviral genomes in the myocardium of HF patients were a biomarker of worse outcomes. An observational study evaluated 41 patients with progressive HF for six months unresponsive to standard therapy who were found to have active lymphocytic myocarditis on biopsy [65]. All 41 were treated with prednisone and azathioprine for six months, and 21 had an improvement in EF at the end of treatment. Of the 20 patients who did not respond to immunosuppressive therapy, 17 had viral genomes (including six with enterovirus) detected by PCR. Of the 21 patients who did respond to treatment, only three had a positive PCR assay (all for hepatitis C virus).
These findings are consistent with those in another study in which persistence of viral genome by PCR was associated with progressive LV dysfunction, while clearance of viral genome was associated with improved LV function [66]. (See "Treatment and prognosis of myocarditis in adults".)
However, viral genome is often present in myocardium without sufficient histologic changes to meet the Dallas criteria [5,9,67]. As an example, viral pathogens, including HHV6 and parvovirus B19, were detected in 67 percent of 245 adults with dilated cardiomyopathy with no accompanying cellular immune response [68].
A case series of 181 adults with clinically suspected viral myocarditis found that neither detection of viral genomes nor Dallas criteria were predictive of time to death or heart transplantation [9]. Outcomes were predicted by immunohistologic evidence of inflammatory infiltrates, and advanced New York Heart Association (NYHA) functional class at entry and inversely related to provision of beta blocker therapy. One interpretation of these data is that certain viruses are pathogenic in acute and chronic dilated cardiomyopathy, but some viral infections may be unrelated to the pathogenesis of cardiomyopathy, especially in the absence of the Dallas histologic criteria for myocarditis. (See 'Identifying the cause of myocarditis' below.)
DIFFERENTIAL DIAGNOSIS — When a patient presents with suspected myocarditis, the differential diagnosis includes other conditions with similar symptoms and signs, including other causes of myocardial injury (including ischemic heart disease and stress cardiomyopathy) and other types of cardiomyopathy, as well as valvular heart disease, congenital heart disease, and pulmonary disease. Echocardiography is helpful for distinguishing many of these disorders. (See "Determining the etiology and severity of heart failure or cardiomyopathy".)
Myocarditis may present similarly to ischemic heart disease with chest pain, ECG abnormalities, and elevated cardiac biomarkers. Coronary spasm, occasionally severe, may accompany myocarditis and cause angina. Wall motion abnormalities seen in myocarditis range from regional wall motion abnormalities (which may be in noncoronary or coronary distributions) to global abnormalities. Exercise-induced wall motion abnormalities may be identified in patients with ischemic heart disease or myocarditis. In patients with myocarditis, these wall motion abnormalities have been attributed to microvascular dysfunction. Coronary angiography is indicated in selected patients with clinical findings suggestive of coronary disease to help differentiate ischemic heart disease from myocarditis (see 'Cardiac catheterization' above). CMR examination is also helpful in distinguishing ischemic heart disease from myocarditis and other causes of late gadolinium enhancement ([LGE]; eg, fibrosis) as the pattern of LGE in myocarditis (largely subepicardial and midwall) generally differs from the typical subendocardial coronary distribution of MI. Of note, LGE related to MI is sometimes detected in the distribution of a patent coronary artery, possibly due to coronary artery recanalization after infarction [69]. (See 'Cardiac catheterization' above.)
Stress (takotsubo) cardiomyopathy may present with similar symptoms (eg, chest pain), signs (eg, physical signs of HF), and test results (including regional wall motion abnormalities and troponin elevation). However, the patterns of wall motion abnormality most commonly seen in stress cardiomyopathy (typically LV apical dysfunction, less commonly mid-ventricular or basal) are generally not seen in myocarditis, and recovery of ventricular function with stress cardiomyopathy is generally more rapid (commonly within one week and generally within four weeks) than with myocarditis. CMR may be helpful since signs of myocardial inflammation and scar, which are typical for myocarditis, are generally absent (except for low intensity LGE) in patients with stress cardiomyopathy. (See "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy" and "Management and prognosis of stress (takotsubo) cardiomyopathy", section on 'Prognosis'.)
The inflammatory phase of several of the inherited arrhythmogenic cardiomyopathies, including arrhythmogenic right ventricular cardiomyopathy, may present with myocarditis with or without sudden death. The presence of inflammation and scar in the absence of other structural abnormalities at autopsy is a well-recognized finding in the arrhythmogenic cardiomyopathies, most notably in those caused by mutations in desmoplakin and filamin C [70-73]. This highlights the importance of family history and, potentially, pedigree analysis and genetic testing to ascertain the underlying cause in patients with myocarditis, particularly as relatives may be at risk [74,75].
Other laboratory testing such as serum protein electrophoresis, fat aspirate and CMR for amyloidosis, and ferritin levels and CMR for myocardial iron overload are helpful in excluding other causes of ventricular dysfunction. (See "Approach to the patient with suspected iron overload", section on 'Sequence and interpretation of testing' and "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)
Identification of another cause of cardiomyopathy does not exclude myocarditis, since biopsy-proven myocarditis may occur in association with other causes of cardiomyopathy, including cardiac amyloidosis [76] and hypertrophic cardiomyopathy [77] and may affect prognosis of these disorders. (See "Hypertrophic cardiomyopathy: Natural history and prognosis".)
IDENTIFYING THE CAUSE OF MYOCARDITIS — The cause of myocarditis may be suggested by information from the clinical evaluation including the history, physical examination, test results (including cardiac imaging), and endomyocardial biopsy. These issues are discussed separately. (See "Myocarditis: Causes and pathogenesis".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults" and "Society guideline links: Myocarditis" and "Society guideline links: Acute rheumatic fever and rheumatic heart disease".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Myocarditis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●When to suspect myocarditis – Myocarditis should be suspected in patients with or without cardiac signs and symptoms (table 2) who present with a rise in cardiac biomarker levels, change in electrocardiogram (ECG) suggestive of acute myocardial injury, arrhythmia, or abnormalities of ventricular systolic function, particularly if these clinical findings are new and unexplained. (See 'When to suspect myocarditis' above.)
●Approach to the diagnosis of myocarditis – The diagnostic evaluation of patients with suspected myocarditis should include the following components (see 'Approach to diagnosis of myocarditis' above):
•Physical examination – History and physical examination to evaluate for symptoms and signs of myocarditis and heart failure (HF) (table 2) and assess possible causes. (See 'Clinical manifestations' above and 'Physical examination' above.)
•Initial laboratory testing – Initial laboratory testing, including an ECG, serum troponin levels, and, generally, a chest radiograph. Some clinicians also check erythrocyte sedimentation rate and c-reactive protein levels, although these have nonspecific markers of inflammation. Natriuretic peptide measurement is indicated if the diagnosis of HF is uncertain. (See 'Initial testing' above.)
•Cardiac imaging – Cardiac imaging for myocarditis includes (see 'Approach to diagnosis of myocarditis' above and 'Cardiac imaging' above):
-Echocardiography – An echocardiogram is performed in all patients with suspected myocarditis to evaluate regional and global ventricular function, valvular function, and other potential causes of cardiac dysfunction. (See 'Echocardiography' above.)
-Coronary angiography – Coronary angiography is indicated in selected patients with clinical presentation indistinguishable from an acute coronary syndrome, lifestyle-limiting coronary disease despite medical therapy, or high-risk features for ischemic heart disease on noninvasive testing. (See 'Cardiac catheterization' above.)
-Cardiovascular magnetic resonance imaging – Cardiovascular magnetic resonance (CMR) imaging is indicated in patients with suspected myocarditis with elevated troponin level and/or ventricular dysfunction, without a clear cause such as ischemic heart disease. CMR may provide supportive evidence of myocarditis. (See 'Cardiovascular magnetic resonance' above.)
•Endomyocardial biopsy – Indications for endomyocardial biopsy (EMB) should be reviewed in patients with clinically suspected myocarditis. The decision on whether to proceed with EMB should be based upon the likelihood that EMB will significantly impact patient management. (See 'Indications for EMB' above.)
Indications for EMB include unexplained new-onset HF of less than two weeks duration associated with hemodynamic compromise or unexplained new onset HF of two weeks to three months duration associated with a dilated left ventricle and new ventricular arrhythmias, Mobitz type II second-degree atrioventricular (AV) block, third-degree AV block, or refractory HF (table 3). Other patient groups who may benefit from EMB are discussed separately. (See "Endomyocardial biopsy", section on 'Indications'.)
●Criteria for diagnosis – A definitive diagnosis of myocarditis is based upon EMB, including histology (Dallas criteria) as well as immunohistochemical stains and detection of viral genomes by molecular techniques, mainly polymerase chain reaction. (See 'EMB diagnostic criteria for myocarditis' above.)
●Differential diagnosis – When a patient presents with suspected myocarditis, the differential diagnosis includes other conditions with similar symptoms and signs, including other causes of myocardial injury (including ischemic heart disease and stress cardiomyopathy) and other types of cardiomyopathy, as well as valvular heart disease, congenital heart disease, and pulmonary disease. Echocardiography is helpful for distinguishing many of these disorders. (See 'Differential diagnosis' above.)
●Causes of myocarditis – The history, physical examination, and clinical evaluation (including cardiac imaging and EMB) may help identify the cause of myocarditis, although the etiology of myocarditis is frequently unknown. (See 'Identifying the cause of myocarditis' above.)
