Myocarditis

Myocarditis is inflammation of the myocardium, usually with necrosis of cardiac myocytes. Biopsy-proven myocarditis typically demonstrates inflammatory infiltrate of the myocardium with lymphocytes, neutrophils, eosinophils, giant cells, granulomas, or a mixture.

The pathophysiology of myocarditis remains a subject of research. Potential mechanisms that lead to myocardial injury include:

• Direct cardiomyocyte injury caused by an infectious or other cardiotoxic agent

• Myocardial injury caused by an autoimmune or inflammatory reaction to an infectious or other cardiotoxic agent

Myocardial inflammation can be diffuse or focal. Inflammation can extend into the pericardium, causing myopericarditis. The extent of myocardial involvement and extension into adjacent pericardium determines the type of symptoms. Diffuse involvement can lead to heart failure, arrhythmias and sometimes sudden cardiac death. Focal involvement is less likely to cause heart failure but can lead to arrhythmias and sudden cardiac death. Involvement of the pericardium leads to chest pain and other symptoms typical of pericarditis. Some patients remain asymptomatic whether myocardial involvement is focal or diffuse.

Myocarditis may result from infectious or noninfectious causes. Many cases are idiopathic (see table Causes of Myocarditis).

Infectious myocarditis is most often viral in North America and Western Europe (1, 2). Viruses that cause myocarditis may be cardiotropic, vasculotropic, lymphotropic, directly cardiotoxic, or angiotensin converting enzyme-2 tropic. Commonly implicated viruses include parvovirus B19, human herpes virus 6, enteroviruses, adenoviruses, Epstein-Barr virus, influenza, and coronaviruses (3). Of these, parvovirus B19 and human herpes virus 6 are the most commonly found in the subset of patients undergoing endomyocardial biopsy (4).

In selected populations, infectious myocarditis with other pathogens (eg, bacteria, parasites) is also often associated with rheumatic carditis, Lyme carditis, Chagas disease, or HIV infection (1, 5). Direct myocardial injury due to infection with SARS-CoV-2, with symptoms ranging from mild chest discomfort to fulminant myocarditis, is uncommon in patients with COVID-19 (< 1%), but the risk of myocarditis is 5 to16 times higher in those with infection than in those not infected (6).

Noninfectious causes include systemic autoimmune and inflammatory disorders, cardiotoxins, certain medications, and radiation therapy. Myocarditis caused by medications is termed hypersensitivity myocarditis. Myocarditis after mRNA-based COVID-19 vaccination is very rare (< 0.01% in the highest risk populations of males 12 to 29 years old) and far less common than COVID-associated myocarditis (6, 7, 8). It occurs mostly in adolescent and young adult males, usually within a week of vaccination, and is generally mild.

Eosinophilic myocarditis has various causes. It is an inflammatory cardiomyopathy characterized by eosinophilic infiltration; among the causes is hypersensitivity myocarditis (9).

Genetic substrate plays a significant role in some cases of myocarditis. Genetic variants, including heterozygous mutations in some genes associated with inherited arrhythmia or cardiomyopathy, may increase susceptibility to infectious or other environmental factors that can cause myocarditis (1, 3). There are also rare familial chronic inflammatory cardiomyopathies.

The clinical presentation of myocarditis is variable. Patients may be minimally symptomatic or have fulminant heart failure and fatal arrhythmias. Symptoms depend on the etiology of the myocarditis as well as the extent and severity of myocardial inflammation.

Patients may report an antecedent viral syndrome, upper respiratory symptoms, or other nonspecific illness, often 1 to 4 weeks before the onset of myocarditis symptoms. Or, they may report a history of exposure to a toxin or medication known to cause myocarditis.

Heart failure symptoms may include fatigue, dyspnea, and edema. Patients may show signs of fluid overload with crackles, elevated jugular venous pulses, and edema. Cardiac examination may be significant for a third (S3) or fourth (S4) heart sound. Systolic murmurs of mitral regurgitation and tricuspid regurgitation may be present in patients with ventricular enlargement. Pulsus alternans, palpable on physical examination or visible on pulse oximeter or arterial pressure waveforms, indicates severe left ventricle systolic dysfunction.

Sudden cardiac death due to a fatal arrhythmia is sometimes the presenting feature. Patients may experience preceding palpitations or syncope.

When patients have concomitant pericardial inflammation, they may present with chest pain typical of pericarditis. Dull or sharp precordial or substernal pain may radiate to the neck, trapezius ridge (especially the left), or shoulders. Pain ranges from mild to severe. Unlike ischemic chest pain, pain due to pericarditis is usually aggravated by thoracic motion, cough, breathing, or swallowing food; it may be relieved by sitting up and leaning forward. A pericardial friction rub may be auscultated in patients with a pericardial effusion.

Certain clinical findings may be indicative of a specific cause of myocarditis. Infectious myocarditis may be preceded by symptoms of fever, myalgias, and other symptoms depending on the exact pathogen. Medication-related or hypersensitivity myocarditis may be accompanied by a rash. Enlarged lymph nodes may be indicative of sarcoidosis as the underlying etiology. Fulminant heart failure and arrhythmias may be indicative of giant cell myocarditis.

Myocarditis can be acute, subacute, or chronic. There are no set time-frames for each phase. The acute phase typically lasts a few days while the subacute phase lasts weeks to months. If myocarditis does not resolve after a few months, it is called chronic myocarditis. In some cases, myocarditis can lead to dilated cardiomyopathy. Fulminant myocarditis (also called acute fulminant myocarditis) is a sudden, severe, and life-threatening subset of myocarditis that requires inotropic and/or mechanical support prior to recovery (or transplant) (1).

• Cardiac troponin and complete blood count

• Cardiac imaging (echocardiography and cardiac MRI)

• Electrocardiography (ECG)

• Sometimes, endomyocardial biopsy

• Tests to identify cause

Myocarditis should be suspected when otherwise healthy patients with no cardiac risk factors present with symptoms of heart failure or arrhythmias. Cardiac enzymes, cardiac imaging, and ECG are not specific for myocarditis but can be diagnostic in the appropriate clinical setting (1).

The stepwise diagnostic approach begins with recognition of the clinical syndrome of myocarditis, with initial testing including a cardiac troponin, a complete blood count, an echocardiogram, and an electrocardiogram (2). Hemodynamic stability and rhythm are evaluated and managed as needed, and the need for hospitalization or transfer to a heart failure center are assessed. Finally, a definitive diagnostic test, either cardiac MRI or endomyocardial biopsy, is performed (see figure Evaluation and Management of Clinically Suspected Myocarditis).

Evaluation and Management of Clinically Suspected Myocarditis

CBC = complete blood count; ECG = electrocardiography; LVAD = left ventricular assist device. Data from Writing Committee, Drazner MH, Bozkurt B, et al. 2024 ACC Expert Consensus Decision Pathway on Strategies and Criteria for the Diagnosis and Management of Myocarditis: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2025;85(4):391-431. doi:10.1016/j.jacc.2024.10.080

Cardiac troponin can be abnormal in patients with acute myocarditis. Cardiac troponin can be elevated due to inflammation and/or necrosis of cardiac myocytes. High-sensitivity troponin assays have a reported sensitivity of 64 to 100% for acute myocarditis (3). Creatine kinase (CK) isoenzymes are not used in the diagnosis of myocarditis.

Cardiac imaging can be abnormal in patients with myocarditis, and cardiac MRI can be diagnostic.

An echocardiogram can be normal in early or mild myocarditis, but segmental wall motion abnormalities (mimicking myocardial ischemia) can be seen. Left ventricular dilation or other morphologic changes and global systolic dysfunction can also be seen as in dilated cardiomyopathy. Global strain may be abnormal. Diastolic function is often abnormal on echocardiography.

Cardiac MRI is important in the diagnosis of myocarditis and in many cases is the definitive diagnostic modality. Cardiac MRI of patients with myocarditis may show a characteristic pattern of late gadolinium enhancement in the subepicardial and mid-myocardial walls (in contrast to ischemia where late gadolinium enhancement is usually subendocardial with extension to mid-myocardial and epicardial walls). Other features of myocarditis on cardiac MRI are the presence of myocardial edema and myocardial hyperemia relative to skeletal muscle. Formal diagnosis based on cardiac MRI requires at least one T1-based finding supporting myocardial edema and at least one T2-based finding supporting non-ischemic myocardial injury, with findings of pericarditis or left ventricle systolic dysfunction providing supporting evidence (4).

ECG can be normal or abnormal in patients with myocarditis. ST segment abnormalities are common and can mimic myocardial ischemia. ST segment elevation is sometimes seen, but more common findings include nonspecific ST-T wave changes. Atrial and ventricular enlargement may also be reflected on ECG. Patients may experience conduction delays and atrial or ventricular arrhythmias, including sinus tachycardia, ventricular tachycardia, and ventricular fibrillation. Heart block may occur in Lyme carditis, giant cell myocarditis, or sarcoidosis. Low QRS voltage may signal severe edema and/or ventricular dysfunction.

MRI of Patient with Myocarditis and Pericardial Effusion

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Patchy mid wall (bottom white arrow) and epicardial (top white arrow) delayed enhancement on MRI is consistent with myocarditis. This patient also has a pericardial effusion (red arrow).

© 2017 Elliot K. Fishman, MD.

Endomyocardial biopsy showing inflammatory infiltrate of the myocardium with necrosis of adjacent myocytes is the gold standard for diagnosis of myocarditis. However, this test has low sensitivity for diagnosis of myocarditis due to sampling error (5). Therefore, a positive biopsy result is diagnostic for myocarditis, but a negative result does not exclude it. In addition, the biopsy carries a risk of complications, including myocardial rupture and death, so is not routinely performed. Endomyocardial biopsy should be performed in cases of fulminant heart failure, ventricular arrhythmias or heart block, or if results would affect management and the potential benefit outweighs the risk (eg, if there is suspicion for giant cell myocarditis where prompt treatment can decrease mortality rates). Endomyocardial biopsy should also be considered in cases of suspected immune checkpoint inhibitor myocarditis with peripheral eosinophilia to evaluate for eosinophilic myocarditis, as well as in cases of dilated cardiomyopathy, high grade heart block, ventricular arrhythmia, and heart failure where the diagnosis is unclear but myocarditis remains a diagnostic possibility (2, 5, 6).

• Treatment of heart failure and arrhythmias

• Treatment of specific etiologies

The overall approach to the treatment of myocarditis is based on disease severity and the underlying cause (1). Hemodynamic or electrical instability is treated first, with invasive therapies when necessary. Heart failure is managed medically once stable. Cause-specific treatment may include removal of inciting agents, use of immunosuppressive agents, and/or antimicrobial therapy. There should also be ongoing surveillance with biomarkers and imaging to guide clinical decisions. The table Myocarditis Staging and Management summarizes management strategies based on disease stage.

Hemodynamic instability and cardiogenic shock in cases of severe or fulminant myocarditis should be identified and managed with diuresis, afterload reduction, inotropic support, and mechanical circulatory support when indicated. Intra-aortic balloon pump (IABP), left ventricular assist device (LVAD), or transplantation may be necessary. Similarly, atrial and ventricular arrhythmias are treated with antiarrhythmic therapy. Heart block can be treated with temporary pacing but may require insertion of a permanent pacemaker if conduction abnormalities persist.

Once the patient is stabilized, heart failure should managed according to established guideline-directed medical therapy. For patients with a reduced left ventricular ejection fraction, management typically includes a combination of angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor/neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists, receptor blockers (ARBs), and sodium-glucose co-transporter 2 (SGLT2) inhibitors.

For non-infectious causes, particularly hypersensitivity myocarditis, removal of the causative agent is a critical part of treatment.

Symptomatic treatment of chest pain may include nonsteroidal anti-inflammatory drugs (NSAIDs) or colchicine, particularly for chest pain with associated pericardial inflammation, although NSAIDS should generally be avoided if left ventricular ejection fraction is significantly reduced (Symptomatic treatment of chest pain may include nonsteroidal anti-inflammatory drugs (NSAIDs) or colchicine, particularly for chest pain with associated pericardial inflammation, although NSAIDS should generally be avoided if left ventricular ejection fraction is significantly reduced (1).

For symptomatic patients meeting diagnostic criteria for myocarditis, strenuous activity including competitive sports is restricted for 3 to 6 months, with the timing of gradual return to play determined by:

• Clinical course

• Resolution of myocardial inflammation on MRI

• Arrhythmia burden on ambulatory ECG (Holter monitor)

• Exercise capacity, symptoms, and ectopy during exercise electrocardiography