Myocarditis Pathology

Updated: Nov 05, 2021
  • Author: Fabio R Tavora, MD, PhD; Chief Editor: L Maximilian Buja, MD, MS  more...
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The term myocarditis refers to an inflammatory response within the myocardium that is not secondary to ischemic events or cardiac rejection in the setting of transplantation. The presence of myocyte necrosis is required for certain types of myocarditis—specifically, lymphocytic myocarditis that is triggered by viruses and augmented by autoimmunity and the myocyte damage is believed to be mediated both by direct invasion of the myocardium and by immune insult.

Histologically, some overlap exists among categories of myocarditis, and no finding is specific for a single etiology (see Microscopic Findings). In general, the histologic patterns can be divided into the following categories:

  • Lymphocytic (including viral and autoimmune forms)

  • Eosinophilic (of which hypersensitivity myocarditis is the most common type, followed by hypereosinophilic syndrome)

  • Granulomatous (cardiac sarcoidosis [CS] and giant-cell myocarditis [GCM])

  • Neutrophilic (bacterial, fungal, and early forms of viral myocarditis)

  • Reperfusion type/contraction band necrosis (present in catecholamine-induced injury and reperfusion injury)

Pathologic classification is complicated, however, because tissue biopsies often are not obtained, and a presumptive clinical diagnosis must sometimes be confirmed by means of indirect methods such as serology. [1]



Most often, myocarditis is a diffuse inflammatory process of the myocardium, although instances of focal myocarditis in either the right or the left ventricle have been reported. Cases of sudden death due to myocarditis show a diffuse infiltrate in all sections examined. However, areas of normal heart can be seen; this may explain the low sensitivity of endomyocardial biopsy (EMB) in this setting.



From an etiologic perspective, myocarditis cases usually fall into one of the following four main categories:

  • Infectious

  • Postviral autoimmune-related

  • Autoimmune-mediated (lupus myocarditis, giant-cell myocarditis [GCM])

  • Drug-associated (hypersensitivity myocarditis, toxic myocarditis)

In over 50% of patients, myocarditis is considered idiopathic and is believed to be postviral immune-related, even in the absence of demonstrable viral antigens.

In viral myocarditis, an identifiable infectious organism is present 10-100% of the time, according to various studies. [2, 3, 4, 5, 6, 7, 8] Several factors influence the yield of detection efforts, including the disease stage, the methods used to detect the infectious agent, the sample studied (eg, heart tissue from endomyocardial biopsy [EMB], autopsy material, or indirectly from serum), the amount of tissue available, and the interpretation of the results.

Drug-associated myocarditis is histologically defined as hypersensitivity myocarditis. Drugs associated with myocarditis include clozapine, penicillin, ampicillin, hydrochlorothiazide, methyldopa, and sulfonamide drugs. Radiation therapy and insect bites have been reported to cause heart injury as well. Toxic myocarditis involves drug-induced injury that is not mediated by hypersensitivity and that persists after discontinuance of the drug. It is also associated with later inflammatory stages of catecholamine-induced myocardial injury.

Myocarditis associated with connective tissue disease has been reported in systemic lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis, and other conditions. GCM is considered idiopathic.

More recently, myocarditis in patients using immune checkpoint inhibitors (ICIs) has been reported. [9, 10, 11] In one series, about 1% of patients receiving ICIs had a clinical diagnosis of myocarditis, and about half of them developed a major cardiac event. [9]  The presentation is usually early, with a median of about 30-40 days from therapy initiation. In a case report of documented pathology, for example, an 86-year-old man with metastatic squamous cell carcinoma was elected to start cemiplimab treatment; weeks later, he presented with decreased vision in the left eye, severe fatigue, lower back pain, and bilateral worsening hip pain, until he needed intensive care support. [12] During the clinical investigation, the endomyocardial biopsy revealed an active necrotizing lymphocytic myocarditis. He was diagnosed with cemiplimab-related myasthenia gravis, myositis, and myocarditis. [12]



The true incidence of myocarditis is difficult to determine, and most instances are believed to be subclinical. Laboratory tests are nonspecific, and endomyocardial biopsy (EMB) is not performed in most cases. A study of military recruits that used electrocardiographic (ECG) changes, clinical symptoms, and cardiac enzyme elevation estimated the annual incidence to be approximately 17 per 100,000 population. [13, 14]

Fewer than 2% of all cases of myocarditis are fatal, and it is these cases that are often presented to pathologists. Fatal myocarditis often manifests as sudden or rapid death, and it is most common in infants and young adults. A slight male predominance is seen.


Clinical Features and Imaging

Patients with myocarditis may be asymptomatic; may have very mild, nonspecific symptoms (eg, fever, chills, and dyspnea); or may exhibit more severe symptoms (eg, palpitations, syncope, sudden death).

Most cases of myocarditis are acute and self-limited. Patients typically show electrocardiographic (ECG) alterations, cardiac enzyme elevation, and some evidence of a systemic inflammatory process (eg, arthralgia, malaise, pharyngitis, tonsillitis, upper respiratory tract infection). In such cases, infection is the most common cause, with viral infections being far more common than bacterial infections. Associated pericarditis is common. In most instances, there is no indication for endomyocardial biopsy (EMB), and the diagnosis is assigned clinically.

Some cases follow a rapidly deteriorating course; these are referred to as acute fulminant myocarditis. Fever is common. The presentation is acute, with rapid onset of heart failure that may cause sudden death. Myocardial involvement is often diffuse, yielding a high sensitivity on EMB. The histologic findings usually reveal a lymphocytic pattern, occasionally showing the eosinophilia typical of hypersensitivity myocarditis. Giant-cell myocarditis (GCM) also occurs in rapid cases.

Overall, these patients have a good prognosis if early immunosuppressive therapy is employed. Antiviral agents seem to be of no significant value, because in most cases, the viruses had already been cleared from the organism.

A few cases of myocarditis are characterized by long-term evolution to cardiomyopathy. In these patients, EMB has low sensitivity for detection of inflammation. The prognosis is poor, with some cases requiring heart transplantation.

Not uncommonly, incidental myocarditis that shows a focal lymphocytic process is seen at autopsy. In these cases, lymphocytic myocarditis is again the most common histologic type, but hypersensitivity myocarditis is also common.

Buja et al analyzed data from patients with acute and persistent heart failure (HF) who were referred over a 6-year period to a quaternary center for advanced HF therapies, including mechanical circulatory support, left ventricular assist device (LVAD) implantation, and/or heart transplantation. [15] The yield of positive EMB for myocarditis in the clinical setting of acute heart failure reached 40%. Myocarditis was identified in 36 patients, with initial diagnoses made in 10 (40%) of 25 by EMB, 1 by atrial biopsy (Maze procedure). There were 20 cases of lymphocytic myocarditis, 4 cases of giant cell myocarditis, 3 cases of eosinophilic myocarditis, and 9 cases of granulomatous myocarditis. EMB was performed in 25 patients and was positive in 10 (40%) of cases. [15]

Cardiovascular magnetic resonance imaging (CMRI) appears to hold promise for diagnosing myocarditis in vivo. [16, 17] Pericardial effusion detected by CMRI might serve as a new diagnostic criterion for the noninvasive diagnosis of myocarditis in patients who have clinical symptoms of recent onset and normal left ventricular function.

The Lake Louise criteria was updated in 2018, consisting of two main criteria (T1-based criterion and T2-based criterion). [18] The T1-based criterion is considered to be positive if there exists an increase of native T1 relaxation times, increase of extracellular volume (ECV), or positive late gadolinium enhancement (LGE). The T2-based criterion is positive in cases of increased T2 relaxation times or in cases with regional high T2-signal intensities on T2-weighted images or increased global T2 signal intensity ratio. [18]


Gross Findings

Gross findings in fatal myocarditis cases are nonspecific and include normal or dilated chambers. Ventricular softening and pallor may be present. Concomitant pericardial effusion and pericarditis may be noted in cases of viral or bacterial myocarditis. Late stages of myocarditis may show fibrosis that can be either focal or diffuse, but the distribution is often random (see the image below), in contrast to the subendocardial fibrosis typically seen in ischemia.

Myocarditis Pathology. Myocarditis with scarring. Myocarditis Pathology. Myocarditis with scarring. This short-axis gross photograph of an autopsy specimen from an 8-year-old child with clinical myocarditis shows scarring of both ventricles, more prominent in the left ventricle. The fibrosis shows a random distribution, with epicardial, myocardial, and pericardial involvement.



Microscopic Findings

Endomyocardial biopsy (EMB) is generally indicated if heart failure exists; therefore, it is not performed in most suspected cases of myocarditis. EMB may be warranted when giant-cell myocarditis (GCM) is suspected (to exclude sarcoidosis) and when unexplained recent onset of heart failure is noted (see the images below). The reported incidence of myocarditis in biopsies for new-onset heart failure is 5-15%, [19, 20]  although, according to one study, 12% of patients with new-onset heart failure were given a clinical diagnosis of myocarditis. [21]

Myocarditis Pathology. Endomyocardial biopsy speci Myocarditis Pathology. Endomyocardial biopsy specimen from 4-year-old child with clinically suspected myocarditis. Low magnification of the myocardium shows lymphocytic infiltrate within myocardial fibers. These histologic findings are consistent with myocarditis and compatible with the clinical history, even in the absence of myocyte necrosis.
Myocarditis Pathology. Immunohistochemical stained Myocarditis Pathology. Immunohistochemical stained section of a biopsy specimen from a 4-year-old child with clinically suspected myocarditis. The image demonstrates positivity for CD3, confirming T-cell phenotype.

The Dallas criteria for biopsy-based diagnosis of myocarditis, established in 1987, consist of myocyte necrosis and inflammation. A positive biopsy, however, does not correlate with clinical symptoms; for example, fulminant from chronic myocarditis, which is diagnosed clinically and may respond to immunosuppressive therapy, may show only minimal inflammation because of sampling.

The Dallas criteria include a “borderline” category for the first biopsy and a “resolving myocarditis” category for subsequent biopsies that show no necrosis. [22] Currently, any chronic inflammation in a heart biopsy for new-onset heart failure is considered diagnostic of myocarditis.

Lymphocytic myocarditis as seen at autopsy is rich in T cells and macrophages, and the inflammation is usually diffuse, with focal myocyte necrosis (see the images below). In the early phases of viral myocarditis, a neutrophilic infiltrate can occur and should not be mistaken for a bacterial etiology. The infiltrate often shows numerous neutrophils, lymphocytes, and macrophages, with prominent necrosis and occasional microabscesses (which are prominent in cases of fungal myocarditis).

Myocarditis Pathology. Lymphocytic myocarditis. Th Myocarditis Pathology. Lymphocytic myocarditis. This intermediate magnification of a myocardium shows diffuse infiltrates composed mostly of lymphocytes but also some neutrophils, macrophages, and plasma cells.
Myocarditis Pathology. Focal lymphocytic myocardit Myocarditis Pathology. Focal lymphocytic myocarditis. The intermediate magnification of a myocardium shown reveals focal lymphocyte-rich infiltrate. The significance of focal inflammation at autopsy is often unclear; such focal lesions can be found incidentally.
Myocarditis Pathology. Lymphocytic myocarditis. Hi Myocarditis Pathology. Lymphocytic myocarditis. High magnification of a myocardium shows myocyte necrosis with lymphohistiocytic infiltrates.
Myocarditis Pathology. Fungal myocarditis. Medium Myocarditis Pathology. Fungal myocarditis. Medium magnification of a myocardium shows nonseptate hyphae within myocardial capillaries in association with lymphocytes and neutrophils.

Inflammation due to ischemia is a major differential diagnosis at autopsy, especially at the edge of reperfusion infarcts, where a diffuse interstitial neutrophilic infiltrate may be present. Characteristic features of ischemia-related inflammation include a subendocardial location, a large proportion of neutrophils, extensive necrosis in relation to inflammation, and zonal necrosis in the case of nonreperfusion infarcts.

The presence of giant cells and granulomas necessitates differentiating between GCM and cardiac sarcoidosis (CS). Some authors use the blanket term granulomatous myocarditis to describe any type of myocarditis featuring giant cells, including both GCM and CS. [23]

Histologic findings in CS (see the image below) are similar to those of sarcoidosis of other organs. The diagnosis is established by the presence of epithelioid granulomas with giant-cell formation in association with a variety of inflammatory cells consisting of activated T cells with increased CD4/CD8 ratios and activated monocytes and macrophages. [24, 25]

Myocarditis Pathology. Cardiac sarcoidosis. Low ma Myocarditis Pathology. Cardiac sarcoidosis. Low magnification of a myocardium in an autopsy case demonstrates numerous giant cells and lymphocytes in a background of fibrosis and scarring. In addition to cardiac findings, the patient had extensive involvement of mediastinal lymph nodes by sarcoidosis.

GCM is characterized by diffuse infiltration of the myocardium by a heterogeneous infiltrate composed of abundant lymphocytes, some eosinophils and plasma cells, occasional neutrophils, and scattered prominent giant cells (see the image below). T cells are more numerous than B cells, with CD8+ T cells predominant. Myocyte degenerative changes and myocyte necrosis are invariably present, especially in the early stages of the disease.

Myocarditis Pathology. Giant-cell myocarditis. In Myocarditis Pathology. Giant-cell myocarditis. In this intermediate magnification of a myocardium in a case of sudden death, diffuse infiltration with numerous giant cells, lymphocytes, neutrophils, and eosinophils are seen. Myocyte damage is also present.

In GCM, in contrast to CS, the giant cells are not part of well-formed granulomas, are associated with myocyte necrosis, and do not involve the interstitium and epicardium. Eosinophils can be easily found in GCM, whereas they are rare in CS. [26]

Eosinophilic myocarditis is usually related to hypersensitivity myocarditis, and it is characterized by the presence of infiltrates rich in macrophages and eosinophils (see the image below). In this setting, myocyte necrosis is usually absent, and scattered poorly formed granulomas can be seen. This histologic pattern is more frequent as an incidental finding in explants from heart transplant candidates or in autopsy specimens from patients with no history of any symptoms.

Myocarditis Pathology. Hypersensitivity myocarditi Myocarditis Pathology. Hypersensitivity myocarditis. High magnification of a myocardium shows perivascular infiltrates rich in eosinophils. The patient had a clinical history compatible with drug-induced hypersensitivity myocarditis.

The main differential diagnosis is eosinophilic endomyocardial disease (Loeffler syndrome), which is characterized by extensive necrosis and mural and intravascular thrombi and is not considered myocarditis in either the clinical or the pathologic settings. Rarely, hypersensitivity myocarditis can result in myocyte damage and severe clinical symptoms; it is important to diagnose this condition by means of endomyocardial biopsy (EMB) because cardiac function may improve or normalize when the offending drug is withheld.



In most instances, the inflammatory cells in myocarditis are mature T cells accompanied by a large population of macrophages. The T cells are a mixture of CD4+ and CD8+ cells. Immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) assays are available for the identification of a multitude of microorganisms, including viruses, bacteria, and parasites (eg, Toxoplasma gondii and Trypanosoma cruzi). [7]



There is great interest in the evaluation of endomyocardial biopsy (EMB) or autopsy material to find the microbiologic agents responsible for cases of myocarditis. However, identification of organisms, especially viruses, in clinical samples is problematic because of a high range of reported positivity.

Several studies have documented the use of polymerase chain reaction (PCR) testing in EMB and autopsy specimens to detect parvovirus, adenovirus, enterovirus (most often coxsackievirus), Epstein-Barr virus, Borrelia burgdorferi, and others. [3, 7, 27, 28, 29, 30]

Other studies, however, have shown that organisms may be present when cardiac tissue lacks evidence of inflammation, raising questions about the specificity of detection and reinforcing the need for clinical-pathologic correlation and accurate histologic diagnosis. [31, 32] The positive PCR results in control tissues hamper interpretation of the findings. [32, 33]

Konishi et al reported that molecular imaging of granzyme B activity can visualize T cell-mediated myocardial injury and monitor the response to an anti-inflammatory intervention. [34]


Prognosis and Predictive Factors

Most cases of lymphocytic myocarditis are subclinical and never come to the attention of a physician. In the majority of patients, the condition resolves spontaneously with no known sequelae. In a small percentage of patients, mostly children and young adults, the myocarditis presents as acute-onset fulminant disease and may progress rapidly to sudden death. In these patients, the infiltrates are usually diffuse.

Another subset of patients who develop congestive heart failure may have late morbidity related to the degree of left ventricular dysfunction. Cases of giant-cell myocarditis (GCM) are usually severe, with a higher percentage progressing to death within a short time. Heart transplantation in association with immunosuppressive therapy is one of the only ways of saving most of these patients.

In one study, investigators analyzed the details of 46 patients with GCM seen at their hospital since 1991 and followed the patients for the occurrence of cardiac death or transplantation until May 2015. The investigators examined the association of transplant-free survival with patient characteristics, laboratory data on admission, and myocardial histology in the 38 patients who were diagnosed prior to death or transplantation. The estimate of transplant-free survival was 42% at 5 years from symptom onset, with markers of myocyte injury and cardiac dysfunction helping to predict the outcome. [35]

Patients with hypersensitivity myocarditis and heart failure can improve and heal if the offending drug is discontinued, but some patients may require heart transplantation. More frequently, the pathologist sees incidental hypersensitivity myocarditis at autopsy or in an explant from an asymptomatic patient. For example, in heart transplant patients, who are often on multiple medications, the incidence of this condition is 7% as diagnosed histologically in the explanted heart. [33]