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. 
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. [2, 3]
Fewer than 2% of all cases of myocarditis are fatal, and these are the cases that are commonly 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.
From an etiologic perspective, myocarditis cases usually fall into 1 of the following 4 main categories:
Autoimmune-mediated (lupus myocarditis, giant-cell myocarditis [GCM])
Drug-associated (hypersensitivity myocarditis, toxic myocarditis)
In more than 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. [4, 5, 6, 7, 8, 9] 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 are 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.
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.
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, and 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, or 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 in 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.
Cardiovascular magnetic resonance imaging (MRI) appears to hold promise for diagnosing myocarditis in vivo. [10, 11] Pericardial effusion detected by cardiovascular MRI 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.
Gross findings in fatal myocarditis cases are nonspecific and include normal or dilated chambers. Softening and pallor of the ventricles may be present. Concomitant pericardial effusion and pericarditis may be present 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.
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%, [12, 13] though, according to one study, 12% of patients with new-onset heart failure were given a clinical diagnosis of myocarditis. 
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.  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 not be mistaken for 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).
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 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. 
Histologic findings in CS (see the image below) are similar to those in 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. [17, 18]
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.
In GCM, as contrasted with 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. 
Eosinophilic myocarditis is usually related to hypersensitivity myocarditis and 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.
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 EMB because cardiac function may improve or normalize when the offending drug is withheld.
In most instances, the inflammatory cells 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). 
Currently, 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. [5, 9, 20, 21, 22, 23]
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. [24, 25] The positive PCR results in control tissues hamper interpretation of the findings. [25, 26]
A study by 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. 
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, 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.
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. 
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Fabio R Tavora, MD, PhD Associate Medical Director, Argos Laboratory, Visiting Scientist, Paulista Medical School, Universidade Federal de São Paulo (EPM/UNIFESP), Brazil
Fabio R Tavora, MD, PhD is a member of the following medical societies: College of American Pathologists, United States and Canadian Academy of Pathology, International Society of Urological Pathology
Disclosure: Nothing to disclose.
Allen Patrick Burke, MD Associate Professor, Department of Pathology, University of Maryland School of Medicine; Chairman, Department of Cardiovascular Pathology, Armed Forces Institute of Pathology
Allen Patrick Burke, MD is a member of the following medical societies: American Academy of Forensic Sciences, American College of Cardiology, American College of Gastroenterology, American Medical Association, Society for Cardiovascular Pathology, United States and Canadian Academy of Pathology
Disclosure: Nothing to disclose.
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