INTRODUCTION — Myocarditis is an inflammatory disease of cardiac muscle, which is definitively diagnosed on endomyocardial biopsy (EMB) by established histologic, immunologic, and immunohistochemical criteria . It can be acute, subacute, or chronic, and there may be either focal or diffuse involvement of the myocardium.
The approach to the etiologic evaluation of myocarditis, causes and pathogenesis of myocarditis will be reviewed here. Issues related to the clinical manifestations, diagnosis, natural history, and treatment of myocarditis are discussed separately. (See "Clinical manifestations and diagnosis of myocarditis in adults" and "Treatment and prognosis of myocarditis in adults".)
APPROACH TO IDENTIFYING THE CAUSE OF MYOCARDITIS — In a patients with suspected or confirmed myocarditis, the history and clinical presentation may suggest specific etiologies of myocarditis such as an infectious agents, toxin, hypersensitivity reactions, systemic disorders (table 1). However, an etiology is often difficult to identify, and the cause is frequently unknown.
Clinical presentation — The clinical presentation may suggest a specific cause of myocarditis:
●Recent exposure to drugs, vaccines, or infectious agents associated with myocarditis should be assessed when hypersensitivity myocarditis is suspected (table 1). Immune checkpoint inhibitors targeting CTLA-4, PD-1, and PD-1 ligand can cause lymphocytic myocarditis. (See "Chronic Chagas cardiomyopathy: Clinical manifestations and diagnosis" and "Lyme carditis", section on 'Evaluation and Diagnosis' and "Trichinellosis", section on 'Diagnosis' and "Toxoplasmosis: Acute systemic disease".)
●Fulminant clinical course (new onset severe heart failure requiring parenteral inotropic or mechanical circulatory support) suggests an acute myocarditis that is likely to show diffuse inflammatory infiltrates on endomyocardial biopsy (EMB) . Causes include giant cell myocarditis, eosinophilic myocarditis, cardiac sarcoidosis, and viral or idiopathic lymphocytic myocarditis. (See 'Giant cell myocarditis' below and 'Eosinophilic myocarditis' below and "Endomyocardial biopsy", section on 'Fulminant HF'.)
●Early AV block, arrhythmias or refractory heart failure – Presentation with new-onset heart failure of 2 weeks to 3 months duration and new ventricular arrhythmias, Mobitz type II second-degree atrioventricular (AV) block, third-degree AV block, or refractory heart failure also suggests giant cell myocarditis or cardiac sarcoidosis. Diphtheria toxin can cause bradycardia. (See 'Giant cell myocarditis' below and "Endomyocardial biopsy", section on 'Early AV block, arrhythmias, or refractory HF'.)
●Eosinophilia is present in most but not all patients with eosinophilic myocarditis (EM). (See 'Eosinophilic myocarditis' below.)
●Nonspecific findings – While a viral prodrome of fever, myalgias, and muscle tenderness may precede viral myocarditis, fever is not specific for viral myocarditis as it may accompany other types of myocarditis including various forms of eosinophilic myocarditis. (See 'Viral or "idiopathic" myocarditis' below and 'Eosinophilic myocarditis' below.)
Also, measurement of acute and convalescent viral antibody titers appear to be of little use in determining the etiology in patients with dilated cardiomyopathy, since there was no difference between the patients and matched community controls who shared the same environment or household contacts .
Cardiovascular magnetic resonance (CMR) findings consistent with myocarditis are not pathognomonic and do not generally distinguish among causes of myocarditis. Although a study suggested that certain LGE focal patterns may be specific for certain viral pathogens , a later study found that CMR findings were not associated with viral genome polymerase chain reaction (PCR) positivity or specific virus type . Late gadolinium enhancement (LGE) has been identified in some patients with nonischemic cardiomyopathy of unclear etiology . Some patients with nonischemic cardiomyopathy with LGE may have myocarditis, although this has not been established.
Endomyocardial biopsy — Indications for EMB are discussed separately. (See "Endomyocardial biopsy", section on 'Indications'.)
Examination of the EMB is diagnostic for some causes of myocarditis (eg, giant cell myocarditis, sarcoidosis, and other autoimmune forms and infectious causes) [7-9]. As described above, detection of viral genome on EMB specimen may suggest a cause in the presence of histologic evidence of myocarditis. However, viral culture of myocardial samples for viruses is rarely successful. (See "Clinical manifestations and diagnosis of myocarditis in adults", section on 'PCR and immunohistochemistry' and "Clinical manifestations and diagnosis of cardiac sarcoidosis".)
Preliminary studies suggest a potential future role for measurement of serum anti-heart autoantibodies. Anti-heart autoantibodies to various autoantigens are found in patients with myocarditis or dilated cardiomyopathy (DCM)  (see 'Autoimmune mechanisms' below). Lack of viral genome on EMB with detectable serum anti-heart autoantibodies suggests immune-mediated DCM or myocarditis and may predict beneficial response to immunosuppression . Among asymptomatic relatives of DCM patients, the presence of anti-heart autoantibodies is an independent predictor for development of DCM .
CAUSES AND THEIR FREQUENCIES — The frequency of myocarditis and its specific causes have not been well defined; the clinical presentation is too variable and there is no accurate and simple test that can be used confirm the diagnosis or cause.
Myocarditis can be caused by a variety of infectious and noninfectious illnesses (table 1). Among the infectious etiologies, viruses are the presumed to be the most frequent pathogens, but bacteria, fungi, protozoa, and helminths can also cause myocarditis. [13,14].
In resource-abundant countries, viral infection is the most frequently identified cause of myocarditis. In many resource-limited countries, rheumatic carditis, Chagas disease, and disorders associated with human immunodeficiency virus (HIV) infection are common causes of myocarditis.
Viral or "idiopathic" myocarditis — Viral infection is the most commonly identified cause of lymphocytic myocarditis [15,16]. In the 1960s, a link was suggested by seroepidemiologic studies between enteroviral infection, particularly coxsackievirus, and human myocarditis . Since that time, approximately 20 viruses have been implicated in human myocarditis (table 1). Molecular techniques, such as PCR and in situ hybridization, have permitted the direct detection of viral genomes in the hearts of patients with acute myocarditis and dilated cardiomyopathy [18,19].
Pathogen — Adenovirus and enterovirus were the most commonly identified viruses in the 1990s. In later studies, parvovirus B-19 and human herpesvirus 6 have been identified more frequently [4,18-24]. In addition, many other viruses have been implicated including HIV, hepatitis C, cytomegalovirus, and varicella [19,20,25-28]. (See 'COVID-19' below and 'HIV' below.)
Viral infection, defined as the presence of viral genomes in heart biopsy specimens, is commonly associated with myocarditis in series from Western Europe and North America. The most frequently implicated viruses in the 1980s and 1990s were Coxsackie B virus [16,18,29-31], adenovirus [18,31], hepatitis C , cytomegalovirus (CMV) [18,33,34], echovirus , influenza virus , Epstein-Barr virus (EBV) [18,35], and the viruses of childhood exanthematous diseases, including parvovirus B19 [13,18,31,36-38]. The most common viral genomes identified in patients with suspected myocarditis are human herpes virus 6 and parvovirus B19 [19,20,39]. Enterovirus still causes myocarditis in small regional outbreaks. H1N1 influenza A infection may cause fulminant myocarditis .
The relative frequency and type of viral infection as a cause of myocarditis was best evaluated in a large multicenter series of patients with biopsy-proven myocarditis . The study included 624 patients, age 1 day to 42 years (mean 6.2 years), with acute HF or cardiovascular collapse and an endomyocardial biopsy (EMB) positive for myocarditis by the Dallas criteria. (See "Clinical manifestations and diagnosis of myocarditis in adults", section on 'Dallas criteria'.)
Cultures were obtained from blood, urine, stool, nasopharynx, and EMB specimens. Serial serologies were obtained, and PCR was performed on blood and cardiac tissue to identify viral nucleic acid. An additional 149 patients had acute HF with a negative EMB and were diagnosed with new onset dilated cardiomyopathy (DCM); 165 control patients with other cardiac disorders were also evaluated. The following observations were made:
●Serology, cultures, and PCR (of cardiac tissue) each detected a viral pathogen in approximately one-third of myocarditis patients; PCR detected a pathogen in 20 percent of DCM patients and only 1.4 percent of controls. Blood samples were positive by PCR in only 1 percent.
In case series, parvovirus 19 has been commonly detected by PCR from myocardial biopsy specimens in patients with acute and chronic dilated cardiomyopathy [10,19,36]. The parvovirus genome has also been found in normal tissues .
The PCR findings should not be interpreted as providing a definitive diagnosis of the cause of myocarditis cases, since intercurrent or previous viral infection unrelated to the episode of myocarditis cannot be ruled out . Furthermore, among patients who had both positive peripheral cultures and a positive PCR, the results were in agreement in only 76 percent of cases. Despite these concerns, these data suggest that viral pathogens are commonly associated with histologic evidence of myocarditis.
COVID-19 — Reports of myocarditis in patients with coronavirus disease 2019 (COVID-19) are discussed separately. (See "COVID-19: Cardiac manifestations in adults", section on 'Myocarditis' and "COVID-19: Cardiac manifestations in adults", section on 'Myocardial histology and viral genome analysis'.)
Myocarditis related to vaccination to prevent SARS-CoV-2 infection is discussed separately. (See "COVID-19: Vaccines".)
HIV — Myocarditis associated with (human immunodeficiency virus) HIV infection is discussed separately. (See "Cardiac and vascular disease in patients with HIV", section on 'Myocarditis'.)
Incidence and prevalence — The true incidence of idiopathic or "viral" myocarditis in the general population is unknown. In early studies, cardiac involvement was suspected to occur in 3.5 to 5 percent of patients during outbreaks of Coxsackievirus infection [29,42,43]. However, there is significant difficulty in establishing a diagnosis of myocarditis because EMB, the diagnostic reference technique, is infrequently used and there is no established noninvasive "gold standard." Furthermore, the sensitivity of EMB, which may reveal a lymphocytic infiltrate, sometimes with evidence of myocardial damage, may be as low as 35 percent by conventional histology (Dallas criteria), although immunohistochemistry and viral PCR have yielded higher sensitivity [10,18,19,31,35,38]. (See "Clinical manifestations and diagnosis of myocarditis in adults", section on 'Endomyocardial biopsy'.)
Autopsy studies have revealed varying estimates on the incidence of myocarditis that vary with the population studied. In a registry of 1866 young athletes who died suddenly, 6 percent had myocarditis . A 5 percent prevalence of active myocarditis was reported in a high-risk group of 186 sudden, unexpected medical deaths in children . Myocarditis is responsible for approximately 2 percent of infant, 5 percent of childhood, and 5 to 12 percent of young athlete sudden cardiovascular death .
Other reports have evaluated the prevalence of myocarditis as a cause of initially unexplained DCM. In a review of 1230 such patients, myocarditis as defined by the Dallas criteria was felt to be responsible in 9 percent , and myocarditis was identified in 10 percent in the over 2200 patients with unexplained HF of less than two years duration in the Myocarditis Treatment Trial .
Certain groups appear to be at increased risk for fulminant viral myocarditis. As an example, children, especially neonates and those who are immunocompromised, may have a severe illness with hemodynamic compromise. In one series, lymphocytic myocarditis was present in 25 of 62 children with dilated cardiomyopathy (40 percent) who underwent cardiac histologic examination within two months of presentation with dilated cardiomyopathy .
Protective effect of initial immune response — By age 30, between 18 and 94 percent of people have antibodies to one or more coxsackie B virus serotypes [50-52]. It is likely that this humoral response soon after infection is beneficial, acting to decrease inflammation.
Compatible with the beneficial effect of the initial immune response is the observation from the Myocarditis Treatment Trial Investigators that findings consistent with a stronger humoral and cellular immune response were associated with less severe initial disease . Supporting this concept, immune deficient mice develop a severe myocarditis between 7 and 14 days after inoculation with a high subsequent mortality .
Among the factors that may be protective in the initial immune response are regulatory T cells , natural killer (NK) cells , nitric oxide , and interferon beta and interferon gamma [57-59]. In a transgenic mouse model in which the pancreatic beta cells express interferon gamma, the spread of an infecting virus is reduced, and infection with coxsackievirus B3 does not produce myocarditis as it does in normal mice . In a mouse strain lacking the interferon beta gene, susceptibility to coxsackievirus B3 is increased . (See 'Role of cytokines' below.)
These data, which come almost entirely from animal models, suggest the importance of reducing the level of viremia early during infection. If, however, the initial immune response is insufficient, persisting and possibly replication deficient viruses may drive an adverse autoimmune immune response or directly cause myocyte damage. (See 'Autoimmune mechanisms' below.)
Giant cell myocarditis — Idiopathic giant cell myocarditis is a rare, severe, virus-negative, and frequently fatal type of autoimmune myocarditis that may respond to immunosuppressive therapy . This disorder has been attributed to T lymphocyte-mediated inflammation and is associated with systemic autoimmune disorder in approximately 20 percent of cases [61-63]. In an animal model, a disorder similar to giant cell myocarditis was induced by immunization with cardiac myosin . Giant cell myocarditis recurs in the native heart of 12 percent of patients followed for an average of 5.5 years .
Eosinophilic myocarditis — Eosinophilic myocarditis (EM) is characterized by myocardial eosinophilic infiltration and is usually accompanied by eosinophilia (75.9 percent of published cases of histologically proven EM) .
Hypersensitivity myocarditis — Hypersensitivity myocarditis (HSM, a form of eosinophilic myocarditis) is an autoimmune reaction in the heart that is often drug-related and is usually characterized by acute rash, fever, peripheral eosinophilia, and ECG abnormalities such as nonspecific ST segment changes or infarct patterns [67,68]. However, some patients present with sudden death or rapidly progressive HF. The true incidence of HSM is unknown. One estimate comes from an autopsy study, which identified 16 cases in more than three thousand consecutive autopsies (<0.5 percent) . In other series, the prevalence of clinically undetected HSM in explanted hearts ranged from 2.4 to 7 percent . Hypersensitivity myocarditis accounts for approximately one-third of published cases of histologically established eosinophilic myocarditis .
HSM is usually temporally related to a recently initiated medication. Numerous drugs have been implicated in this drug-induced hypersensitivity syndrome, including antibiotics (including minocycline, tetracycline, beta-lactam antibiotics, and azithromycin), central nervous system agents (clozapine, carbamazepine, phenytoin, benzodiazepines, and tricyclic antidepressants), vaccines, antitubercular agents, methyldopa, diuretics (hydrochlorothiazide, furosemide), and aminophylline [70-72]. However, HSM does not always develop early in the course of drug use. As an example, patients taking the antipsychotic agent clozapine have been reported to develop myocarditis more than two years after the drug was started . (See "Drug allergy: Pathogenesis".)
HSM has also been seen in 2.4 to 23 percent of patients treated with dobutamine infusion [74-78]. It is uncertain whether this reaction represents hypersensitivity to the drug itself or a reaction to sodium bisulfite, which is a preservative in many dobutamine preparations [74,76]. It has been diagnosed either on EMB or retrospectively after explantation of the native heart. In some cases, tapering or discontinuation of dobutamine infusion has resulted in diminution of the peripheral eosinophilia and histologic improvement .
Histologically, HSM is usually characterized by an interstitial infiltrate with prominent eosinophils, but little myocyte necrosis . However, occasional patients with apparent drug hypersensitivity have giant cell myocarditis, granulomatous myocarditis, or necrotizing eosinophilic myocarditis [79,80]. These disorders can usually be distinguished from hypersensitivity myocarditis only by EMB. (See "Treatment and prognosis of myocarditis in adults", section on 'Eosinophilic myocarditis'.)
Vaccine-related — A history of vaccination (particularly with smallpox) within the 30 days prior to symptom onset should prompt consideration of the diagnosis of hypersensitivity myocarditis or myopericarditis. Because tests for vaccinia viremia are only rarely positive and viral antibody titers rise after successful vaccination, these tests are not helpful, and the clinical suspicion is based primarily upon the temporal relationship . (See 'Pathogen' above and "Myopericarditis", section on 'Vaccinia-associated myopericarditis'.)
Vaccinia virus inoculation for protection against smallpox infection resulted in myocarditis with or without associated pericarditis in approximately 1.2 per 10,000 military vaccinees and 6 per 10,000 civilian vaccinees [82,83]. In the civilian vaccination program, the incidence of myocarditis with or without associated pericarditis was 1.3 per 10,000 vaccinees if only probable cases are included and 5.5 per 10,000 vaccinees if suspected cases are included . The lower rate in military vaccinees could reflect a highly selected fit population without underlying disease. (See "Vaccines to prevent smallpox, mpox (monkeypox), and other orthopoxviruses", section on 'Complications'.)
Case reports have reported temporal association between other vaccines and eosinophilic myocarditis, including conjugate meningococcal C and hepatitis B vaccines , and tetanus toxoid immunization .
Myocarditis related to vaccination to prevent SARS-CoV-2 infection is discussed separately. (See "COVID-19: Vaccines".)
Eosinophilic granulomatosis with polyangiitis — EGP accounted for 12.8 percent of published cases of eosinophilic myocarditis in a 2017 review .
Hypereosinophilic syndrome — Hypereosinophilic syndrome accounted for 8.4 percent of published cases of eosinophilic myocarditis in a 2017 review .
Idiopathic or undefined — Approximately one-third of published cases of EM have no identified cause.
Celiac disease — Reports from Italy suggest that celiac disease, which is often clinically unsuspected, accounts for as many as 5 percent of patients with autoimmune myocarditis or idiopathic DCM [86,87]. In one review, 187 consecutive patients with myocarditis were screened for IgA antiendomysial and anti-tissue transglutaminase antibodies; patients with a positive test underwent duodenal endoscopy and biopsy . (See "Diagnosis of celiac disease in adults".)
The following findings were noted:
●Nine patients (4.8 percent) had celiac disease, compared with 1 of 306 controls (0.3 percent). All nine had anti-heart antibodies in the serum.
●None of these patients had classic gastrointestinal symptoms of celiac disease (recurrent abdominal pain, diarrhea, and weight loss), but all had iron deficiency anemia that was refractory to iron replacement.
●Four patients with ventricular arrhythmia and normal cardiac function improved with a gluten-free diet alone. Five patients had progressive HF that failed to respond to more than six months of conventional HF therapy; they were then treated with immunosuppression and a gluten-free diet with a marked improvement in symptoms and left ventricular ejection fraction (LVEF; absolute 18 to 35 percent increase). Although spontaneous improvement is common in patients with myocarditis, these patients had failed a prolonged course of standard therapy.
In a study of 45 children with celiac disease, subclinical systolic dysfunction was present in those children who had high titers of antiendomysial antibodies . Autoimmune disorders occur with increased frequency in patients with celiac disease and may be related in part to antigen overload resulting from increased intestinal permeability. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults".)
Although these findings are intriguing, it would be premature to screen all patients with otherwise unexplained myocarditis for celiac disease. However, it is reasonable to ask about a history of gastrointestinal complaints or refractory iron deficiency.
Arrhythmogenic cardiomyopathy — Arrhythmogenic cardiomyopathy (ACM) is an arrhythmic heart muscle disorder that is not explained by ischemic, hypertensive, or valvular heart disease, in which the clinical presentation is symptomatic and/or documented arrhythmia. Cohorts with arrhythmogenic right ventricular cardiomyopathy (ARVC) are the best characterized of patients with ACM, in part because of the early recognition of the unusual finding of predominantly RV disease. Since the identification of the genetic determinants of ARVC as a disease of the desmosome, the broader spectrum of disease, including biventricular and predominantly LV disease, has been recognized. ACM may be the clinical presentation of a systemic disorder (eg, sarcoidosis), infection (eg, Chagas disease), or may represent an apparently isolated cardiac abnormality (eg, myocarditis). The potential importance of inherited forms of ACM presenting with myocarditis warrants greater awareness within the clinical community . When systemic and infectious causes of myocarditis have been excluded, before accepting idiopathic as a "diagnosis," inherited forms should be excluded. The increasing availability and expertise with CMR and fluorodeoxyglucose positron emission tomography provide a more widely accessible and accurate means of establishing myocardial inflammation than previous reliance on biopsy and clinical features. Data from CMR and postmortem studies of patients with ACM have revealed evidence of active myocarditis and/or evidence of previous myocarditis based on patterns of fibrosis. ACM caused by mutations in desmoplakin, filamin C, and desmin, in particular, has been associated with either CMR or postmortem evidence of active or previous myocarditis [90-96]. ARVC is discussed further separately. (See "Arrhythmogenic right ventricular cardiomyopathy: Pathogenesis and genetics" and "Arrhythmogenic right ventricular cardiomyopathy: Anatomy, histology, and clinical manifestations".)
Hypertrophic cardiomyopathy — Histologic findings compatible with myocarditis can occur in patients with hypertrophic cardiomyopathy and have been associated with rapid deterioration in LV systolic performance; viral genomes have been identified in some of these patients [89,97].
Endomyocardial fibrosis — Isolated endomyocardial inflammation and fibrosis is seen with Löffler cardiomyopathy, tropical endomyocarditis, hypereosinophilic syndrome, and some adverse drug reactions. (See "Endomyocardial fibrosis".)
Sarcoidosis — The clinical manifestations of cardiac sarcoidosis are discussed separately. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis".)
Sequelae of non-viral infections — Myocarditis is a sequelae of other infectious diseases including acute rheumatic fever due to group A streptococci and Chagas disease. (See "Acute rheumatic fever: Epidemiology and pathogenesis" and "Chronic Chagas cardiomyopathy: Clinical manifestations and diagnosis".)
Autoimmune disorders — Myocarditis is a complication of autoimmune disorders such as systemic lupus erythematosus, granulomatosis with polyangiitis , giant cell arteritis, and Takayasu arteritis [98-100]. Among patients with lupus, myocarditis has been clinically suspected in approximately 9 percent of cases, including approximately 6 percent with global hypokinesis on echocardiography . Postmortem studies have suggested that the majority of patients dying of lupus have myocardial involvement. (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults", section on 'Myocarditis'.)
Cocaine abuse — Myocarditis associated with cocaine abuse is discussed separately. (See "Clinical manifestations, diagnosis, and management of the cardiovascular complications of cocaine abuse", section on 'Myocarditis'.)
PATHOGENESIS — Myocarditis results from interaction between a wide variety of environmental exposures (including infectious agents, drugs, toxins, and radiation exposure) (table 1) with an individual’s immune system which may be modulated by genetic factors . Of note, a number of inherited cardiomyopathies (eg, Fabry disease, arrhythmogenic right ventricular cardiomyopathy, or hypertrophic cardiomyopathy), may present with features of acute or chronic myocarditis, although the relationship between inflammatory and gene-mediated processes is uncertain [97,102].
Models for acute and chronic myocarditis in response to viral infection have been postulated (figure 1). The acute and chronic models do not exclude each other, and may account for the progression from myocarditis to DCM in distinct patient subsets as described in the following sections .
Acute model — The acute model (figure 1) occurs in individuals with a non-predisposing immunogenetic background and involves a self-limited immune-mediated process that in some cases in initiated by a self-limited viral infection.
Chronic model — The chronic model (figure 1) occurs in individuals with a predisposing immunogenetic background and involves two phases:
●A long asymptomatic latency period of myocardial tissue inflammation and damage, resulting in detectable markers of immune activation in situ (inflammatory cells, increased human leukocyte antigen (HLA), and adhesion molecules in the myocardium) and in the periphery (circulating anti-heart autoantibodies, raised cytokine levels) may occur in genetically predisposed individuals.
●Viral infections or other environmental noxae may act as a second hit or as precipitating/accelerating factors.
The finding that anti-heart autoantibodies precede by several years and predict the subsequent development of DCM or LV dysfunction in relatives of patients with DCM from both familial and nonfamilial pedigrees supports this model  and mirrors what happens in other extra-cardiac autoimmune diseases (figure 1) .
A variation on the chronic model is used to characterize the progression from acute viral infection to dilated cardiomyopathy (DCM) in three phases:
●The first phase is comprised of viral infection with myocyte death within hours of viral cell entry. In this acute stage, myocyte death results from direct viral damage to myocytes and leads to exposure of host proteins to the immune system.
●The second phase, which rapidly follows, is an innate immune response comprised of altered regulatory T cell function, natural killer (NK) cells, interferon gamma, and nitric oxide.
●In the third phase, a virus-specific immune response includes antibodies to pathogen. While non-genetically susceptible humans recover with few consequences, in genetically susceptible humans there is a breakdown of T cell tolerance to self-myocardial autoantigens (eg, cardiac myosin) ensues. This leads to chronic myocardial inflammation, necrosis/apoptosis, and fibrosis mediated by humoral (autoantibody-mediated) and/or cell-mediated organ-specific autoimmunity.
Autoimmune mechanisms — Autoimmune mechanisms have been implicated in the pathogenesis of myocarditis, with or without a virus trigger. A subset of patients with biopsy-proven virus-negative myocarditis fulfill the Witebsky-Rose criteria for an autoimmune disease [9,10,16,60,64,86,87]. Autoimmune myocarditis may occur in isolation or in the context of extra-cardiac autoimmune disorders (eg, SLE) . Autoimmunity may also account for 30 to 40 percent of patients with idiopathic dilated cardiomyopathy . (See "Causes of dilated cardiomyopathy", section on 'Autoimmunity'.)
In patients with viral myocarditis, the initial immune response limits the degree of viremia early during infection and protects against myocarditis (see 'Protective effect of initial immune response' above). If, however, this response is insufficient, the virus may not be eliminated and further myocyte injury may ensue. In addition to direct viral-induced injury, persisting viral genomic fragments that may not be capable of replicating as intact virus may drive an adverse autoimmune response (figure 1) . However, in genetically predisposed experimental models and in patients, autoimmune inflammatory heart disease may develop in the absence of a viral infection.
Besides the well-characterized effector elements of the immune response, regulatory elements can modify the severity of myocarditis. Tissue resident dendritic cells and infiltrating macrophages help to both maintain immune homeostasis and contribute to inflammation. Cardiac stromal cells can also modulate inflammation [106-108].
Potentially pathogenic autoantibodies to a variety of cellular components are found in a high percentage of patients with myocarditis and DCM. Autoantigens include alpha and beta cardiac myosin heavy chain, the beta-1 adrenoreceptor, adenine nucleotide translocator (ANT), branched chain keto acid dehydrogenase (BCKD), a variety of sarcolemmal and myolemmal proteins, connective tissue, and extracellular matrix proteins, including laminin [109-115].
The pathogenesis of anti-heart antibodies in post-viral autoimmune cases may start with direct viral-induced myocyte damage, with associated release of intracellular proteins. Intracellular antigens may be recognized as foreign due to molecular mimicry between enteroviral proteins and cardiac proteins or because they were previously sequestered from immune surveillance. CD4-positive T cells produce myocyte damage by stimulating B cells, cytotoxic cytokines, and cytotoxic CD8+ T cells. The presence of the organ and disease-specific anti-heart autoantibodies of immunoglobulin G (IgG) class detected by indirect immunofluorescence on human heart predicts the subsequent development of DCM or LV dysfunction in relatives of patients with DCM from both familial and nonfamilial pedigrees .
The subclass of immunoglobulin may be important in antibody-mediated DCM. In one study of 82 DCM patients, levels of immunoglobulin subclass IgG3, but not IgG1 or IgG2, were elevated compared with controls . In another report of 76 patients with clinically suspected myocarditis or DCM, there was a significant correlation between the plasma concentration of IgG3 and both hemodynamic and echocardiographic indices of HF severity .
The role of IgG3 may have implications for therapy. Immunoadsorption for the removal of autoantibodies may be performed either with protein A columns (which bind to and remove most IgG, but have a low affinity for IgG3), or with anti-IgG columns (which have specificity for all IgG subclasses). In a trial in which the two types of columns were compared for the monthly treatment of DCM, only the anti-IgG column was associated with significant improvement in cardiac index with the first treatment and at three months . The benefit may be increased with more efficient IgG3 removal .
Anti-alpha myosin antibodies — The potential importance of anti-alpha myosin antibodies has been illustrated in several reports. In one study of 53 patients with clinical myocarditis, for example, 17 percent had anti-alpha myosin antibodies, compared with only 4 percent of patients with ischemic heart disease and 2 percent of normal controls .
In another series of 33 patients, anti-alpha myosin antibodies were present in 17 . The antibodies persisted in the majority of patients for at least six months, and did not develop in any patient after the diagnosis of clinical myocarditis had been made. The presence of anti-alpha myosin antibodies was associated with a lower likelihood of improvement in LV systolic and diastolic function at six months compared with patients without these antibodies (no increase in LVEF compared with a 9 percent absolute increase in those without antibodies). (See "Treatment and prognosis of myocarditis in adults".)
Anti-beta-1 adrenoceptor antibodies — Anti-beta-1 adrenoceptor antibodies also may play a role in the progression of myocarditis to DCM. In a rabbit model, immunization with sequences of the beta-1 adrenoreceptor results in the production of anti-beta-1 adrenoceptor antibodies and the development of a cardiomyopathy that resembles the human idiopathic disease . These findings appear to be applicable to humans since these autoantibodies can be detected in as many as 38 percent of patients with an idiopathic DCM [112,113].
Removal of anti-beta-1 adrenoreceptor antibodies by selective immunoadsorption has been associated with clinical improvement in patients with idiopathic DCM . (See "Causes of dilated cardiomyopathy", section on 'Autoimmunity'.)
In addition to promoting myocardial injury, one subgroup of these autoantibodies, directed at the second extracellular domain of the beta-1 adrenoceptor, exerts agonist-like activity on the beta adrenoceptor and may play a role in the development of serious ventricular arrhythmias . (See "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy", section on 'Pathogenesis'.)
Autoreactive T cells — Cellular immunity also may be involved in the development of a DCM. This was suggested in a study that evaluated myocardial, lymph node, and thymic tissue samples from patients with idiopathic DCM . Damage from activated helper and cytotoxic T cells may occur as the result of overexpression of major histocompatibility complex caused by the presence of viral infection (figure 1).
In animal models, cellular immunity is a major mechanism of myocardial injury in post-coxsackie B virus myocarditis [122,123]. This was illustrated in a study in which genetically susceptible mice were crossed with knockout mice lacking CD4+ and/or CD8+ T cells . There was a small decrease in inflammatory infiltrate at 14 days after coxsackie B virus inoculation in mice that lacked CD4+ T cells and a major decrease in mice that lacked both CD4+ and CD8+ T cells. In addition to Th1 and Th2 T cell-mediated myocardial injury, Th17 positive T cells, a T cell subtype that releases interleukin (IL)-17, can mediate autoimmune myocarditis. The Th17 pathway is interesting since it can be selectively blocked without affecting neutrophil activation . In experimental myocarditis, differentiated CD4+ T cells (Th17 and regulatory T cells) may change their functional programs under certain cytokine environments, altering the types of cytokines they produce .
Role of cytokines — In the postviral setting, cytokines regulate lymphocyte function in a positive and negative manner and exert a marked influence on the activities of many other cell types engaged in tissue repair and restoration of homeostasis. Th17 pathway activation is important in postviral autoimmune-mediated cardiomyopathy [126-128]. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Cytokines'.)
In animal models, progression from myocarditis to a DCM is characterized by a change in cytokine expression . Th1 cytokines, including IL-2, interferon gamma, and IL-1-beta, are expressed early in the lesions . The transition to fibrosis and a DCM is heralded by a decrease in the Th1 cytokines and an increase in IL-10, a Th2 cytokine. Gene transfer of IL-10 can protect against autoimmune myocarditis in rats, probably by suppressing the early Th1 type response . However, in one study of patients with myocarditis of unspecified etiology, higher serum levels of IL-10 were associated with greater disease severity and higher mortality .
Tumor necrosis factor-alpha (TNFa) has been implicated in the pathogenesis of myocarditis and DCM in a few animal and human studies  (see "Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling", section on 'Other factors'). Support for the role of TNFa in myocarditis comes from a study of transgenic mice with myocardial expression of TNFa . Production of this cytokine by cardiac myocytes was sufficient to cause severe cardiac disease, including transmural myocarditis and ultimately biventricular fibrosis, chamber dilatation, and LV dysfunction. In addition, there is a strong linear relationship between mortality and TNFa levels in a mouse model of HF due to viral myocarditis .
In human myocarditis, endomyocardial biopsy specimens show higher levels of a TNFa precursor and the TNFa converting enzyme (TACE), which converts the precursor to its mature form within the myocytes and interstitial cells . TACE and TNFa expression were greater in patients with NYHA class III and IV HF than in those in NYHA class I and II, and increased expression was correlated positively with LV volume and negatively with LV systolic function. However, the clinical importance of TNFa in DCM remains uncertain as randomized trials of anti-TNFa therapy have failed to show benefit. Cytokine expression profiles should be studied in human myocarditis/DCM of defined viral versus autoimmune pathogenesis prior to translating results from experimental models to the clinical arena.
ROLE OF VIRAL MYOCARDITIS AS A CAUSE OF DILATED CARDIOMYOPATHY — The role of viral myocarditis as a cause of dilated cardiomyopathy (DCM) is an important clinical issue. There are several potential mechanisms by which a viral myocarditis might cause acute or chronic DCM, including direct viral damage or as a result of humoral or cellular immune responses to persistent viral infection.
Direct viral injury
Intracellular events — Viral entry into the myocyte is mediated by cell surface receptors. The coxsackie-adenovirus receptor (CAR) is a common receptor for coxsackievirus type B and for adenovirus subgroups A, C, D, E, and F [137-139]. The CAR gene has been localized to chromosome 21q11.2 . With rare exceptions, CAR expression is required for virus entry into cells. Observations have established the role for a dominant negative C terminal dystrophin fragment in viral cardiomyopathy and added a new pathway and potential therapeutic target in viral myocarditis .
The discovery of the CAR receptor raises the possibility of interventional therapy to block CAR in severe cases of coxsackie B virus or adenoviral myocarditis. Coreceptors, including decay-accelerating factor (DAF, CD55) for some coxsackie B virus strains  and integrins, help determine the efficiency of infection [143,144]. The activity of signaling pathways in cardiac myocytes also may determine susceptibility to coxsackie B myocarditis via effects on viral replication .
After entry into the cell through the CAR receptor, the coxsackie B viral genome is translated into structural capsid proteins and several proteases that cleave the viral polyprotein. Viral protease 2A can also cleave certain host proteins, and one mechanism of ongoing myocyte injury is through direct interaction of viral proteins with the cytoskeleton. In a transgenic mouse model, cardiac-restricted expression of protease 2A was sufficient to induce dilated cardiomyopathy .
Protease 2A cleaves dystrophin in vivo, leading to disruption of the dystrophin-glycoprotein complex that is essential for normal cardiac function . Disruption of the dystrophin-glycoprotein complex is also present in hereditary cardiomyopathies that are related to a dystrophin mutation, such as Duchenne muscular dystrophy  (see "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis"). There is more efficient release of the coxsackie B virus from dystrophin-deficient cells . Thus, dystrophin-deficient mice have greater viral replication and more severe cardiomyopathy.
Persistent viral infection — Serologic testing, PCR, and probe hybridization studies in animals and human have suggested that persistent viral myocardial infection may lead to development of DCM [18,31,150-154]. In studies of coxsackie B virus myocarditis in immunocompetent mouse strains in which enteroviral RNA was present in acute myocarditis and persisted during a chronic phase of cardiomyopathy [150-152]. Indirect support for a pathogenetic role of persistent viral infection was provided in a report cited above of 172 consecutive patients with PCR evidence of viral infection of the myocardium . The LVEF increased in the one-third of patients who had spontaneous clearance of the viral genome on follow-up biopsy at a median of 6.8 months (58 versus 50 percent); in contrast, the LVEF fell in the remaining patients with persistence of the viral genome (54 versus 51 percent).
Enterovirus — A possible role of persistent enteroviral infection in the development of DCM was suggested by studies identifying enterovirus in which patients with LV systolic dysfunction (some with DCM) with or without myocarditis [18,23,24]. The prognostic significance of persistent enterovirus genome is uncertain since reports have yielded conflicting results [19,24,155].
Adenovirus — Adenoviruses, which were frequently present in children with cardiomyopathy in the 1980s and 90s , are now less common in children and adults . A review of 94 adults with idiopathic DCM and 14 controls detected adenoviral type 2 genomic DNA in 13 percent and enteroviral RNA in another 13 percent . All control samples were negative for both viruses. In two later series, adenovirus was an uncommon pathogen in adult with biopsy-proven myocarditis [10,19] or dilated cardiomyopathy .
HIV — DCM, occasionally due to myocarditis, develops frequently in advanced HIV infection and is associated with poor prognosis. DCM in HIV may be caused by toxicity of the gp120 protein, adverse reaction to antiviral agents, or to opportunistic infections [26,157]. HIV rarely infects cardiac myocytes, and current opinion is that direct HIV cardiotoxicity is uncommon. Myocarditis was found in 6 of 14 (44 percent) heart biopsies from patients with HIV who had an average CD4 count of 246 and who were not treated with antiretroviral therapy. The most common viruses identified were EBV and HSV . (See "Cardiac and vascular disease in patients with HIV", section on 'Myocardial disease'.)
Hepatitis C — Hepatitis C virus (HCV) infection has been proposed to be associated with myocarditis and a cardiomyopathy in Japan. A multicenter study of 697 Japanese patients found that HCV antibody was present in 10.6 percent of patients with hypertrophic cardiomyopathy, 6.3 percent with a DCM, and 2.4 percent of normal controls . These data suggest that HCV infection may be associated with hypertrophic cardiomyopathy in the Japanese population. Studies to determine the association with HCV infection in populations from North American and Western Europe are lacking. Independent confirmation of these intriguing observations is needed. HCV is not an established cardiotropic virus and it is not known how it might cause a cardiomyopathy. In an animal model, mice that were transgenic for the HCV core gene developed a cardiomyopathy by 12 months . This observation suggests a possible pathogenetic role for HCV core protein.
Other — In contrast to the above report that evaluated specific viruses as a cause of DCM, one study performed PCR analysis for multiple viral genomes on endomyocardial biopsy from 245 patients with idiopathic DCM, none of whom had evidence of active or borderline myocarditis . Viral genomes were identified in 67 percent, including 27 percent with multiple infections. The most common viruses isolated were parvovirus B19 (51 percent), human herpesvirus-6 (22 percent), enterovirus (9 percent), and Epstein-Barr virus, adenovirus, and cytomegalovirus, each of which was present in ≤2 percent of biopsies. Parvovirus B19 viral genomes have also been associated with idiopathic LV diastolic dysfunction .
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: 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
●In a patients with suspected or confirmed myocarditis, the history and clinical presentation may suggest specific etiologies of myocarditis such as an infectious agents, toxin, hypersensitivity reactions, systemic disorders (table 1). However, an etiology is often difficult to identify and the cause is frequently unknown. (See 'Approach to identifying the cause of myocarditis' above.)
●A fulminant clinical course (new onset severe heart failure requiring parenteral inotropic or mechanical circulatory support) suggests an acute myocarditis that is likely to show diffuse inflammatory infiltrates on endomyocardial biopsy (EMB). Causes include giant cell myocarditis, eosinophilic myocarditis, cardiac sarcoidosis, and viral or idiopathic lymphocytic myocarditis. (See 'Clinical presentation' above and 'Giant cell myocarditis' above and 'Eosinophilic myocarditis' above and "Endomyocardial biopsy", section on 'Fulminant HF'.)
●Presentation with new-onset heart failure of 2 weeks to 3 months duration and new ventricular arrhythmias, Mobitz type II second-degree atrioventricular (AV) block, third-degree AV block, or refractory heart failure also suggests giant cell myocarditis. (See 'Giant cell myocarditis' above and "Endomyocardial biopsy", section on 'Early AV block, arrhythmias, or refractory HF'.)
●Examination of the EMB is diagnostic for some causes of myocarditis (eg, giant cell myocarditis, sarcoidosis, eosinophilic myocarditis and other autoimmune forms and infectious causes). Detection of viral genome on EMB specimen may suggest a cause in the presence of histologic evidence of myocarditis. (See 'Endomyocardial biopsy' above and "Endomyocardial biopsy".)
●In resource-abundant countries, viral infection is the most frequently presumed cause of myocarditis. In many resource-limited countries, rheumatic carditis, Chagas disease, and disorders associated with HIV infection are important causes of myocarditis.
●Eosinophilic myocarditis is characterized by myocardial eosinophilic infiltration and is usually, but not always, accompanied by eosinophilia. (See 'Eosinophilic myocarditis' above.)
1 : Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.
2 : Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Expert Consensus Document.
3 : A prospective case-control study of antibodies to coxsackie B virus in idiopathic dilated cardiomyopathy.
5 : Suspected chronic myocarditis at cardiac MR: diagnostic accuracy and association with immunohistologically detected inflammation and viral persistence.
6 : Differentiation of heart failure related to dilated cardiomyopathy and coronary artery disease using gadolinium-enhanced cardiovascular magnetic resonance.
7 : Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.
8 : Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases.
10 : A prospective study of biopsy-proven myocarditis: prognostic relevance of clinical and aetiopathogenetic features at diagnosis.
11 : Immunosuppressive therapy for active lymphocytic myocarditis: virological and immunologic profile of responders versus nonresponders.
12 : Prospective familial assessment in dilated cardiomyopathy: cardiac autoantibodies predict disease development in asymptomatic relatives.
17 : Coxsackie B viral myocarditis and valvulitis identified in routine autopsy specimens by immunofluorescent techniques.
18 : Detection of viruses in myocardial tissues by polymerase chain reaction. evidence of adenovirus as a common cause of myocarditis in children and adults.
21 : Detection of adenoviral genome in the myocardium of adult patients with idiopathic left ventricular dysfunction.
22 : Tracheal aspirate as a substrate for polymerase chain reaction detection of viral genome in childhood pneumonia and myocarditis.
23 : Enteroviral RNA replication in the myocardium of patients with left ventricular dysfunction and clinically suspected myocarditis.
24 : Clinical and prognostic significance of detection of enteroviral RNA in the myocardium of patients with myocarditis or dilated cardiomyopathy.
26 : Frequency of development of acute global left ventricular dysfunction in human immunodeficiency virus infection.
35 : Intramyocyte detection of Epstein-Barr virus genome by laser capture microdissection in patients with inflammatory cardiomyopathy.
36 : Viral epidemiologic shift in inflammatory heart disease: the increasing involvement of parvovirus B19 in the myocardium of pediatric cardiac transplant patients.
39 : Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology.
43 : The global burden of myocarditis: part 1: a systematic literature review for the Global Burden of Diseases, Injuries, and Risk Factors 2010 study.
44 : Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980-2006.
45 : Sudden unexpected death from cardiovascular disease in children. A cooperative international study.
46 : Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 3: Hypertrophic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy and Other Cardiomyopathies, and Myocarditis: A Scientific Statement From the American Heart Association and American College of Cardiology.
47 : Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy.
48 : A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators.
53 : Enteroviral infection of mice with severe combined immunodeficiency. Evidence for direct viral pathogenesis of myocardial injury.
54 : Coxsackievirus B3 induces T regulatory cells, which inhibit cardiomyopathy in tumor necrosis factor-alpha transgenic mice.
57 : Pancreatic expression of interferon-gamma protects mice from lethal coxsackievirus B3 infection and subsequent myocarditis.
59 : Coxsackie B3 virus can replicate in cultured human foetal heart cells and is inhibited by interferon.
61 : Idiopathic giant-cell myocarditis--natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators.
63 : Diagnosis, treatment, and outcome of giant-cell myocarditis in the era of combined immunosuppression.
64 : A novel experimental model of giant cell myocarditis induced in rats by immunization with cardiac myosin fraction.
73 : Clozapine-associated myocarditis: a review of 116 cases of suspected myocarditis associated with the use of clozapine in Australia during 1993-2003.
74 : Eosinophilic myocarditis in the explanted hearts of cardiac transplant recipients: Interesting pathologic finding or pathophysiologic entity of clinical significance?
78 : Hypersensitivity myocarditis in the explanted hearts of transplant recipients. Reappraisal of pathologic criteria and their clinical implications.
82 : A prospective study of the incidence of myocarditis/pericarditis and new onset cardiac symptoms following smallpox and influenza vaccination.
83 : From the Centers for Disease Control and Prevention. Update: cardiac-related events during the civilian smallpox vaccination program-- United States, 2003.
84 : Adverse events associated with smallpox vaccination in the United States, January-October 2003.
88 : Cardiac functions in children with coeliac disease during follow-up: insights from tissue Doppler imaging.
91 : The Novel Desmin Variant p.Leu115Ile Is Associated With a Unique Form of Biventricular Arrhythmogenic Cardiomyopathy.
92 : Preventing Sudden Death in Arrhythmogenic Cardiomyopathy: Careful Family and Genetic Evaluation Key to Appropriate Diagnosis and Management.
93 : 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy.
94 : Familial Recurrent Myocarditis Triggered by Exercise in Patients With a Truncating Variant of the Desmoplakin Gene.
95 : Familial screening in case of acute myocarditis reveals inherited arrhythmogenic left ventricular cardiomyopathies.
96 : Inflammatory Episodes of Desmoplakin Cardiomyopathy Masquerading as Myocarditis: Unique Features on Cardiac Magnetic Resonance Imaging.
100 : Predictors of left ventricular dysfunction in patients with Takayasu's or giant cell aortitis.
102 : Cardiac Fabry Disease With Late Gadolinium Enhancement Is a Chronic Inflammatory Cardiomyopathy.
104 : Identification of alpha- and beta-cardiac myosin heavy chain isoforms as major autoantigens in dilated cardiomyopathy.
105 : Autoimmune response in chronic ongoing myocarditis demonstrated by heterotopic cardiac transplantation in mice.
107 : A CD103+ Conventional Dendritic Cell Surveillance System Prevents Development of Overt Heart Failure during Subclinical Viral Myocarditis.
109 : The significance of autoantibodies against the ADP/ATP carrier for the pathogenesis of myocarditis and dilated cardiomyopathy--clinical and experimental data.
110 : Circulating cardiac-specific autoantibodies as markers of autoimmunity in clinical and biopsy-proven myocarditis. The Myocarditis Treatment Trial Investigators.
111 : Antimyosin autoantibodies are associated with deterioration of systolic and diastolic left ventricular function in patients with chronic myocarditis.
112 : Autoantibodies against the second extracellular loop of beta1-adrenergic receptors predict ventricular tachycardia and sudden death in patients with idiopathic dilated cardiomyopathy.
113 : Administration of the cyclic peptide COR-1 in humans (phase I study): ex vivo measurements of anti-β1-adrenergic receptor antibody neutralization and of immune parameters.
114 : Autoreactivity to the cardiac myocyte, connective tissue and the extracellular matrix in heart disease and postcardiac injury.
116 : Subclass specificity of autoantibodies against myosin in patients with idiopathic dilated cardiomyopathy: pro-inflammatory antibodies in DCM patients.
117 : Immunoglobulin G3 cardiac myosin autoantibodies correlate with left ventricular dysfunction in patients with dilated cardiomyopathy: immunoglobulin G3 and clinical correlates.
118 : Potential role of autoantibodies belonging to the immunoglobulin G-3 subclass in cardiac dysfunction among patients with dilated cardiomyopathy.
119 : Role of immunoglobulin G3 subclass in dilated cardiomyopathy: results from protein A immunoadsorption.
120 : Peptides derived from cardiovascular G-protein-coupled receptors induce morphological cardiomyopathic changes in immunized rabbits.
122 : Susceptibility to myocarditis is dependent on the response of alphabeta T lymphocytes to coxsackieviral infection.
127 : Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy.
130 : Characterization of cytokine and iNOS mRNA expression in situ during the course of experimental autoimmune myocarditis in rats.
131 : Protection against autoimmune myocarditis by gene transfer of interleukin-10 by electroporation.
132 : Serum levels of interleukin-10 on admission as a prognostic predictor of human fulminant myocarditis.
136 : Expression of tumor necrosis factor-alpha--converting enzyme and tumor necrosis factor-alpha in human myocarditis.
139 : HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses.
140 : Genomic organization and chromosomal localization of the human Coxsackievirus B-adenovirus receptor gene.
141 : Severe dystrophic cardiomyopathy caused by the enteroviral protease 2A-mediated C-terminal dystrophin cleavage fragment.
142 : A decay-accelerating factor-binding strain of coxsackievirus B3 requires the coxsackievirus-adenovirus receptor protein to mediate lytic infection of rhabdomyosarcoma cells.
146 : Inducible cardiac-restricted expression of enteroviral protease 2A is sufficient to induce dilated cardiomyopathy.
147 : Enteroviral protease 2A cleaves dystrophin: evidence of cytoskeletal disruption in an acquired cardiomyopathy.
148 : Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy.
150 : Ongoing enterovirus-induced myocarditis is associated with persistent heart muscle infection: quantitative analysis of virus replication, tissue damage, and inflammation.
151 : Low-level expression of a mutant coxsackieviral cDNA induces a myocytopathic effect in culture: an approach to the study of enteroviral persistence in cardiac myocytes.
152 : Transgenic expression of replication-restricted enteroviral genomes in heart muscle induces defective excitation-contraction coupling and dilated cardiomyopathy.
155 : Myocardial enterovirus infection with left ventricular dysfunction: a benign disease compared with idiopathic dilated cardiomyopathy.
157 : Myocarditis and cardiotropic viral infection associated with severe left ventricular dysfunction in late-stage infection with human immunodeficiency virus.
158 : Prevalence of myocarditis and cardiotropic virus infection in Africans with HIV-associated cardiomyopathy, idiopathic dilated cardiomyopathy and heart transplant recipients: a pilot study: cardiovascular topic.
160 : High prevalence of viral genomes and multiple viral infections in the myocardium of adults with "idiopathic" left ventricular dysfunction.
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