I.Introduction. Myocarditis is defined as an inflammatory infiltration of the myocardium with associated necrosis or degeneration, or both. The disease is also known as inflammatory cardiomyopathy (or myocarditis with cardiac dysfunction in the World Health Organization 1995 classification for cardiomyopathy). The incidence and prevalence of myocarditis are unclear; the syndrome is underdiagnosed because of the large number of asymptomatic cases. Myocarditis usually affects younger individuals; the median age of patients with lymphocytic myocarditis is 42 years.
A.Clinicopathologic classification of myocarditis is clinically oriented but not widely used.
1.Fulminant myocarditis (17%) usually has a distinct onset. It can result in either complete, spontaneous resolution or rapid deterioration and death due to severe cardiac compromise. Usually, there are multiple active foci of inflammatory infiltrate on histology with complete resolution.
2.Acute myocarditis (65% of myocarditis cases) has an indistinct onset, with moderate cardiovascular compromise and incomplete recovery, often resulting in cardiac dysfunction or subsequent death. Histologically, there are active or borderline inflammatory infiltrates that resolve completely over time.
3.Chronic active myocarditis (11% of myocarditis cases) has a presentation similar to that of acute myocarditis, but the chronic form usually progresses to only mild or moderate cardiac dysfunction, occasionally with restrictive physiology. Histologic examination often shows ongoing fibrosis, suggesting chronic inflammatory changes.
4.Chronic persistent myocarditis (7% of myocarditis cases) has an indistinct onset, with nonresolving active or borderline inflammatory infiltrates seen on histologic examination. Usually, there is no cardiovascular compromise.
B.Histologic classification of myocarditis, also called the Dallas classification (1986)
1.Initial biopsy
a.Myocarditis: myocardial necrosis or degeneration, or both, in the absence of significant coronary artery disease with adjacent inflammatory infiltrates or fibrosis, or both
b.Borderline myocarditis: inflammatory infiltrates too sparse or myocyte damage not apparent
c.No myocarditis: no inflammatory infiltrates or myocyte damage
2.Subsequent biopsy
a.Ongoing (persistent) myocarditis or fibrosis, or both
b.Resolving (healing) myocarditis or fibrosis, or both
c.Resolved (healed) myocarditis or fibrosis, or both
C.World Health Organization (Marburg Criteria, 1996). A minimum of 14 infiltrating leukocytes per mm (1), preferably T lymphocytes, and up to four macrophages may be included.
II.Clinical presentation
A.Signs and symptoms
1.Myocarditis can be totally asymptomatic or can manifest with chest pain syndromes ranging from mild persistent chest pain of acute myopericarditis (35% of cases) to severe symptoms that mimic acute myocardial infarction. Chest pain associated with coronary artery vasospasm may rarely occur in patients with myocarditis. Alternatively, chest pain may be more typical for pericarditis, suggesting pericardial involvement.
2.About 60% of patients may have antecedent arthralgias, malaise, fever, sweats, or chills consistent with viral infections (e.g., pharyngitis, tonsillitis, and upper respiratory tract infection) 1 to 2 weeks before onset.
3.The hallmark symptoms are those of heart failure (e.g., dyspnea, fatigue, and edema). In many patients who develop heart failure, fatigue and decreased exercise capacity are the initial manifestations. However, diffuse, severe myocarditis can progress rapidly and result in acute myocardial failure and cardiogenic shock. The diagnosis is usually presumptive, based on patient demographics and the clinical course (i.e., spontaneous recovery after supportive care).
4.In some instances, patients may present with arrhythmia in the form of syncope, palpitations caused by heart block (i.e., Stokes–Adams attack), ventricular tachyarrhythmia, or even sudden cardiac death. Sinus tachycardia is more frequent than serious atrial or ventricular arrhythmias. Palpitations secondary to premature atrial or ventricular extrasystoles are common.
B.Physical findings. Patients often present with signs of acute decompensated heart failure, including an S3 (third heart sound) gallop, central and peripheral edema, jugular venous distention, and tachycardia (see Chapter 8). An audible pericardial friction rub may accompany concomitant myopericarditis. Specific findings in special cases are as follows:
1.Sarcoid myocarditis: lymphadenopathy, also with arrhythmias, and sarcoid involvement in other organs (up to 70%)
2.Acute rheumatic fever (usually affects the heart in 50% to 90%): associated signs such as erythema marginatum, polyarthralgia, chorea, and subcutaneous nodules (i.e., Jones criteria)
3.Hypersensitive or eosinophilic myocarditis: pruritic maculopapular rash and history of onset temporally related to initiation of potential culprit medications
4.Giant cell myocarditis (GCM): sustained ventricular tachycardia in rapidly progressive heart failure
5.Peripartum cardiomyopathy: heart failure developing in the last month of pregnancy or within 5 months after delivery (see Chapter 38)
III.Laboratory evaluation
A.Inflammatory markers of myocarditis
1.Complete blood count. Leukocytosis is common (often lymphocytic), although the presence of eosinophilia may suggest hypersensitive (eosinophilic) myocarditis.
2.Elevated acute phase reactants such as erythrocyte sedimentation rates or ultrasensitive C-reactive protein are good monitors of clinical progression or response to therapy, but they have low specificity for myocarditis. Novel inflammatory markers under investigation include tumor necrosis factor-α, interleukins, interferon-γ, serum-soluble Fas, and soluble Fas ligand levels. Elevation of these markers portends a worse prognosis.
3.Serum viral antibody titers are usually increased fourfold or more acutely and gradually fall during convalescence. However, measurement of viral antibody titers is rarely indicated.
4.Anticardiac antibody titers. Because of their low specificity, measurement of anticardiac antibody titers (against sarcolemma, myosin, laminin, ADP/ATP translocator, or β-adrenergic receptors) is not indicated (only 62% of myocarditis cases have titers ≥1:40).
B.Rheumatologic screening. Screening of antinuclear antibodies and rheumatoid factor is often indicated. Disease-specific testing is indicated if the following conditions are suspected:
1.Systemic lupus erythematosus: anti-dsDNA (reported positive anti-Ro/SSA and anti-La/SSB in lupus carditis in children)
2.Polymyositis: anti-Jo1
3.Wegener granulomatosis: c-ANCA (antineutrophil cytoplasmic antibody)
4.Scleroderma: anti-Scl70
C.Serum cardiac enzymes (markers of myonecrosis): creatinine kinase (myoglobin subfraction) is elevated in only 7.5% of patients with biopsy-proven myocarditis, whereas the cardiac troponin I or T is elevated in at least 50% of patients with biopsy-proven myocarditis (89% to 94% specificity and 34% to 53% sensitivity).
IV.Diagnostic testing
A.Electrocardiogram. The electrocardiogram often reveals sinus tachycardia, although the presence of nonspecific ST-segment and T-wave abnormalities may represent focal or global ischemia. Occasionally, the changes in electrocardiogram are suggestive of an acute myocardial infarction and may include ST-segment elevation. Pericarditis can accompany myocarditis and is often manifested in pericarditis like changes seen on electrocardiography. The sensitivity of the electrocardiogram for myocarditis is low (47%). In some cases, fascicular block or atrioventricular conduction disturbances and ventricular tachyarrhythmia may be hemodynamically significant.
B.Echocardiogram. A complete echocardiogram is standard procedure for patients with suspected myocarditis in order to exclude alternative causes of heart failure, detect the presence of intracardiac thrombi and associated valvular disease, and quantify the degree of left ventricular (LV) dysfunction to monitor response to therapy.
1.Occasionally, focal wall motion abnormalities and presence of pericardial fluid may prompt further workup or intervention.
2.Fulminant myocarditis is often characterized by near-normal diastolic dimensions and increased septal wall thickness, whereas acute myocarditis often has increased diastolic dimensions but normal septal wall thickness.
3.In a series of 23 patients with biopsy-proven myocarditis, significant reduction in right ventricular function was a powerful predictor of death or the need for cardiac transplantation.
C.Other imaging modalities
1.Antimyosin scintigraphy (indium III monoclonal antimyosin antibody) provides identification of myocardial inflammation, with a high sensitivity (91% to 100%) and negative predictive value (93% to 100%) but low specificity (28% to 33%).
2.Gallium scanning identifies severe myocardial cellular infiltration with high specificity (98%) but low sensitivity (36%).
3.Gadolinium-enhanced magnetic resonance imaging (MRI) is being used more frequently for diagnosis based on several small observational studies that have found up to 100% sensitivity and specificity depending on the protocol. In one study, MRI was also used for guiding biopsy to areas of focal increased uptake of gadolinium in patients with clinically suspected myocarditis with significantly higher diagnostic yield compared with those who did not have enhancing areas with which to guide the bioptome.
D.Coronary angiography. Cardiac angiography is often indicated to rule out coronary artery disease as the cause of new-onset heart failure, because the clinical presentation of myocarditis may mimic myocardial infarction (i.e., pseudoinfarct pattern), especially if there are focal wall motion abnormalities and localizing electrocardiographic changes.
V.Etiology. Up to 50% of all cases may not have a clear underlying cause (i.e., idiopathic cases).
A.Infective causes (Table 11.1)
TABLE 11.1 Causes of Myocarditis |
|
Cause |
Examples |
|
Infectious Causes |
|
Viruses |
Enteroviruses, coxsackievirus A and B, echovirus, influenza virus, poliovirus, herpesviruses, adenovirus, mumps, rubella, rubeola, hepatitis B or C virus, human immunodeficiency virus, Epstein–Barr virus, cytomegalovirus, and parvovirus B19 |
Rickettsia |
Rocky Mountain spotted fever |
Fungi |
Cryptococcosis, aspergillosis, coccidioidomycosis, and histoplasmosis |
Protozoa |
Trypanosoma cruzi (Chagas disease) and Toxoplasmosis gondii |
Helminths |
Trichinosis and schistosomiasis |
Bacteria |
Legionella, Clostridium, streptococci, staphylococci, Salmonella, and Shigella |
Spirochetes |
Borrelia burgdorferi (Lyme disease) |
|
Noninfectious Causes |
|
Hypersensitive reaction |
Eosinophilic myocarditis |
Cardiotoxic drugs |
Catecholamines, amphetamines, cocaine, chemotherapeutic drugs (e.g., anthracyclines, fluorouracil, streptomycin, cyclophosphamide, interleukin-2, trastuzumab [Herceptin]), and smallpox vaccine |
Collagen vascular diseases |
Systemic lupus erythematosus (i.e., lupus carditis), Wegener granulomatosis or Churg–Strauss syndrome, dermatomyositis or polymyositis, and scleroderma |
Systemic illnesses |
Sarcoidosis, giant cell myocarditis, Kawasaki disease, large-vessel vasculitis (e.g., polyarteritis nodosa and Takayasu arteritis), and inflammatory bowel diseases (e.g., ulcerative colitis and Crohn disease) |
Acute rheumatic fever |
|
Bites and stings |
Venoms of scorpions, snakes, wasps, and black widow spiders |
Chemicals |
Hydrocarbons, carbon monoxide, thallium, lead, arsenic, and cobalt |
Physical injury |
Irradiation, heat stroke, and hypothermia |
Childbirth |
Peripartum cardiomyopathy |
Alloantigens |
Posttransplantation cellular rejection |
1.Viral myocarditis. Cardiotropic viruses such as enteroviruses (specifically, the coxsackie group B and echoviruses) may cause direct cardiotoxic injuries, cytokine activation, cytoskeletal damage, and autoimmune responses. However, data suggest that the incidence of myocarditis after infection is lower than previously projected. Viral myocarditis is often considered when accompanied by a clinical picture of recent febrile illness, often with prominent myalgias, followed by rapid onset of cardiac symptoms. However, direct proof is lacking (and often unnecessary), and many cases of idiopathic dilated cardiomyopathies have been attributed to antecedent viral myocarditis. Antiviral therapies have not proved to be useful.
2.Chagas disease. Cardiomyopathy caused by Trypanosoma cruzi in South and Central America, particularly in persons aged 30 to 50 years. It is estimated that 16 to 18 million persons are infected with T. cruzi in Latin America. Cardiac involvement usually appears decades after initial treatment and is the leading cause of death of persons aged 30 to 50 years in the endemic areas.
a.Diagnosis
(1)Serologic test results should be positive for at least two types of tests (i.e., indirect immunofluorescence, indirect hemagglutination, complement fixation, immunoenzymatic, and radioimmune assays).
(2)Cardiac lesions diagnosed by in situ polymerase chain reaction methods of analyzing biopsies
(3)Typical electrocardiographic changes include right bundle branch block with left anterior hemiblock, premature ventricular complexes, T-wave inversions, abnormal Q waves, variable atrioventricular blocks, low QRS voltage, and sick sinus syndrome.
(4)Echocardiographic findings include LV aneurysm with or without thrombi, posterior basal akinesis or hypokinesis with preserved septal contraction, and diastolic dysfunction.
(1)The acute and subacute phases (i.e., 4 to 8 weeks of acute inflammation) consist, for the most part, of local inflammation at the parasite entry site and flulike symptoms. Occasionally hepatosplenomegaly and lymphadenopathy occur, but concomitant meningoencephalitis is rare. These manifestations often result from pathogen-induced cytotoxicity and inflammatory responses. More than 90% of cases resolve in 4 to 8 weeks without therapy.
(2)The chronic phase (up to 10 to 30 years after acute infection) manifests with symptoms of palpitations, syncope, chest pain, and, subsequently, heart failure. Approximately 5% to 10% of affected patients may develop direct acute-to-chronic progression.
(a)Heart failure (predominantly right sided in advanced stages) may develop in 25% to 30% of those affected.
(b)Cerebral or pulmonary thromboembolism may occur in 10% to 15% of those affected.
(c)Concomitant megaesophagus or megacolon may develop.
(d)Apical LV aneurysm and apical fibrosis may develop.
(3)Chagas disease is highly arrhythmogenic.
(a)Frequent, complex ectopic beats and ventricular tachyarrhythmia occur in 40% to 90% of affected patients, with sudden cardiac death occurring in 55% to 65%.
(b)Bundle branch block occurs in 50% of affected patients, and bradyarrhythmia with high-grade atrioventricular block occurs in 7% to 8%.
(c)Atrial fibrillation develops in 7% to 10% of affected patients.
c.Antibiotic therapy aims to reduce parasitemia and prevent complications.
(1)Benznidazole (5 to 10 mg/kg/d q12h for 60 days) or
(2)Nifurtimox (8 to 10 mg/kg po q24h for 90 to 120 days)
3.Human immunodeficiency virus (HIV)–related cardiomyopathy. HIV disease has been recognized as an important cause of dilated cardiomyopathy, with an estimated incidence of 1.6%. HIV type 1 (HIV-1) virions appear to infect myocardial cells in patchy distributions, leading to cytokine activation and progressive tissue damage. Cardiac autoimmunity, nutritional deficiencies, and drug toxicities (i.e., mitochondrial damage from zidovudine and vasculitis or coronary artery disease associated with highly active antiretroviral therapy regimens) are possible contributing causes. In addition, other known viral pathogens, including cytomegalovirus, Epstein–Barr virus, and coxsackievirus B, have been isolated from endomyocardial biopsy (EMB) specimens of HIV-positive patients with myocarditis in conjunction with HIV nucleic acid sequences, suggesting that opportunistic viral infections may play an important role in the pathogenesis of this type of cardiomyopathy.
B.Peripartum cardiomyopathy (see Chapter 38)
C.GCM (i.e., pernicious myocarditis, Fiedler myocarditis, granulomatous myocarditis, or idiopathic interstitial myocarditis): This is a rare disorder with an unclear origin. The hallmark feature is the presence of fused, multinucleated (>20 nuclei) epithelioid giant cells of histocytic origin within a diffuse, intramyocardial inflammatory infiltrate with lymphocytes.
1.GCM often presents with an aggressive clinical course, with progression over days to weeks. Rapidly progressive heart failure is the presentation in 75% of affected patients. Sustained ventricular tachyarrhythmia occurs in 29% of patients with GCM and atrioventricular block occurs in 50%.
2.The prognosis is dismal without therapy, but the disease is often refractory to standard medical therapy, with a 1-year mortality rate of up to 80% (median survival of 3 to 5 months from symptom onset).
3.Small observational series have suggested potential benefits of immunosuppressive therapy, and a randomized, prospective multicenter study is ongoing. Consideration for early cardiac transplantation is appropriate (71% 5-year survival after successful transplantation). Often, mechanical support may be required as a temporary bridge to recovery or transplantation. A 20% to 25% rate of histologic recurrence in surveillance EMBs has been observed after transplantation.
D.Hypersensitive reaction (i.e., eosinophilic myocarditis). Eosinophilic endomyocardial disease (i.e., Loeffler endomyocardial fibrosis, see Chapter 9) occurs as a major complication of idiopathic hypereosinophilic syndrome as a result of direct toxic damage caused by eosinophil granule proteins within the heart. Drug-induced eosinophilic myocarditis is independent of cumulative dose and duration of therapy.
The absence of peripheral eosinophilia does not rule out eosinophilic myocarditis. Although observational series suggest potential clinical benefits of corticosteroid therapy, the best strategy is to remove the causative agent when known.
1.Medications that may cause eosinophilic myocarditis include the following:
a.Antibiotics (e.g., ampicillin, chloramphenicol, tetracycline, and sulfisoxazole)
b.Diuretics (e.g., hydrochlorothiazide and spironolactone)
c.Anticonvulsants (e.g., phenytoin and carbamazepine)
d.Other drugs (e.g., lithium, clozapine, and indomethacin)
e.Tetanus toxoid
2.Collagen vascular diseases such as Wegener granulomatosis or Churg–Strauss syndrome (i.e., allergic granulomatosis and vasculitis) may also lead to eosinophilic myocarditis.
3.Other causes include parasitic infection, drug hypersensitivity, and cellular rejection after cardiac transplantation, as well as postvaccinia myocarditis after smallpox vaccination.
E.Systemic autoimmune disorders with myocarditis. Although the histologic appearance of myocarditis occurring as part of sarcoidosis, systemic lupus erythematosus, or polymyositis is similar to that seen in isolated myocarditis, the natural history is different. Systemic causes of myocarditis often respond poorly to medical therapy and cardiac transplantation, and their prognoses are often unfavorable. However, small retrospective surveys and case series have identified a significant decrease in mortality and improved clinical course among cardiac sarcoid patients treated with corticosteroids and other immunosuppression strategies.
VI.Prognosis. On the basis of population studies, adults with myocarditis may present with few symptoms or with an acute toxic state of cardiogenic shock or frank heart failure (i.e., fulminant myocarditis). However, adults may present with heart failure years after the initial index event of myocarditis (up to 12.8% of patients with idiopathic dilated cardiomyopathy had presumed prior myocarditis in one case series).
A.Natural history and sequelae of myocarditis. The outlook is poor in the acute phase, regardless of clinicopathologic classification, but those surviving the acute phase have a more favorable prognosis (except for those with chronic active myocarditis).
1.Many patients may have full spontaneous clinical recovery, even after weeks of mechanical support (e.g., intra-aortic balloon counterpulsation and mechanical assist devices).
2.In the Myocarditis Treatment Trial, the 1-year mortality rate was 20%, and the 4-year mortality rate was 56%.
3.In-hospital case series point to an 11-year survival rate of 93% for patients with fulminant myocarditis and 45% for nonfulminant myocarditis.
4.Evolution to dilated cardiomyopathy
a.Up to one-half of patients with myocarditis develop subsequent cardiomyopathy over a range of 3 months to 13 years.
b.Histologic evidence of myocarditis is seen in 4% to 10% of EMBs of patients with idiopathic dilated cardiomyopathy.
5.Severe heart block requiring permanent pacemaker placement occurs in 1% of patients.
B.Predictors for morbidity and mortality
1.Unfavorable factors for survival include extremes of age (i.e., very old or very young), electrocardiographic abnormalities (e.g., QRS alterations, atrial fibrillation, and low voltages), syncope, and specific diagnoses (e.g., peripartum cardiomyopathy and GCM).
2.Favorable factors for survival include normal ventricular function, shorter clinical history, and fulminant presentation at onset.
VII.Treatment
A.Heart failure management
1.Patients who present with myocarditis with acute dilated cardiomyopathy should be treated according to the current American Heart Association, the American College of Cardiology, the European Society of Cardiology, and the Heart Failure Society of America (HFSA) guidelines. Standard heart failure therapy consists of diuretics, angiotensin-converting enzyme inhibitors, β-blockers, and aldosterone antagonists. Studies have not been done to determine when and how to discontinue standard heart failure therapy in patients who recover LV function.
2.Because of its proarrhythmic properties in animal models, digoxin should be avoided.
3.Anticoagulation to prevent thromboembolic events is usually recommended in patients with apical aneurysm with thrombus (e.g., Chagas disease, atrial fibrillation, and prior embolic episodes).
4.Inotropic therapy is reserved for severe hemodynamic compromise, particularly in fulminant myocarditis.
5.Aggressive support with mechanical and surgical intervention is often indicated (see Chapters 8 and 12).
a.Intra-aortic balloon counterpulsation for hemodynamic support and afterload reduction
b.Mechanical assistive devices (LV assist device)
c.Extracorporeal membrane oxygenation
6.Early consideration for cardiac transplantation should be given, especially for patients with progressive, biopsy-proven GCM or peripartum cardiomyopathy. However, patients with myocarditis have increased rates of rejection and reduced survival after heart transplantation compared with those without myocarditis, and recurrent disease may affect the allograft.
B.Exercise restriction
1.There is a theoretical increased risk of myocardial inflammation and necrosis, cardiac remodeling, and death, as shown in animal models.
2.Patients are usually advised to abstain from vigorous exercise for up to 6 months or longer after the onset of symptoms. The length of activity restriction can be based on recovery of LV function.
C.Arrhythmia management
1.Antiarrhythmics provide first-line treatment using standard therapy such as β-blockers, amiodarone, and sotalol.
2.Implantable cardioverter–defibrillators are used for patients stabilized in the chronic phase with persistently low ejection fraction (EF) and for those with malignant arrhythmias that are refractory to medical therapy.
3.Permanent pacemakers are used for heart block or bradyarrhythmia.
D.Follow-up
1.Clinical follow-up should be close because persistent chronic inflammation may lead to dilated cardiomyopathy. Initially, 1- to 3-month intervals are used for drug and physical activity titration.
2.Serial echocardiographic assessment of ventricular structure and function is often performed, although there is no agreement regarding the frequency of echocardiographic assessment after myocarditis.
E.Immunosuppressive therapy is reserved for refractory disease or biopsy-proven GCM. No benefits have been established for antiviral regimens or nonsteroidal anti-inflammatory agents (see Section VIII.B). The most recent HFSA guidelines do not recommend routine use of immunosuppressive therapy in patients with myocarditis. More work is needed to identify patient cohorts who will benefit from tailored antiviral and immunosuppressive therapy.
VIII.Controversies in myocarditis
A.Endomyocardial biopsy
1.Routine EMB confirmation of myocarditis is unnecessary
a.EMB can be considered in those patients with a rapid deterioration in cardiac function of unknown etiology who do not respond to standard medical therapy.
b.Incidence of biopsy-proven myocarditis in recent-onset, unexplained heart failure can be as low as 8% to 10%. Concerns have emerged that this is caused by low sensitivity of the Dallas criteria, and several recent trials of immunosuppressive therapy have utilized supplemental pathologic criteria to assess myocarditis, including upregulation of human leukocyte antigen, presence of virus, and anticardiac antibodies.
c.False-negative rates are high (50% even in four or five biopsies) because of the small number of lymphocytes and difficulties in distinguishing cell types, with wide interobserver variability.
2.However, EMB may be considered in patients with the following conditions in which a diagnostic biopsy may provide information on prognosis and/or therapeutic possibilities (see Table 11.2):
TABLE 11.2 Relevant ACC/AHA Recommendations for the Role of Endomyocardial Biopsy Scenario |
|
Class of Recommendation |
|
New-onset heart failure of <2-wk duration associated with a normal-sized or dilated left ventricle and hemodynamic compromise |
I |
New-onset heart failure of 2-wk to 3-mo duration associated with a dilated left ventricle and new ventricular arrhythmias, second- or third-degree heart block, or failure to respond to usual care within 1–2 wk |
I |
Heart failure of >3-mo duration associated with a dilated left ventricle and new ventricular arrhythmias, second- or third-degree heart block, or failure to respond to usual care within 1–2 wk |
IIa |
Heart failure associated with a dilated cardiomyopathy of any duration associated with suspected allergic reaction and/or eosinophilia |
IIa |
New-onset heart failure of 2-wk to 3-mo duration associated with a dilated left ventricle, without new ventricular arrhythmias, or second- or third-degree heart block that responds to usual care within 1–2 wk |
IIb |
Heart failure of >3-mo duration associated with a dilated left ventricle, without new ventricular arrhythmias, or second- or third-degree heart block that responds to usual care within 1–2 wk |
IIb |
Unexplained ventricular arrhythmias |
IIb |
Adapted from Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease. Circulation. 2007;116:2216–2233; American Heart Association, Inc.
a.Rapidly progressive heart failure symptoms despite conventional therapy or new-onset frequent ventricular tachyarrhythmia or conduction disturbances
b.Suspected specific causes of myocarditis (e.g., GCM, eosinophilic myocarditis, cardiac sarcoidosis, and vaccinia myocarditis)
3.Although specificity is high (98%), sensitivity has been found in some series to be as low as 10% to 22%. It increases with multiple biopsies, but postmortem examinations have found that more than 17 specimens were needed to make the diagnosis with 80% sensitivity in proven myocarditis cases.
4.Biopsy for staging of myocarditis
a.Cell types include lymphocytic, eosinophilic, neutrophilic, giant cell, granulomatous, and mixed.
b.Amount of cells: none (grade 0), mild (grade 1), moderate (grade 2), and severe (grade 3)
c.Distribution: focal (i.e., outside of vessel lumen), confluent, diffuse, and reparative (i.e., in fibrotic areas)
5.Other tests
a.Immunohistochemical staining to examine upregulation of major histocompatibility complex antigens and quantify inflammation, although rates of correlation with biopsy-proven myocarditis have not been consistent between studies.
b.Approximately 12% to 50% of patients with acute or chronic myocarditis have persistent viral mRNA detected in biopsy samples.
B.Immunosuppressive therapy in acute myocarditis
1.Routine immunosuppressive therapy is not recommended because of the neutral findings from multiple trials, including the Myocarditis Treatment Trial and the Intervention in Myocarditis and Acute Cardiomyopathy (IMAC) study. There is no Food and Drug Administration–approved regimen for the treatment of acute or chronic myocarditis.
2.Considerations are reserved for patients with new-onset, rapidly deteriorating, advanced heart failure with suspicion of the following conditions:
a.GCM is treated with combination therapy (Table 11.3).
TABLE 11.3 Treatment Regimens for Myocarditis in Clinical Trials |
Intervention in Myocarditis and Acute Cardiomyopathy (IMAC) Studya |
Intravenous immune globulin (Gamimune N, 10%): 1 g/kg/d IV × 2 d |
Giant Cell Myocarditis Studyb |
Cyclosporine: 25 mg po bid, increase by 25 mg increments to target level |
Monoclonal whole-blood immunoassay: 200–300 ng/mL |
High-performance liquid chromatography assay: 150–250 ng/mL |
Fluorescence polarization immunoassay serum-based polyclonal assay: 100–150 ng/mL |
Dose reduction if renal dysfunction develops |
Muromonab-CD3 (OKT-3): 5 mg IV qd × 10 d |
Dose reduction if hypotension develops |
Corticosteroid: methylprednisolone, 10 mg/kg IV qd × 3 d, followed by prednisone, 1–1.25 mg/kg with extended taper |
Azathioprine: 200 mg po qd |
Myocarditis Treatment Trialc |
Corticosteroid/cyclosporine versus corticosteroid/azathioprine versus placebo (biopsy-proven myocarditis, LVEF < 45%, NYHA ≥ class II) |
Oral prednisone: 1.25 mg/kg/d in divided doses × 1 wk; reduce oral dose by 0.08 mg/kg/wk until dose is 0.33 mg/kg/d at week 12; maintain oral dose until week 20, and then reduce dose by 0.08 mg/kg/wk until week 24; then off |
Oral cyclosporine: 5 mg/kg bid to achieve level of 200–300 ng/mL × 1 wk; adjust oral dose to achieve level of 100–200 ng/mL from weeks 2 to 4; adjust oral dose to achieve level of 60–150 ng/mL from weeks 4 to 24 |
Immunosuppressive Therapy for Active Lymphocytic Myocarditisd |
Prednisone 1 mg/kg/d for 4 wk; reduced to 0.33 mg/kg/d for 5 mo; azathioprine 2 mg/kg/d for 6 mo |
LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.
aMcNamara DM, Holubkov R, Starling RC, et al. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation. 2001;103:2254–2259.
bRosenstein ED, Zucker MJ, Kramer N. Giant cell myocarditis: most fatal of autoimmune diseases. Semin Arthritis Rheum. 2000;30:1–16.
cMason JW, O’Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med. 1995;333:269–275.
dFrustaci A, Chimenti C, Calabrese F, et al. Immunosuppressive therapy for active lymphocytic myocarditis: virological and immunologic profile of responders versus nonresponders. Circulation. 2003;107:857–863.
b.Eosinophilic or sarcoid myocarditis is treated with high-dose steroids.
c.Specific therapy is used for underlying collagen vascular diseases, if present.
3.Studies are ongoing in an attempt to identify markers to predict favorable response to immunosuppressive regimens. A study of 112 patients with histopathologic acute lymphocytic myocarditis who failed to improve with conventional therapy and subsequently received prednisone and azathioprine found that one-half of the treated group improved, with EF rising from 26% to 47% and improvement in biopsy findings. Of those who failed conventional therapy, those patients who responded to immunosuppression were significantly more likely to have positive cardiac antibodies (90% vs. 0%) and less likely to have viral persistence when compared with nonresponders (14% vs. 85%).
ACKNOWLEDGMENTS: The authors acknowledge the contributions of Mosi K. Bennett to a prior edition of this chapter.
Reference
1.Cooper LT, Virmani R, Chapman NM, et al. National Institutes of Health-sponsored workshop on inflammation and immunity in dilated cardiomyopathy. Mayo Clin Proc. 2006;81:199–204.
Landmark Articles
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Cooper LT Jr, Berry GJ, Shabetai R. Idiopathic giant-cell myocarditis: natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators. N Engl J Med. 1997;336:1860–1866.
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