3. Magnani and Dec Diagnosis and Treatment of Myocarditis 877
Figure 1. The pathological diagnosis of lymphocytic (viral) myo- Figure 3. Giant cell myocarditis is a rare disorder characterized
carditis requires the presence of a lymphocyte-rich inflammatory pathologically by the presence of a mixed inflammatory infiltrate
infiltrate associated with myocyte degeneration or necrosis. The containing lymphocytes, plasma cells, macrophages, and eosin-
infiltrate is typically predominantly lymphocytic, with lesser ophils along with numerous giant cells. In the active phase of
amounts of plasma cells, macrophages, and neutrophils. The the disease, the giant cells are typically located immediately
features of the injury and inflammatory infiltrate should be dis- adjacent to necrotic cardiac myocytes. Granulomas are typically
tinct from those of ischemic injury and toxic injuries such as not present. Giant cell myocarditis must be distinguished from
catecholamine myocardial toxicity. The inflammatory infiltrates more common disorders that may contain giant cells, including
of lymphocytic myocarditis are typically not rich in eosinophils, sarcoidosis and hypersensitivity myocarditis. Endomyocardial
the presence of which would suggest other entities including biopsy with hematoxylin and eosin; magnification ϫ400. Text
hypersensitivity myocarditis. Endomyocardial biopsy with hema- and image courtesy of James R. Stone, MD, PhD.
toxylin and eosin; magnification ϫ400. Text and image courtesy
of James R. Stone, MD, PhD. ence of adenoviral genome in patients with idiopathic left
ventricular dysfunction with a greater frequency than entero-
titers.18 However, Keeling et al19 subsequently reported virus.23,24 Hepatitis C has been more frequently reported in
similar levels of serotype-specific Coxsackievirus B IgM Japanese patients, whereas parvovirus B19 genome is more
antibodies in household contacts and myocarditis cases. commonly identified via nested PCR techniques in German
Molecular techniques such as polymerase chain reaction cases.24 –26 Kuhl et al27 have reported identification of Ն2
(PCR) have facilitated extensive testing of myocardial tissue different viral genomes in Ͼ25% of cases when genome
for potential viral etiologies.20 –22 Nested PCR analyses of could be amplified. These findings suggest that age-related
adult and pediatric myocardium have demonstrated the pres- and regional differences in viral etiology may be more
important in the causation of acute and chronic myocarditis
than previously appreciated.
Hepatitis C virus (HCV) has also been associated with
myocarditis by identification of HCV antibodies and RNA in
sera and cardiac tissue of patients with biopsy-proven myo-
carditis.25,28 The causative relationship between HCV infec-
tion and dilated cardiomyopathy remains ambiguous; in-
creased tumor necrosis factor (TNF) and cytokine expression
have been implicated.29
Bowles et al24 conducted a multicenter study of 624
patients with biopsy-proven myocarditis (66%) or borderline
myocarditis (34%). Evidence of viral genome (adenovirus,
enterovirus, and cytomegalovirus in decreasing frequency)
was identified in 239 (38%) of subjects’ endomyocardial
biopsies. Thus, contemporary molecular techniques have
substantiated the long-held perception that viral infection
plays a key role in the development of active myocarditis.
Figure 2. The presence of a lymphocytic infiltrate without asso- Human immunodeficiency virus (HIV) has been associated
ciated myocyte degeneration or necrosis is not diagnostic of
lymphocytic myocarditis and is typically described as “border-
with cardiotropic viral infection resulting in myocarditis and
line myocarditis.” The pathological features of borderline myo- left ventricular dysfunction. In a postmortem study of HIV-
carditis are not specific; because of sampling error, other enti- infected patients, 14 of 21 patients (67%) had myocarditis by
ties such as sarcoidosis and catecholamine toxicity could be histopathological criteria.30 In another study, EMB of patients
responsible for the pathological findings. Endomyocardial biopsy
with hematoxylin and eosin; magnification ϫ400. Text and with advanced HIV disease and global left ventricular dyski-
image courtesy of James R. Stone, MD, PhD. nesis detected myocarditis in 17 of 33 subjects (52%).31
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4. 878 Circulation February 14, 2006
TABLE 1. Major Etiologies of Myocarditis* patients.33 The incidence was higher among patients with
Viral
CD4ϩ counts Ͻ400 cells/mm3. Histological evidence of
myocarditis was detected in 63 of 76 (83%) of these high-risk
Adenovirus
patients. In situ hybridization identified HIV-infected myo-
Coxsackievirus
cytes in 58 of 76 (76%) of this population.33 It is often unclear
HCV clinically whether the HIV virus itself, medications used for
HIV its treatment, or myocardial coinfection is responsible for the
Bacterial observed left ventricular systolic dysfunction. Furthermore,
Mycobacterial the long-term effects of intensive antiretroviral treatment for
Streptococcal species HIV myocarditis and its clinical sequelae are undergoing
Mycoplasma pneumoniae additional study.
Treponema pallidum Smallpox vaccination has recently been recognized as
causing myopericarditis. Cases have been identified by their
Fungal
close proximity to smallpox vaccination (4 to 30 days),
Aspergillus
clinical manifestations, and elevation of cardiac biomarkers.
Candida
The Department of Defense Smallpox Vaccination Clinical
Coccidiodes Evaluation Unit identified a significantly increased incidence
Cryptococcus of myocarditis after widespread vaccination in late 2002.34
Histoplasma Individuals without prior vaccine exposure had higher rates
Protozoal of the syndrome, with a reported incidence of 7.8 cases per
Trypanosoma cruzi 100 000 vaccine administrations.35 One case of eosinophilic
Parasitic myocarditis has been confirmed by endomyocardial biopsy.36
Numerous medications have been implicated in hypersen-
Schistosomiasis
sitivity myocarditis including antidepressants37 (tricyclics),
Larva migrans
antibiotics38 (penicillins, cephalosporins, sulfonamides), and
Toxins
antipsychotics39 (clozapine). A hypersensitivity reaction may
Anthracyclines be heralded by fever, peripheral eosinophilia, sinus
Cocaine tachycardia, and a drug rash that occurs days to weeks after
Interleukin-2 administration of a previously well-tolerated agent. Myocar-
Cocaine dial involvement varies but usually does not result in fulmi-
Hypersensitivity nant heart failure or hemodynamic collapse; symptoms re-
Sulfonamides cede with drug cessation with or without administration of
Cephalosporins
corticosteroids. EMB typically reveals variable degrees of
histiocytic, eosinophilic, lymphocytic, or occasionally gran-
Diuretics
ulomatous infiltration; surprisingly, a poor correlation exists
Digoxin
between the degree of myocardial inflammation or necrosis
Tricyclic antidepressants and the likelihood of arrhythmias or hemodynamic collapse.38
Dobutamine Eosinophilic necrotizing myocarditis may represent an ex-
Immunologic syndromes treme form of hypersensitivity myocarditis that rapidly re-
Churg-Strauss sults in cardiovascular deterioration and circulatory
Inflammatory bowel disease collapse.37
Giant cell myocarditis Autoimmune diseases that are associated with active myo-
Diabetes mellitus carditis include celiac disease40 and Whipple’s disease41;
rheumatoid diseases such as systemic lupus erythematosus,42
Sarcoidosis
mixed connective tissue disease,43 and systemic sclerosis44;
Systemic lupus erythematosus
and certain hematologic abnormalities such at thrombocyto-
Thyrotoxicosis
penic purpura.45
Takayasu’s arteritis
Wegener’s granulomatosis Pathogenesis
*Adapted with permission from Dec.67 Our current understanding of the pathogenesis of myocarditis
derives largely from animal models. Three essential pathways
HIV-related myocarditis is associated with a significantly have been elucidated.46 Direct myocardial invasion by car-
poorer prognosis than is lymphocytic myocarditis; multivar- diotropic virus or other infectious agents rapidly progresses to
iate modeling has identified HIV-related myocarditis as the a second phase of immunologic activation. In the last phase,
strongest predictor of death among a large cardiomyopathy CD4ϩ activation prompts clonal expansion of B cells, result-
population.32 A prospective study of asymptomatic HIV- ing in further myocytolysis, additional local inflammation,
infected patients revealed a mean annual incidence of pro- and production of circulating anti-heart antibodies.46 All 3
gression to dilated cardiomyopathy of 15.9 cases per 1000 mechanisms may interact within the same host; the predom-
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5. Magnani and Dec Diagnosis and Treatment of Myocarditis 879
inant pathogenic mechanism may vary according to host to identify specific viral or other infectious agents.63 Animal
defenses and the specific infectious agent. and human models have increasingly implicated an autoim-
During the period of active viremia, cardiotropic RNA mune pathogenesis, as supported by isolation of macrophage
viruses such as Coxsackie B or encephalomyocarditis virus antigens from giant cells along with prominent T-cell lym-
are taken into myocytes by receptor-mediated endocytosis phocytic proliferation in the surrounding myocardium.63,64
and are directly translated intracellularly to produce viral The relationship of myocarditis to idiopathic dilated car-
protein.47 Viral genomic persistence via incorporated double- diomyopathy has been partially clarified by molecular tech-
stranded RNA may also contribute to myocyte dysfunction by niques. Detection of viral RNA at early, intermediate, and late
cleaving dystrophin or eukaryotic initiation factor-4. The next stages of myocardial infection has been demonstrated in
phase is characterized by inflammatory cellular infiltration, animal models of myocarditis, particularly those produced by
including natural killer cells and macrophages, with the Coxsackievirus B3.65 The presence of low levels of ongoing
subsequent expression of proinflammatory cytokines, partic- viral replication may result in continued myocardial damage,
ularly interleukin-1, interleukin-2, TNF, and interferon-␥.48,49 including apoptotic cell death, as a component of the immu-
TNF activates endothelial cells, recruits additional inflamma- nologic response to infection.48 The presence of HIV- and
tory cells, further enhances cytokine production, and has HCV-infected myocytes at autopsy argues that these infec-
direct negative inotropic effects.50 Cytokines also activate tions are capable of producing ongoing myocardial injury that
inducible NO synthase (NOS) in cardiac myocytes.51 The role ultimately results in an acute or chronic dilated
of NO in the development and progression of myocarditis is cardiomyopathy.33,66
complex. NO can inhibit viral replication by targeting spe-
cific viral proteases, and peroxynitrate formation has potent Clinical Presentation
antiviral effects.52 Mice deficient in NOS have greater viral Clinical manifestations range from asymptomatic ECG ab-
titers, a higher viral mRNA load, and more widespread normalities to cardiogenic shock.67 Transient ECG abnormal-
myocyte necrosis.53 Conversely, in experimental myosin- ities suggesting myocardial involvement commonly occur
induced autoimmune myocarditis, NOS expression in myo- during community viral endemics; most patients remain
cytes and macrophages is associated with more intense entirely asymptomatic. In contrast, myocarditis can also
inflammation, whereas NOS inhibitors have been shown to result in fulminant heart failure presenting as new-onset
reduce myocarditis severity.51,54 Cell-mediated immunity also cardiomyopathy. Patients may report a viral prodrome of
plays an important role in viral clearing. Cytotoxic (CD8ϩ) fever, myalgias, respiratory symptoms, or gastroenteritis
cells recognize degraded viral protein fragments that are followed by an abrupt onset of hemodynamic collapse. The
presented by major histocompatibility-complex class I anti- incidence of a reported infectious viral prodrome is highly
gens on the myocyte surface.55 Finally, circulating autoanti- variable, ranging from 10% to 80% of patients with docu-
bodies directed against contractile, structural, and mitochon- mented myocarditis.6,16,50
drial proteins have been described in both murine and human Acute dilated cardiomyopathy is one of the most dramatic
myocarditis. One or more autoantibodies have been observed and clinically relevant presentations of acute lymphocytic
in 25% to 73% of patients with biopsy-proven disease.56 myocarditis.7 The link between clinical myocarditis and acute
These autoantibodies may have direct cytopathic effects on dilated cardiomyopathy is most convincingly provided by
energy metabolism, calcium homeostasis, and signal trans- EMB findings.67 The 2 largest biopsy series have confirmed
duction; they also can induce complement activation, leading myocarditis in 9% to 16% of cases of new-onset dilated
to lysis of antibody-coated cells.57 Removal of circulating cardiomyopathy.68,69 The Giant Cell Myocarditis Study
autoantibodies by immunoadsorption has been shown to Group identified heart failure symptoms as the primary
improve cardiac function and decrease myocardial inflamma- presentation in 75% of patients with giant cell myocarditis.70
tion.58 – 60 It is now hypothesized that normal immunorespon- Neither symptoms nor clinical course of myocarditis has been
siveness facilitates viral clearing and allows healing to occur, shown to correlate with histopathological features such as the
whereas abnormal immunologic activity can alter the delicate extent of lymphocytic infiltrate or fibrosis.7
balance by promoting either ineffective viral clearance or The classification of Lieberman et al15 differentiates ful-
favoring persistent T-cell and/or antibody-mediated myocyte minant from active myocarditis. Fulminant myocarditis, man-
destruction.48,50,61 ifested by severe hemodynamic compromise requiring high-
HIV myocarditis may result from a similar pathogenic dose vasopressor support or mechanical circulatory support,
mechanism because virus has been identified within myo- was identified in 15 of 147 patients (10.2%) in the largest
cytes and is associated with disruption of myocyte integrity prospective study to use this classification system.5 Fulminant
and replacement with endocardial fibrosis.62 In addition, a cases were additionally characterized by a distinct viral
secondary form of myocarditis may result from direct inva- prodrome, fever, and abrupt onset (generally Ͻ3 days) of
sion by toxoplasmosis, candidiasis, aspergillosis, or Crypto- advanced heart failure symptoms. These patients typically
coccus; all have been associated with HIV coinfection. have severe global left ventricular dysfunction and minimally
Giant cell myocarditis is a rare disorder of uncertain increased left ventricular end-diastolic dimensions. Of note,
etiology that results in progressive acute or subacute heart either borderline or active lymphocytic myocarditis can
failure, is often rapidly lethal, and is diagnosed by the produce this dramatic clinical presentation.
presence of multinucleated giant cells on biopsy.63 Studies of Myocarditis masquerading as an acute coronary syndrome
human tissue with the use of electron microscopy have failed has also been well described.9,71,72 Elevated troponin levels
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6. 880 Circulation February 14, 2006
have proven to be a more reliable predictor of myocardial TABLE 2. Indications for Endomyocardial Biopsy*
injury than levels of creatine kinase.73 ECG changes sugges- Exclusion of potential common etiologies of dilated cardiomyopathy (familial;
tive of acute myocardial ischemia typically may include ischemic; alcohol; postpartum; cardiotoxic exposures) and the following:
ST-segment elevation in Ն2 contiguous leads (54%), T-wave Subacute or acute symptoms of heart failure refractory to standard
inversions (27%), widespread ST-segment depressions management
(18%), and pathological Q waves (18% to 27%).9,71 Segmen- Substantial worsening of EF despite optimized pharmacological therapy
tal or global echocardiographic wall motion abnormalities are
Development of hemodynamically significant arrhythmias, particularly
frequently evident despite angiographically normal coronary progressive heart block and ventricular tachycardia
anatomy.71 Sarda et al,72 using myocardial indium111-labeled Heart failure with concurrent rash, fever, or peripheral eosinophilia
antimyosin antibody and rest thallium imaging, identified 35
History of collagen vascular disease such as systemic lupus
of 45 patients (78%) who presented with acute chest pain, erythematosus, scleroderma, or polyarteritis nodosum
ischemic ECG abnormalities, and elevated cardiac biomark-
New-onset cardiomyopathy in the presence of known amyloidosis,
ers as having myocarditis. However, biopsy verification of sarcoidosis, or hemachromatosis
actual myocarditis was not undertaken in this series. In
Suspicion for giant cell myocarditis (young age, new subacute heart
another series of 34 patients with known normal coronary failure, or progressive arrhythmia without apparent etiology)
anatomy presenting with symptoms and ECG changes con-
Adapted with permission from Wu et al.78
sistent with an acute coronary syndrome, 11 (32%) of the
patients were found to have myocarditis on biopy.9 Clinicians
in a patient with a systemic disease known to cause left
should consider acute myocarditis in younger patients who
ventricular dysfunction78 (Table 2).
present with acute coronary syndromes when coronary risk
factors are absent, ECG abnormalities extend beyond a single Use of Cardiac Biomarkers
coronary artery territory, or global rather than segmental left Serum cardiac biomarkers (creatine kinase [CK], troponin I
ventricular dysfunction is evident on echocardiography. and T) are routinely measured when myocarditis is suspected.
Myocarditis can produce variable effects on the cardiac CK or its isoform (CK-MB) is not generally useful for
conduction system. Ventricular tachycardia is an uncommon noninvasive screening because of its low predictive value.
initial manifestation of myocarditis but often develops during Lauer et al79 reported that only 28 of 80 patients (35%) with
long-term follow-up.74 The Giant Cell Myocarditis Study suspected myocarditis had elevated troponin levels. Using a
Group reported an initial incidence of ventricular tachycardia serum troponin T cutoff Ͼ0.1 ng/mL, these investigators
of Ͻ5% in a multicenter cohort.70 Ventricular tachycardia due reported a sensitivity for detecting myocarditis of 53%, a
to either lymphocytic or granulomatous myocarditis may specificity of 94%, a positive predictive value of 93%, and a
infrequently result in sudden cardiac death.75 negative predictive value of 56%.79 Smith and coworkers73
also examined the value of troponin I in a subgroup of the
Diagnostic Evaluation Multicenter Myocarditis Treatment trial. Although the sensi-
Biopsy tivity of an elevated troponin I for the entire group was low
The Dallas criteria10 have standardized the histopathological (34%), its specificity was high (89%). Not surprisingly, a
definition of myocarditis. Despite its considerable limitations, short duration of symptoms (Ͻ4 weeks) was associated with
yielding diagnostic information in only 10% to 20% of a significantly higher sensitivity for detecting biopsy-proven
cases,76 EMB findings remain the gold standard for unequiv- disease.73 More importantly, the positive predictive value was
ocally establishing the diagnosis. The largest case series of acceptable at 82%. Most clinicians now routinely measure
patients with an unexplained cardiomyopathy used biopsy either troponin T or I whenever a clinical diagnosis of
findings to diagnose 111 of 1230 patients (9%) with myocar- myocarditis is considered.80
ditis.68 Fewer than 10% of 2233 patients with idiopathic heart An early trial used the erythrocyte sedimentation rate to
failure referred to the Myocarditis Treatment Trial6 had characterize a population with “reactive” myocardial disease
EMBs deemed positive by the Dallas criteria. However, but found its sensitivity and specificity to be extremely low.81
multiple investigators have described strong clinical, ven- Other serum immunologic biomarkers have included comple-
triculographic, and laboratory evidence of myocarditis among ment,82 cytokines,49 and anti-heart antibodies.83 None of these
patients with negative biopsies.7,69 Biopsies performed within approaches has been prospectively validated to accurately
weeks of symptom onset have a higher yield than those screen for biopsy-proven myocarditis.
undertaken when symptoms have been more longstanding.
Current American College of Cardiology/American Heart Immunologic Approaches
Association (ACC/AHA) guidelines for the treatment of heart Advances in immunology have expanded the diagnostic
failure77 describe EMB as a class IIb recommendation. capabilities of the EMB. Immunohistochemical staining has
Biopsy is generally reserved for patients with rapidly pro- enabled more precise characterization of infiltrating lympho-
gressive cardiomyopathy refractory to conventional therapeu- cytes subtypes84 and can accurately define and help quantify
tic management or an unexplained cardiomyopathy that is upregulation of major histocompatibility (MHC) antigens.
associated with progressive conduction system disease or Some investigators have adopted myocyte-specific MHC
life-threatening ventricular arrhythmias. It should also be expression as an essential criterion for diagnosing inflamma-
considered when cardiovascular signs or symptoms develop tory cardiomyopathy. This approach has greater sensitivity
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7. Magnani and Dec Diagnosis and Treatment of Myocarditis 881
than the Dallas criteria and has reopened the discussion acterization may prove to be more useful. Transmission and
concerning the true incidence of myocarditis among patients reflection of ultrasound energy depends on tissue density,
with “idiopathic” dilated cardiomyopathy.85 Herskowitz et elasticity, and acoustical impedance. Changes in 1 or more of
al86 compared quantitative MHC antigen expression in 13 these factors lead to different ultrasonic backscatter and an
active myocarditis patients with 8 control patients with other altered image texture. Lieback et al91 evaluated mean gray-
forms of cardiac disease. MHC class I and II expression was scale values (indicative of average brightness) in 52 patients
increased by 10-fold in the myocarditis cohort. Eleven of 13 with biopsy-proven myocarditis; 12 patients had persistent
myocarditis patients (85%) had either myocyte or microvas- myocarditis, 9 patients had healed myocarditis but lacked
cular endothelial MHC class I or class II expression com- fibrosis, and 17 patients had healed myocarditis and fibrosis.
pared with only 1 of 8 controls (12%). The sensitivity and Tissue characterization was highly effective in differentiating
specificity of any MHC expression for detecting biopsy- myocarditis from healthy control myocardium, with sensitiv-
proven myocarditis were 80% and 85%, respectively. This ity and specificity values of 100% and 90%, respectively.91
methodology was more recently evaluated in a larger cohort However, ultrasonic tissue characterization could not accu-
of 83 patients with clinically suspected myocarditis.17 Sur- rately differentiate between idiopathic dilated cardiomyopa-
prisingly, these investigators found no correlation between thy and active myocarditis. More recent techniques, particu-
MHC immunostaining and histopathological findings of ac- larly tissue Doppler imaging and myocardial velocity
tive myocarditis by Dallas criteria. As discussed by the measurements, are better able to characterize tissue changes
investigators, MHC expression could represent a more in acute myocarditis and to monitor changes in these param-
chronic form of myocardial injury and may not be responsible eters over time. Additional validation studies will be required
for the patients’ clinical presentation. The discordance be- to determine their clinical utility.
tween these findings is currently unexplained because the Indium111-labeled monoclonal antibody fragments (directed
staining methods and patient populations appeared to be against heavy chain myosin) bind to cardiac myocytes that
similar. Despite these shortcomings, biopsy assessment of have lost the integrity of their sarcolemmal membranes and
MHC expression has recently been used to guide therapy of have exposed their intracellular myosin to the extracellular
patients with inflammatory cardiomyopathy (see below).87 fluid space. Unlike gallium67, which detects the extent of
myocardial inflammation, antimyosin cardiac uptake reflects
Myocardial Imaging the extent of myocyte necrosis. Dec et al92 evaluated the
Noninvasive diagnostic myocardial imaging techniques for utility of antimyosin imaging in a large cohort of patients
detection of myocarditis may include echocardiography, nu- with clinically suspected myocarditis. On the basis of EMB,
clear imaging with gallium67- or indium111-labeled antimyosin antimyosin uptake was found to be highly sensitive (83%) but
antibodies, and MRI. only moderately specific (53%) for detecting myocardial
Echocardiography is currently recommended in the initial necrosis. However, the predictive value of a negative scan
diagnostic evaluation of all patients with suspected myocar- was high at 92%. More recently, Margari et al93 have reported
ditis. Several studies have specifically evaluated the role of that the presence of both a positive antimyosin scan and a
transthoracic echocardiography for diagnosing myocardi- nondilated left ventricular cavity (left ventricular end-diastol-
tis.88,89 Pinamonti et al88 retrospectively analyzed echocardio- ic dimension Յ62 mm) was highly predictive for detecting
graphic findings among 42 patients with biopsy-proven myo- myocarditis on biopsy.
carditis. Left ventricular dysfunction was commonly Contrast-enhanced MRI appears to be the most promising
observed (69%), but left ventricular cavity enlargement was technique for diagnosing myocardial inflammation and myo-
frequently minimal or absent, consistent with other forms of cyte injury on the basis of small, observational clinical
acute dilated cardiomyopathy. Right ventricular dysfunction studies. Besides providing anatomic and morphological in-
was present in only 23% of this cohort. Not surprisingly, formation, MRI can provide accurate tissue characterization
patients who presented with chest pain or heart block rather by measuring T1 and T2 relaxation times and spin densities.
than heart failure almost always had preserved ventricular Because active myocarditis is typically associated with myo-
size and function. Segmental wall motion abnormalities were cyte injury, including edema and cellular swelling, assess-
observed in 64% of patients and included hypokinetic, ment of relaxation times provides a sensitive measure for its
akinetic, or frankly dyskinetic regions. Reversible left ven- detection.94 Friedrich et al95 evaluated the diagnostic utility of
tricular hypertrophy was noted in 15% of patients and contrast-enhanced cardiac MRI in 19 patients with suspected
typically resolved over several months. Thus, echocardio- myocarditis. Early after presentation, myocardial enhance-
graphic findings can be varied but relatively nonspecific. ment was generally focal in distribution (Figure 4A). Global
Serial studies have been shown to be useful in assessing the enhancement became prominent during later imaging times
response to treatment of several forms of myocarditis. Reso- (Figure 4B) and returned to baseline within 90 days. Unfor-
lution of marked concentric left ventricular hypertrophy in tunately, the study did not examine the ability of MRI to
eosinophilic myocarditis after corticosteroid treatment has differentiate viral myocarditis from other causes of acute
been reported.90 dilated cardiomyopathy.
Although anatomic features on echocardiography (ie, Roditi et al96 evaluated 20 patients with T1 spin-echo cine
chamber dimensions, ejection fraction [EF], wall motion MR angiography and gadolinium-enhanced spin-echo imag-
abnormalities) are insufficient to differentiate myocarditis ing. Focal myocardial enhancement was associated with
from other forms of cardiomyopathy, ultrasonic tissue char- regional wall motion abnormalities in 10 of the 12 patients
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9. Magnani and Dec Diagnosis and Treatment of Myocarditis 883
to immunosuppressive treatment. Of these “nonresponders,”
17 of 20 patients (85%) had evidence of viral genome on
biopsy. Additional prospective, controlled studies are needed
to determine whether genomic analysis can help to predict the
likelihood of a therapeutic response to a specific immuno-
suppressive strategy.
Survival in cardiac sarcoidosis has been shown to be
similar to that of lymphocytic myocarditis and idiopathic
cardiomyopathy.107 The prognosis of cardiac sarcoidosis may
be further determined by the extent of extracardiac lesions.
Patients with giant cell myocarditis have been shown to have
the poorest outcomes, with median survival averaging only
5.5 months from the onset of heart failure symptoms or
arrhythmias.70
Figure 5. Kaplan-Meier survival curves for 38 patients with Treatment
biopsy-proven myocarditis and 111 patients with lymphocytic
myocarditis enrolled in the Myocarditis Treatment Trial. Duration
Supportive care is the first line of treatment. A minority of
refers to the time from biopsy diagnosis. PϽ0.001 by log-rank patients who present with fulminant or acute myocarditis will
test. Reproduced with permission from Cooper et al.70 require an intensive level of hemodynamic support and
aggressive pharmacological intervention, including vasopres-
predict survival. Most significantly, serum levels of soluble sors and positive inotropic agents, similar to other patients
Fas and soluble Fas ligand were significantly higher among with advanced heart failure due to profound left ventricular
patients with fatal myocarditis, suggesting that extent of dysfunction. Elevated ventricular filling pressures should be
cytokine activation may provide important prognostic infor- treated with intravenous diuretics and vasodilators (when
mation. In a series of biopsy-proven lymphocytic myocarditis feasible) such as nitroprusside or intravenous nitroglycerin. A
cases, Magnani et al11 used a multivariate predictive model ventricular assist device or extracorporeal membrane oxygen-
and identified presentation with syncope, bundle branch ation may rarely be required to sustain patients with refrac-
block, or an EF Ͻ40% as significant predictors of increased tory cardiogenic shock.108 These devices favorably alter
risk of death or transplantation. Advanced heart failure ventricular geometry, reduce wall stress, decrease cytokine
symptoms (NYHA classes III or IV) and elevated left activation, and improve myocyte contractile function. Al-
ventricular filling pressures have also been reported to predict though the data on survival after ventricular assist device or
a poorer prognosis.22 Pulmonary hypertension has also been extracorporeal membrane oxygenation implantation are
shown to predict increased mortality in heart failure popula- largely observational, the high likelihood of spontaneous
tions, and this relationship also applies to patients with recovery of ventricular function argues for aggressive short-
myocarditis.103 At our institution,11 we have demonstrated a term hemodynamic support.
survival advantage for patients diagnosed with borderline After initial hemodynamic stabilization, treatment should
compared with active myocarditis, but other centers have not follow current ACC/AHA recommendations for the manage-
found such a clear-cut relationship between histopathology ment of left ventricular systolic dysfunction and include an
and outcome. Finally, histological resolution of active myo- angiotensin-converting enzyme inhibitor and -adrenergic
carditis on repeated endomyocardial biopsy has been shown blocking agent in all patients and the selective use of an
to predict favorable clinical outcome.104 aldosterone antagonist in patients with persistent NYHA
Genomic analysis of biopsy specimens has, to date, pro- functional class III or IV symptoms.77 The decision to
vided conflicting prognostic information. An initial single- prophylactically implant an implantable cardioverter-
center study of 77 patients by Figulla et al105 reported a defibrillator in patients with advanced left ventricular dys-
significantly better 4-year transplant-free survival rate for function should be deferred for several months whenever
enterovirus-positive (Coxsackie B3 viral genome) patients possible to allow sufficient time for recovery of ventricular
compared with enterovirus-negative patients (95% versus function.
55%; PϽ0.05). Furthermore, LVEF increased significantly Because the long-term sequelae of viral myocarditis appear
from 35Ϯ13% to 43Ϯ9% (PϽ0.05) in the virus-positive to be related to abnormal cellular and humoral immunity,
group but remained unchanged in the virus-negative group many clinicians believe that immunosuppression should be
(34Ϯ12% to 37Ϯ14%; PϭNS). In distinct contrast, Why et beneficial for myocarditis treatment.50 Although Ͼ20 uncon-
al22 detected enteroviral RNA in 34% of 120 consecutive trolled observational studies have reported success with the
patients with unexplained cardiomyopathy. Enteroviral RNA use of a variety of immunosuppressive agents,109,110 several
presence was found to be an independent predictor of adverse caveats should be emphasized. First, histological resolution
outcome. Actuarial survival at 24 months for enterovirus- of myocardial inflammation does not closely correlate with
negative patients was substantially better than that for improvement in ventricular function. Second, the high inci-
enterovirus-positive patients (92% versus 68%; Pϭ0.02). dence of spontaneous improvement in contractile function
Most recently, Frustaci et al106 retrospectively studied 20 supports the need for a control group whenever treatment
patients with lymphocytic myocarditis who failed to respond success is evaluated. Finally, the specific viral agent (eg,
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10. 884 Circulation February 14, 2006
adenovirus, enterovirus, or parvovirus) and the immunologic in serum antiinflammatory markers (eg, interleukin-10, solu-
state of the host may result in different response rates to ble TNF), which correlated with significant improvement in
immunosuppression. Despite these considerable obstacles, LVEF (26Ϯ2% to 31Ϯ3%; PϽ0.01) at 6 months. These
several controlled clinical trials have been completed suc- changes were not observed in the control group. The long-
cessfully (Table 3). term benefit of this treatment strategy remains unknown.
Parrillo et al81 conducted the first immunosuppressive trial Immunohistochemical studies have recently led to a refor-
of patients presenting with unexplained dilated cardiomyop- mulation of our therapeutic paradigm by focusing on the
athy. Patients were classified as reactive or nonreactive on the presence of an inflammatory cardiomyopathy rather than
basis of histopathology (fibroblastic or lymphocytic infil- biopsy-proven myocarditis per se.115,116 Wojnicz et al87 used
trate), immunoglobulin deposition on EMB, a positive gal- HLA expression on endomyocardial specimens to identify an
lium scan, or an elevated erythrocyte sedimentation rate. inflammatory cardiomyopathy cohort. A total of 84 patients
Reactive patients treated with prednisone (60 mg daily) had a who demonstrated increased HLA expression and chronic
statistically greater likelihood of achieving a predefined end dilated cardiomyopathy were randomized to receive 3 months
point of an increase in LVEF Ն5% at 3 months. This of placebo or immunosuppression with prednisone and aza-
improvement was not sustained at 6 or 9 months because the thioprine. Although no difference was observed in the pri-
reactive control group showed comparable spontaneous im- mary composite end point of death, transplantation, or hos-
provement in function. It should be noted that the prednisone pital readmission with 2 years, significant increases in LVEF
dose was decreased to 60 mg on alternate days in the reactive were noted at 3 months and 2 years only among the
group after 3 months, and this change may have confounded immunosuppressive group. Whether increased HLA upregu-
later end point analyses. lation on EMB can be used to identify a cohort of patients
The Myocarditis Treatment Trial6 randomized 111 patients who are more likely to respond to immunosuppression will
with biopsy-verified myocarditis to receive placebo or an require a prospective, controlled trial. Our understanding,
immunosuppressive regimen of prednisone and either cyclo- based on the results of the trials by Gullestad et al114 and
sporine or azathioprine. Analysis compared the placebo group Wojnicz et al,87 suggests that immunomodulatory therapy is
with the combined immunosuppressive cohorts. No differ- most likely to benefit patients who have a chronic inflamma-
ence in mortality was evident between treatment groups; tory cardiomyopathy, persistent immune activation, and on-
furthermore, the degree of improvement in LVEF at 28 weeks going symptoms despite optimal medical therapy.
was identical (control, 24% to 36%; immunosuppression, A more recent observational analysis106 examined the role
24% to 36%). Multivariate analysis identified higher initial of circulating cardiac autoantibodies and viral genomic ex-
LVEF, less intensive conventional therapy, and shorter dura- pression in a cohort of 41 patients with biopsy-proven active
tion of symptoms to be independent predictors of subsequent lymphocytic myocarditis who had failed to respond to con-
improvement. These 2 controlled trials suggest that immuno- ventional therapy. All patients were treated empirically with
suppression should not be prescribed for the routine treatment azathioprine and prednisone immunosuppression. Patients
of viral myocarditis. Immunosuppression can benefit patients were subsequently classified as responders or nonresponders
with myocarditis due to systemic autoimmune diseases, after 1 year of follow-up. Cardiotropic viral genome was
particularly lupus erythematosus, scleroderma, and polymy- present in 17 of 20 (85%) of nonresponders compared with
ositis. Patients with idiopathic giant cell myocarditis have only 3 of 21 responders (14%). In addition, cardiac autoan-
also been shown to benefit from aggressive immunosuppres- tibodies were found in the sera of 19 of 21 responders (91%)
sive protocols.70 and none of the nonresponders in this study. The lack of
Intravenous immune globulin has been used to treat both randomization and lack of a control group limit the general-
giant cell and lymphocytic myocarditis in uncontrolled stud- izability of these potentially important observations and call
ies.111,112 The Intervention in Myocarditis and Acute Cardio- for additional studies to evaluate their significance.
myopathy Study113 was a double-blind, randomized, con- Finally, both interferon-␣ and interferon- have been
trolled trial of intravenous immune globulin in 62 patients described as producing hemodynamic and clinical improve-
with recent-onset (Ͻ6 months) heart failure and unexplained ment in dilated cardiomyopathy and myocarditis.
dilated cardiomyopathy. Myocarditis was detected on EMB Interferon-␣ benefit was described in a case study117 and in a
in 16% of patients. No treatment-related differences were single-center, randomized trial comparing its efficacy to
observed in all-cause mortality or improvement in LVEF at 6 placebo or thymomodulin.118 Although mortality did not
or 12 months. Both groups demonstrated substantial increases differ, LVEF rose significantly more in the treatment than the
in LVEF (Ͼ10 EF units) during the study period. The placebo group. Interferon- has also been shown to produce
spontaneous increase in LVEF observed in the control group benefit in a phase II, single-center study of patients with
once again limited the ability of a small trial to detect PCR-detected enteroviral or adenoviral genome on endomyo-
meaningful differences between treatment regimens. cardial biopsy.119 Data on the efficacy of interferon-␣ or -
Gullestad et al114 also studied the efficacy of intravenous have yet to be confirmed in large-scale, multicenter clinical
immune globulin in a randomized trial of 40 patients with trials.
chronic (mean duration, 3.5Ϯ0.5 years) rather than acute
dilated cardiomyopathy. Biopsy was not performed, and Future Directions and Conclusions
therefore the percentage of patients with myocarditis remains Myocarditis is the end result of both myocardial infection and
unknown. IgG therapy was associated with a marked increase autoimmunity that results in active inflammatory destruction
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11. Magnani and Dec Diagnosis and Treatment of Myocarditis 885
TABLE 3. Immunosuppressive Therapy for Myocarditis and Dilated Cardiomyopathy
Clinical Trial (Publication Date) Study Design Entry Criteria
Interferon- treatment of cardiotropic viruses Phase II observational study; not blinded, no History of cardiac symptoms for 44Ϯ27 mo;
(2003)119 control group; single center endomyocardial presence of adenovirus or
enterovirus; no other medical reason for cardiac
disease
Immunosuppressive therapy in active Responders vs nonresponders to conventional Active lymphocytic myocarditis; immunosuppressive
lymphocytic myocarditis (2003)106 and immunologic therapies; retrospective; and conventional treatment for 6 mo with
single center progressive heart failure
Immunosuppression with prednisone and Randomized, placebo-controlled; not blinded; 1. Increased expression of HLA molecules on
azathioprine vs placebo (2001)87 single center endomyocardial biopsy.
2. Chronic heart failure (Ն6 mo) and LVEF Յ40%
by echocardiography and radionuclide
ventriculography.
3. No evidence of other cardiovascular, renal, or
endocrine disease
Intervention in Myocarditis and Acute Randomized clinical trial, placebo-controlled; LVEF Յ40%, no other cause of idiopathic dilated
Cardiomyopathy (2001)113 double-blinded; cointerventions not matched; cardiomyopathy, Յ6 mo of symptoms.
multiple centers No evidence of giant cell myocarditis, sarcoidosis, or
hemachromatosis on biopsy
Immunomodulating therapy with IVIG in Randomized clinical trial, placebo-controlled; LVEF Յ40%, NYHA class II/III, stable and optimized
chronic heart failure (2001)114 double-blinded; single center regimen; history of CAD or idiopathic DCM
Myocarditis Treatment Trial (1995)6 Randomized clinical trial; not blinded; Histological evidence of myocarditis per Dallas
cointerventions not matched; multiple centers criteria
Interferon-␣ or thymic hormone (1996)118 Randomized clinical trial; not blinded; Histological evidence of myocarditis or idiopathic
cointerventions not matched cardiomyopathy; LVEF Ͻ45% by angiography. No
other reason for cardiac disease; no evidence of
giant cell myocarditis
Prednisone in DCM (1989)81 Randomized clinical trial; not blinded; single History of idiopathic DCM and no evidence of other
center; cointerventions discontinued cardiovascular disease
Active myocarditis in acute DCM (1985)7 Matched cohort; varied interventions; single Heart failure of Յ6 mo secondary to dilated
center cardiomyopathy; LVEF Յ40%; no cause of DCM
identified by biopsy
CAD indicates coronary artery disease; DCM, dilated cardiomyopathy; IV, intravenous; IVIG, intravenous immunoglobulin; LVEDD, left ventricular end-diastolic
dimension; and LVESD, left ventricular end-systolic dimension.
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12. 886 Circulation February 14, 2006
TABLE 3. Continued
Cohorts, Subjects (n), and Interventions Results Strengths/Limitations
22 patients; 1. Eradication of enterovirus and adenovirus on 1. Only 2 biopsies assessed for histological
group Aϭenteroviral (14); group Bϭadenoviral biopsy. evidence of myocarditis; no patients had
(8). All patients received interferon-ß, 18ϫ106 2. 15/22 (68%) had NYHA improvement by 1 histopathological evidence of active myocarditis.
IU weekly by subcutaneous injection for 24 wk class. 2. Lack of control group (albeit phase II study).
3. Significant improvement in LVEF, LVEDD, and 3. Nonrandomized design
LVESD in all (12) patients with baseline LVEF
Ͻ50%
41 patients; Group A: 3/21 (14%) had viral genome, 19/21 1. Limited sample size.
group Aϭresponders (21); (90%) had circulating cardiac antibodies. 2. Lack of nonimmunosuppressed treatment group.
group Bϭnonresponders. (21). Group B: 17/20 (85%) had viral genome, 0/20 3. Retrospective analysis.
All patients received conventional therapy plus had circulating cardiac antibodies 4. Lack of negative biopsy as control.
prednisone and azathioprine 5. Nonrandomized design
84 patients, with chronic heart failure and No significant difference in mortality; 1. Excluded patients with symptoms Ͻ6 mo.
dilated cardiomyopathy; significant difference in LVEF improvement from 2. No immunohistological control.
group Aϭcontrol (43); 6 mo to 2 y 3. 61/84 (73%) had no evidence of myocarditis by
group Bϭimmunotherapy (41) Dallas criteria.
4. Not blinded despite use of placebo.
5. EF did not normalize in either group.
62 patients; No difference in mortality; no difference in LVEF 1. Limited incidence of myocarditis on biopsy (7/62
group Aϭcontrol (29); at 6 or 12 mo after randomization ͓11.3%͔) and no follow-up biopsies.
group BϭIVIG, 2 g/kg by IV infusion (33). 2. No difference in normalization of LVEF at 1 y
All patients received conventional therapy (20/56 (͓36%͔).
3. Single administration of IVIG with dosage based
on pediatric myocarditis study.
4. Did not examine other tissue or humoral
indicators of inflammation
40 patients; Significant decrease in cytokine and 1. Short-term trial; no mortality data provided.
group Aϭcontrol (20); immunomodulator levels in treatment group; 2. No intermediate follow-up of sustainability of
Group Bϭ IVIG (19) significant increase in LVEF by Ͼ5% results.
3. Small size of study groups limits generalizability
and statistical power.
4. Mixed etiologies limit applicability of findings
111 patients; No difference in mortality at 1 y; no difference 1. Lack of consensus regarding histopathology;
group Aϭcontrol (47); in change in LVEF at 28 wk unresolved before analysis.
group Bϭprednisone and azathioprine or 2. No distinction between patients receiving
cyclosporine azathioprine or cyclosporine in analysis.
3. Definition of myocarditis limited to
histopathological criteria
38 patients; No difference in mortality. Limited sample sizes 1. No predefined end point, including use of
group Aϭcontrol (12); precluded statistical comparisons radionuclide ventriculography at 2 y without prior
group Bϭinterferon (13); baseline measurement.
group Cϭthymomodulin (13) 2. Open-label trial.
3. Small size of study groups limited statistical
power
102 patients; No difference in mortality between groups A and 1. Diverse nonspecific criteria to distinguish
group Aϭnonreactive (42) per study criteria; B or within either group receiving prednisone vs “reactive” disease.
group Bϭreactive (60) per study criteria. placebo. 2. Cessation of cointerventions aside from
Both groups randomized to prednisone vs Group A: increase in LVEF Ն5% at 3 mo, not antiarrhythmic and anticoagulation.
placebo sustained at 6 mo; no significant change in 3. Nonspecific entry criterion of history of
other end points. idiopathic DCM.
Group B: no significant change in LVEF or other 4. Only patients described as reactive had follow-up
end points biopsies.
5. Diverse histopathology classified as reactive,
fibroblastic (38), or lymphocytic (2) disease
27 patients; No difference in improvement between groups; 1. Lack of standardized protocol, thus duration of
group Aϭnegative biopsy (9); no difference in improvement within or between symptoms to biopsy, immunosuppressive
group Bϭpositive biopsy (18) groups receiving immunosuppression regimens, follow-up, and monitoring varied.
2. Small cohort size
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13. Magnani and Dec Diagnosis and Treatment of Myocarditis 887
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Acknowledgments 20. Grumbach IM, Heim A, Pring-Akerblom P, Vonhof S, Hein WJ, Muller
The authors would like to acknowledge James Stone, MD, PhD, who G, Figulla HR. Adenoviruses and enteroviruses as pathogens in myo-
prepared and contributed the photomicrographs for Figures 1, 2, and 3. carditis and dilated cardiomyopathy. Acta Cardiol. 1999;54:83– 88.
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Disclosures dium from patients with dilated cardiomyopathy by nucleotide
None. sequencing of reverse transcription-nested polymerase chain reaction
products. Hum Pathol. 1998;29:578 –584.
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