1. ISSN: 1524-4539
Copyright © 2006 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online
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Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX
DOI: 10.1161/CIRCULATIONAHA.105.589663
2006;113;593-595Circulation
Kenneth L. Baughman
Diagnosis of Myocarditis: Death of Dallas Criteria
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2. Diagnosis of Myocarditis
Death of Dallas Criteria
Kenneth L. Baughman, MD
Determining the etiology of cardiac dysfunction in pa-
tients with heart failure influences management and
prognosis.1 Myocarditis, diagnosed by the current histopatho-
logical Dallas criteria, accounts for Ϸ10% of patients with
new-onset cardiac dysfunction submitted to endomyocardial
biopsy.1,2 Despite complete evaluation including history,
physical examination, blood work, echocardiography, coro-
nary angiography, and endomyocardial biopsy, Ϸ50% of
patients with dilated cardiomyopathy have no etiology iden-
tified.1 Recent data suggest that patients in the “idiopathic”
category may be suffering from myocardial inflammation due
to persistent viral replication or autoimmune activation after
a viral infection. These studies raise the question of whether
the current histopathological criteria for myocardial inflam-
mation (the Dallas criteria) are sensitive enough to identify
the population with viral or autoimmune-related heart
compromise.
The Dallas criteria were proposed in 1986 and provided a
histopathological categorization by which the diagnosis of
myocarditis could be established. Dallas criteria myocarditis
requires an inflammatory infiltrate and associated myocyte
necrosis or damage not characteristic of an ischemic event.
Borderline myocarditis requires a less intense inflammatory
infiltrate and no light microscopic evidence of myocyte
destruction.3 These criteria have been used exclusively by
American investigators over the last 2 decades. Sampling
error, variation in expert interpretation, variance with other
markers of viral infection and immune activation in the heart,
and variance with treatment outcomes all suggest that the
Dallas criteria are no longer adequate.
Chow et al and Hauck et al4,5 demonstrated by biopsying
postmortem hearts of patients who had died with myocarditis
that, from a single endomyocardial biopsy, histological myo-
carditis could be demonstrated in only 25% of samples. With
Ͼ5 biopsies, Dallas criteria myocarditis could be diagnosed
in approximately two thirds of subjects. A recent MRI study
used focal imaging abnormalities to guide heart biopsy
investigation of possible myocarditis. The authors showed
that the earliest myocardial inflammatory abnormalities were
evident in the lateral wall of the left ventricle, and only these
sites revealed myocarditis by histological examination.6
Therefore, there is considerable sampling error associated
with establishing the diagnosis of myocarditis.
In addition, there are variations in the interpretation of
histological samples. Of the 111 patients included in the
Myocarditis Treatment Trial diagnosed with myocarditis by
heart biopsy,7 only 64% had that diagnosis confirmed by the
expert pathology panel who reviewed the histopathological
material. In a separate analysis, 7 expert pathologists’ inter-
pretations of histopathological findings from endomyocardial
biopsies of 16 patients with dilated cardiomyopathy varied
remarkably in the assessment of significant fibrosis (25% to
69%), hypertrophy (19% to 88%), nuclear changes (31% to
94%), lymphocyte count per high-power field (0% to 38%),
and the diagnosis of myocarditis. Definite or probable myo-
carditis was diagnosed in 11 of 16 patients by at least 1
pathologist. However, of the 11 patients, 3 of 7 pathologists
agreed on the diagnosis of myocarditis in 3 patients, and 2 of
7 pathologists agreed on the diagnosis of myocarditis in 5
patients.8 Therefore, even expert observers do not agree on
the interpretation of histopathological material that has un-
dergone routine staining.
Myocarditis may be associated with a number of condi-
tions including HIV/AIDS, ischemia, and inflammatory states
such as sarcoidosis and immune disease such as lupus
erythematosus. Excluding causes of myocardial inflammation
of known etiology allows investigators to address the larger
and more important category of patients with “primary” (or
postviral) myocarditis. Primary viral myocarditis includes
several forms of myocarditis that are defined by their clinical
pathological manifestations. These include fulminant, chronic
active, eosinophilic, and giant cell myocarditis. Fulminant
myocarditis has a distinct onset usually within 2 weeks of
presentation. Patients present with profound left ventricular
dysfunction but usually not left ventricular dilatation. The
endomyocardial biopsy shows multiple foci of active inflam-
mation and necrosis. Patients recover or die within 2 weeks
with complete histological and functional recovery of the
myocardium in survivors.9 Chronic active myocarditis has an
indistinct onset with moderate ventricular dysfunction on
presentation and active or borderline myocarditis by biopsy.
These patients display ongoing inflammation and fibrosis
resulting in the development of a restrictive cardiomyopathy
usually 2 to 4 years after presentation.10 Eosinophilic myo-
carditis may be attributed to eosinophilic syndromes or
allergic reactions resulting in left ventricular compromise,
From the Advanced Heart Disease Section, Division of Cardiovascular Medicine, Harvard Medical School, Boston, Mass.
Correspondence to Kenneth Lee Baughman, MD, Brigham and Women’s Hospital, Cardiovascular Division, 75 Francis St, Boston, MA 02115. E-mail
kbaughman@partners.org
(Circulation. 2006;113:593-595.)
© 2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.105.589663
593
Special Report
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3. with eosinophil and myocyte damage demonstrated by endo-
myocardial biopsy.11–13 These patients respond to treatment
of the eosinophilic disorder and/or withdrawal of the offend-
ing agent. Patients with giant cell myocarditis present with
congestive heart failure, ventricular arrhythmias, or heart
block. Despite institution of medical therapy, patients with
giant cell myocarditis continue to have poorly controlled
congestive heart failure or ventricular arrhythmias. Untreated,
patients will die in Ͻ6 months. Patients have a characteristic
endomyocardial biopsy with giant cells and active inflamma-
tion that may respond to aggressive immunosuppressive
therapy.14,15 Therefore, several forms of myocarditis are
characterized by their clinical pathological manifestations.
The largest population of patients presenting with subacute
myocardial deterioration is indistinct from patients presenting
with idiopathic cardiomyopathy.
A number of investigators have shown that virus may be
present in the myocardium without Dallas criteria myocardi-
tis. Martin et al16 demonstrated in 34 children with clinical
presentations compatible with myocarditis that 26 heart
biopsy samples were positive for viral pathogens, and 13 of
the 26 positive samples had no evidence of myocarditis by
histopathological examination. Other investigators have con-
firmed the presence of viral pathogens in samples of cardiac
tissue from patients with cardiomyopathy and myocarditis.
Pauschinger et al17 found 24 of 94 patients with idiopathic
dilated cardiomyopathy to have either adenoviral or entero-
viral polymerase chain reaction positivity. A meta-analysis of
polymerase chain reaction studies in patients who had heart
biopsies with presumed myocarditis or cardiomyopathy dem-
onstrated an odds ratio of 3.8 for viral presence in both
categories compared with control patients.18 In a selected
sample of 45 patients with left ventricular dysfunction and
suspected myocarditis and 26 controls, nonreplicative entero-
virus was demonstrated in 18 of 45 patients (40%) compared
with none of the controls. Of the 18 patients with nonrepli-
cative virus, 10 (56%)19 were found to have active viral
replication as well (strand negative). Why et al20 discovered
in 120 patients with idiopathic dilated cardiomyopathy that
the 34% who were enteroviral positive had a significantly
worse outcome over 2 years (Pϭ0.02) compared with those
who were enteroviral negative. Therefore, virus can exist in
the myocardium (even in a replicative form) in the absence of
myocardial inflammation adequate to meet Dallas criteria and
may adversely affect outcome.
There is also dissociation between Dallas criteria myocar-
ditis and response to immune modulation therapy. In the
Myocarditis Treatment Trial, there was no difference in the 1-
or 5-year survival or 28-week ejection fraction in patients
with Dallas criteria myocarditis treated with immunosuppres-
sive therapy or placebo.7 Other authors have used alternative
criteria to diagnose immune-related heart disease. Wojnicz et
al21 found 84 of 202 patients with new-onset cardiomyopathy
to be HLA positive, while only 27% were positive by Dallas
criteria for myocarditis. HLA has previously been shown to
be upregulated in patients with myocarditis and is less “focal”
than lymphocytic infiltration. HLA-identified patients were
treated with immunosuppressive therapy or placebo. Al-
though there was no difference in primary outcome (death,
transplant, or hospitalization), the ejection fraction in the
immunosuppressive group increased from 24% to 36%,
whereas it remained stagnant in the placebo group (25% to
27%). Even in patients demonstrating Dallas criteria myocar-
ditis, response to treatment may be influenced by the presence
of virus or immunological response to infection. Frustaci et
al22 identified Dallas criteria myocarditis in 112 of 652
patients with new-onset heart failure. Forty-one of the 112
had progressive congestive heart failure despite standard
medical therapy. These patients were treated with prednisone
and azathioprine for 6 months. Twenty responded, and 21
failed to respond. Those responding increased their ejection
fraction from 23% to 47%, whereas the ejection fraction of
the nonresponders remained stable. Those who responded had
evidence of antiheart antibodies (90%) verses nonresponders
(0%). Those who failed to respond displayed viral persistence
in heart tissue (84% of patients), whereas only 13% of
responders had viral persistence. Therefore, the presence of
Dallas criteria myocarditis does not identify patients who
respond to immune modulation therapy. Evidence of viral
persistence may imply a worse prognosis and identify pa-
tients who fail to respond to immunosuppressive therapy.
Alternatively, patients with immune activation, demonstrated
by HLA upregulation or antiheart antibodies, may respond to
immunosuppressive therapy despite absence of Dallas criteria
myocarditis.
Defining the etiology of the 50% of patients currently
labeled as idiopathic with new-onset heart failure is critical to
determining their outcome and treatment options. We must
now redefine the diagnosis of viral and postviral immune-
related heart dysfunction. This classification should include
clinicopathological entities such as fulminant, chronic persis-
tent, eosinophilic, and giant cell myocarditis that are easily
recognized by their clinical course and/or histology on heart
biopsy. Those without distinct clinical pathological manifes-
tations encompass a much broader category and will include
patients with viral persistence and immune upregulation.
With this approach, we may identify clinical pathological
correlates and natural history of disease specific for a given
virus.
McNamara et al23 and Mason et al7 demonstrated that some
patients with new-onset left ventricular compromise display
significant recovery of ventricular function with or without
histological evidence of myocardial inflammation by the
Dallas criteria. The ability to modify the outcome of those
who fail to improve spontaneously or to enhance the recovery
of those who increase their ejection fraction may significantly
alter the prognosis of this population and lessen the burden of
chronic disabling heart failure that they otherwise will face.
The time has come to redefine viral and autoimmune heart
disease with the use of methodologies available in the 21st
century. Clinicians, pathologists, immunologists, and molec-
ular cardiologists must contribute to the new criteria, which
should include clinical presentation, histopathology, immu-
nohistochemistry, viral polymerase chain reaction, cardiac
antibody assessment, and imaging results.
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KEY WORDS: cardiomyopathy Ⅲ heart failure Ⅲ myocarditis
Ⅲ pathology Ⅲ biopsy
Baughman Myocarditis Diagnosis 595
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