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DOI: 10.1161/CIRCULATIONAHA.105.589663 2006;113;593-595 Circulation

Kenneth L. Baughman Diagnosis of Myocarditis: Death of Dallas Criteria

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Diagnosis of MyocarditisDeath 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 �10% of patients withnew-onset cardiac dysfunction submitted to endomyocardialbiopsy.1,2 Despite complete evaluation including history,physical examination, blood work, echocardiography, coro-nary angiography, and endomyocardial biopsy, �50% ofpatients with dilated cardiomyopathy have no etiology iden-tified.1 Recent data suggest that patients in the “idiopathic”category may be suffering from myocardial inflammation dueto persistent viral replication or autoimmune activation aftera viral infection. These studies raise the question of whetherthe current histopathological criteria for myocardial inflam-mation (the Dallas criteria) are sensitive enough to identifythe population with viral or autoimmune-related heartcompromise.

The Dallas criteria were proposed in 1986 and provided ahistopathological categorization by which the diagnosis ofmyocarditis could be established. Dallas criteria myocarditisrequires an inflammatory infiltrate and associated myocytenecrosis or damage not characteristic of an ischemic event.Borderline myocarditis requires a less intense inflammatoryinfiltrate and no light microscopic evidence of myocytedestruction.3 These criteria have been used exclusively byAmerican investigators over the last 2 decades. Samplingerror, variation in expert interpretation, variance with othermarkers of viral infection and immune activation in the heart,and variance with treatment outcomes all suggest that theDallas criteria are no longer adequate.

Chow et al and Hauck et al4,5 demonstrated by biopsyingpostmortem hearts of patients who had died with myocarditisthat, from a single endomyocardial biopsy, histological myo-carditis could be demonstrated in only 25% of samples. With�5 biopsies, Dallas criteria myocarditis could be diagnosedin approximately two thirds of subjects. A recent MRI studyused focal imaging abnormalities to guide heart biopsyinvestigation of possible myocarditis. The authors showedthat the earliest myocardial inflammatory abnormalities wereevident in the lateral wall of the left ventricle, and only thesesites revealed myocarditis by histological examination.6

Therefore, there is considerable sampling error associatedwith establishing the diagnosis of myocarditis.

In addition, there are variations in the interpretation ofhistological samples. Of the 111 patients included in theMyocarditis Treatment Trial diagnosed with myocarditis byheart biopsy,7 only 64% had that diagnosis confirmed by theexpert pathology panel who reviewed the histopathologicalmaterial. In a separate analysis, 7 expert pathologists’ inter-pretations of histopathological findings from endomyocardialbiopsies of 16 patients with dilated cardiomyopathy variedremarkably in the assessment of significant fibrosis (25% to69%), hypertrophy (19% to 88%), nuclear changes (31% to94%), 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 1pathologist. However, of the 11 patients, 3 of 7 pathologistsagreed on the diagnosis of myocarditis in 3 patients, and 2 of7 pathologists agreed on the diagnosis of myocarditis in 5patients.8 Therefore, even expert observers do not agree onthe 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 statessuch as sarcoidosis and immune disease such as lupuserythematosus. Excluding causes of myocardial inflammationof known etiology allows investigators to address the largerand more important category of patients with “primary” (orpostviral) myocarditis. Primary viral myocarditis includesseveral forms of myocarditis that are defined by their clinicalpathological manifestations. These include fulminant, chronicactive, eosinophilic, and giant cell myocarditis. Fulminantmyocarditis has a distinct onset usually within 2 weeks ofpresentation. Patients present with profound left ventriculardysfunction but usually not left ventricular dilatation. Theendomyocardial biopsy shows multiple foci of active inflam-mation and necrosis. Patients recover or die within 2 weekswith complete histological and functional recovery of themyocardium in survivors.9 Chronic active myocarditis has anindistinct onset with moderate ventricular dysfunction onpresentation and active or borderline myocarditis by biopsy.These patients display ongoing inflammation and fibrosisresulting in the development of a restrictive cardiomyopathyusually 2 to 4 years after presentation.10 Eosinophilic myo-carditis may be attributed to eosinophilic syndromes orallergic 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

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Special Report

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with eosinophil and myocyte damage demonstrated by endo-myocardial biopsy.11–13 These patients respond to treatmentof the eosinophilic disorder and/or withdrawal of the offend-ing agent. Patients with giant cell myocarditis present withcongestive heart failure, ventricular arrhythmias, or heartblock. Despite institution of medical therapy, patients withgiant cell myocarditis continue to have poorly controlledcongestive heart failure or ventricular arrhythmias. Untreated,patients will die in �6 months. Patients have a characteristicendomyocardial biopsy with giant cells and active inflamma-tion that may respond to aggressive immunosuppressivetherapy.14,15 Therefore, several forms of myocarditis arecharacterized by their clinical pathological manifestations.The largest population of patients presenting with subacutemyocardial deterioration is indistinct from patients presentingwith idiopathic cardiomyopathy.

A number of investigators have shown that virus may bepresent in the myocardium without Dallas criteria myocardi-tis. Martin et al16 demonstrated in 34 children with clinicalpresentations compatible with myocarditis that 26 heartbiopsy samples were positive for viral pathogens, and 13 ofthe 26 positive samples had no evidence of myocarditis byhistopathological examination. Other investigators have con-firmed the presence of viral pathogens in samples of cardiactissue from patients with cardiomyopathy and myocarditis.Pauschinger et al17 found 24 of 94 patients with idiopathicdilated cardiomyopathy to have either adenoviral or entero-viral polymerase chain reaction positivity. A meta-analysis ofpolymerase chain reaction studies in patients who had heartbiopsies with presumed myocarditis or cardiomyopathy dem-onstrated an odds ratio of 3.8 for viral presence in bothcategories compared with control patients.18 In a selectedsample of 45 patients with left ventricular dysfunction andsuspected myocarditis and 26 controls, nonreplicative entero-virus was demonstrated in 18 of 45 patients (40%) comparedwith none of the controls. Of the 18 patients with nonrepli-cative virus, 10 (56%)19 were found to have active viralreplication as well (strand negative). Why et al20 discoveredin 120 patients with idiopathic dilated cardiomyopathy thatthe 34% who were enteroviral positive had a significantlyworse outcome over 2 years (P�0.02) compared with thosewho were enteroviral negative. Therefore, virus can exist inthe myocardium (even in a replicative form) in the absence ofmyocardial inflammation adequate to meet Dallas criteria andmay adversely affect outcome.

There is also dissociation between Dallas criteria myocar-ditis and response to immune modulation therapy. In theMyocarditis Treatment Trial, there was no difference in the 1-or 5-year survival or 28-week ejection fraction in patientswith Dallas criteria myocarditis treated with immunosuppres-sive therapy or placebo.7 Other authors have used alternativecriteria to diagnose immune-related heart disease. Wojnicz etal21 found 84 of 202 patients with new-onset cardiomyopathyto be HLA positive, while only 27% were positive by Dallascriteria for myocarditis. HLA has previously been shown tobe upregulated in patients with myocarditis and is less “focal”than lymphocytic infiltration. HLA-identified patients weretreated with immunosuppressive therapy or placebo. Al-though there was no difference in primary outcome (death,

transplant, or hospitalization), the ejection fraction in theimmunosuppressive group increased from 24% to 36%,whereas it remained stagnant in the placebo group (25% to27%). Even in patients demonstrating Dallas criteria myocar-ditis, response to treatment may be influenced by the presenceof virus or immunological response to infection. Frustaci etal22 identified Dallas criteria myocarditis in 112 of 652patients with new-onset heart failure. Forty-one of the 112had progressive congestive heart failure despite standardmedical therapy. These patients were treated with prednisoneand azathioprine for 6 months. Twenty responded, and 21failed to respond. Those responding increased their ejectionfraction from 23% to 47%, whereas the ejection fraction ofthe nonresponders remained stable. Those who responded hadevidence of antiheart antibodies (90%) verses nonresponders(0%). Those who failed to respond displayed viral persistencein heart tissue (84% of patients), whereas only 13% ofresponders had viral persistence. Therefore, the presence ofDallas criteria myocarditis does not identify patients whorespond to immune modulation therapy. Evidence of viralpersistence may imply a worse prognosis and identify pa-tients who fail to respond to immunosuppressive therapy.Alternatively, patients with immune activation, demonstratedby HLA upregulation or antiheart antibodies, may respond toimmunosuppressive therapy despite absence of Dallas criteriamyocarditis.

Defining the etiology of the 50% of patients currentlylabeled as idiopathic with new-onset heart failure is critical todetermining their outcome and treatment options. We mustnow redefine the diagnosis of viral and postviral immune-related heart dysfunction. This classification should includeclinicopathological entities such as fulminant, chronic persis-tent, eosinophilic, and giant cell myocarditis that are easilyrecognized by their clinical course and/or histology on heartbiopsy. Those without distinct clinical pathological manifes-tations encompass a much broader category and will includepatients with viral persistence and immune upregulation.With this approach, we may identify clinical pathologicalcorrelates and natural history of disease specific for a givenvirus.

McNamara et al23 and Mason et al7 demonstrated that somepatients with new-onset left ventricular compromise displaysignificant recovery of ventricular function with or withouthistological evidence of myocardial inflammation by theDallas criteria. The ability to modify the outcome of thosewho fail to improve spontaneously or to enhance the recoveryof those who increase their ejection fraction may significantlyalter the prognosis of this population and lessen the burden ofchronic disabling heart failure that they otherwise will face.

The time has come to redefine viral and autoimmune heartdisease with the use of methodologies available in the 21stcentury. Clinicians, pathologists, immunologists, and molec-ular cardiologists must contribute to the new criteria, whichshould include clinical presentation, histopathology, immu-nohistochemistry, viral polymerase chain reaction, cardiacantibody assessment, and imaging results.

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KEY WORDS: cardiomyopathy � heart failure � myocarditis� pathology � biopsy

Baughman Myocarditis Diagnosis 595

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