Giant cell myocarditis: Most fatal of autoimmune diseases

Giant Cell Myocarditis: Most Fatal of Autoimmune Diseases

Elliot D. Rosenstein, Mark J. Zucker, and Neil Kramer

Objective: To increase awareness of giant cell myocarditis (GCM), its patho-

genesis, and treatment.

Methods: Review of relevant publications from the English-language litera-

ture.

Results: GCM is a rare, frequently fatal inflammatory disorder of cardiac

muscle of unknown origin, characterized by widespread degeneration and

necrosis of myocardial fibers. Congestive heart failure and ventricular tachy-

cardia are common clinical manifestations. GCM occurs primarily in previously

healthy adults, although it is frequently associated with various systemic

diseases, primarily of autoimmune causes. The inflammatory infiltrate is char-

acterized by the presence of multinucleated giant cells and is distinct from

cardiac sarcoidosis. Animal models of GCM are similar to models of other

autoimmune disorders such as rheumatoid arthritis. The prognosis, which is

poor despite partial responsiveness to immunosuppressive medications, is

improved with cardiac transplantation.

Conclusions: The clinical and immunopathogenetic similarities with classical

rheumatologic diseases, the differential diagnosis with sarcoidosis and other

inflammatory conditions, and the use of standard immunosuppressive medi-

cations make GCM a disease process that should be added to the rheumatol-

ogist’s expertise.

Semin Arthritis Rheum 30:1-16. Copyright © 2000 by W.B. Saunders Com-pany

INDEX WORDS: Myocarditis; giant cells; autoimmunity; immunosuppressive

therapy.

ALTHOUGH its roots will always be in thediagnosis and treatment of the classical

musculoskeletal disorders, the field of rheuma-tology has expanded to include a wide variety ofinflammatory diseases, no longer constrained bydefined organ systems. As will become clearfrom further reading, despite its rarity, giant cellmyocarditis (GCM) is a condition with which therheumatologist should become well acquainted.Since its first description by Saltikow in 1905,

GCM has been recognized as a rapidly fatalinflammatory cardiac disease (1,2). Fortunately,some patients with GCM respond to aggressiveimmunosuppressive measures.

GCM has clinical and immunopathogenic fea-tures of the more traditional “autoimmune” condi-tions. The differential diagnosis of GCM includessarcoidosis, the vasculitic conditions, and classicalrheumatic diseases. Especially because the thera-peutic interventions used in the treatment of GCM

From the Division of Rheumatology and Arthritis and RheumaticDisease Center, St. Barnabas Medical Center, Livingston, NJ; andHeart Failure Treatment & Transplant Center, Newark Beth IsraelMedical Center, Newark, NJ.

Elliot D. Rosenstein, MD:Clinical Associate Professor ofMedicine, Mount Sinai School of Medicine, New York, NY;Medical Director, Arthritis and Rheumatic Disease Center, StBarnabas Medical Center, Livingston, NJ; Mark J. Zucker,MD: Associate Clinical Professor of Medicine, Mount SinaiSchool of Medicine, New York, NY; Director, CardiothoracicTransplantation, Newark Beth Israel Medical Center, Newark,

NJ; Neil Kramer, MD: Clinical Associate Professor of Medi-cine, Mount Sinai School of Medicine, New York, NY; MedicalDirector, Arthritis and Rheumatic Disease Center, St. BarnabasMedical Center, Livingston, NJ.

Address reprint requests to Elliot D. Rosenstein, MD, Arthri-tis and Rheumatic Disease Center, St Barnabas Medical Cen-ter, 200 South Orange Ave, Livingston, NJ 07039. E-mail:[email protected]

Copyright © 2000 by W.B. Saunders Company0049-0172/00/3001-00001$10.00/0doi:10.1053/sarh.2000.8367

1Seminars in Arthritis and Rheumatism, Vol 30, No 1 (August), 2000: pp 1-16

involve the same armamentarium used in the man-agement of inflammatory conditions that threatenother essential organs, the rheumatologist has theunique facility and experience to evaluate and treatthis condition.

OVERVIEW

Inflammatory diseases of the myocardium arerelatively rare. In a review of 377,841 autopsiesperformed over a 20-year period from 1958through 1977, idiopathic, nonspecific, interstitial,or viral myocarditis was observed in only 0.11% ofindividuals (3). Other autopsy studies have notedan incidence as high as 5% (4). Although myocar-ditis can be associated with various causes, bothlocal and systemic, most cases are considered id-iopathic. Some cases are subclinical, ultimatelyleading to dilated cardiomyopathy. But in mostcases of myocarditis, the condition is a benign,self-limited illness. Cardiac symptoms may be sub-tle or incidental, and full recovery is the expecta-tion. However, particular presentations of myocar-ditis can be devastating, resulting in severe andprogressive heart failure and arrhythmias, oftenresulting in death (5,6).

In that clinical findings can only allow a pre-sumptive diagnosis of myocarditis, “conclusive”diagnosis requires histologic analysis of myocar-dial tissue obtained by endomyocardial biopsy(EMB). The diagnosis of myocarditis can bemissed because of sampling error, so the absenceof histologic changes does not totally exclude thepossibility of myocarditis. Other techniques maybe required to substantiate the clinical diagnosis ofmyocarditis (7).

Even with tissue in hand, the varying definitionsof what histologic findings constitute myocarditisand the different types of myocarditis has resultedin a literature that is rife with imprecision andcontradiction. The presence of inflammatory cellsalone is not sufficient to make the diagnosis ofmyocarditis, because a condition such as lym-phoma may present with lymphocytic infiltrationwithout myocardial damage. On the contrary, earlyischemic damage may cause myocyte degenerationin the absence of a significant inflammatory cellu-lar reaction. For these reasons, the consensusamong pathologists is that the diagnosis of myo-carditis is dependent on recognition of both acellular infiltrate and myocyte degeneration.

The formulation of the Dallas Classification

System in 1987 has allowed for standardization ofthe definition and staging of the disease (8). Ac-cording to these criteria, myocarditis has beendefined by the presence of an inflammatory infil-trate in myocardium with necrosis or degenerativechanges of adjacent myocytes, not typical of isch-emic damage. The termborderline myocarditis hasbeen introduced to describe the presence of onlysparse inflammatory cells, without necrosis ofmyocytes. The histologic description should in-clude information about the extent and distributionof the infiltrate and the predominant cell type, suchas lymphocytic, neutrophilic, eosinophilic, giantcell (GC), granulomatous. The presence and distri-bution of fibrosis also must be noted (8) (Table 1).

The prevailing situation has been improved bycategorization of the varying causes of myocardi-tis, utilizing histologic characteristics and associ-ated causes, as proposed by Mason (9), whichinclude: 1) active (acute) viral; 2) other infectious,e.g. Chagas’ disease, toxoplasmosis, diphtheria; 3)hypersensitivity due to drugs or other exogenousagents; 4) autoimmune, including peripartum; 5)lymphocytic, usually representing postviral, oftencharacterized as idiopathic; 6) and a distinct myo-carditis in which GCs are the most impressivehistologic feature (9).

Over the years, GCM has been recognized byvarious other names, including idiopathic GCM,

Table 1: The Dallas Criteria for Classification

of Myocarditis

Initial Biopsy

• Myocarditis: myocyte necrosis, degeneration, or

both in the absence of significant coronary artery

disease with adjacent inflammatory infiltrate �

fibrosis

• Borderline myocarditis: inflammatory infiltrate

too sparse or myocyte damage not apparent

• No myocarditis

Subsequent Biopsy

• Ongoing (persistent) myocarditis � fibrosis

• Resolving (healing) myocarditis � fibrosis

• Resolved (healed) myocarditis � fibrosis

NOTE: The inflammatory infiltrate to be subclassified as lym-

phocytic, neutrophilic, giant cell, granulomatous, or mixed.

The amount of inflammatory infiltrate and its distribution to be

described as mild, moderate, or severe and focal, confluent, or

diffuse (8).

2 ROSENSTEIN, ZUCKER, AND KRAMER

pernicious myocarditis, Fiedler’s myocarditis,acute idiopathic interstitial myocarditis, giant cellgranulomatous myocarditis, and granulomatousmyocarditis (10). Tesluk (1) in 1956 first attemptedto distinguish between chronic inflammatory myo-carditis with GCs, with and without the presence ofgranuloma formation, to avoid confusion with car-diac sarcoidosis (1). As much as possible, thisreview addresses GCM in the absence of granu-loma.

As with most autoimmune conditions, exoge-nous factors, in particular viruses and mycobacte-ria, were investigated as possible causes for thedevelopment of GCM. Researchers were unable toshow a microbiologic agent by direct microscopy,direct culture of human tissues, or inoculation intoexperimental animals (10). Similar to those foundin the renal lesions of patients with systemic lupuserythematosus (SLE), filamentous structures anddense granules have been observed in GCs anddegenerated myocardial fibers by electron micros-copy (EM). However, these lack the internal struc-tures or organization of established viral particles(10) and are now thought to reflect interferon-stimulated histologic changes without specificallydenoting viral infection.

Clinical Presentation and Course

GCM is an uncommon disorder, which typicallyaffects young to middle-aged adults. However, theage range extends from 10 days to 70 years, with amean age of 43 years. There is a slight malepreponderance (3,11-13). Usually, previouslyhealthy patients present with symptoms character-istic of a flu-like syndrome. Although the earlysymptoms of GCM may not be different from othertypes of acute myocarditis, the condition oftenprogresses rapidly to death, often within days tomonths. Congestive heart failure (CHF) is the mostcommon cardiac presentation (75%), with symp-toms including exertional dyspnea, decreased ex-ercise tolerance, and peripheral edema (11,12).Palpitations and chest pain are less common pre-senting symptoms. Sustained, refractory ventricu-lar tachycardia was noted in half of patients duringthe course of their illness (11). On occasion, theinitial manifestations may be quite dramatic, in-cluding rapidly progressive hemodynamic deterio-ration, intractable arrhythmias, and sudden death.Fewer than 10% of patients had pericarditis.

Nonspecific laboratory reflections of systemic

inflammation (leukocytosis, elevated erythrocytesedimentation rate) may be present, but this is notinvariable (7). Electrocardiographic abnormalitiesrange from nonspecific ST and T wave changes toevidence of widespread acute myocardial damagewith Q wave development in the absence of coro-nary artery disease (11, 14). Atrial or ventriculararrhythmias, a variety of conduction system abnor-malities, including complete heart block, are com-mon. Cardiac enzymes characteristically showsustained moderate elevation, although normal cre-atine phosphokinase (CPK) levels have been noted(14,15). Cardiac troponin-I levels, a specificmarker of myocyte injury, may be a more sensitiveindicator of myocarditis (7).

Although treatment with diuretics, angiotensin-converting enzyme (ACE) inhibitors, vasodilators,and antiarrhythmics may moderate some of thecardiac dysfunction, GCM tends to follow a rap-idly deteriorating course unless immunosuppres-sive therapy is instituted or heart transplantation isperformed. Cooper et al (12) reported a mediansurvival rate of 5.5 months from symptom onsetuntil time of death or transplantation. Patients withonly mild depression of left ventricular (LV) func-tion, who seek treatment because of arrhythmias orconduction abnormalities, may follow a more in-dolent course. There are rare reports of 2- to10-year survival without immunosuppressive ther-apy (16). Davidoff et al (14) have described a lessdisastrous prognosis in some patients with GCM,with 50% survival at 4 years (14). This highersurvival rate in some of the more recent studiesmay reflect earlier diagnosis, the use of antiar-rhythmic agents and pacemaker insertion, and themore widespread use of immunosuppressive ther-apy (12).

Compared with the more commonly encoun-tered lymphocytic myocarditis, GCM is more ag-gressive and associated with greater mortality, inpart related to the greater likelihood of ventriculartachycardia and progressive decline in ventricularfunction (12,14) (Fig 1).

GCM is more likely to require permanent pace-maker insertion or cardiac transplantation (15). Incases of fatal myocarditis, 20% were attributed toGCM (2), although in the autopsy study citedpreviously, GCM was documented in 0.007% ofautopsies, or 6% of all cases of myocarditis (3).

Despite attempts to segregate GCM from gran-ulomatous myocarditis by the absence or presence

3GIANT CELL MYOCARDITIS

of well-defined granulomata, the inconsistent dis-tinction between these two conditions has blurredthe reported incidence of the disease. Davidoff etal’s review supports the validity of 60 cases before1990 (14). In good part because of the registryestablished in the last several years by the Multi-center Giant Cell Myocarditis Study Group, thenumber of cases has now exceeded 100 (12).

In the absence of documented underlying dis-eases, rare cases of GCM with extracardiac in-volvement have been reported. However, on closescrutiny, these may represent localized manifesta-tions of other conditions characterized by GC in-filtration (1,17,18). For example, the case of a37-year-old woman with a fatal cardiac arrhythmiawho was found to have GC inflammation at au-topsy in extraocular, pharyngeal, and laryngealsites, as well as in cardiac muscle, in associationwith lymphocytic adenohypophysitis and lepto-meningitis, may represent an atypical presentationof sarcoidosis (19). Another patient has been re-ported with involvement of liver, thyroid, andaorta, and extensive vasculitis in fibrotic areas ofmyocardium, possibly representing extravascularmanifestations of GC arteritis (20). Other casesdefy categorization. Consider the patient describedby Klein who presented with bilateral proptosis,hoarseness, dysphagia, and had a deltoid biopsyconsistent with inflammatory myopathy (21). Atautopsy, the patient showed lymphocytic and

plasma cell infiltrate in myocardium, with multinu-cleated GCs, some with erythrophagocytosis andan apparent tendency to form granuloma reminis-cent of Aschoff bodies, such as those seen inrheumatic heart disease (21).

Diagnostic and Pathologic Findings

In addition to the standard noninvasive docu-mentation of cardiac involvement, cardiac nuclearscans may be helpful in establishing the presenceof myocardial inflammation. With gallium-67 scin-tigraphy, in which radioisotope is taken up byinfiltrating inflammatory cells, the test had highspecificity for myocarditis (98%) but low sensitiv-ity (36%) (22). Alternatively, the indium-111-anti-myosin scan can help differentiate myocarditis(diffuse activity) from myocardial infarction (focaluptake) (23). Recently, magnetic resonance imag-ing has been evaluated as a means of detectingmyocarditis, as indicated by alteration in signalintensity, among infants and children with myocar-ditis (24).

But the diagnosis of GCM, in distinction to othertypes of myocarditis, is established by the demon-stration of a diffuse, intramyocardial inflammatoryinfiltrate consisting of abundant lymphocytes, feweosinophils and plasma cells, and prominentmultinucleated GCs, often at the margins of theinfiltrate, associated with myocyte degeneration,and circumscribed areas of myocardial necrosis.The hallmark finding, the GCs, represents fusedepithelioid cells, usually 40 to 50�m in diameter,with large cytoplasmic mass containing typicallygreater than 20 nuclei, usually of the Langhanstype. Peripheral areas of fibrosis may be present,perhaps reflecting the chronicity of the process(25) (Fig 2).

Historically, multinucleated GCs have long beenconsidered to be of myogenic origin: GCs occa-sionally show rod-shaped cytoplasm lying parallelto the surrounding muscle fibers; contiguous ar-rangement of GCs with myocytes can be observed(26); light and EM have shown the presence ofvarious components of muscle fibers, such as myo-fibrils, intercalated disks, myoglobin, and lipofus-cin granules, in the cytoplasm of GCs (9-11,27,28). Normally, however, cardiac myocytes have asingle nucleus. To form the multinucleated GC,excessive mitosis or cell fusion would be neces-sary—unfamiliar processes for cardiac myocytes,although commonplace among histiocytes.

Fig 1. Kaplan-Meier survival curve for patients

with giant cell myocarditis as compared with

lymphocytic myocarditis. The graph shows the

duration of survival from the onset of symp-

toms. (From Cooper et al [12]. Reproduced with

permission of the author and publisher.)


There is additional support for the histiocyticorigin of GC. Myocardial GCs have been shown tohave well-developed endoplasmic reticulum andlysosomal vacuoles characteristic of macrophages(11). Additionally, fragmentation of myofibrils hasbeen noted, suggesting lysosomal degradation ofingested myocytes (16). Furthermore, recent im-munohistochemical studies using myocyte-specificmarkers have failed to confirm their myogenicorigin, supporting the macrophage/histiocytic ori-gin of GCs (12,16,29-33).

The presence or absence of well-defined granu-lomas has been a major source of confusion in theolder literature, in which no distinction was madebetween granulomatous and GC infiltrates. Thisdistinction between GCM and granulomatousmyocarditis may be a bit tenuous, as evidenced bya report of the evolution of GCM in a cardiactransplant patient in whom serial biopsies indicateddiffuse inflammatory changes acutely, followed byan alternating remitting and worsening course withprogression into chronic myocarditis with granulo-matous aspects (34).

As previously noted, as much as possible, wehave restricted the discussion herein to GCM, inthe absence of granulomatous infiltration. Thiswould exclude rheumatic carditis, with interstitialAschoff bodies and infectious granulomatous myo-carditis, such as tuberculosis (35), cryptococcosis(36), coccidioidomycosis (37), syphilis (38), lep-rosy (39), or Whipple’s disease (14), in which

palisading histiocytes, typically around necroticcenters, have been shown. In GCM, there is no truevasculitis, because there is no direct involvementof major blood vessels within the heart. Unless theinflammatory infiltrate is pervasive, there is noinvolvement of pericardium or endocardium (26).

Although the availability of immunophenotyp-ing assists in determining the nature of the cellularinfiltrate, results have been inconsistent with re-gard to the predominant population of the mono-nuclear infiltrate, variously noted to have lympho-cyte or macrophage dominance (32), with mostshowing CD8 (40) but others CD4 excess (41).Immunofluorescent examination of cardiac tissueusually indicates no specific staining pattern (5),although deposits of anti-Ig and anti-C1q havebeen reported (42).

More elaborate testing will be necessary to de-finitively identify the source of cardiac GCs. Thecurrently available evidence argues more stronglyfor a histiocytic origin, with the intracellular myo-cardial constituents probably a result of phagocy-tosis.

Biopsy Characteristics

Although other noninvasive techniques maysuggest the presence of myocardial inflammation,the critical diagnostic test to establish a diagnosisof GCM is an EMB. The sensitivity of an EMB forthe diagnosis of myocarditis, in general, is notknown. Studies to correlate the biopsy findings in

Fig 2. Histologic find-

ings in giant cell myo-

carditis. The photo-

micrograph shows an

intense mononuclear cell

infiltrate, consisting of

lymphocytes, histiocytes,

few eosinophils, and

abundant giant cells, ad-

jacent to degenerating

myocytes. (Hematoxylin

and eosin, original mag-

nification �200.)


patients with clinically diagnosed myocarditisfound confirmatory pathology in only 17% to 22%(43). Paradoxically, 31 of 36 patients with evi-dence of myocardial cell damage by antimyosinscintigraphy were histologically negative for myo-carditis (44). Because a negative biopsy does notrule out the diagnosis of myocarditis, it is imper-ative to optimize pathologic confirmation by per-forming selective tissue sampling. It has been sug-gested that at least five specimens be obtained ofthe right ventricle, in particular from apical andnonapical portions of the ventricular septum (8, 11,43-47). In general, left ventricular biopsy does notprovide a higher yield and is associated with highermorbidity (46).

Despite the attempt to establish objective criteriafor the diagnosis of myocarditis, pathologic inter-pretations remain highly subjective, showing greatinterobserver variability (9,43). The accuracy ofbiopsy specimens was less than 50% in a series of14 patients with myocarditis proven at autopsy ortransplantation (45). Overall, greater than 33% ofpatients with myocarditis by Dallas criteria may bemissed or incorrectly diagnosed as having border-line myocarditis because of the inherent limitationsof EMB (48,49). In addition to the Dallas criteria,attempts have been made to identify myocarditisby immunohistology. The number of T cells iscounted under high power, with myocarditis de-fined as the mean number of CD2 or CD3� lym-phocytes per high-power field. Kuhl et al (44)diagnosed myocarditis in 5% of cardiomyopathypatients using the Dallas criteria while identifying37% of patients using immunohistology. Addition-ally, the use of prior immunosuppressive therapymay obscure the typical histologic changes.

Despite its limitations, an EMB remains essen-tial for antemortem diagnosis in those patients withunexplained, recent-onset heart failure, LV dilationwith or without mural thrombus, and unexplainedarrhythmias, especially if the course exceeds a fewdays (47,50).

Autoimmune Processes

Although the cause of GCM remains unknown,there are striking associations with other diseasescharacterized as autoimmune disorders. GCM hadbeen most frequently reported with myastheniagravis, generally in association with malignantthymomas (1,39,51-55). In Cooper’s more recentseries, 8% of patients had either preceding Crohn’s

disease or ulcerative colitis (12). Cases of GCMalso have been reported in conjunction with rheu-matoid arthritis (RA), SLE, Sjogren’s syndrome,Hashimoto’s thyroiditis, and other autoimmunesyndromes (5,7,9,12,19,21,26,29,42,55-58) (Table2). Cases also have been associated with diseaseprocesses causing GC inflammation in other tissuesites, such as GCA and Takayasu’s arteritis. Aswith some other cardiac conditions causing pro-duction of heart-reactive autoantibodies that maycross-react with the associated infectious agent, forexample, group A �-hemolytic streptococcus,Trypanosoma cruzi, the suspicion remains thatGCM may be the sequela of an infectious disease,possibly an enteroviral infection (see Pathogene-sis).

Anti-skeletal muscle and anti-myocardial anti-bodies have been identified in most patients withGCM, but these are not unique to the condition(42). Western immunoblotting has shown that vir-tually all sera, including those of healthy volun-teers, reacted with cardiac antigens present in nor-mal heart extract (59). Numerous studies indicatethat heart autoantibodies, most often to myosin, areassociated with bacterial infections (poststrepto-coccal rheumatic fever), viral infections, surgery(postpericardiotomy syndrome), and acute isch-

Table 2: Autoimmune Diseases Associated

With Giant Cell Myocarditis

• Sarcoidosis

• Systemic lupus erythematosus

• Takayasu’s arteritis

• Poly-(dermato-)myositis

• Rheumatoid arthritis*

• Giant cell (temporal) arteritis

• Autoimmune thyroid disease

• Pernicious anemia

• Alopecia totalis

• Vitiligo

• Orbital myositis

• Myasthenia gravis

• Inflammatory bowel disease

• Insulin dependent diabetes mellitus

• Sjogren’s syndrome

• Chronic active (autoimmune) hepatitis

• Optic neuritis

* Often cited but probably Langhans and foreign-body type

giant cells in association with cardiac rheumatoid nodules.


emic heart injury (postinfarction or Dressler syn-drome) (60). In fact, antibodies to several differentcardiac antigens have been identified in some pa-tients with other types of myocarditis and idio-pathic dilated cardiomyopathy, including antibod-ies to adenosine nucleotide translator (ADP-ATPcarrier protein), heart mitochondria (61), branched-chain keto-acid dehydrogenase, beta-adrenergic re-ceptors (62,63), laminin (64), and certain structuraland heat shock proteins (65) (Table 3). The anti-myosin antibodies identified bind to myosin heavychain, without organ specificity, and with equalavidity to myosin of cardiac or skeletal muscleorigin.

In Neumann’s series of cardiac patients, 59% ofpatients with myocarditis and 20% of patients withidiopathic cardiomyopathy had a high titer of an-tibodies to heart tissue by indirect immunofluores-cence (62). In Lauer’s series, 30 of 62 (48%)patients with myocarditis had anti-myosin antibod-ies, whereas 10 of 41 (24%) with dilated cardio-myopathy and 9 of 43 (21%) with other cardiacdiseases had antibodies (59). Thus, the controversypersists whether anti-heart antibodies have etio-logic relevance to GCM or are simply a nonspe-cific indication of myocardial damage (61,65-67).The finding of anti-myosin antibodies in 20% ofthe symptom-free relatives of patients with dilatedcardiomyopathy strongly suggests that these anti-bodies have pathogenetic significance and argues

that at least some patients with this disease have anautoimmune basis (68).

Further argument for the pathophysiologic sig-nificance of anti-heart antibodies has been made byKodama et al (69), who noted that fluctuation ofanti-myosin titers have correlated with clinicalcourse. When anti-cardiac myosin antibodies weremeasured in patients with various cardiac condi-tions, high titers were only seen in two of eightwith myocarditis, both of whom had GCM, 1 of 58patients with dilated cardiomyopathy, and not at allin patients with pericarditis, hypertrophic cardio-myopathy, or miscellaneous heart diseases, or incontrols. The direct pathogenetic involvement ofthese antibodies has been supported by the findingsof Maisch et al (66), who showed in vitro thatheart-reactive autoantibodies can lyse myocytesand participate in antibody-dependent cell-medi-ated cytotoxicity (ADCC) reactions (66). Autoan-tibodies also have the potential to influence cardiacmetabolism and contractility by interaction withkey cell constituents (�1-adrenergic receptor, mi-tochondrial proteins) (63). Models of GCM havebeen established in animals by autoimmunizationwith cardiac myosin (see Pathogenesis) (69-71).

As has been well substantiated in animal mod-els, and as we conclude from the clinical reports inhuman disease, the improvement in clinical coursein response to immunosuppressive therapy is fur-ther evidence for the autoimmune basis of thecondition (69-72).

As with other autoimmune disorders, our suspi-cion is that the development of GCM is a reflectionof the (mis)fortuitous convergence of genetic pre-disposition and environmental exposure; that is,those patients who are genetically at risk and whoexperience heart infection or injury go on to de-velop chronic autoimmune myocarditis. Those in-dividuals lacking the genetic vulnerability maydevelop transient heart-reactive antibodies but beprotected against chronic autoimmune disease(65).

Models for development of autoimmune myo-carditis have been developed in laboratory animals.However, it remains unclear whether the mecha-nisms for autoimmune myocarditis are more likelyto involve cross-reactive antigens shared by vari-ous pathogens and host tissues, as seen in rheu-matic fever, or alteration or aberrant expression ofself-antigens as a consequence of infection, inflam-mation or necrosis, as suspected in Hashimoto’s

Table 3: Auto-antigens Associated With

Human Myocarditis

• Skeletal muscle, myocardial cell

• Heat shock proteins (HSP-60)

• Myosin (heavy chain)

• Mitochondrial proteins (ADP-ATP carrier

protein, branched-chain alpha keto-acid

dehydrogenase, M7 antigen)

• Sarcolemmal, myolemmal epitopes

• Actin

• Tubulin

• Laminin

• Calcium channel

• Muscarinic receptor, �1-adrenergic receptor

and other G-protein–linked receptors

• Creatine kinase

From references (7) and (60-65).


thyroiditis (65). We suggest that the insult to themyocardium, whatever its origin, must be presentfor a substantial amount of time before the devel-opment of clinical manifestations. Otherwise, therapid clinical deterioration would not offer a timecourse consistent with either a primary or second-ary immunologic reaction.

PATHOGENESIS

In many respects, similar to what has been seenwith experimental models of arthritis, several ani-mal models of myocarditis have been established,none of which are exact analogs of the humanpathology. The differences among these forms ofexperimental autoimmune myocarditis (EAM)hinge to great extent on the species utilized (ratvmouse) and the provocative agent (Coxsackie B3virus or myosin) responsible for inciting theimmunologic reaction against myocardial tissue(73-78).

In the murine model of viral myocarditis, usingCoxsackie B3 virus (CVB3), virus-induced lysis ofmyocytes takes place during the first 3 days ofinfection. Infectious CVB3 is undetectable by cul-ture in the blood and in the myocardium by day 15,and most animals recover fully. However, in ge-netically susceptible mice, continued tissue dam-age will occur. This is believed to represent im-mune-mediated injury as a result of virus-specificcytotoxic T lymphocytes causing lysis of infectedmyocytes, and of autoreactive T lymphocytes thatdestroy uninfected myocytes, resulting in myocar-ditis that may persist for weeks or months, in theabsence of virus (4,68,73).

In this chronic, postviral autoimmune myocar-ditis, heart-specific autoantibodies against cardiacmyosin heavy chains are produced. Immunophe-notype analysis shows the presence of abundantnatural killer cells, macrophages, and primarilyCD8� T cells. Despite this intense chronic inflam-matory infiltrate, pathologic examination does notshow the presence of GCs (74).

The other popular animal model involves immu-nizing Lewis rats with cardiac myosin (mixed withcomplete Freund’s adjuvant supplemented withMtuberculosis, administered by subcutaneous injec-tion on days 0 and 7). Symptoms typically developaround day 14 and follow a severe course charac-terized by CHF. This form of EAM is charac-terized by cardiomegaly, pericardial effusion,extensive myocardial necrosis, and the frequent

occurrence of multinucleated GCs in the lesions(70). The period of active inflammation of EAM inrats continues over 2 weeks and exceeds that ofmurine viral myocarditis. Macrophages and CD4�

T cells are the predominant components of infil-trating mononuclear cells throughout the diseasecourse (71), in contrast to experimental viral myo-carditis. ADCC by macrophages and neutrophilsmay play a role in the myocardial injury (70). Thismodel of disease can be passively transferred tohealthy rats by concanavalin-A–stimulated T cells,but not by using sera or immunoglobulin G (IgG)subfractions from diseased rats. This form of EAMmore closely resembles human GCM in its mor-phologic findings and clinical course (71).

The sequence of immunopathologic events hasbeen most clearly defined in a similar model usinggenetically susceptible A/J mice. After immuniza-tion with cardiac myosin, T cells are locally acti-vated and liberate cytokines, which result in sys-temic activation of the immune system. Heartinterstitial cells purified from normal mice arecapable of presenting cardiac myosin in associa-tion with MHC class II molecules and stimulatemyosin-specific T cells. T cells recognize immu-nodominant peptides within cardiac myosin heavychains. Autoreactive T cells then circulate throughthe organism and recognize heart-specific peptidein association with MHC class II molecules ex-pressed on heart interstitial cells. “Professional”antigen-presenting cells located within the myocar-dium appear to be the primary target of autoreac-tive T cells during the initial phases of autoimmuneheart disease. After initiation of the inflammatoryprocess by CD4� T cells, CD8� cells and mac-rophages are recruited into heart muscle and con-tribute to disease pathogenesis (75,76). Inductionof myocarditis is mediated by CD4 cells, but CD8cells are involved in the progression of myocardialinflammation (77). Cellular infiltrates are diffuseand consist of CD4� T cells, CD8� T cells,macrophages (70% to 80% of infiltrating cells),and some B cells, with local deposition of heartmuscle protein-specific autoantibodies. Similar tothe Lewis rat model, adoptive immunity will onlyoccur with purified T cells from mice with activemyocarditis. Transfer of anti-cardiac myosin anti-bodies does not cause myocarditis, although it isunknown whether such antibodies may participatein the progression of myocyte destruction (78).


TREATMENT OF ANIMAL MODELS

In the various animal models of EAM, manydifferent treatment modalities have been used, withdiffering degrees of success dependent on themodel, the timing, dose, and route of administra-tion. A placebo-controlled trial examining the ef-fects of cyclosporine (1 mg/kg), prednisolone, andaspirin therapy (21 days intraperitoneal) in Lewisrats immunized with cardiac myosin in completeFreund’s adjuvant (days 0, 7) indicated that alldeveloped severe GCM, whereas myocarditis waseffectively prevented with cyclosporine 5 and 20mg/kg. Furthermore, production of anti-myosin an-tibodies was suppressed in rats in the two higher-dose cyclosporine groups (79). Administration ofcyclosporine after clinically recognizable diseasewas not effective in altering the course. Similarly,effective doses of tacrolimus administered afterimmunization but before clinical disease sup-pressed development of cardiac inflammation, butdid not prevent development of anti-myosin IgGantibodies (80). Other immunosuppressives, suchas deoxyspergualin (DSG), had effects similar tocyclosporine, preventing development of EAM andadditionally suppressing antibody production (81).Infusion of anti-�� T cell receptor (TCR) antibodyprevents progression of cardiac dysfunction, pre-sumably by impairment of antigen recognition,rather than depletion of TCR (82). As one wouldsuspect from its putative pathogenesis, neonataldepletion of T cells, but not B cells, preventsexperimental autoimmune myocarditis.

As seen in other experimental autoimmune dis-eases, depletion of either CD4� or CD8� T cellsby anti-CD4 or anti-CD8 monoclonal antibodiescan prevent induction of cardiac myosin-inducedautoimmune myocarditis. This suggests that bothare involved in the disease process, presumablyCD4 in the induction of the autoimmune responseand CD8 in mediating myocardial injury (76).MHC class II binding peptides can block inductionof disease if present in adequate amounts duringthe initial stages of presentation of immunogenicmyosin epitopes to autoreactive T cells (76).

Tumor necrosis factor, interleukin-1, and othercytokines have been shown to affect myocardialfunction, possibly through induction of nitric oxide(NO) synthesis. NO may be a crucial factor leadingto alteration of cardiac physiology because of itsnegative inotropic effects and toxicity for cardiac

myocytes (83,84). Anti-tumor necrosis factor treat-ment has been shown to significantly reduce theseverity of myocarditis when given before myosinimmunization. Neutralization of interferon-�, how-ever, has resulted in increased severity of myocar-ditis in A/J mice immunized with cardiac myo-sin (85).

Some investigators emphasize that the murinemodel of cardiac myosin-induced myocarditisclosely resembles the subacute phase of murineCVB3 myocarditis, which is considered a postviralautoimmune disease (77,86).

In contrast, the rat model is histologically simi-lar to human GCM and different from murineCVB3 myocarditis (70,79). Although it remainsunclear which type of human myocarditis bestcorresponds with which animal model of cardiacmyosin-induced autoimmune myocarditis, the sim-ilarities with GCM are clear. However, as with theanimal models of RA, EAM is clearly differentfrom the human disease in its initiation process.Immunization with the antigen in immunoadju-vants does not occur naturally in humans. Otherevents such as viral infection or other exposuresmay serve a similar role, resulting in antigen pre-sentation, “auto-reactive” lymphocytes and en-hanced immune responsiveness (70).

OTHER SYSTEMIC INFLAMMATORY

DISEASES THAT PRESENT WITH

MYOCARDITIS

Among the rheumatic diseases, cardiac manifes-tations may be seen in many disorders. We haverestricted our discussion here to those rheumaticdisorders in which evidence of myocarditis (CHF,life-threatening arrhythmias, or sudden death) wasthe sole clinical manifestation of the underlyingdisease.

Takayasu’s arteritis is a large vessel vasculitisinvolving the aorta and its major branches, as wellas the pulmonary arteries. Congestive heart failure,an important complication of Takayasu’s arteritis,is usually attributed to the residua of aortic andlarge vessel inflammation: hypertension, aortic re-gurgitation, or, rarely, myocardial infarction. Iso-lated myocarditis must also be added to the list ofearly, potentially reversible disease manifestations.In a series of 120 consecutive cases of Takayasu’sarteritis, seven patients presented with a clinicalpicture of congestive cardiomyopathy. Autopsywas performed in two of these patients, both of


which showed changes consistent with myocarditis(87). In a prospective study of 54 patients withTakayasu’s arteritis, EMB performed in the 24patients with overt signs of CHF showed evidenceof myocarditis (88). All patients with biopsy evi-dence of myocarditis were treated with a combi-nation of prednisone and daily cyclophosphamide,with preliminary favorable clinical and histologicresponse in the first three patients so treated (89). Asingle case of TA associated with a granulomatousmyocarditis has been described (90).

Myocarditis, documented in up to 40% of au-topsies in SLE, has been recognized clinically inless than 10% of patients. Three cases have beenpresented in the literature in which fulminant CHFrepresented the initial manifestation of SLE. Inonly one of these cases was myocarditis truly thesolitary clinical feature of possible underlyingSLE: a 42-year-old woman with fulminant acuteCHF and cardiogenic shock, in whom serologicfindings (positive antinuclear antobody, LEcells, anti-SSA, lupus anticoagulant, hypocomple-mentemia and lymphopenia) were consistent withthe diagnosis (91). The other two reported casespresented with other clinical features that shouldhave suggested the correct diagnosis.

Although myocarditis with histologic featuressimilar to those seen in skeletal muscle may occurearly in the course of inflammatory myopathy,muscle, skin, and joint manifestations have almostalways been present, facilitating an accurate diag-nosis (92, 93). A report of two patients in whomclinically significant myocarditis presented severalweeks before muscle weakness became evidentunderscores the importance of evaluating patientsfor polymyositis in whom CPK MM isoenzymesare elevated (94). In the recently recognized subsetof patients with polymyositis associated with anti-bodies to signal recognition particle, early severemyocarditis may occur (95). In such patients, theunderlying myopathy may be overshadowed byCHF. However, persistent CPK elevations of skel-etal origin should clarify the diagnosis even inthese cases.

DISTINCTION OF GCM FROM

CARDIAC SARCOIDOSIS

The major distinction to be made, and probablythe most difficult, is from sarcoidosis, a systemicdisease defined by the presence of epithelioid gran-ulomas in multiple organs. Lymph node, cutane-

ous, pulmonary, and ocular presentations of thedisease are most common. Whereas granulomatousinvolvement of the heart produces clinically overtcardiac sarcoid (CS) in only about 5% of cases,autopsy series suggest that myocardial involve-ment occurs in up to 27% of unselected cases (96).

Cardiac manifestations of sarcoidosis aremyriad, including arrhythmias, conduction distur-bances, heart block, sudden death, CHF, patholog-ical Q waves simulating myocardial infarction,papillary muscle dysfunction, ventricular aneu-rysm formation, and pericardial effusion (97-99).Unfortunately, clinically significant cardiac in-volvement generally presents in the absence ofovert granulomatous involvement in other organsystems, and the disease may be difficult to diag-nose antemortem. In one series of 42 cases of fatalmyocardial sarcoidosis, only 5 had a diagnosis ofsarcoidosis during life; 7 might have been diag-nosed retrospectively on the basis of isolated clin-ical symptoms such as cranial neuropathy anduveitis; but in 27 (69%), myocardial involvementwas the only clinical manifestation, with involve-ment of other organ systems only discovered byautopsy (100). In another series of 89 patients withCS, 60 died suddenly, and in 10 of these patients,the episode of sudden death was the initial mani-festation of sarcoidosis (101). ACE determinationsmay help distinguish the two conditions, but ACEelevations are found inconsistently in nonpulmo-nary sarcoidosis and have not been routinely as-sayed in patients with GCM (102). Thus, sarcoid-osis is a systemic autoimmune disease, which canpresent a diagnostic dilemma when myocarditis isthe sole overt clinical manifestation.

EMB detects granulomatous inflammation inonly about one quarter to one third of cases of CSand nonspecific changes of myocarditis in the re-mainder (103). Careful differentiation at the immu-nohistopathologic level is sometimes required todistinguish CS from GCM. In contrast to CS, theGCs of GCM are not part of well-formed granulo-mas, are associated with myocytic necrosis, andeosinophils are a common component of the acuteinflammatory reaction. Whereas immunopheno-typing shows a variable predominance of CD4 andCD8 T cells and elements of both myocyte andmacrophage origin of GCs in GCM, CD4-positiveT cells and purely macrophage origin of GCsconsistently characterize CS (11,16,40,104).

The response to immunosuppression therapy


tends to be more impressive with CS, with signif-icant clinical, histologic, and electrocardiographicimprovement noted after corticosteroid therapy(97, 101, 105). However, this has not yet beendemonstrated convincingly in a controlled thera-peutic trial.

TREATMENT OF GCM

Initial therapy should be directed toward controlof heart failure, preventing thrombosis and control-ling arrhythmias (106,107). As indicated, patientswith left ventricular dysfunction may be treatedwith diuretics, digoxin, ACE inhibitors, nitrates,and other vasodilators. Those patients with severemyocardial dysfunction may require inotropicagents or mechanical support with intra-aortic bal-loon pump or other ventricular assist devices. Be-cause of the risk of intramural thrombi related toatrial fibrillation or ventricular wall motion abnor-malities, anticoagulant therapy is frequently indi-cated. Significant rhythm disturbances may requireformal electrophysiologic testing, anti-arrhythmictherapy, pacemakers, or implantable cardioverter/defibrillators.

The specific therapeutic approach to humanmyocarditis (suppressing inflammation) is incon-sistent, in part because of uncertainty as to severityof disease, the underlying pathologic process, andthe need to tailor therapies accordingly. Nonsteroi-dal anti-inflammatory drugs (NSAIDs), especiallyindomethacin, have been frequently employed,mainly for treatment of accompanying pericarditis,but without any observable benefit beyond theiranalgesic effects (79). Based on experimental evi-dence in mice, in which various NSAIDs werenoted to exacerbate histopathologic changes, in-cluding myocardial necrosis, this is unlikely to bean effective therapeutic modality (108).

The usefulness of immunosuppressive therapyhas not been adequately substantiated in humandisease and remains controversial. In studies ofpatients with myocarditis of all histologies, there isno consistent response—some respond well, othersdo not respond or worsen. As has been seen inanimal models, when human myocarditis is attrib-utable directly to virus-induced inflammation, im-munosuppression may actually do more harm thangood.

The use of corticosteroids and other immuno-suppressives in the treatment of myocarditis ingeneral is contentious. In an analysis of all immu-

nosuppressive trials performed before 1995 (only250 patients), improvement was seen in 61% ofpatients (109). After selecting only randomizedcontrolled trials from this analysis, no benefit wasshown for the use of immunosuppressive therapy(107).

Attempting to resolve some of the contradictoryand inadequately answered issues, the MyocarditisTreatment Trial addressed immunosuppressivetherapy in a more rigorous fashion. In this 28-weekstudy of 111 patients with biopsy-confirmed myo-carditis, patients were randomly assigned to treat-ment with either azathioprine and prednisone orcyclosporine and prednisone compared with noimmunosuppressive therapy. Patients received aza-thioprine 1 mg/kg twice daily or cyclosporine,administered at a dose of 5 mg/kg orally twicedaily, and adjusted to a blood concentration of 200to 300�g/L, tapered to 60 to 150�g/L by week 5,with prednisone 1.25 mg/kg/d tapered over thecourse of the study. Although overall no beneficialeffect of immunosuppression could be documentedwith regard to LV function or survival, subgroupanalysis suggested that those patients with lesssevere disease had a better response. Patients withGCM were excluded from this study (110).

When the underlying process is presumably(auto-)immune mediated, the argument for immu-nosuppressive therapy can be made more force-fully, although not without circumspection. Specif-ically with regard to GCM, there have been norandomized controlled studies. The efficacy of cor-ticosteroids, as monotherapy or in combination,remains unproven, but prednisone alone is proba-bly inadequate (5,27). Nine of 10 patients in Dav-idoff’s study underwent immunosuppression withprednisone alone or in combination with eitherazathioprine or cyclosporine. Despite therapy,mean LV ejection fraction decreased from 0.43 to0.26, with only one patient showing improvementin ventricular function. Although seven patientsimproved histologically, 70% of those treated ei-ther died or required cardiac transplantation (14).Costanzo-Nordin et al (111), however, reportedlong-lasting hemodynamic and histologic improve-ment after azathioprine and prednisone in onepatient.

In Cooper et al’s recent series (12), therapeuticend points (time until death, transplantation, or endof follow-up) were delayed in patients treatedwith various combinations of immunosuppressive


agents as compared with those who were nottreated with immunosuppressive medications. Thesurvival rate seemed to relate directly to the mag-nitude of immunosuppression, ranging from un-treated patients surviving for 3 months to thosewho received intensive combination immunosup-pressive therapy for 12.6 months (12) (Table 4).

Other patients with GCM have responded dra-matically to triple-combination therapy using com-binations of cyclosporine, cyclophosphamide, orazathioprine, and prednisone (12,112). Interest-ingly, one of these patients had recurrence ofmyocarditis after cardiac transplantation while be-ing maintained on cyclosporine and azathioprine,requiring the reintroduction of prednisone for dis-ease control.

A recent report has documented a favorableresponse to anti-CD3 (muromonab-CD3), in con-junction with cyclosporine, azathioprine, and pred-nisone (41), although two other patients did nothave prolonged improvement (12,113). Contrari-wise, aggressive immunosuppression did not pre-vent development of GCM in a patient with non-Hodgkin’s lymphoma who had been treated withchemoradiotherapy myeloablation, autologousstem cell transplantation, and interleukin-2 immu-notherapy (114).

Despite anecdotal success of intensive immuno-suppressive therapy, the most consistently effec-tive therapy remains cardiac allograft transplanta-tion (115). Even this aggressive intervention isproblematic, however, in that cardiac transplanta-tion for GCM has a poorer outcome than for other

diagnoses (12,34,116). Among the patients in Coo-per’s series, 9 of 34 patients receiving cardiacallografts died during an average follow-up of 3.7years after symptom onset (12). In theory, whentransplantation is performed in the setting of animmune system specifically activated against myo-cardial antigens, the addition of alloantigens maypotentiate the immune response, resulting in severerejection and persistent allograft dysfunction, de-spite immunosuppression (116). GC infiltrateswere noted on EMB in 26% of the patients inCooper et al’s series. (12) Asymptomatic or mini-mally symptomatic patients with recurrent GCMafter cardiac transplantation (12,34,72,116,117)are generally responsive to increased immunosup-pression, particularly high-dose corticosteroids.But those who have severe LV dysfunction gener-ally have fatal outcomes (12).

A multicenter treatment trial of GCM, sponsoredby the Mayo Foundation, is to start in early 2000.Patients will be enrolled at 20 United States and 10international sites. Those patients with biopsy-proven GCM will be randomized to receive noimmunosuppression or treatment with anti-CD3antibodies, cyclosporine, and methylprednisolone(followed by prednisone) for 1 year (Cooper LT,personal communication).

Until the results of the multicenter trial areknown, our approach is to initiate triple-immuno-suppressive therapy, hoping to alter disease pro-gression and increase the available time until ahistocompatible cardiac allograft transplant be-comes available. We will administer methylpred-

Table 4: The Effect of Immunosuppression on Survival in Patients With Giant Cell Myocarditis

Patient Group

No. of

Patients

Median Survival From

Symptom Onset (mo) P*

No immunosuppression 30 3.0 —

Corticosteroids alone 11 3.8 .68

Corticosteroids plus azathioprine 11 11.5 .025

Cyclosporine combination therapy† 10 12.6 .003

All treatment groups except corticosteroids alone 22‡ 12.3 .001

All treatment groups including corticosteroids alone 33 8.2 .014

* P values are for the comparison of median survival with that in the group that received no immunosuppressive therapy, by the

log-rank test.

† Cyclosporine was combined with corticosteroids (three patients), with corticosteroids and azathioprine (five patients), or with

corticosteroids, azathioprine, and muromonab-CD3 (OKT3, two patients).

‡ This group includes one patient treated with corticosteroids and muromonab-CD3 only.

Reproduced with permission of the author and publisher (12).


nisolone 1 g/d for 3 days, followed by prednisone1 mg/kg, in combination with azathioprine 2 mg/kg, and micro-emulsified cyclosporine 4 to 8mg/kg (72).

Advances in immunology may offer more effec-tive therapies in the near future, including morepotent immunosuppressive therapies, such as nu-cleoside analogs, DSG, leflunomide, mycopheno-late mofetil, and sirolimus. Other options includedirected immunomodulatory therapies, such as cy-tokine antagonists, inhibitors of adhesion mole-cules, agents to block antigen at the level of classII MHC presentation, antigen-specific T-cell recep-tor, or co-stimulatory molecules (118,119).

CONCLUSIONS

GCM is a rare disorder, accounting for aminority of cases of clinically detectable myo-carditis. A condition that affects young adults, it

may occur in association with other autoimmunediseases, especially myasthenia gravis and in-flammatory bowel disease. The course of GCMis more fulminant than that seen in other types ofmyocarditis, especially the most common, lym-phocytic myocarditis. EMB allows direct exam-ination of myocardial pathology and can helpidentify the specific inflammatory process. Al-though traditional histologic examination of car-diac tissue provides inconsistent results, ad-vances in immunohistology have offered greaterspecificity and sensitivity. Animal models ofGCM suggest pathogenetic mechanisms verysimilar to those seen in animal models of RA.Considering the rapidly fatal course in mostpatients, the use of intensive immunosuppressivetherapy that includes cyclosporine, at a mini-mum, appears to be necessary to postpone thetime to transplantation or death.

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Giant cell myocarditis: Most fatal of autoimmune diseases