Annals of Clinical & Laboratory Science 38:83-87 (2008)
© 2008 Association of Clinical Scientists
IgG Anti-Cardiomyocyte Antibodies in Giant Cell Myocarditis
Kim HooKim1,
Stephen deRoux2,
Anne Igbokwe1,
Albert Stanek1,
Jaik Koo1,
Jean Hsu1,
Matthew R. Pincus1 and
Martin H. Bluth1,3
1 Departments of Pathology and 3 Surgery, SUNY Downstate Medical Center, Brooklyn, New York; 2 Office of the Chief Medical Examiner, New York City, New York
Address correspondence to Martin H. Bluth, M.D., Ph.D., SUNY Downstate Medical Center, Box 40, 450 Clarkson Avenue, Brooklyn, N.Y. 11203, USA; tel 718 270 6772; fax 718 221 6132; e-mail martin.bluth{at}downstate.edu
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Abstract
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Giant cell myocarditis, a rare, fatal, and poorly understood cause of myocarditis, requires pathological examination for diagnosis. It is considered to be an autoimmune disease and is frequently associated with other conditions, in particular thymoma and myasthenia gravis. The typical patient with giant cell myocarditis is young and has severe, progressive congestive cardiac failure that is unresponsive to standard medical therapy and ultimately requires cardiac transplantation. Hence giant cell myocarditis is the most dangerous form of myocarditis. Here we report an unusual presentation of giant cell myocarditis, which mimicked acute myocardial infarction in an elderly woman with myasthenia gravis and a previous diagnosis of thymoma. This patient had evidence of anti-myocyte antibodies, consistent with an autoimmune mechanism.
Keywords: giant cell myocarditis, IgG, anti-cardiomyocye antibodies, autoantibodies
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Introduction
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Giant cell myocarditis is a severe autoimmune myocarditis with pathological features that are characteristic but not pathognomonic. The features include areas of myonecrosis and a serpiginous infiltrate of chronic inflammatory cells and giant cells between myocardial fibers. To diagnose this rare form of myocarditis, it is necessary to exclude the more common etiologies, such as infectious myocarditis caused by bacterial, mycobacterial, viral, or fungal organisms. An interesting feature of this disease is its frequent association with other autoimmune conditions such as systemic lupus erythematosus, thyroiditis, and polymyositis. Anti-cardiac antibodies have been demonstrated in the serum of affected patients. In this case report, we provide further evidence for autoimmunity in the pathogenesis of giant cell myocarditis. The atypical presentation of the current case underscores the fascinating but obscure nature of this disease. Currently, giant cell myocarditis carries a grave prognosis. Further understanding of its pathogenesis may provide avenues to future targeted therapy.
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Case Report
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A 72-yr-old woman presented with a 5-day history of chest pain that worsened with activity and was attended by dyspnea on exertion. Her past medical history was significant for thymoma, myasthenia gravis (MG), and hypercholesterolemia. The thymoma had been treated by thymectomy 7 yr prior and the myasthenia gravis was controlled with azathioprine (50 mg/day, po). Physical examination revealed bilateral pedal edema, bilateral basal crepitation in the lungs, and an ejection systolic murmur. There were no signs of myasthenia gravis. Relevant laboratory tests of serum included elevated troponin T, 4.38 ng/ml (normal 0.01–0.1 ng/ml); CPK-MB, 71 mg/ml (normal <5 mg/ml); cholesterol, 258 mg/dl (normal <200 mg/dl); and LDL 151 mg/dl (normal <160 mg/dl). An EKG showed elevation of the ST segment in inferior leads. Chest X-ray showed pulmonary congestion. The preliminary diagnosis was acute myocardial infarction, and the patient was admitted to the hospital and treated accordingly. An echocardiogram revealed abnormal left ventricular wall motion with an associated ejection fraction of 40%. Coronary angiography showed no significant stenosis. Her symptoms improved 24 hr post-admission, and she was sent home on hospital day 5.
Two days following discharge she was admitted to another hospital with clinical features suggestive of congestive cardiac failure. On the day after her second admission she had a cardiac arrest and died. At autopsy she weighed 147 pounds, measured 60 inches in height, and displayed a median sternotomy scar. Both pleural and pericardial cavities contained dense fibrous adhesions. In addition, the left pleural cavity contained 580 ml of serous effusion.
The heart weighed 450 gm, and the myocardium of the anterior and posterior left ventricle and the interventricular septum exhibited patchy areas of softening with areas of brown to red discoloration (Fig. 1A
). The coronary arteries showed minimal atherosclerosis. No thymic remnants or evidence of metastatic disease were identified. The lungs and liver were congested, and the other organs were unremarkable.
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Fig. 1. (A) Gross image of cross-section of heart demonstrating mottled areas of discoloration in the left ventricle. (B) Microscopic image of left ventricle demonstrating areas of myonecrosis (H&E stain, 40X magnification). (C & D) Microscopic images of left ventricle demonstrating areas of chronic inflammatory cells with prominent giant cells (H&E stain, magnification: C, 100X; D, 400X).
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The hematoxylin sections of the myocardium showed extensive areas of serpiginous myonecrosis (Fig. 1B
) associated with a mixture of chronic inflammatory cells and giant cells consistent with giant cell myocarditis (GCM) (Fig. 1C,D). In less involved areas the myocardial fibers were intersected by bundles of fibrous tissue (Fig. 2E). Histochemical stains for organisms (Gomori methanamine silver and Ziehl Nielsen) were negative. There was no evidence of viral cytopathic effect nor were there any granulomas. Sections of the lungs showed extensive intraalveolar neutrophilic infiltrate consistent with bronchopneumonia.
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Fig. 2. (E) Microscopic image of left ventricle demonstrating areas of myocardium with zones of fibrous tissue (H&E stain, 40X magnification). (F, G, & H) Immunohistochemical staining for IgG on myocardium demonstrates positive reactivity at the surface of myocardial fibers, most marked in the cells adjacent to vessels. Positive staining controls consisted of normal thymus and/or lymph node. All sections were counterstained with hematoxylin (F, G, & H: 400X magnification).
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In view of the patient’s history of autoimmune disease, immmunohistochemical analysis of heart tissue was preformed. The presence of IgG antibodies was demonstrated on the surface of myocardial fibers; the staining pattern was maximally observed at the tissue adjacent to the interstitium and vasculature (Fig. 2F,G,H). Although IgG antibodies were present, the relationship to areas of inflammation was minimal.
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Discussion
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This is a unique and intriguing case of GCM arising in a woman with a prior history of myasthenia gravis (late onset, age >50 yr) and thymoma. GCM is a rare, rapidly fatal, autoimmune disease of the myocardium that has a poorly defined pathogenesis and no definitive treatment. The disease has no sex predilection and usually affects young, previously healthy adults with an average age at presentation of 48 yr [1]. To date, worldwide, in the English language literature, 22 cases of thymoma associated with GCM have been reported [2]. This is only the second case of thymoma and MG associated with GCM. Like other forms of myocarditis, the clinical presentation includes congestive cardiac failure, cardiac arrhythmia, and in some cases sudden death. Unlike other types of myocarditis, congestive cardiac failure in GCM is progressive and refractory to conventional therapy [1]. Its high morbidity and mortality are due to its refractory response to all forms of treatment, including combined immuno-suppressive drugs. For patients who are unresponsive to medical therapy, cardiac transplantation remains the only viable option, despite the risk of recurrence in the transplanted heart.
In our patient, GCM occurred at an advanced age and with a background of other autoimmune diseases. Her presentation was that of acute myocardial infarction, a far more common condition in this age group. Despite 7 yr of remission from thymoma and the presence of MG, she still developed GCM. Her MG was treated with azathioprine, an immunosupressive drug that may have had the additional benefit of delaying the onset of GCM. Clinically the diagnosis of GCM is made through endomyocardial biopsy or ultimately, as in this case, at autopsy. The classic histological picture is that of extensive, serpiginous myocardial necrosis associated with a chronic inflammatory infiltrate, and abundant giant cells without granulomas. GCM, like MG, is an autoimmune disease that may or may not be associated with thymoma [6]. Support for an underlying auto-immune pathogenesis includes the association of GCM with other autoimmune diseases, such as thyroiditis, inflammatory bowel disease, myasthenia gravis, polymyositis, lupus, and Addison’s disease. Such multiple autoimmune syndromes have been described by Humber et al [3] and Schumannn et al [4]. GCM and the associated autoimmune conditions possibly share a common pathogenesis. Anti-cardiac antibodies have been detected in patients with GCM [5]. Although the pathogenesis is poorly understood, the overall mechanisms for the generation of autoantibodies in GCM include self-sensitization to cardiac antigens in the thymus, production of self-reactive T cells, stimulation of B cells, and production of cardiac autoantibodies and myonecrosis.
The presence of IgG anti-cardiomyocyte antibodies in our patient is intriguing. Although autoantibodies have been described in the serum of GCM patients, to our knowledge, this is the first report of autoantibodies demonstrated in heart tissue (as revealed by immunohistochemistry). The anti-myocyte antibodies may provide an underlying mechanism for heart damage. In particular, the demonstration of autoantibodies present in greater concentrations in areas of heart tissue may indicate the initial port of entry into the cardiac parenchyma and provide the initial nidus or contribute to the subsequent total tissue inflammatory response. It is interesting that the pattern of IgG deposition was not consistent with tissue inflammation. Furthermore, there was no evidence of complement involvement in either IgG or leukocyte infiltrated areas. It could be that IgG deposition occurs early in the disease and facilitates complement mediated lysis at a later time, either independently or in concert with leukocyte Fc-receptor signaling. How and what antigens promote these autoantibodies and how these antibodies are involved in the pathogenesis remain unknown.
The cardiac antigens, titin and ryanodine receptor, along with costimulatory molecules have been detected in the thymus of patients with MG [7]. This is believed to be the first step in failure of self-tolerance. These antibodies include anti-titin, anti-ryanodine, anti-alpha actinin, anti-actin, and anti-myosin. The antibodies bind to the striational architecture of cardiac and skeletal muscle and hence are called striational antibodies. Almost all patients with MG and thymoma and half of all patients with late onset MG show a broad striational antibody profile [7]. Striational antibodies are also indicators for severe disease and poor outcome. The strong association between disease expression and striational antibodies, along with the detection of IgG anti-cardiomyocyte antibodies in heart tissue of GCM, provide possible evidence of involvement of these antibodies in the pathogenesis of GCM. Tests for the presence of anti-cardiac antibodies in the serum of our patient might have provided correlative evidence for an autoimmune component, however serum was not available. It is interesting that up to 35% of healthy individuals have cardiac autoantibodies [8]. Such antibodies may also be present in non-autoimmune conditions as a physiologic response to cardiac damage, viral myocarditis, post-cardiac surgery, myocardial infarction, and rheumatic heart disease. Nonetheless, case reports of GCM unassociated with these conditions have also been published.
GCM is a fatal disease that fails to respond to medical and surgical treatment. It is well known that the severity of autoimmune diseases is affected by the inflammatory milieu. At present, drugs that decrease cardiac damage by altering the inflammatory response are under investigation in an effort to improve treatment options and clinical outcome. This has been demonstrated by the use of antibodies to chemokines that block the effects of main inflammatory cells in GCM, such as macrophages, by the use of antibodies to macrophage inflammatory protein 1-alpha [9]. Blocking the effects of other inflammatory mediators or treatment with immunoglobulin components may also provide novel approaches for targeted therapy [10,11].
Conversely, certain inflammatory cells and their mediators have been shown to mitigate cardiac damage. These include type 2 T-helper cells and a subset of T-regulatory cells [12]. The extent of cardiac damage in GCM is based on the balanced effects of opposing inflammatory cell components.
Our patient serves as a reminder of the poorly understood and rare entity, GCM, that masqueraded as acute myocardial infarction. The patient did not fit the usual profile of GCM. When refractory congestive cardiac failure occurs in patients with thymoma and MG, GCM should be included in the differential diagnosis irrespective of the patient’s age. In addition, a better understanding is needed as to the role of the immune system in the development of autoimmune diseases.
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Abstract
Introduction
