Phenotypic analysis of infiltrating cells in human myocarditis. An immunohistochemical study in paraffin-embedded tissue

To define the cellular subpopulations that infiltrate the heart in human myocarditis, formaldehyde-fixed, paraffin-embedded sections from 18 hearts with histologically proved myocarditis were examined immunohistochemically. Disease was classified on routine stains as follows: mixed mononuclear cell (7 cases), granulomatous (3), giant cell (1), rheumatic (2), and fungal (5) myocarditis, respectively. On immunohistochemical examination, T-lymphocyte and macrophage predominance was found in nearly every case, except in fungal myocarditis, in which polymorphonuclear leukocytes and macrophages prevailed. In contrast, B lymphocytes and natural killer cells were conspicuously absent, regardless of histologic classification. Giant cells in giant cell myocarditis and in the Aschoff lesions of rheumatic carditis expressed macrophage, but not myocyte, antigens, suggesting derivation along macrophage lineage. Immunohistochemical data obtainable in paraffin-embedded tissues supplement the study of myocarditis, providing information potentially relevant to immunopathogenesis, natural history, and therapy.     

Giant cell myocarditis in association with drug-induced skin eruption

A case of giant cell myocarditis in a 19-year-old woman is presented. She had high fever, vomiting, epigastralgia, cardiomegaly, and disseminated papular erythema probably due to anti-epileptic agents. At autopsy, giant cell myocarditis and the myositis of the systemic skeletal muscles were found. To our knowledge, no case of giant cell myocarditis in association with drug-induced skin eruption was reported. This is a rare case of giant cell myocarditis.     

GIANT CELL MYOCARDITIS IN ASSOCIATION WITH DRUG-INDUCED SKIN ERUPTION

A case of giant cell myocarditis In a 19-year-old woman is presented. She had high fever, vomiting, epigastralgia, cardiomegaly, and disseminated papular erythema probably due to anti-epileptic agents. At autopsy, giant cell myocarditis and the myositis of the systemic skeletal muscles were found. To our knowledge, no case of giant cell myocarditis in association with drug-induced skin eruption was reported. This is a rare case of giant cell myocarditis.     

Giant cell myocarditis of the left atrium

Here we describe an unusual case of giant cell myocarditis (GCM) found in the left atrial appendage. Giant cell myocarditis is a rare entity in itself, while isolated left atrial GCM has only been reported on a few occasions. We describe a patient who underwent mitral valve replacement for rheumatic mitral stenosis and excision of a grossly abnormal, thickened, and enlarged left atrial appendage. Histological examination confirmed the presence of GCM.     

Survival outcomes of patients with giant cell myocarditis bridged by ventricular assist devices

Giant cell myocarditis is a highly lethal disorder characterized by rapidly progressive congestive heart failure. The aim of this study was to describe the clinical course of patients with giant cell myocarditis who received a ventricular assist device. Patients with giant cell myocarditis were identified from the Multicenter Giant cell Myocarditis Registry. Bridging to cardiac transplantation in the giant cell myocarditis patients who received a ventricular assist device was compared with bridging in the general population of heart failure patients, as reported in the literature. Median posttransplantation survival for patients with giant cell myocarditis who received and did not receive ventricular assist devices was calculated by the Kaplan-Meier method and compared with use of the log-rank test. Nine patients with giant cell myocarditis who received ventricular assist devices were identified. Seven patients survived to transplantation, four were alive 30 days posttransplantation, and two survived to 1 year. The rate of successful bridging to transplantation in seven of nine patients (78%) is similar to that reported for other ventricular assist device recipients. Posttransplantation survival of 57% (4 of 7) at 30 days and 29% (2 of 7) at 1 year was significantly lower compared with 93% 1-year survival of the 30 patients with giant cell myocarditis who did not receive ventricular assist devices before transplantation (p<0.001). Ventricular assist devices can be an effective bridge to transplantation for patients with heart failure caused by giant cell myocarditis. Although their posttransplantation survival was poor in our series, a few patients had long-term survival.     

心肌扩张型心脏病的病理形态特征及其临床意义

目的探讨单纯心壁病损造成的心脏扩张者的病理形态特征及其意义。方法收集2004年6月至2006年8月中国医学科学院北京协和医学院阜外心血管病医院60例心脏移植的受体心脏在离体后立即进行了肉眼观察、测量和摄影记录,并进行了全面的组织病理学观察。以其中40例单纯心壁病损造成的心脏扩张者进行临床-病理对照分析,并观察其形态特点。结果40例单纯心壁病损造成的心脏扩张者中21例（52．5％）为原发性扩张型心肌病,9例（22．5％）为致心律失常性右心室心肌病,6例（15．0％）为缺血性心肌病,其余的4例（10．0％）为局灶性心肌致密化不全、巨细胞性心肌炎和特异性心肌病中的酒精性心肌病和高血压性心肌病。40例中临床诊断与病理诊断不符15例（37．5％）,不相符率较高的依次为致心律失常性右心室心肌病（7／9）、缺血性心肌病（5／6）和巨细胞性心肌炎（1／1）。不相符的这几种病的原临床和影像学诊断都是扩张型心肌病。致心律失常性右心室心肌病、缺血性心肌病、心肌致密化不全和巨细胞性心肌炎都有特征性的病理形态表现,酒精性心肌病和高血压性心肌病等的病理诊断需要参考临床病史。该组病例没有观察到慢性心肌炎样病变发展成扩张型心肌病的形态学迹象。结论进行心脏移植病例受体心脏的病理学检查有利于提高心脏病的临床和影像诊断的正确率,病理形态检查是不可忽视的重要手段。     

A novel experimental model of giant cell myocarditis induced in rats by immunization with cardiac myosin fraction

It is suspected that autoimmune disease processes are involved in the pathogenesis of a part of giant cell myocarditis. However, evidence for autoimmunity has rarely been demonstrated in clinical investigations. In this study, we have demonstrated a new animal model of autoimmune myocarditis characterized by the appearance of multinucleated giant cells. Lewis rats were immunized twice with human cardiac myosin fraction in complete Freund's adjuvant. Cardiac myosin fraction was prepared from the ventricular muscle of human hearts. Three weeks after the first immunization, acute and severe myocarditis was elicited in all rats. This myocarditis was characterized by massive pericardial effusion, enlargement of the heart, and gray discoloration of the cardiac muscle. Microscopically, there was marked cellular infiltration consisting of mononuclear cells, neutrophils, fibroblasts, and a considerable number of multinucleated giant cells. Extensive myocardial necrosis was also present. The heart weights increased from the third week to the fourth week and then gradually decreased. The titer of anti-myosin antibodies began to elevate from the second week and remained high until the sixth week. In the sixth week, inflammation became smoldering and the multinucleated giant cells disappeared. These findings indicate that the cardiac myosin fraction contains myocarditogenic antigen and that giant cell myocarditis can be induced by autoimmune involvement. To our knowledge, this is the first report of experimental giant cell myocarditis, which is closely similar to human giant cell myocarditis in its histology and clinical course.     

Giant cell myocarditis associated with lymphoma: an immunocytochemical study.

A case of giant cell myocarditis in a patient with non-Hodgkin's lymphoma is reported. To our knowledge, this is a previously unrecorded association and supports the hypothesis that the aetiology of giant cell myocarditis is related to a changed immune state. Immunohistochemical investigation of this case with a panel of monoclonal antibodies against a range of leucocyte and muscle antigens supports the view that the giant cells have a histiocytic rather than a myogenic origin.     

IgG anti-cardiomyocyte antibodies in giant cell myocarditis

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.     

THREE CASES OF GRANULOMATOUS MYOCARDITIS WITH GIANT CELLS

Three autopsy cases of granulomatous myocarditis were presented, which showed numerous multinucleated giant cells and diffuse proliferation of collagenous tissue. The first case revealed limited lesions only in the myocardium and classified as isolated myocarditis. The second and third cases disclosed classical generalized sarcoidosis with emphasis of myocardial involvement. The interrelationship between these two entities was discussed. Giant cell myocarditis, a disease entity, should be differentiated from the myocardial manifestation of sarcoidosis. ACTA PATH.JAP. 17: 503–515, 1967     

T cell mimicry in inflammatory heart disease

Inflammatory heart diseases such as myocarditis and rheumatic heart disease result from the infiltration of the myocardium or valve with T cells and macrophages that result in scarring of the myocardium or valve and alteration in cardiac function. Our studies of T cells from these diseases have identified cardiac myosin in both rheumatic carditis and myocarditis as an important autoantigen. In rheumatic heart disease, streptococcal M protein specific T cells migrate to valves. By investigating streptococcal M protein and cardiac myosin in the Lewis rat model of myocarditis and valvulitis, T cell mimicry is supported as a potential mechanism in disease. Structural and immunological mimicry between the streptococcal M protein and cardiac myosin is shown directly in the Lewis rat model. Rat T cell lines demonstrate mimicry between cardiac myosin and M protein, and T cells isolated directly from inflammatory lesions in myocarditis respond to streptococcal M protein peptides. Studies in BALB/c mice also support the immunological crossreactivity of T cells primed against cardiac myosin with streptococcal M protein peptides containing cardiac myosin homologies. T cell lines produced from the Lewis rat specific to the cardiac myosin like sequences of streptococcal M protein migrated to the valves after passive transfer of the M protein specific T cell lines. In coxsackieviral myocarditis in the MRL mouse strain, cardiac myosin mimicking M protein peptide NT4 was found to induce tolerance and prevent coxsackieviral induced myocarditis, suggesting T cell mimicry between coxsackievirus and streptococcal M protein, both of which are associated with inflammatory heart disease. T cell mimicry between cardiac myosin and microbial antigens such as the streptococcal M protein may prime the immune system for inflammatory heart disease.     

Hyperacute graft rejection during heart transplantation for giant cell myocarditis: A case report

We report the case of a patient with giant cell myocarditis who was bridged to transplantation with mechanical circulatory support and developed a fatal perioperative hyperacute rejection. The patient had received abundant transfusions that had raised her anti-HLA antibody titers. The cross-match test was positive. No pre-transplantation immunosuppressive therapy had been administered given concomitant infection. The severity and acuteness of the rejection in this case likely reflect the combined effect of preformed anti-HLA antibodies in the context of an active organ-specific immune process at the time of transplantation. This case raises the questions of the need for intensive immunosuppressive therapy before transplantation in giant cell myocarditis and of the management of patients with positive cross-match in the context of a giant cell myocarditis.     

Giant cell myocarditis as a manifestation of drug hypersensitivity.

Adverse drug effects on the myocardium are often classified into toxic and hypersensitivity forms of myocarditis, each with distinct histologic findings. In contrast, giant cell myocarditis (GCM) is generally not associated with adverse drug reactions and has unique histopathologic features. We report four cases of adverse drug reactions in which the histologic findings were characteristic of GCM. The clinical recognition that GCM may be a manifestation of an adverse drug reaction is important, since the prognosis and treatment of this entity may be different from that of other forms of myocarditis.     

Immunohistochemical characterization of infiltrating mononuclear cells in the rat heart with experimental autoimmune giant cell myocarditis.

The pathogenesis of giant cell myocarditis remains unclear. Subsets of inflammatory infiltrating cells may reflect the pathogenesis and etiology of the disease. Therefore, we examined subsets of infiltrating mononuclear cells in the heart of the rat with experimental giant cell myocarditis. Lewis rats were immunized with cardiac myosin in Freund's complete adjuvant (FCA). Severe myocarditis characterized by congestive heart failure and multinucleated giant cells were elicited. The lesions were composed of predominant mononuclear cells, polymorphonuclear neutrophils and fragments of degenerated myocardial fibres. The subsets of infiltrating mononuclear cells were investigated using MoAbs against rat CD4+ T cell (W3/25), CD8+ T cell (CX8), B cell (OX33) and macrophage (OX42). By serial examination, bound immunoglobulin could only be found on degenerated myocardial fibres. In this model, most infiltrating mononuclear cells were composed of macrophages and CD4+ T cells. The frequencies of macrophages and CD4+ T cells were 73.7% and 13.8%, respectively. CD8+ T cells were scarce and B cells were rare in the lesions. The frequencies of CD8+ T cells and B cells were 4.5% and 0.4%, respectively. The dominance of macrophages and CD4+ T cells was the constant finding among the sites of the lesions and throughout the course of the disease. These characteristic subsets of infiltrating cells were in contrast to those of murine viral myocarditis which were mainly composed of natural killer (NK) cells and CD8+ T cells. Clarifying the subsets of infiltrating cells in myocarditis may contribute to differential diagnosis of myocarditis between viral and autoimmune types. From this study, the pathogenesis of experimental autoimmune giant cell myocarditis seemed to be closely related to CD4+ T cells and macrophages.     

An investigation into the nature of giant cells in cardiac and skeletal muscle

In an immunohistochemical study of six cases of giant cell myocarditis, the typical giant cells have been shown to express up to four different macrophage-associated antigens, but not desmin, the intermediate filament protein characteristic of muscle cells. These results support the view that the giant cells have a macrophage rather than a myogenic origin. In contrast, the giant cells found in regenerating skeletal muscle have the immunophenotype of muscle cells and not of macrophages supporting their muscle origin.     

Idiopathic giant cell myocarditis--a case report and review of literature

Idiopathic giant cell myocarditis (IGCM) is a rare clinicopathological entity which is usually known to cause in more than half the cases sudden death. The histological features are characteristic with a central area of myocardial necrosis and a rich cellular infiltration of lymphocytes with a few eosinophils, plasma cells, macrophages and multinucleated giant cells. We hereby report a case of IGCM in a 72 year old male with history of sudden death. This case is being presented for its rarity and a review of literature is made.     

An autopsy case of giant cell myocarditis probably due to a non-steroidal anti-inflammatory drug

An autopsy case of giant cell myocarditis (GCM) in a 74-year-old woman is presented. She suffered from hepatic dysfunction, skin eruption and disseminated intravascular coagulation due to the side-effects of a non-steroidal anti-inflammatory drug. After admission, heart failure progressed rapidly, and the patient died suddenly. At autopsy, her heart was slightly enlarged and the heart muscle was thickened with many small whitish nodules. She was diagnosed with GCM because of the infiltration of multinuclear giant cells, histiocytes, eosinophils and lymphocytes into the heart. We did not find any similar lesions in any other organs. Giant cell myocarditis, the etiology of which is not defined, is a rare disease with unfavorable prognosis. This case suggests the possibility of drug-induced GCM.     

Quantitation of mast cells in 100 normal and 92 diseased human hearts. Implications for interpretation of endomyocardial biopsy specimens

In endomyocardial specimens from 100 normal hearts from autopsy, the mean number of mast cells per high-power field was calculated. A peak occurred in the third decade and was more marked in women than men. In the fourth through seventh decades, mean values were greater in men than women. For both sexes, the number of mast cells in the left ventricle tended to exceed that in the right ventricle. The number of mast cells was similarly determined in 92 diseased hearts. The range of mean values overlapped considerably with that of normal hearts. The highest mean values occurred in subjects with mast cell neoplasia, giant cell myocarditis, and lymphocytic myocarditis; and the lowest occurred in the group with amyloidosis. The values in patients with eosinophilic myocarditis did not differ appreciably from normal. Increased numbers of mast cells tended to be associated with areas of fibrosis more than with inflammatory infiltrates.     

Myocardial sarcoidosis--pathological studies on 7 autopsy cases with particular reference to histological variations]

The present report consists of seven autopsy cases of myocardial sarcoidosis terminating in death 1 month to 5 years after the onset of symptoms. Histologically, they were classified into the following 4 types: a) diffuse nonspecific granulation, b) specific granuloma with giant cells, c) diffuse fibrosis with giant cells, and d) nonspecific fibrosis. Types a) and b) demonstrate active changes, while c) and d) are sequelae of active inflammation. Morphological changes of sarcoidosis were found not only in myocardium but also in both pericardium and endocardium. Although no final conclusions could be obtained as to whether the giant cells appearing in myocardium were of mesenchymal or myogenic origin, the authors favor the latter concept. Changes compatible to sarcoidosis found in other organs in acute cases were scarce and old. On the contrary, more active and variable changes were encountered in protracted cases. The authors consider giant cell myocarditis to be one type of sarcoidosis occurring in the heart.     

Giant cell myocarditis: evidence for the macrophage origin of the giant cells.

In order to elucidate the origin of giant cells in giant cell myocarditis a case has been studied immunohistologically using monoclonal antibodies against a variety of antigens, including those associated with muscle and macrophages. The results strongly suggest that the giant cells are derived from macrophages rather than the muscle cells.