Case Reports

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Patient 1

A 34-year-old woman was hospitalized for angina. Electrocardiography showed acute injury, and treatment included aspirin, heparin, and tissue plasminogen activator. Coronary arteriography showed no coronary artery disease. Ventricular tachycardia developed, and left ventricular ejection fraction declined to 19%. Endomyocardial biopsy showed giant-cell myocarditis. Immunosuppression with methylprednisolone (10 mg/kg of body weight every 24 hours for 3 days) was initiated, and a 7-day course of muromonab-CD3 was administered. Cyclosporine, prednisone, and azathioprine were given to maintain immunosuppression.

Diagnostic investigations to identify an associated disease had normal or negative results. Tests included assays to determine the presence of anti-double-stranded DNA; anti-smooth-muscle antibody; syphilis; and HIV infection, babesiosis, and ehrlichiosis. Viral serologic testing was done, and the erythrocyte sedimentation rate was measured. Polymerase chain reaction was performed to detect Lyme disease and chlamydial infection. The patient's condition improved: Her left ventricular ejection fraction increased to 40%, and endomyocardial biopsy showed resolution of myocarditis. The patient is alive and well 3.5 years after the diagnosis.

Patient 2

A 44-year-old man developed palpitations and progressive dyspnea. Endomyocardial biopsy showed giant-cell myocarditis. Immunosuppression was initiated with intravenous corticosteroids and immunoglobulin followed by prednisone, azathioprine, and cyclosporine. Progressive left ventricular dysfunction required placement of a ventricular assist device. Immunosuppression was discontinued. After undergoing orthotopic heart transplantation, the patient developed cytomegalovirus pneumonia and died.

Methods

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Myocardial tissue was obtained before immunosuppression and examined by light microscopy. We looked for transcription of inflammatory cytokines and T-cell receptor chains as described elsewhere [5] (Appendix Table). Flow cytometry and study for T-cell gene rearrangements of peripheral lymphocytes were performed for patient 1.

Immunophenotyping was performed on paraffin-embedded tissue from both patients for the following antibodies: CD3 (T lymphocytes) (DAKO [Carpenteria, California] polyclonal, 1:100), CD8/144 (cytotoxic suppressor T cells) (DAKO, 1:20), CD56 (natural killer cells) (Monosan-Coltag [San Francisco, California], 1:30), CD68 (macrophages) (DAKO, 1:1000), and TIA-1 (subsets of cytotoxic suppressor T cells and natural killer cells) (Coulter [Hialeah, Florida], 1:200). Standard methods were used, except that slides were microwaved at a pH of 6.0 in citrate buffer.

Results

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Histologic findings are shown in the (Figure 1). Flow cytometric peripheral lymphocyte subtyping done in patient 1 showed the following results: lymphocyte count, 0.62 cells x 10³/µL (normal range, 0.66 to 4.6 cells x 10³/microL); CD3 cell count (T cells), 322 (normal range, 812 to 2318); CD19 cell count (B cells), 180 (normal range, 99 to 426); CD16 cell count (natural killer cells), 118 (normal range, 78 to 602); CD4 cell count (helper cells), 167 (normal range, 589 to 1505); and CD8 cell count (suppressor cells), 149 (normal range, 325 to 997). The ratio of helper T cells to suppressor T cells in patient 1 was 1.1 (normal ratio, 1.0). Results of quantitation of T-cell receptor -chains and cytokine analysis for patients 1 and 2 are shown in the Table. Studies for T-cell gene rearrangements of lymphocytes showed no evidence of clonal proliferation. Immunosuppressive therapy led to markedly reduced T-cell counts and chains. Macrophage cytokine expression was unaffected.

View larger version (134K): [in this window] [in a new window]   Figure 1. Giant-cell myocarditis.Top. Active giant-cell myocarditis. Initial pretreatment biopsy showed several giant cells and a mixed lymphocyte-eosinophilic infiltrate (hematoxylin and eosin; original magnification, x250). Bottom. Healing giant-cell myocarditis. Biopsy after therapy showed interstitial fibrosis with residual mononuclear cells but no giant cells or myocyte necrosis (hematoxylin and eosin; original magnification, x250).

Immunophenotyping showed that most cells were reactive with antibodies to CD3; a small population (20%) of CD8/144-reactive cells was found. Therefore, most lymphocytes were T-helper lymphocytes. Small numbers of CD68⁺ giant cells and numerous histiocytes were identified. No cells reactive with antibodies to CD56 or TIA-1 were found.

Discussion

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We describe two patients with giant-cell myocarditis in whom evaluation of the myocardium showed a lymphocyte population composed primarily of T-helper cells. This observation contrasts with findings from another study [4] that reported a predominant population of suppressor T cells. Cytokine analysis showed that macrophage-derived cytokines were not decreased by immunosuppressive therapy despite a favorable clinical response in one patient.

Our observations were limited to two patients and should be interpreted with caution. A pretreatment biopsy result represents a single point in the pathogenesis of giant-cell myocarditis; the immunophenotypic profile may vary during evolution [4]. Accordingly, our observations may differ from those previously reported because of the timing of tissue procurement. The persistence of macrophage-derived cytokines despite clinical improvement suggests that formation of giant cells and release of macrophage-derived cytokines may be consequences of tissue destruction, but it does not rule out a possible role in myocyte injury [3, 6, 7].

In experimental giant-cell myocarditis, there is a T cell inflammatory infiltrate that can be prevented with cyclosporine and anti-T-lymphocyte antibody [8, 9]. This may explain the efficacy of cytolytic therapy directed at T cells in patient 1. Endomyocardial biopsy should be considered for patients with rapidly progressive left ventricular dysfunction because the diagnosis of giant-cell myocarditis identifies patients who may benefit from immunosuppression or transplantation [10, 11].

Drs. Olson, Weyand, Tazelaar, Edwards, and Hammill: Mayo Clinic, 200 First Street SW Rochester, MN 55905.

Dr. Brack: Gravelotpestr. 12A, D12167 Berlin, Germany.