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(Circulation. 1997;95:2476.)
© 1997 American Heart Association, Inc.
Articles |
Intravenous Immune Globulin in the Therapy of Myocarditis and Acute Cardiomyopathy
From the University of Pittsburgh (Pa) Medical Center, Division of Cardiology.
Correspondence to Dennis M. McNamara, MD, University of Pittsburgh Medical Center, Division of Cardiology, S558 Scaife Hall, Pittsburgh, PA 15213.
Abstract
Background Although an autoimmune pathogenesis has been postulated for dilated cardiomyopathy, immunosuppressive therapy has not been shown to be effective in clinical trials. Immune modulatory therapy with immune globulin is an effective therapy for Kawasaki disease in children, and recent data suggest that it improves ventricular function in children with new-onset dilated cardiomyopathies. The role of immune globulin therapy in adults with this disorder has not previously been evaluated.
Methods and Results Ten patients were treated with high-dose intravenous immune globulin infusions (2 g/kg). All were hospitalized with NYHA class III to IV heart failure, left ventricular ejection fraction (LVEF) <0.40, and symptoms for <6 months at the time of presentation. One patient died before the completion of therapy. The remaining 9 were discharged, and LVEF was reassessed 12 months after therapy. LVEF improved from 0.24±0.02 (mean±SEM) at baseline to 0.41±0.04 at follow-up (P=.003). All 9 patients improved functionally to NYHA class I to II, and there have been no subsequent hospitalizations for heart failure during the course of follow-up.
Conclusions In this series of patients with new-onset dilated cardiomyopathy treated with high-dose immune globulin, LVEF improved 17 EF units. The effectiveness of intravenous immune globulin therapy in this disorder should be evaluated in a randomized, multicenter trial.
Key Words: cardiomyopathy • myocarditis • immune globulin
Congestive heart
failure due to DCM affects more than 2 million people in the United
States and causes 200 000 deaths annually.1 In 
50% of
patients with DCM, the cardiomyopathy is primary
and the cause of cardiac muscle dysfunction is obscure. Studies in
experimental animals and patients with idiopathic DCM suggest that a
viral infection may be a cause2 ; however, secondary
autoimmune pathogenesis involving both cellular and humoral pathways
might have a greater role in altering myocardial function than the
viral infection itself.
Initial efforts to abrogate the development of cardiac dilatation and dysfunction in patients with inflammatory myocarditis by immunosuppressive therapy were unsuccessful.3 4 However, Drucker et al5 recently reported potential benefits of intravenous immune globulin, pooled polyclonal human antibodies (IgG), in the therapy of children with a recent onset of DCM. When children with or without cellular inflammation shown by endomyocardial biopsy were treated with high-dose intravenous immune globulin, significant improvements were noted in left ventricular function, and there was a trend toward improved survival in relation to historical controls.
The role of intravenous immune globulin in the therapy of adults with recent onset of idiopathic DCM or acute myocarditis has not been previously evaluated. Although primary DCM in the adult population is a more heterogeneous disorder than in children, most patients are suspected of sharing a similar viral/autoimmune pathogenesis and may benefit from immune modulatory therapy. The present study was performed to evaluate the use of high doses of intravenous immune globulin in addition to conventional therapy in the treatment of 10 patients admitted with acute cardiomyopathy or myocarditis at our medical center over a period of 10 months.
Methods
Patients were eligible for this study if they presented with signs or symptoms of congestive heart failure of <6 months’ duration, an EF of <40%, and a heart failure evaluation supporting the diagnosis of idiopathic DCM. Patients were identified from those admitted to the University of Pittsburgh Hospitals between October 1994 and August 1995. LVEF was assessed by either nuclear scintigraphy (8 patients) or transthoracic echocardiography (2 patients). Patients received follow-up evaluations with the same technique as used in baseline measurements. All patients underwent a pretreatment right ventricular catheterization. An endomyocardial biopsy was obtained by standard techniques in all but one patient, in whom biopsy was deferred because of a marked coagulopathy. To exclude coronary disease as a pathogenetic factor, all but 1 patient (a 20-year-old woman) underwent coronary arteriography.
Intravenous immune globulin was administered during the index hospitalization within 24 hours of the right ventricular catheterization and endomyocardial biopsy. Baseline LVEF was assessed before therapy. All patients received a total dose of 2 g/kg of immune globulin, based on previously published pediatric experience.5 In the first 4 patients, this was administered as 0.5 g/kg IV over a period of 6 hours on each of 4 consecutive days, whereas the remaining 6 patients received 1 g/kg IV over 12 hours on each of 2 successive days. All patients received continuous cardiac monitoring during therapy. LVEF was reassessed 12 months after therapy. Statistical analysis was performed with a two-sample t test. Values are presented as mean±SEM.
Results
All patients were hospitalized with NYHA class III or IV symptoms. Hemodynamic evaluation by right ventricular catheterization revealed a mean pulmonary capillary wedge pressure of 21.0±2.6 mm Hg, right atrial pressure of 9.4±2.1 mm Hg, and cardiac output by the thermodilution method of 4.8±0.5 L/min. Histological analysis of endomyocardial biopsy samples revealed borderline myocarditis (by Dallas criteria)6 in 1 patient and nonspecific inflammation in 2 (a single focus of myocyte necrosis with histolytic reaction in 1 and increased perivascular lymphocytes in 1). The remaining 6 biopsies revealed no evidence of cellular inflammation.
Six of 10 patients received intravenous inotropic therapy
with dobutamine during the index hospitalization, and 2 of
10 required support with an intra-aortic balloon pump at the time of
immune globulin therapy. One patient with refractory
ventricular arrhythmias who was receiving
intravenous antiarrhythmic therapy and intra-aortic balloon
pump support at the time of treatment died of ventricular
tachycardia/fibrillation during the infusion. The remaining
9 patients tolerated the immune globulin therapy without complications
and were followed up for a median of 18 months after therapy (range, 14
to 24 months). The clinical characteristics of these patients are
listed in the Table
. All patients
received an ACE inhibitor, digoxin, and a diuretic
at the time of discharge, and 2 of 9 patients received a
ß-blocker.
|
As shown in the Figure, all patients demonstrated an
improvement in LVEF (range of increase, 6 to 28 EF units), and mean
LVEF for the entire population improved significantly, from 0.24±0.02
to 0.41±0.04 (P=.003). All patients demonstrated functional
improvement and at 1-year follow-up were NYHA class I or II. No patient
has been rehospitalized for congestive failure.
|
Discussion
In the present study, the use of intravenous immune globulin was associated with a significant increase in left ventricular performance at 1-year follow-up and a marked absence of 1-year mortality in a population that presented with class III or IV heart failure. These clinical outcomes are disparate, with two previous reports of patients with recent-onset DCM in which substantial improvements in EF were seen in between 29% and 37% of patients, and mortality was between 24% and 37%.7 8
The patients in the present study were referred to the University of Pittsburgh for consideration of cardiac transplantation with a diagnosis of idiopathic DCM. During 1994 and 1995, 72 additional patients were referred for evaluation with idiopathic DCM who were treated conventionally. In this conventionally treated group, 31% were dead or had received transplants at 1 year. Of the patients who received transplants, 79% (11 of 14) required support with either continuous inotropic therapy or a mechanical assist device, suggesting that the decision to transplant represented a significant deterioration of their cardiac function. Alternatively, 25% of patients (18 of 72) had clinical improvement that resulted in their removal from the transplant waiting list. The clinical outcomes of this conventionally treated group are similar to those previously reported by others8 and are in marked contrast to the patients treated with immune globulin.
Immune globulin was well tolerated in the patients in the present study. The most common side effects of therapy are mild flulike symptoms or headaches, which are seen in 5% to 10% of patients. There are rare case reports of worsening renal function in patients treated with immune globulin. Patients with baseline creatinine >2.5 were excluded from the present study, and no significant elevations in the serum creatinine after therapy were observed.
Although our results suggest a role for immune globulin therapy in the treatment of DCM of recent origin, we can only speculate as to the pathophysiological mechanisms responsible. Autoantibodies directed against myocardial proteins have been isolated from the sera of patients with myocarditis9 and idiopathic DCM,10 demonstrating the potential role of humoral immunity in the pathogenesis of myocardial dysfunction. Therefore, the well-described anti-idiotype properties of immune globulin11 12 may be important. This mechanism has been proposed for the therapeutic effects of immune globulin in immune thrombocytopenic purpura13 and Guillain-Barré syndrome14 and may be critical to its beneficial effects in cardiac disease. The modulatory effects of immune globulin are not limited to humoral immunity, because cellular immune regulation is also altered during therapy.15
The possible therapeutic role of immune modulation is consistent with studies in animal models. The autoimmune pathogenesis of virally initiated inflammatory heart disease has been extensively studied in a murine model of coxsackievirus-induced myocarditis.16 In these animals, immune suppression can actually increase myocardial necrosis and worsen survival when given early in the course of the myocarditis.17 By contrast, high-dose immune globulin markedly improves survival when given at the time of viral infection, even though it does not reduce viral titers.18 When used later in the post-viremic phase of this model, immune globulin–treated mice had less necrosis and myocyte inflammation than control animals.19
Our data suggest that patients with the recent onset of symptomatic DCM benefit from treatment with immune globulin; however, our study has several limitations. First, the endomyocardial biopsy has limited sensitivity in detecting inflammatory disease. Therefore, we cannot ascertain whether the beneficial effects of immune globulin require the presence of myocardial inflammation. Second, the open-label, nonrandomized design of the trial and the limited number of study patients temper our enthusiasm for the results. However, our results are similar to those reported in the pediatric patients with acute DCM and are consistent with evidence of the protective effects of immune globulin in murine models. Coupled with these earlier positive results, the present data are intriguing and support the rationale for a randomized, placebo-controlled trial in a larger population of patients with recent onset of congestive failure secondary to idiopathic DCM.
Selected Abbreviations and Acronyms
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Received January 8, 1997; revision received March 31, 1997; accepted April 2, 1997.
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