Short-term Hemodynamic Effects of Immunoadsorption in Dilated Cardiomyopathy
Background Previous studies have shown that the sera of many patients with dilated cardiomyopathy (DCM) are positive for several antibodies directed against cardiac antigens. Anti–β1-adrenergic receptor antibodies occur in 70% to 90% of DCM patients. These antibodies are extractable by immunoadsorption (IA). In an investigation of the functional significance of antibodies for hemodynamics, IA was performed throughout 5 consecutive days on nine patients with severe DCM who were on stable drug therapy.
Methods and Results Immunoglobulins were eliminated in nine patients with severe DCM (mean age, 43.5 years; range, 25 to 58 years; left ventricular ejection fraction, <25%). IA was performed over 5 consecutive days with an immunoadsorber for immunoglobulin. All patients were on stable medication, including ACE inhibitors, digitalis, and diuretics. All patients received β-blockers. During therapy, hemodynamic parameters (mean±SD) were monitored with a Swan-Ganz thermodilution catheter. IA elicited a decrease of anti–β1-adrenergic receptor antibodies from 6.4±1.3 to 1.0±0.5 relative units. During IA, cardiac output increased from 3.7±0.8 to 5.5±1.8 L/min, P<.01. Mean arterial pressure decreased from 76.0±9.9 to 65.0±11.2 mm Hg, P<.05; mean pulmonary arterial pressure, from 27.6±7.7 to 22.0±6.5 mm Hg, P<.05; left ventricular filling pressure, from 16.8±7.4 to 12.8±4.7 mm Hg, P<.05; and systemic vascular resistance, from 1465±332 to 949±351 dyne·s·cm−5, P<.01.
Conclusions In addition to conventional medical treatment, IA may be an additional therapeutic possibility for acute hemodynamic stabilization of patients with severe DCM.
By definition, the cause of injury to the myocardium in DCM is unknown. Consequently, until now we have not been able to direct the treatment toward the cause. In recent years, accumulated evidence has shown that autoimmunological mechanisms may play an important role in the initiation and progression of myocardial injury in DCM. Several cardiac autoantibodies have been found in DCM. Immunoreactive antibodies, such as antibodies against the ADP-ATP carrier and against contractile proteins of cardiomyocytes, have been detected in patients with DCM.1 2 Recent findings have indicated that autoantibodies against the cardiac β1-adrenergic receptors are present in the serum of patients with idiopathic DCM.3 These autoantibodies are part of the IgG fraction and are capable of inducing a positive chronotropic effect on neonatal rat cardiomyocytes in culture.4 To answer the question of whether autoantibodies contribute to cardiac malfunction in DCM, immunoglobulins were eliminated in nine patients with severe DCM by IA. Analysis of β-receptor antibodies was used as a marker for autoimmunological reactions occurring in DCM. Some previously published preliminary data of our study indicate a shift to lower NYHA classes during IA.5 Because dyspnea as the primary symptom according to the NYHA classification reflects only subjective symptom relief, we decided to present the hemodynamic data to clarify the question of whether IA leads to measurable improvement of cardiac function as well.
Nine patients (eight men and one woman; age range, 25 to 58 years; mean, 44.6 years) with severe chronic congestive heart failure refractory to medical therapy participated in the study. All patients suffered from DCM, NYHA functional class III or IV. The LVEF was <25% as assessed by cineangiography and echocardiography. All patients were on stable medication, including ACE inhibitors, digitalis, and diuretics. Since anti–β-receptor antibodies are competitively displaced by β-blockers,3 patients were additionally treated with β-blockers. Intravenous β-blocker therapy was started 1 day before IA with esmolol (25 μg·kg−1·min−1), which was followed by oral therapy with metoprolol (mean daily dose, 59.4 mg; range, 25 to 100 mg) on the same day.
Written informed consent was obtained from each patient, and the protocol was approved by the Charité Ethics Committee.
Extracorporeal IA System
After completion of baseline measurements, immunoglobulin extractions were performed with an immunoadsorber for immunoglobulin, Ig Therasorb (Baxter). The extracorporeal treatment system consisted of conventional plasmapheresis to obtain plasma and the immunoapheresis system. We used a plasma-separation device (plasma filter OP 05, Diamed) for conventional plasmapheresis. The plasma was separated at a maximal plasma flow rate of 40 mL/min, passed through the IA column, and then reinfused. The IA system (ADA, Baxter) consists of two parallel columns. Plasma is passed through one of the columns while the other is being regenerated. All patients underwent one IA session daily on 5 consecutive days. At each session, IgG plasma levels were decreased by 20% to 30%. After the last IA session, all patients received an infusion of ≈35 g polyclonal IgG to restore serum IgG levels. During each session of IA, anticoagulation was performed with intravenous infusion of heparin.
Right-heart catheterization with a Swan-Ganz thermodilution catheter was performed to evaluate hemodynamics. The following measurements were carried out four times a day: systolic and diastolic arterial blood pressure, systolic and diastolic PAP, PCWP, mean right atrial pressure, and CO. The derived hemodynamic variables included cardiac index, stroke volume, SVI, SVR, and pulmonary vascular resistance.
Two-dimensional echocardiography was used before and after IA for the assessment of LVEF.
The anti–β-receptor antibodies were determined as previously described.5 Antibody activity was measured after each IA session.
Results are expressed as mean±SD. Comparisons of measurements before and after IA therapy were made with the Wilcoxon test, and significance was assessed at the P<.05 level. Hemodynamic parameters were compared before IA on day 1 and on day 6, 1 day after the last IA session was performed.
In all patients, IA procedures were well tolerated, and no major complications occurred. On day 6, after five sessions of IA, all patients described a mitigation of dyspnea. IA was effective in reducing β1-adrenergic receptor–stimulating antibodies in all patients. A decrease was detected in IgG (from 11.5±3.4 to 1.5±0.5 g/L), IgA (from 3.3±1.7 to 1.4±0.9 g/L), and IgM (from 1.9±1.4 to 0.4±0.1 g/L) (Fig 1a⇓). At the same time, we observed a consistent decrease of β1-adrenergic receptor antibodies (from 6.4±1.3 to 1.0±0.5 relative units) (Fig 1b⇓). Although each session of IA did not significantly influence the invasively measured hemodynamic parameters, there was a marked improvement of hemodynamics within 6 days, after five sessions of IA had been performed: heart rate tended to decrease (88.0±23.1 to 84.0±20.8 bpm, P=NS). Mean blood pressure and mean PAP decreased significantly (from 76.0±9.9 to 65.0±11.2 mm Hg, P<.05, and from 27.6±7.7 to 22.0±6.5 mm Hg, P<.05, respectively) (Fig 2a⇓). There was a significant decrease in PCWP (from 16.8±7.4 to 12.8±4.7 mm Hg, P<.05, Fig 2b⇓) and right atrial pressure (from 9.1±3.7 to 5.3±3.2 mm Hg, P<.05). CO increased significantly, from 3.7±0.8 to 5.5±1.8 L/min, P<.01. Cardiac index and SVI (Fig 2c⇓) increased from 2.0±0.42 to 2.9±0.79 L·min−1·m−2, P<.01, and from 24.0±7.4 to 35.9±10.3 mL/m2, P<.05, respectively. According to the hemodynamic changes mentioned above, decreases of SVR and pulmonary vascular resistance were calculated (from 1465±331 to 949±351 dyne·s·cm−5, P<.01, and from 199±57 to 145±69 dyne·s·cm−5, P=NS, respectively) (Fig 2d⇓). LVEF as assessed by echocardiography failed to show significant improvement (20% versus 21.9%).
IA has been successfully used for treatment of a number of autoimmune diseases. It has been shown to remove antiglomerular basement membrane antibodies in Goodpasture’s syndrome,6 anti-acetylcholine antibodies in myasthenia gravis,7 and anti-dsDNA antibodies in systemic lupus erythematosus.8 Highly sensitized patients awaiting renal transplantation have undergone extracorporeal IA to remove anti-HLA antibodies.9
To the best of our knowledge, this is the first pilot study to investigate the hemodynamic effects of IA in patients suffering from DCM. After IA was performed, the invasively measured hemodynamic parameters had markedly improved.
Some objections can be made to the results of the present study. The question arises as to whether the beneficial hemodynamic effects are related to IA and/or to concomitant medical treatment. Patients were on stable medication (ACE inhibitors, digitalis, diuretics), and the additional treatment with β-blockers was well tolerated. Initiation of β-blocker therapy 1 day before IA induced a slight decrease of cardiac index, which, however, did not attain statistical significance. On day 1, before initiation of IA, hemodynamic measurements showed a stable baseline of all measured parameters. β-Blocker therapy in chronic heart failure usually does not lead to such marked increases in CO or such decreases in SVR in as short a period of time as observed in our investigation.10 11 Moreover, several studies have shown that ventricular function in patients with heart failure improves only after long-term treatment with β-blockers.11 12 In particular, improvement in LVEF takes several months to develop. Using echocardiography, Hall et al13 demonstrated that patients treated with metoprolol do not demonstrate an improvement in systolic performance until after 1 month of therapy. These data suggest that additional therapy with β-blockers is probably not a significant factor influencing the hemodynamic changes observed in our study.
The underlying mechanism by which IA improves hemodynamics in patients with severe DCM remains to be elucidated. It is not evident from this study whether anti–β1-adrenergic receptor autoantibodies in DCM are an epiphenomenon or a causal factor triggering the disease. Because of the uniform high titers of β-receptor antibody activity, we were not able to predict hemodynamic improvement on the basis of the antibody titers before intervention. Hence, the pathophysiological significance of β-receptor antibodies is completely unclear. Interestingly, however, Limas et al14 demonstrated that in most patients with idiopathic DCM and β-receptor antibodies, cardiac transplantation results in a dramatic decrease in antibody titers, probably due to the removal of the autoantigen and/or the postoperative use of immunosuppressants. In addition to β-receptor antibodies, elimination of other autoimmunoreactive antibodies detected in DCM should also be considered. For example, antibodies against the ADP-ATP carrier of the mitochondrial membrane can influence the carrier function and impair cardiac performance.1 Removal of antibodies against contractile proteins may have also contributed to improvement of cardiac function. Because IA is successfully used in effectively eliminating all immunoglobulins from plasma, it is difficult to clarify the potential role of a separate antibody directed against cardiac tissue. This point underlines the hypothesis that different autoantibodies may play a role in contributing to hemodynamic deterioration.
In theory, the acute beneficial effects of IA may also be caused by the removal of putative cardiodepressant factors or by unspecific effects on the immune system, such as changes in cytokine metabolism.
At least theoretically, IA may have influenced SVR. From the hemodynamic measurements, we cannot exclude the possibility that the improvement of hemodynamics is primarily related to a decrease of SVR rather than to an increase in myocardial contractility. In addition, IA may have changed plasma volume. But in contrast to plasmapheresis, IA does not influence plasma volume. After adsorption of the immunoglobulins, plasma is completely reinfused. Thus, hematocrit readings before and after IA did not differ significantly, indicating that plasma volume remained stable. Further investigations are necessary to verify whether the rebound of antibodies is accompanied by hemodynamic changes and whether the hemodynamic results of IA are confirmed when IA is repeated. Long-term follow-up of these patients is assumed to be essential to investigate the possible anti-idiotypic effect of immunoglobulin substitution after the IA procedure.
This is the first study indicating that IA may have positively influenced cardiac function in DCM. According to the design as a pilot study, we did not include a control group. It was agreed by the Local Ethics Committee of Charité Hospital to initially perform a pilot study with the purpose of ascertaining the safety and feasibility of IA in patients with severe DCM and compromised hemodynamics. Depending on the results of this pilot study, a randomized large-scale study including a control group is planned.
The aim of this pilot study was to ascertain the effects of IA in patients with DCM. At present, no data are available on the long-term effects of IA. In summary, we hypothesize that IA may be a promising alternative therapeutic possibility for acute hemodynamic stabilization of patients with DCM. This hypothesis should be investigated by randomized clinical trials including a control group. Further studies are also required to define the influence of IA on long-term hemodynamics and mortality in DCM patients.
Selected Abbreviations and Acronyms
|LVEF||=||left ventricular ejection fraction|
|NYHA||=||New York Heart Association|
|PAP||=||pulmonary arterial blood pressure|
|PCWP||=||pulmonary capillary wedge pressure|
|SVI||=||stroke volume index|
|SVR||=||systemic vascular resistance|
This study was supported by grant BMBF (German Ministry of Research and Technology) 01 ZZ 9101.
- Received November 27, 1996.
- Revision received February 19, 1997.
- Accepted February 21, 1997.
- Copyright © 1997 by American Heart Association
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