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CLINICAL STUDY: DILATED CARDIOMYOPATHY

Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption

Stephan B. Felix, MD^*,*, Alexander Staudt, MD^*, Martin Landsberger, PhD^*, Yvonne Grosse, MD^*, Verena Stangl, MD, Thomas Spielhagen, MD, Gerd Wallukat, PhD, Klaus D. Wernecke, PhD, Gert Baumann, MD and Karl Stangl, MD

^* Klinik für Innere Medizin B, Universität Greifswald, Greifswald, Germany
Medizinische Klinik, Charité, Campus-Mitte, Berlin, Germany
Max Delbrück Zentrum für Molekulare Kardiologie, Berlin, Germany
Institut für Medizinische Biometrie, Charité, Humboldt-Universität, Berlin, Germany

Manuscript received May 21, 2001; revised manuscript received November 9, 2001, accepted November 30, 2001.

^* Reprint requests and correspondence: Dr. Stephan B. Felix, Klinik für Innere Medizin B, Universität Greifswald, Friedrich-Loeffler-Str. 23a, 17487 Greifswald, Germany.
felix{at}uni-greifswald.de

OBJECTIVES: The objective of this study was to investigate whether immunoadsorption (IA) removes cardiodepressant antibodies from the plasma of patients with dilated cardiomyopathy (DCM), as well as to describe their effects on isolated rat cardiomyocytes.

BACKGROUND: Immunoadsorption induces early hemodynamic improvement in patients with DCM. The mechanisms for this improvement remain to be elucidated.

METHODS: Patients with DCM (n = 11; left ventricular ejection fraction <30%, cardiac index [CI] <2.5 l/min per m²) were treated with IA on three consecutive days, with one IA session daily, by application of specific antibody columns directed against human immunoglobulin (Ig). Immunoadsorption was also conducted on 500 ml of blood taken from nine healthy donors (control subjects). After passage of plasma, the IA columns were regenerated. Column eluent (CE) was collected and dialyzed (100 kD). Confocal laser scanning microscopy was used to analyze the effects of CE on cell contraction and on Ca²⁺-dependent fluorescence in isolated, field-stimulated adult rat cardiomyocytes loaded with cell-permeable Fluo-3. Immunoprecipitation with different preparations of myocardial protein fractions was used for characterization of cardiotropic antibodies.

RESULTS: During IA, the IgG plasma level decreased from 10.7 ± 0.6 to 2.4 ± 0.1 g/l (mean ± SEM), and the CI increased from 2.2 ± 0.1 to 2.7 ± 0.2 l/min per m² (p < 0.01). The CE obtained from control subjects did not influence Ca²⁺ transients or cell shortening of cardiomyocytes. In contrast, in patients with DCM, the CE collected during the first regeneration cycle of the first IA session caused an immediate and dose-related decrease of Ca²⁺ transients (dilution 1:5; –22.7 ± 5.5%; p < 0.01) and cell shortening (dilution 1:5; –29.9 ± 6.0%, p < 0.01). Early hemodynamic improvement among the patients correlated with the cardiodepressant effect of CE on the isolated cardiomyocytes. Purification of CE by protein A adsorption indicated that the cardiodepressant substances are antibodies. Immunoprecipitation revealed that the eliminated antibodies are capable of binding to various myocardial proteins.

CONCLUSIONS: Cardiac autoantibodies play a functional role in DCM, and their removal may induce early hemodynamic improvement.

Abbreviations and Acronyms   LVEF   CE   column eluent   CI   cardiac index   DCM   dilated cardiomyopathy   IA   immunoadsorption   Ig   immunoglobulin   IL   interleukin   LVEF   left ventricular ejection fraction   rfu   relative fluorescence units   TNF   tumor necrosis factor

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