Fcγ-Receptor IIa Polymorphism and the Role of Immunoadsorption in Cardiac Dysfunction in Patients With Dilated Cardiomyopathy

Abstract

In patients with dilated cardiomyopathy (DCM), cardiac autoantibodies are able to bind with their Fab fragment to epitopes on cardiomyocytes, but thereafter they crosslink through their Fc fragment to cardiac Fc(gamma)-receptor IIa. Polymorphic variability of the Fc(gamma)-receptor IIa is associated with modified affinity of immunoglobin G (IgG) binding and may influence therapeutic effects. In this study, 103 consecutive DCM patients were treated with immunoadsorption (IA) therapy with subsequent IgG substitution (IA/IgG). Echocardiography was performed at baseline and again at 3 and 6 months after IA/IgG. Fc(gamma)-receptor IIa polymorphism R/H131 was genotyped using a nested sequence-specific primer polymerase chain reaction (PCR). Patients with the Fc(gamma)-receptor IIa genotype R/R131 showed significantly greater improvement in left ventricular (LV) function than patients with the R/H131 or H/H131 genotypes did. Irrespective of the Fc(gamma)-receptor polymorphism, patients with shorter disease duration and a more impaired LV function responded with a greater increase in LV ejection fraction (LVEF). Therefore, the Fc(gamma)-receptor polymorphism influences the efficacy of immunomodulatory therapy involving IA/IgG.

Use of Biomarkers for the Prediction of Treatment Response: Immunoadsorption in Dilated Cardiomyopathy as a Clinical Example

“…Thus, currently available data have demonstrated that IA/IgG resulted in significant increase in cardiac functional and morphological parameters, symptoms' relief, heart failure related clinical biomarkers (Dörffel et al 1997;Felix et al 2000;Müller et al 2000;Felix et al 2002;Staudt et al 2002Staudt et al , 2005Staudt et al , 2006Staudt et al , 2010Doesch et al 2010;Pokrovsky et al 2013), increased exercise tolerance , and improvement of endothelial function (Bulut et al 2011). Two studies have also shown long-term effects of IA with respect to the improvement of cardiac function, morphology, and the symptom state (Dandel et al 2012;Müller et al 2000).…”

“…Another study revealed a novel potential mechanism for the antibody-induced impairment of cardiac function in DCM patients, indicating that the interaction of immunoglobulins obtained from DCM patients with cardiomyocytes implements the binding of DCM-IgG-F(ab')2 to their cardiac antigens, but the Fc part might trigger the negative inotropic effects via a newly detected Fcγ receptor on cardiomyocytes (Staudt et al 2007). Interestingly, it could also be shown that the degree of hemodynamic improvement after IA/IgG may be related to the genotype of the Fcγ-receptor (Staudt et al 2010).…”

Advances in monoclonal antibody application in myocarditis

“…Autoimmune inflammation continued without the virus for weeks and months, eventually resulting in dilated cardiomyopathy which presents itself as diffuse myocardial necrosis with multinucleated giant cell infiltration. The detection rate of cardiac muscle globulin (or other primary autoimmune) autoantibodies in circulation for patients with autoimmune myocarditis is high (Nussinovitch and Shoenfeld, 2010;Staudt et al, 2010).…”

Lack in Treatment Options for Virus-Induced Inflammatory Cardiomyopathy

“…Immunosuppressive therapies can exert beneficial effects in chronic, virus-negative inflammatory cardiomyopathy, 3,4 whereas immunoadsorption might be effective in a subset of dilated cardiomyopathy patients with autoantibodies against heart tissue antigens. 5 8,9 or targeting B lymphocytes are further attempts to develop new therapeutic options for inflammatory cardiomyopathy via targeting immunocompetent cells.…”