Myocardial gene expression profiles and cardiodepressant autoantibodies predict response of patients with dilated cardiomyopathy to immunoadsorption therapy

Abstract

AimsImmunoadsorption with subsequent immunoglobulin G substitution (IA/IgG) represents a novel therapeutic approach in the treatment of dilated cardiomyopathy (DCM) which leads to the improvement of left ventricular ejection fraction (LVEF). However, response to this therapeutic intervention shows wide inter-individual variability. In this pilot study, we tested the value of clinical, biochemical, and molecular parameters for the prediction of the response of patients with DCM to IA/IgG.Methods and resultsForty DCM patients underwent endomyocardial biopsies (EMBs) before IA/IgG. In eight patients with normal LVEF (controls), EMBs were obtained for clinical reasons. Clinical parameters, negative inotropic activity (NIA) of antibodies on isolated rat cardiomyocytes, and gene expression profiles of EMBs were analysed. Dilated cardiomyopathy patients displaying improvement of LVEF (≥20 relative and ≥5% absolute) 6 months after IA/IgG were considered responders. Compared with non-responders (n = 16), responders (n = 24) displayed shorter disease duration (P = 0.006), smaller LV internal diameter in diastole (P = 0.019), and stronger NIA of antibodies. Antibodies obtained from controls were devoid of NIA. Myocardial gene expression patterns were different in responders and non-responders for genes of oxidative phosphorylation, mitochondrial dysfunction, hypertrophy, and ubiquitin–proteasome pathway. The integration of scores of NIA and expression levels of four genes allowed robust discrimination of responders from non-responders at baseline (BL) [sensitivity of 100% (95% CI 85.8–100%); specificity up to 100% (95% CI 79.4–100%); cut-off value: −0.28] and was superior to scores derived from antibodies, gene expression, or clinical parameters only.ConclusionCombined assessment of NIA of antibodies and gene expression patterns of DCM patients at BL predicts response to IA/IgG therapy and may enable appropriate selection of patients who benefit from this therapeutic intervention.

Defective circulating CD4+LAP+ regulatory T cells in patients with dilated cardiomyopathy

“…These autoantibodies belong to IgG3 and are independent predictors of disease development within 5 years among healthy relatives of DCM patients [42]. Moreover, immunoadsorption to eliminate IgG or IgG3 with subsequent IgG substitution (IA/IgG) results in the improvement of LVEF and represents a novel, therapeutic approach in the treatment of DCM [11][12][13][14][15][16]. Consistent with previous studies [43][44][45] + LAP + T regs and B cells from controls (n = 4) were purified by FACS sorting and cocultured alone or at a 1:1 ratio for suppression and proliferation assay.…”

“…These autoantibodies belong to the IgG3 [9] and play an important role in the pathogenesis of DCM by initiating the disease process [10] or contributing to the progression of contractile dysfunction [6]. Several studies indicate that the use of immunoadsorption to eliminate IgG or IgG3 significantly improves cardiac performance and clinical status in heart-failure patients [11][12][13][14][15]. T regs are a subgroup of T cells that play a vital role in maintaining peripheral tolerance, preventing autoimmune diseases, and restraining chronic inflammatory diseases [16].…”

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

“…According to currently available data, response to IA/IgG treatment in patients with DCM shows wide inter-individual variability of changes in cardiac function after intervention with responder rates of about 60 % of treated patients (Staudt et al 2004(Staudt et al , 2010Ameling et al 2013). In view of the high treatment costs and the invasive character of this therapeutic procedure, determinants that predetermine differential outcome after IA/IgG are therefore of particular interest.…”

“…In accordance with these approaches we performed a pilot study aiming to test the value of clinical, biochemical and molecular parameters for the prediction of the response to IA/IgG therapy (Ameling et al 2013). After application of exclusion, criteria, data of 40 DCM patients with left ventricular dysfunction (LVEF < 45 %), and symptoms of chronic heart failure, according to NYHA class II and III, could be included into the analyses.…”

Activated Circulating Myeloid-Derived Suppressor Cells in Patients with Dilated Cardiomyopathy

“…Moreover, several antibodies against antigens within the myocardium, whether they are microbial, self, or alloantigens, impair cardiac function, cause permanent damage to the cardiac tissue, and often lead to ventricular dilation [5,6]. Several trails have indicated that immunomodulation has the potential to offer a novel and future therapeutic strategy for the management of myocarditis and DCM patients [7][8][9].…”