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

In this pilot study, Ameling et al. tested the value of clinical, biochemical, and molecular parameters for the prediction of the responseof patients with DCM to immunoadsorption with subsequent immunoglobulin G substitution (IA/IgG). Forty 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 [sensitivity of 100% (95% CI 85.8–100%); specificity up to 100% (95% CI 79.4–100%); cut-off value:20.28] and was superior to scores derived from antibodies, gene expression, or clinical parameters only.The authors conclude that combined assessment of NIA of antibodies and gene expression patterns of DCM patients at baseline predicts response to IA/IgG therapy and may enable appropriate selection of patients who benefit from this therapeutic intervention.
Myocardial Disease

Dilated cardiomyopathy (DCM), the third most common cause of heart failure and the leading cause for heart transplantation (HTX), may be familial/genetic, viral and/or immune-mediated.  Experimental and clinical data indicate that in a large proportion of patients myocarditis and DCM represent the acute and subacute/chronic stages of an organ-specific cardiac autoimmune disease, occurring in genetically predisposed subjects, with or without a recognized viral trigger. Serum anti-heart autoantibodies (AHA), directed against multiple antigens, are found in patients and family members and in about 60% of familial and nonfamilial pedigrees. AHA in myocarditis/DCM may be directed against mitochondrial proteins, cardiac myosin heavy chain, cardiac b1-adrenergic receptors, muscarinergic receptors, the sarcolemmal Na-K-ATPase, cardiac troponin I (cTNI), and other yet unknown targets. AHA predict DCM development among relatives, years before disease onset. Some AHA, being associated with phases of activation/relapse of the autoimmune process, provide negative prognostic markers. In addition AHA against the ADP/ATP carrier, cardiac myosin, cardiac b1-adrenergic receptors, and cTNI, as well as the cardio-depressive AHA, have been shown to possess functional effects on cardiac myocytes in vitro, in animals and possibly in a DCM subset, responsive to extracorporeal immunoadsorption (IA). This is the rationale for the clinical application of IA in an ongoing double-blind randomized multicenter trial in end-stage DCM ( identifier: NCT00558584). Another ongoing international prospective study aims at providing us with more information about the frequency, disease-specificity for inflammatory cardiomyopathy of multiple AHA types,and their potential role as prognostic markers either alone or in combinations. However, IA is expensive and invasive and only a subset of patients shows a benefit in terms of clinical and functional parameters at follow-up. Therefore, it is key to identify non-invasive predictors of clinical response to IA.
Ameling et al. provide an important proof-of concept study. In fact the combination of genetic expression profiles from EMB and the presence of serum autoantibodies with functional effects in terms of negative inotropism in isolated cardiomyocytes was the most powerful predictor of response to IA compared to the genetic markers and the immune markers alone. These findings are in keeping with what is seen in other autoimmune diseases, where the association of genetic markers, e.g. predisposing HLA haplotypes or gene expression profiles, and specific serum autoantibody types, provides the basis of risk stratification in affected patients and of disease prediction in first-degree relatives and other symptom-free individuals at risk. In addition, it supports the view that etiology-directed diagnosis, with integration of invasive tools, such as EMB using state-of the art criteria, and non-invasive etiology-specific markers, such as AHA, is key for providing personalized new therapy in DCM as well as optimization of financial resources.


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Notes to editor

Presented by Alida LP Caforio, MD, PhD, FESC, Cardiology, Dept of Cardiological Thoracic and Vascular Sciences, University of Padova, Italy.

Sabine Ameling 1, Lars R. Herda 2, Elke Hammer1, Leif Steil 1, Alexander Teumer 1,Christiane Trimpert 2, Marcus Dorr 2, Heyo K. Kroemer 3, Karin Klingel 4, Reinhard Kandolf 4, Uwe Volker 1*, and Stephan B. Felix 2*

1- Interfakultares Institut fur Genetik und Funktionelle Genomforschung, Universitatsmedizin Greifswald, Friedrich-Ludwig-Jahn-Strasse 15a, Greifswald D – 17487, Germany
2 - Klinik und Poliklinik fur Innere Medizin B, Universitatsmedizin Greifswald, Ferdinand-Sauerbruch-Str., Greifswald, D-17475 Germany
3 - Center of Drug Absorption and Transport (C_DAT), Abteilung Allgemeine Pharmakologie, Universitatsmedizin Greifswald, Greifswald, Germany
4 - Abteilung Molekulare Pathologie, Universitatskrankenhaus Tubingen,Tubingen, Germany

European Heart Journal (2013) 34, 666–675

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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