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

Ameling S, Herda LR, Hammer E, Steil L, Teumer A, Trimpert C, Dörr M, Kroemer HK, Klingel K, Kandolf R, Völker U, Felix SB - Eur. Heart J. (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Interfakultäres Institut für Genetik und Funktionelle Genomforschung, Universitätsmedizin Greifswald, Friedrich-Ludwig-Jahn-Strasse 15a, Greifswald D - 17487, Germany.

ABSTRACT

Aims: Immunoadsorption 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 results: 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 (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.

Conclusion: Combined 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.

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Negative inotropic activity of cardiac autoantibodies in responders and non-responders. Negative inotropic activity was determined by measuring percentage change of maximum cell shortening of RCM during immunoglobulin G superfusion compared with the baseline value. Green, responders; red, non-responders.
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EHS330F2: Negative inotropic activity of cardiac autoantibodies in responders and non-responders. Negative inotropic activity was determined by measuring percentage change of maximum cell shortening of RCM during immunoglobulin G superfusion compared with the baseline value. Green, responders; red, non-responders.

Mentions: The presence of negative inotropic cardiac antibodies has previously been shown to be associated with response to IA/IgG.15,16 Thus, NIA of antibodies was determined in this patient cohort and the respective controls. Immunoglobulin G purified from plasma of controls did not induce a negative inotropic reaction in isolated RCM (relative change to the BL value of cell shortening: 2.0 ± 5.7%), whereas IgG of DCM patients showed a significant NIA (range: −29.2 to 7.5; mean: −11.1 ± 8.4%, P < 0.001 vs. controls). Furthermore, stronger NIA was observed after the treatment of isolated RCM with antibodies from responders (−16.7 ± 5.3%) than with those from non-responders (−2.8 ± 4.0%, Figure 2, responders vs non-responders P < 0.0001).Figure 2


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

Ameling S, Herda LR, Hammer E, Steil L, Teumer A, Trimpert C, Dörr M, Kroemer HK, Klingel K, Kandolf R, Völker U, Felix SB - Eur. Heart J. (2012)

Negative inotropic activity of cardiac autoantibodies in responders and non-responders. Negative inotropic activity was determined by measuring percentage change of maximum cell shortening of RCM during immunoglobulin G superfusion compared with the baseline value. Green, responders; red, non-responders.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3584995&req=5

EHS330F2: Negative inotropic activity of cardiac autoantibodies in responders and non-responders. Negative inotropic activity was determined by measuring percentage change of maximum cell shortening of RCM during immunoglobulin G superfusion compared with the baseline value. Green, responders; red, non-responders.
Mentions: The presence of negative inotropic cardiac antibodies has previously been shown to be associated with response to IA/IgG.15,16 Thus, NIA of antibodies was determined in this patient cohort and the respective controls. Immunoglobulin G purified from plasma of controls did not induce a negative inotropic reaction in isolated RCM (relative change to the BL value of cell shortening: 2.0 ± 5.7%), whereas IgG of DCM patients showed a significant NIA (range: −29.2 to 7.5; mean: −11.1 ± 8.4%, P < 0.001 vs. controls). Furthermore, stronger NIA was observed after the treatment of isolated RCM with antibodies from responders (−16.7 ± 5.3%) than with those from non-responders (−2.8 ± 4.0%, Figure 2, responders vs non-responders P < 0.0001).Figure 2

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Interfakultäres Institut für Genetik und Funktionelle Genomforschung, Universitätsmedizin Greifswald, Friedrich-Ludwig-Jahn-Strasse 15a, Greifswald D - 17487, Germany.

ABSTRACT

Aims: Immunoadsorption 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 results: 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 (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.

Conclusion: Combined 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.

Show MeSH
Related in: MedlinePlus