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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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Simulation of robustness of the prediction of therapy outcome. The robustness of the prediction based on the expression of the four signature genes, negative inotropic activity of antibodies, and their combination was determined by adding a random noise to the parameter values of each sample prior to the classification to simulate the variation of values in the population. Added random noise is displayed on the X-axis as fold-values of the standard deviation (SD). Predictions are based on the expression level of four signature genes (red line), negative inotropic activity of antibodies (blue line), and a combination of both values (black line).
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EHS330F5: Simulation of robustness of the prediction of therapy outcome. The robustness of the prediction based on the expression of the four signature genes, negative inotropic activity of antibodies, and their combination was determined by adding a random noise to the parameter values of each sample prior to the classification to simulate the variation of values in the population. Added random noise is displayed on the X-axis as fold-values of the standard deviation (SD). Predictions are based on the expression level of four signature genes (red line), negative inotropic activity of antibodies (blue line), and a combination of both values (black line).

Mentions: The evaluation of the robustness of the prediction by an independent test set was not feasible due to limited number of EMBs, which could not be increased given the invasiveness of this procedure. Therefore, the variation of values in the population was simulated by adding incrementally increasing measurement errors to the data available and by assessing the effect of these errors on classification. Figure 5 illustrates that the sensitivity was more error-tolerant when the combined information of molecular signature and NIA of antibodies were exposed to increasing variations in values. The combined score allowed much better assessment of responders than molecular signature or NIA of antibodies alone, which is important in order to assure appropriate identification of patients who could benefit from IA/IgG.Figure 5


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)

Simulation of robustness of the prediction of therapy outcome. The robustness of the prediction based on the expression of the four signature genes, negative inotropic activity of antibodies, and their combination was determined by adding a random noise to the parameter values of each sample prior to the classification to simulate the variation of values in the population. Added random noise is displayed on the X-axis as fold-values of the standard deviation (SD). Predictions are based on the expression level of four signature genes (red line), negative inotropic activity of antibodies (blue line), and a combination of both values (black line).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

EHS330F5: Simulation of robustness of the prediction of therapy outcome. The robustness of the prediction based on the expression of the four signature genes, negative inotropic activity of antibodies, and their combination was determined by adding a random noise to the parameter values of each sample prior to the classification to simulate the variation of values in the population. Added random noise is displayed on the X-axis as fold-values of the standard deviation (SD). Predictions are based on the expression level of four signature genes (red line), negative inotropic activity of antibodies (blue line), and a combination of both values (black line).
Mentions: The evaluation of the robustness of the prediction by an independent test set was not feasible due to limited number of EMBs, which could not be increased given the invasiveness of this procedure. Therefore, the variation of values in the population was simulated by adding incrementally increasing measurement errors to the data available and by assessing the effect of these errors on classification. Figure 5 illustrates that the sensitivity was more error-tolerant when the combined information of molecular signature and NIA of antibodies were exposed to increasing variations in values. The combined score allowed much better assessment of responders than molecular signature or NIA of antibodies alone, which is important in order to assure appropriate identification of patients who could benefit from IA/IgG.Figure 5

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