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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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Related in: MedlinePlus

Assessment of the value of clinical parameters (A), gene signature (B), and a combination of gene signature and antibody status (C) for the classification of responders and non-responders at BL. The correlation of the individual patients to the responder template is displayed in the left column, and that to the non-responder template in the right column. Green, responders; red, non-responders. Validity of the classification of patients into responders or non-responders increases with the degree of positive correlation to the corresponding template (maximum value 1) and negative correlation with the other template (minimum value −1).
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EHS330F3: Assessment of the value of clinical parameters (A), gene signature (B), and a combination of gene signature and antibody status (C) for the classification of responders and non-responders at BL. The correlation of the individual patients to the responder template is displayed in the left column, and that to the non-responder template in the right column. Green, responders; red, non-responders. Validity of the classification of patients into responders or non-responders increases with the degree of positive correlation to the corresponding template (maximum value 1) and negative correlation with the other template (minimum value −1).

Mentions: A combination of the four clinical parameters (disease duration, inflammation, LVIDd, and LVEF) which significantly determined ΔLVEF did not allow reliable discrimination between responders and non-responders at BL (cut-off value 1) because similar correlation patterns were generated irrespective of the use of the responder or non-responder template (Figure 3A).Figure 3


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)

Assessment of the value of clinical parameters (A), gene signature (B), and a combination of gene signature and antibody status (C) for the classification of responders and non-responders at BL. The correlation of the individual patients to the responder template is displayed in the left column, and that to the non-responder template in the right column. Green, responders; red, non-responders. Validity of the classification of patients into responders or non-responders increases with the degree of positive correlation to the corresponding template (maximum value 1) and negative correlation with the other template (minimum value −1).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

EHS330F3: Assessment of the value of clinical parameters (A), gene signature (B), and a combination of gene signature and antibody status (C) for the classification of responders and non-responders at BL. The correlation of the individual patients to the responder template is displayed in the left column, and that to the non-responder template in the right column. Green, responders; red, non-responders. Validity of the classification of patients into responders or non-responders increases with the degree of positive correlation to the corresponding template (maximum value 1) and negative correlation with the other template (minimum value −1).
Mentions: A combination of the four clinical parameters (disease duration, inflammation, LVIDd, and LVEF) which significantly determined ΔLVEF did not allow reliable discrimination between responders and non-responders at BL (cut-off value 1) because similar correlation patterns were generated irrespective of the use of the responder or non-responder template (Figure 3A).Figure 3

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