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

ABSTRACT: Background: Immunoadsorption with subsequent IgG substitution (IA/IgG) represents a novel therapeutic approach in treatment of dilated cardiomyopathy (DCM) which leads to 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 prediction of the response of patients with DCM to IA/IgG. Methods & Results: Forty DCM patients underwent endomyocardial biopsies (EMBs) before IA/IgG. In 8 patients with normal LVEF (controls) EMB were obtained for clinical reasons. Clinical parameters, negative inotropic activity (NIA) of antibodies on isolated rat cardiomyocytes and gene expression profiles of EMBs were analyzed. DCM patients displaying improvement of LVEF (≥ 20% relative and ≥ 5% absolute) six month after IA/IgG were considered responders. Compared to non-responders (n=16), responders (n=24) displayed shorter disease duration (p=0.006), smaller LV internal diameter in diastole (LVIDd) (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. 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: -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 baseline predicts response to IA/IgG therapy and may enable appropriate selection of patients who benefit from this therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE17800 | GEO | 2012/12/01

SECONDARY ACCESSION(S): PRJNA118333

REPOSITORIES: GEO

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Project description:Dilated cardiomyopathy (DCM) is a disease of the heart muscle characterized by left ventricular or biventricular dilation and systolic dysfunction. It presents one of the most common causes of heart failure worldwide and also the most common indication for heart transplantation. Despite the discharge treatment possibilities, the outcome of patients with recent onset DCM often remains unpredictable and major adverse events may occur in the first months following the diagnosis. Enhancement in the left ventricular ejection fraction – designed as the left ventricular reverse remodeling (LVRR) – has been considered one of the most important determinants of the improvement and treatment response in the prognosis of DCM. In the present study we performed a comprehensive quantitative proteomic analysis of DCM patients’ plasma samples. First we searched for the differences against healthy control group and found several proteins and biological processes to be significantly regulated. The most DCM up-regulated terms corresponded to inflammatory response, wound healing and complement. Among the most relevant DCM up-regulated proteins were CRP, CD163, AOC3, PF4, IGF2, IGFBP2 and TNC. Down-regulation in DCM samples was observed in the biological processes of blood coagulation and lipid metabolism, both of which present risk factors in cardiovascular diseases. The most relevant down-regulated proteins in DCM were TTN, GSN, FCN3, PON1, PON3, and COMP. In the second part of the study, we observed the clinical fate of the DCM patients one year after admission. We divided them according to their treatment response into subgroups of responders (LVRR+) and non-responders (LVRR-) and searched for proteins that would help to predict the patient’s fate or to elucidate the molecular consequences of the disease progression. The protein with the best prognostic potential was ALDOB, its elevated plasma level was found in patients with worse or fatal outcome. The patients with no or poor treatment response had also up-regulated immunoglobulins and pathways corresponding to immunoglobulin-mediated immune response together with cell adhesion which points to the importance of these processes in the DCM pathology.

Project description:Dysregulated cardiac function after sepsis is common in intensive care unit (ICU) and known to predict poor long-term outcome and increase mortality. Effective therapeutic strategies are largely lacking. Moreover, the pathological feature and the molecular mechanism underlying cardiac dysfunction induced by sepsis remain unclear. Here, by performing echocardiograms on rodents after induction of polymicrobial sepsis with cecum ligation and puncture (CLP), we assessed the temporal dynamics of left ventricular ejection fraction (LVEF) and a serial of hemodynamics parameters on animals at different time point after CLP. Intriguingly, the mean LVEF is comparable in mice induced by CLP and sham, whereas survivors post CLP had stable LVEF and non-survivors had markedly fluctuated LVEF at early phase of CLP induction, suggesting LVEF away from normal range is highly associated with mortality. Consistent with clinical observations of depressed, preserved or hyperdynamic LVEF in septic patients from data compiled using our ICU cohort and from other studies, CLP-induced mice fall into three groups based on LVEF measured at 24 hours after surgery: high LVEF (HEF, LVEF>=90%), low LVEF (LEF, LVEF<65%), and normal LVEF (NEF, 65%=<LVEF<90%). We performed genome-wide transcriptomic and proteomic profiling on left ventricle samples collected from three CLP groups and sham mice. By implementing pathway analysis, gene set enrichment and coexpression network analysis, we identified jointly and distinctively changed genes, proteins and biologically-essential processes and pathways in three CLP groups with different LVEF. Notably, transmission electron microscopy examination shows remarkable mitochondrial and sarcomere defects in three CLP groups with different phenotypes associated with LVEF variances. Together, this study systematically characterizes the molecular, morphological, and functional alterations in CLP-induced cardiac injury, serving as a framework for future research into pathology and molecular mechanism of sepsis-induced cardiomyopathy.

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

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