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Changes of myocardial gene expression and protein composition in patients with dilated cardiomyopathy after immunoadsorption with subsequent immunoglobulin substitution

ABSTRACT: Immunoadsorption with subsequent immunoglobulin substitution (IA/IgG) represents a therapeutic approach for patients with dilated cardiomyopathy (DCM). Here, we studied which molecular cardiac alterations are initiated after this treatment. Transcription profiling of endomyocardial biopsies with Affymetrix whole genome arrays was performed on 33 paired samples of DCM patients collected before and six months after IA/IgG. Therapy-related effects on myocardial protein levels were analysed by label free proteome profiling for a subset of 23 DCM patients. Data were analysed regarding therapy-associated differences in gene expression and protein levels by comparing responders (defined by improvement of left ventricular ejection fraction ≥ 20% relative and ≥5% absolute) and non-responders. Responders to IA/IgG showed a decrease in serum N-terminal proBNP levels in comparison to baseline which was accompanied by a decreased expression of heart failure markers such as angiotensin converting enzyme 2 or periostin. However, despite clinical improvement even in responders IA/IgG did not trigger general inversion of DCM associated molecular alterations in myocardial tissue. Transcriptome profiling revealed reduced gene expression for connective tissue growth factor, fibronectin, and collagen type I in responders. In contrast, in non-responders after IA/IgG, for fibrosis associated genes and proteins showed elevated levels whereas values were reduced or maintained in responders. Thus, improvement of LV function after IA/IgG seems to be related to a reduced gene expression of heart failure markers and pro-fibrotic molecules as well as reduced fibrosis progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE19303 | GEO | 2016/12/01

SECONDARY ACCESSION(S): PRJNA120893

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.

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Changes of myocardial gene expression and protein composition in patients with dilated cardiomyopathy after immunoadsorption with subsequent immunoglobulin substitution

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