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      Detection of Soluble ED-A + Fibronectin and Evaluation as Novel Serum Biomarker for Cardiac Tissue Remodeling

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          Abstract

          Background and Aims. Fibronectin containing the extra domain A (ED-A + Fn) was proven to serve as a valuable biomarker for cardiac remodeling. The study was aimed at establishing an ELISA to determine ED-A + Fn in serum of heart failure patients. Methods. ED-A + Fn was quantified in serum samples from 114 heart failure patients due to ischemic (ICM, n = 44) and dilated (DCM, n = 39) cardiomyopathy as well as hypertensive heart disease (HHD, n = 31) compared to healthy controls ( n = 12). Results. In comparison to healthy volunteers, heart failure patients showed significantly increased levels of ED-A + Fn ( p < 0.001). In particular in ICM patients there were significant associations between ED-A + Fn serum levels and clinical parameters, for example, increased levels with rising NYHA class ( p = 0.013), a negative correlation with left ventricular ejection fraction ( p = 0.026, r: −0.353), a positive correlation with left atrial diameter ( p = 0.008, r: 0.431), and a strong positive correlation with systolic pulmonary artery pressure ( p = 0.002, r: 0.485). In multivariate analysis, ED-A + Fn was identified as an independent predictor of an ischemic heart failure etiology. Conclusions. The current study could clearly show that ED-A + Fn is a promising biomarker in cardiovascular diseases, especially in heart failure patients due to an ICM. We presented a valid ELISA method, which could be applied for further studies investigating the value of ED-A + Fn.

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          The extra domain A of fibronectin activates Toll-like receptor 4.

          Y Okamura, M Watari, E S Jerud … (2001)
          Cellular fibronectin, which contains an alternatively spliced exon encoding type III repeat extra domain A (EDA), is produced in response to tissue injury. Fragments of fibronectin have been implicated in physiological and pathological processes, especially tissue remodeling associated with inflammation. Because EDA-containing fibronectin fragments produce cellular responses similar to those provoked by bacterial lipopolysaccharide (LPS), we examined the ability of recombinant EDA to activate Toll-like receptor 4 (TLR4), the signaling receptor stimulated by LPS. We found that recombinant EDA, but not other recombinant fibronectin domains, activates human TLR4 expressed in a cell type (HEK 293 cells) that normally lacks this Toll-like receptor. EDA stimulation of TLR4 was dependent upon co-expression of MD-2, a TLR4 accessory protein. Unlike LPS, the activity of EDA was heat-sensitive and persisted in the presence of the LPS-binding antibiotic polymyxin B and a potent LPS antagonist, E5564, which completely suppressed LPS activation of TLR4. These observations provided a mechanism by which EDA-containing fibronectin fragments promote expression of genes involved in the inflammatory response.
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            The extracellular matrix: at the center of it all.

            Stephanie Bowers, Indroneal Banerjee, Troy A Baudino (2010)
            The extracellular matrix is not only a scaffold that provides support for cells, but it is also involved in cell-cell interactions, proliferation and migration. The intricate relationships among the cellular and acellular components of the heart drive proper heart development, homeostasis and recovery following pathological injury. Cardiac myocytes, fibroblasts and endothelial cells differentially express and respond to particular extracellular matrix factors that contribute to cell communication and overall cardiac function. In addition, turnover and synthesis of ECM components play an important role in cardiac function. Therefore, a better understanding of these factors and their regulation would lend insight into cardiac development and pathology, and would open doors to novel targeted pharmacologic therapies. This review highlights the importance of contributions of particular cardiac cell populations and extracellular matrix factors that are critical to the development and regulation of heart function. 2009 Elsevier Ltd. All rights reserved.
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              Serum cellular fibronectin and matrix metalloproteinase-9 as screening biomarkers for the prediction of parenchymal hematoma after thrombolytic therapy in acute ischemic stroke: a multicenter confirmatory study.

              Mónica Millán, Mar Castellanos, David Brea … (2007)
              Plasma levels of cellular fibronectin (c-Fn) > or =3.6 microg/mL and of matrix metalloproteinase-9 (MMP-9) > or =140 ng/mL have been associated with parenchymal hematoma (PH) after treatment with tissue-type plasminogen activator (t-PA) in patients with acute ischemic stroke. In this prospective study, we sought to validate the predictive capacity of the preestablished cutoff values of these biomarkers for PH in a larger series of patients. We studied 134 patients treated with t-PA within 3 hours from symptom onset according to the SITS-MOST criteria (median time to infusion, 152 minutes; median National Institutes of Health Stroke Scale score, 14) in 4 university hospitals. Hemorrhagic transformation was classified according to the European-Australasian Acute Stroke Study II definitions on computed tomography scans performed 24 to 36 hours after treatment. Relevant hemorrhagic transformation was defined as hemorrhagic infarction type 2 or any PH. Serum c-Fn and MMP-9 levels were determined by an ELISA om blood samples obtained before treatment. Cranial computed tomography showed hemorrhagic transformation in 27 patients (20%), hemorrhagic infarction in 15 (type 2 in 8 patients), and PH in 12 patients (symptomatic in 4). Serum c-Fn and MMP-9 concentrations at baseline were significantly higher in patients with relevant hemorrhagic transformation and PH than in those without (all P or =3.6 microg/mL were 100%, 60%, 20%, and 100%, respectively, whereas corresponding values were 92%, 74%, 26%, and 99% for MMP-9 levels > or =140 ng/mL. When both biomarkers were at levels above the cutoff points, specificity increased to 87% and the positive predictive value increased to 41%. This prospective study confirmed the high sensitivity and negative predictive value, with retained good specificity, of c-Fn and MMP-9 for the prediction of PH in patients treated with t-PA. Development of faster analytic methods will prove the applicability of these biomarkers in routine clinical practice.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Dis Markers
                Journal ID (iso-abbrev): Dis. Markers
                Journal ID (publisher-id): DM
                Title: Disease Markers
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 0278-0240
                ISSN (Electronic): 1875-8630
                Publication date (Print): 2016
                Publication date (Electronic): 18 August 2016
                Volume: 2016
                Electronic Location Identifier: 3695454
                Affiliations
                1Jena University Hospital, Department of Internal Medicine I, 07747 Jena, Germany
                2Swiss Federal Institute of Technology, Department of Chemistry and Applied Biosciences, 8093 Zurich, Switzerland
                3Jena University Hospital, Department of Internal Medicine III, 07747 Jena, Germany
                4Medical Faculty, Division of Cardiology, Pulmonology, and Vascular Medicine, University of Duesseldorf, 40225 Duesseldorf, Germany
                5Jena University Hospital, Institute of Pathology, 07743 Jena, Germany
                Author notes

                Academic Editor: Dennis W. T. Nilsen

                Author information
                http://orcid.org/0000-0002-7341-6117
                http://orcid.org/0000-0001-7859-5444
                http://orcid.org/0000-0001-6543-4684
                Article
                DOI: 10.1155/2016/3695454
                PMC ID: 5007333
                PubMed ID: 27635109
                SO-VID: ba63905d-d3e7-40ac-a8eb-9c42230d0558
                Copyright © Copyright © 2016 Barbara Ziffels et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 9 April 2016
                Date accepted : 10 July 2016
                Funding
                Funded by: Seventh Framework Programme
                Award ID: F4-2012-305309
                Categories
                Subject: Research Article

                Data availability:

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