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High Plasma Microfibrillar-Associated Protein 4 Is Associated with Reduced Surgical Repair in Abdominal Aortic Aneurysms

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High Plasma Microfibrillar-Associated Protein 4 Is Associated with Reduced Surgical Repair in Abdominal Aortic Aneurysms University of Southern Denmark High plasma microfibrillar-associated protein 4 is associated with reduced surgical repair in abdominal aortic aneurysms Lindholt, Jes Sanddal; Madsen, Mathilde; Kirketerp-Møller, Katrine Lindequist; Schlosser, Anders; Kristensen, Katrine Lawaetz; Andersen, Carsten Behr; Sorensen, Grith Lykke Published in: Journal of Vascular Surgery DOI: 10.1016/j.jvs.2019.08.253 Publication date: 2020 Document version: Final published version Document license: CC BY-NC-ND Citation for pulished version (APA): Lindholt, J. S., Madsen, M., Kirketerp-Møller, K. L., Schlosser, A., Kristensen, K. L., Andersen, C. B., & Sorensen, G. L. (2020). High plasma microfibrillar-associated protein 4 is associated with reduced surgical repair in abdominal aortic aneurysms. Journal of Vascular Surgery, 71(6), 1921-1929. https://doi.org/10.1016/j.jvs.2019.08.253 Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim. Please direct all enquiries to [email protected] Download date: 28. Sep. 2021 High plasma microfibrillar-associated protein 4 is associated with reduced surgical repair in abdominal aortic aneurysms Jes Sanddal Lindholt, PhD,a Mathilde Madsen, BSc,b Katrine Lindequist Kirketerp-Møller, PhD,b Anders Schlosser, PhD,b Katrine Lawaetz Kristensen, MD,c Carsten Behr Andersen, PhD,a and Grith Lykke Sorensen, PhD, DMSci,d,e Viborg and Odense, Denmark ABSTRACT Objective: Identifying biomarkers for abdominal aortic aneurysms (AAA) could prove beneficial in prognosis of AAA and thus the selection for treatment. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein that is highly expressed in aorta. MFAP4 is involved in several tissue remodeling-related diseases. We aimed to investigate the potential role of plasma MFAP4 (pMFAP4) as a biomarker of AAA. Methods: Plasma samples and data were obtained for 504 male AAA patients and 188 controls in the Viborg Vascular (VIVA) screening trial. The pMFAP4 levels were measured by Alphalisa. The Mann-Whitney U test assessed differences in pMFAP4 levels between the presence and absence of different exposures of interest. The correlation between pMFAP4 and aorta growth rate were investigated through spearman’s correlation analysis. Immunohistochemistry and multiple logistic regression adjusted for potential confounders assessed the association between pMFAP4 and AAA. Multiple linear regression assessed the correlation between pMFAP4 and aorta growth rate. Cox regression and competing risk regression were used to investigate the correlation between AAA patients with upper tertile pMFAP4 and the risk of undergoing later surgical repair. Results: A significant negative correlation between pMFAP4 and aorta growth rate was observed using spearman’s correlation analysis (r ¼0.14; P ¼ .0074). However, this finding did not reach significance when applying multiple linear regression. A tendency of decreased pMFAP4 was observed in AAA using immunohistochemistry. Competing risk regression adjusted for potential confounders indicated that patients with upper tertile pMFAP4 had a hazard ratio of 0.51 (P ¼ .001) for risk of undergoing later surgical repair. Conclusions: High levels of pMFAP4 are associated with a decreased likelihood of receiving surgical repair in AAA. This observation warrants confirmation in an independent cohort. (J Vasc Surg 2019;-:1-9.) Keywords: MFAP4; Abdominal aorta aneurysms; Surgical repair; Growth rate; Extracellular matrix An abdominal aortic aneurysm (AAA) is a severe cardio- prevalence of AAA is 3.3% in men ages 65 to 74, and vascular disease with a very high mortality rate. It is clin- 0.7% in woman ages 61 to 76.2,3 Patients rarely display ically defined as a permanent and localized dilation of symptoms before rupture, and once the aneurysm rup- the aorta of at least 50% of the normal vessel diameter tures the survival rate is only 10% to 15%.4 Diagnosis or being at least 3 cm in diameter.1 Population-based and prognosis currently depend on technologies such ultrasound screening for AAA has showed that the as ultrasound examination and computed tomography From the Cardiovascular Research Unit, Viborg Hospital, Viborga; the Cancer Author conflict of interest: A.S. and G.L.S. are inventors of U.S. Patent No. and Inflammation Research, Department of Molecular Medicine, University 9,988,442 and EP17199552.5 owned by University of Southern Denmark. of Southern Denmark, Odenseb; the Department of Cardiac, Thoracic, and Correspondence: Grith Lykke Sorensen, PhD, DMSci, Department of Molecular Vascular Surgery,c and Centre of Individualized Medicine in Arterial Diseases Medicine, Cancer and Inflammation Research, University of Southern (CIMA), Department of Cardiothoracic and Vascular Surgery,d Odense Univer- Denmark, J.B. Winsløws Vej 25, 3rd floor 5000, Odense, Denmark (e-mail: sity Hospital, Odense; and the Vascular Research Unit, Department of [email protected]). Vascular Surgery, Viborg Regional Hospital, Viborg.e The editors and reviewers of this article have no relevant financial relationships to Funded by the Danish Research Council, The Lundbeck Foundation, The Novo disclose per the JVS policy that requires reviewers to decline review of any Nordisk Foundation, Brødrene Hartmann Foundation, Augustinus Founda- manuscript for which they may have a conflict of interest. tion, The A.P. Møller Foundation for the Advancement of Medical Science, 0741-5214 Direktør Kurt Bønnelycke og Hustru fru Grethe Bønnelyckes Fond, The Maj- Copyright Ó 2019 The Authors. Published by Elsevier Inc. on behalf of the So- gaards Eftf. Fru Lily Benthine Lunds Fond af 1.6. 1978, Henry og Astrid Møllers ciety for Vascular Surgery. This is an open access article under the CC BY- Fond, Torben og Alice Frimodts Fond, Handelsgartner Ove William Buhl Ole- NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). sen og ægtefælle fru Edith Buhl Olesen Mindelegat, Bagermester August https://doi.org/10.1016/j.jvs.2019.08.253 Jensen og Hustrus Legat. The funding bodies had no roles in the design of the study and collection, analysis, interpretation of data or in writing the manuscript. 1 2 Lindholt et al Journal of Vascular Surgery --- 2019 scanning. Biomarkers could be helpful, particularly in the prognosis of AAA, including the need for preventive ARTICLE HIGHLIGHTS repair and rupture and in understanding the individual d Type of Research: Prospective case control study pathogenesis of AAA development. d Key Findings: In this study of 504 male abdominal The extracellular matrix (ECM) protein microfibrillar- aortic aneurysm (AAA) patients and 188 controls associated protein 4 (MFAP4) is highly expressed in hu- AAA patients with upper tertile plasma microfi- man elastic tissues and localized in elastic fibers in blood brillar-associated protein 4 (pMFAP4), 49% had vessels.5 MFAP4 binds to ECM fibers including collagen, reduced likelihood of receiving later surgical repair tropoelastin, and fibrillin, and it has been shown to pro- (subhazard ratio, 0.51; 95% confidence interval, 0.35- mote elastic fiber formation in vitro.6-10 This role was 0.76; P ¼ .001). partially supported by observations of pulmonary airspace d Take Home Message: AAA patients with the highest enlargement and elastic defects in MFAP4-deficient levels of pMFAP4 have significantly reduced risk of mice.11 Furthermore, MFAP4 has been shown to bind receiving later surgical repair. RGD-dependent integrins and induce smooth muscle cell proliferation and migration, and to promote mono- cyte chemotaxis.12 These effects might be part of the screening by three mobile teams at 14 venues. Enrolment mechanism by which MFAP4 is involved in several tissue started October 2008 and stopped in January 2011. Over- remodeling-related diseases including liver fibrosis, pul- all, 18,749 men attended the screening.24 Participants monary airspace enlargement, bronchial hyperplasia in with positive test results were offered secondary pro- allergic asthma, and arterial neointimal formation.11-14 phylaxis and/or referred to their general practitioner. A Circulating MFAP4 may reflect a spillover from vascular major registry-based follow-up report including AAA wall EMC turnover and has been suggested as a potential repair after 5 years was recently published.2 biomarker for chronic obstructive pulmonary disease, liver Diagnostic criterium for AAA was aortic diameter of fibrosis and cirrhosis, and peripheral artery disease.5,13,15-19 least 30 mm.24 AAA was diagnosed in 615 cases (3.3%; Several studies have supported that MFAP4 levels may 95% confidence interval [CI], 3.0-3.6).25 Cases with an be influenced by the presence of vascular aneurysms; AAA of greater than 50 mm were referred for vascular however, the regulation of the protein has shown inconsis- surgical evaluation, and those less than 50 mm were tency in these studies. Two studies, both including prote- invited annually to a control scan to check for expansion. omic analyses of human AAA tissue,
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