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Endothelial Dysfunction, Atherosclerosis, and Increase of von Willebrand Factor and Factor VIII: A Randomized Controlled Trial in Swine
Erasmus MC, Rotterdam, Netherlands.ORCID iD: 0000-0002-3769-9148
Erasmus MC, Rotterdam, Netherlands.ORCID iD: 0000-0001-7133-3046
Erasmus MC, Rotterdam, Netherlands.ORCID iD: 0000-0003-3713-4136
Halmstad University, School of Business, Innovation and Sustainability, The Rydberg Laboratory for Applied Sciences (RLAS).ORCID iD: 0000-0001-8608-4839
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2021 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, E-ISSN 2567-689X, Vol. 121, no 5, p. 676-686Article in journal (Refereed) Published
Abstract [en]

All rights reserved.It is well known that high von Willebrand factor (VWF) and factor VIII (FVIII) levels are associated with an increased risk of cardiovascular disease. It is still debated whether VWF and FVIII are biomarkers of endothelial dysfunction and atherosclerosis or whether they have a direct causative role. Therefore, we aimed to unravel the pathophysiological pathways of increased VWF and FVIII levels associated with cardiovascular risk factors. First, we performed a randomized controlled trial in 34 Göttingen miniswine. Diabetes mellitus (DM) was induced with streptozotocin and hypercholesterolemia (HC) via a high-fat diet in 18 swine (DM + HC), while 16 healthy swine served as controls. After 5 months of follow-up, FVIII activity (FVIII:C) was significantly higher in DM + HC swine (5.85 IU/mL [5.00-6.81]) compared with controls (4.57 [3.76-5.40], p = 0.010), whereas VWF antigen (VWF:Ag) was similar (respectively 0.34 IU/mL [0.28-0.39] vs. 0.34 [0.31-0.38], p = 0.644). DM + HC swine had no endothelial dysfunction or atherosclerosis during this short-term follow-up. Subsequently, we performed a long-term (15 months) longitudinal cohort study in 10 Landrace-Yorkshire swine, in five of which HC and in five combined DM + HC were induced. VWF:Ag was higher at 15 months compared with 9 months in HC (0.37 [0.32-0.42] vs. 0.27 [0.23-0.40], p = 0.042) and DM + HC (0.33 [0.32-0.37] vs. 0.25 [0.24-0.33], p = 0.042). Both long-term groups had endothelial dysfunction compared with controls and atherosclerosis after 15 months. In conclusion, short-term hyperglycemia and dyslipidemia increase FVIII, independent of VWF. Long-term DM and HC increase VWF via endothelial dysfunction and atherosclerosis. Therefore, VWF seems to be a biomarker for advanced cardiovascular disease. © 2021 Georg Thieme Verlag. 

Place, publisher, year, edition, pages
Stuttgart: Georg Thieme Verlag , 2021. Vol. 121, no 5, p. 676-686
Keywords [en]
atherosclerosis, cardiovascular disease, diabetes mellitus, endothelial dysfunction, swine, von Willebrand disease, von Willebrand factor
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:hh:diva-45822DOI: 10.1055/s-0040-1722185ISI: 000608146700001PubMedID: 33506473Scopus ID: 2-s2.0-85099602895OAI: oai:DiVA.org:hh-45822DiVA, id: diva2:1608225
Funder
EU, FP7, Seventh Framework Programme, MEDIA-261409
Note

Övriga finansiärer:

Dutch Heart FoundationCVON2014-11, CVON2016-ARENA-Prime 

European Commission FP7-Health-2010: MEDIA-261409

German Center for Cardiovascular Research  

Shire/Takeda  

CSL Behring

Deutsches Zentrum für Herz-Kreislaufforschung: DZHK81Z0600207, DZHK

Suomen Akatemia: 251272

Novo Nordisk

Sydäntutkimussäätiö

Available from: 2021-11-03 Created: 2021-11-03 Last updated: 2023-08-28Bibliographically approved

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Heinonen, Ilkka

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Atiq, FerdowsVan De Wouw, JensSorop, OanaHeinonen, IlkkaDe Maat, Moniek P. M.Merkus, DaphneDuncker, Dirk J.Leebeek, Frank W. G.
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