Thromb Haemost 2021; 121(05): 676-686
DOI: 10.1055/s-0040-1722185
Atherosclerosis and Ischaemic Disease

Endothelial Dysfunction, Atherosclerosis, and Increase of von Willebrand Factor and Factor VIII: A Randomized Controlled Trial in Swine

Ferdows Atiq*
1  Department of Hematology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
,
2  Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
,
2  Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
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2  Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
3  Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland
4  Rydberg Laboratory of Applied Sciences, University of Halmstad, Halmstad, Sweden
,
1  Department of Hematology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
,
2  Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
5  Walter Brendel Center of Experimental Medicine (WBex), LMU Munich, Munich, Germany
6  German Center for Cardiovascular Research (DZHK), Partner Site Munich, Munich Heart Alliance (MHA), Munich, Germany
,
2  Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
,
1  Department of Hematology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
› Author Affiliations
Funding This study was supported by grants from the European Commission FP7-Health-2010 grant MEDIA-261409, the German Center for Cardiovascular Research (DZHK; 81Z0600207 to D.M.), the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation [CVON2014-11 (RECONNECT), CVON2016-ARENA-Prime], and the Academy of Finland 251272, Finnish Diabetes Research Foundation, and Finnish Foundation for Cardiovascular Research.

Abstract

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.

Authors' Contributions

F.A. and J.v.d.W. designed the study, collected the data, performed the statistical analysis, interpreted the data, and wrote the manuscript. O.S., I.H., M.P.M.d.M., D.M., D.J.D., and F.W.G.L. designed the study, collected the data, interpreted the data, and critically revised the manuscript. All authors gave their consent to the final version of the manuscript.


Data Sharing Statement

Original data can be obtained by sending an e-mail to the corresponding author ([email protected]).


* These authors contributed equally to this work.


Supplementary Material



Publication History

Received: 14 August 2020

Accepted: 09 November 2020

Publication Date:
14 January 2021 (online)

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