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

Ferdows Atiq; Jens van de Wouw; Oana Sorop; Ilkka Heinonen; Moniek P. M. de Maat; Daphne Merkus; Dirk J. Duncker; Frank W. G. Leebeek

doi:10.1055/s-0040-1722185

Thrombosis and Haemostasis, Inhaltsverzeichnis

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 ‡^*

¹Department of Hematology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands

,

Jens van de Wouw ‡^*

²Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands

,

Oana Sorop

²Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands

,

Ilkka Heinonen

²Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands

³Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland

⁴Rydberg Laboratory of Applied Sciences, University of Halmstad, Halmstad, Sweden

,

Moniek P. M. de Maat

¹Department of Hematology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands

,

Daphne Merkus

²Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands

⁵Walter Brendel Center of Experimental Medicine (WBex), LMU Munich, Munich, Germany

⁶German Center for Cardiovascular Research (DZHK), Partner Site Munich, Munich Heart Alliance (MHA), Munich, Germany

,

Dirk J. Duncker

²Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands

,

Frank W. G. Leebeek

¹Department of Hematology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands

› Institutsangaben

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.

Keywords

von Willebrand factor - von Willebrand disease - diabetes mellitus - endothelial dysfunction - atherosclerosis - cardiovascular disease - swine

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Referenzen

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