Department of Hematology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Thromb Haemost. 2021 May;121(5):676-686. doi: 10.1055/s-0040-1722185. Epub 2021 Jan 14.
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], = 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], = 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], = 0.042) and DM + HC (0.33 [0.32-0.37] vs. 0.25 [0.24-0.33], = 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.
众所周知，高血管性血友病因子 (VWF) 和因子 VIII (FVIII) 水平与心血管疾病风险增加有关。目前仍存在争议，即 VWF 和 FVIII 是内皮功能障碍和动脉粥样硬化的生物标志物，还是它们具有直接的因果关系。因此，我们旨在阐明与心血管危险因素相关的 VWF 和 FVIII 水平升高的病理生理途径。首先，我们在 34 头哥廷根小型猪中进行了一项随机对照试验。18 头猪（DM+HC）用链脲佐菌素诱导糖尿病（DM），并用高脂肪饮食诱导高胆固醇血症（HC），而 16 头健康猪作为对照。随访 5 个月后，DM+HC 猪的 FVIII 活性（FVIII:C）明显高于对照组（5.85 IU/mL [5.00-6.81] 与 4.57 [3.76-5.40]， = 0.010），而 VWF 抗原（VWF:Ag）相似（分别为 0.34 IU/mL [0.28-0.39] 与 0.34 [0.31-0.38]， = 0.644）。在这个短期随访期间，DM+HC 猪没有内皮功能障碍或动脉粥样硬化。随后，我们在 10 头长白-约克夏猪中进行了一项为期 15 个月的纵向队列研究，其中 5 头猪诱导 HC，5 头猪诱导 DM+HC。与 9 个月时相比，HC（0.37 [0.32-0.42] 与 0.27 [0.23-0.40]， = 0.042）和 DM+HC（0.33 [0.32-0.37] 与 0.25 [0.24-0.33]， = 0.042）猪的 VWF:Ag 在 15 个月时更高。与对照组相比，这两个长期组在 15 个月时都出现了内皮功能障碍，并且在 15 个月时出现了动脉粥样硬化。总之，短期高血糖和血脂异常会增加 FVIII，而与 VWF 无关。长期的 DM 和 HC 通过内皮功能障碍和动脉粥样硬化增加 VWF。因此，VWF 似乎是心血管疾病进展的生物标志物。
