BackgroundGastrointestinal bleeding from angiodysplasia is a major problem in continuous-flow left ventricular assist device (LVAD) patients. LVAD shear stress causes pathologic degradation of VWF (von Willebrand factor). A mechanistic relationship between VWF degradation and angiodysplasia has not been explored. We tested 2 novel hypotheses: (1) clinical hypothesis: VWF fragments are elevated in LVAD patients that develop angiodysplasia and (2) in vitro hypothesis: VWF fragments generated during LVAD support alter angiogenesis, which may contribute to angiodysplasia.Methods and ResultsClinical study: Paired blood samples were collected from continuous-flow LVAD patients (n=35). VWF was quantified with immunoblotting. In vitro experiments: (1) To investigate whether LVAD support alters angiogenesis, human endothelial cells were cultured with LVAD patient plasma (n=11). To investigate mechanism, endothelial cells were cultured with VWF fragments produced by exposing human VWF and ADAMTS-13 (VWF protease) to LVAD-like shear stress (175 dyne/cm², n=8). Clinical study results: in all patients (n=35, mean support 666±430 days), LVAD support degraded high-molecular-weight VWF multimers (P<0.0001) into low-molecular-weight VWF multimers (P<0.0001) and VWF fragments (P<0.0001). In patients with gastrointestinal bleeding from angiodysplasia (n=7), VWF fragments were elevated (P=0.02) versus nonbleeders. In contrast, in patients with gastrointestinal bleeding without angiodysplasia, VWF fragments were not elevated versus nonbleeders (P=0.96). In vitro experiments results: LVAD patient plasma caused abnormal angiogenesis with reduced tubule length (P=0.04) and migration (P=0.05). Similarly, endothelial cells grown with VWF degradation fragments exhibited reduced tubule length (P<0.001) and migration (P=0.01).ConclusionsLVAD patients who bled from angiodysplasia had higher levels of VWF fragments than nonbleeders and gastrointestinal bleeders without angiodysplasia. VWF fragments caused abnormal angiogenesis in vitro. These findings suggest that VWF fragments may be a mechanistic link between LVAD support, abnormal angiogenesis, angiodysplasia, and gastrointestinal bleeding.

中文翻译：

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左心室辅助装置引起的von Willebrand因子降解改变血管生成的临床和体外证据

背景血管增生引起的胃肠道出血是连续流左心室辅助装置（LVAD）患者的主要问题。LVAD剪切应力导致VWF（von Willebrand因子）的病理降解。尚未探讨VWF降解与血管增生之间的机制关系。我们测试了2个新的假设：（1）临床假设：LVAD发生血管增生的患者中VWF片段升高，（2）体外假设：LVAD期间产生的VWF片段支持改变血管生成，这可能有助于血管增生。方法和结果临床研究：从连续流LVAD患者（n = 35）中收集配对的血液样本。用免疫印迹定量VWF。体外实验：（1）研究LVAD的支持是否会改变血管生成，将人内皮细胞与LVAD患者血浆（n = 11）一起培养。为了研究机制，将内皮细胞与通过将人VWF和ADAMTS-13（VWF蛋白酶）暴露于LVAD样剪切应力（175达因/厘米）而产生的VWF片段一起培养²，n ＝ 8）。临床研究结果：在所有患者中（n = 35，平均支持666±430天），LVAD支持将高分子量VWF多聚体（P <0.0001）降解为低分子量VWF多聚体（P <0.0001）和VWF碎片（P <0.0001）。在患有血管增生引起的胃肠道出血的患者中（n = 7），与无出血者相比，VWF片段升高（P = 0.02）。相反，在没有血管增生的胃肠道出血患者中，VWF片段与无出血者相比没有升高（P = 0.96）。体外实验结果：LVAD患者血浆引起异常的血管生成，肾小管长度减少（P = 0.04）和迁移减少（P= 0.05）。同样，生长有VWF降解片段的内皮细胞的肾小管长度减少（P <0.001）和迁移减少（P = 0.01）。VWF片段在体外引起异常的血管生成。这些发现表明，VWF片段可能是LVAD支持，异常血管生成，血管增生和胃肠道出血之间的机制联系。