Research Centre, Montreal Heart Institute, Montreal, Canada.
Department of Medicine, Montreal Heart Institute, Montreal, Canada.
Thromb Haemost. 2018 Feb;118(2):288-297. doi: 10.1160/TH17-10-0729. Epub 2018 Jan 29.
Infusions of apolipoprotein A-I (apoA-I), the major protein component of high-density lipoproteins (HDL), result in aortic valve stenosis (AVS) regression in experimental models. Severe AVS can be complicated by acquired von Willebrand syndrome, a haemorrhagic disorder associated with loss of high-molecular-weight von Willebrand factor (vWF) multimers (HMWM), the latter being a consequence of increased shear stress and enhanced vWF-cleaving protease (ADAMTS-13) activity. Although antithrombotic actions of HDL have been described, its effects on ADAMTS-13 and vWF in AVS are unknown.
We assessed ADAMTS-13 activity in plasma derived from a rabbit model of AVS ( = 29) as well as in plasma collected from 64 patients with severe AVS (age 65.0 ± 10.4 years, 44 males) undergoing aortic valve replacement (AVR). In both human and rabbit AVS plasma, ADAMTS-13 activity was higher than that in controls ( < 0.05). Accordingly, AVS patients had less HMWM than controls (66.3 ± 27.2% vs. 97.2 ± 24.1%, < 0.0001). Both ADAMTS-13 activity and HMWM correlated significantly with aortic transvalvular gradients, thereby showing opposing correlations ( = 0.3, = 0.018 and = -0.4, = 0.003, respectively). Administration of an apoA-I mimetic peptide reduced ADAMTS-13 activity in AVS rabbits as compared with the placebo group (2.0 ± 0.5 RFU/sec vs. 3.8 ± 0.4 RFU/sec, < 0.05). Similarly, a negative correlation was found between ADAMTS-13 activity and HDL cholesterol levels in patients with AVS ( = -0.3, = 0.045).
Our data indicate that HDL levels are associated with reduced ADAMTS-13 activity and increased HMWM. HDL-based therapies may reduce the haematologic abnormalities of the acquired von Willebrand syndrome in AVS.
载脂蛋白 A-I（apoA-I）是高密度脂蛋白（HDL）的主要蛋白成分，在实验模型中可导致主动脉瓣狭窄（AVS）的消退。严重的 AVS 可并发获得性血管性血友病（von Willebrand 综合征），这是一种与高分子量 von Willebrand 因子（vWF）多聚体（HMWM）丢失相关的出血性疾病，后者是由于剪切力增加和 vWF 切割蛋白酶（ADAMTS-13）活性增强所致。尽管已描述了 HDL 的抗血栓作用，但它在 AVS 中的 ADAMTS-13 和 vWF 中的作用尚不清楚。
我们评估了来自 AVS 兔模型的血浆（ = 29）和 64 名接受主动脉瓣置换术（AVR）的严重 AVS 患者（年龄 65.0 ± 10.4 岁，44 名男性）的血浆中 ADAMTS-13 活性。在人和兔 AVS 血浆中，ADAMTS-13 活性均高于对照组（ < 0.05）。因此，与对照组相比，AVS 患者的 HMWM 较少（66.3 ± 27.2%比 97.2 ± 24.1%， < 0.0001）。ADAMTS-13 活性和 HMWM 与主动脉瓣跨瓣梯度均呈显著相关性，呈相反相关性（ = 0.3， = 0.018 和 = -0.4， = 0.003）。与安慰剂组相比，apoA-I 模拟肽给药后 AVS 兔的 ADAMTS-13 活性降低（2.0 ± 0.5 RFU/sec 比 3.8 ± 0.4 RFU/sec， < 0.05）。同样，在 AVS 患者中，ADAMTS-13 活性与 HDL 胆固醇水平之间存在负相关（ = -0.3， = 0.045）。
我们的数据表明，HDL 水平与 ADAMTS-13 活性降低和 HMWM 增加有关。基于 HDL 的治疗方法可能会减少 AVS 中获得性血管性血友病的血液学异常。
