肿瘤坏死因子-α水平与连续流左心室辅助装置的非手术性出血。
Tumor necrosis factor-α levels and non-surgical bleeding in continuous-flow left ventricular assist devices.
机构信息
Section of Cardiology, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Section of Cardiology, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
出版信息
J Heart Lung Transplant. 2018 Jan;37(1):107-115. doi: 10.1016/j.healun.2017.06.001. Epub 2017 Jun 8.
BACKGROUND
Non-surgical bleeding (NSB) due to angiodysplasia is common in left ventricular assist device (LVAD) patients. Thrombin-induced angiopoietin-2 (Ang-2) expression in LVAD patients leads to altered angiogenesis and is associated with lower angiopoietin-1 (Ang-1) and increased NSB. However, the mechanism for decreased Ang-1, made by pericytes, is unknown and the origin of thrombin in LVAD patients is unclear. We hypothesized that high tumor necrosis factor-α (TNF-α) levels in LVAD patients induce pericyte apoptosis, tissue factor (TF) expression and vascular instability.
METHODS
We incubated cultured pericytes with serum from patients with heart failure (HF), LVAD or orthotopic heart transplantation (OHT), with or without TNF-α blockade. We performed several measurements: Ang-1 expression was assessed by reverse transcript-polymerase chain reaction (RT-PCR) and pericyte death fluorescently; TF expression was assessed by RT-PCR in cultured endothelial cells incubated with patient plasma with or without TNF-α blockade; and TF expression was assessed in endothelial biopsy samples from these patients by immunofluorescence. We incubated cultured endothelial cells on Matrigel with patient serum with or without TNF-α blockade and determined tube formation by microscopy.
RESULTS
Serum from LVAD patients had higher levels of TNF-α, suppressed Ang-1 expression in pericytes, and induced pericyte death, and there was accelerated endothelial tube formation compared with serum from patients without LVADs. TF was higher in both plasma and endothelial cells from LVAD patients, and plasma from LVAD patients induced more endothelial TF expression. All of these effects were reversed or reduced with TNF-α blockade. High levels of TNF-α were associated with increased risk of NSB.
CONCLUSIONS
Elevated TNF-α in LVAD patients is a central regulator of altered angiogenesis, pericyte apoptosis and expression of TF and Ang-1.
背景
左心室辅助装置（LVAD）患者常发生非外科性出血（NSB），这是由于 LVAD 患者中的凝血酶诱导血管生成素-2（Ang-2）表达导致血管生成改变，并与血管生成素-1（Ang-1）降低和 NSB 增加有关。然而，周细胞产生的 Ang-1 减少的机制尚不清楚，LVAD 患者中的凝血酶来源也不清楚。我们假设 LVAD 患者中高水平的肿瘤坏死因子-α（TNF-α）诱导周细胞凋亡、组织因子（TF）表达和血管不稳定。
方法
我们用心力衰竭（HF）、LVAD 或原位心脏移植（OHT）患者的血清培养周细胞，并用或不用 TNF-α 阻断剂处理。我们进行了几项测量：通过逆转录聚合酶链反应（RT-PCR）评估 Ang-1 表达，并用荧光标记评估周细胞死亡；用 RT-PCR 评估培养的内皮细胞中 TF 表达，这些内皮细胞用含有或不含 TNF-α 阻断剂的患者血浆孵育；并用免疫荧光法评估这些患者的内皮活检样本中的 TF 表达。我们用含有或不含 TNF-α 阻断剂的患者血清培养培养的内皮细胞，并用显微镜评估管形成。
结果
LVAD 患者的血清中 TNF-α 水平较高，抑制了周细胞中 Ang-1 的表达，并诱导了周细胞死亡，与没有 LVAD 的患者的血清相比，内皮细胞管形成速度加快。LVAD 患者的血浆和内皮细胞中的 TF 均较高，LVAD 患者的血浆诱导更多的内皮 TF 表达。所有这些作用均被 TNF-α 阻断剂逆转或减少。TNF-α 水平升高与 NSB 风险增加有关。
结论
LVAD 患者中 TNF-α 水平升高是血管生成改变、周细胞凋亡以及 TF 和 Ang-1 表达的核心调节剂。
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