Abstract

Background

Beside the pulmonary vasoconstriction observed in pulmonary arterial hypertension (PAH), severe proliferative and antiapoptotic cellular phenotypes result in vascular remodelling. Many recent findings indicate similarities between PAH and tumour pathology. For instance, insulin-like growth factor (IGF)-1 signalling, which is known to promote tumour development, is implicated in PAH. Higher circulating IGF binding protein (IGFBP)-1 levels are associated with worse survival in PAH. The present study aimed to investigate the relationship between plasma levels of various tumour-related biomarkers and PAH. Methods: IGFBP-1, -2 and -7, along with other tumour-related biomarkers, were measured in plasma from 48 treatment-naïve PAH patients and 16 healthy controls, using proximity extension assays. Among the PAH patients, 33 were also studied at an early treatment follow-up. Results: Plasma IGFBP-1 (p < .003), IGFBP-2 (p < .001), IGFBP-7 (p < .008), vimentin (p < .001), carbonic anhydrase 9 (p < .001), S100A11 (p < .001), human epididymis protein 4 (p < .001) and folate receptor-α (p < .004) were elevated in PAH, compared to controls. IGFBP-1 exhibited the most interesting correlations to clinical parameters and was selected for further analyses. IGFBP-1 correlated specifically to N-terminal prohormone of brain natriuretic peptide (NT-proBNP) (r = 0.44, p < .002), mean right atrial pressure (r = 0.41, p < .004), venous oxygen saturation (r = –0.43, p < .003), cardiac index (r = –0.32, p < .03) and 6-minute walking distance (r = –0.29, p < .05). Plasma IGFBP-1 also correlated to risk scores based on the European Society of Cardiology/European Respiratory Society (ESC/ERS) PAH guidelines (r = 0.43, p < .003) and the REVEAL model (r = 0.46, p < .001). PAH patients with supra-median baseline IGFBP-1 levels showed a trend for worse overall survival than those with infra-median levels (p = .087). IGFBP-1 was unaltered between baseline and an early treatment follow-up. However, IGFBP-1 changes, between baseline and follow-up, correlated to changes in NT-proBNP (r = 0.48, p < .006). Conclusion: Plasma IGFBP-1 levels at PAH diagnosis show moderate association to NT-proBNP and hemodynamics as well as with ESC/ERS and REVEAL risk scores.

中文翻译：

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肺动脉高压中的血浆胰岛素样生长因子结合蛋白1

摘要

背景

除了在肺动脉高压 (PAH) 中观察到的肺血管收缩外，严重的增殖和抗凋亡细胞表型会导致血管重塑。最近的许多发现表明 PAH 和肿瘤病理学之间存在相似性。例如，已知可促进肿瘤发展的胰岛素样生长因子 (IGF)-1 信号传导与 PAH 相关。较高的循环 IGF 结合蛋白 (IGFBP)-1 水平与 PAH 中较差的存活率相关。本研究旨在调查各种肿瘤相关生物标志物的血浆水平与 PAH 之间的关系。方法：IGFBP-1、-2 和 -7 以及其他与肿瘤相关的生物标志物，在来自 48 名未接受过治疗的 PAH 患者和 16 名健康对照者的血浆中使用邻近扩展分析进行测量。在 PAH 患者中，33 名也在早期治疗随访中接受了研究。结果：血浆 IGFBP-1 ( p  < .003)、IGFBP-2 ( p  < .001)、IGFBP-7 ( p  < .008)、波形蛋白 ( p  < .001)、碳酸酐酶 9 ( p  < .001) , S100A11 ( p  < .001)、人附睾蛋白 4 ( p  < .001) 和叶酸受体-α ( p < .004) 在 PAH 中升高，与对照相比。IGFBP-1 表现出与临床参数最有趣的相关性，并被选中进行进一步分析。IGFBP-1 与脑钠肽 N 末端激素原 (NT-proBNP) 特异性相关 ( r  = 0.44, p  < .002)、平均右心房压 ( r  = 0.41, p  < .004)、静脉血氧饱和度 ( r)  = –0.43, p  < .003)、心脏指数 ( r  = –0.32, p  < .03) 和 6 分钟步行距离 ( r  = –0.29, p < .05）。根据欧洲心脏病学会/欧洲呼吸学会 (ESC/ERS) PAH 指南 ( r  = 0.43, p  < .003) 和 REVEAL 模型 ( r  = 0.46, p  < .001 )，血浆 IGFBP-1 还与风险评分相关）。基线 IGFBP-1 水平高于中位数的 PAH 患者的总体生存率低于中位数以下的 PAH 患者 ( p  = .087)。IGFBP-1 在基线和早期治疗随访之间没有改变。然而，IGFBP-1 在基线和随访之间的变化与 NT-proBNP 的变化相关（r  = 0.48，p  < .006）。结论： PAH 诊断时的血浆 IGFBP-1 水平显示与 NT-proBNP 和血流动力学以及 ESC/ERS 和 REVEAL 风险评分中度相关。