Instituto do Coração, Universidade de São Paulo, SP, Brasil.
Braz J Med Biol Res. 2011 Dec;44(12):1269-75. doi: 10.1590/s0100-879x2011007500149. Epub 2011 Nov 8.
Biomarkers have been identified for pulmonary arterial hypertension, but are less well defined for specific etiologies such as congenital heart disease-associated pulmonary arterial hypertension (CHDPAH). We measured plasma levels of eight microvascular dysfunction markers in CHDPAH, and tested for associations with survival. A cohort of 46 inoperable CHDPAH patients (age 15.0 to 60.2 years, median 33.5 years, female:male 29:17) was prospectively followed for 0.7 to 4.0 years (median 3.6 years). Plasma levels of von Willebrand factor antigen (VWF:Ag), tissue plasminogen activator (t-PA) and its inhibitor (PAI-1), P-selectin, reactive C-protein, tumor necrosis factor alpha, and interleukin-6 and -10 were measured at baseline, and at 30, 90, and 180 days in all subjects. Levels of six of the eight proteins were significantly increased in patients versus controls (13 to 106% increase, P < 0.003). Interleukin-10 level was 2.06 times normal (P = 0.0003; Th2 cytokine response). Increased levels of four proteins (t-PA, PAI-1, P-selectin, and interleukin-6) correlated with disease severity indices (P < 0.05). Seven patients died during follow-up. An average VWF:Ag (mean of four determinations) above the level corresponding to the 95th percentile of controls (139 U/dL) was independently associated with a high risk of death (hazard ratio = 6.56, 95%CI = 1.46 to 29.4, P = 0.014). Thus, in CHDPAH, microvascular dysfunction appears to involve Th2 inflammatory response. Of the biomarkers studied, plasma vWF:Ag was independently associated with survival.
生物标志物已被确定用于肺动脉高压，但对于特定病因（如先天性心脏病相关肺动脉高压 [CHDPAH]）的定义较少。我们测量了 CHDPAH 患者的 8 种微血管功能障碍标志物的血浆水平，并检测了与生存率的关联。对 46 名无法手术的 CHDPAH 患者（年龄 15.0 至 60.2 岁，中位数 33.5 岁，女性：男性 29:17）进行了前瞻性随访 0.7 至 4.0 年（中位数 3.6 年）。在所有患者中，基线时以及在第 30、90 和 180 天时测量了 von Willebrand 因子抗原（VWF:Ag）、组织型纤溶酶原激活物（t-PA）及其抑制剂（PAI-1）、P 选择素、反应性 C 蛋白、肿瘤坏死因子-α、白细胞介素-6 和 -10 的血浆水平。与对照组相比，患者的八种蛋白质中有六种水平显著升高（13%至 106%增加，P<0.003）。白细胞介素-10 水平为正常的 2.06 倍（P=0.0003；Th2 细胞因子反应）。四种蛋白质（t-PA、PAI-1、P 选择素和白细胞介素-6）水平升高与疾病严重程度指数相关（P<0.05）。在随访期间有 7 名患者死亡。平均 VWF:Ag（四次测定的平均值）高于对照组第 95 百分位数对应的水平（139 U/dL），与死亡风险高独立相关（危险比=6.56，95%CI=1.46 至 29.4，P=0.014）。因此，在 CHDPAH 中，微血管功能障碍似乎涉及 Th2 炎症反应。在所研究的生物标志物中，血浆 VWF:Ag 与生存率独立相关。
