Abstract：
OBJECTIVE: Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), components of the vascular endothelial growth factor (VEGF) system, play key roles in angiogenesis. Reports of elevated plasma levels of sFlt-1 and PlGF in coronary heart disease and heart failure (HF) led us to investigate their utility, and VEGF system gene single nucleotide polymorphisms (SNPs), as prognostic biomarkers in HF.
RESULTS: ELISA assays for sFlt-1, PlGF and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were performed on baseline plasma samples from the PEOPLE cohort (n = 890), a study of outcomes among patients after an episode of acute decompensated HF. Eight SNPs potentially associated with sFlt-1 or PlGF levels were genotyped. sFlt-1 and PlGF were assayed in 201 subjects from the Canterbury Healthy Volunteers Study (CHVS) matched to PEOPLE participants. All-cause death was the major endpoint for clinical outcome considered. In PEOPLE participants, mean plasma levels for both sFlt-1 (125 ± 2.01 pg/ml) and PlGF (17.5 ± 0.21 pg/ml) were higher (both p < 0.044) than in the CHVS cohort (81.2 ± 1.31 pg/ml and 15.5 ± 0.32 pg/ml, respectively). sFlt-1 was higher in HF with reduced ejection fraction compared to HF with preserved ejection fraction (p = 0.005). The PGF gene SNP rs2268616 was univariately associated with death (p = 0.016), and was also associated with PlGF levels, as was rs2268614 genotype. Cox proportional hazards modelling (n = 695, 246 deaths) showed plasma sFlt-1, but not PlGF, predicted survival (hazard ratio 6.44, 95% confidence interval 2.57-16.1; p < 0.001) in PEOPLE, independent of age, NT-proBNP, ischaemic aetiology, diabetic status and beta-blocker therapy.
CONCLUSIONS: Plasma sFlt-1 concentrations have potential as an independent predictor of survival and may be complementary to established prognostic biomarkers in HF.
RESULTS: ELISA assays for sFlt-1, PlGF and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were performed on baseline plasma samples from the PEOPLE cohort (n = 890), a study of outcomes among patients after an episode of acute decompensated HF. Eight SNPs potentially associated with sFlt-1 or PlGF levels were genotyped. sFlt-1 and PlGF were assayed in 201 subjects from the Canterbury Healthy Volunteers Study (CHVS) matched to PEOPLE participants. All-cause death was the major endpoint for clinical outcome considered. In PEOPLE participants, mean plasma levels for both sFlt-1 (125 ± 2.01 pg/ml) and PlGF (17.5 ± 0.21 pg/ml) were higher (both p < 0.044) than in the CHVS cohort (81.2 ± 1.31 pg/ml and 15.5 ± 0.32 pg/ml, respectively). sFlt-1 was higher in HF with reduced ejection fraction compared to HF with preserved ejection fraction (p = 0.005). The PGF gene SNP rs2268616 was univariately associated with death (p = 0.016), and was also associated with PlGF levels, as was rs2268614 genotype. Cox proportional hazards modelling (n = 695, 246 deaths) showed plasma sFlt-1, but not PlGF, predicted survival (hazard ratio 6.44, 95% confidence interval 2.57-16.1; p < 0.001) in PEOPLE, independent of age, NT-proBNP, ischaemic aetiology, diabetic status and beta-blocker therapy.
CONCLUSIONS: Plasma sFlt-1 concentrations have potential as an independent predictor of survival and may be complementary to established prognostic biomarkers in HF.
摘要：
目的：可溶性fms样酪氨酸激酶-1（sFlt-1）和胎盘生长因子（PlGF），血管内皮生长因子（VEGF）系统的组成部分，在血管生成中起关键作用。关于sFlt-1和PlGF在冠心病和心力衰竭（HF）中血浆水平升高的报道使我们研究了它们的效用，和VEGF系统基因单核苷酸多态性（SNP），作为HF的预后生物标志物。
结果：对来自PEOPLE队列（n=890）的基线血浆样品进行sFlt-1，PlGF和N末端B型利钠肽前体（NT-proBNP）的ELISA测定，一项关于急性失代偿性HF发作后患者结局的研究.对可能与sFlt-1或PlGF水平相关的八个SNP进行基因分型。在来自与PEOPLE参与者匹配的坎特伯雷健康志愿者研究(CHVS)的201名受试者中测定sFlt-1和PlGF。全因死亡是临床结局的主要终点。在人们的参与者中，sFlt-1(125±2.01pg/ml)和PlGF(17.5±0.21pg/ml)的平均血浆水平高于CHVS组(81.2±1.31pg/ml和15.5±0.32pg/ml,分别)。与保留射血分数的HF相比，射血分数降低的HF的sFlt-1更高（p=0.005）。PGF基因SNPrs2268616与死亡单因素相关(p=0.016),也与PlGF水平有关，rs2268614基因型也是如此。Cox比例风险模型（n=695，246例死亡）显示血浆sFlt-1，而不是PlGF，预测生存率（风险比6.44，95%置信区间2.57-16.1；p<0.001），独立于年龄,NT-proBNP,缺血性病因，糖尿病状态和β受体阻滞剂治疗。
结论：血浆sFlt-1浓度有可能作为生存的独立预测因子，并且可能与已确定的HF预后生物标志物互补。
结果：对来自PEOPLE队列（n=890）的基线血浆样品进行sFlt-1，PlGF和N末端B型利钠肽前体（NT-proBNP）的ELISA测定，一项关于急性失代偿性HF发作后患者结局的研究.对可能与sFlt-1或PlGF水平相关的八个SNP进行基因分型。在来自与PEOPLE参与者匹配的坎特伯雷健康志愿者研究(CHVS)的201名受试者中测定sFlt-1和PlGF。全因死亡是临床结局的主要终点。在人们的参与者中，sFlt-1(125±2.01pg/ml)和PlGF(17.5±0.21pg/ml)的平均血浆水平高于CHVS组(81.2±1.31pg/ml和15.5±0.32pg/ml,分别)。与保留射血分数的HF相比，射血分数降低的HF的sFlt-1更高（p=0.005）。PGF基因SNPrs2268616与死亡单因素相关(p=0.016),也与PlGF水平有关，rs2268614基因型也是如此。Cox比例风险模型（n=695，246例死亡）显示血浆sFlt-1，而不是PlGF，预测生存率（风险比6.44，95%置信区间2.57-16.1；p<0.001），独立于年龄,NT-proBNP,缺血性病因，糖尿病状态和β受体阻滞剂治疗。
结论：血浆sFlt-1浓度有可能作为生存的独立预测因子，并且可能与已确定的HF预后生物标志物互补。
