背景:肺动脉高压(PAH)是一种复杂的疾病,其特征是进行性右心室(RV)衰竭,导致显着的发病率和死亡率。研究与RV扩张相关的代谢特征和途径,死亡率,疾病严重程度的测量可以提供对分子机制的洞察,确定亚型,并提出潜在的治疗靶点。
方法:我们从PAH参与者的前瞻性队列中收集数据,并对循环血液中的1045种代谢物进行非靶向代谢组学分析。分析旨在确定PAH中一系列常见指标的代谢组学差异(例如,扩张和非扩张右心室)。首先应用偏最小二乘判别分析来评估相关结果的可区分性。然后使用线性回归鉴定显著改变的代谢物,和Cox回归模型(适用于特定结果),并调整了年龄,性别,身体质量指数,和PAH原因。探索RV适应不良的模型进一步针对肺血管阻力进行了调整。进行途径富集分析以鉴定显著失调的过程。
结果:共纳入117名PAH患者。偏最小二乘判别分析显示,扩张型和非扩张型房车参与者之间存在聚类差异,幸存者与非幸存者,以及一系列的NT-proBNP(N-末端脑钠肽)水平,显示2.0综合分数,和6分钟步行距离。多胺和组氨酸通路与RV扩张的差异有关,死亡率,NT-proBNP,REVEAL得分,和6分钟的步行距离。酰基肉碱通路与NT-proBNP相关,REVEAL得分,和6分钟的步行距离。调整肺血管阻力后,鞘磷脂通路与RV扩张和NT-proBNP相关。
结论:不同的血浆代谢谱与RV扩张相关,死亡率,以及PAH疾病严重程度的测量。多胺,组氨酸,和鞘磷脂代谢途径代表了很有希望的候选者,可用于识别预后不良的高风险患者,并研究其作为疾病进展和RV适应的标志物或介质的作用.
Pulmonary arterial hypertension (PAH) is a complex disease characterized by progressive right ventricular (RV) failure leading to significant morbidity and mortality. Investigating metabolic features and pathways associated with RV dilation, mortality, and measures of disease severity can provide insight into molecular mechanisms, identify subphenotypes, and suggest potential therapeutic targets.
We collected data from a prospective cohort of PAH participants and performed untargeted metabolomic profiling on 1045 metabolites from circulating blood. Analyses were intended to identify metabolomic differences across a range of common metrics in PAH (eg, dilated versus nondilated RV). Partial least squares discriminant analysis was first applied to assess the distinguishability of relevant outcomes. Significantly altered metabolites were then identified using linear regression, and Cox regression models (as appropriate for the specific outcome) with adjustments for age, sex, body mass index, and PAH cause. Models exploring RV maladaptation were further adjusted for pulmonary vascular resistance. Pathway enrichment analysis was performed to identify significantly dysregulated processes.
A total of 117 participants with PAH were included. Partial least squares discriminant analysis showed cluster differentiation between participants with dilated versus nondilated RVs, survivors versus nonsurvivors, and across a range of NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, REVEAL 2.0 composite scores, and 6-minute-walk distances. Polyamine and histidine pathways were associated with differences in RV dilation, mortality, NT-proBNP, REVEAL score, and 6-minute walk distance. Acylcarnitine pathways were associated with NT-proBNP, REVEAL score, and 6-minute walk distance. Sphingomyelin pathways were associated with RV dilation and NT-proBNP after adjustment for pulmonary vascular resistance.
Distinct plasma metabolomic profiles are associated with RV dilation, mortality, and measures of disease severity in PAH. Polyamine, histidine, and sphingomyelin metabolic pathways represent promising candidates for identifying patients at high risk for poor outcomes and investigation into their roles as markers or mediators of disease progression and RV adaptation.