Metabolic Profiling of Right Ventricular-Pulmonary Vascular Function Reveals Circulating Biomarkers of Pulmonary Hypertension.
Metabolic Profiling of Right Ventricular-Pulmonary Vascular Function Reveals Circulating Biomarkers of Pulmonary Hypertension.
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DOI：
10.1016/j.jacc.2015.10.072
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发表时间：
2016-01-19
影响因子：
24
通讯作者：
Gerszten RE
中科院分区：
文献类型：
--
作者：
Lewis GD;Ngo D;Hemnes AR;Farrell L;Domos C;Pappagianopoulos PP;Dhakal BP;Souza A;Shi X;Pugh ME;Beloiartsev A;Sinha S;Clish CB;Gerszten RE
肺动脉高压和相关的右室(RV)功能障碍是发病率和死亡率的重要决定因素，有创性血流动力学测量是其最佳特征。这项研究试图确定代谢物图谱是否可以识别右室-肺血管(RV-PV)功能障碍的血浆特征。我们用靶向质谱仪测定了71名受试者(发现队列)的105种代谢物的血浆浓度，这些受试者在休息和运动时接受了右心导管术和核素心脏造影术的全面生理评估。我们的发现在接受侵入性血流动力学评估的第二个队列(n=71)以及在有或没有已知的肺动脉(PA)高血压的独立队列(n=30)中得到了验证。在发现的队列中，21种代谢产物与RV-PV功能的两个或两个以上血流动力学指标(即运动时的静息右心房压、平均PA压、肺血管阻力以及PVR和PA压力-流量反应[ΔPQ])相关。我们确定了RV-PV功能障碍与循环吲哚胺2，3-双加氧酶(IDO)依赖的色氨酸代谢物(TMS)、三羧酸中间体和嘌呤代谢物的新关联，并证实了先前描述的与精氨酸-一氧化氮代谢途径成分的关联。IDO-TM水平与右室射血分数呈负相关，与运动PVR和ΔPQ呈显著正相关。多点采样显示IDO-TMS经肺释放。IDO-TMS还在一项确认队列中发现了RV-PV功能障碍，该队列中存在已知的肺动脉高压危险因素和已确定的PA高血压患者。代谢谱确定了RV-PV功能障碍的可重复特征，突出了新的生物标记物和进一步功能表征的途径。
Pulmonary hypertension and associated right ventricular (RV) dysfunction are important determinants of morbidity and mortality, which are optimally characterized by invasive hemodynamic measurements. This study sought to determine whether metabolite profiling could identify plasma signatures of right ventricular-pulmonary vascular (RV-PV) dysfunction. We measured plasma concentrations of 105 metabolites using targeted mass spectrometry in 71 individuals (discovery cohort) who underwent comprehensive physiological assessment with right-sided heart catheterization and radionuclide ventriculography at rest and during exercise. Our findings were validated in a second cohort undergoing invasive hemodynamic evaluations (n = 71), as well as in an independent cohort with or without known pulmonary arterial (PA) hypertension (n = 30). In the discovery cohort, 21 metabolites were associated with 2 or more hemodynamic indicators of RV-PV function (i.e., resting right atrial pressure, mean PA pressure, pulmonary vascular resistance [PVR], and PVR and PA pressure-flow response [ΔPQ] during exercise). We identified novel associations of RV-PV dysfunction with circulating indoleamine 2,3-dioxygenase (IDO)–dependent tryptophan metabolites (TMs), tricarboxylic acid intermediates, and purine metabolites and confirmed previously described associations with arginine–nitric oxide metabolic pathway constituents. IDO-TM levels were inversely related to RV ejection fraction and were particularly well correlated with exercise PVR and ΔPQ. Multisite sampling demonstrated transpulmonary release of IDO-TMs. IDO-TMs also identified RV-PV dysfunction in a validation cohort with known risk factors for pulmonary hypertension and in patients with established PA hypertension. Metabolic profiling identified reproducible signatures of RV-PV dysfunction, highlighting both new biomarkers and pathways for further functional characterization.