Lewis Gregory D, Ngo Debby, Hemnes Anna R, Farrell Laurie, Domos Carly, Pappagianopoulos Paul P, Dhakal Bishnu P, Souza Amanda, Shi Xu, Pugh Meredith E, Beloiartsev Arkadi, Sinha Sumita, Clish Clary B, Gerszten Robert E
Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
J Am Coll Cardiol. 2016 Jan 19;67(2):174-189. doi: 10.1016/j.jacc.2015.10.072.
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.
肺动脉高压及相关右心室（RV）功能障碍是发病率和死亡率的重要决定因素，通过有创血流动力学测量能对其进行最佳特征描述。
本研究旨在确定代谢物谱分析是否能识别右心室 - 肺血管（RV - PV）功能障碍的血浆特征。
我们使用靶向质谱法测量了71名个体（发现队列）血浆中105种代谢物的浓度，这些个体在静息和运动时接受了包括右侧心导管检查和放射性核素心室造影的全面生理评估。我们的研究结果在另一组接受有创血流动力学评估的队列（n = 71）以及一组有或无已知肺动脉（PA）高压的独立队列（n = 30）中得到验证。
在发现队列中，21种代谢物与RV - PV功能的2个或更多血流动力学指标相关（即静息右心房压力、平均肺动脉压力、肺血管阻力[PVR]以及运动时的PVR和肺动脉压力 - 流量反应[ΔPQ]）。我们发现RV - PV功能障碍与循环中吲哚胺2,3 - 双加氧酶（IDO）依赖性色氨酸代谢物（TMs）、三羧酸中间体和嘌呤代谢物之间存在新的关联，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 - TMs水平与RV射血分数呈负相关，并且与运动时的PVR和ΔPQ特别相关。多部位采样显示IDO - TMs的经肺释放。IDO - TMs还在具有已知肺动脉高压危险因素的验证队列以及已确诊PA高压的患者中识别出RV - PV功能障碍。
代谢物谱分析确定了RV - PV功能障碍的可重复特征，突出了新的生物标志物和进一步功能特征描述的途径。
