Plasma metabolomic profile in chronic thromboembolic pulmonary hypertension

Abstract

We aimed to characterize the plasma metabolome of chronic thromboembolic pulmonary hypertension patients using a high-throughput unbiased omics approach. We collected fasting plasma from a peripheral vein in 33 operable chronic thromboembolic pulmonary hypertension patients, 31 healthy controls, and 21 idiopathic pulmonary arterial hypertension patients matched for age, gender, and body mass index. Metabolomic analysis was performed using an untargeted approach (Metabolon Inc. Durham, NC). Of the total of 862 metabolites identified, 362 were different in chronic thromboembolic pulmonary hypertension compared to controls: 178 were higher and 184 were lower. Compared to idiopathic pulmonary arterial hypertension, 147 metabolites were different in chronic thromboembolic pulmonary hypertension: 45 were higher and 102 were lower. The plasma metabolome allowed us to distinguish subjects with chronic thromboembolic pulmonary hypertension and healthy controls with a predictive accuracy of 89%, and chronic thromboembolic pulmonary hypertension versus idiopathic pulmonary arterial hypertension with 80% accuracy. Compared to idiopathic pulmonary arterial hypertension and healthy controls, chronic thromboembolic pulmonary hypertension patients had higher fatty acids and glycerol; while acyl cholines and lysophospholipids were lower. Compared to healthy controls, both idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients had increased acyl carnitines, beta-hydroxybutyrate, amino sugars and modified amino acids and nucleosides. The plasma global metabolomic profile of chronic thromboembolic pulmonary hypertension suggests aberrant lipid metabolism characterized by increased lipolysis, fatty acid oxidation, and ketogenesis, concomitant with reduced acyl choline and phospholipid moieties. Future research should investigate the pathogenetic and therapeutic potential of modulating lipid metabolism in chronic thromboembolic pulmonary hypertension.

Keywords: chronic thromboembolic pulmonary hypertension; ketogenesis; lipolysis; metabolism.

Fig. 1.

Principle component analysis. CTEPH: chronic thromboembolic pulmonary hypertension; IPAH: idiopathic pulmonary arterial hypertension.

Fig. 2.

In CTEPH, the long-chain fatty acids, eicosenoate and dihomo-linoleate, are associated with cardiac index (a and b). Eicosenoate also correlates with total pulmonary resistance (c). The acyl choline oleoylcholine is associated with cardiac index (d). r are the Pearson correlation coefficients. p Values are from a multivariable linear regression model adjusting for age, gender, body mass index, statin use, thyroid replacement therapy, steroids, and diabetes drug therapy. CTEPH: chronic thromboembolic pulmonary hypertension; CI: cardiac index; TPR: total pulmonary resistance.

Fig. 3.

Plasma fatty acids measured by high-performance liquid chromatography (HPLC) Online Tandem Mass Spectrometry (LC/MS/MS). Data are box plots with median, 25th and 75th quartile (bottom and top of the box), and minimal and maximal distribution (whiskers). p Value from ANOVA. *p < .0001 for the CTEPH vs control comparison; ^#p < 0.01 for the CTEPH vs IPAH comparison; both from Tukey test for multiple comparisons adjustment. CTEPH: chronic thromboembolic pulmonary hypertension; IPAH: idiopathic pulmonary arterial hypertension.