Abstract
Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality. We conducted a comprehensive study of plasma metabolites using ultraperformance liquid chromatography mass spectrometry to identify patients at high risk of early death, to identify patients who respond well to treatment, and to provide novel molecular insights into disease pathogenesis. Fifty-three circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy control subjects (n=121) after correction for multiple testing (P<7.3e-5) and confounding factors, including drug therapy, and renal and hepatic impairment. A subset of 20 of 53 metabolites also discriminated patients with PAH from disease control subjects (symptomatic patients without pulmonary hypertension, n=139). Sixty-two metabolites were prognostic in PAH, with 36 of 62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), tricarboxylic acid cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan, and polyamine metabolites and decreased levels of steroids, sphingomyelins, and phosphatidylcholines distinguished patients from control subjects. The largest differences correlated with increased risk of death, and correction of several metabolites over time was associated with a better outcome. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to those of healthy control subjects. Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterization of this disease. Our results support the investigation of targeted therapeutic strategies that seek to address the alterations in translational regulation and energy metabolism that characterize these patients.
Highlights
Pulmonary arterial hypertension (PAH) is a progressive vascular disorder that leads to increased pulmonary vascular resistance, right ventricular (RV) dysfunction 1 and premature death 2
Control plasma samples were obtained from healthy subjects and disease controls, the latter being symptomatic patients presenting to the service but in whom pulmonary hypertension was excluded by cardiac catheterisation
Changes in the levels of metabolites over time were associated with survival in a direction that suggests that correction of these disturbances is linked to improved outcomes
Summary
Pulmonary arterial hypertension (PAH) is a progressive vascular disorder that leads to increased pulmonary vascular resistance, right ventricular (RV) dysfunction 1 and premature death 2. A complementary approach to identifying the molecular drivers of PAH is to conduct deep molecular phenotyping of patients beyond standard clinical tests Metabolomic technologies, such as ultra-performance liquid chromatography mass spectrometry, enable the detection and semi-quantitative measurement of hundreds of unique metabolites, representing a broad range of metabolic pathways, in small volumes of biofluids 7. These approaches have identified differences in circulating metabolites that distinguish physiological and disease states, such as diabetes and systemic cardiovascular disorders, and predict clinical outcomes 8-10.
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