Plasma metabolomics implicates modified transfer RNAs and altered bioenergetics in the outcomes of pulmonary arterial hypertension

CJ Rhodes, P Ghataorhe, J Wharton… - Circulation, 2017 - Am Heart Assoc
CJ Rhodes, P Ghataorhe, J Wharton, KC Rue-Albrecht, C Hadinnapola, G Watson, M Bleda
Circulation, 2017Am Heart Assoc
Background: Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high
mortality. Methods: 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. Results: Fifty-three circulating metabolites
distinguished well-phenotyped patients with idiopathic or heritable PAH (n= 365) from …
Background
Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality.
Methods
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.
Results
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.
Conclusions
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.
Am Heart Assoc