Metabolomic Signatures Associated With Pulmonary Arterial Hypertension Outcomes

Abstract

Background: Pulmonary arterial hypertension (PAH) is a complex disease characterized by progressive right ventricular (RV) failure leading to significant morbidity and mortality. Investigating metabolic features and pathways associated with RV dilation, mortality, and measures of disease severity can provide insight into molecular mechanisms, identify subphenotypes, and suggest potential therapeutic targets. Methods: We collected data from a prospective cohort of PAH participants and performed untargeted metabolomic profiling on 1045 metabolites from circulating blood. Analyses were intended to identify metabolomic differences across a range of common metrics in PAH (eg, dilated versus nondilated RV). Partial least squares discriminant analysis was first applied to assess the distinguishability of relevant outcomes. Significantly altered metabolites were then identified using linear regression, and Cox regression models (as appropriate for the specific outcome) with adjustments for age, sex, body mass index, and PAH cause. Models exploring RV maladaptation were further adjusted for pulmonary vascular resistance. Pathway enrichment analysis was performed to identify significantly dysregulated processes. Results: A total of 117 participants with PAH were included. Partial least squares discriminant analysis showed cluster differentiation between participants with dilated versus nondilated RVs, survivors versus nonsurvivors, and across a range of NT-proBNP (N-terminal probrain natriuretic peptide) levels, REVEAL 2.0 composite scores, and 6-minute-walk distances. Polyamine and histidine pathways were associated with differences in RV dilation, mortality, NT-proBNP, REVEAL score, and 6-minute walk distance. Acylcarnitine pathways were associated with NT-proBNP, REVEAL score, and 6-minute walk distance. Sphingomyelin pathways were associated with RV dilation and NT-proBNP after adjustment for pulmonary vascular resistance. Conclusions: Distinct plasma metabolomic profiles are associated with RV dilation, mortality, and measures of disease severity in PAH. Polyamine, histidine, and sphingomyelin metabolic pathways represent promising candidates for identifying patients at high risk for poor outcomes and investigation into their roles as markers or mediators of disease progression and RV adaptation.

Altered adolescents obesity metabolism is associated with hypertension: a UPLC-MS-based untargeted metabolomics study

“…The lipid profile of obesity identified in this study has previously been found to predict the development of hypertension risk, diabetes, and insulin resistance (53)(54)(55). Consistent with prior studies, our findings demonstrate that the OMS constructed from obesity-based differential metabolites, three of which were welldistributed in the lipid metabolism (thymidine, SM d40:1, Llysinamide), was strongly correlated with developing hypertension risk and positively correlated with systolic blood pressure, but it did not demonstrate a similar relationship with diastolic blood pressure, which was also an interesting finding.…”

Lipidomics for diagnosis and prognosis of pulmonary hypertension

“…Spanning over two decades, extensive basic, translational, and clinical analyses have supported a causative link between metabolic reprogramming and PAH 28,29 . Similar to the Warburg effect in cancer, a shift from mitochondrial oxidation to glycolysis appears to occur in the right ventricle of PAH patients 22,23 .…”

Premorbid weight in pulmonary arterial hypertension

“…We included adult participants from a singleinstitution PAH cohort. 4 Participants provided informed consent and the University of Washington Institutional Review Board approved the study (#3387). Participants were diagnosed with PAH using the standard definition at the time of enrollment, had PAH diagnosed after age 20, and were followed for up to 3 years or until death.…”