NHLBI-CMREF Workshop Report on Pulmonary Vascular Disease Classification

Oldham, William M.; Hemnes, Anna R.; Aldred, Micheala A.; Barnard, John; Brittain, Evan L.; Chan, Stephen Y.; Cheng, Feixiong; Cho, Michael H.; Desai, Ankit A.; Garcia, Joe G.N.; Geraci, Mark W.; Ghiassian, Susan Dina; Hall, Kathryn T.; Horn, Evelyn M.; Jain, Mohit; Kelly, Rachel S.; Leopold, Jane A.; Lindström, Sara; Modena, Brian D.; Nichols, William C.; Rhodes, Christopher J.; Sun, Wei; Sweatt, Andrew J.; Vanderpool, Rebecca; Wilkins, Martin R.; Wilmot, Beth; Zamanian, Roham T.; Fessel, Joshua P.; Aggarwal, Neil R.; Loscalzo, Joseph; Xiao, Lei

doi:10.1016/j.jacc.2021.02.056

Cited by 14 publications

(10 citation statements)

References 72 publications

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“…Here, we used network medicine to integrate various big data elements (i.e., metabolic pathways, transcriptomics, and protein-protein interactions) for experimental validation. In doing so, this work achieves a scientific benchmark ( 43 ) in which interconnecting omics optimize the specificity and rigor of outputs ( 44 , 45 ). Since an overarching objective of this study was to ignore a priori assumptions regarding potential links between specific aa and PAH, a strategy such as network medicine that could reduce the initial data set according to functionally relevant pathways was essential.…”

Section: Discussionmentioning

confidence: 99%

Proline and glucose metabolic reprogramming supports vascular endothelial and medial biomass in pulmonary arterial hypertension

Wertheim¹,

Wang²,

Guillermier³

et al. 2023

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In pulmonary arterial hypertension (PAH), inflammation promotes a fibroproliferative pulmonary vasculopathy. Reductionist studies emphasizing single biochemical reactions suggest a shift toward glycolytic metabolism in PAH; however, key questions remain regarding the metabolic profile of specific cell types within PAH vascular lesions in vivo. We used RNA-seq to profile the transcriptome of pulmonary artery endothelial cells (PAECs) freshly isolated from an inflammatory vascular injury model of PAH ex vivo, and these data were integrated with information from human gene ontology pathways. Network medicine was then used to map all amino acid and glucose pathways to the consolidated human interactome, which includes data on 233,957 physical protein-protein interactions. Glucose and proline pathways were significantly close to the human PAH disease module, suggesting that these pathways are functionally relevant to PAH pathobiology. To test this observation in vivo, we used multi-isotope imaging mass spectrometry (MIMS) to map and quantify utilization of glucose and proline in the PAH pulmonary vasculature at subcellular resolution. Our findings suggest that elevated glucose and proline avidity underlies increased biomass in PAECs and the media of fibrosed PAH pulmonary arterioles. Overall, these data show that anabolic utilization of glucose and proline are fundamental to the vascular pathology of PAH.

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Section: Discussionmentioning

confidence: 99%

Proline and glucose metabolic reprogramming supports vascular endothelial and medial biomass in pulmonary arterial hypertension

Wertheim¹,

Wang²,

Guillermier³

et al. 2023

JCI Insight

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“…This approach has proven successful in the OPTICS study [ 88 ] or DETECT study [ 89 ] to exclude iPAH, and in the European Respiratory Society (ERS)/European Respiratory Journal (ERJ) risk criteria and the REVEAL risk stratification [ 90 ] to predict outcome in PAH. A third approach may involve unbiased collection of large data sets, including proteomics, transcriptomics and metabolomics, which measure multiple diagnostic biomarkers representative for multiple disease domains in PAH [ 91 ]. A PAH-like signature can be used to distinguish iPAH from other diseases.…”

Section: Discussionmentioning

confidence: 99%

A systematic review with meta-analysis of biomarkers for detection of pulmonary arterial hypertension

et al. 2022

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RationaleThe blood is a rich source of potential biomarkers for the diagnosis of idiopathic and hereditary pulmonary arterial hypertension (iPAH and hPAH, referred to as “PAH”). While a lot of biomarkers have been identified for PAH, the clinical utility of these biomarkers often remains unclear. Here, we used unbiased meta-analysis of published biomarkers to identify biomarkers with the highest performance in the detection of PAH.MethodsA literature search (in PubMed, Embase.com, Clarivate Analytics/Web of Science Core Collection and Wiley/Cochrane Library) was performed up to January 28, 2021. Primary end points were blood biomarker levels in PAH versus asymptomatic controls or patients suspected of pulmonary hypertension (PH) with proven normal haemodynamic profiles.Results149 articles were identified by the literature search. Meta-analysis of 26 biomarkers yielded 17 biomarkers that were differentially expressed in PAH and non-PH control subjects. Red cell distribution width, LDL-c, d-dimer, NT-proBNP, IL-6 and uric acid were biomarkers with the largest observed differences, largest sample sizes and a low risk of publication bias. Receiver operating characteristic curves and sensitivity/specificity analyses demonstrated that NT-proBNP had a high sensitivity, but low specificity for PAH. For the other biomarkers, insufficient data on diagnostic accuracy with receiver operating characteristic curves were available for meta-analysis.ConclusionThis meta-analysis validates NT-proBNP as a biomarker with high sensitivity for PAH, albeit with low specificity. The majority of biomarkers evaluated in this meta-analysis lacked either external validation or data on diagnostic accuracy. Further validation studies are required, and studies that test combinations of biomarkers to improve specificity.

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“…The inclusion of PAH in future iterations of the GBD study may provide the impetus for broader data collection efforts. More sophisticated proteomic and metabolomic approaches to classification may help guide future efforts to assess its true burden 83 . The results of this search will be used to inform GBD estimation of PAH and help to quantify its global burden, thereby guiding global efforts to prioritize and treat this often‐overlooked condition.…”

Section: Discussionmentioning

confidence: 99%

Prevalence, incidence, and survival of pulmonary arterial hypertension: A systematic review for the global burden of disease 2020 study

et al. 2022

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Pulmonary arterial hypertension (PAH) is characterized by increased resistance in the pulmonary arterioles as a result of remodeled blood vessels. We sought all available epidemiologic data on population‐based prevalence, incidence, and 1‐year survival of PAH as part of the Global Burden of Disease Study. We performed a systematic review searching Global Index Medicus (GIM) for keywords related to PAH between 1980 and 2021 and identified population‐representative sources of prevalence, incidence, and mortality for clinically diagnosed PAH. Of 6772 articles identified we found 65 with population‐level data: 17 for prevalence, 17 for incidence, and 58 reporting case fatality. Reported prevalence ranged from 0.37 cases/100,000 persons in a referral center of French children to 15 cases/100,000 persons in an Australian study. Reported incidence ranged from 0.008 cases/100,000 person‐years in Finland, to 1.4 cases/100,000 person‐years in a retrospective chart review at a clinic in Utah, United States. Reported 1‐year survival ranged from 67% to 99%. All studies with sex‐specific estimates of prevalence or incidence reported higher levels in females than males. Studies varied in their size, study design, diagnostic criteria, and sampling procedures. Reported PAH prevalence, incidence, and mortality varied by location and study. Prevalence ranged from 0.4 to 1.4 per 100,000 persons. Harmonization of methods for PAH registries would improve efforts at disease surveillance. Results of this search contribute to ongoing efforts to quantify the global burden of PAH.

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NHLBI-CMREF Workshop Report on Pulmonary Vascular Disease Classification

Cited by 14 publications

References 72 publications

Proline and glucose metabolic reprogramming supports vascular endothelial and medial biomass in pulmonary arterial hypertension

Proline and glucose metabolic reprogramming supports vascular endothelial and medial biomass in pulmonary arterial hypertension

A systematic review with meta-analysis of biomarkers for detection of pulmonary arterial hypertension

Prevalence, incidence, and survival of pulmonary arterial hypertension: A systematic review for the global burden of disease 2020 study

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