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Pulmonary arterial hypertension (PAH) is a life-threatening disease with a poor prognosis, and metabolic abnormalities play a critical role in its development. This study used metabolomics, machine learning algorithms and bioinformatics to screen for potential metabolic biomarkers associated with the diagnosis of PAH. In this study, plasma samples were collected from 17 patients diagnosed with idiopathic pulmonary arterial hypertension (IPAH) and 20 healthy controls. Plasma metabolomic profiling was performed by high-performance liquid chromatography-mass spectrometry. Gene profiles of PAH patients were obtained from the GEO database. Key differentially expressed metabolites (DEMs) and metabolism-related genes were subsequently identified using machine learning algorithms. Twenty differential plasma metabolites associated with IPAH were identified (VIP score > 1 and p  < 0 0.05), and enrichment analysis revealed the arginine biosynthesis pathway as the most altered pathway. Using machine learning models, including least absolute shrinkage and selection operator (LASSO), random forest (RF) and support vector machine (SVM), we extracted key metabolites that correlated with clinical phenotypes. Our results suggested that five metabolites, kynurenine, homoserine, tryptophan, AMP, and spermine, are potential biomarkers for IPAH. Bioinformatics analysis also identified 3 metabolism-related genes, MAPK6, SLC7A11 and CDC42BPA, that are strongly correlated with pulmonary hypertension, demonstrating strong predictive power and clinical relevance. Our findings revealed some key genes associated with metabolism in PH, and provided crucial information about complex metabolic reprogramming signals and may lead to the identification of useful metabolic biomarkers for the diagnosis of PAH.

Background Insulin resistance (IR) plays an important role in the pathophysiology of cardiovascular disease. Recent studies have shown that diabetes mellitus and impaired lipid metabolism are associated with the severity and prognosis of idiopathic pulmonary arterial hypertension (IPAH). However, the relationship between IR and pulmonary hypertension is poorly understood. This study explored the association between four IR indices and IPAH using data from a multicenter cohort. Methods A total of 602 consecutive participants with IPAH were included in this study between January 2015 and December 2022. The metabolic score for IR (METS-IR), triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, triglyceride and glucose (TyG) index, and triglyceride-glucose-body mass index (TyG-BMI) were used to quantify IR levels in patients with IPAH. The correlation between non-insulin-based IR indices and long-term adverse outcomes was determined using multivariate Cox regression models and restricted cubic splines. Results During a mean of 3.6 years’ follow-up, 214 participants experienced all-cause death or worsening condition. Compared with in low to intermediate-low risk patients, the TG/HDL-C ratio (2.9 ± 1.7 vs. 3.3 ± 2.1, P = 0.003) and METS-IR (34.5 ± 6.7 vs. 36.4 ± 7.5, P < 0.001) were significantly increased in high to intermediate-high risk patients. IR indices correlated with well-validated variables that reflected the severity of IPAH, such as the cardiac index and stroke volume index. Multivariate Cox regression analyses indicated that the TyG-BMI index (hazard ratio [HR] 1.179, 95% confidence interval [CI] 1.020, 1.363 per 1.0-standard deviation [SD] increment, P = 0.026) and METS-IR (HR 1.169, 95% CI 1.016, 1.345 per 1.0-SD increment, P = 0.030) independently predicted adverse outcomes. Addition of the TG/HDL-C ratio and METS-IR significantly improved the reclassification and discrimination ability beyond the European Society of Cardiology (ESC) risk score. Conclusions IR is associated with the severity and long-term prognosis of IPAH. TyG-BMI and METS-IR can independently predict clinical worsening events, while METS-IR also provide incremental predictive performance beyond the ESC risk stratification.

Idiopathic/heritable pulmonary arterial hypertension has a poor prognosis despite the available therapeutic options. Survival of Japanese patients with this disease entity has not been reported in the multicenter setting. A retrospective study of 141 patients with idiopathic/heritable pulmonary arterial hypertension treated at 3 pulmonary hypertension centers in Japan from 1992 to 2012 investigated survival and determinants of survival. Mean survival time from treatment initiation was 14.7 ± 0.8 years (95% confidence interval, 13.1 to 16.3 years) and the 1-, 3-, 5-, and 10-year survival rates were 97.9%, 92.1%, 85.8%, and 69.5%, respectively. Patients showed significant improvement in exercise capacity and hemodynamics after treatment. Patients with 6-minute walk distance >372 m, mean pulmonary arterial pressure ≤46 mm Hg, and cardiac index >2.5 L/min/m2 at follow-up had a significantly better prognosis. Most patients (99.2%) were receiving pulmonary hypertension-targeted drugs at follow-up. Use of endothelin receptor antagonists and intravenous epoprostenol were related to survival in the univariate analysis. Among the patients who were on intravenous epoprostenol therapy, those with endothelin receptor antagonists had a significantly better prognosis, whereas patients on warfarin had a significantly worse prognosis. In conclusion, survival of Japanese patients with idiopathic/heritable pulmonary arterial hypertension in this study was good, showing improvement in hemodynamic parameters supported by pulmonary hypertension-targeted drugs.

Background Hyperglycemia upon admission is associated with poor prognosis of many cardiovascular diseases. However, the relationship of stress hyperglycemia ratio (SHR), admission blood glucose (ABG), and hemoglobin A1c (HbA1c) with pulmonary hypertension has not been reported. This study aimed to explore the association of hyperglycemia indices with disease severity and long-term adverse outcomes in patients with idiopathic pulmonary arterial hypertension (IPAH). Methods This multi-center cohort study included 625 consecutive patients diagnosed with or treated for IPAH between January 2015 and June 2023. SHR was calculated using the followings: ABG (mmol/L)/(1.59 × HbA1c [%] − 2.59). The primary endpoint was defined as clinical worsening events. Multivariable Cox regression and restricted cubic spline analyses were employed to evaluate the association of SHR, ABG, and HbA1c with endpoint events. The mediating effect of pulmonary hemodynamics was evaluated to investigate the potential mechanism between hyperglycemia and clinical outcomes. Results During a mean follow-up period of 3.8 years, 219 (35.0%) patients experienced all-cause death or clinical worsening events. Hyperglycemia indices correlated with well-validated variables that reflected the severity of IPAH, such as the World Health Organization functional class, 6-min walk distance, and N-terminal pro-brain natriuretic peptide levels. Multivariable Cox regression analyses indicated that SHR (hazard ratio [HR] 1.328, 95% confidence intervals [CI]: 1.185, 1.489 per 0.1-unit increment, P  < 0.001) and ABG (HR 1.317, 95% CI: 1.134, 1.529 per 1.0-unit increment, P  < 0.001) were independent predictors of primary endpoint events. Mediation analysis indicated that pulmonary vascular resistance mediated 5.65% and 14.62% of the associations between SHR and ABG and clinical worsening events, respectively. The addition of SHR significantly improved reclassification, discrimination ability, and model fit beyond the clinical risk prediction model. Conclusions SHR is positively associated with clinical worsening in patients with IPAH. The association appeared to be partially mediated through the pathway of pulmonary vascular remodeling, indicating that SHR may serve as a valuable indicator for providing additional risk information.

Pulmonary arterial hypertension (PAH) is frequently complicated by sleep disordered breathing (SDB), and previous studies have largely focused on hypoxemic SDB. Even though nocturnal hypercapnia was shown to exacerbate pulmonary hypertension, the clinical significance of nocturnal hypercapnia among PAH patients has been scarcely investigated. Seventeen patients with PAH were identified from 246 consecutive patients referred to Kyoto University Hospital for the evaluation of lung transplant registration from January 2010 to December 2017. Included in this study were 13 patients whose nocturnal transcutaneous carbon dioxide partial pressure (PtcCO2) monitoring data were available. Nocturnal hypercapnia was diagnosed according to the guidelines of the American Academy of Sleep Medicine. Associations of nocturnal PtcCO2 measurements with clinical features, the findings of right heart catheterization and pulmonary function parameters were evaluated. Nocturnal hypercapnia was diagnosed in six patients (46.2%), while no patient had daytime hypercapnia. Of note, nocturnal hypercapnia was found for 5 out of 6 patients with idiopathic PAH (83.3%). Mean nocturnal PtcCO2 levels correlated negatively with the percentage of predicted total lung capacity (TLC), and positively with cardiac output and cardiac index. Nocturnal hypercapnia was prevalent among advanced PAH patients who were waiting for lung transplantation, and associated with %TLC. Nocturnal hypercapnia was associated with the increase in cardiac output, which might potentially worsen pulmonary hypertension especially during sleep. Further studies are needed to investigate hemodynamics during sleep and to clarify whether nocturnal hypercapnia can be a therapeutic target for PAH patients.

Treprostinil is applied for pulmonary arterial hypertension (PAH) therapy. However, the mechanism by which the drug achieves its beneficial effects in PAH vessels is not fully understood. This study investigated the effects of treprostinil on PDGF-BB induced remodelling parameters in isolated human pulmonary arterial smooth muscle cells (PASMC) of four PAH patients. The production of TGF-β1, CTGF, collagen type-I and -IV, and of fibronectin were determined by ELISA and PCR. The role of cAMP was determined by ELISA and di-deoxyadenosine treatment. Proliferation was determined by direct cell count. Treprostinil increased cAMP levels dose and time dependently, which was not affected by PDGF-BB. Treprostinil significantly reduced PDGF-BB induced secretion of TGF-β1 and CTGF, both was counteracted when cAMP generation was blocked. Similarly, the PDGF-BB induced proliferation of PASMC was dose dependently reduced by treprostinil through signalling via cAMP-C/EBP-α p42 -p21(WAf1/Cip1). In regards to extracellular matrix remodelling, treprostinil significantly reduced PDGF-BB-TGF-β1-CTGF induced synthesis and deposition of collagen type I and fibronectin, in a cAMP sensitive manner. In contrast, the deposition of collagen IV was not affected. The data suggest that this action of treprostinil in vessel wall remodelling may benefit patients with PAH and may reduce arterial wall remodelling.

Childhood-onset pulmonary arterial hypertension (PAH) is considered complex and multifactorial, with relatively poor estimates of the natural history of the disease. Strategies allowing earlier detection, establishment of disease aetiology together with more accurate and sensitive biomarkers could enable better estimates of prognosis and individualise therapeutic strategies. Evidence is accumulating that genetic defects play an important role in the pathogenesis of idiopathic and hereditary forms of PAH. Altogether nine genes have been reported so far to be associated with childhood onset PAH suggesting that comprehensive multigene diagnostics can be useful in the assessment. Identification of disease-causing mutations allows estimates of prognosis and forms the most effective way for risk stratification in the family. In addition to genetic determinants the analysis of blood biomarkers are increasingly used in clinical practice to evaluate disease severity and treatment responses. As in genetic diagnostics, a multiplex approach can be helpful, as a single biomarker for PAH is unlikely to meet all requirements. This consensus statement reviews the current evidence for the use of genetic diagnostics and use of blood biomarkers in the assessment of paediatric patients with PAH.

Background Chemokine CXC ligand 13 (CXCL13) has been implicated in perivascular inflammation and pulmonary vascular remodeling in patients with idiopathic pulmonary artery hypertension (IPAH). We wondered whether CXCL13 may also play a role in chronic thromboembolic pulmonary hypertension (CTEPH) and whether serum levels of CXCL13 might serve as biomarkers in these conditions. Methods Lung tissue from patients with IPAH or CTEPH was immunostained for CXCL13. Serum samples were obtained from patients with IPAH ( n  = 42) or CTEPH ( n  = 50) and from healthy controls ( n  = 13). Serum CXCL13 concentrations were measured by enzyme-linked immunosorbent assay technology and were evaluated for associations with markers of disease severity and survival. Results CXCL13 was expressed in pulmonary vascular lesions and lymphocytes of patients with IPAH and inoperable CTEPH, respectively. Serum CXCL13 was elevated in patients compared to healthy controls [median, interquartile range, 83 (55,114) pg/ml versus 40 (28, 48) pg/ml; p  < 0.001]. Serum CXCL13 showed only weak and inconsistent correlations with markers of inflammation or disease severity. In both populations, patients with serum CXCL13 above the median of the respective groups did not have a higher risk of death than patients with lower serum CXCL13. Conclusions CXCL13 was overexpressed in pulmonary vascular lesions of patients with IPAH and CTEPH, and increased serum concentrations were found in patients with IPAH and CTEPH, suggesting a potential pathogenic role of CXCL13 in both diseases. However, given the weak associations between serum CXCL13 and markers of disease severity and outcome, CXCL13 is unlikely to become a promising biomarker in these patient populations.

Activation of inflammatory processes has been identified as a major driver of pulmonary vascular remodeling that contributes to the development of precapillary pulmonary hypertension (PH). We hypothesized that circulating markers of leukocyte activation, reflecting monocytes/macrophages (sCD163, sCD14), T-cells (sCD25) and neutrophils (myeloperoxidase [MPO], neutrophil gelatinase-associated lipocalin [NGAL]) activity, could give prognostic information in precapillary PH. Circulating markers of leucocyte activation, sCD163, sCD14, sCD25, MPO and NGAL were measured by enzyme immunoassays in plasma from patients with idiopathic PAH (IPAH; n = 30); patients with PAH related to associated conditions (APAH; n = 44) and patients with chronic thromboembolic PH (CTEPH) (n = 32), and compared with 23 healthy controls. Markers of leucocyte activation were elevated in precapillary PH with particularly high levels in APAH. The elevated levels of monocyte/macrophage marker sCD163 was independently associated with poor long-term prognosis in the group as a whole, and elevated levels of sCD25 was associated with poor prognosis in APAH, while elevated levels of sCD163 and NGAL was associated with poor prognosis in IPAH and CTEPH. Our data show leucocyte activation in precapillary PH with different profiles and impact on prognosis according to etiology. The association of sCD163 with poor outcome in fully adjusted model may be of particular interest.

Elastase is implicated in the pathobiology of PAH, with evidence including ultrastructural studies showing increased elastase activity in pulmonary arteries from children with congenital heart disease-associated PAH (1), increased elastase release from peripheral blood neutrophils isolated from patients with pulmonary hypertension compared with healthy control subjects (2), and elevated plasma concentrations of elastase in patients with idiopathic PAH (IPAH) (3). [...]when pooled sera are examined by 2D gel electrophoresis, AAT is represented by multiple spots and the intensity change in one spot is unlikely to reflect the changes in the total amount of AAT. [...]our data still support the exploration of elastase inhibitors as a potential therapy for PAH. ? Royal Papworth Hospital Cambridge, United Kingdom Mark Toshner, M.D., F.R.C.P. University of Cambridge School of Clinical Medicine Cambridge, United Kingdom and Royal Papworth Hospital Cambridge, United Kingdom Nicholas W. Morrell, M.D., Sc.D., F.R.C.P. Wei Li, Ph.D· University of Cambridge School of Clinical Medicine Cambridge, United Kingdom ORCID IDs: 0000-0002-1568-4842 (J.G.); 0000-0001-5700-9792 (N.W.M.); 0000-0002-1924-3120 (W.L.). *These authors contributed equally to this work. †Corresponding author (e-mail: wl225@cam.ac.uk).