Severe diffusion impairment in pulmonary arterial hypertension (PAH), particularly in idiopathic PAH (IPAH), has garnered considerable attention. However, comprehensive data on low diffusion capacity of the lungs for carbon monoxide (DLCO) with preserved lung function remain limited in broader pulmonary hypertension (PH) cohorts. We analyzed patients with PH, preserved lung function, low DLCO, and available computed tomography (CT) scans. The analysis included 117 patients, with 34% cases of combined pulmonary fibrosis and emphysema (CPFE), 22% IPAH, 15% interstitial lung disease (ILD), 9% pulmonary veno-occlusive disease (PVOD), and 8% connective tissue disease (CTD). Based on hemodynamic and CT imaging features, the overall population could be broadly categorized into two phenotypic patterns. "Parenchymal Type" ( = 81; 69%), predominantly consisted of CPFE and ILD, with an average age of 69 ± 9 years, 89% male. The median mean pulmonary arterial pressure (mPAP) was 39 mmHg, and lung abnormalities observed included emphysema, interstitial fibrosis, and diffuse ground-glass opacities (GGO). "Vascular Type" ( = 36; 31%), mainly composed of PVOD and CTD cases. with average age of 52 ± 19 years, 64% female, median mPAP of 53 mmHg and centrilobular GGO (78%). IPAH patients were distributed across both phenotypic categories, exhibiting mixed characteristics of the "Parenchymal Type" and "Vascular Type". The 5-year survival rate for the overall patient cohort was 31%. In conclusion, PH patients with low DLCO and preserved lung function represent two distinct phenotypic patterns and are associated with a poor prognosis.

The American Lung Association and Pulmonary Hypertension Association convened a scientific roundtable of pulmonary hypertension experts to discuss the latest recommendations from the European Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension (PH) and from the 7th World Symposium on Pulmonary Hypertension (WSPH). The aim of the roundtable was to discuss changes that were made compared to earlier recommendations and guidelines set out by the European Society of Cardiology and the European Respiratory Society in 2015, the 6th World Symposium on Pulmonary Hypertension in 2018, and the CHEST Guideline on Therapy for Pulmonary Arterial Hypertension in 2019. The overall objectives were to: 1) Create an educational resource for providers that summarizes currently available PAH guidelines, 2) Provide an expert critique of current guidelines, outlining strengths and weaknesses and resolving differences where guidelines do not agree. 3) Provide guidance for the incorporation of the recently approved drug, sotatercept into current guidelines. An executive summary was drafted following the roundtable meeting on April 8, 2024, and revised by the panel in September 2024, following publication of the proceedings from the 7th WSPH held in Barcelona June 29-July 1, 2024. The Executive Summary reviews changes to the hemodynamic criteria for defining pre- and post-capillary PH, exercise-induced PH, and PH associated with lung disease. Recommendations are given for proper diagnosis and clinical classifications of the various forms of PH. The role of screening for PH in high-risk populations and the use of risk scores for disease stratification are discussed. Finally, treatment algorithms for managing pulmonary arterial hypertension, PH associated with lung disease, and chronic thromboembolic pulmonary hypertension are presented.

Macitentan 10 mg and tadalafil 40 mg single-tablet combination therapy (M/T STCT) has been evaluated in the global A DUE study (NCT03904693). Here, we report the results of a subgroup analysis in participants from China. This double-blind, active-controlled, Phase 3 A DUE study randomized patients with symptomatic pulmonary arterial hypertension (PAH) to receive M/T STCT, macitentan, or tadalafil depending on their baseline PAH treatment (treatment-naïve, endothelin receptor antagonist, or phosphodiesterase Type 5 inhibitor monotherapy). The primary end point was change in pulmonary vascular resistance (PVR) expressed as the ratio of geometric means (GMR) of Week 16 to baseline. A total of 187 patients were randomized, including 23 patients in China. PVR reduction was significantly greater with M/T STCT compared with macitentan (50%) and tadalafil (41%) (adjusted GMRs were 0.50; 95% confidence level [CL]: 0.35-0.72;  = 0.0017 and 0.59; 95% CL: 0.43-0.80;  = 0.0040, respectively) in Chinese patients. M/T STCT was well tolerated in Chinese patients; the safety profile was consistent with that of macitentan and tadalafil monotherapies, and that of the overall population. In conclusion, in Chinese patients with PAH, PVR was reduced with M/T STCT versus either monotherapy after 16 weeks of treatment; the safety profile of M/T STCT was in line with the known safety profile of the individual components and appeared consistent with the overall population, although data should be interpreted with caution due to the small sample size. Our findings support the use of M/T STCT for PAH in China. : ClinicalTrials.gov https://clinicaltrials.gov/ NCT03904693 (April 5, 2019).

Pulmonary arterial hypertension (PAH) is a fatal disease with limited available treatments and is characterized by pulmonary vascular remodeling. Substance P (SP) may be involved in vascular remodeling in patients with PAH. However, the underlying mechanism is currently unknown. In this study, we found that plasma SP levels were elevated and correlated with pulmonary hemodynamic parameters in PAH patients. SP receptor inhibitors significantly suppressed pulmonary vascular remodeling and improved pulmonary circulation hemodynamics in PAH rats. Multiple omics analyses suggested that downregulation of Fibulin-2 (Fbln2) may play a role in promoting pulmonary vascular remodeling by SP. In addition, the downregulation of Fbln2 expression by SP was further verified by Western blot analysis and immunofluorescence. In vitro experiments showed that SP negatively regulated β-catenin expression by downregulating Fbln2 expression. Moreover, SP promoted the DNA methylation of Fbln2. A methylation inhibitor alleviated SP mediated low expression of Fbln2 and high expression of β-catenin. Overexpression of Fbln2 inhibited the proliferation and migration of pulmonary artery smooth muscle cells induced by SP. These data provide a novel mechanism through which SP promotes the proliferation and migration of PASMCs, leading to pulmonary hypertension and suggesting that Fbln2 is a potential therapeutic target for PAH.

Pulmonary hypertension due to interstitial lung disease (PH-ILD) is associated with high morbidity and mortality. Real-world patients initiating inhaled treprostinil are not well-characterized. This retrospective cohort study aimed to evaluate healthcare resource utilization in patients with PH-ILD who initiated treatment with inhaled treprostinil vs patients who remained untreated. Adult patients diagnosed with PH-ILD were indexed on initiation of inhaled treprostinil and patients who remained untreated were indexed on first observed PH diagnosis (31 March 2021-30 September 2024). Patients were excluded if they were ever treated with any pulmonary arterial hypertension therapy. Inhaled treprostinil patients were matched to up to four untreated patients. All-cause per-patient per-month (PPPM) hospitalizations and ICU-related hospitalizations were the primary outcomes of interest. 294 patients treated with inhaled treprostinil and 736 untreated patients were identified. Mean all-cause PPPM hospitalizations remained unchanged in the pre-index vs post-index periods in the inhaled treprostinil cohort (0.11 vs 0.12;  = 0.42) but significantly increased in untreated patients (0.12 vs 0.23;  < 0.01). ICU utilization also remained unchanged in the pre-index vs post-index periods for the inhaled treprostinil cohort (0.06 vs 0.07;  = 0.11) compared to the untreated cohort (0.06 vs 0.13;  < 0.01). Untreated patients had significantly higher post-index PPPM hospitalizations ( < 0.01) and ICU utilization ( < 0.01) compared to inhaled treprostinil patients. Patients who initiated inhaled treprostinil had a 30% decreased risk of hospitalization compared to untreated patients (relative risk: 0.70; 95% CI: 0.59-0.83;  < 0.01). Among real-world patients with PH-ILD, treatment with inhaled treprostinil is associated with fewer all-cause hospitalizations and ICU-related hospitalizations compared to untreated patients with PH-ILD.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of pulmonary embolism that is characterized by chronic obstruction of pulmonary arteries because of organized thrombi. Pulmonary endarterectomy (PEA) is the primary treatment of choice for CTEPH, which aims to clear the pulmonary arteries as completely as possible to decrease right ventricular afterload, thereby improving pulmonary hypertension (PH). PEA is a complex surgical procedure involving cardiopulmonary bypass and deep hypothermic circulatory arrest. Although it provides excellent outcomes, it is associated with frequent complications, including lung reperfusion injury, endobronchial hemorrhage, and persistent PH. Therefore, patients with CTEPH need to be referred to specialized centers. Germany performs approximately 150 PEA procedures annually. However, in Japan, the availability of PEA facilities is limited. The present study aims to delineate the differences in CTEPH management between Japan and Germany, evaluate the underlying reasons for the limited implementation of PEA in Japan, and underscore the need for specialized assessment and referral of patients who are eligible for PEA. The limited utilization of PEA in Japan appears to be attributable not to underestimation of the procedure itself, but rather to anatomical and institutional constraints.

Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by elevated pulmonary vascular resistance. Despite recent advances, early diagnosis remains challenging due to nonspecific symptoms. By utilizing RNA sequencing (RNA-seq) data from the GEO database, we conducted bioinformatics analyses to identify potential diagnostic biomarkers. Differentially expressed genes (DEGs) were screened in blood from PAH patients, followed by functional enrichment and protein-protein interaction (PPI) network analyses. Thirteen overlapping DEGs were identified, which were enriched in erythrocyte development, heme biosynthesis, and chloride transport. Five hub genes (SLC4A1, AHSP, ALAS2, FECH, and CA1), exhibited strong diagnostic potential, with an area under the curve (AUC) ≥ 0.7 in training datasets (GSE38267, GSE22356). External validation using datasets GSE33463 and GSE117261 confirmed their efficacy in blood samples, although AHSP showed reduced performance in lung tissue. Experimental validation in hypoxic human pulmonary artery smooth muscle cells (hPASMCs) supported the bioinformatics findings. These results underscore SLC4A1, AHSP, ALAS2, FECH, and CA1 as promising noninvasive diagnostic biomarkers for PAH, linking transcriptional dysregulation to clinical application.

Pericardial effusion (PEF) in PAH may be a marker of worsening disease or associated with autoimmune conditions. Sotatercept was not initially reported as associated with the development or progression of PEF. We describe PAH patients taking sotatercept who were found to have new or worsening PEF and examine associated comorbidities.

High-risk acute pulmonary embolism (PE) is associated with significant in-hospital mortality. Large-Bore Mechanical Thrombectomy (LBMT) is a treatment option for acute PE, but data on its efficacy in high-risk PE was limited. This prospective case series reported the outcomes of 14 patients with high-risk PE treated using a novel multipurpose mechanical aspiration system (MMAS). Most patients were in hemodynamic decompensation, requiring inotropic or mechanical circulatory support. The mean procedural time was 73.5 ± 39.2 min. Complete procedural success was achieved in 78.6% of the cases, while two patients required bailout therapies. The mean pulmonary arterial pressure decreased by 27.2%, and the right-ventricle/left-ventricle ratio normalized in 85.7% of patients. The primary endpoint-in-hospital mortality-was 0%, while the major bleeding rate was 27.2%. These findings suggest that MMAS is a safe and effective intervention for acute high-risk PE.

Pulmonary arterial hypertension (PAH) is a life-threatening condition with no cure, making research into its underlying mechanisms critical. The platelet-derived growth factor (PDGF) signaling pathway plays a crucial role in vascular remodeling, a key factor in PAH progression. Anti-PDGF receptor therapies, such as imatinib, show promise but are associated with significant side effects. Recent research identified PDGF-D as a new risk gene in idiopathic PAH, highlighting the need for further investigation into the PDGF pathway in the disease. In this study, we investigated PDGF-D, a specific PDGFRβ ligand, as a potential therapeutic target. RNA-Seq data from healthy lungs indicated that PDGF-D is predominantly expressed in inflammatory cells, whereas in vascular lesions of idiopathic PAH patients, PDGF-D was produced by various cell types. In vitro, PDGF-D induced mitogenic effects on pulmonary arterial smooth muscle cells. However, genetic deletion of PDGF-D in the chronic hypoxia mouse model of pulmonary hypertension showed no significant impact on vascular muscularization, hemodynamic parameters, or right ventricular hypertrophy. But, the absence of hypoxia-induced upregulation and the lack of increased expression of PAH-regulated genes, and , in PDGF-D-deficient mice, suggests activation of alternative mechanisms. MicroRNA analyses revealed PDGF-d-related alterations in the expression of miR-21 and miR-451, both important regulators in PAH, further supporting the notion that PDGF-D plays a unique role in PAH development. Taken together, our data suggest that PDGF-D may target a distinct population of PDGFRβ-expressing cells, separate from those stimulated by PDGF-B, positioning PDGF-D as a potentially unique and compelling therapeutic target for PAH.

Pulmonary Arterial Hypertension (PAH) is a rare, chronic and progressive disease affecting the heart and lungs. Endothelin receptor antagonist (ERA) + phosphodiesterase type 5 inhibitor (PDE5i) treatment is recommended for all PAH patients. The two approved PDE5is are tadalafil and sildenafil. To determine the efficacy and safety outcomes for tadalafil and sildenafil as monotherapies or in combination with ERAs for treating PAH, from randomized controlled trials (RCTs) and real-world evidence studies (RWEs) identified by a systematic literature review (SLR). MEDLINE, Embase and Cochrane Libraries were searched in May 2024. Relevant outcomes included 6-min walk distance (6MWD), pulmonary vascular resistance (PVR) and safety. This report includes studies where patients were treated with either sildenafil or tadalafil. Fifteen RCTs and three RWEs investigated tadalafil (tadalafil 40 mg or 20 mg once daily) or sildenafil (20 mg three times a day). Mean 6MWD change from baseline (CFB) in patients receiving tadalafil or sildenafil monotherapy were comparable, however, in combination with an ERA, tadalafil may be more effective. Generally, there was more data for tadalafil + ERAs, showing marked improvement in mean PVR CFB, compared with patients receiving sildenafil. Conclusions on safety were limited. Risk of bias in RCTs was generally low but moderate in RWEs. Two studies reported patients who switched from sildenafil to tadalafil treatment, treatment transition was feasible. Although comparable when used as monotherapy, this qualitative analysis suggests that tadalafil + ERA combination therapy may have more favorable 6MWD improvements than sildenafil + ERA combination therapy.

Pulmonary artery wedge pressure is a crucial measurement for differentiating between hemodynamic categories of pulmonary hypertension (PH), particularly Groups 1 and 2. In this prospective study, we analyzed the diagnostic utility of checking wedge oxygen saturation to confirm wedge position during right heart catheterization in patients referred for PH.

During the COVID-19 pandemic, Brazil was one of the most affected countries. Patients presented higher risk of acute venous thromboembolism (VTE), in particular, pulmonary embolism (PE). However, long-term implications of these events remain unknown. A retrospective analysis from the FENIX study was conducted, and patients with COVID-19-related VTE during hospitalization were included. Further analysis, up to 6 months after the acute event, was performed exclusively in patients with PE. Persistence of dyspnea and exercise intolerance was evaluated through imaging, rest, and exercise functional tests. Cumulative incidence of VTE during hospitalization among COVID-19 survivors followed at the outpatient clinic was 17.7% ( = 75/423) and of acute PE was 9.9% ( = 42/423). Patients with PE were mostly male (66%), 56 ± 16 years old, and mainly classified as intermediate-low risk (74%). Dyspnea (mMRC≥ 1) up to 6 months of PE was present in 56% ( = 19/34), with a borderline association with parenchymal lung sequelae on chest CT scan ( = 0.069). Symptomatic patients upon follow-up presented lower FEV1 and FVC, as well as increased peak VD/VT ratio and ventilatory inefficiency. No signs of pulmonary hypertension (PH) were identified on echocardiogram (ECHO) and cardiopulmonary exercise testing (CPET). Persistence of dyspnea among post-PE related to COVID-19 was high. However, no cases of PH were found; follow-up findings may be related to pulmonary parenchymal and microvascular injury. Also, we cannot exclude association with long-COVID, in which pathophysiological mechanisms are multifactorial, involving chronic inflammatory changes and multiorgan dysfunction, highlighting the need for comprehensive evaluation of exercise intolerance through invasive CPET.

Pulmonary arterial hypertension (PAH) is a chronic, progressive, and ultimately life-threatening disease characterized by vascular remodeling and increasing pulmonary vascular resistance. Despite significant advances in diagnostic tools and therapeutic strategies, clinical intervention often begins only when patients become symptomatic-typically at New York Heart Association (NYHA) functional class II or higher. Paradoxically, while early detection of PAH is strongly encouraged to preempt irreversible vascular, cardiac, and multisystem damage, treatment remains largely restricted to those already exhibiting symptoms. Patients in NYHA class I, though experiencing pathophysiological progression, are systematically excluded from approved pharmacological therapies. This disjunction represents not only a clinical and ethical conundrum but also a conceptual paradox: why invest in early diagnosis if early treatment is withheld? Emerging evidence on various chronic diseases, including cancer, infectious diseases like HIV and hepatitis, and even other cardiovascular diseases, underscores the benefits of initiating treatment before the onset of symptoms. In contrast, the current approach to PAH inadvertently promotes a nihilistic "wait and see" policy, exposing asymptomatic patients to preventable deterioration. Herein, we call for a reassessment of clinical guidelines, regulatory frameworks, and access policies with the goal of better aligning them with the biological realities of PAH. While we advocate for a paradigm shift toward the inclusion of NYHA class I patients in treatment strategies, we explicitly acknowledge the current limitations of the evidence base and emphasize the need for ongoing, high-quality research including counterarguments and the practical challenges of early treatments.

Pulmonary arterial hypertension (PAH) significantly impacts mortality and quality of life. Access to specialized care may differ between urban and rural patients, potentially influencing outcomes. This study compared the clinical course and treatment patterns of PAH patients from urban and rural settings treated at a single comprehensive care center. Adult patients with WHO Group I PAH evaluated between August 2020 and August 2024 at the University of Utah Pulmonary Hypertension Comprehensive Care Center were prospectively enrolled in a program-specific registry. A total of 263 patients were categorized as urban or rural based on residential address. Baseline characteristics, diagnostics, treatments, and outcomes were compared. No significant differences were observed in baseline characteristics, 6-min walk distance (6MWD), right ventricular function, hemodynamics, or NT-proBNP levels. In-person and virtual clinic utilization were also similar. However, among patients receiving triple therapy, rural patients were significantly more likely to receive inhaled treprostinil as the prostacyclin component ( = 0.03). In a subset of patients ( = 146), REVEAL Lite 2 scores were available at baseline and follow-up. Risk distributions and mean scores were similar at each time point. However, urban patients showed significant improvement in REVEAL risk category over time ( = 0.007), while no significant change occurred in rural patients. These findings suggest that although care delivery appeared comparable across settings, differences in treatment selection and risk trajectories emerged over time. Further investigation is needed to understand the drivers of these differences and their implications for disease management and progression.

Children with single ventricle heart disease (SVHD) demonstrate decreased arginine/NO metabolism following Stage 2 (Glenn) palliation, associated with poor postoperative outcomes. It is unknown if arginine dysregulation persists at Stage 3 (Fontan). The purpose of this study is to quantify circulating arginine metabolites in children undergoing Fontan palliation for SVHD to evaluate the relationship between metabolite concentrations and outcomes. Prospective cohort study of children undergoing Fontan operation ( = 82) and similar age healthy controls ( = 49). We measured circulating arginine metabolites pre- and post-op by tandem mass spectrometry. Postoperative outcomes included length of stay (LOS) and pleural drainage. Pre-op cases showed lower arginine, argininosuccinate, cysteine, NMMA, higher glutathione, and lower arginine/ADMA, arginine/citrulline, and arginine/ornithine ratios compared to controls. Post-op cases experienced progressively decreasing citrulline concentration and higher arginine/ADMA, arginine/citrulline, and arginine/ornithine ratios compared to pre-op. In uncorrected analysis, postoperative decreased citrulline level (31.4% and 33.9% longer LOS for 50% decrease in [citrulline] at 2 and 24 h, respectively) was associated with longer LOS. Decreased arginine/ADMA and arginine/ornithine ratios were significantly associated with longer LOS and greater pleural drainage. Arginine metabolism is altered in children with SVHD in both the pre- and post-Stage 3 period. Patients with greater postoperative derangements, including lower arginine/ADMA and arginine/ornithine ratios, experienced more morbidity. We speculate that alterations in arginine metabolism may be a modifiable risk factor for adverse post-Stage 3 outcomes in SVHD.

Patients with Eisenmenger syndrome (ES) are at increased risk of thrombotic events, especially in pulmonary vessels. However, both the prevalence and risk factors of pulmonary arterial thrombosis (PAT) have been varied greatly. In this study we sought to examine the prevalence of PAT in adult patients with ES and to identify risk factors. A cross-section descriptive study examining 57 adult patients with ES. All patients underwent computed tomography pulmonary angiography (CTPA) and echocardiography. Echocardiographic parameters and laboratory data were analysed from 57 patients. PAT prevalence was 22.8% (13/57), with all thrombi localized to dilated proximal pulmonary arteries (main pulmonary artery diameter: 52.6 ± 6.2 vs. 40.1 ± 6.9 mm in non-thrombosis group,  < 0.05). Thrombotic patients exhibited higher D-dimer (0.7 [IQR: 0.5-1.9] vs. 0.3 [IQR: 0.2-0.6] mg/L,  < 0.05) and NT-proBNP levels (2561.0 [1389.0-5904.3] vs. 695.4 [180.6-2452.7] pg/mL,  < 0.05), alongside reduced right ventricular fractional area change (RV FAC: 23.9 ± 5.5% vs. 32.4 ± 10.0%,  < 0.05). No differences were observed in age, oxygen saturation, hemoglobin, coagulation profiles, or right heart catheterization parameters (mPAP, PVR, mRAP). PAT affects nearly one-quarter of ES patients, routine CTPA screening should be considered even in asymptomatic cases. The lack of association with conventional risk factors underscores the need for thrombosis risk stratification integrating anatomical and biomarker criteria.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but severe complication of pulmonary embolism (PE), yet its underlying mechanisms remain poorly understood. Peptidyl-prolyl cis/trans isomerase (Pin1), a regulatory enzyme involved in thrombosis, inflammation, and vascular remodeling, may contribute to pulmonary vascular disease. We investigated whether circulating Pin1 levels are associated with the risk of CTEPH and its severity. In this case-control study, we measured circulating Pin1 levels by ELISA and compared them across 329 patients with CTEPH, 350 patients after acute PE, and 350 healthy individuals. Associations between Pin1 levels and clinical parameters were assessed with multivariable regression, stratified by sex. Overall, circulating Pin1 levels did not differ between patients with CTEPH, patients after acute PE, and healthy individuals. However, male patients with CTEPH had higher Pin1 levels than the two control groups, while female patients with CTEPH had slightly lower levels than female healthy individuals. Elevated Pin1 levels were associated with improved hemodynamics and exercise capacity, lower N-terminal prohormone of brain natriuretic peptide, and increased probability of CTEPH in men. Among healthy individuals, circulating Pin1 levels varied based on age, sex, and history of cancer. In conclusion, circulating Pin1 did not distinguish between patients with CTEPH, acute PE or healthy individuals. Nonetheless, our results suggest a possible sex-specific association between circulating Pin1 levels and CTEPH. Although Pin1 is unlikely to serve as a standalone biomarker, it may reflect underlying sex-specific pathological mechanisms, and further investigation on its utility within multimodal strategies for early risk stratification of CTEPH is warranted.

Pulmonary hypertension (PH) is a common complication in interstitial lung disease (ILD), but the additional burden it imposes on patients and healthcare systems is not well characterized. This retrospective analysis of claims data from the US Merative MarketScan database assessed hospitalization rates and costs over 2 years in patients with connective tissue disease-related ILD (CTD-ILD) and non-CTD-ILD with or without PH (between January 2017 and December 2019). Index was the date of first ILD claim; baseline was the 12-month preindex period. In total, 16,129 patients with non-CTD-ILD (1502 [9%] with PH) and 4545 patients with CTD-ILD (663 [15%] with PH) were identified. A higher proportion of patients with non-CTD-ILD with PH, compared with patients without PH, had all-cause and heart failure (HF)-related hospitalizations during baseline (all-cause, 37.0% vs. 22.3%; HF-related, 14.2% vs. 3.1%), 0-12 months (62.4% vs. 43.0%; 29.0% vs. 7.0%), and 13-24 months (44.7% vs. 18.3%; 21.5% vs. 3.2%) follow-up ( < 0.0001 for all). A significantly higher proportion of patients with CTD-ILD with PH, compared with patients without PH, had all-cause and HF-related hospitalizations during baseline (all-cause: 30.0% vs. 20.6%; HF-related: 9.1% vs. 1.9%), 0-12 months (41.9% vs. 29.1%; 15.5% vs. 3.9%), and 13-24 months (37.9% vs. 18.9%; 13.9% vs. 2.5%) follow-up ( < 0.0001 for all). In both cohorts, total all-cause and HF-related costs were significantly higher in patients with PH at baseline, 0-12 months, and 13-24 months follow-up ( < 0.05 for all). PH substantially increased hospitalization risks and costs in both types of ILD, underscoring the importance of improving outcomes in patients with ILD-PH.

Pulmonary arterial hypertension (PAH) is a pulmonary disease associated with alterations in gut microbiota. We aimed to identify potential diagnostic genes causally associated with gut microbiota and PAH. Mendelian randomization (MR) was performed to screen gut microbiota causally associated with PAH and to identify gut microbiota-related genes. A regulatory network was constructed to reveal the relationships among genes, gut microbiota and PAH. Diagnostic genes were screened and used to construct a diagnostic model for PAH. Characteristics of immune infiltration and diagnostic gene expression in each cell type were evaluated at the transcriptome and single-cell levels. Family. Porphyromonadaceae and genus. Eubacteriumfissicatena were risk factors for PAH, whereas phylum. Actinobacteria, class. Bacilli, genus. Erysipelatoclostridium, and genus. Ruminococcaceae were protective factors for PAH. The gene-gut microbiota-PAH network showed causal associations among six gut microbiota taxa, 13 PAH-associated genes and PAH. Copper metabolism MURR1 domain (COMMD) containing 10 (COMMD10), FES proto-oncogene, tyrosine kinase (FES), nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1), solute carrier family 22 member 4 (SLC22A4), and synaptogyrin 1 (SYNGR1) were identified as diagnostic genes, with Area Under Curve (AUC) values ranging from 0.79 to 0.99. The abundances of activated B cells, activated CD8 T cells, eosinophils, mast cells, and T helper cells were increased, whereas the abundances of activated dendritic cells (DCs), gamma delta T cells, MDSCs, macrophages, neutrophils, plasmacytoid DCs, and regulatory T cells were decreased in PAH. NUCKS1 was expressed in each cell type and was lower in T/NK and NK cells. The study deepens the understanding of PAH pathogenesis, and may provide diagnostic targets for PAH.