INTRODUCTION:Home noninvasive ventilation (HNIV) is an established therapy for chronic obstructive pulmonary disease (COPD) with chronic respiratory failure. However, outcomes following HNIV initiation after discharge from the hospital after acute COPD exacerbation remain poorly investigated, in particular sex-related factors. METHODS:We conducted a single-center, retrospective cohort study on COPD patients admitted to our respiratory care unit (RCU) for acute exacerbation with respiratory failure who were discharged home with newly established HNIV between 2013 and 2019. The primary endpoint was all-cause mortality after discharge from RCU. Sex-stratified survival analysis was performed using Kaplan-Meier curves, Cox proportional hazards models, and interaction models incorporating sex and clinical covariates, including lung function test and blood gases assessed at discharge. RESULTS:A total of 84 patients fulfilled all inclusion and exclusion criteria. The median age was 74 (IQR: 68-77) years, the male-to-female ratio was 1.4:1, and the median forced expiratory volume in 1 s (FEV1) at discharge was 25 (19.3-35.6)% predicted. Median survival was 158 (47-301) weeks, and Kaplan-Meier analysis demonstrated a longer survival time in males than in females (217 [77-434] vs. 130 [26-226] weeks; p = 0.036). After adjustment for age, FEV1% and other significant sex-dependent variables, female sex remained an independent predictor of increased mortality (HR [95% CI], 2.13 [1.01-4.49]; p = 0.046). Interaction analysis confirmed improved model fit with sex-by-covariate terms (χ2 = 12.85, p = 0.045; C-index = 0.71). Higher FEV1% was protective overall (HR [95% CI], 0.94 [0.86-0.99]; p = 0.028), but this benefit was only present in men (interaction p = 0.016). In a subgroup of patients, diffusing capacity of the lung for carbon monoxide (DLCO) data were available. Compared to males, females had lower DLCO and higher pCO2 levels at hospital discharge, which may explain the observed sex difference in survival. CONCLUSION:In COPD patients released home with newly established HNIV after hospitalization for acute exacerbation with respiratory failure, even after adjustment for established clinical covariates, female sex was associated with worse survival. FEV1% was also associated with survival; however, only in males and not in females, indicating sex-specific disease trajectories. These findings highlight the importance of incorporating sex-by-covariate interactions into prognostic models and the need for sex-tailored management strategies in advanced COPD.

Purpose of review To synthesize emerging evidence supporting genetic susceptibility to pulmonary vascular phenotypes in chronic obstructive pulmonary disease (COPD) and to provide a rationale for focused genomic investigation of pulmonary hypertension associated with COPD (PH-COPD). Recent findings Multiancestry genome-wide association studies and integrative genomic analyses have identified COPD risk loci involved in pathways related to lung development, extracellular matrix remodeling, angiogenesis, immune signaling, and hypoxia responses, processes that intersect with pulmonary vascular biology. Concurrent advances in pulmonary arterial hypertension (PAH) genetics demonstrate that rare pathogenic variants in developmental and endothelial signaling genes produce vascular phenotypes often accompanied by reduced diffusing capacity, parenchymal abnormalities, and proliferative vasculopathy. Consistent with these observations, data from independent PAH cohorts reveal phenotypic overlap and biological heterogeneity between group 1 and group 3 classifications. Collectively, these findings suggest that a subset of COPD patients with pulmonary hypertension may harbor unrecognized genetic susceptibility influencing pulmonary vascular remodeling. However, dedicated genetic studies specifically examining PH-COPD remain limited. Summary PH-COPD may represent, in part, a genetically influenced disease that extends beyond the traditional PH group boundaries. Systematic genomic sequencing coupled with clinical, imaging, and physiological phenotyping will be essential to identify biologically defined subgroups and guide precision therapeutic strategies.

ABSTRACT Sex differences in COPD patients with concomitant pulmonary hypertension remain unexplored. Analyzing 171 patients from the GRAPHIC registry in Graz, Austria, we found that male sex was independently associated with increased mortality risk, despite comparable comorbidities and airflow obstruction, which may be explained by the increased rate of severe PH.

AIMS:Pulmonary arterial hypertension (PAH) is a chronic condition of elevated pulmonary arterial pressure caused by vascular remodelling due to increased proliferation of pulmonary arterial smooth muscle cells (PASMC). Initially described as a disease primarily affecting young women, it now increasingly affects the elderly. Age-related pathomechanisms of PAH remain, however, unclear. In a translational approach combining preclinical disease models and analyses of human cohorts, we probed for a role of the anti-ageing protein Klotho, which acts as a co-receptor for fibroblast growth factor 23 (FGF23) in the pathogenesis of PAH. METHODS AND RESULTS:Mice aged 114-117 weeks showed moderate spontaneous PAH with right ventricular (RV) hypertrophy and dysfunction relative to young mice aged < 40 weeks. This effect was further pronounced upon hypoxic exposure (10% O2) for 14 days. Histological sections showed pulmonary vascular wall thickening of small pulmonary arterioles. Similar findings were obtained in mice with a partial Klotho deficiency (kl/+) that developed RV systolic pressures (RVSP) of 72.58 ± 3.3 mmHg within two weeks of hypoxia. Aged mice and kl/+ mice had elevated plasma levels of FGF23, further amplified by hypoxic exposure. ELISA-based measurements in serum of patients from a cross-sectional study with PAH aged 60 years or older confirmed an increase in circulatory FGF23. Immunohistochemistry staining of lung tissue showed increased proliferative activity of PASMC in kl/+ mice, and recombinant FGF23 elevated proliferative activity of PASMC in vitro. The hyperproliferative response to FGF23 was prevented by siRNA-mediated knockdown of fibroblast growth factor receptor 1 in PASMC. In kl/+ mice, FGF23 neutralisation using an anti-FGF23 antibody reduced RVSP, improved RV dysfunction and RV hypertrophy and prevented pulmonary vascular remodelling. CONCLUSION:Our findings identify the accumulation of FGF23 as novel mechanism of pulmonary vascular remodeling in PAH. Targeting dysregulated Klotho/FGF23 signalling may present a promising therapeutic strategy in elderly patients.

Background/Objectives: Cirrhosis is associated with increased mortality. In this study, we aimed to investigate the prognostic relevance of 6-min-walk-distance- and cardiopulmonary exercise testing (CPET)-derived peak oxygen uptake (VO2) as estimates of exercise capacity in outpatients with cirrhosis. Methods: Patients underwent a comprehensive clinical characterization including cardiopulmonary exercise testing, six-minute-walking-test-derived distance, and echocardiography. We stratified the cohort using established prognostic thresholds for the six-minute-walking-test-derived distance (440 m) and peak VO2 (65% predicted) and Child–Pugh class (A vs. B/C). Competing risk analyses were performed using cumulative incidence functions and subdistribution hazard models to assess the impact of baseline variables on mortality, accounting for liver transplantation (LT) as a competing event and for age and sex. The prognostic value of exercise performance was analyzed first, followed by the stepwise inclusion of additional variables; multicollinearity precluded a full multivariable model. Results: We enrolled 197 patients in Child–Pugh Class A, B, and C (N = 92, N = 80, N = 25 patients; male N = 146, age: 56 ± 9 years). During the observation time of 85 (25–105) months, 48 patients underwent a liver transplant, and 88 died. Both the six-minute-walking-test-derived distance ≤ 440 m (p = 0.002, sHR: 0.996 95% CI: 0.993–0.998) and peak VO2 ≤ 65% predicted (p = 0.023, sHR: 0.987 95% CI: 0.976–0.998) were strong independent predictors of mortality. While the six-minute-walking-test-derived distance consistently remained significant across most models, the peak VO2 retained significance only when adjusted for creatinine. Combining exercise capacity and the Child–Pugh classification identified patients at a particularly high mortality risk. Conclusions: In patients with liver cirrhosis outside the liver transplant setting, the impaired six-minute-walking-test-derived distance and peak VO2 serve as predictors of mortality and may help to identify patients at a particularly high mortality risk. These results suggest that functional capacity provides complementary information to established liver disease severity scores and could be considered in a multidimensional risk assessment approach in patients with liver cirrhosis.

#ERSCongress 2025 highlighted key advances in the pathobiology, phenotyping and management of pulmonary vascular diseases, reflecting a shift towards precision medicine in these complex patients https://bit.ly/425cVX6.

Abstract Rationale Pulmonary hypertension is defined by pulmonary hemodynamics, but diagnostic and prognostic biomarkers remain limited. Nuclear magnetic resonance (NMR) spectroscopy provides detailed insights, particularly in the lipid metabolism. Objectives To explore circulating NMR-derived metabolites and lipoprotein-related parameters for their association with pulmonary hemodynamics and to analyse their prognostic properties in pulmonary arterial hypertension (PAH). Methods Retrospective analysis of a PAH cohort with complete diagnostic workup including right heart catheterization and baseline serum samples, from the prospective GRaz Pulmonary Hypertension-Metabolism (GRAPH-M) registry. Measurements NMR-derived metabolites and lipoprotein-related parameters were analyzed for their association with clinically relevant parameters of PAH. We defined PHIHDL, a score derived from high-density lipoprotein (HDL) related measures based on their strong association with pulmonary hemodynamics, and evaluated its prognostic value. Results We included 100 patients with PAH treated at the PH clinic of LKH University Hospital, Medical University of Graz, between 2011 and 2021. Age was 61±15 years, female/male ratio 2.5, BMI 26±7 kg/m 2 , mPAP 41±16 mmHg, PAWP 8.8±3.2 mmHg, PVR 8.0±4.9 WU, and median survival was 8.0 years. During follow-up, 46 patients died. We identified a cluster of 12 HDL-related measures that showed significant inverse association to pulmonary hemodynamics and derived PHIHDL from the reversed scaled average of these particles. PHIHDL was associated with all-cause mortality after adjustment for age and sex (HR 2.96, 95% CI 1.52-5.70), independent of the clinical risk scores COMPERA 2.0 and REVEAL Lite 2. Conclusion PHIHDL, a pulmonary hemodynamics-based metabolomic score, provides independent prognostic information beyond established risk scores in PAH.

mPAP/V'O2 slope may serve as a noninvasive surrogate of pulmonary exercise haemodynamics predicting both EPH and prognosis in patients at risk for pulmonary vascular disease. Larger prospective studies are needed to validate its clinical utility. https://bit.ly/47Ey1yU.

Rationale:Pulmonary artery (PA) enlargement is a non-invasive imaging biomarker associated with pulmonary hypertension and mortality in COPD; however, its genetic determinants remain incompletely understood. Objectives:To characterize the genetic architecture of PA size across COPD-enriched and population-based cohorts. Methods:We performed genome-wide association analyses of PA diameter using whole-genome sequencing in COPDGene (n=9,418) and ECLIPSE (n=1,859), and imputed-genotype data from the UK Biobank (n=37,073). We replicated lead variants in the Framingham Heart Study (FHS; n=3,289), incorporated all four studies into a joint meta-analysis, and identified independent signals through conditional analyses. Candidate effector genes were prioritized using coding variant annotation, colocalization, and integrative regulatory evidence. Measurements and Main Results:We identified 44 independent genome-wide significant PA diameter signals within 39 loci, including 8 variants replicated in FHS, novel associations near FRMD4B , SLC20A2 , BORCS7-ASMT , and KCNRG , and 5 signals in conditional analysis including multiple signals at ANO1 . Genetic effects were concordant across imaging modalities and cohorts of differing COPD burden. Effector-gene prioritization nominated ABCC8 , PDGFD , HMCN1 , CCNE1 , and TBX20 , implicating pathways in vascular remodeling, developmental regulation, smooth muscle and endothelial function, ion-channel signaling, and extracellular matrix organization. Colocalization with pulse pressure GWAS demonstrated substantial shared causal variation between pulmonary and systemic vascular biology. Conclusions:In this largest genetic study of pulmonary vascular imaging to date, PA diameter exhibits a polygenic architecture consistent across imaging modalities and cohorts of differing COPD burden. The prioritized effector genes bridge rare-variant pulmonary hypertension biology with common-variant systemic vascular biology.

Pulmonary hypertension associated with chronic lung diseases (PH-CLD) is one of the most common but frequently underdiagnosed forms of pulmonary hypertension (PH). Its presence has been consistently associated with worse prognosis and reduced quality of life for affected patients. Recent epidemiological data highlight the heterogeneity of this patient population, demonstrating that both the underlying lung disease and the severity of PH are critical determinants of prognosis and therapeutic decisions. The 7th World Symposium on Pulmonary Hypertension (WSPH) emphasized the importance of systematic diagnostic approaches and detailed phenotyping of PH-CLD. While some studies have shown potential benefits of PH-targeted therapies, others - particularly in COPD - have reported adverse outcomes. This position statement by the PH-DACH working group summarizes the key recommendations of the 11th Task Force of the 7th WSPH, critically assesses the current evidence, and comments specifically on deviations from the original text. The aim is to contribute to the development of practical diagnostic and therapeutic algorithms for patients with PH-CLD.

This article highlights hot topics presented at the #ERSCongress 2024 on pulmonary embolism, right heart failure and personalised medicine for pulmonary hypertension https://bit.ly/3Yvb7VR.

Die pulmonale Hypertonie bei chronischen Lungenerkrankungen (PH-CLD) ist eine der häufigsten, jedoch häufig unterdiagnostizierten Formen der pulmonalen Hypertonie (PH). Ihr Auftreten verschlechtert nachweislich Prognose und Lebensqualität der betroffenen Patient*innen. Neue epidemiologische Daten betonen die Heterogenität dieser Patientengruppe und zeigen, dass sowohl die zugrunde liegende Lungenerkrankung als auch der Schweregrad der PH für Prognose und Therapie entscheidend sind. Der 7. Weltkongress für pulmonale Hypertonie (WSPH) hat daher die Bedeutung einer systematischen Diagnostik und differenzierten Phänotypisierung von PH-CLD unterstrichen. Während einzelne Studien einen potenziellen Nutzen PH-spezifischer Therapien zeigen, berichten andere, etwa bei COPD, auch von negativen Effekten. Die vorliegende Stellungnahme der PH-DACH-Arbeitsgruppe fasst die wesentlichen Empfehlungen der 11. Task Force des 7. WSPH zusammen, bewertet die Evidenzlage kritisch und kommentiert gezielt Abweichungen vom Originaltext. Ziel ist es, einen Beitrag zur Entwicklung praxisnaher Diagnose- und Therapiealgorithmen für PH-CLD-Patienten zu leisten.

There is an unmet need for breath-based markers for pulmonary vascular disease (PVD). We developed a fully-automatic algorithm to analyze expiratory CO2flow from resting ventilation and evaluated the clinical associations of our readouts. We enrolled patients with chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary arterial hypertension (PAH) and healthy controls and evaluated fractionated volumes for dead space, mixed space (MSV) and alveolar space, their respective CO2volumes and ventilatory equivalents for CO2(EqCO2) and the maximum slope of the first derivative of the cumulative expiratory CO2volume over expired volume (MSV-slope) as primary readouts. Differences between groups were analyzed using non-parametric tests. Associations were analyzed by Spearman correlation. The discriminatory power was determined with receiver operating characteristic analysis. Eleven COPD (median (IQR) age 64 (63-69) years), 10 ILD (61 (54-77) years), 10 PAH (64 (61-73) years) and 21 healthy controls (56 (52-61) years) were investigated. Patients vs healthy controls showed increased MSV and mixed space CO2(221 (164-270) ml vs 144 (131-167) ml, and 3.9 (3.2-4.9) ml vs 3.0 (2.7-3.4) ml,p< 0.001 andp= 0.002) and EqCO2(38 (34-42) vs 30 (29-35),p< 0.001), and decreased MSV-slopes (0.16 (0.12-0.21) vs 0.27 (0.23-0.32) l CO2l-2,p< 0.001). Area under the curve (AUC) for MSV and MSV-slope for disease prediction was 0.81 (95% CI 0.69-0.93) and 0.84 (0.73-0.95), respectively. MSV and mixed space CO2were only strongly increased in COPD and ILD but not PAH, resulting in a significant difference between PAH and COPD&ILD (AUC 0.74 (95% CI: 0.56-0.92). MSV and MSV-slope were significantly correlated with DLCO (ρ=-0.69 andρ= 0.72, respectively; bothp< 0.001). Fully-automatic high-fidelity expiratory CO2flow analysis is technically feasible, easy and safe to perform, and may represent a novel approach to detect PVD with or without structural changes of the airways and lung parenchyma. Prospective studies with larger sample size are needed to validate these findings.

Chronic obstructive pulmonary disease (COPD) is a severe, progressive, and heterogeneous disease with a poor outcome. Inflammation plays a central role in disease pathogenesis; however, the interplay between immune changes and disease heterogeneity has been difficult to unravel. We performed a multilevel immunoinflammatory characterization of patients with COPD using flow cytometry, cytokine profiling, single-cell, or spatial transcriptomics in combination with machine learning algorithms. Our cross-cohort analysis demonstrated shared skewing of immune profiles in COPD lungs toward adaptive immune cells. We furthermore identified a subgroup of patients with COPD with a distinct immune profile, characterized by increased antigen-presenting cells, mast cells, and CD8+ cells, and circulating IL-1β, IFN-β, and GM-CSF, that were associated with increased emphysema severity and decreased gas exchange parameters independent of their GOLD-stage. Our findings suggest that unbiased immune profiling can refine disease classification and reveal inflammation-driven disease subtypes with potential relevance for prognosis and treatment strategies.

Evaluating the predictive role of endothelial dysfunction in the development of vasculopathy-mediated complications in patients with limited cutaneous systemic sclerosis (lcSSc). 38 patients with lcSSc who were naïve for vasculopathy-mediated complications, defined as absent pre-existing digital ulcers (DU), pulmonary hypertension (PH) and symptomatic atherosclerotic cardiovascular diseases, were prospectively observed during a 3-years follow-up period. At study enrolment, functional and laboratory parameters of endothelial dysfunction were assessed. Microvascular events, defined as the development of DU and PH, macrovascular events, defined as newly symptomatic atherosclerotic cardiovascular diseases, and clinical events, defined as additional interstitial lung disease (ILD), renal crisis and esophageal dysfunction, were recorded annually. 33 patients (86.8