Pulmonary arterial hypertension (PAH) is a fatal disease marked by pulmonary vascular remodeling. Although endothelial dysfunction and immune cell infiltration are central to its pathogenesis, the specific signaling mechanisms linking these elements remain unclear. This study investigates a novel pathway whereby endothelial cell-derived GM-CSF drives macrophage-dependent inflammation via the CCL2/CCR2 axis, ultimately promoting PAH progression through NLRP3 inflammasome activation. PAH mouse model was established using a high-fat diet (HFD) combined with L-NAME. Comprehensive in vivo assessments included echocardiography to evaluate cardiac function, Masson's Trichrome to measure vascular remodeling. In vitro, a co-culture system of mouse pulmonary arterial endothelial cells (MPAECs) and bone marrow-derived macrophages (BMDMs) was used, with palmitic acid (PA) stimulation to mimic PAH conditions. Key interventions involved administering a GM-CSF neutralizing antibody, depleting macrophages with clodronate liposomes, and utilizing Ccr2-/- mice. PAH mice exhibited significant pulmonary arterial wall thickening, right heart dysfunction, and increased lung wet-to-dry weight ratio. This was accompanied by early and sustained upregulation of GM-CSF and CCL2 in lung tissues, extensive infiltration of CCR2+ macrophages, and activation of the NLRP3 inflammasome cascade. In vitro, PA-stimulated MPAECs released GM-CSF, which promoted macrophage migration and CCL2 secretion, induced a pro-inflammatory M1 phenotype, and activated the NLRP3 pathway. Crucially, in vivo therapeutic interventions demonstrated that neutralizing GM-CSF, depleting macrophages, or knocking out Ccr2 all significantly alleviated PAH pathology. This study confirms that endothelial cell-derived GM-CSF promotes macrophage-NLRP3 inflammasome via the CCL2/CCR2 axis, thereby driving the progression of PAH. This axis may represent a promising therapeutic target for PAH.

Therapeutic effects of fingolimod through sphingosine-1-phosphate signaling in pulmonary arterial hypertension.

USP15 promotes proliferation, migration, and apoptosis resistance of pulmonary arterial smooth muscle cells by targeting MDM2.

The impact of age on six-minute walk distance, functional class, and right ventricular function in pulmonary arterial hypertension.

Improving mitochondrial health by pyrroloquinoline quinone (PQQ) prevents ultrafine carbon particle (UFCP) induced emphysema and associated pulmonary hypertension.

Silencer-regulated circLSM14A inhibits autophagy of pulmonary artery smooth muscle cells through parental protein LSM14A.

Hypoxia-inducible factor-1α in cardiovascular disease, mechanistic insights, pathophysiological roles, and therapeutic targeting strategies.

Introduction: Bronchial anthracosis is a chronic respiratory condition characterised by the deposition of carbon particles in the bronchial mucosa. It is frequently associated with prolonged exposure to environmental pollutants, biomass smoke, and occupational dust, particularly in low-resource and rural settings. Aim: To elucidate the clinical and microbiological profile of patients with bronchial anthracosis in the mountainous valley of Kashmir, India. Materials and Methods: This cross-sectional study involved 88 patients diagnosed with bronchial anthracosis who were recruited from a tertiary care hospital. Data were collected on demographics, co-morbidities, exposure history, and microbiological findings through Bronchoalveolar Lavage (BAL). Statistical analysis was performed using percentage distribution and logistic regression analysis. Results: The mean age of the patients was 62.4±8.7 years, with females comprising 59.0% of the study population. Biomass fuel exposure (34.1%) and smoking (39.8%) were identified as significant risk factors. Common co-morbidities included Chronic Obstructive Pulmonary Disease (COPD) and hypertension. The chief complaints were cough (26.1%) and breathlessness (13.6%). BAL analysis revealed various pathogens, with Mycobacterium tuberculosis identified in 10.2% of cases. Logistic regression analysis demonstrated significant associations between bronchial anthracosis and age, smoking, and biomass fuel exposure, emphasising the influence of environmental risk factors. Conclusion: The findings highlight the significant role of environmental and occupational exposures—particularly biomass fuel use and smoking—in the development of bronchial anthracosis. Older adults, especially housewives and farmers, were the most affected groups, emphasising the need for targeted public health interventions. The association of bronchial anthracosis with respiratory infections and comorbidities such as COPD underscores the importance of early detection and appropriate management. Preventive strategies, including reduction of indoor air pollution and implementation of smoking cessation programmes, are essential to mitigate the disease burden in the ethnic population of Kashmir, India.

Therapeutic venesection is a cornerstone in the management of polycythaemia to reduce hyperviscosity and thrombotic risk. However, its application in patients receiving anticoagulation, particularly heparin, is complex due to the potential for bleeding complications. The current case report describes a 40-year-old male who presented with progressive breathlessness, fatigue, and pedal oedema. Laboratory investigations revealed polycythaemia with elevated haemoglobin and haematocrit levels. The patient was diagnosed with acute pulmonary thromboembolism and severe pulmonary artery hypertension. He was initiated on unfractionated heparin therapy. Due to persistent symptoms and hyperviscosity, therapeutic venesection was performed after temporarily withholding heparin. A total volume of 450 mL of blood was removed. The procedure was well tolerated, with stable vital signs, and the patient showed symptomatic improvement following venesection. The present case highlights the therapeutic benefit and safety of venesection in a patient with polycythaemia and pulmonary thromboembolism receiving anticoagulation. Meticulous risk assessment, temporary cessation of anticoagulation at the time of venesection, and strict procedural monitoring were critical in preventing complications. A multidisciplinary approach ensured optimal patient outcomes. The novelty of the current case lies in the successful integration of therapeutic venesection in a high-risk anticoagulated patient, guided by an individualized risk-benefit assessment and coordinated multidisciplinary management to optimise safety and outcomes in complex thrombotic scenarios.

Calycosin ameliorates high-altitude pulmonary edema by regulating macrophage polarization through the PPAR-γ/NF-κB pathway: a comprehensive analysis of network pharmacology, molecular docking, and experimental validation.

Association of pulmonary arterial end-diastolic forward flow and right heart remodeling in dogs with congenital pulmonic stenosis and precapillary pulmonary hypertension.

Rheumatic fever is endemic in our part of the world. Arthritis is the most common clinical presentation and is characteristically migratory in nature. Rheumatoid-like arthritis in acute rheumatic fever is not described in literature. Although arthritis is typically treated with nonsteroidal anti-inflammatory drugs, the role of hydroxychloroquine remains less well studied. A 24-year-old Pakistani female individual presented with symmetrical polyarthritis involving the small joints of the hands along with morning stiffness. She was diagnosed with rheumatic heart disease in 2011, when she initially presented with arthritis and mild mitral regurgitation. On current evaluation, her echocardiography showed worsening heart disease, with severe mitral regurgitation, moderate aortic regurgitation, moderate tricuspid regurgitation, severe pulmonary hypertension, and good biventricular systolic function. Her antistreptolysin O titer and C-reactive protein levels were raised. She was started on nonsteroidal anti-inflammatory drugs but showed no response.The patient was referred to a rheumatologist and managed with immunosuppressive drugs, including hydroxychloroquine. Her arthritis settled, the aortic regurgitation regressed, and she was discharged in stable condition following mitral valve replacement. Features favoring rheumatic arthritis in this case included the presence of rheumatic heart disease, elevated antistreptolysin O titer, and response to benzathine penicillin. Features suggestive of rheumatoid arthritis included poor response to nonsteroidal anti-inflammatory drugs and the pattern of joint involvement (symmetrical polyarthritis of the small joints of the hands with morning stiffness). Group A streptococcal infection can trigger interleukin-1 beta-mediated granulocyte-monocyte colony-stimulating factor and interferon gamma + CD4 T cell expansion, mechanisms implicated in autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus. Similarly, granulocyte-monocyte colony-stimulating factor plays an important role in the pathogenesis of rheumatic heart disease following acute rheumatic fever. Hydroxychloroquine suppresses granulocyte-monocyte colony-stimulating factor and may therefore be effective in these patients. Immunosuppressive drugs may be beneficial in treating these patients, as they behave exactly the same way as patients of other autoimmune disorders. Streptococcus acts as a trigger for the activation of the immune system. The clinical picture can vary depending upon the immune response activated.

Exercise testing in chronic thromboembolic pulmonary hypertension and chronic thromboembolic pulmonary disease without pulmonary hypertension: a comprehensive systematic review and meta-analysis.

Platelet gene signatures detecting pulmonary artery stenosis in patients with pulmonary hypertension.

Persistent pulmonary hypertension of newborn (PPHN) occurs due to the impairment in the expected fall in pulmonary vascular resistance during the fetal to neonatal circulatory transition, with a prevalence of 1.9 per 1000 live births, and a significant mortality rate of 4-33%. We aimed to systematically review the genetic variants associated with PPHN in term and late preterm infants without a known genetic syndrome. In February 2025, the MEDLINE OVID, SCOPUS, and COCHRANE databases were searched for eligible studies without publication date restriction. Our review included cohort studies, case-control studies, and case series that examined the association of PPHN and genetic variants in term and late preterm infants. We extracted data regarding the methodology, participant characteristics, and outcome measures. We included nine studies (7 case-control studies and 2 cohort studies) that enrolled 1,494 participants. The risk of bias assessment using the Quality of Genetic Association Studies tool showed that 91% of the studies were of moderate or good quality. Our review found reports of positive associations between specific genetic variants in genes such as CPS1, CRHR1, NOTCH3, EDN1, EPAS1, WWC2, ABCA3, RFX3, EP300, GNA11, PKLR, SLC2A1, BMPR2, and EGLN1. One study reported no association between an ACE gene variant and PPHN. Studies of common genetic variants associated with an increased risk of PPHN in term and late preterm infants are limited, based on small cohorts and frequently focused on small sets of candidate genes, yielding inconsistent results across studies.

Eisenmenger syndrome and pulmonary arterial hypertension (PAH) due to unrepaired congenital shunts, including atrial septal defect (ASD), ventricular septal defect (VSD) and patent ductus arteriosus (PDA), remain life-threatening conditions despite advances in congenital heart disease (CHD) care. In this population, vasodilator-based therapies effective in other forms of PAH have shown limited benefit, and no disease-modifying treatment has been established. Sotatercept, an activin-signalling inhibitor, improved exercise capacity and haemodynamics in phase 2/3 PAH trials; however, patients with unrepaired CHD, including Eisenmenger syndrome, were excluded. The efficacy and safety of sotatercept in this population remain unknown. The SuMILE trial is a prospective, exploratory, multicentre, open-label, randomised, controlled trial conducted at 11 Japanese tertiary centres. 36 adults with vasodilator-resistant PAH due to unrepaired ASD, VSD or PDA, including Eisenmenger syndrome, will be randomised 2:1 to sotatercept add-on therapy plus vasodilator-based PAH therapy versus vasodilator-based PAH therapy alone. Sotatercept will be administered subcutaneously every 3 weeks in accordance with label-approved dose-modification rules for haemoglobin and platelet changes. The primary endpoint is the change in 6-min walk distance from baseline to week 24. Key clinical events will be independently adjudicated. Secondary endpoints include all-cause mortality or lung transplantation; pulmonary hypertension-related hospitalisation or initiation of parenteral prostacyclin and changes in WHO functional class, N-terminal pro-brain natriuretic peptide and emPHasis-10. Exploratory endpoints include genotype, right heart catheterisation and cardiac MRI parameters. The primary analysis will use ANCOVA, adjusting for baseline 6-min walk distance and randomisation stratum in the intention-to-treat population. The protocol has been reviewed and approved by the certified central review board (Kyushu University Hospital Clinical Ethics Review Board) and participating institutions. Written informed consent will be obtained from all participants. Findings will be disseminated through peer-reviewed journals, scientific conferences and trial registries. Japan Registry of Clinical Trials no. 1071250069; ClinicalTrials.gov NCT07356778. Protocol version and date: V.1.3; 23 October 2025.

Right atrial phasic strain in risk stratification of patients with Pulmonary Arterial Hypertension.

In the A DUE study, a fixed-dose combination of macitentan 10mg and tadalafil 40mg (M/T FDC) as a single tablet significantly improved pulmonary vascular resistance at Week 16 versus corresponding monotherapies in patients with pulmonary arterial hypertension (PAH). Safety was consistent with known profiles of macitentan and tadalafil. The open-label (OL) period of A DUE provides long-term safety/efficacy data for M/T FDC. In A DUE (NCT03904693), patients were randomized (2:1:1) to double-blind M/T FDC, macitentan 10 mg or tadalafil 40 mg and followed for 16 weeks. They then transitioned to OL M/T FDC and were followed for up to 2years to end of study (EOS). Efficacy analyses, including survival, changes in six-minute walk distance (6MWD) and N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline, are reported in patients randomized to M/T FDC at start of A DUE (efficacy set). Safety is reported for all patients receiving M/T FDC at any time during the double-blind (DB) and/or OL (safety set). In A DUE, 185 patients received M/T FDC for median (range) of 105.1 (0.6, 182.6) weeks. In the efficacy set, 91% of patients were alive at EOS. Mean (SD) change in 6MWD from M/T FDC initiation to OL Week 120 was 60.5m (84.2). For NT-proBNP, geometric mean percent of baseline was 50.2% at OL Week 120. In the safety set, adverse events (AEs) occurred in 94.1% and serious AEs in 33.5% of patients; 10.3% discontinued study treatment due to an AE. Seven on-treatment deaths occurred in those receiving M/T FDC; all were evaluated as unrelated to treatment. Long-term treatment with single-tablet combination of macitentan/tadalafil was well tolerated, with no new safety findings identified. Most patients were alive at EOS. Incremental improvements in 6MWD and NT-proBNP observed in the DB with M/T FDC were sustained over 2years. ClinicalTrials.gov Identifier NCT03904693. A graphical abstract is also available for this article.

This review focuses on describing the potential pathogenic roles of endothelial Ca2+ and K+ signaling in the development and progression of pulmonary hypertension through its putative regulation of cellular senescence and inflammasome activation. Ca2+ influx through mechanosensitive and receptor-operated cation channels and Ca2+ release from the endoplasmic reticulum are involved in upregulating the cell cycle inhibitors p53, p21, and p16 (which result in cellular senescence) by activating the AKT/mTORC1 pathway in lung vascular endothelial cells. A rise in cytosolic Ca2+ concentration, resulting from Ca2+ influx and release in lung vascular endothelial cells, is also necessary to activate both canonical (NLRP3 [NOD-like receptor family pyrin domain-containing 3]) and noncanonical inflammasomes, thereby promoting vascular and perivascular inflammation. Furthermore, K+ efflux through multiple types of K+-permeable channels and pores (eg, K+ ionophores, toxin-formed pores/channels, nonselective cation channels, and Ca2+-activated K+ channels) is sufficient for canonical (NLRP3) inflammasome activation. The senescent endothelial cells release senescence-associated secretory phenotype factors that subsequently cause endothelial-to-mesenchymal transition in adjacent endothelial cells and promote cell proliferation/migration in adjacent smooth muscle cells and (myo)fibroblasts, leading to vascular remodeling and occlusive intimal lesions, and pulmonary hypertension.

Pulmonary hypertension (PH) is a common sequela of interstitial lung diseases (ILDs) and is associated with poor prognosis and quality of life. The diagnosis and management of PH associated with ILD (ILD-PH) are challenging, due in part to the heterogeneity of ILD subtypes, difficulty distinguishing symptoms and signs of ILD progression from manifestations of PH, lack of specific biomarkers, and the requirement of invasive right heart catheterisation (RHC) to diagnose and assess the severity of PH. This state-of-the-art review provides a comprehensive overview of the clinical characteristics, pathophysiology, diagnosis, prognosis, and treatment of ILD-PH. It also identifies promising areas for future research, such as the development and validation of novel biomarkers and imaging techniques and further evaluation of the efficacy and safety of pharmacologic therapies for PH in patients with ILD. Given the inherent complexity of diagnosing and managing heterogeneous ILD subtypes, there is a clear need for multidisciplinary and personalised care strategies for ILD-PH. Dedicated attention and further research to improve diagnostic and treatment interventions are warranted to help develop much-needed, evidence-based guidelines and to improve outcomes that are meaningful for patients with ILD-PH.