Erythrophagocytosis induced ferroptosis contribute to pulmonary microvascular thrombosis and thrombotic vascular remodeling in pulmonary arterial hypertension.

BACKGROUND: Whether primary or just as a complication from the progression of pulmonary arterial hypertension (PAH), thrombosis seems to be an important player in this condition. The cross-talk between red blood cells (RBCs) and pulmonary microvascular endothelial cells (PMVECs) and their role in PAH remain undefined. OBJECTIVES: The goals of this study were to assess the role of RBC-PMVEC interaction in microvascular thrombosis and thrombotic vascular remodeling under hypoxic conditions. METHODS: We established an in vitro hypoxic co-incubation model of RBC and PMVEC as well as a hypoxic mice model. We investigated erythrophagocytosis (EP), ferroptosis, thrombosis tendency, and pulmonary hemodynamics in experimental PAH. RESULTS: We showed that increased EP in PMVEC triggered ferroptosis, enhanced procoagulant activity, and exacerbated vessel remodeling under hypoxic conditions. In the PAH mice model induced by chronic hypoxia, EP-induced ferroptosis followed by upregulated TMEM16F led to a high tendency of thrombus formation and thrombotic vascular remodeling. Inhibition of ferroptosis or silence of TMEM16F could alleviate hypercoagulable phenotype, reverse right ventricular (RV) systolic pressure, RV hypertrophy index, and remodeling of pulmonary vessels. CONCLUSIONS: These results illustrate the pathogenic RBC-PMVEC interactions in PAH. Inhibition EP, ferroptosis, or TMEM16F could be a novel therapeutic target to prevent PAH development and thrombotic complications.

Alpha-adducin 1 (rs4961) gene and its expression associated with sodium sensitivity in hypertensive patients: a cohort study in the western Ukrainian population.

Objective. The aim of this study was to evaluate the association of the α-adducin-1 gene (ADD1) (Gly460Trp [rs4961]) polymorphism and its expression in association with renal dysfunction and sodium sensitivity in hypertensive patients in western Ukrainian population. Methods. One-hundred patients with essential arterial hypertension (EAH) and hypertensive-mediated target organ damage (stage 2), moderate, high, and very high cardiovascular risk were enrolled in case-control study. Sixty healthy individuals were assigned as controls. Sodium sensitivity and sodium resistance were determined by salt load reaction. The ADD1 (rs4961) genotyping was performed in RT-PCR. Results. The expression of the quantitative trait loci (eQTL) of ADD1 gene (rs4961) (chr4:2906707 [hg19]) was confirmed in 37 tissues and organs with 23 phenotypic traits. Two hundred eQTL associations revealed - all cis-variants (cis-QTL); 73 methylation QTL (mQTL), 34 splicing QTL (sQTL), 14 histone modification QTL (hQTL), 2 protein QTL (pQTL), 23 transcript utilization QTL (tuQTL), and 4 loci of incorporated long noncoding areas of RNA (lncRNA). GG-genotype unreliably enhances EAH risk (OR=1.92; 95%CI: 0.90-4.10; p=0.066). Sodium sensitivity was observed in 54.0% of patients and in 20.0% of controls (c2=17.89; p<0.001). Sodium sensitivity in T-allele carriers of the ADD1 gene (1378G>T; rs4961) dominated 12-fold in general (OR 95%CI: 2.24-64.29; p=0.001), in women - 4.71 times (OR 95%CI: 1.92-11.56; p<0.001), and in men - 4.09 times (OR 95%CI: 1.03-16.28; p=0.041). Sodium sensitivity elevated the likelihood of severe EAH twice (OR=2.19; OR 95%CI: 1.00-5.05; p=0.049). Conclusion. T-allele associates with sodium sensitivity in essential arterial hypertension patients and increases the risk of hypertension regardless the gender. Sodium sensitivity enhances the probability of severe essential arterial hypertension in observed population.

Sex-specific Genetic Determinants of Right Ventricular Structure and Function.

RATIONALE: While sex differences in right heart phenotypes have been observed, the molecular drivers remain unknown. OBJECTIVES: To provide biological insights into sex differences in the structure and function of the right ventricle (RV) using common genetic variation. METHODS: RV phenotypes were obtained from cardiac magnetic resonance imaging in 18,156 women and 16,171 men from the UK Biobank. Observational analyses and sex-stratified genome-wide association studies were performed. Candidate female-specific loci were evaluated against invasively measured cardiac performance in 479 female patients with idiopathic or heritable pulmonary arterial hypertension (PAH), recruited to the UK NIHR BioResource Rare Diseases study. MEASUREMENTS AND MAIN RESULTS: Sex was associated with differences in RV volumes and ejection fraction in models adjusting for left heart counterparts, blood pressure, lung function and sex hormone levels. Six genome-wide significant loci (13%) revealed heterogeneity of allelic effects between women and men, and significant sex-by-genotype interaction. These included two sex-specific candidate loci present in women only: a locus for RV ejection fraction in BMPR1A and a locus for RV end-systolic volume near DMRT2. Epigenetic data in RV tissue indicate that variation at the BMPR1A locus likely alters transcriptional regulation. In female patients with PAH, a variant located in the promoter of BMPR1A was significantly associated with cardiac index (effect size 0.16 l/min/m2), despite similar RV afterload. CONCLUSIONS: BMPR1A has emerged as a biologically plausible candidate gene for female-specific genetic determination of RV function, showing associations with cardiac performance under chronically increased afterload in female patients with PAH.

A Belgian consensus on sotatercept for the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare disease affecting the small pulmonary vessels, ultimately leading to right ventricular failure and death. Current treatment options target three different pathways (endothelin, nitric oxide/cGMP and prostacyclin pathways). Despite their demonstrated efficacy, these therapies (commonly used in combination) do not cure the disease which is why novel pathways beyond the traditional 'big three' are being developed. Sotatercept is a ligand trap for multiple proteins within the TGF-ß superfamily that was recently approved in the US for the treatment of PAH. Unlike currently available therapies, sotatercept has the potential to act as an anti-remodelling agent rather than a vasodilator. The safety and efficacy of subcutaneous (SC) sotatercept have been established in two multicentre, placebo-controlled randomised-controlled trials. The compound has been shown to consistently improve a variety of measurable endpoints, including exercise capacity, haemodynamics, quality of life and delay of clinical worsening. The drug appears to have an acceptable safety profile, although it is associated with an increased risk in developing telangiectasia and biological changes affecting platelet counts and haemoglobin. This study reviews the current evidence on SC sotatercept and provides a Belgian perspective on its place in the future treatment strategy for PAH.

The role of anticoagulation on the long-term survival of patients with pulmonary arterial hypertension: A meta-analysis of 15 cohort studies.

INTRODUCTION: Anticoagulation was once recommended for patients with pulmonary arterial hypertension (PAH). However, its survival benefit still remained controversial. We performed a meta-analysis to evaluate the effect of anticoagulation on the long-term survival of PAH patients. METHODS: The PubMed, EMBASE, Web of Science, and WanFang electronic database were searched for eligible studies. Pooled hazard ratios (HRs) with 95 % confidence intervals (CIs) were calculated for effect estimate regarding anticoagulation on the survival of PAH patients. RESULTS: Fifteen cohort studies involving 4266 PAH patients were included. Approximately 45.8 % patients received anticoagulation. The mean follow-up period ranged from 2.1 to 14 years. Anticoagulation had a tendency to, however, did not significantly reduce mortality of PAH patients (HR: 0.86, 95 % CI: 0.73-1.02). In subgroup analysis, anticoagulation decreased the mortality risk as analyzed from retrospective studies (HR: 0.80, 95 % CI: 0.65-0.98), but not prospective studies (HR: 0.95, 95 % CI: 0.70-1.29). For both idiopathic PAH (IPAH) and connective tissue disease associated PAH (CTD-PAH), anticoagulation therapy did not significantly improve the long-term survival rate (HR: 0.83, 95 % CI: 0.65-1.07, and HR: 1.05, 95 % CI: 0.77-1.42, respectively), and this result remained unchanged when pooling data from either retrospective or prospective studies. Further analysis showed that anticoagulation had no advantage in reducing mortality in patients with systemic sclerosis associated PAH, systemic erythematosus lupus related PAH (free of antiphospholipid syndrome), or CTD-PAH of non-specified etiology. CONCLUSION: Anticoagulation may not reduce the long-term mortality of PAH patients, including those with IPAH and CTD-PAH. In the management of PAH, anticoagulants should be prescribed with caution before comprehensive risk to benefit evaluation. Larger and more vigorously designed controlled trials are warranted.

Prolonged Time-to-antihypertensive Therapy Worsens Organ Damage and Blood Pressure Control in Arterial Hypertension.

INTRODUCTION: Delay in arterial hypertension (AH) diagnosis and late therapy initiation may affect progression towards hypertensive-mediated organ damage (HMOD) and blood pressure (BP) control. AIM: We aimed to assess the impact of time-to-therapy on BP control and HMOD in patients receiving AH diagnosis. METHODS: We analysed data from the Campania Salute Network, a prospective registry of hypertensive patients (NCT02211365). At baseline visit, time-to-therapy was defined as the interval between the first occurrence of BP values exceeding guidelines-directed thresholds and therapy initiation; HMOD included left ventricular hypertrophy (LVH), carotid plaque, or chronic kidney disease. Optimal BP control was considered for average values < 140/90 mmHg. Low-risk profile was defined as grade I AH without additional cardiovascular risk factors. RESULTS: From 14,161 hypertensive patients, we selected 1,627 participants who were not on antihypertensive therapy. This population was divided into two groups based on the median time-to-therapy (≤ 2 years n = 1,009, > 2 years n = 618). Patients with a time-to-therapy > 2 years had higher risk of HMOD (adjusted odds ratio, aOR:1.51, 95%, CI:1.19-1.93, p < 0.001) due to increased risks of LVH (aOR:1.43, CI:1.12-1.82, p = 0.004), carotid plaques (aOR:1.29, CI:1.00-1.65, p = 0.047), and chronic kidney disease (aOR:1.68, CI:1.08-2.62, p = 0.022). Time-to-therapy > 2 years was significantly associated with uncontrolled BP values (aOR:1.49, CI:1.18-1.88, p < 0.001) and higher number of antihypertensive drugs (aOR:1.68, CI:1.36-2.08, p < 0.001) during follow-up. In low-risk subgroup, time-to-therapy > 2 years did not impact on BP control and number of drugs. CONCLUSIONS: In hypertensive patients, a time-to-therapy > 2 years is associated with HMOD and uncontrolled BP.

Effects of Catheter-Based Renal Denervation in Hypertension: A Systematic Review and Meta-Analysis.

BACKGROUND: Several sham-controlled trials have investigated the efficacy and safety of catheter-based renal denervation (RDN) with mixed outcomes. We aimed to perform a comprehensive meta-analysis of all randomized, sham-controlled trials investigating RDN with first- and second-generation devices in hypertension. METHODS: We searched MEDLINE and the Cochrane Library for eligible trials. Outcomes included both efficacy (24-hour and office systolic [SBP] and diastolic blood pressure [DBP]) and safety (all-cause death, vascular complication, renal artery stenosis >70%, hypertensive crisis) of RDN. We performed a study-level, pairwise, random-effects meta-analysis of the summary data. RESULTS: Ten trials comprising 2478 patients with hypertension while being either off or on treatment were included. Compared with sham, RDN reduced 24-hour and office systolic blood pressure by 4.4 mm Hg (95% CI, 2.7 to 6.1; P<0.00001) and 6.6 mm Hg (95% CI, 3.6 to 9.7; P<0.0001), respectively. The 24-hour and office diastolic blood pressure paralleled these findings (-2.6 mm Hg [95% CI, -3.6 to -1.5]; P<0.00001; -3.5 mm Hg [95% CI, -5.4 to -1.6]; P=0.0003). There was no difference in 24-hour and office systolic blood pressure reduction between trials with and without concomitant antihypertensive medication (P for interaction, 0.62 and 0.73, respectively). There was no relevant difference in vascular complications (odds ratio, 1.69 [95% CI, 0.57 to 5.0]; P=0.34), renal artery stenosis (odds ratio, 1.50 [95% CI, 0.06 to 36.97]; P=0.80), hypertensive crisis (odds ratio, 0.65 [95% CI, 0.30 to 1.38]; P=0.26), and all-cause death (odds ratio, 1.76 [95% CI, 0.34 to 9.20]; P=0.50) between RDN and sham groups. Change of renal function based on estimated glomerular filtration rate was comparable between groups (P for interaction, 0.84). There was significant heterogeneity between trials. CONCLUSIONS: RDN safely reduces ambulatory and office systolic blood pressure/diastolic blood pressure versus a sham procedure in the presence and absence of antihypertensive medication.

A new day has come: Sotatercept for the treatment of pulmonary arterial hypertension.

Despite increasing therapeutic options and evolving treatment strategies, including targeting three therapeutic pathways, in the management of pulmonary arterial hypertension (PAH), morbidity and mortality have remained unacceptably high. Sotatercept is a first-in-class, novel activin signaling inhibitor approved for treating PAH based on evolving efficacy and safety evidence. This state-of-the-art review summarizes the current understanding of the mechanism of action, the impact on outcomes that improve how patients feel, function, and survive, and the safety and adverse event profile to inform readers of this breakthrough novel therapy.

Circulating extracellular vesicles as novel biomarkers for pulmonary arterial hypertension in patients with systemic lupus erythematosus.

Introduction: Pulmonary arterial hypertension (PAH) is a serious complication of systemic lupus erythematosus (SLE) with increased mortality. A prothrombotic state may contribute to pathogenesis of SLE-PAH. Extracellular vesicles (EVs) are known to be associated with thrombosis. Here, we investigated circulating EVs and their associations with SLE-PAH. Methods: Eighteen SLE-PAH patients, 36 SLE-non-PAH patients, and 36 healthy controls (HCs) were enrolled. Flow cytometry was used to analyze circulating EVs from leukocytes (LEVs), red blood cells (REVs), platelets (PEVs), endothelial cells (EEVs), and Annexin V+ EVs with membrane phosphatidylserine (PS) exposure. Results: Plasma levels of all EV subgroups were elevated in SLE patients with or without PAH compared to HCs. Furthermore, plasma Annexin V+ EVs, LEVs, PEVs, REVs, EEVs, and Annexin V+ REVs were significantly elevated in SLE-PAH patients compared to SLE-non-PAH patients. Additionally, PAH patients with moderate/high SLE showed a significant increase in LEVs, PEVs, REVs, Annexin V+ EVs, and Annexin V+ REVs compared to SLE-non-PAH patients. However, PAH patients with inactive/mild SLE only exhibited elevations in Annexin V+ EVs, REVs, and Annexin V+ REVs. In the SLE-PAH patients, EEVs were positively correlated with pulmonary arterial systolic pressure, while PEVs and EEVs were positively correlated with right ventricular diameter. Moreover, the receiver operating characteristic curve indicated that Annexin V+ EVs, LEVs, PEVs, REVs, EEVs and Annexin V+ REVs could predict the presence of PAH in SLE patients. Importantly, multivariate logistic regression analysis showed that circulating levels of LEVs or REVs, anti-nRNP antibody, and serositis were independent risk factors for PAH in SLE patients. Discussion: Findings reveal that specific subgroups of circulating EVs contribute to the hypercoagulation state and the severity of SLE-PAH. Higher plasma levels of LEVs or REVs may serve as biomarkers for SLE-PAH.

Suppressing the expression of steroidogenic acute regulatory protein (StAR) in the myocardium by spironolactone contributes to the improvement of right ventricular remodeling in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive condition that frequently leads to right ventricular (RV) remodeling. Aldosterone promotes vascular and RV remodeling. The upregulation of steroidogenic acute regulatory protein (StAR) stimulates aldosterone synthesis. However, the expression of StAR in the myocardium under PAH conditions remains unknown. To investigate the expression of StAR in the myocardium and its association with RV remodeling in PAH, utilizing spironolactone as a treatment. A PAH model was created using male Sprague-Dawley rats, which received a subcutaneous injection of Sugen5416 (20 mg/kg) and were exposed to hypoxia (10% O2) for 2 weeks, followed by 2 weeks of normoxia. The animals were then divided into two groups, with one group receiving spironolactone (25 mg/kg/day) for an additional 4 weeks, while the other group did not. H9c2 cells were cultured under hypoxic conditions (37 °C, 1% O2, 5% CO2) with or without spironolactone treatment. In the model rats, RV systolic pressure and the Fulton index, both of which increased upon exposure to Sugen5416 and hypoxia, significantly decreased with spironolactone treatment. In H9c2 cells, hypoxic exposure elevated aldosterone levels, while spironolactone treatment significantly suppressed aldosterone production. Suppression of StAR expression in the myocardium via spironolactone contributes to the improvement of RV remodeling in PAH. Spironolactone may offer a valuable therapeutic strategy for RV remodeling in patients with PAH.

Diagnostic utility of sortilin & other biomarkers in the diagnosis of carotid & coronary atherosclerosis in individuals with arterial hypertension.

Background & objectives Cardiovascular diseases (CVDs) are a leading cause of mortality worldwide. The aim of this investigation was to study the role of biological markers in predicting the risk of carotid and coronary artery atherosclerosis. Methods A total of 161 males in the age group of 30-65 yr were included in this study. All participants underwent biochemical analyses [cholesterol, low density lipoprotein cholesterol (LDL-C), triglycerides, glucose, (interleukin) IL-8, IL-10, (proprotein convertase inhibitors subtilisin/kexin type 9) PCSK9, sortilin, creatinine]; ECG; echocardiography; coronary angiography; ultrasound doppler of brachiocephalic arteries. Based on PCSK9 levels, participants were divided into four groups: group 1, n=41 individuals with PCSK9 level of 100-250 ng/ml; group 2, n=37 individuals with PCSK9 level of 251-400 ng/ml; group 3, n=51 individuals with PCSK9 level of 401-600 ng/ml and group 4, n=32 individuals with PCSK9 level of 601-900 ng/ml. Results Sortilin level was the highest in group 2. Group 3 individuals had the highest level of IL-8. Correlation analysis of the entire data set revealed the relationship of relative left ventricular thickness index with age, cardiovascular risk, body mass index, intima-media thickness and left ventricular mass index; sortilin had a negative relationship of weak strength with age and smoking, a direct relationship between the risk of cardiovascular complications and with IL-10. Interpretation & conclusions Sortilin is the innovative marker of CVDs. In the present investigation, we demonstrated the clear increase in the inflammatory markers (IL-8) in individuals with subclinical atherosclerosis. This fact can be explained by the oxygen stress activation. In individuals with coronary artery stenosis (50% and more), the increase in IL-10 levels demonstrates, to our opinion, the activation of antioxidant protection activation.

Coronary artery calcification is prevalent in systemic sclerosis and is associated with adverse prognosis.

Objective: Coronary artery calcification assessed on thoracic computed tomography represents the calcific component of established coronary artery disease, is a biomarker of total atheromatous plaque burden and predicts mortality. Systemic sclerosis is a pro-inflammatory condition, and inflammation is also a driver of coronary artery disease. We assessed coronary artery calcification prevalence, mortality risk and potential clinical impact on primary prevention in a cohort of patients with systemic sclerosis, differentiated by clinical phenotype including the presence of interstitial lung disease and pulmonary arterial hypertension. Methods: Retrospective analysis of 258 computed tomographies in systemic sclerosis patients from three prospectively maintained clinical and research databases at a single tertiary rheumatology/pulmonary hypertension (PH) service between March 2007 and September 2020 (mean age = 65 ± 12, 14% male). Co-morbidities, statin prescription and all-cause mortality were recorded. Patients were subtyped according to underlying systemic sclerosis complications. Computed tomographies were re-reviewed for coronary artery calcification; severity was graded using a 4-point scale per vessel and summed for total coronary artery calcification score. The impact of reporting coronary artery calcification was assessed against pre-existing statin prescriptions. Results: Coronary artery calcification was present in 58% (149/258). Coronary artery calcification was more prevalent in systemic sclerosis-pulmonary arterial hypertension than in systemic sclerosis subgroups with interstitial lung disease or without pulmonary arterial hypertension, controlling for age, sex, co-morbidities and smoking status (71%; χ 2(13) = 81.4; p < 0.001). The presence and severity of coronary artery calcification were associated with increased risk of mortality independently of age and co-morbidities (hazard ratio = 2.8; 95% confidence interval = 1.2-6.6; p = 0.018). The 'number needed to report' coronary artery calcification presence to potentially impact management was 3. Conclusions: Coronary artery calcification is common in systemic sclerosis. Coronary artery calcification predicts mortality independently of age and confounding co-morbidities which suggests this finding has clinical relevance and is a potential target for screening and therapeutic intervention.

Immunoregulatory Macrophages Modify Local Pulmonary Immunity and Ameliorate Hypoxic Pulmonary Hypertension.

BACKGROUND: Macrophages play a significant role in the onset and progression of vascular disease in pulmonary hypertension, and cell-based immunotherapies aimed at treating vascular remodeling are lacking. To evaluate the effect of pulmonary administration of macrophages modified to have an anti-inflammatory/proresolving phenotype in attenuating early pulmonary inflammation and progression of experimentally induced pulmonary hypertension. METHODS: Mouse bone marrow-derived macrophages were polarized in vitro to a regulatory (M2reg) phenotype. M2reg profile and anti-inflammatory capacity were assessed in vitro upon lipopolysaccharide/IFNγ (interferon-γ) restimulation, before their administration to 8- to 12-week-old mice. M2reg protective effect was evaluated at early (2-4 days) and late (4 weeks) time points during hypoxia (8.5% O2) exposure. Levels of inflammatory markers were quantified in alveolar macrophages and whole lung, while pulmonary hypertension development was ascertained by right ventricular systolic pressure (RVSP) and right ventricular hypertrophy measurements. Bronchoalveolar lavage from M2reg-transplanted hypoxic mice was collected and its inflammatory potential evaluated on naive bone marrow-derived macrophages. RESULTS: M2reg macrophages expressing Tgfß, Il10, and Cd206 demonstrated a stable anti-inflammatory phenotype in vitro, by downregulating the induction of proinflammatory cytokines and surface molecules (Cd86, Il6, and Tnfα) upon a subsequent proinflammatory stimulus. A single dose of M2reg attenuated hypoxic monocytic recruitment and perivascular inflammation. Early hypoxic lung and alveolar macrophage inflammation leading to pulmonary hypertension development was significantly reduced, and, importantly, M2reg attenuated right ventricular hypertrophy, right ventricular systolic pressure, and vascular remodeling at 4 weeks post-treatment. CONCLUSIONS: Adoptive transfer of M2reg halts the recruitment of monocytes and modifies the hypoxic lung microenvironment, potentially changing the immunoreactivity of recruited macrophages and restoring normal immune functionality of the lung. These findings provide new mechanistic insights into the diverse role of macrophage phenotype on lung vascular homeostasis that can be explored as novel therapeutic targets.

Appraisal and evaluation of the quality of life in pulmonary arterial hypertension instruments: A systematic review using COSMIN methodology.

AIM: The aim of this review was to identify specific instruments currently available for measuring quality of life in patients with pulmonary arterial hypertension (PAH) and to evaluate their psychometric properties in order to provide robust evidence for their application in clinical practice. BACKGROUND: Pulmonary arterial hypertension is a rare pulmonary vascular disorder predominantly affecting women aged 30-50 years. It leads to elevated pulmonary artery pressure, causing increased cardiac workload. Symptoms such as dyspnea and fatigue progressively deteriorate. Given the substantial impact on patient well-being, quality of life assessment is a critical concern. Generic quality of life measures often fail to capture the unique challenges associated with PAH. Therefore, identifying a PAH-specific quality of life instrument is essential for optimising patient management. DESIGN: A systematic literature review. METHODS: A systematic review was performed to assess the psychometric properties of quality of life instruments for PAH patients, following the 2018 Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) guidelines. The literature search was conducted across Pubmed, Scopus, CINAHL, EMBASE, and APA PsycINFO databases. RESULTS: This review included four quality of life instruments: CAMPHOR, LPHQ, emPHasis-10, and PAH-SYMPACT. CAMPHOR and PAH-SYMPACT received a GRADE A rating, while LPHQ and emPHasis-10 were rated GRADE B. Despite some sample size limitations, these instruments demonstrated varying degrees of internal reliability, validity, and content coverage for assessing quality of life in pulmonary arterial hypertension patients. CONCLUSIONS: This review provides an overview of available tools for assessing quality of life in patients with pulmonary arterial hypertension. Critical evaluation of these tools highlights incomplete psychometric assessments and methodological limitations in reference studies. Future research should prioritise more rigorous methodologies to ensure comprehensive psychometric evaluations.

Cathepsin L Promotes Pulmonary Hypertension via BMPR2/GSDME-Mediated Pyroptosis.

BACKGROUND: Pulmonary hypertension (PH) is a fatal progressive disease characterized by pulmonary endothelial injury and occlusive pulmonary vascular remodeling. Lysosomal protease cathepsin L degrades essential molecules to participate in the human pathophysiological process. BMPR2 (bone morphogenetic protein type II receptor) deficiency, an important cause of PH, results from mutational inactivation or excessive lysosomal degradation and induces caspase-3-mediated cell death. Given recent evidence that pyroptosis, as a new form of programmed cell death, is induced by caspase-3-dependent GSDME (gasdermin E) cleavage, we hypothesized that cathepsin L might promote PH through BMPR2/caspase-3/GSDME axis-mediated pyroptosis. METHODS: Cathepsin L expression was evaluated in the lungs and plasma of patients with pulmonary arterial hypertension. The role of cathepsin L in the progression of PH and vascular remodeling was assessed in vivo. Small interfering RNA, specific inhibitors, and lentiviruses were used to explore the mechanisms of cathepsin L on human pulmonary arterial endothelial cell dysfunction. RESULTS: Cathepsin L expression is elevated in pulmonary artery endothelium from patients with idiopathic pulmonary arterial hypertension and experimental PH models. Genetic ablation of cathepsin L in PH rats relieved right ventricular systolic pressure, pulmonary vascular remodeling, and right ventricular hypertrophy, also restoring endothelial integrity. Mechanistically, cathepsin L promotes caspase-3/GSDME-mediated endothelial cell pyroptosis and represses BMPR2 signaling activity. Cathepsin L degrades BMPR2 via the lysosomal pathway, and restoring BMPR2 signaling prevents the pro-pyroptotic role of cathepsin L in PAECs and experimental PH models. CONCLUSIONS: These results show for the first time that cathepsin L promotes the development of PH by degrading BMPR2 to induce caspase-3/GSDME-mediated endothelial pyroptosis.

A comprehensive analysis of genes associated with hypoxia and cuproptosis in pulmonary arterial hypertension using machine learning methods and immune infiltration analysis: AHR is a key gene in the cuproptosis process.

Background: Pulmonary arterial hypertension (PAH) is a serious condition characterized by elevated pulmonary artery pressure, leading to right heart failure and increased mortality. This study investigates the link between PAH and genes associated with hypoxia and cuproptosis. Methods: We utilized expression profiles and single-cell RNA-seq data of PAH from the GEO database and genecad. Genes related to cuproptosis and hypoxia were identified. After normalizing the data, differential gene expression was analyzed between PAH and control groups. We performed clustering analyses on cuproptosis-related genes and constructed a weighted gene co-expression network (WGCNA) to identify key genes linked to cuproptosis subtype scores. KEGG, GO, and DO enrichment analyses were conducted for hypoxia-related genes, and a protein-protein interaction (PPI) network was created using STRING. Immune cell composition differences were examined between groups. SingleR and Seurat were used for scRNA-seq data analysis, with PCA and t-SNE for dimensionality reduction. We analyzed hub gene expression across single-cell clusters and built a diagnostic model using LASSO and random forest, optimizing parameters with 10-fold cross-validation. A total of 113 combinations of 12 machine learning algorithms were employed to evaluate model accuracy. GSEA was utilized for pathway enrichment analysis of AHR and FAS, and a Nomogram was created to assess risk impact. We also analyzed the correlation between key genes and immune cell types using Spearman correlation. Results: We identified several diagnostic genes for PAH linked to hypoxia and cuproptosis. PPI networks illustrated relationships among these hub genes, with immune infiltration analysis highlighting associations with monocytes, macrophages, and CD8 T cells. The genes AHR, FAS, and FGF2 emerged as key markers, forming a robust diagnostic model (NaiveBayes) with an AUC of 0.9. Conclusion: AHR, FAS, and FGF2 were identified as potential biomarkers for PAH, influencing cell proliferation and inflammatory responses, thereby offering new insights for PAH prevention and treatment.

EULAR recommendations for the treatment of systemic sclerosis: 2023 update.

OBJECTIVES: To update the 2017 European Alliance of Associations for Rheumatology (EULAR) recommendations for treatment of systemic sclerosis (SSc), incorporating new evidence and therapies. METHODS: An international task force was convened in line with EULAR standard operating procedures. A nominal group technique exercise was performed in two rounds to define questions underpinning a subsequent systematic literature review. The evidence derived was discussed and overarching principles, recommendations and future research agenda were iteratively developed with voting rounds. RESULTS: The task force agreed on 22 recommendations covering 8 clinical/organ domains including Raynaud's phenomenon, digital ulcers, pulmonary arterial hypertension, scleroderma renal crisis, skin fibrosis, interstitial lung disease (ILD), gastrointestinal manifestations and arthritis. Most new recommendations are related to skin fibrosis and ILD. These included novel recommendations for the use of mycophenolate mofetil, nintedanib, rituximab and tocilizumab for the treatment of these crucial disease manifestations. The recommendations also included first-line and second-line interventions, providing increased utility for rheumatology practitioners. Important additions to the future research agenda included consideration of novel interventions for the management of vascular, musculoskeletal and gastrointestinal manifestations and calcinosis, as well as for the local management of digital ulcers. CONCLUSION: These updated recommendations include the first set of synthetic and biological targeted therapies recommended for key fibrotic manifestations of SSc as well as first-line combination treatment for newly diagnosed pulmonary artery hypertension and prioritise a new research agenda for the coming years.

Clinical adverse events to letairis: a real-world drug safety study based on FDA adverse event reporting system (FAERS).

BACKGROUND: Letairis (ambrisentan), an endothelin receptor antagonist (ERA), is a critical medication for pulmonary arterial hypertension (PAH). Despite its efficacy, its safety profile is under scrutiny, warranting a detailed analysis. RESEARCH DESIGN AND METHODS: This study leveraged the FDA Adverse Event Reporting System (FAERS) from Q1 2007 to Q4 2023, focusing on Letairis as the primary suspect in adverse events. Employing advanced data mining techniques such as Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS), the study aimed to uncover safety signals. RESULTS: A total of 43,774 cases were identified, with Letairis implicated in 16,038,963 adverse event reports. There was a notable predominance of female patients (75.30%), with a median age around 64 years. Severe outcomes, including hospitalization (51.63%) and fatalities (20.44%), were prevalent. Signal strength analysis highlighted concerns in infections and infestations, as well as cardiac disorders. CONCLUSION: The analysis underscores the need for vigilant pharmacovigilance and highlights Letairis's potential to induce serious AEs, particularly in female and elderly populations. These findings are instrumental in guiding clinical practice and future drug safety assessments.

Sleep Quality and Its Predictors among Dyspnea, Fatigue and Exercise Capacity in Pulmonary Arterial Hypertension.

Background: Poor sleep quality is an overlooked symptom in patients with pulmonary arterial hypertension (PAH), however it may significantly contribute to disease burden. Objectives: The aim of this study was to assess the sleep quality of patients with PAH and investigate its association with dyspnea, fatigue, and exercise capacity. Methods: Forty-five patients were included. Sleep quality of the patients was assessed by the Pittsburgh Sleep Quality Index (PSQI), dyspnea levels were assessed by the UCSD-Shortness of Breath Questionnaire (UCSD-SOBQ), Baseline Dyspnea Index (BDI), Modified Medical Research Council (MMRC) dyspnea scale and Modified Borg Dyspnea scale, fatigue levels were evaluated with the Fatigue Severity Scale and Borg Rating of Perceived Exertion, and functional exercise capacity was evaluated with the 6-minute walk test (6MWT). Results: Among the patients with PAH, 64% had poor sleep quality (PSQI > 5). PSQI score was significantly correlated with MMRC scale (r = -0.561), UCSD-SOBQ (r = 0.497), BDI (r = -0.468), and 6MWT (r = -0.412) (p < 0.05). There was no significant relationship between sleep quality and fatigue. A regression model including MMRC and 6MWT could explain 32% of variance in PSQI (p < 0.05), and MMRC score was an independent predictor for PSQI (p < 0.05). In addition, MMRC score had a greater influence on PSQI than 6MWT (ß = 0.548 vs. 0.019). Conclusions: Poor sleep quality is common in patients with PAH and is associated with poor exercise capacity and dyspnea. Patients with severe dyspnea are particularly at higher risk of poor sleep quality. Consideration of sleep-related complaints and underlying mechanisms when planning symptomatic treatments for these patients may help provide better management for PAH.