Postnatal hypoxia in high-altitude regions drives pulmonary developmental impairment in neonates, which may subsequently progress to pulmonary hypertension and right ventricular failure. N6-methyladenosine (m6A) RNA modification regulates mRNA fate and cellular responses to stress; however, its role in neonatal PH remains unknown. In this study, we established a neonatal rat model of PH by chronic hypoxia exposure and investigated the role of the m6A demethylase AlkB homolog 5 (ALKBH5) using pharmacological inhibition, siRNA knockdown, and integrated m6A‑seq/RNA‑seq. Hypoxia reproduced the key features of pulmonary developmental impairment and pulmonary hypertension, including alveolar simplification, reduced vascular density, increased medial wall thickness, elevated right ventricular systolic pressure, and right ventricular hypertrophy. Hypoxia increased ALKBH5 protein in pulmonary vascular smooth muscle, which was inhibited by an ALKBH5 inhibitor 5-Carboxy-8-hydroxyquinoline. In pulmonary artery smooth muscle cells (PASMCs), hypoxia increased ALKBH5 protein levels. ALKBH5 knockdown increased total m6A levels and suppressed proliferation and migration of PASMCs. Integrated MeRIP-seq/RNA-seq identified enolase 2 (ENO2) as a downstream target of ALKBH5 in PASMCs. ALKBH5 knockdown decreased ENO2 mRNA stability; ENO2 overexpression rescued proliferation and migration suppressed by ALKBH5 knockdown in PASMCs. Furthermore, hypoxia increased ALKBH5 promoter activity and expression via hypoxia-inducible factor-1 alpha (HIF-1α), thereby promoting proliferation of PASMCs and pulmonary vascular remodeling. Targeting the HIF-1α/ALKBH5/ENO2 axis may represent a therapeutic strategy for neonatal PH.

BACKGROUND:Recombinant human prourokinase (rhPro-UK) is a novel plasminogen activator under investigation for acute pulmonary embolism (aPE). We aimed to explore the efficacy and safety of rhPro-UK vs. alteplase (recombinant tissue plasminogen activator [rt-PA]) in patients with aPE. METHODS:In this phase 2, randomized, single-blind, multicenter, active-controlled, randomized trial involved eighteen centers from university-affiliated tertiary hospitals across China. Patients aged 18-75 years with high or intermediate-to-high risk aPE were randomized to receive intravenous rhPro-UK (40 mg, n = 37; 50 mg, n = 35) or rt-PA (n = 35) and were followed for 7-30 days. The primary efficacy outcome was the change from baseline in systolic pulmonary artery pressure (sPAP) at 24 h post-treatment. Secondary outcomes include changes in right ventricular function parameters. Safety outcomes include all-cause mortality, recurrent PE, hemodynamic deterioration within 7 days, and bleeding events within 30 days. FINDINGS:All treatment groups showed a reduction in sPAP at 24 h (mean change: 40 mg rhPro-UK, -13.40 mmHg [95% confidence interval (CI): -24.10 to -2.71]; 50 mg rhPro-UK, -15.42 mmHg [95% CI: -25.93 to -4.91], and rt-PA: -16.02 mmHg [95% CI: -25.53 to -6.51]), with improvements sustained through 30 days. The incidence of non-major bleeding events was numerically lower in the rhPro-UK groups (40 mg: 63.9%; 50 mg: 55.6%) compared to the rt-PA group (82.9%; p = 0.04). Two deaths occurred, each in the 40 mg rhPro-UK group and rt-PA group. CONCLUSION:rhPro-UK tended to result in early hemodynamic improvement comparable to rt-PA and seemed to have a numerically lower risk of non-major bleeding events. The ClinicalTrials.gov identifier is NCT03108833. FUNDING:This work was funded by Tasly Biopharmaceuticals Co., Ltd.

Pulmonary hypertension (PH) is a progressive, life-threatening cardiovascular disorder. It features irreversible pulmonary vascular remodeling and causes right ventricular failure and mortality. The underlying pathogenesis of PH is incompletely elucidated. Ubiquitination is a reversible post-translational modification. It regulates protein degradation and membrane trafficking and contributes critically to PH development and progression. The ubiquitin-proteasome system (UPS), especially E3 ubiquitin ligases and Deubiquitinases, modulates the function of pulmonary artery endothelial cells and pulmonary artery smooth muscle cells in PH. These molecules exert distinct roles and regulatory mechanisms in PH-related signaling pathways. The pathways include bone morphogenetic protein, nuclear factor kappa B (NF-κB), hypoxia inducible factor-1α, P53, Hippo, and mitochondrial quality control. UPS-targeted small-molecule agents, proteasome inhibitors, and proteolysis-targeting chimeras have therapeutic potential for PH. They also face notable translational challenges. Ubiquitination provides new mechanistic insights into PH pathogenesis and identifies innovative avenues for targeted therapy.

BACKGROUND:Accurate risk stratification is crucial for guiding therapy in medically treated chronic thromboembolic pulmonary hypertension (CTEPH), in which inflammation plays a key pathogenic role. This study aimed to identify and validate prognostic inflammatory biomarkers in medically treated CTEPH, with the goal of refining risk assessment and improving clinical management. METHODS:This dual-cohort study enrolled 576 medically treated CTEPH patients (discovery cohort: n=372; validation cohort: n=204) from 2009 to 2021. Plasma levels of inflammatory biomarkers, including soluble suppression tumorigenicity-2 (sST2), galectin-3 and a panel of cytokines, were measured in all participants. The study end-point was all-cause mortality. The prognostic significance of inflammatory markers was evaluated using Kaplan-Meier survival analysis, Cox regression models, C-index, net reclassification improvement and integrated discrimination improvement. RESULTS:Plasma sST2 and interleukin-6 (IL-6) were identified as predictors of survival, and remained robust predictors of mortality after comprehensive adjustment for clinical covariates in both cohorts. Risk stratification using the sST2/IL-6 panel revealed distinct 5-year survival rate gradients: high sST2/high IL-6 (34.4%), low sST2/high IL-6 (61.4%), high sST2/low IL-6 (78.3%) and low sST2/low IL-6 (90.5%) in the discovery cohort (p<0.001), with consistent validation. Furthermore, integrating the sST2/IL-6 panel with existing risk models (COMPERA, COMPERA 2.0, French Pulmonary Hypertension Network (invasive and noninvasive) and REVEAL 2.0) significantly enhanced their prognostic discriminatory power, as evidenced by increased C-indexes, net reclassification improvement and integrated discrimination improvement in both cohorts. CONCLUSIONS:sST2 and IL-6 are independent prognostic biomarkers in medically treated CTEPH. Their combined use enhances risk stratification and adds incremental value to existing risk models.

Background Balloon pulmonary angioplasty (BPA) is recommended for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Objectives The aim of this study was to evaluate the long-term survival benefit of BPA for inoperable CTEPH, especially partial BPA sessions. Methods In this multicenter cohort study, 232 patients undergoing BPA (the BPA group) and 70 patients refusing the BPA procedure (the non-BPA group) were enrolled. The BPA group was further divided into the full-BPA group (129 patients) and the partial-BPA group (103 patients). The primary outcome was all-cause mortality. Results During a median follow-up time of 6.0 years (Q1-Q3: 3.7-7.3), 17 and 26 patients in the BPA and non-BPA groups died, contributing to 8-year survival rates of 86.7% (95% CI: 80.1%-93.8%) and 57.8% (95% CI: 45.9%-72.8%) in the BPA and non-BPA groups, respectively (P < 0.001, log-rank test). BPA was associated with significantly reduced all-cause mortality in inoperable CTEPH patients (HR: 0.20; 95% CI: 0.12-0.32; P < 0.001). In secondary analysis, the 8-year survival rates were 97.1% (95% CI: 93.8%-99.9%) and 70.0% (95% CI: 55.8%-87.8%) in the full-BPA and partial-BPA groups, respectively, both better than the non-BPA group (P < 0.001, log-rank test). Compared with the non-BPA group, partial BPA was associated with significantly reduced all-cause mortality in inoperable CTEPH patients (HR: 0.38; 95% CI: 0.22-0.70; P = 0.001). Conclusions BPA tended to be associated with a reduced risk for all-cause mortality in patients with inoperable CTEPH, even those undergoing partial BPA sessions. These findings are preliminary and must be confirmed in randomized controlled trials.

INTRODUCTION/BACKGROUND:Oral imatinib, a tyrosine kinase inhibitor, demonstrated efficacy in pulmonary arterial hypertension (PAH) studies but was poorly tolerated. We report here the findings of a study using a dry powder inhaled version of imatinib (AV-101). AIMS AND OBJECTIVES:IMPAHCT (NCT05036135) was designed to assess the efficacy, safety, tolerability, and optimal dose of AV-101 as an add-on treatment for PAH, using a novel phase 2b/3 adaptive study design. Here we report the phase 2b results. METHODS:The phase 2b part assessed 3 doses of AV-101 (10 mg, 35 mg, and 70 mg), administered twice a day, vs placebo for 24 weeks as an add-on treatment in adults with PAH. Change in pulmonary vascular resistance (PVR) was the primary endpoint. Secondary endpoints included the change in other hemodynamic variables, 6-minute walk distance (6MWD), World Health Organization functional class, Registry to Evaluate Early and Long-Term PAH Disease Management Lite 2 risk score, clinical worsening, clinical improvement, N-terminal proB-type natriuretic peptide, quality of life, safety, and tolerability. RESULTS:In total, 202 patients were randomized. Baseline characteristics were broadly well balanced between groups. There were no significant improvements vs placebo in PVR (42.8 dyn·s·cm-5 in the AV-101 10-mg group, -5.5 dyn·s·cm-5 in the AV-101 35-mg group, -57.0 dyn·s·cm-5 in the AV-101 70-mg group, and 19.5 dyn·s·cm-5 in the placebo group), 6MWD, or other secondary endpoints at any dose. Pharmacokinetic measures supported delivery of drug to the lung and into the plasma. The incidence of cough increased with dose. No safety concerns were identified. CONCLUSIONS:Add-on dry powder inhaled imatinib (AV-101) was not effective in lowering PVR at any of the studied doses in patients with PAH. The phase 3 part of the IMPAHCT study was halted.

Pulmonary arterial hypertension (PAH) has a poor prognosis despite available treatments. TPN171H, structurally modified from traditional Chinese medicine (Epimedium), was reported to have a high affinity for phosphodiesterase type 5 and exhibited anti-inflammatory and vasodilatory effects in preclinical studies. This phase 2a randomized trial (NCT04483115) evaluated the hemodynamic effects and safety of TPN171H in PAH. Sixty patients with PAH were randomly assigned to receive placebo, TPN171H (2.5, 5, or 10 mg) or tadalafil (20 or 40 mg) and evaluated for hemodynamic changes for 24 h. The primary endpoint was the maximum change (%) in pulmonary vascular resistance (PVR) from baseline. The key secondary endpoint was the change (%) in PVR to systemic vascular resistance (SVR) ratio at each observation point from baseline. Compared to the placebo group, the least square mean differences in the maximum change in PVR were -16.8% (95% CI, -29.1 to -4.5, p = 0.008) in TPN171H 5 mg, -15.4% (95% CI, -28.2 to -2.7, p = 0.019) in tadalafil 20 mg, and -13.3% (95% CI, -25.6 to -0.9, p = 0.036) in the tadalafil 40 mg group. Moreover, TPN171H 5 mg, but none of the tadalafil doses, showed a significant reduction in PVR/SVR ratio at 2 h (p = 0.026), 3 h (p = 0.030), and 5 h (p = 0.046) compared to the placebo group. No serious adverse events occurred. TPN171H 5 mg demonstrated favorable acute hemodynamic effects and an acceptable short-term safety profile in this exploratory trial, supporting further evaluation in adequately powered trials.

BackgroundPulmonary arterial hypertension (PAH) exhibits significant sex disparities; however, the impact on women aged ≥55 years—a population-level proxy for postmenopausal women who experience substantial hormonal and cardiometabolic changes—has not been comprehensively assessed. This research assessed long-term trends, regional variations, and structural factors influencing PAH in women aged ≥55 years.MethodThis study utilizes standardized estimation data from GBD 2023, focusing on women aged 55 years and older as a population-level proxy for postmenopausal status. Joinpoint regression analysis was employed to investigate the trends in load. Decomposition analysis was utilized to measure the distinct impacts of population increase, aging, and epidemiological shifts. Frontier analysis was utilized to assess health output efficiency across different nations, while the ARIMA model was employed to forecast data until 2040.ResultsIn 2023, the Age-Standardized Incidence Rate (ASIR) showed a six-fold variation among nations (0.18–1.06 per 100,000), whilst the Age-Standardized Mortality Rate (ASMR) demonstrated almost a 160-fold disparity (0.007–1.13 per 100,000), with Central Asia and sub-Saharan Africa identified as high-burden hotspots. Between 1990 and 2023, global ASMR decreased by over 40%, while ASDR diminished by almost 35%. In persons aged 55 years and older, the age-specific incidence rate (ASIR) and age-specific prevalence rate (ASPR) for females were 1.3 to 1.8 times greater than those for males. Population growth accounted for 40–65% of the increases in burden in South Asia, East/Southeast Asia, and Africa, while aging was the predominant factor in China and high-SDI regions. By 2040, global mortality and disability-adjusted life years (DALYs) are anticipated to persist in their decline, whereas incidence and prevalence are likely to stabilize; China’s age-standardized incidence rate (ASIR) is forecasted to maintain a high plateau, while age-standardized mortality rate (ASMR) and age-standardized DALY rate (ASDR) will continue to diminish, exhibiting a steady trajectory.ConclusionThis study reveals significant and enduring geographical disparities in the prevalence of PAH among women aged 55 years and older worldwide. Women aged 55–69 years represented the age group with the highest population-level incidence of PAH in the GBD estimates and may therefore warrant priority in surveillance and preventive strategies. High and middle SDI countries must swiftly establish long-term monitoring and chronic management systems specifically designed for women aged ≥55 years. Targeted policies and healthcare services are crucial for mitigating the global impact of PAH.

Background Differences in the clinical outcomes and level of risk among Asian versus non-Asian patients with atrial fibrillation (AF) have been sparsely investigated.Objective To provide a contemporary prospective comparison of outcomes for newly diagnosed patients with AF, between Asian and non-Asian regions.Methods Six Asian countries (China, Japan, India, Singapore, South Korea and Thailand) and 29 countries outside Asia participated in the Global Anticoagulant Registry in the FIELD-AF (GARFIELD-AF) study. Newly diagnosed patients with AF, enrolled between 2010 and 2016, were followed up for≥2 years. The outcome studies were all-cause, cardiovascular and non-cardiovascular mortality, non-haemorrhagic stroke/systemic embolism (SE), major bleeding. The association of geographical region with clinical outcomes (event rates per 100 person-years) were estimated using multivariable Cox models.Results 13 841/52 057 (26.6%) GARFIELD-AF participants were enrolled in Asia. Average age and prevalence of cardiovascular comorbidities were lower than in non-Asian countries and patients at high risk of stroke (ie, CHA2DS2-VASc≥2 excl. sex) were less frequently anticoagulated (60.1% vs 73.2%). Non-vitamin K oral anticoagulant (NOAC) was similar in both regions (∼28%), though Asian patients were more frequently underdosed. Both Asian and non-Asian patients who received NOAC at enrolment experienced lower all-cause mortality and non-haemorrhagic stroke/SE compared with patients on other treatments or none.All-cause mortality, non-cardiovascular mortality and major bleeding were less frequent in patients from Asia versus non-Asia (HR (95% CI): 0.62 (0.39 to 0.99), 0.52 (0.28 to 0.97), 0.58 (0.36 to 0.96), respectively). Associations of moderate-to-severe chronic kidney disease and vascular disease with increased risk of all-cause mortality were stronger in Asian versus non-Asian patients (interaction p values: 0.0250 and 0.0076, respectively). There was notable heterogeneity in oral anticoagulant (OAC) usage within the Asian countries.Conclusions Patients in Asian countries had a lower risk of all-cause mortality and major bleeding compared to the rest of the world. NOAC had evident benefits for reducing mortality and stroke across populations. Further studies on sociocultural impacts on OAC outcomes are needed.Trial registration number ClinicalTrials.gov NCT01090362.

BACKGROUND:In a phase 2 study of inoperable chronic thromboembolic pulmonary hypertension (CTEPH), macitentan 10 mg improved hemodynamics and exercise capacity. METHODS:MACiTEPH (NCT04271475) was a prospective, double-blind, placebo-controlled, phase 3 study. Adult patients with inoperable CTEPH (with/without balloon pulmonary angioplasty [BPA]) or persistent/recurrent CTEPH after pulmonary endarterectomy (PEA) (with/without BPA) were randomized 1:1 to macitentan 75 mg or placebo once daily. Primary endpoint was change from baseline to Week 28 in 6-minute walk distance (6MWD). RESULTS:Following a pre-planned interim analysis, the study was stopped for futility. 127 patients were randomized, predominantly with inoperable CTEPH with BPA (36.2%) or persistent/recurrent CTEPH after PEA without BPA (30.7%). The majority (81.9%) were receiving pulmonary hypertension (PH)-specific therapy at baseline. 47 patients in the macitentan 75 mg and 48 in the placebo group had Week 28 assessments. Primary endpoint was not met; mean change in 6MWD from baseline to Week 28 versus placebo was -16.1 m (95% confidence limit: -32.3, 0.16). Clinical worsening events occurred in 6.3% and 14.3% of patients in the macitentan 75 mg and placebo groups, respectively. A slightly higher proportion of the macitentan 75 mg group had ≥1 adverse event (AE) or serious AE versus placebo; no pattern was identified. More patients in macitentan 75 mg versus placebo group discontinued treatment due to an AE (21.9% versus 7.9%, respectively). CONCLUSIONS:MACiTEPH was discontinued for futility, as no treatment effect on 6MWD (primary endpoint) was observed. Despite the higher discontinuation rate in the macitentan 75 mg group, no unexpected safety signals were observed in CTEPH patients.