肺動脈性肺高血圧症

BACKGROUND AND AIMS: Systemic sclerosis (scleroderma; SSc) patients can develop pulmonary arterial hypertension (PAH), which is a leading cause of death. We sought to evaluate severity, therapeutic strategy and survival of SSc-PAH in the Australian Scleroderma Cohort Study (ASCS). METHODS: Among patients with 2013 American College of Rheumatology/European League Against Rheumatism-defined SSc, PAH was defined as mean pulmonary artery pressure (mPAP) ≥20 mmHg, pulmonary arterial wedge pressure (PAWP) ≤15 mmHg and pulmonary vascular resistance (PVR) >2 WU. Characteristics of those with and without PAH and those with incident PAH in 2014-2020 versus 2007-2013 were compared using descriptive statistics. Survival was evaluated using the Kaplan-Meier method and a multivariable Cox regression model. RESULTS: Among 1612 patients, 71 (4.4%) had incident PAH prior to censoring on 13 February 2024. Significantly more patients received PDE5i monotherapy in the first 12 months after PAH diagnosis in the later epoch (30 (63.8%) vs 6 (25.0%), P = 0.002). Dual therapy (any endothelin reception antagonist (ERA) and any PDE5i) was more common in the later epoch (26 (55.3%) vs 4 (16.7%), P = 0.002). Overall survival of those diagnosed with PAH between 2007 and 2013 was 91.67%, 87.50% and 56.88% at 1, 3 and 5 years. Overall survival of those diagnosed between 2014 and 2020 was 100.00%, 77.62% and 48.98% at 1, 3 and 5 years (P = 0.414). CONCLUSIONS: Despite increased use of dual therapy in the more recent epoch, we observed no significant improvement in overall survival in SSc-PAH in our cohort. Our cohort's 1-, 3- and 5-year mortality is comparable to those reported for other contemporary SSc-PAH cohorts.

BACKGROUND: Current biomarkers for idiopathic pulmonary arterial hypertension (IPAH) lack disease specificity and provide limited biological insight. We hypothesized that integrating population-based proteomics with genetic evidence would identify robust IPAH-associated proteins relevant to risk stratification, early detection, prognosis, sex differences, and candidate drug-repurposing opportunities. METHODS: We analyzed 2,918 plasma proteins in 44,137 predominantly European-ancestry UK Biobank participants aged 40-69 years, including 252 incident and 141 prevalent IPAH cases. Proteins associated with IPAH were identified using Cox and logistic regression analyses, prioritized by cis-Mendelian randomization, and assessed through cross-ancestry effect-direction concordance and sensitivity analyses. Unsupervised clustering, nested cross-validated prediction models, and target-drug annotation were used for downstream evaluation. RESULTS: Eighteen proteins showed convergent epidemiological and genetic evidence, and 12 remained supported in cross-ancestry and sensitivity analyses. These proteins defined a high-mortality endotype characterized by vascular and ventricular remodeling. Combined clinical and proteomic models achieved AUCs of 0.779 for incident IPAH and 0.768 for mortality. Proteomic contributions differed by sex, and target-drug annotation identified six drug-linked proteins, highlighting ANXA2-linked Artenimol as a repurposing candidate. CONCLUSIONS: Twelve biologically plausible IPAH-associated proteins inform risk stratification, prediction, sex-related characterization, and therapeutic prioritization. Independent multi-ancestry validation and mechanistic studies are warranted.

Generalized Arterial Calcification of Infancy (GACI) is a rare genetic vascular disease characterized by the early onset (between in utero and infancy) of extensive calcification and stenosis of the large and medium-sized arteries. Presentation is typically with respiratory distress, congestive heart failure, and systemic hypertension. With approximately 300 cases reported worldwide in the medical literature. The prevalence is unknown; however, based on the carrier frequency of the recognized pathogenic variants, a frequency of 1 in 200,000 has been suggested. The autosomal recessive form of GACI disorder is caused by mutations in the ENPP1 or ABCC6 genes. To the best of our knowledge, this study represents the first genetically confirmed case of GACI in an Egyptian fetus detected during the perinatal period. In this report, we describe a case of GACI in a fetus with a pathogenic ENPP1 gene mutation at 29 weeks of gestation. Ultrasound examination revealed aortic and pulmonary valve stenosis, biventricular hypertrophy, and a hypercalcified aorta and ductal arch. Genetic testing identified a homozygous pathogenic variant in the ENPP1 gene: c.749C>T (p.Pro250Leu). In conclusion, early diagnosis of GACI is vital due to its severe prognosis and early symptom onset. Expert fetal echocardiography plays a key role in detecting arterial calcification during pregnancy. Genetic testing enhances diagnostic accuracy, informs treatment strategies, and supports family counselling.

BACKGROUND: Pulmonary hypertension (PH) frequently coexists with type 2 diabetes mellitus, obesity, and heart failure with preserved ejection fraction (HFpEF), particularly in World Symposium on Pulmonary Hypertension (WSPH) Group 2 disease. Glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists improve several cardiometabolic conditions and have anti-inflammatory and vascular effects. Whether these agents directly modify pulmonary haemodynamics or clinical outcomes in PH remains unknown. METHODS: A structured narrative review was conducted using PubMed/MEDLINE and Google Scholar from database inception through March 2026, with additional studies identified by reference-list screening. Search terms encompassed GLP-1 receptor agonists, dual GIP/GLP-1 receptor agonists, pulmonary hypertension, pulmonary vascular remodelling, endothelial dysfunction, inflammation, and HFpEF. The structured search yielded 491 unique PubMed/MEDLINE records. Of these, 189 were assessed at full-text level alongside 40 additional articles identified through reference-list screening; 67 publications were included in the final synthesis. Evidence was organized by mechanism, experimental model, WSPH group, and whether PH evidence was direct or indirect. RESULTS: GLP-1 receptor expression has been demonstrated in pulmonary arterial smooth muscle in human and non-human primate tissue and in selected alveolar cell populations in rodent studies; however, available studies do not establish greater expression in pulmonary than systemic vascular smooth muscle. GLP-1 receptor signalling modulates inflammatory, endothelial nitric oxide, endothelin-1, and mitochondrial pathways relevant to PH. In monocrotaline- and hypoxia-induced models that primarily resemble Group 1 pre-capillary pulmonary arterial hypertension (PAH), liraglutide reduced right ventricular pressures or hypertrophy and pulmonary vascular remodelling, while semaglutide improved right ventricular mitochondrial and functional measures in an experimental pressure-overload model. By contrast, available human evidence is observational or derived indirectly from HFpEF studies, involves populations likely enriched for Group 2 or unclassified PH, and lacks prespecified, catheterization-confirmed PH endpoints. Consequently, these studies do not establish that GLP-1-based therapy prevents or treats PH. CONCLUSIONS: Current evidence supports a mechanistic hypothesis and a preclinical signal, not clinical efficacy in PH. Future cardiometabolic and HFpEF trials should incorporate standardized PH and right ventricular measures, and dedicated prospective studies with haemodynamic classification are required before GLP-1-based therapies can be considered for PH.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary vascular remodeling, leading to hemodynamic impairment and right heart dysfunction, and ultimately right heart failure and death. Despite advances in understanding its pathogenesis, PAH remains associated with poor prognosis and high mortality compared with other respiratory diseases, posing a significant global health burden. Current therapies primarily target the endothelin, nitric oxide, and prostacyclin pathways to achieve vasodilation and symptomatic relief; however, they have limited efficacy in reversing established vascular remodeling. The nuclear factor-κB (NF-κB) signaling pathway, a central regulator of inflammation and immune responses, plays a critical role in pulmonary vascular remodeling and endothelial-to-mesenchymal transition (EndMT). Targeting NF-κB has therefore emerged as a promising therapeutic strategy for PAH. Nevertheless, controversies remain regarding its mechanisms, therapeutic efficacy, and potential risks, particularly in combination strategies. This review summarizes current understanding of PAH pathogenesis and recent advances in targeting the NF-κB pathway.