Pulmonary Circulation最新文献

Pulmonary arterial hypertension (PAH) is a chronic, progressive, and ultimately life-threatening disease characterized by vascular remodeling and increasing pulmonary vascular resistance. Despite significant advances in diagnostic tools and therapeutic strategies, clinical intervention often begins only when patients become symptomatic-typically at New York Heart Association (NYHA) functional class II or higher. Paradoxically, while early detection of PAH is strongly encouraged to preempt irreversible vascular, cardiac, and multisystem damage, treatment remains largely restricted to those already exhibiting symptoms. Patients in NYHA class I, though experiencing pathophysiological progression, are systematically excluded from approved pharmacological therapies. This disjunction represents not only a clinical and ethical conundrum but also a conceptual paradox: why invest in early diagnosis if early treatment is withheld? Emerging evidence on various chronic diseases, including cancer, infectious diseases like HIV and hepatitis, and even other cardiovascular diseases, underscores the benefits of initiating treatment before the onset of symptoms. In contrast, the current approach to PAH inadvertently promotes a nihilistic "wait and see" policy, exposing asymptomatic patients to preventable deterioration. Herein, we call for a reassessment of clinical guidelines, regulatory frameworks, and access policies with the goal of better aligning them with the biological realities of PAH. While we advocate for a paradigm shift toward the inclusion of NYHA class I patients in treatment strategies, we explicitly acknowledge the current limitations of the evidence base and emphasize the need for ongoing, high-quality research including counterarguments and the practical challenges of early treatments.

Children with single ventricle heart disease (SVHD) demonstrate decreased arginine/NO metabolism following Stage 2 (Glenn) palliation, associated with poor postoperative outcomes. It is unknown if arginine dysregulation persists at Stage 3 (Fontan). The purpose of this study is to quantify circulating arginine metabolites in children undergoing Fontan palliation for SVHD to evaluate the relationship between metabolite concentrations and outcomes. Prospective cohort study of children undergoing Fontan operation (n = 82) and similar age healthy controls (n = 49). We measured circulating arginine metabolites pre- and post-op by tandem mass spectrometry. Postoperative outcomes included length of stay (LOS) and pleural drainage. Pre-op cases showed lower arginine, argininosuccinate, cysteine, NMMA, higher glutathione, and lower arginine/ADMA, arginine/citrulline, and arginine/ornithine ratios compared to controls. Post-op cases experienced progressively decreasing citrulline concentration and higher arginine/ADMA, arginine/citrulline, and arginine/ornithine ratios compared to pre-op. In uncorrected analysis, postoperative decreased citrulline level (31.4% and 33.9% longer LOS for 50% decrease in [citrulline] at 2 and 24 h, respectively) was associated with longer LOS. Decreased arginine/ADMA and arginine/ornithine ratios were significantly associated with longer LOS and greater pleural drainage. Arginine metabolism is altered in children with SVHD in both the pre- and post-Stage 3 period. Patients with greater postoperative derangements, including lower arginine/ADMA and arginine/ornithine ratios, experienced more morbidity. We speculate that alterations in arginine metabolism may be a modifiable risk factor for adverse post-Stage 3 outcomes in SVHD.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but severe complication of pulmonary embolism (PE), yet its underlying mechanisms remain poorly understood. Peptidyl-prolyl cis/trans isomerase (Pin1), a regulatory enzyme involved in thrombosis, inflammation, and vascular remodeling, may contribute to pulmonary vascular disease. We investigated whether circulating Pin1 levels are associated with the risk of CTEPH and its severity. In this case-control study, we measured circulating Pin1 levels by ELISA and compared them across 329 patients with CTEPH, 350 patients after acute PE, and 350 healthy individuals. Associations between Pin1 levels and clinical parameters were assessed with multivariable regression, stratified by sex. Overall, circulating Pin1 levels did not differ between patients with CTEPH, patients after acute PE, and healthy individuals. However, male patients with CTEPH had higher Pin1 levels than the two control groups, while female patients with CTEPH had slightly lower levels than female healthy individuals. Elevated Pin1 levels were associated with improved hemodynamics and exercise capacity, lower N-terminal prohormone of brain natriuretic peptide, and increased probability of CTEPH in men. Among healthy individuals, circulating Pin1 levels varied based on age, sex, and history of cancer. In conclusion, circulating Pin1 did not distinguish between patients with CTEPH, acute PE or healthy individuals. Nonetheless, our results suggest a possible sex-specific association between circulating Pin1 levels and CTEPH. Although Pin1 is unlikely to serve as a standalone biomarker, it may reflect underlying sex-specific pathological mechanisms, and further investigation on its utility within multimodal strategies for early risk stratification of CTEPH is warranted.

Pulmonary arterial hypertension (PAH) is a fatal disease with limited available treatments and is characterized by pulmonary vascular remodeling. Substance P (SP) may be involved in vascular remodeling in patients with PAH. However, the underlying mechanism is currently unknown. In this study, we found that plasma SP levels were elevated and correlated with pulmonary hemodynamic parameters in PAH patients. SP receptor inhibitors significantly suppressed pulmonary vascular remodeling and improved pulmonary circulation hemodynamics in PAH rats. Multiple omics analyses suggested that downregulation of Fibulin-2 (Fbln2) may play a role in promoting pulmonary vascular remodeling by SP. In addition, the downregulation of Fbln2 expression by SP was further verified by Western blot analysis and immunofluorescence. In vitro experiments showed that SP negatively regulated β-catenin expression by downregulating Fbln2 expression. Moreover, SP promoted the DNA methylation of Fbln2. A methylation inhibitor alleviated SP mediated low expression of Fbln2 and high expression of β-catenin. Overexpression of Fbln2 inhibited the proliferation and migration of pulmonary artery smooth muscle cells induced by SP. These data provide a novel mechanism through which SP promotes the proliferation and migration of PASMCs, leading to pulmonary hypertension and suggesting that Fbln2 is a potential therapeutic target for PAH.

Macitentan 10 mg and tadalafil 40 mg single-tablet combination therapy (M/T STCT) has been evaluated in the global A DUE study (NCT03904693). Here, we report the results of a subgroup analysis in participants from China. This double-blind, active-controlled, Phase 3 A DUE study randomized patients with symptomatic pulmonary arterial hypertension (PAH) to receive M/T STCT, macitentan, or tadalafil depending on their baseline PAH treatment (treatment-naïve, endothelin receptor antagonist, or phosphodiesterase Type 5 inhibitor monotherapy). The primary end point was change in pulmonary vascular resistance (PVR) expressed as the ratio of geometric means (GMR) of Week 16 to baseline. A total of 187 patients were randomized, including 23 patients in China. PVR reduction was significantly greater with M/T STCT compared with macitentan (50%) and tadalafil (41%) (adjusted GMRs were 0.50; 95% confidence level [CL]: 0.35-0.72; p = 0.0017 and 0.59; 95% CL: 0.43-0.80; p = 0.0040, respectively) in Chinese patients. M/T STCT was well tolerated in Chinese patients; the safety profile was consistent with that of macitentan and tadalafil monotherapies, and that of the overall population. In conclusion, in Chinese patients with PAH, PVR was reduced with M/T STCT versus either monotherapy after 16 weeks of treatment; the safety profile of M/T STCT was in line with the known safety profile of the individual components and appeared consistent with the overall population, although data should be interpreted with caution due to the small sample size. Our findings support the use of M/T STCT for PAH in China. Trial registration: ClinicalTrials.gov https://clinicaltrials.gov/ NCT03904693 (April 5, 2019).

During the COVID-19 pandemic, Brazil was one of the most affected countries. Patients presented higher risk of acute venous thromboembolism (VTE), in particular, pulmonary embolism (PE). However, long-term implications of these events remain unknown. A retrospective analysis from the FENIX study was conducted, and patients with COVID-19-related VTE during hospitalization were included. Further analysis, up to 6 months after the acute event, was performed exclusively in patients with PE. Persistence of dyspnea and exercise intolerance was evaluated through imaging, rest, and exercise functional tests. Cumulative incidence of VTE during hospitalization among COVID-19 survivors followed at the outpatient clinic was 17.7% (n = 75/423) and of acute PE was 9.9% (n = 42/423). Patients with PE were mostly male (66%), 56 ± 16 years old, and mainly classified as intermediate-low risk (74%). Dyspnea (mMRC≥ 1) up to 6 months of PE was present in 56% (n = 19/34), with a borderline association with parenchymal lung sequelae on chest CT scan (p = 0.069). Symptomatic patients upon follow-up presented lower FEV1 and FVC, as well as increased peak VD/VT ratio and ventilatory inefficiency. No signs of pulmonary hypertension (PH) were identified on echocardiogram (ECHO) and cardiopulmonary exercise testing (CPET). Persistence of dyspnea among post-PE related to COVID-19 was high. However, no cases of PH were found; follow-up findings may be related to pulmonary parenchymal and microvascular injury. Also, we cannot exclude association with long-COVID, in which pathophysiological mechanisms are multifactorial, involving chronic inflammatory changes and multiorgan dysfunction, highlighting the need for comprehensive evaluation of exercise intolerance through invasive CPET.

The American Lung Association and Pulmonary Hypertension Association convened a scientific roundtable of pulmonary hypertension experts to discuss the latest recommendations from the European Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension (PH) and from the 7th World Symposium on Pulmonary Hypertension (WSPH). The aim of the roundtable was to discuss changes that were made compared to earlier recommendations and guidelines set out by the European Society of Cardiology and the European Respiratory Society in 2015, the 6th World Symposium on Pulmonary Hypertension in 2018, and the CHEST Guideline on Therapy for Pulmonary Arterial Hypertension in 2019. The overall objectives were to: 1) Create an educational resource for providers that summarizes currently available PAH guidelines, 2) Provide an expert critique of current guidelines, outlining strengths and weaknesses and resolving differences where guidelines do not agree. 3) Provide guidance for the incorporation of the recently approved drug, sotatercept into current guidelines. An executive summary was drafted following the roundtable meeting on April 8, 2024, and revised by the panel in September 2024, following publication of the proceedings from the 7th WSPH held in Barcelona June 29-July 1, 2024. The Executive Summary reviews changes to the hemodynamic criteria for defining pre- and post-capillary PH, exercise-induced PH, and PH associated with lung disease. Recommendations are given for proper diagnosis and clinical classifications of the various forms of PH. The role of screening for PH in high-risk populations and the use of risk scores for disease stratification are discussed. Finally, treatment algorithms for managing pulmonary arterial hypertension, PH associated with lung disease, and chronic thromboembolic pulmonary hypertension are presented.

Severe diffusion impairment in pulmonary arterial hypertension (PAH), particularly in idiopathic PAH (IPAH), has garnered considerable attention. However, comprehensive data on low diffusion capacity of the lungs for carbon monoxide (DLCO) with preserved lung function remain limited in broader pulmonary hypertension (PH) cohorts. We analyzed patients with PH, preserved lung function, low DLCO, and available computed tomography (CT) scans. The analysis included 117 patients, with 34% cases of combined pulmonary fibrosis and emphysema (CPFE), 22% IPAH, 15% interstitial lung disease (ILD), 9% pulmonary veno-occlusive disease (PVOD), and 8% connective tissue disease (CTD). Based on hemodynamic and CT imaging features, the overall population could be broadly categorized into two phenotypic patterns. "Parenchymal Type" (n = 81; 69%), predominantly consisted of CPFE and ILD, with an average age of 69 ± 9 years, 89% male. The median mean pulmonary arterial pressure (mPAP) was 39 mmHg, and lung abnormalities observed included emphysema, interstitial fibrosis, and diffuse ground-glass opacities (GGO). "Vascular Type" (n = 36; 31%), mainly composed of PVOD and CTD cases. with average age of 52 ± 19 years, 64% female, median mPAP of 53 mmHg and centrilobular GGO (78%). IPAH patients were distributed across both phenotypic categories, exhibiting mixed characteristics of the "Parenchymal Type" and "Vascular Type". The 5-year survival rate for the overall patient cohort was 31%. In conclusion, PH patients with low DLCO and preserved lung function represent two distinct phenotypic patterns and are associated with a poor prognosis.

Pulmonary arterial hypertension (PAH) significantly impacts mortality and quality of life. Access to specialized care may differ between urban and rural patients, potentially influencing outcomes. This study compared the clinical course and treatment patterns of PAH patients from urban and rural settings treated at a single comprehensive care center. Adult patients with WHO Group I PAH evaluated between August 2020 and August 2024 at the University of Utah Pulmonary Hypertension Comprehensive Care Center were prospectively enrolled in a program-specific registry. A total of 263 patients were categorized as urban or rural based on residential address. Baseline characteristics, diagnostics, treatments, and outcomes were compared. No significant differences were observed in baseline characteristics, 6-min walk distance (6MWD), right ventricular function, hemodynamics, or NT-proBNP levels. In-person and virtual clinic utilization were also similar. However, among patients receiving triple therapy, rural patients were significantly more likely to receive inhaled treprostinil as the prostacyclin component (p = 0.03). In a subset of patients (n = 146), REVEAL Lite 2 scores were available at baseline and follow-up. Risk distributions and mean scores were similar at each time point. However, urban patients showed significant improvement in REVEAL risk category over time (p = 0.007), while no significant change occurred in rural patients. These findings suggest that although care delivery appeared comparable across settings, differences in treatment selection and risk trajectories emerged over time. Further investigation is needed to understand the drivers of these differences and their implications for disease management and progression.

Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by elevated pulmonary vascular resistance. Despite recent advances, early diagnosis remains challenging due to nonspecific symptoms. By utilizing RNA sequencing (RNA-seq) data from the GEO database, we conducted bioinformatics analyses to identify potential diagnostic biomarkers. Differentially expressed genes (DEGs) were screened in blood from PAH patients, followed by functional enrichment and protein-protein interaction (PPI) network analyses. Thirteen overlapping DEGs were identified, which were enriched in erythrocyte development, heme biosynthesis, and chloride transport. Five hub genes (SLC4A1, AHSP, ALAS2, FECH, and CA1), exhibited strong diagnostic potential, with an area under the curve (AUC) ≥ 0.7 in training datasets (GSE38267, GSE22356). External validation using datasets GSE33463 and GSE117261 confirmed their efficacy in blood samples, although AHSP showed reduced performance in lung tissue. Experimental validation in hypoxic human pulmonary artery smooth muscle cells (hPASMCs) supported the bioinformatics findings. These results underscore SLC4A1, AHSP, ALAS2, FECH, and CA1 as promising noninvasive diagnostic biomarkers for PAH, linking transcriptional dysregulation to clinical application.