Sleep-disordered breathing and nocturnal hypoxemia in chronic thromboembolic pulmonary disease.

BACKGROUND AND AIMS: Sleep-disordered breathing (SDB) and nocturnal hypoxemia were known to be present in patients with chronic thromboembolic pulmonary hypertension (CTEPH), but the difference between SDB and nocturnal hypoxemia in patients who have chronic thromboembolic pulmonary disease (CTEPD) with or without pulmonary hypertension (PH) at rest remains unknown. METHODS: Patients who had CTEPH (n = 80) or CTEPD without PH (n = 40) and who had undergone sleep studies from July 2020 to October 2022 at Shanghai Pulmonary Hospital were enrolled. Nocturnal mean SpO2 (Mean SpO2) <90% was defined as nocturnal hypoxemia, and the percentage of time with a saturation below 90% (T90%) exceeding 10% was used to evaluate the severity of nocturnal hypoxemia. Logistic and linear regression analyses were performed to investigate the difference and potential predictor of SDB or nocturnal hypoxemia between CTEPH and CTEPD without PH. RESULTS: SDB was similarly prevalent in CTEPH and CTEPD without PH (P = 0.104), both characterised by obstructive sleep apnoea (OSA). Twenty-two patients with CTEPH were diagnosed with nocturnal hypoxemia, whereas only three were diagnosed with CTEPD without PH (P = 0.021). T90% was positively associated with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance in patients with CTEPH and CTEPD without PH (P < 0.001); T90% was also negatively related to cardiac output in these patients. Single-breath carbon monoxide diffusing capacity, sex and mPAP were all correlated with nocturnal hypoxemia in CTEPH and CTEPD without PH (all P < 0.05). CONCLUSION: Nocturnal hypoxemia was worse in CTEPD with PH; T90%, but not SDB, was independently correlated with the hemodynamics in CTEPD with or without PH.

The management pattern and outcomes of chronic thromboembolic pulmonary hypertension: rationale and design for a Chinese real-world study.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive pulmonary vascular disorder with substantial morbidity and mortality, also a disease underdiagnosed and undertreated. It is potentially curable by pulmonary endarterectomy (PEA) in patients with surgically accessible thrombi. Balloon pulmonary angioplasty (BPA) and targeted medical therapy are options for patients with distal lesions or persistent/recurrent pulmonary hypertension after PEA. There is an urgent need to increase the awareness of CTEPH. Qualified CTEPH centers are still quite limited. Baseline characteristics, management pattern and clinical outcome of CTEPH in China needs to be reported. METHODS AND DESIGN: The CHinese reAl-world study to iNvestigate the manaGEment pattern and outcomes of chronic thromboembolic pulmonary hypertension (CHANGE) study is designed to provide the multimodality treatment pattern and clinical outcomes of CTEPH in China. Consecutive patients who are ≥ 14 year-old and diagnosed with CTEPH are enrolled. The diagnosis of CTEPH is confirmed in right heart catheterization and imaging examinations. The multimodality therapeutic strategy, which consists of PEA, BPA and targeted medical therapy, is made by a multidisciplinary team. The blood sample and tissue from PEA are stored in the central biobank for further research. The patients receive regular follow-up every 3 or 6 months for at least 3 years. The primary outcomes include all-cause mortality and changes in functional and hemodynamic parameters from baseline. The secondary outcomes include the proportion of patients experiencing lung transplantation, the proportion of patients experiencing heart and lung transplantation, and changes in health-related quality of life. Up to 31 December 2023, the study has enrolled 1500 eligible patients from 18 expert centers. CONCLUSIONS: As a real-world study, the CHANGE study is expected to increase our understanding of CTEPH, and to fill the gap between guidelines and the clinical practice in the diagnosis, assessment and treatment of patients with CTEPH. REGISTRATION NUMBER IN CLINICALTRIALS.GOV: NCT05311072.

Imaging Features in BMPR2 Mutation-associated Pulmonary Arterial Hypertension.

Background Germline mutation in the BMPR2 gene is common in patients with pulmonary arterial hypertension (PAH). However, its association with imaging findings in these patients is, to the knowledge of the authors, unknown. Purpose To characterize distinctive pulmonary vascular abnormalities at CT and pulmonary artery angiography in patients with and without BMPR2 mutation. Materials and Methods In this retrospective study, chest CT scans, pulmonary artery angiograms, and genetic test data were acquired for patients diagnosed with idiopathic PAH (IPAH) or heritable PAH (HPAH) between January 2010 and December 2021. Perivascular halo, neovascularity, centrilobular ground-glass opacity (GGO), and panlobular GGO were evaluated at CT and graded on a four-point severity scale by four independent readers. Clinical characteristics and imaging features between patients with BMPR2 mutation and noncarriers were analyzed using the Kendall rank-order coefficient and the Kruskal-Wallis test. Results This study included 82 patients with BMPR2 mutation (mean age, 38 years ± 15 [SD]; 34 men; 72 patients with IPAH and 10 patients with HPAH) and 193 patients without the mutation, all with IPAH (mean age, 41 years ± 15; 53 men). A total of 115 patients (42%; 115 of 275) had neovascularity, and 56 patients (20%; 56 of 275) had perivascular halo at CT, and so-called frost crystals were observed on pulmonary artery angiograms in 14 of 53 (26%) patients. Compared with patients without BMPR2 mutation, patients with BMPR2 mutation more frequently showed two distinctive radiographic manifestations, perivascular halo and neovascularity (38% [31 of 82] vs 13% [25 of 193] in perivascular halo [P < .001] and 60% [49 of 82] vs 34% [66 of 193] in neovascularity [P < .001], respectively). "Frost crystals" were more frequent in patients with BMPR2 mutation compared with noncarriers (53% [10 of 19] vs 12% [four of 34]; P < .01). Severe perivascular halo frequently coexisted with severe neovascularity in patients with BMPR2 mutation. Conclusion Patients with PAH with BMPR2 mutation showed distinctive features at CT, specifically perivascular halo and neovascularity. This suggested a link between the genetic, pulmonary, and systemic manifestations that underly the pathogenesis of PAH. © RSNA, 2023 Supplemental material is available for this article.

The Impact of Abnormal Lipid Metabolism on the Occurrence Risk of Idiopathic Pulmonary Arterial Hypertension.

The aim was to determine whether lipid molecules can be used as potential biomarkers for idiopathic pulmonary arterial hypertension (IPAH), providing important reference value for early diagnosis and treatment. Liquid chromatography-mass spectrometry-based lipidomic assays allow for the simultaneous detection of a large number of lipids. In this study, lipid profiling was performed on plasma samples from 69 IPAH patients and 30 healthy controls to compare the levels of lipid molecules in the 2 groups of patients, and Cox regression analysis was used to identify meaningful metrics, along with receiver operator characteristic curves to assess the ability of the lipid molecules to predict the risk of disease in patients. Among the 14 lipid subclasses tested, 12 lipid levels were significantly higher in IPAH patients than in healthy controls. Free fatty acids (FFA) and monoacylglycerol (MAG) were significantly different between IPAH patients and healthy controls. Logistic regression analysis showed that FFA (OR: 1.239, 95%CI: 1.101, 1.394, p < 0.0001) and MAG (OR: 3.711, 95%CI: 2.214, 6.221, p < 0.001) were independent predictors of IPAH development. Among the lipid subclasses, FFA and MAG have potential as biomarkers for predicting the pathogenesis of IPAH, which may improve the early diagnosis of IPAH.

CircGSAP alleviates pulmonary microvascular endothelial cells dysfunction in pulmonary hypertension via regulating miR-27a-3p/BMPR2 axis.

BACKGROUND: Our previous study showed that circular RNA-gamma-secretase-activating protein (circGSAP) was down-regulated in pulmonary microvascular endothelial cells (PMECs) in response to hypoxia, and regulated the cell cycle of PMECs via miR-942-5p sponge in pulmonary hypertension (PH). However, the mechanism whether circGSAP affects the dysfunction of PEMCs through other microRNAs (miRNAs) remains largely unknown. Therefore, we aimed to demonstrate the underlying mechanisms of circGSAP regulating PMECs dysfunction by absorbing other miRNAs to regulate target genes in idiopathic pulmonary arterial hypertension (IPAH). METHODS: Quantitative real-time polymerase chain reaction, immunofluorescence staining, Cell Counting Kit-8, Calcein-AM/PI staining, Transwell assay, dual-luciferase reporter assay, and ELISA were used to elucidate the roles of circGSAP. RESULTS: Here we showed that plasma circGSAP levels were significantly decreased in patients with IPAH and associated with poor outcomes. In vivo, circGSAP overexpression improved survival, and alleviated pulmonary vascular remodeling of monocrotaline-induced PH (MCT-PH) rats. In vitro, circGSAP overexpression inhibited hypoxia-induced PMECs proliferation, migration and increased mortality by absorbing miR-27a-3p. BMPR2 was identified as a miR-27a-3p target gene. BMPR2 silencing ameliorated the effect of the miR-27a-3p inhibitor on PMECs proliferation,migration and mortality. The levels of BMPR2 were upregulated in circGSAP-overexpressed PMECs and lung tissues of MCT-PH rats. CONCLUSION: Our findings demonstrated that circGSAP alleviated the dysfunction of PMECs via the increase of BMPR2 by competitively binding with miR-27a-3p, and mitigated pulmonary vascular remodeling of MCT-PH rats, providing potential therapeutic strategies for IPAH.

Peak oxygen uptake is a strong prognostic predictor for pulmonary hypertension due to left heart disease.

BACKGROUND: Pulmonary hypertension in left heart disease (PH-LHD), which includes combined post- and precapillary PH (Cpc-PH) and isolated postcapillary PH (Ipc-PH), differs significantly in prognosis. We aimed to assess whether cardiopulmonary exercise testing (CPET) predicts the long-term survival of patients with PH-LHD. METHODS: A single-center observational cohort enrolled 89 patients with PH-LHD who had undergone right heart catherization and CPET (mean pulmonary arterial pressure > 20 mm Hg and pulmonary artery wedge pressure ≥ 15 mm Hg) between 2013 and 2021. A receiver operating characteristic curve was plotted to determine the cutoff value of all-cause death. Survival was estimated using the Kaplan-Meier method and analyzed using the log-rank test. The Cox proportional hazards model was performed to determine the association between CPET and all-cause death. RESULTS: Seventeen patients died within a mean of 2.2 ± 1.3 years. Compared with survivors, nonsurvivors displayed a significantly worse 6-min walk distance, workload, exercise time and peak oxygen consumption (VO2)/kg with a trend of a lower oxygen uptake efficiency slope (OUES) adjusted by Bonferroni's correction. Multivariate Cox regression revealed that the peak VO2/kg was significantly associated with all-cause death after adjusting for Cpc-PH/Ipc-PH. Compared with Cpc-PH patients with a peak VO2/kg ≥ 10.7 ml kg-1 min-1, Ipc-PH patients with a peak VO2/kg < 10.7 ml kg-1 min-1 had a worse survival (P < 0.001). CONCLUSIONS: The peak VO2/kg is independently associated with all-cause death in patients with PH-LHD. The peak VO2/kg can also be analyzed together with Cpc-PH/Ipc-PH to better indicate the prognosis of patients with PH-LHD.

The Different Effects of Direct Bilirubin on Portopulmonary Hypertension and Idiopathic Pulmonary Arterial Hypertension.

Background: To observe different roles of direct bilirubin (Dbil) on portopulmonary hypertension (POPH) and idiopathic pulmonary arterial hypertension (IPAH). Methods: Thirty incident patients with POPH and 180 with IPAH (matched by the WHO functional classification in a 1 : 6 ratio) between March 2010 and December 2020 were included. The receiver operating curve and Kaplan-Meier method were applied to estimate the ability to distinguish between the two and survival, respectively. Univariate and forward multiple stepwise regression analyses were performed to access the relationship between pulmonary vascular resistance (PVR) and clinical indices. Results: Compared to IPAH, the POPH group had better hemodynamics including PVR (7.08 ± 3.95 vs. 14.89 ± 7.11, P < 0.001) and higher total bilirubin (Tbil) and Dbil. Tbil and Dbil had a negative correlation with PVR in the POPH group (r = -0.394, P=0.031; r = -0.364, P=0.048, respectively) but positive correlation in the IPAH group (r = 0.218, P=0.003; r = 0.178, P=0.018, respectively). Increased neutrophil counts (r = 0.394, P=0.031) and elevated NT-proBNP (r = 0.433, P < 0.001) would help predict the elevation of PVR in POPH and IPAH groups independent of Dbil, respectively. Dbil could distinguish POPH from IPAH (AUC = 0.799, P=0.009), and the ability was elevated when taking aspartate aminotransferase together (AUC = 0.835, P < 0.001). The overall survival was better in POPH than in IPAH (7 dead cases of POPH and 96 of IPAH, P=0.002). Survival was better in POPH than in IPAH in the group of Dbil ≥7 µmol/L (P=0.001) but showed no significant difference between POPH and IPAH in the group of Dbil <7 µmol/L (P=0.192). Conclusions: The POPH group had a better hemodynamic profile than IPAH. Dbil was associated oppositely with the elevation of PVR in POPH and IPAH. Patients with POPH had better survival than those with IPAH in the total cohort and in the group of Dbil ≥7 µmol/L, but limited dead cases of POPH should be noted.

Variation of PetCO2 during incremental exercise and severity of IPAH and CTEPH.

BACKGROUND AND OBJECTIVE: End-tidal PCO2 (PetCO2) patterns during exercise testing as well as ventilatory equivalents for CO2 have been reported for different pulmonary vascular diseases but seldomly for the significant differences in exercise response depending on the etiology of pulmonary hypertension. We aimed to compare PetCO2 change pattern in IPAH and CTEPH with varying severity during incremental cardiopulmonary exercise testing (CPET). METHODS: 164 IPAH patients and 135 CTEPH patients referred to Shanghai Pulmonary Hospital between 2012 and 2019 were retrospectively recruited into the study. All patients performed CPET and also underwent right-heart catheterization (RHC). Forty-four healthy subjects also performed CPET and were included as controls. RESULTS: PetCO2 was significantly lower in IPAH and CTEPH patients as compared to normal subjects. Moreover, the PetCO2 did not rise, in fact fell from rest to anaerobic threshold (AT), then further decreased until peak in both IPAH and CTEPH. PetCO2 value at rest, unloaded, AT and peak were proportionately reduced as the World Health Organization functional class (WHO-Fc) increased in both IPAH and CTEPH patients. The PETCO2 in IPAH patients had significant differences during all phases of exercise between WHO-Fc I-II and III-IV subgroup. CTEPH also demonstrated significant difference except for PetCO2 at peak. PetCO2 values were significantly higher in IPAH during all phases of exercise as compared to CTEPH patients (all P < 0.001). PeakVO2%pred correlated significantly with PetCO2 at rest (r = 0.477, P < 0.001), AT (r = 0.609, P < 0.001) and peak exercise (r = 0.576, P < 0.001) in IPAH. N-terminal natriuretic peptide type-B (NT-proBNP) also correlated markedly with PetCO2, with a correlation coefficient of - 0.326 to - 0.427 (all P < 0.001). Additionally, PetCO2 at rest, at AT and at peak correlated positively with peakVO2%pred and showed an inverse correlation with NT-proBNP in CTEPH patients (all P < 0.05). CONCLUSIONS: PetCO2 during exercise in IPAH and CTEPH patients was significantly different from normal subjects. Moreover, PetCO2 values were significantly higher in IPAH during all phases of exercise as compared to CTEPH patients (all P < 0.001). PetCO2 was progressively more abnormal with increasing disease severity according to peakVO2%pred and WHO-Fc.

Characteristics of exercise capacity in female systemic lupus erythematosus associated pulmonary arterial hypertension patients.

BACKGROUND: To study the oxygen uptake efficiency and determine usefulness of submaximal parameters of oxygen uptake in systemic lupus erythematosus associated pulmonary arterial hypertension (SLE PAH) on performing a cardiopulmonary exercise test (CPET). METHODS: CPET was performed in 21 SLE PAH patients, equal number of idiopathic pulmonary arterial hypertension (IPAH) patients and controls. Peak VO2, anaerobic threshold (AT), oxygen uptake efficiency slope (OUES) and oxygen uptake efficiency plateau (OUEP) and other CPET parameters were examined. All subjects had pulmonary function test (PFT) at rest, which included FEV1, FVC, FEV1/FVC, DLCO measurements. Right heart catheterization (RHC) was also done in SLE PAH and IPAH patients. CPET parameters were compared with RHC parameters to determine potential correlations. RESULTS: Peak VO2, PETCO2 and peak O2 pulse were lower in SLE PAH than IPAH and controls with OUE being lower during all stages of exercise in SLE PAH. DLCO and FVC values were significantly lower in SLE PAH (p < 0.05). Peak O2 pulse and VO2@AT in SLE PAH and IPAH was low (p < 0.05) and significant difference between SLE PAH and IPAH was seen (p < 0.05). PVR correlated with the lowest VE/VCO2, O2 pulse, peak PETCO2 and OUE in SLE PAH patients (all p < 0.05). CONCLUSIONS: SLE PAH patients have cardiopulmonary exercise limitation with reduced oxygen uptake efficiency. VO2@ at AT, peak O2 pulse and O2 pulse at AT were significantly reduced (p < 0.05). Key CPET parameters correlated with elevated pulmonary vascular resistance (PVR). Submaximal parameters of oxygen uptake are equally useful in SLE PAH.

Oxygen uptake is more efficient in idiopathic pulmonary arterial hypertension than in chronic thromboembolic pulmonary hypertension.

BACKGROUND AND OBJECTIVE: The responses of oxygen uptake efficiency (OUE) during cardiopulmonary exercise training (CPET) have not been reported in patients with pulmonary hypertension. We aimed to investigate the differences in OUE between patients with idiopathic pulmonary arterial hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Forty-four patients with IPAH and 29 patients with CTEPH were retrospectively enrolled into our study. All patients underwent right-heart catheterization, pulmonary function test and performed the 6-min walk test and CPET. RESULTS: We found that oxygen uptake efficiency plateau (OUEP) and oxygen uptake efficiency at anaerobic threshold (OUE@AT) was significantly higher in IPAH than that in CTEPH (both P = 0.002). However, patients with CTEPH had lower mean pulmonary artery pressure, pulmonary vascular resistance and transpulmonary gradient (all P < 0.05). The correlation between OUEP and heart rate at anaerobic threshold (HR_AT) was significant (r = 0.376, P < 0.05); however, no statistically significant correlation was found with ventilation at anaerobic threshold (VE_AT) (r = -0.074, P > 0.05) in patients with IPAH. In patients with CTEPH, both anaerobic threshold (r = 0.307, P > 0.05) and VE_AT (r = -0.709, P < 0.0001) were reduced. OUEP were higher in WHO functional class I/II patients than in WHO functional class III/IV patients (all P < 0.05). CONCLUSIONS: OUEP and OUE@AT are higher in IPAH than that in CTEPH not in proportion to haemodynamics, probably due to differences in cardiac function and pulmonary vascular occlusion. OUEP correlates well with the exercise capacity and the severity of the disease.

[Correlation between submaximal exercise measurements and peak oxygen uptake in patients with pulmonary arterial hypertension].

OBJECTIVE: To explore the correlation between submaximal exercise measurements and peak oxygen uptake in patients with pulmonary arterial hypertension (PAH). METHODS: The clinical data were retrospectively analyzed for 106 patients with PAH from Affiliated Shanghai Pulmonary Hospital, Tongji University from October 2010 to October 2013. The examinations included routine pulmonary function test, N-terminal pro-brain natriuretic peptide (NT-proBNP), 6-minute walk test, right heart catheterization and cardiopulmonary exercise testing. And within the same period, matched 20 healthy subjects without smoking and cardiopulmonary diseases were selected as control group. RESULTS: Peak oxygen uptake (P-VO2), anaerobic threshold (AT), oxygen uptake efficiency slope (OUES) and oxygen uptake efficiency plateau (OUEP) were significantly lower in patients with PAH than control group ((841 ± 257) vs (1 682 ± 284) ml/min, (661 ± 171) vs (1 041 ± 243) ml/min, 1.1 ± 0.4 vs 2.3 ± 0.4, 25.8 ± 5.2 vs 35.5 ± 4.0, respectively) (all P < 0.001). And the predicted parametric values (%pred) were also lower in PAH group than control group (all P < 0.001). While the lowest ventilation (VE)/CO2 output (VCO2) (L-VE/VCO2) and VE/VCO2 slope were significantly higher in PAH group than control group (50.5 ± 15.9 vs 30.5 ± 3.0 and 57.2 ± 23.2 vs 25.6 ± 2.8, both P < 0.001). Pearson correlation analysis showed, except for VE/VCO2 slope%pred, AT%pred, L-VE/VCO2%pred, OUES%pred and OUEP%pred were correlated with P-VO2 (all P < 0.001). According to multiple linear regression analysis, only AT%pred and OUES%pred were the independent predictors of P-VO2 (ß = 0.394, 0.384, both P < 0.001) and OUES%pred might be better than AT%pred (the adjusted ß = 0.674). When AT%pred < 58.0% or OUES%pred < 65.0%, exercise capacity in PAH declined obviously with the sensitivity was 92.3% and 96.2% and the specificity 81.2% and 75.5% respectively. CONCLUSIONS: Exercise capacity in patients with PAH is significantly lower than healthy subjects. OUES%pred and AT%pred may be used as an independent predictor of exercise capacity. And OUES%pred may be more powerful.

Pulmonary vascular resistance predicts the mortality in patients with bronchiectasis-associated pulmonary hypertension.

OBJECTIVE: Pulmonary hypertension is a severe complication of bronchiectasis, characterized by elevated pulmonary vascular resistance (PVR) and subsequent right heart failure. The association between PVR and mortality in bronchiectasis-associated pulmonary hypertension has not been investigated previously. METHODS: In the present study, a retrospective analysis was conducted on 139 consecutive patients diagnosed with bronchiectasis-associated pulmonary hypertension based on right heart catheterization, enrolled between January 2010 and June 2023. Baseline clinical characteristics and hemodynamic assessment were analyzed. The survival time for each patient was calculated in months from the date of diagnosis until the date of death or, if the patient was still alive, until their last visit. RESULTS: Patients with bronchiectasis-associated pulmonary hypertension exhibited estimated survival rates of 89.5, 70, and 52.9 at 1-year, 3-year, and 5-year intervals respectively, with a median survival time of 67 months. Multivariable Cox regression analysis revealed that increased age [(adjusted hazard ratio per year 1.042, 95% confidence interval (CI) 1.008-1.076, P = 0.015] and elevated PVR (adjusted HR per 1 Wood Units 1.115, 95% CI 1.015-1.224, P = 0.023) were associated with an increased risk of all-cause mortality. In contrast, higher BMI was associated with a decreased risk of all-cause death (adjusted hazard ratio per 1 kg/m2 0.915, 95% CI 0.856-0.979, P = 0.009). Receiver-operating characteristic analyses identified a cutoff value for PVR at 4 Wood Units as predictive for all-cause death within 3 years [area under the curve (AUC) = 0.624; specificity= 87.5%; sensitivity= 35.8%; P < 0.05]. Patients with a PVR greater than 4 Wood Units had a significantly higher risk of all-cause death compared with those with 4 Wood Units or less (adjusted hazard ratio 2.392; 95% CI 1.316-4.349; P = 0.019). Notably, there were no significant differences in age, sex, BMI, WHO functional class, 6-min walk distance, and NT-proBNP levels at baseline between patients categorized as having 4 Wood Units or less or greater than 4 Wood Units for PVR. CONCLUSION: Based on these data, PVR could serve as a discriminative marker for distinguishing between nonsevere pulmonary hypertension (PVR ≤ 4 Wood Units) and severe pulmonary hypertension (PVR > 4 Wood Units). The utilization of a PVR cutoff value of 4.0 Wood Units provides enhanced prognostic capabilities for predicting mortality.

CircALMS1 Alleviates Pulmonary Microvascular Endothelial Cell Dysfunction in Pulmonary Hypertension.

BACKGROUND: Circular RNAs can serve as regulators influencing the development of pulmonary hypertension (PH). However, their function in pulmonary vascular intimal injury remains undefined. Thus, we aimed to identify specifically expressed circular RNAs in pulmonary microvascular endothelial cells (PMECs) under hypoxia and PH. METHODS AND RESULTS: Deep RNA sequencing and quantitative real-time polymerase chain reaction revealed that circALMS1 (circular RNA Alstrom syndrome protein 1) was reduced in human PMECs under hypoxia (P<0.0001). Molecular biology and histopathology experiments were used to elucidate the roles of circALMS1 in regulating PMEC dysfunction among patients with PH. The circALMS1 expression was decreased in the plasma of patients with PH (P=0.0315). Patients with lower circALMS1 levels had higher risk of death (P=0.0006). Moreover, the circALMS1 overexpression of adeno-associated viruses improved right ventricular function and reduced pulmonary vascular remodeling in monocrotaline-PH and sugen/hypoxia-PH rats (P<0.05). Furthermore, circALMS1 overexpression promoted apoptosis and inhibited PMEC proliferation and migration under hypoxia by directly downregulating miR-17-3p (P<0.05). Dual luciferase assay confirmed the direct binding of circALMS1 to miR-17-3p and miR-17-3p binding to its target gene YT521-B homology domain-containing family protein 2 (YTHDF2) (P<0.05). The YTHDF2 levels were also downregulated in hypoxic PMECs (P<0.01). The small interfering RNA YTHDF2 reversed the effects of miR-17-3p inhibitors on PMEC proliferation, migration, and apoptosis. Finally, the results indicated that, although YTHDF2, as an N(6)-methyladenosine reader protein, contributes to the degradation of many circular RNAs, it could not regulate the circALMS1 levels in PMECs (P=0.9721). CONCLUSIONS: Our study sheds new light on circALMS1-regulated dysfunction of PMECs by the miR-17-3p/YTHDF2 pathway under hypoxia and provides insights into the underlying pathogenesis of PH.

Impact of different sequential triple oral combination therapies based selexipag on outcomes in pulmonary arterial hypertension.

BACKGROUND: While the GRIPHON study and others have confirmed the efficacy and safety of selexipag with single, dual, and initial triple combination therapy for patients with pulmonary arterial hypertension (PAH), multicenters studies concerning diverse triple oral combination therapies based on selexipag are limited. HYPOTHESIS: This study was conducted to evaluate the effects of various sequential triple oral combination therapies on PAH outcomes. METHODS: A retrospective study was carried out involving 192 patients from 10 centers, who were receiving sequential triple oral combination therapy consisting of an endothelin receptor antagonist (ERA), a phosphodiesterase 5 inhibitor (PDE5i)/riociguat and selexipag. Clinical parameters, event-free survival, and all-cause survival were assessed and analyzed at baseline and posttreatment. RESULTS: Among the 192 patients, 37 were treated with ERA + riociguat + selexipag, and 155 patients received ERA + PDE5i + selexipag. Both sequential triple oral combination therapies improved the World Health Organization functional class and raised the count of low-risk parameters. As a result of the larger patients' population in the ERA + PDE5i + selexipag group, these individuals exhibited significant increases in 6-minute walking distance (6MWD), pulmonary arterial systolic pressure, pulmonary arterial pressure, right ventricle, and eccentricity index, and significant decreases in N-terminal probrain natriuretic peptide after 6 months of treatment. Nevertheless, both sequential triple oral combination therapy groups demonstrated similar shifts in these clinical parameters between baseline and 6 months. Baseline 6MWD and mean pulmonary arterial pressure were independent predictors of survival in patients undergoing ERA + PDE5i + selexipag therapy. Importantly, no significant differences were found in 6-month event-free survival and all-cause survival between two groups. CONCLUSIONS: Different oral sequential triple combination therapies based on selexipag could comparably improve outcomes in patients with PAH.

Evaluating the efficacy and safety of oral triple sequential combination therapy for treating patients with pulmonary arterial hypertension: A multicenter retrospective study.

This study aimed to evaluate the effectiveness and safety of an oral sequential triple combination therapy with selexipag after dual combination therapy with endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE5I)/riociguat in pulmonary arterial hypertension (PAH) patients. A total of 192 PAH patients from 10 centers had received oral sequential selexipag therapy after being on dual-combination therapy with ERA and PDE5i/riociguat for a minimum of 3 months. Clinical data were collected at baseline and after 6 months of treatment. The study analyzed the event-free survival at 6 months and all-cause death over 2 years. At baseline, the distribution of patients among the risk groups was as follows: 22 in the low-risk group, 35 in the intermediate-low-risk group, 91 in the intermediate-high-risk group, and 44 in the high-risk group. After 6 months of treatment, the oral sequential triple combination therapy resulted in reduced NT-proBNP levels (media from 1604 to 678 pg/mL), a decline in the percentage of WHO-FC III/IV (from 79.2% to 60.4%), an increased in the 6MWD (from 325 ± 147 to 378 ± 143 m) and a rise in the percentage of patients with three low-risk criteria (from 5.7% to 13.5%). Among the low-risk group, there was an improvement in the right heart remodeling, marked by a decrease in right atrium area and eccentricity index. The intermediate-low-risk group exhibited significant enhancements in WHO-FC and tricuspid annular plane systolic excursion. For those in the intermediate-high and high-risk groups, there were marked improvements in activity tolerance, as reflected by WHO-FC and 6MWD. The event-free survival rate at 6 months stood at 88%. Over the long-term follow-up, the survival rates at 1 and 2 years were 86.5% and 86.0%, respectively. In conclusion, the oral sequential triple combination therapy enhanced both exercise capacity and cardiac remodeling across PAH patients of different risk stratifications.

Serum ASGR2 level: an efficacy biomarker for balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension.

Background: This study aimed to employ plasma proteomics to investigate the molecular changes, pathway alterations, and potential novel biochemical markers associated with balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods: Pre- and post-BPA plasma samples from five CTEPH patients in the PRACTICE study were analyzed to identify differentially expressed proteins. Proteomic and bioinformatics analyses were conducted, and the identified proteins were further validated using ELISA assays in a separate cohort of the same study. Correlation and multivariate regression analyses were performed to investigate the associations between these differentially expressed proteins and clinical parameters. Results: Significantly higher serum levels of asialoglycoprotein receptor 2 (ASGR2) were detected in 5 CTEPH patients compared to those in healthy individuals but decreased significantly after successful BPA procedures. The decrease in serum levels of ASGR2 after the completion of BPA procedures was further validated in a separate cohort of 48 patients with CTEPH [0.70 (0.51, 1.11) ng/mL vs. 0.38 (0.27, 0.59) ng/mL, P < 0.001]. Significant associations were found between the pre-BPA ASGR2 level and clinical parameters, including neutrophil percentage (R = 0.285, P < 0.05), platelet (PLT) count (R = 0.386, P < 0.05), and high-density lipoprotein cholesterol (HDL-C) before BPA (R = -0.285, P < 0.05). Significant associations were detected between post-BPA serum ASGR2 levels and lymphocyte percentage (LYM%) (R = 0.306, P < 0.05), neutrophil-to-lymphocyte ratio (R = -0.294, P < 0.05), and pulmonary vascular resistance after BPA (R = -0.35, P < 0.05). Multivariate stepwise regression analysis revealed that pre-BPA ASGR2 levels were associated with HDL-C and PLT count (both P < 0.001), while post-BPA ASGR2 levels were associated with LYM% (P < 0.05). Conclusion: Serum levels of ASGR2 may be a biomarker for the effectiveness of BPA treatment in CTEPH patients. The pre-BPA serum level of ASGR2 in CTEPH patients was associated with HDL-C and the PLT count. The post-BPA serum level of ASGR2 was correlated with the LYM%, which may reflect aspects of immune and inflammatory status.

The role of prolactin/vasoinhibins in cardiovascular diseases.

Prolactin (PRL) is a polypeptide hormone that is mainly synthesized and secreted by the lactotroph cells of the pituitary. There are two main isoforms of PRL: 23-kDa PRL (named full-length PRL) and vasoinhibins (including 5.6-18 kDa fragments). Both act as circulating hormones and cytokines to stimulate or inhibit vascular formation at different stages and neovascularization, including endothelial cell proliferation and migration, protease production, and apoptosis. However, their effects on vascular function and cardiovascular diseases are different or even contrary. In addition to the structure, secretion regulation, and signal transduction of PRL/vasoinhibins, this review focuses on the pathological mechanism and clinical significance of PRL/vasoinhibins in cardiovascular diseases.