Hsa_circ_0046159 is involved in the development of chronic thromboembolic pulmonary hypertension.

The present study was performed to screen for potential molecular biomarkers and to assess the underlying mechanisms of chronic thromboembolic pulmonary hypertension (CTEPH) by using sequencing data analysis of microRNAs (miRNAs) and circular RNAs (circRNAs). Total RNA was isolated from peripheral-blood samples from five CTEPH patients and from five normal individuals. Based upon the identification of differentially expressed miRNAs (Affymetrix miRNA chip) and circRNAs (Agilent circRNA chip), target predictions for these differentially expressed miRNAs and functional enrichment analyses of the miRNAs and circRNAs were performed. Subsequently, the miRNA partner predictions of these differentially expressed circRNAs and co-expression analyses of differentially expressed circRNAs and miRNAs were conducted. Based on the results of these analyses, a competing endogenous RNA (ceRNA) network was constructed. Finally, the expression of circRNAs was detected by quantitative real-time PCR (qRT-PCR). Within the miRNA-circRNA regulatory network, hsa_circ_0026480 and hsa_circ_0046159 were predicted to interact with miR-27a-3p and miR-1226-3p, respectively with greater degree. Specially, ATP2A2-that had a ceRNA relationship with hsa_circ_0046159-was predicted as a target of miR-1226-3p. The results of RT-PCR also revealed a significantly increased expression of hsa_circ_0046159 in CTEPH samples than that in normal samples.

Efficacy and Safety of Bronchial Artery Embolization on Hemoptysis in Chronic Thromboembolic Pulmonary Hypertension: A Pilot Prospective Cohort Study.

OBJECTIVES: Managing hemoptysis in chronic thromboembolic pulmonary hypertension can be challenging due to the difficulties in maintaining coagulation homeostasis in affected patients. In this study, we evaluated the efficacy and safety of bronchial artery embolization in treating hemoptysis in chronic thromboembolic pulmonary hypertension patients. DESIGN: Pilot, prospective cohort study. SETTING: A large respiratory medical institute. PATIENTS: From January 1, 2012, to December 31, 2017, hospitalized chronic thromboembolic pulmonary hypertension patients were eligible for inclusion. Patients with pulmonary hypertension caused by other conditions, or who failed to participate in the follow-up were excluded. INTERVENTIONS: Hemoptysis in chronic thromboembolic pulmonary hypertension patients was treated with or without bronchial artery embolization based on whether the bleeding could be stopped with medication alone and patient willingness for bronchial artery embolization treatment. MEASUREMENTS AND MAIN RESULTS: A total of 328 patients diagnosed with chronic thromboembolic pulmonary hypertension were consecutively collected, 317 patients were completed the follow-up. There were 15 chronic thromboembolic pulmonary hypertension patients with hemoptysis in total, and the occurrence rate of hemoptysis in chronic thromboembolic pulmonary hypertension patients was 4.7%. Among the hemoptysis chronic thromboembolic pulmonary hypertension patients, 10 (67%) underwent bronchial artery embolization, and five (33%) were treated with medication only. The median follow-up period for hemoptysis patients was 7.6 months. In patients underwent bronchial artery embolization treatment, oxygenation index and right heart function showed no significant difference between pre bronchial artery embolization and post bronchial artery embolization. Hemoptysis relapse (20% vs 80%; p = 0.025) and hemoptysis-related mortality (0% vs 40%; p = 0.032) were significantly lower, whereas the overall survival (90% vs 40%; p = 0.040) was higher in patients treated with bronchial artery embolization than in patients treated without bronchial artery embolization. CONCLUSIONS: Bronchial artery embolization procedure demonstrated effectiveness and safety to treat hemoptysis in chronic thromboembolic pulmonary hypertension patients at our center, but further controlled studies are needed before it can be considered as an effective therapy for these patients.

A Case of Pulmonary Hypertension Due to Fistulas Between Multiple Systemic Arteries and the Right Pulmonary Artery in an Adult Discovered for Occulted Dyspnoea.

BACKGROUND: Pulmonary hypertension (PH) can be caused by a fistula between the systemic and pulmonary arteries. Here, we report a case of PH due to multiple fistulas between systemic arteries and the right pulmonary artery where the ventilation/perfusion scan showed no perfusion in the right lung. METHODS: A 32-year-old male patient was hospitalised for community-acquired pneumonia. After treatment with antibiotics, the pneumonia was alleviated but dyspnoea persisted. Pulmonary hypertension was diagnosed using right heart catheterisation, which detected the mean pulmonary artery pressure as 37mmHg. The anomalies were confirmed by contrast-enhanced CT scan (CT pulmonary angiography), systemic arterial angiography and pulmonary angiography. RESULTS: Following embolisation of the largest fistula, the haemodynamics and oxygen dynamics did not improve, and even worsened to some extent. After supportive therapy including diuretics and oxygen, the patient's dyspnoea, WHO function class and right heart function by transthoracic echocardiography all improved during follow-up. CONCLUSIONS: Pulmonary hypertension can be present even when the right lung perfusion is lost. Closure of fistulas by embolisation, when those fistulas act as the proliferating vessels, may be harmful.

[Effects of thrombolytic therapy in patients with cardiac arrest from suspected pulmonary thromboembolism].

OBJECTIVE: To explore the effects of thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA) in patients with cardiac arrest from suspected pulmonary thromboembolism (PTE). METHODS: A total of 12 hospitalized patients with cardiac arrest from suspected pulmonary embolism at Beijing Chaoyang Hospital from January 2010 to June 2014 were retrospectively studied. Thrombolysis was given only as a single dose of 50 mg of rt-PA during cardiopulmonary resuscitation. And their clinical features, effocacies and outcomes of thrombolysis were analyzed. RESULTS: There were 6 males and 6 females with a mean age of (54.8±18.6) (16-81) years. Seven patients were hospitalized in surgery ward while another 6 perioperatively. The mean time of resuscitation before thrombolysis was (47.8±26.0) (17-90) min. Nine patients regained spontaneous circulation. The mean time of restored spontaneous circulation was (15.8±5.4) (5-20). The 24-hour survival rate was 8/12. Four patients had bleeding complications, but only 2 life-threatening major cases. Four patients obtained a long-term survival. CONCLUSION: For suspected PTE patients with sudden cardiac arrest, thrombolysis therapy with 50 mg of rt-PA may restore spontaneous circulation and boost 24-hour survival rate.

[Analysis of clinical relevant bleeding events in the elderly patients with acute pulmonary thromboembolism after treatment].

OBJECTIVE: To investigate the incidences of clinical relevant bleeding events and risk factors in elderly patients with acute pulmonary thromboembolism (PTE). METHODS: Between January of 2009 and December of 2013, a total of 539 initially diagnosed PTE patients were recruited in our study in Beijing Chao Yang hospital. Basic clinical characteristics, medical history, imaging results, laboratory tests, therapy and outcomes (including mortality, recurrence and incidences of bleeding events) were collected during 3 months' follow-up. All the patients were divided into two groups according to age (≤ 65 years and >65 years ), and these parameters were compared between the two groups. RESULTS: Compared with younger patients (≤ 65 years old), older patients (>65 years) had higher incidences of total bleeding, clinical relevant non-major bleeding (20.2% vs 13.4%, P=0.038; 16.7% vs 10.5%, P=0.043). The incidence of gastrointestinal bleeding of the elderly was also higher than that of younger patients (6.0% vs 1.4%, P=0.005) and majority of bleeding events were within 1 month after initial treatment. For the elderly, chronic liver diseases (P=0.001, OR=9.229), ischemic stroke (P=0.001, OR=6.323) and anemia (P=0.014, OR=3.774) were independent risk factors for major bleeding, and malignancy (P<0.001, OR=3.140) was independent risk factor for clinical relevant non-major bleeding. The independent risk factors for gastrointestinal bleeding were diabetes mellitus (P=0.012, OR=3.711) and anemia (P<0.001, OR=5.863). CONCLUSIONS: The older PTE patients had higher incidences of total bleeding and clinical relevant non-major bleeding. Gastrointestinal bleeding of the elderly was also higher than that of younger patients and mainly occurred within 1 month after initial treatment. Complications can increase the risk of bleeding in older PTE patients.

Better efficacy of sequential combination with balloon pulmonary angioplasty after long-term riociguat for patients with inoperable chronic thromboembolic pulmonary hypertension.

The present study aimed to evaluate the efficacy of long-term riociguat sequentially combined with balloon pulmonary angioplasty (BPA) for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Eight inoperable CTEPH patients were enrolled in this study, who have been administrated riociguat 2.5 mg three times daily for about 8 years, then underwent several sessions of BPA procedures. Data are prospectively collected to evaluate clinical outcomes, hemodynamics, exercise capacity, and right heart size and function by echocardiography at baseline, 8 years after riociguat, and 3 months after the final BPA. Eight patients (mean age 54.9 ± 11.4 years) were treated with riociguat 2.5 mg three times daily for 95.0 ± 10.7 months. Cardiac index (CI) (1.5 ± 0.5 L/min/m2 to 2.4 ± 0.6 L/min/m2, p = 0.005), 6 min walking distance (6MWD) (329.6 ± 87.5 m to 418.1 ± 75.8 m, p = 0.016), and pulmonary vascular resistance (PVR) (1336.9 ± 320.2 dyn·s·cm-5 to 815.4 ± 195.6 dyn·s·cm-5, p = 0.008) were significant improvement after riociguat treatment. Mean 4.1 ± 1.6 additional combinational BPA sessions and mean 18.8 ± 8.1 balloon dilations were performed. Mean pulmonary artery pressure (54.1 ± 11.1 mmHg to 33.6 ± 7.7 mmHg, p = 0.002) and PVR (815.4 ± 195.6 dyn·s·cm-5 to 428.3 ± 151.2 dyn·s·cm-5, p＜0.001) were further decreased. CI (2.4 ± 0.6 L/min/m2 to 2.7 ± 0.7 L/min/m2, p = 0.028) and 6MWD (418.1 ± 75.8 m to 455.7 ± 100.0 m, p = 0.038) were increased significantly. After long-term riociguat treatment, sequential combination with BPA delivered considerably incremental benefits on exercise capacity and pulmonary hemodynamics, as well as right heart size and function of technically inoperable CTEPH patients.

Insufficiency of quality of life as the treatment endpoint for balloon pulmonary angioplasty in inoperable chronic thromboembolic pulmonary hypertension.

Background and Objectives: The ability of a quality of life (QoL) to guide balloon pulmonary angioplasty (BPA) among patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) has not been fully investigated. This study explored the relationship between QoL scores and hemodynamics in CTEPH patients after BPA and examined whether QoL could be applied as a treatment endpoint. Materials and Methods: This cohort study included patients with inoperable CTEPH who had undergone at least four sessions of BPA. The patients' demographic and clinical data as well as hemodynamic parameters and scores from the RAND 36-item short-form QoL questionnaire were recorded and compared before and after BPA. Results: After BPA treatments, clinical characteristics, hemodynamic parameters, as well as QoL score improved significantly. A physical component summary (PCS) score of 35 or 46 can be used as the cutoff value for predicting better World Health Organization functional classification (WHO FC). Patients who had a higher PCS would have longer 6-min walk distance (6MWD), lower pulmonary vascular resistance (PVR), and better cardiac output (CO) both before and after BPA. However, 19 patients (55.9%) with a higher PCS score after BPA did not achieve the goal of mean pulmonary arterial pressure (mPAP) ≤30 mmHg. During the follow-up period, a significant reduction of PVR was observed, but the PCS score improved a little. Conclusions: QoL is a useful tool for assessing the exercise endurance of patients with inoperable CTEPH treated with BPA, but is insufficient to serve as a treatment endpoint for BPA.

The Role of Strain by Cardiac Magnetic Resonance Imaging in Predicting the Prognosis of Patients with Chronic Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombotic obstruction of the pulmonary arteries, and right ventricular (RV) dysfunction is a major cause of death. Cardiac magnetic resonance (CMR) is the gold standard for assessing heart wall deformation; therefore, we aimed to determine the prognostic value of CMR strain in patients with CTEPH. Strain derived by CMR was measured at the time of diagnosis in 45 patients with CTEPH, and the relationship between RV strain and prognosis was determined through follow-up. The value of RV strain in the prognostic model was compared with that of pulmonary arterial hypertension (PAH) risk stratification. The RV global peak longitudinal strain (GLS) and global peak circumferential strain (GCS) in CTEPH patients were lower than the normal references of RV strain in the control group. GLS and longitudinal strain in the basal segment were independent risk factors for adverse events (P < .050). Adding CMR parameters to PAH risk stratification improved its predictive power in patients with CTEPH. GLS and GCS scores were impaired in patients with chronic RV overload. RV strain derived by CMR imaging is a promising noninvasive tool for the follow-up of patients with CTEPH.

Padua prediction score may be inappropriate for VTE risk assessment in hospitalized patients with acute respiratory conditions: A Chinese single-center cohort study.

Background: The Padua Prediction Score (PPS) recommended by the guidelines lacks effective external validation in a Chinese cohort. This study sought to assess the accuracy of the PPS to predict venous thromboembolism (VTE) risk in medical inpatients with acute respiratory conditions. Methods: This consecutive cohort study included 1,574 inpatients from January to August 2019. The occurrence rate of VTE in patients classified at high-risk and low-risk groups according to PPS and Caprini risk assessment model (RAM) was compared. The discriminatory capability of the RAMs was evaluated in all the patients and the subgroup without pharmacological prophylaxis. Reclassification parameters were also used to assess the clinical utility. Results: 170 (10.8%) patients were objectively confirmed as having VTE during hospitalization. The incidence rate of VTE in low-risk patients was 6.3% by PPS, which was significantly higher than that by Caprini RAM (2.6%, p < 0.001). The area under the curve (AUC) for PPS and Caprini RAM was 0.714 (95%CI, 0.672-0.756) and 0.760 (95%CI, 0.724-0.797), respectively (p = 0.003). The AUC of Caprini RAM was larger than PPS even in subgroups without pharmacological prophylaxis (0.774 vs 0.709, p = 0.002). Compared with Caprini RAM, the net reclassification index was estimated at 0.037 (p = 0.436), and integrated discrimination improvement was 0.015 (p = 0.495) by PPS. Conclusions: According to our cohort study, PPS may not be appropriate to predict VTE risk in hospitalized patients with acute respiratory conditions. An accurate, widely applicable, validated RAM needs to be further constructed in Chinese medical inpatients.

Analysis of clinical features between active and inactive patients of Takayasu's arteritis with pulmonary arteries involvement.

BACKGROUND: The aim of this study was to investigate the clinical characteristics of patients between active and inactive Takayasu's arteritis with pulmonary artery involvement (PTA) and to identify better markers of disease activity in these patients. METHODS: Sixty-four PTA patients in Beijing Chao-yang hospital (2011 to 2021) were included. According to National Institutes of Health criteria, 29 patients were in active stage and 35 were in inactive stage. Their medical records were collected and analyzed. RESULTS: Compared with inactive group, patients in active group were younger. More patients in active stage presented fever (41.38% vs 5.71%), chest pain (55.17% vs 20%), increased C-reactive protein (2.91 vs 0.46 mg/L), erythrocyte sedimentation rate (35.0 vs 9 mm/h), and platelet count (291 vs 221 × 109/L). Pulmonary artery wall thickening was more common in active group (51.72% vs 11.43%). These parameters were restored after treatment. The incidence of pulmonary hypertension was comparable between groups (34.48% vs 51.43%), but patients in active group had lower pulmonary vascular resistance (PVR) (361.0 vs 891.0 dyn·s·cm-5) and higher cardiac index (2.76 ± 0.72 vs 2.01 ± 0.58 L/min/m2). On multivariate logistic regression analysis, chest pain [odds ratio (OR) 9.37, 95%CI (1.98-44.38), P = 0.005], increased platelet count (>242.5 × 109/L) [OR 9.03, 95%CI (2.10-38.87), P = 0.003] and pulmonary artery wall thickening [OR 7.08, 95%CI (1.44-34.89), P = 0.016] were independently associated with disease activity. CONCLUSION: Chest pain, increased platelet count, and pulmonary artery wall thickening are potential new indicators of disease activity in PTA. Patients in active stage may have lower PVR and better right heart function.

Free fatty acids inhibit TM-EPCR expression through JNK pathway: an implication for the development of the prothrombotic state in metabolic syndrome.

Metabolic syndrome is associated with significant hypercoagulable prothrombotic tendency; however, the mechanism for the prothrombotic state is not completely understood. We hypothesize that higher circulating plasma free fatty acids (FFAs) in metabolic syndrome inhibit the endothelial thrombomodulin (TM)-endothelial protein C receptor (EPCR) pathway, thereby promoting thrombus formation. Human umbilical vein endothelial cells were cultured in media supplemented with various doses of palmitic acid (PA), in the presence or absence of JNK inhibitor, and the expression of TM and EPCR was measured by western blot. The thrombotic state of high fat fed C57BL/6J mice was examined by tail bleeding time and deep venous thrombosis (DVT) model. As a result, PA inhibited the expression of TM and EPCR in endothelial cells, and this effect was blunted by inhibiting JNK signaling. High fat diet fed mice had higher level of circulating FFAs and exhibited prothrombotic state, evidenced by increased tail bleeding time and enlarged thrombotic size in DVT model, compared to the control diet fed mice. Hence, FFAs inhibit TM-EPCR-Protein C system in endothelial cells through activating JNK signaling, which may be a mechanism for the prothrombotic state in metabolic syndrome.

Long-term Outcomes and Predictors of Chronic Thromboembolic Pulmonary Hypertension After Pulmonary Endarterectomy.

BACKGROUND: Pulmonary endarterectomy (PEA) is the preferred treatment for CTEPH patients which can significantly improve symptoms and pulmonary hemodynamics. Therefore, this retrospective study evaluated the long-term outcomes after pulmonary endarterectomy (PEA) and analyze the predictors of long-term outcomes for chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: From 2002-2020, 76 CTEPH patients successfully discharged after PEA in Beijing Chaoyang Hospital were followed-up by scheduled clinical visits or telephone interviews. The follow-up time lasted for 18 years and median time was 7.29 years. RESULTS: The survival rate at 1,3,5,10,15 years postoperatively was 100.00%, 97.10%, 95.40%, 89.80% and 82.90%, respectively. Multivariate logistics regression analysis showed that postoperative mPAP (hazard ratio: 1.144; 95%confidence interval: 1.018-1.285; P = 0.023) was associated with a higher risk of late death, right atrium right and left diameters (hazard ratio: 1.113; 95%confidence interval, 1.006-1.231; P = 0.038) were associated with a higher risk of major adverse events. CONCLUSION: Pulmonary endarterectomy is an effective way to treat CTEPH. Long-term outcome is excellent for patients who undergoing pulmonary endarterectomy who survived from peri-operation time. Postoperative mPAP is a significant prognostic factor for long-term death and right atrium right and left diameters is a significant prognostic factor for major adverse events. That shows patients with high postoperative mPAP and right atrium right and left diameter should be followed up closely.

Single-cell RNA-sequencing and microarray analyses to explore the pathological mechanisms of chronic thromboembolic pulmonary hypertension.

Objective: The present study aimed to explore the pathological mechanisms of chronic thromboembolic pulmonary hypertension (CTEPH) using a gene chip array and single-cell RNA-sequencing (scRNA-seq). Materials and methods: The mRNA expression profile GSE130391 was downloaded from the Gene Expression Omnibus database. The peripheral blood samples of five CTEPH patients and five healthy controls were used to prepare the Affymetrix microRNA (miRNA) chip and the Agilent circular RNA (circRNA) chip. The pulmonary endarterectomized tissues from five CTEPH patients were analyzed by scRNA-seq. Cells were clustered and annotated, followed by the identification of highly expressed genes. The gene chip data were used to identify disease-related mRNAs and differentially expressed miRNAs and circRNAs. The protein-protein interaction (PPI) network and the circRNA-miRNA-mRNA network were constructed for each cell type. Results: A total of 11 cell types were identified. Intersection analysis of highly expressed genes in each cell type and differentially expressed mRNAs were performed to obtain disease-related genes in each cell type. TP53, ICAM1, APP, ITGB2, MYC, and ZYX showed the highest degree of connectivity in the PPI network of different types of cells. In addition, the circRNA-miRNA-mRNA network for each cell type was constructed. Conclusion: For the first time, the key mRNAs, miRNAs, and circRNAs, as well as their possible regulatory relationships, during the progression of CTEPH were analyzed using both gene chip and scRNA-seq data. These findings may contribute to a better understanding of the pathological mechanisms of CTEPH.

Examining the Development of Chronic Thromboembolic Pulmonary Hypertension at the Single-Cell Level.

BACKGROUND: The mechanism of chronic thromboembolic pulmonary hypertension (CTEPH) is known to be multifactorial but remains incompletely understood. METHODS: In this study, single-cell RNA sequencing, which facilitates the identification of molecular profiles of samples on an individual cell level, was applied to investigate individual cell types in pulmonary endarterectomized tissues from 5 patients with CTEPH. The order of single-cell types was then traced along the developmental trajectory of CTEPH by trajectory inference analysis, and intercellular communication was characterized by analysis of ligand-receptor pairs between cell types. Finally, comprehensive bioinformatics tools were used to analyze possible functions of branch-specific cell types and the underlying mechanisms. RESULTS: Eleven cell types were identified, with immune-related cell types (T cells, natural killer cells, macrophages, and mast cells) distributed in the left (early) branch of the pseudotime tree, cancer stem cells, and CRISPLD2+ cells as intermediate cell types, and classic disease-related cell types (fibroblasts, smooth muscle cells, myofibroblasts, and endothelial cells) in the right (later) branch. Ligand-receptor interactions revealed close communication between macrophages and disease-related cell types as well as between smooth muscle cells and fibroblasts or endothelial cells. Moreover, the ligands and receptors were significantly enriched in key pathways such as the PI3K/Akt signaling pathway. Furthermore, highly expressed genes specific to the undefined cell type were significantly enriched in important functions associated with regulation of endoplasmic reticulum stress. CONCLUSIONS: This single-cell RNA sequencing analysis revealed the order of single cells along a developmental trajectory in CTEPH as well as close communication between different cell types in CTEPH pathogenesis.

Haemodynamic effects of riociguat in CTEPH and PAH: a 10-year observational study.

BACKGROUND: Long-term treatment with riociguat has been shown to enhance exercise capacity in patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH). This study sought to evaluate the long-term haemodynamic effects of riociguat in patients with PAH and inoperable CTEPH. METHODS: During this single-centre long-term observational study, riociguat was administered at a three-times-daily dose of up to 2.5 mg. The primary outcome was pulmonary vascular resistance (PVR). The secondary outcomes included mean pulmonary arterial pressure (PAP), cardiac index, mortality, clinical worsening events, 6-min walk distance (6MWD) and World Health Organization functional class (WHO FC). RESULTS: 37 patients (CTEPH n=19; PAH n=18) were included. The median follow-up period was 96 months. The survival estimates for all the patients at 1/3/5/8 years were 0.97/0.86/0.72/0.61, without significant differences between patients with CTEPH and PAH. At the final data cut-off, PVR decreased (1232±462 dyn·s·cm-5 versus 835±348 dyn·s·cm-5, p<0.001), cardiac index increased (1.7±0.4 L·min-1·m-2 versus 2.4±0.5 L·min-1·m-2, p<0.001), 6MWD increased by 43.1±59.6 m, and WHO FC improved/stabilised/worsened in 40%/35%/25% of patients versus baseline. Improvement in PAP was not shown. Compared with patients in WHO FC I/II and III/IV at baseline, the 8-year clinical worsening-free survival estimates were 0.51 versus 0.19 (p=0.026). CONCLUSIONS: Riociguat improved PVR and cardiac index for up to 8 years, but not PAP. WHO FC may have certain predictive value for the long-term prognosis.

Expression of miR-93-5p as a Potential Predictor of the Severity of Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: MicroRNAs (miRNAs) play an important role in the pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH). However, the potential correlation between miRNA expression and the severity of CTEPH remains unclear. Our previous study indicated that miRNAs hsa-let-7b-3p, hsa-miR-17-5p, hsa-miR-106b-5p, hsa-miR-3202, hsa-miR-665, and hsa-miR-93-5p are closely involved in CTEPH. This study assessed the associations between the expression levels of these miRNAs and clinical parameters in CTEPH patients. METHODS: A total of eight CTEPH patients and eight healthy adults as a reference group were included, and clinical data including total protein (TP), albumin (Alb), lactate dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBDH), uric acid (UA), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were collected. Right heart catheterization was conducted to obtain hemodynamic data including cardiac index (CI). The expression levels of let-7b-3p, miR-17-5p, miR-106b-5p, miR-3202, miR-665, and miR-93-5p were measured by quantitative real-time PCR (qPCR). Correlation analysis was applied to estimate the associations between miRNA expression levels and clinical parameters in CTEPH patients. RESULTS: Serum TP and Alb levels were decreased, while LDH, HBDH, and UA levels were increased in CTEPH patients compared with the reference group (P < 0.05). miR-3202 and miR-665 were upregulated, whereas let-7b-3p, miR-17-5p, miR-106b-5p, and miR-93-5p were downregulated in CTEPH patients relative to the reference group (P < 0.05). miR-93-5p expression was positively correlated with NT-proBNP level and negatively correlated with CI (P < 0.05). Moreover, let-7b-3p tended to be positively correlated with mean pulmonary arterial pressure. CONCLUSIONS: miR-93-5p expression was associated with the severity of CTEPH and could act as a potential predictor of high-risk CTEPH.

Possible immune regulation mechanisms for the progression of chronic thromboembolic pulmonary hypertension.

PURPOSE: This study aimed to screen key genes significantly associated with chronic thromboembolic pulmonary hypertension (CTEPH) and predicted suitable drugs for the treatment of CTEPH from the perspective of immune cells. METHODS: The dataset GSE130391 was used for this analysis. Differentially expressed genes (DEGs) between the CTEPH and control groups were screened. Abundance of infiltrating immune cells was analyzed and immune-related DEGs were identified. Next, the circular RNA (circRNA)-micro RNA (miRNA)-mRNA network was constructed, followed by functional enrichment analysis. Then, the protein-protein interaction (PPI) network was constructed and drug-gene interactions were predicted. Finally, miRNA and circRNA prediction results were verified by our previously published studies. RESULTS: Five key immune cell-related DEGs [CD83 molecule (CD83), complement c5a receptor 1 (C5AR1), atypical chemokine receptor 1 (ACKR1), profilin 2 (PFN2), and solute carrier family 2 member 3 (SLC2A3)] were identified. Several circRNA-miRNA-mRNA interactions were obtained, including circ_0022342miR-503-5pSLC2A3 and circ_0002062miR-92b-3p/miR-92a-3pmannosidase alpha class 2A member 1 (MAN2A1). Immune cell for SLC2A3 was eosinophils and for MAN2A1 was regulatory T cells (Tregs). Additionally, Glufosfamide and Kifunensine might be suitable as candidate drugs for CTEPH treatment. CONCLUSIONS: SLC2A3 and MAN2A1 may be important genes for the pathogenesis of CTEPH. Possible immune regulation mechanisms in CTEPH may be circ_0022342miR-503-5pSLC2A3 and circ_0002062miR-92b-3p/miR-92a-3pMAN2A1. These results may be helpful for the diagnosis and treatment of CTEPH from the perspective of immunology.

Cell landscape atlas for patients with chronic thromboembolic pulmonary hypertension after pulmonary endarterectomy constructed using single-cell RNA sequencing.

This study aimed to construct an atlas of the cell landscape and comprehensively characterize the cellular repertoire of the pulmonary endarterectomized tissues of patients with chronic thromboembolic pulmonary hypertension (CTEPH). Five pulmonary endarterectomized tissues were collected. 10× Genomics single-cell RNA sequencing was performed, followed by the identification of cluster marker genes and cell types. Gene Ontology (GO) enrichment analysis was conducted. Seventeen cell clusters were characterized, corresponding to 10,518 marker genes, and then classified into eight cell types, including fibroblast/smooth muscle cell, endothelial cell, T cell/NK cell, macrophage, mast cell, cysteine rich secretory protein LCCL domain containing 2 (CRISPLD2)+ cell, cancer stem cell, and undefined. The specific marker genes of fibroblast/smooth muscle cell, endothelial cell, T cell/NK cell, macrophage, mast cell, and cancer stem cell were significantly enriched for multiple functions associated with muscle cell migration, endothelial cell migration, T cell activation, neutrophil activation, erythrocyte homeostasis, and tissue remodeling, respectively. No functions were significantly enriched for the marker gene of CRISPLD2+ cell. Our study, for the first time, provides an atlas of the cell landscape of the pulmonary endarterectomized tissues of CTEPH patients at single-cell resolution, which may serve as a valuable resource for further elucidation of disease pathophysiology.

Combination of sildenafil and simvastatin ameliorates monocrotaline-induced pulmonary hypertension in rats.

Sildenafil, a phosphodiesterase-5 inhibitor, and simvastatin, a cholesterol lowering drug, both have therapeutic effects on PAH; however, the combination of these drugs has not been tested in the treatment of PAH. The purpose of this study was to determine whether the combination of sildenafil and simvastatin is superior to each drug alone in the prevention of MCT-induced PAH. Phosphorylated Smad levels were decreased in lung tissue in MCT-injected rats, whereas ERK protein levels were increased. This indicates a possible role for an increase in mitogenic ERK activity in addition to decreased proapoptotic Smad signaling in the MCT model of PAH. Combination sildenafil and simvastatin treatment prevented the MCT-induced increases in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH), exerted an anti-proliferative effect on pulmonary artery smooth muscle cells (PASMC). Our results indicate that combination therapy with sildenafil and simvastatin attenuated the development of pulmonary hypertension more than either treatment alone.

[Association between the erythrocyte sedimentation rate, serum C-reactive protein and risk of lung cancer].

OBJECTIVE: To explore the association between the erythrocyte sedimentation rate, serum C-reactive protein (CRP) and the risk of lung cancer. METHODS: One hundred and three patients with newly diagnosed lung cancer and 85 homochronous hospitalized patients with chronic respiratory diseases (including chronic obstructive pulmonary disease, asthma, bronchiectasis and pulmonary fibrosis) were included in this study. ESR, serum levels of CRP, CEA, CA19-9 and CA125 were analyzed in the two groups before the initiation of any therapy after hospitalization. The association with clinicopathological characteristics of lung cancer and the risk of lung cancer were estimated by logistic regression. RESULTS: Both the ESR and CRP levels were significantly higher in the lung cancer group, as compared with that in the chronic respiratory diseases group (P < 0.001). There was no significant association of ESR and CRP with lung cancer stage and type. Spearman correlation analysis showed a positive correlation between ESR and CRP (r = 0.56, P < 0.001), ESR and CA125 (r = 0.33, P < 0.001), and CRP and CA125 (r = 0.32, P < 0.001). The results of multivariate logistic analysis showed that the level of CRP was associated with an increased risk of lung cancer. Adjusting the confounding factors such as age, gender and smoking condition, the risk increased along with the elevation of CRP. Compared with the first quantile patients, the risk of the second quantile patients increased twice (OR: 2.46, 95%CI: 1.16 - 5.20), the risk of the third quantile patients increased ten-fold (OR: 10.52, 95%CI: 4.40 - 25.18). CONCLUSION: The level of CRP is associated with an increased risk of lung cancer. The results of this study suggest that early detection of CRP may have a potential predicting value for high risk group of lung cancer.