The prognosis and management of reclassified systemic lupus erythematosus associated pulmonary arterial hypertension according to 2022 ESC/ERS guidelines.

BACKGROUND AND AIMS: The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guideline has recently revised the hemodynamic definition of pulmonary arterial hypertension. However, there is currently limited research on the prognosis and treatment of system lupus erythematosus-associated pulmonary arterial hypertension (SLE-PAH) patients that have been reclassified by the new hemodynamic definition. This study aims to analyze the prognosis of newly reclassified SLE-PAH patients and provide recommendations for the management strategy. METHODS: This retrospective study analyzed records of 236 SLE-PAH patients who visited Peking Union Medical College Hospital (PUMCH) from 2011 to 2023, among whom 22 patients were reclassified into mild SLE-PAH (mean pulmonary arterial pressure (mPAP) of 21-24 mmHg, pulmonary vascular resistance (PVR) of 2-3 WU, and PAWP ≤ 15 mmHg) according to the guidelines and 14 were defined as unclassified SLE-PAH patients (mPAP 21-24 mmHg and PVR ≤ 2 WU). The prognosis was compared among mild SLE-PAH, unclassified SLE-PH, and conventional SLE-PAH patients (mPAP ≥ 25 mmHg and PVR > 3WU). Besides, the effectiveness of pulmonary arterial hypertension (PAH)-specific therapy was evaluated in mild SLE-PAH patients. RESULTS: Those mild SLE-PAH patients had significantly longer progression-free time than the conventional SLE-PAH patients. Among the mild SLE-PAH patients, 4 did not receive PAH-specific therapy and had a similar prognosis as patients not receiving specific therapy. CONCLUSIONS: This study supports the revised hemodynamic definition of SLE-PAH in the 2022 ESC/ERS guideline. Those mild and unclassified SLE-PH patients had a better prognosis, demonstrating the possibility and significance of early diagnosis and intervention for SLE-PAH. This study also proposed a hypothesis that IIT against SLE might be sufficient for those reclassified SLE-PAH patients.

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.

Cross-cultural validation of the Chinese version of the EmPHasis-10 questionnaire in connective tissue disease patients with pulmonary arterial hypertension and its relationship with risk stratification.

BACKGROUNDS: The EmPHasis-10 questionnaire is a disease-specific quality of life (QoL) measurement in patients with pulmonary hypertension. We report the results of cross-cultural validation of the Chinese version of the EmPHasis-10 and its relationship with risk stratification in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). METHODS: The Emphasis-10 was administered to 75 CTD-PAH patients along with the 36-item Medical Outcomes Study Short Form Survey (SF-36) and EuroQol five dimensions questionnaire (EQ-5D). The diagnosis of PAH was confirmed by right heart catheterization. Demographic and clinical data were obtained. Multivariable logistic regression was conducted based on the low risk profile assessed by a 4-strata risk assessment model (COMPERA 2.0) at follow-up. RESULTS: Date from 75 patients with CTD-PAH were analysed. The EmPHasis-10 demonstrated satisfactory reliability (Cronbach α = 0.95) and convergent validity showed by the significant relationship with WHO Functional Class (P = 0.003), SF-36 (P < 0.001) and EQ-5D (P = 0.002). EmPHasis-10 was significantly associated with achieving the low risk profile at 12 months of follow-up (Odds ratio: 0.928, P = 0.029) after adjusting for WHO Functional Class. CONCLUSION: EmPHasis-10 has acceptable reliability and validity in CTD-PAH patients and may serve as an additional parameter in risk stratification.

Diversity of hemodynamic types in connective tissue disease associated pulmonary hypertension: more than a subgroup of pulmonary arterial hypertension.

OBJECTIVE: Connective tissue disease associated pulmonary hypertension (CTD-PH) is classified as a subgroup of WHO group 1 PH, also called pulmonary arterial hypertension (PAH). However, not all CTD-PH fit hemodynamic definition of PAH. This study investigates the diversity of hemodynamic types of CTD-PH, their differences in clinical characteristics and outcomes. METHOD: We performed a retrospective cohort study. CTD-PH patients were enrolled and divided into WHO group1 PH, WHO group 2 PH and hyperdynamic PH (mPAP > 20 mmHg, PVR < 3WU, PAWP < 15 mmHg) according to hemodynamics obtained by right heart catheterization. Patients with severe lung diseases, heart failure with reduced ejection fraction, pulmonary embolism, and hepatic cirrhosis were excluded. Baseline characteristics, autoantibodies, cardiac function, echocardiogram parameters, hemodynamics and survival rates were compared. RESULT: A total of 202 CTD-PH patients were included, 138 in WHO group 1 PH, 33 in WHO group 2 PH and 31 in hyperdynamic PH. We found hyperdynamic PH is less severe, presenting lower NT-proBNP level, better WHO function class, lower mPAP and PVR, higher cardiac output, and less cardiac remodeling. Incidence of anti-RNP was significantly lower in patients with elevated PAWP. Short-term survival was worse in WHO group 2 PH, yet 5-year survival rates didn't differ between groups. CONCLUSION: Considering diversity in hemodynamic types, CTD-PH is more than a subgroup of PAH. Different types of CTD-PH present different clinical phenotypes and outcome. Phenotyping PH in CTD-PH patients is important.

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.

Quality of life in ambulatory pulmonary arterial hypertension in connective tissue diseases and its relationship with risk stratification.

The Pulmonary Arterial Hypertension Symptoms and Impact Questionnaire (PAH-SYMPACT) is a PAH-specific patient-reported outcome scale assessing patients' quality of life from four aspects: cardiopulmonary symptoms, cardiovascular symptoms, physical impacts and cognitive/emotional impacts. This study aimed to validate the Chinese version of PAH-SYMPACT and explore its relationship with risk stratification in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). In addition, 75 patients with CTD-PAH confirmed by right heart catheterization were invited to complete questionnaires including PAH-SYMPACT, the 36-item Medical Outcomes Study Short Form Survey (SF-36) and EuroQol five dimensions questionnaire (EQ-5D). The demographic, clinical, laboratory and treatment data were collected. The endpoint was treatment goal achievement status in 6-12 months after completing the questionnaires, defined as an integrated outcome. Participants' mean age was 36.4 ± 11.9 years and the mean pulmonary arterial pressure was 38.9 ± 13.67 mmHg. The reliability of the PAH-SYMPACT domains ranged from 0.83 to 0.88. Results of factor analysis basically conformed the original PAH-SYMPACT. The treatment goal achievement (TGA) status in 6-12 months was significantly associated with physical impacts scores (odds ratio: 0.180, 95% confidence interval: 0.036-0.908, P=0.038). The Chinese version of PAH-SYMPACT is a reliable measurement to evaluate quality of life in CTD-PAH patients and is also a potential predictor of patient's condition change in routine clinical practice.

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.

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.

hsa-miR-106b-5p participates in the development of chronic thromboembolic pulmonary hypertension via targeting matrix metalloproteinase 2.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by elevated pressure in pulmonary arteries. This study was performed to explore the critical miRNAs and genes affecting the pathogenesis of CTEPH. METHODS: GSE56914 dataset (10 CTEPH whole blood samples and 10 control samples) was downloaded from the Gene Expression Omnibus database. Using limma package, the differentially expressed miRNAs (DE-miRNAs) were acquired. After miRNA-target pairs were obtained using miRWalk2.0 tool, a miRNA-target regulatory network was built by Cytoscape software. Using DAVID tool, significantly enriched pathways involving the target genes were identified. Moreover, the protein-protein interaction network and transcription factor-target regulatory network were built by the Cytoscape software. Additionally, quantitative real-time PCR (qRT-PCR) experiments and luciferase assay were conducted to validate miRNA/gene expression and miRNA-target regulatory relationship, respectively. RESULTS: There were 25 DE-miRNAs (8 up-regulated and 17 down-regulated) between CTEPH and control groups. The target genes of has-let-7b-3p, has-miR-17-5p, has-miR-3202, has-miR-106b-5p, and has-miR-665 were enriched in multiple pathways such as "Insulin secretion". qRT-PCR analysis confirmed upregulation of hsa-miR-3202, hsa-miR-665, and matrix metalloproteinase 2 (MMP2) as well as downregulation of hsa-let-7b-3p, hsa-miR-17-5p, and hsa-miR-106b-5p. Luciferase assay indicated that MMP2 was negatively mediated by hsa-miR-106b-5p. CONCLUSIONS: These miRNAs and genes were associated with the pathogenesis of CTEPH. Besides, hsa-miR-106b-5p was involved in the development of CTEPH via targeting MMP2.