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Abstract Background: Acute pulmonary embolism (APE) is a fatal cardiovascular disease, yet missed diagnosis and misdiagnosis often occur due to non-specific symptoms and signs. A simple, objective technique will help clinicians make a quick and precise diagnosis. In population studies, machine learning (ML) plays a critical role in characterizing cardiovascular risks, predicting outcomes, and identifying biomarkers. This work sought to develop an ML model for helping APE diagnosis and compare it against current clinical probability assessment models. Methods: This is a single-center retrospective study. Patients with suspected APE were continuously enrolled and randomly divided into two groups including training and testing sets. A total of 8 ML models, including random forest (RF), Naïve Bayes, decision tree, K-nearest neighbors, logistic regression, multi-layer perceptron, support vector machine, and gradient boosting decision tree were developed based on the training set to diagnose APE. Thereafter, the model with the best diagnostic performance was selected and evaluated against the current clinical assessment strategies, including the Wells score, revised Geneva score, and Years algorithm. Eventually, the ML model was internally validated to assess the diagnostic performance using receiver operating characteristic (ROC) analysis. Results: The ML models were constructed using eight clinical features, including D-dimer, cardiac troponin T (cTNT), arterial oxygen saturation, heart rate, chest pain, lower limb pain, hemoptysis, and chronic heart failure. Among eight ML models, the RF model achieved the best performance with the highest area under the curve (AUC) (AUC = 0.774). Compared to the current clinical assessment strategies, the RF model outperformed the Wells score (P = 0.030) and was not inferior to any other clinical probability assessment strategy. The AUC of the RF model for diagnosing APE onset in internal validation set was 0.726. Conclusions: Based on RF algorithm, a novel prediction model was finally constructed for APE diagnosis. When compared to the current clinical assessment strategies, the RF model achieved better diagnostic efficacy and accuracy. Therefore, the ML algorithm can be a useful tool in assisting with the diagnosis of APE.

Background Atrial fibrillation (AF) after acute pulmonary embolism (PE) may lead to a poor prognosis. We conducted this study to explore influencing factors of new-onset AF in patients after acute PE. Methods Patients with objectively confirmed acute PE at the China-Japan Friendship Hospital from first January 2015 to 31st May 2022 were retrospectively included in the study, and patients with new-onset AF confirmed by electrocardiography were defined as the case group. The control group was obtained from the above PE patients without new-onset AF in age matching. Patients with a history of AF, pulmonary hypertension, acute myocardial infarction, valvular heart disease and hyperthyroidism were excluded. Logistic regression was conducted to identify potential influencing factors for the development of new-onset AF in patients with acute PE. To assess the prediction value of potential variables, receiver operating characteristic curves were plotted. Results Among 853 patients diagnosed with acute PE, 732 patients met the including criteria, and 29 patients with new-onset AF were identified. The median age of all patients was 74 years, with 77.6% being male. No statistically significant differences were observed between the case and control groups regarding demographic characteristics. Patients with new-onset AF had significantly enlarged right atrium, right ventricle and left atrium in echocardiography compared with control group, but no significant differences were observed in the diameter of the left ventricle and the proportion of left ventricular ejection fraction (LVEF) ≤ 40%. Right atrial enlargement (OR, 4.19; 95%CI, 1.24-15.09; P = 0.023), left atrial enlargement (OR, 14.76; 95%CI, 4.79–57.28; P < 0.001) and the simplified pulmonary embolism severity index (sPESI) (OR, 2.04; 95%CI, 1.19–3.67; P = 0.012) were associated with increased risk of new-onset AF. Conclusions Both severity of acute PE and enlargement of left and right atrium were associated with an increased risk of new-onset AF in patients with acute PE. In patients with high-risk acute PE, greater vigilance is needed for the occurrence of new-onset AF.

Genetic risk factors are important for the occurrence and prognosis of venous thromboembolism (VTE). The studies of thrombophilia families are important for dissecting the genetic background of the thrombotic disease. We conducted the systematic review of all published family-based studies on VTE genetics across all racial groups through PubMed and Embase prior to 13th April 2020. This systematic review of 287 families (including 225 Caucasian families, 52 East Asian families, and families of other ethnicities) revealed a total of 21 different genes; the five most reported mutated genes were F5 (88/287, 30.7%), SERPINC1 (67/287, 23.3%), PROC (65/287, 22.6%), F2 (40/287, 13.9%) and PROS1 (48/287, 16.7%). For Caucasian families, F5 mutations were most frequently reported at 37.8% (85/225), while PROS1 mutations were most frequently reported, at 40.4% (21/52), for East Asian families (Chinese, Japanese and Korean). Factor V Leiden was reported more frequently in Caucasians than in East Asians. Missense mutations were reported frequently in the SERPINC1, PROC and PROS1 genes. In conclusion, our study found the most likely mutated genes associated with VTE among different ethnic groups and provided indications for VTE genetic testing and research in the future.

CTEPH significantly impacts patients’ quality of life, causing symptoms such as shortness of breath and fatigue, which lead to increased healthcare utilization and economic burden. In China, limited awareness and delayed diagnosis further complicate the management of CTEPH, underscoring the need for studies that address the disease’s burden and enhance recognition among healthcare providers. [...]this systematic review aimed to estimate the prevalence of CTEPH using data from PE patients and to investigate the characteristics and management patterns of CTEPH in the Chinese population. Common comorbidities included diabetes mellitus (2.00–33.33%), hypertension (8.33–75.00%), coronary heart disease (6.35–16.67%), and chronic obstructive pulmonary disease (COPD, 2.78–27.27%). Among these, three studies reported additional estimated survival rates: 1-year survival rate was from 93.3% to 97.1%, 3-year survival rate was from 84.6% to 93.3%, 5-year survival rate was from 73.4% to 86.9%, 7-year survival rate was 82.0%, and 8-year survival rate was 66.6%, respectively [Supplementary Table 5, http://links.lww.com/CM9/C403].

Background Patients with congenital myopathies may experience respiratory involvement, resulting in restrictive ventilatory dysfunction and respiratory failure. Pulmonary hypertension (PH) associated with this condition has never been reported in congenital ryanodine receptor type 1( RYR1) -related myopathy. Case presentation A 47-year-old woman was admitted with progressively exacerbated chest tightness and difficulty in neck flexion. She was born prematurely at week 28. Her bilateral lower extremities were edematous and muscle strength was grade IV − . Arterial blood gas analysis revealed hypoventilation syndrome and type II respiratory failure, while lung function test showed restrictive ventilation dysfunction, which were both worse in the supine position. PH was confirmed by right heart catheterization (RHC), without evidence of left heart disease, congenital heart disease, or pulmonary artery obstruction. Polysomnography indicated nocturnal hypoventilation. The ultrasound revealed reduced mobility of bilateral diaphragm. The level of creatine kinase was mildly elevated. Magnetic resonance imaging showed myositis of bilateral thigh muscle. Muscle biopsy of the left biceps brachii suggested muscle malnutrition and congenital muscle disease. Gene testing revealed a missense mutation in the RYR1 gene (exon33 c.C4816T). Finally, she was diagnosed with RYR1 -related myopathy and received long-term non-invasive ventilation (NIV) treatment. Her symptoms and cardiopulmonary function have been greatly improved after 10 months. Conclusions We report a case of RYR1 -related myopathy exhibiting hypoventilation syndrome, type II respiratory failure and PH associated with restrictive ventilator dysfunction. Pulmonologists should keep congenital myopathies in mind in the differential diagnosis of type II respiratory failure, especially in patients with short stature and muscle weakness.

Limited data exist on changes in the extracellular matrix (ECM) collagen biomarkers levels during chronic thromboembolic pulmonary hypertension (CTEPH) development. This study aimed to investigate ECM collagen biomarkers levels in stable patients with CTEPH. Patients with CTEPH and healthy persons were enrolled. Serum levels of procollagen III N-terminal peptide (PIIINP), carboxyterminal propeptide of type I procollagen (PICP), matrix metalloproteinases (MMP2), MMP9, and tissue inhibitor of metalloproteinases 1(TIMP1) were measured by ELISA. Clinical data coincident with samples were collected. The pulmonary endarterectomy (PEA) and control pulmonary artery tissue samples were analyzed for genetic and immunohistochemical differences. The serum concentrations of PIIINP, PICP, MMP2, and MMP9 decreased significantly in CTEPH patients compared to healthy controls (P < 0.001 for each). CTEPH patients had higher serum concentrations of TIMP1 (median, 111.97 [interquartile range, 84.35–139.93]) compared to healthy controls (74.97 [44.03–108.45] ng/mL, P < 0.001). The MMP2 to TIMP1 ratio was lower in patients than in the controls (P < 0.001). After adjusting for the body mass index (BMI), the MMP2 to TIMP1 ratio correlated negatively with pulmonary vascular resistance (PVR) (r = − 0.327, P = 0.025). Increased TIMP1 (P = 0.04) gene expression was identified in tissues of CTEPH patients. Immunohistochemistry results of vascular walls substantiated qRT-PCR results. This study indicates that ECM collagen biomarkers levels were significantly different in stable patients with CTEPH and healthy controls with significantly increased TIMP1 and decreased MMP2 and MMP9. Differences in TIMP1 expression should be expected not only among healthy controls and patients serum, but also across pathological tissue regions. These findings suggest that the state of vascular remodeling in pulmonary vascular bed in stable patients may be represented by ECM collagen biomarkers levels. We conclude that TIMP1 may play an important role in pulmonary vascular reconstruction in stable CTEPH patients.

Background Identification and validation of potential biomarkers could facilitate the identification of pulmonary arterial hypertension (PAH) and thus aid to study their roles in the disease process. Methods We used the isobaric tag for relative and absolute quantitation approaches to compare the protein profiles between the serum of PAH patients and the controls. Bioinformatics analyses and enzyme-linked immunosorbent assay (ELISA) identification of PAH patients and the controls were performed to identify the potential biomarkers. The receiver operating characteristic curve (ROC) analysis was used to evaluate the diagnostic performance of these potential biomarkers. Mendelian randomization (MR) analysis further clarified the relationship between the potential biomarkers and PAH. Additionally, the expression levels of the potential biomarkers were further validated in two PAH animal models (monocrotaline-PH and Sugen5416 plus hypoxia-PH) using ELISA and reverse transcription-quantitative PCR (RT-qPCR). Results We identified significant changes in three proteins including heparanase (HPSE), gelsolin (GSN), and hepatocyte growth factor activator (HGFA) in PAH patients. The ROC analysis showed that the areas under the curve of HPSE, GSN, and HGFA in differentiating PAH patients from controls were 0.769, 0.777, and 0.964, respectively. HGFA was correlated with multiple parameters of right ventricular functions in PAH patients. Besides proteomic analysis, we also used MR method to demonstrate the causal link between genetically reduced HGFA levels and an increased risk of PAH. In subsequent validation study in PAH animal models, the mRNA expression levels of HGFA in the lung tissues were significantly lower in PAH rat models than in controls. In the rat models, serum levels of HGFA were lower compared to the control group and showed a negative correlation with right ventricular systolic pressure. Conclusion The study demonstrated that HGFA might be a promising biomarker for noninvasive detection of PAH.

Background A large proportion of pulmonary embolism (PE) heritability remains unexplained, particularly among the East Asian (EAS) population. Our study aims to expand the genetic architecture of PE and reveal more genetic determinants in Han Chinese. Methods We conducted the first genome-wide association study (GWAS) of PE in Han Chinese, then performed the GWAS meta-analysis based on the discovery and replication stages. To validate the effect of the risk allele, qPCR and Western blotting experiments were used to investigate possible changes in gene expression. Mendelian randomization (MR) analysis was employed to implicate pathogenic mechanisms, and a polygenic risk score (PRS) for PE risk prediction was generated. Results After meta-analysis of the discovery dataset (622 cases, 8853 controls) and replication dataset (646 cases, 8810 controls), GWAS identified 3 independent loci associated with PE, including the reported loci FGG rs2066865 ( p -value = 3.81 × 10 −14 ), ABO rs582094 ( p -value = 1.16 × 10 −10 ) and newly reported locus FABP2 rs1799883 ( p -value = 7.59 × 10 −17 ). Previously reported 10 variants were successfully replicated in our cohort. Functional experiments confirmed that FABP2-A163G (rs1799883) promoted the transcription and protein expression of FABP2 . Meanwhile, MR analysis revealed that high LDL-C and TC levels were associated with an increased risk of PE. Individuals with the top 10% of PRS had over a fivefold increased risk for PE compared to the general population. Conclusions We identified FABP2 , related to the transport of long-chain fatty acids, contributing to the risk of PE and provided more evidence for the essential role of metabolic pathways in PE development.

Background Inflammation and dysregulated immunity play vital roles in idiopathic pulmonary arterial hypertension (IPAH), while the mechanisms that initiate and promote these processes are unclear. Methods Transcriptomic data of lung tissues from IPAH patients and controls were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA), differential expression analysis, protein-protein interaction (PPI) and functional enrichment analysis were combined with a hemodynamically-related histopathological score to identify inflammation-associated hub genes in IPAH. The monocrotaline-induced rat model of pulmonary hypertension was utilized to confirm the expression pattern of these hub genes. Single-cell RNA-sequencing (scRNA-seq) data were used to identify the hub gene-expressing cell types and their intercellular interactions. Results Through an extensive bioinformatics analysis, CXCL9, CCL5, GZMA and GZMK were identified as hub genes that distinguished IPAH patients from controls. Among these genes, pulmonary expression levels of Cxcl9, Ccl5 and Gzma were elevated in monocrotaline-exposed rats. Further investigation revealed that only CCL5 and GZMA were highly expressed in T and NK cells, where CCL5 mediated T and NK cell interaction with endothelial cells, smooth muscle cells, and fibroblasts through multiple receptors. Conclusions Our study identified a new inflammatory pathway in IPAH, where T and NK cells drove heightened inflammation predominantly via the upregulation of CCL5, providing groundwork for the development of targeted therapeutics.

Background Inflammation and immunological dysregulation are involved in the uncommon pulmonary thromboembolism (PTE) consequence known as chronic thromboembolic pulmonary hypertension (CTEPH). Although tissue samples are provided by pulmonary endarterectomy (PEA), accessibility is restricted by its technical complexity. Immune cells found in peripheral blood may provide information on how a disease develops. Methods We developed a 7-color flow cytometry method using 200 µl of peripheral blood to analyze immune cell subpopulations and platelet immune cell aggregates in CTEPH. PEA tissues were used for immunofluorescence validation. We employed correlation analysis and linear regression to examine the relationships between immune cell dysregulation and the severity of CTEPH. Results There were 36 age- and sex-matched healthy controls, 10 patients with other subtypes of pulmonary hypertension (PH) except CTEPH, 20 PTE patients, and 62 CTEPH patients. CTEPH patients had markedly dysregulated immune cell subpopulations. There was an increase in T lymphocytes from 60.59 ± 9.94% to 69.05 ± 4.90% ( p  < 0.0001) in CTEPH patients. Classical monocytes decreased (87.94 ± 9.93% vs. 82.02 ± 9.92%, p  < 0.0001), while non-classical monocytes increased (3.69 ± 5.42% vs. 8.44 ± 5.91%, p  = 0.02) in CTEPH patients. The same trend was also observed in PH group. Dysregulated immune cells were primarily localized in thrombus and neointima regions. Platelet-monocyte aggregates (PMAs) and their subpopulations were positively correlated with hemodynamic and ultrasound indicators. PTE patients had greater levels of PMAs than CTEPH patients ( p  = 0.0007), and these levels decreased during treatment ( p  = 0.0168). Conclusion Immune cell subpopulations in CTEPH can be efficiently analyzed using the low blood volume flow cytometry approach. Peripheral blood immune cell dysregulation points to an active immune response in CTEPH. Insights into the pathophysiology of CTEPH may be gained by using PMA as a biomarker for assessing the severity and treatment outcomes of CTEPH. However, more research is needed to determine PMA's role in CTEPH for disease diagnosis assessment and pathogenesis.