Genome-wide association analyses identified novel susceptibility loci for pulmonary embolism among Han Chinese population.

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.

Extracellular matrix collagen biomarkers levels in patients with chronic thromboembolic pulmonary hypertension.

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.

Patient-Completed Caprini Risk Score for Venous Thromboembolism Risk Assessment: Developed and Validated from 1,017 Medical and Surgical Patients.

Background The Caprini Risk Score (CRS) is one of the most widely used risk assessment models for venous thromboembolism (VTE). A well-validated patient-completed CRS form may allow patients to self-report and simplify the evaluation by health care workers. Methods The Chinese version of the CRS was optimized for easy understanding in a pilot study. The amended CRS form was completed by prospectively recruited patients and blinded nurses. The agreement levels of the individual questions and the total scores of patient and nurse-completed forms were compared using the Kappa value. The total scores were used for risk stratification of patients. Correlation and differences between patient and nurse-completed forms were analyzed using the Spearman correlation and Bland-Altman method, respectively. Results We recruited 504 medical patients and 513 surgical patients, aged 52.7 ± 16.3 years, of which 443 (43.6%) were men, and 91.6% of the patients were educated beyond junior high school. The patients spent less time to complete the form compared with trained nurses. There was good question-to-question agreement between patient and nurse-completed CRS ( k >0.6 for most questions, p < 0.0001). The total scores also showed good agreement ( k = 0.6097, p < 0.0001), and enabled the classification of patients into different risk groups. The patient and nurse-derived scores were highly correlated (Spearman's r = 0.84), and without extreme values ( p < 0.0001). Conclusion We have created and verified a Chinese version of the patient-completed CRS, which showed good agreement and correlation with nurse-completed CRS. CRS represents a suitable tool for VTE risk assessment of hospitalized patients in China.

Clinicopathological Correlation of Chronic Thromboembolic Pulmonary Hypertension: A Retrospective Study.

The pathophysiology of chronic thromboembolic pulmonary hypertension (CTEPH) is largely unknown. Although pulmonary endarterectomy (PEA) is potentially curative, inoperable patients and persistent pulmonary hypertension (PH) following surgery remain a significant problem. In this study, we aim to describe the histopathological characteristics of CTEPH and explore the potential relationship between pulmonary arterial lesions, radiological parameters, and clinical manifestations. Endarterectomized tissues from 81 consecutive patients of CTEPH were carefully collected, sectioned, and examined by experienced pathologists. Pertinent clinical and radiological data were obtained from medical records and operative reports. Neointima, fresh/organized thrombi, recanalized regions, and atherosclerotic lesions were microscopically examined as previously described. Thrombi and atherosclerosis were dominant in UCSD classification level I PEA materials, while recanalized neo-vessels were more frequently observed in UCSD classification level III cases. Degenerative changes of the extracellular matrix were also noticed in the vascular bed. Atherosclerotic lesions were more frequently observed in cases with higher ratio of the pulmonary artery diameter to ascending aorta diameter (PA/AA) reflected by computed tomographic pulmonary arterial scanning. Furthermore, the removal of pulmonary artery complex lesions (with the combination of three to four types of lesions) by PEA was associated with lower postoperative mean pulmonary arterial pressure (mPAP) and decreased incidences of persistent PH. Our study demonstrates that the histopathological features of CTEPH are strongly linked with clinical manifestations and the postoperative outcome after PEA. These data may provide possible evidence for further studies in searching for appropriate causal factors underlying this disease.

Higher Incidence of Chronic Thromboembolic Pulmonary Hypertension After Acute Pulmonary Embolism in Asians Than in Europeans: A Meta-Analysis.

Aim: To summarize the incidence of right heart catheter diagnosed chronic thromboembolic pulmonary hypertension (CTEPH) after acute pulmonary embolism (PE) in a meta-analysis. Methods: Cohort studies reporting the incidence of CTEPH after acute PE were identified via search of Medline, Embase, China National Knowledge Infrastructure and WanFang databases. Results: Twenty-two cohort studies with 5,834 acute PE patients were included. Pooled results showed that the overall incidence of CTEPH was 2.82% (95% CI: 2.11-3.53%). Subgroup analyses showed higher incidence of CTEPH in Asians than Europeans (5.08 vs. 1.96%, p = 0.01), in retrospective cohorts than prospective cohorts (4.75 vs. 2.47%, p = 0.02), and in studies with smaller sample size than those with larger sample size (4.57 vs. 1.71%, p < 0.001). Stratified analyses showed previous venous thromboembolic events and unprovoked PE were both significantly associated with increased risk of CTEPH (OR = 2.57 and 2.71, respectively; both p < 0.01). Conclusions: The incidence of CTEPH after acute PE is ~3% and the incidence is higher in Asians than Europeans. Efforts should be made for the early diagnosis and treatment of CTEPH in PE patients, particularly for high-risk population.

Awareness and Prophylaxis of Venous Thromboembolism in Patients with COVID-19: A National Cross-Sectional Survey in Epidemic Era.

AIM: Patients with acute infectious diseases are at an increased risk of venous thromboembolism (VTE). Clinicians should be aware of the VTE risk in patients with COVID-19, many of whom present with severe coagulation disorders. METHOD: We used an online platform to conduct a cross-sectional questionnaire survey among doctors in mainland China in March 2020. The questionnaire was designed to figure out the clinician's current awareness of VTE prevention and detection rates, as well as the current status of VTE prophylaxis in patients with COVID-19. RESULTS: We collected 1,636 replies, of which 1,579 were valid. Among these, 991 (63%) clinicians were involved directly in frontline treatment. Most of the clinicians (1,492, or 94%) thought it was necessary to assess the VTE risk in patients with COVID-19. However, only 234 (24%) clinicians performed appropriate assessment during the COVID-19 outbreak. For patients with mild/moderate COVID-19, 752 (76%) clinicians would prescribe exercise and water to prevent VTE. For patients with severe COVID-19, 448 (45%) clinicians would prescribe mechanical devices if the patient had a high bleeding risk, and 648 (65%) clinicians would choose LMWH as prophylaxis if the patient had a low bleeding risk. The VTE detection rate was not that high in both mild/moderate and severe patients. CONCLUSION: Although most clinicians recommended prescribing VTE prophylaxis to patients with COVID-19, the practice still needs to be improved. A real-world registry to investigate the true incidence of VTE, and the effect of prescribing appropriate prophylaxis for patients with COVID-19, is necessary in the future.

Circulating biomarkers in chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious condition characterized with chronic organized thrombi that obstruct the pulmonary vessels, leading to pulmonary hypertension (PH) and ultimately right heart failure. Although CTEPH is the only form of PH that can be cured with surgical intervention, not all patients with CTEPH will be deemed operable. Some CTEPH patients still have a poor prognosis. Therefore, the determination of diagnostic and prognostic biomarkers of CTEPH is of great importance for the early intervention to improve prognosis of patients with CTEPH. Several markers related to multiple mechanisms of CTEPH have been recently identified as circulating diagnostic and prognostic biomarkers in these patients. However, the existing literature review of biomarkers of CTEPH is relatively sparse. In this article, we review recent advances in circulating biomarkers of CTEPH and describe future applications of these biomarkers in the management of CTEPH.

Microarray Analysis and Detection of MicroRNAs Associated with Chronic Thromboembolic Pulmonary Hypertension.

The aim of this study was to understand the importance of chronic thromboembolic pulmonary hypertension- (CTEPH-) associated microRNAs (miRNAs). miRNAs differentially expressed in CTEPH samples compared with control samples were identified, and the target genes were predicted. The target genes of the key differentially expressed miRNAs were analyzed, and functional enrichment analyses were carried out. Finally, the miRNAs were detected using RT-PCR. Among the downregulated miRNAs, MiR-3148 regulated the most target genes and was significantly enriched in pathways in cancer, glioma, and ErbB signaling pathway. Furthermore, the number of target genes coregulated by miR-3148 and other miRNAs was the most. AR (androgen receptor), a target gene of hsa-miR-3148, was enriched in pathways in cancer. PRKCA (Protein Kinase C Alpha), also a target gene of hsa-miR-3148, was enriched in 15 of 16 KEGG pathways, such as pathways in cancer, glioma, and ErbB signaling pathway. In addition, the RT-PCR results showed that the expression of hsa-miR-3148 in CTEPH samples was significantly lower than that in control samples (P < 0.01). MiR-3148 may play an important role in the development of CTEPH. The key mechanisms for this miRNA may be hsa-miR-3148-AR-pathways in cancer or hsa-miR-3148-PRKCA-pathways in cancer/glioma/ErbB signaling pathway.