Background: Pulmonary artery hypertension (PAH) is a fatal disease characterized by a complex pathogenesis. Exosomes containing microRNAs (miRs) have emerged as a novel biomarker. Transpulmonary exosomal miRs offer valuable insights into pulmonary circulation microenvironments. Hereby, we aimed to explore the potentials of transpulmonary exosomal miRs as differentiating factors between idiopathic PAH and congenital heart disease (CHD)–related PAH. Methods and Results: During right heart catheterization, we collected exosomes at pulmonary arteries in 25 patients diagnosed with idiopathic PAH and 20 patients with CHD‐related PAH. Next‐generation sequencing identified several candidate exosomal miRs. Using quantitative polymerase chain reaction, we validated the expressions of these miRs and revealed significantly elevated expressions of miR‐21, miR‐139‐5p, miR‐155‐5p, let‐7f‐5p, miR‐328‐3p, miR‐330‐3p, and miR‐103a‐3p in patients with CHD‐related PAH, in contrast to patients with idiopathic PAH. Among these miRs, miR‐21 exhibited the highest expression in patients with CHD‐related PAH. These findings were further corroborated in an external cohort comprising 10 patients with idiopathic PAH and 8 patients with CHD‐related PAH. Using an in vitro flow model simulating the shear stress experienced by pulmonary endothelial cells, we observed a significant upregulation of miR‐21. Suppressing miR‐21 rescued the shear stress–induced downregulation of the RAS/phosphatidylinositol 3‐kinase/protein kinase B pathway, leading to a mitigation of apoptosis. Conclusions: Our study identified a pronounced expression of transpulmonary exosomal miR‐21, particularly in patients with CHD‐related PAH, through next‐generation sequencing analysis. Further investigation is warranted to elucidate the regulatory mechanisms involving miR‐21 in the pathophysiology of PAH.

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Background: Direct oral anticoagulants (DOACs) have demonstrated non‐inferiority to low‐molecular‐weight heparin (LMWH) for preventing recurrent venous thromboembolism (VTE) in cancer‐associated thrombosis. However, patients with gastrointestinal (GI) cancer receiving DOACs have reported increased major bleeding events. Hereby, we aim to compare the risks of recurrent thromboembolism and bleeding between those treated with DOACs and LMWH. Methods: Using Taiwan's National Health Insurance Research Database, we retrospectively identified GI cancer patients with newly diagnosed VTE from 2011 to 2020. Outcomes were recurrent VTE and major bleeding. Covariate balancing was performed using inverse probability weighting, and Cox proportional hazards models compared risks, with a competing risk model for death. Follow‐up was 12 months. Results: Among 1895 patients (1038 on DOACs, 857 on enoxaparin), recurrent VTE occurred in 20.71% of DOAC and 19.25% of enoxaparin patients. Competing risk analysis showed relatively higher recurrent VTE risk with DOACs (subdistribution HR, 1.27; 95% CI, 1.09–1.48; p < 0.01). Regarding composite bleeding risk, DOACs were similar compared with LMWH (subdistribution HR, 0.99; 95% CI, 0.68–1.45; p = 0.97). However, DOACs presented with an increased GI bleeding risk (subdistribution HR, 2.59; 95% CI, 1.48–4.54; p < 0.01) but a reduced intracranial hemorrhage risk (subdistribution HR, 0.35; 95% CI, 0.16–0.78; p = 0.01). Conclusions: Compared with DOACs, LMWH expressed a lower risk of recurrent VTE in GI cancer patients. However, DOAC presented with a lower intracranial hemorrhage risk but a higher GI bleeding risk. Further research is needed to confirm these findings.