Prior Venous Thromboembolism Defines Distinct Genetic and Molecular Phenotypes in Chronic Thromboembolic Pulmonary Hypertension

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) has traditionally been considered a long-term complication of pulmonary embolism. However, a substantial proportion of patients have no history of venous thromboembolism (VTE), suggesting underlying biological heterogeneity. METHODS: We analyzed clinical and imaging characteristics of 712 patients with CTEPH stratified by prior VTE history. Whole-genome sequencing was performed in all patients and 2952 healthy controls to assess common variants. Bulk RNA sequencing of pulmonary endarterectomy tissues and plasma protein quantification were integrated to identify and validate subgroup-specific molecular signatures, with further validation in tissue and primary endothelial cells. RESULTS: Patients with CTEPH and prior VTE (n=576, 80.9%) exhibited a distinct thrombotic phenotype with more proximal disease distribution (92.5% versus 66.2%) and greater likelihood of undergoing pulmonary endarterectomy (22.6% versus 3.7%). Genome-wide association study in CTEPH-VTE(+) patients versus controls identified coagulation-related loci at ABO (rs676996, P =1.1×10 –9 ) and FGG (rs7681423, P =2.5×10 –8 ), with high genetic correlation with pulmonary embolism (rg=0.52, P =0.028). In contrast, no consistent genomic signal was identified in patients without prior VTE. Integrative multiomics (transcriptome-wide association study, MAGMA, and bulk RNA sequencing differential expression analysis) convergently prioritized CTSS (cathepsin S) as a key molecular candidate in CTEPH-VTE(+). CTSS was consistently elevated in plasma, pulmonary endarterectomy tissue, and primary endothelial cells from CTEPH-VTE(+) patients and promoted endothelial proliferation via ERK signaling, which was attenuated by the selective CTSS inhibitor LY3000328. CONCLUSIONS: Stratification by prior VTE history reveals biologically distinct CTEPH phenotypes with divergent genetic architectures and identifies cathepsin S as a genetically nominated therapeutic target for thrombosis-associated pulmonary vascular remodeling.