2026-07-08 | Chronic Thromboembolic Pulmonary Hypertension as an Inflammation-Angiogenesis Disorder: From Thrombus Persistence to Dual Pulmonary Vasculopathy.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious but potentially treatable complication of acute pulmonary embolism. CTEPH is characterized by persistent obstruction of the pulmonary arteries and elevated pulmonary pressure. Although organized blood clots have long been considered the primary cause, recent research indicates that CTEPH is more complex. Indeed, CTEPH encompasses ongoing endothelial dysfunction and dysregulated angiogenic recanalization within organized thrombi. Unlike previous reviews that address these pathways in isolation, this review integrates inflammation and angiogenesis into a unified mechanistic framework, incorporating recent single-cell transcriptomic data and epigenetic findings to outline the development and progression of CTEPH. The review also examines both established and emerging pathomechanisms of CTEPH, focusing on how local blood flow and endothelial activation shape the disease. Moreover, this review highlights the concept of dual vasculopathy, encompassing both significant vessel occlusions and small-vessel changes, similar to those observed in pulmonary arterial hypertension. Additionally, the review examines the role of inflammation in CTEPH, including the involvement of neutrophils, neutrophil extracellular traps, high-mobility group box 1 protein, monocytes, macrophages, and adaptive immune responses, as revealed by single-cell analyses. This review further discusses how endothelial dysfunction is linked to inflammation, thrombosis, and remodeling of the pulmonary vasculature. Particular attention is provided to abnormal von Willebrand factor levels, NF-κB signaling, and changes in gene regulation. Impaired angiogenesis appears to be a central mechanism underlying impaired thrombus resolution and the persistence of pulmonary hypertension, as shown in both human and animal studies. Collectively, these findings support the view that CTEPH is fundamentally an inflammatory and angiogenic disorder and suggest novel therapeutic targets that may complement surgery and other interventions.
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2026-07-03 | Targeting pathogenic VWF/ADAMTS13 dysregulation attenuates CTEPH progression.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening pulmonary vascular disease, characterized by persistent thrombotic obstruction and progressive pulmonary vascular remodeling, yet the molecular mechanisms linking persistent thrombosis to vascular remodeling remain incompletely understood. Clinical studies have reported elevated plasma von Willebrand factor (VWF) levels and reduced ADAMTS13 in patients with CTEPH, but whether VWF/ADAMTS13 dysregulation contributes directly to disease pathogenesis remains unclear. Here, using newly established rat models of CTEPH, we identify a causative role for dysregulation of the VWF-ADAMTS13 axis in chronic thromboembolic progression. CTEPH rats developed persistent, unresolved VWF- and fibrin-rich thrombi accompanied by markedly increased endothelial VWF deposition. In contrast, ADAMTS13 expression and activity were significantly reduced in CTEPH rats. Consistent with these findings, genetic Adamts13 deficiency further exacerbates pulmonary microvascular thrombosis and accelerated early mortality following disease induction. Mechanistically, ultra-large (UL)-VWF accumulated on the pulmonary endothelial surface, promoting robust platelet recruitment under shear. This platelet-VWF interaction stimulated the release of platelet-derived pro-remodeling mediators, including TGF-β1 and PDGF-BB. Genetic ablation of Vwf markedly reduced in situ microvascular thrombosis within pulmonary arterioles, attenuated pulmonary arterial remodeling, and improved pulmonary hemodynamics. Moreover, treatment with recombinant ADAMTS13 reduced endothelial UL-VWF accumulation, suppressed platelet activation, and effectively prevented thrombosis and platelet-driven pro-remodeling signaling in CTEPH rats. Collectively, these findings identify dysregulation of the VWF-ADAMTS13 axis as a key driver of pulmonary thrombosis and vascular remodeling in CTEPH and support therapeutic targeting of this pathway as a potential disease-modifying strategy. VWF-ADAMTS13 dysregulation promotes persistent pulmonary thrombosis and platelet-driven arterial remodeling within pulmonary arterioles.Recombinant ADAMTS13 treatment or VWF ablation abrogates pulmonary arterial thrombosis and halts vascular remodeling in CTEPH.
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2026-06-26 | Efficacy of short-term, low-dose pulmonary vasodilators for chronic thromboembolic pulmonary hypertension: a retrospective pilot study.
Chronic thromboembolic pulmonary hypertension (CTEPH) is treated with pulmonary endarterectomy, pulmonary vasodilators (PVs), and balloon pulmonary angioplasty (BPA). PV therapy may be initiated before BPA; however, dose adjustment can delay BPA. Therefore, short-term, low-dose administration is sometimes used to enable earlier BPA; however, its efficacy and safety remain unclear. Twenty patients with World Health Organization functional class III/IV CTEPH, who received low-dose PVs (riociguat or selexipag) and underwent right heart catheterization and first BPA within 60 days, were retrospectively analyzed. Hemodynamic parameters and brain natriuretic peptide (BNP) levels were compared before and after PV therapy. First-session BPA complications were evaluated. After a median of 18 days of therapy, mean pulmonary arterial pressure (mPAP) decreased from 42 to 40 mmHg (mean difference, -2.1 mmHg; 95% confidence limits [CL], -4.2 to -0.02; p = 0.0482), pulmonary vascular resistance (PVR) decreased from 829 to 632 dyne s·cm-5 (mean difference, -197 dyne s·cm-5; 95% CL, -227 to -117; p < 0.0001), and BNP decreased from 284 to 146 pg/mL (mean difference, -139 pg/ml; 95% CL, -203 to -75; p = 0.0002). Cardiac output and cardiac index increased significantly. Higher baseline mPAP and PVR values were associated with greater reductions in the corresponding parameters. BPA-related complications occurred in four patients (20%), all of which involved hemoptysis from peripheral lesions. Short-term, low-dose PV therapy before BPA was associated with improvements in hemodynamic parameters and BNP levels. Baseline mPAP, PVR, and cardiac index may predict treatment response. Prospective studies are needed to refine pre-BPA strategies.
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