RARE DISEASE
Chronic thromboembolic pulmonary hypertension
Chronic thromboembolic pulmonary hypertension
Chronic thromboembolic pulmonary hypertension
Synonyms: CTEPH
Synonyms: CTEPH
Synonyms: CTEPH
Drug discovery
17
drugs
With orphan designations
Overview
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, progressive form of pulmonary hypertension caused by unresolved thromboemboli and fibrotic vascular remodeling, leading to pulmonary artery obstruction and elevated pressures. Diagnosis requires right heart catheterization (mean PAP ≥25 mmHg) and imaging (V/Q scan, CT angiography). It arises in 0.4–4.8% of acute pulmonary embolism survivors, with risks including splenectomy, non-O blood type, and chronic inflammation. Treatment involves surgery, interventional procedures, or targeted therapy [1][2][4][7][12].
Population
Incidence: ~5 cases per million annually (up to 30 in some reports), with median age of 63 years [1][2][4][12].
Predisposing factors: History of pulmonary embolism, anti-phospholipid antibodies, chronic inflammatory conditions, and splenectomy [1][4][16].
No gender predominance; ~50–75% of patients lack prior symptomatic embolism history [7][17].
Therapies
Pulmonary endarterectomy (PEA): First-line curative surgery for operable proximal lesions, with <2% mortality in expert centers [3][13][18].
Balloon pulmonary angioplasty (BPA): Percutaneous intervention for distal disease or inoperable cases, improving hemodynamics and exercise tolerance [3][8][17].
Medical therapy: Riociguat (sGC stimulator) is approved for inoperable cases; anticoagulation is lifelong [8][12][13].
Categories: rare respiratory diseases
Research Papers
1,785 drug discovery papers about Chronic thromboembolic pulmonary hypertension, with 2 first-in-class and 22 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,785 drug discovery papers about Chronic thromboembolic pulmonary hypertension, with 2 first-in-class and 22 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
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.
2026-04-29 | Personalised viscoelastometry-guided systemic thrombolysis for high- and intermediate-high-risk acute pulmonary embolism in the ICU: a single-centre randomised controlled interventional feasibility trial.
Systemic thrombolysis is recommended for high-risk pulmonary embolism, but is associated with a substantial bleeding risk due to thrombolysis-induced coagulopathy. However, recent advances in precision and personalised care offer the potential to reduce mortality as well as the incidence of chronic thromboembolic pulmonary hypertension and post-pulmonary embolism impairment, thereby improving long-term outcomes. Our primary objective was to evaluate the feasibility of a viscoelastic testing-guided, low-dose, prolonged systemic thrombolysis protocol in acute pulmonary embolism. Exploratory secondary objectives included assessment of the safety and efficacy of the protocol using an individualised approach tailored to each patient's coagulation profile. This single-centre, prospective, randomised interventional feasibility trial was conducted at Semmelweis University (Budapest, Hungary). Adult pulmonary embolism patients were randomly assigned to a control group (CG) receiving the ESC-recommended 100 mg/2 h dose of rtPA or a viscoelastometry-guided group (VGG), in which the rtPA dose and duration were adjusted based on viscoelastic tests. Transthoracic echocardiography (TTE) was performed every two hours to monitor right ventricular (RV) function and determine cessation of systemic thrombolysis in VGG. The primary outcome was feasibility; the secondary outcome was safety and efficacy. Among 33 enrolled patients, 19 were included in the analysis (CG: 7; VGG: 12). Patients in the VGG received significantly lower doses of rtPA (median 32.00 mg [IQR 20.95-42.75 mg]) despite longer infusion duration (median 8.5 h [IQR 6.6-10.0]) and showed no coagulopathy. RV dysfunction persisted in two CG patients, whereas in the VGG it resolved in all patients. Major bleeding occurred in two patients in the CG and in one patient in the VGG. Viscoelastometry-guided, individualised, low-dose systemic thrombolysis is feasible and supports a personalised approach to thrombolysis in the management of pulmonary embolism.
2025-12-11 | Overexpression of PRDX2 alleviates chronic thromboembolic pulmonary hypertension by modulating inflammation and mitophagy.
Chronic thromboembolic pulmonary hypertension (CTEPH) results from thrombi-induced endothelial injury, inflammation, and oxidative stress in pulmonary vessels, leading to vascular remodelling, increased resistance, and elevated pulmonary arterial pressure. Peroxiredoxin 2 (PRDX2) is an antioxidant enzyme involved in regulating cellular redox balance and inflammation, its role in CTEPH is not yet fully understood. The aim is to investigate the expression and functional role of PRDX2 in CTEPH and explore its potential mechanisms in modulating inflammation and mitochondrial autophagy. Proteomics was used to analyse peripheral blood samples from patients with CTEPH and healthy controls to identify differentially expressed proteins. A rat model of CTEPH was developed through the intravenous injection of amino-crosslinked polystyrene microspheres. PRDX2 expression was assessed in lung tissues and primary pulmonary artery endothelial cells (PAECs) using immunohistochemistry, Western blotting, and qRT-PCR. The effects of PRDX2 overexpression and silencing on inflammation and mitochondrial autophagy were evaluated using ELISA, Western blotting, and transmission electron microscopy. The expression of PRDX2 was significantly increased in the peripheral blood of patients with CTEPH and in the pulmonary vasculature of rats with CTEPH.Overexpression of PRDX2 in PAECs attenuated the inflammatory response by NF-κB signaling pathway. Additionally, overexpression of PRDX2 regulated the expression of mitophagy-related proteins (LC3II/I, Beclin-1, and p62) and restored mitochondrial morphology. Further verification in rats showed that PRDX2 overexpression significantly improved haemodynamic parameters and pulmonary vascular remodelling in CTEPH. Overexpression of PRDX2 alleviates pulmonary vascular remodeling in CTEPH by reducing inflammation and Modulating mitophagy, suggesting its protective role and potential as a therapeutic target for the disease.
2025-11-17 | American Lung Association Pulmonary Hypertension Roundtable: Executive Summary.
The American Lung Association and Pulmonary Hypertension Association convened a scientific roundtable of pulmonary hypertension experts to discuss the latest recommendations from the European Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension (PH) and from the 7th World Symposium on Pulmonary Hypertension (WSPH). The aim of the roundtable was to discuss changes that were made compared to earlier recommendations and guidelines set out by the European Society of Cardiology and the European Respiratory Society in 2015, the 6th World Symposium on Pulmonary Hypertension in 2018, and the CHEST Guideline on Therapy for Pulmonary Arterial Hypertension in 2019. The overall objectives were to: 1) Create an educational resource for providers that summarizes currently available PAH guidelines, 2) Provide an expert critique of current guidelines, outlining strengths and weaknesses and resolving differences where guidelines do not agree. 3) Provide guidance for the incorporation of the recently approved drug, sotatercept into current guidelines. An executive summary was drafted following the roundtable meeting on April 8, 2024, and revised by the panel in September 2024, following publication of the proceedings from the 7th WSPH held in Barcelona June 29-July 1, 2024. The Executive Summary reviews changes to the hemodynamic criteria for defining pre- and post-capillary PH, exercise-induced PH, and PH associated with lung disease. Recommendations are given for proper diagnosis and clinical classifications of the various forms of PH. The role of screening for PH in high-risk populations and the use of risk scores for disease stratification are discussed. Finally, treatment algorithms for managing pulmonary arterial hypertension, PH associated with lung disease, and chronic thromboembolic pulmonary hypertension are presented.
2025-07-18 | Fluid management of cardiopulmonary bypass during pulmonary endarterectomy for CTEPH patients impacts perioperative outcome.
Pulmonary endarterectomy (PEA) using deep hypothermic circulatory arrest (DHCA) and cardiopulmonary bypass (CPB) is the preferred treatment for chronic thromboembolic pulmonary hypertension (CTEPH). Crystalloid priming solutions cause hemodilution with disadvantages, and no standard exists for PEA. This study evaluates CTEPH patient outcomes after adding 5% human albumin (HA) to the CPB-prime and hemodilution solution during PEA. The effect of the CPB-protocol change was evaluated by comparing patients operated under the old and new protocols in a 1:1 propensity score match based on age, sex, and preoperative peripheral vascular resistance (PVR). Matching resulted in 56 patients (28 per group) between July 1, 2010, and May 31, 2020. The new protocol group had a lower intraoperative fluid balance (1.85 vs 6.76 liters, p < 0.001), vasoactive-inotropic score (VIS) (8.7 vs 17.7, p = 0.04), shorter operative- (407 vs 451 min, p = 0.03), and hospitalization time (LOS) (18 vs 27 days, p = 0.008). Morbidity and mortality at 30- and 90-days were similar in both groups. The new protocol was associated with reduced intraoperative fluid balance after adjustment for operative time (-3.7 liters [95% CI -5.2, -2.1], p < 0.0001). Lower intraoperative fluid balance was associated with shorter hospitalization in the intensive care unit, intubation time, LOS, and lower VIS (p = 0.0011, 0.0013, 0.008, <0.0001, respectively). The protocol change shortened LOS, independent of operative time, by 27% [95% CI, 44%, 6%], p = 0.02. Priming and maintenance protocol for CPB with the addition of 5% HA had a beneficial effect on intraoperative fluid balance and improved outcome after PEA for patients with CTEPH.
small molecules
2026-09-18 | Riociguat as inpatient rescue therapy for acute decompensation of inoperable chronic thromboembolic pulmonary hypertension.
A man in his 70s, a retired coal miner with prior asbestos exposure and no smoking history, presented with syncope and progressive exertional dyspnoea. Initial CT pulmonary angiogram (CTPA) revealed bilateral lobar pulmonary emboli, and transthoracic echocardiography (TTE) showed evidence of pulmonary hypertension. He was discharged on rivaroxaban and referred to the heart failure and respiratory clinic. At the respiratory clinic follow-up, he reported worsening breathlessness and was initiated on long-term oxygen therapy (LTOT). Outpatient investigations were arranged, including a ventilation/perfusion (V/Q) scan, which demonstrated extensive mismatched perfusion defects consistent with chronic thromboembolic pulmonary hypertension (CTEPH). He was also referred for right heart catheterisation (RHC) and to the Irish National Pulmonary Hypertension Unit.Before he was reviewed in the pulmonary hypertension unit, he re-presented to the emergency department with worsening dyspnoea, haemoptysis and bilateral lower limb oedema, with clinical signs of right heart failure. Repeat imaging with TTE and CTPA confirmed persistent findings of chronic embolic disease. Despite optimal diuresis and anticoagulation, his symptoms remained refractory and required high-flow oxygen without decreasing requirements after 14 days. Riociguat was initiated and titrated inpatient, resulting in rapid clinical improvement and reduced oxygen requirement within 72 hours. Subsequent right heart catheterisation confirmed inoperable CTEPH. He was reviewed at the National Pulmonary Hypertension Clinic, and following multidisciplinary discussion, given insufficient surgically accessible thromboembolic burden and coexisting left ventricular dysfunction, the decision was made to continue riociguat as long-term medical therapy.
2026-09-18 | Endothelial Cell Transcriptomics Reveal Activation of Ribosomal-related Pathways in Chronic Thromboembolic Pulmonary Hypertension.
Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are rare, severe forms of pulmonary hypertension (PH) characterized by elevated mean pulmonary arterial pressure (mPAP) and ∼20% mortality at 3 years. PAH is defined by progressive obliterative vasculopathy, whereas CTEPH results from persistent pulmonary artery obstruction by fibrotic thrombotic material, leading to vascular remodelling, right ventricular hypertrophy, and heart failure. Endothelial colony-forming cells (ECFCs) derived from PAH and CTEPH patients and healthy-controls were analysed to identify disease-specific molecular and functional alterations. Transcriptomic profiling was integrated with functional assays, including global protein synthesis, mitochondrial bioenergetics, intracellular Ca2+ dynamics, and cellular ultrastructural assessment by transmission electron microscopy (TEM). The effects of riociguat, the approved therapy for inoperable or persistent post-surgical CTEPH, were also evaluated. Significant differences in gene expression profiles were observed among PAH-ECFCs, CTEPH-ECFCs, and control-ECFCs. CTEPH-ECFCs, exhibited a unique upregulation of ribosomal and translation-related genes, accompanied by increased global protein synthesis. Network analysis revealed a highly connected ribosomal-translational hub within CTEPH transcriptome signature. CTEPH-ECFCs also exhibited mitochondrial remodelling, increased endoplasmic reticulum-mitochondria contacts, altered intracellular Ca2+ handling, and reduced maximal respiratory capacity. Riociguat did not reverse these abnormalities. Dysregulated protein biosynthesis is a characteristic feature of CTEPH, distinguishing them from PAH. Our findings highlight a coordinated translation-mitochondria-MAM axis potentially involved in endothelial dysfunction and vascular remodelling, supporting the need for therapies targeting disease-specific molecular pathways beyond soluble guanylate cyclase stimulation.
2026-09-11 | Phase 1b ATMOS trial of the inhaled sGC activator mosliciguat in patients with PAH/CTEPH.
Mosliciguat, a soluble guanylate cyclase (sGC) activator, is designed for lung-targeted delivery via dry powder inhalation. Nitric oxide (NO) binds sGC's prosthetic heme group, catalysing cyclic guanosine monophosphate (cGMP) production, resulting in increased vasodilation, reduced inflammation/apoptosis, reverse vascular remodelling and antifibrotic effects. sGC is redox sensitive, losing heme in pulmonary hypertension (PH) oxidative stress conditions. Mosliciguat's novel 'activator' mechanism directly binds the sGC heme-binding pocket to induce cGMP, allowing it to target NO-insensitive heme-free sGC, potentially rescuing additional enzymatic activity. A Proof-of-Concept Trial of Inhaled Mosliciguat, a First-in-Class Soluble Guanylate Cyclase Activator (ATMOS; non-randomised, open-label phase 1b trial) assessed single-dose escalation of mosliciguat in participants with pulmonary arterial hypertension or chronic thromboembolic PH. 38 participants received mosliciguat. The per protocol set (PPS, n=20) included NO-non-responsive participants with baseline pulmonary vascular resistance (PVR) ≥5 Wood units (n=4/dose). The pharmacodynamic set (PDS, n=37) included NO-responsive participants. Five PPS participants underwent a ≥24-hour washout from background therapy. In the PPS, doses of 0.24, 0.48, 1.0, 2.0 and 4.0 mg resulted in mean peak per cent PVR reductions from baseline (95% CI) of 21.0% (31.6% to 10.4%), 16.1% (32.8% to -0.7%), 25.9% (60.3% to -8.4%), 38.1% (55.9% to 20.3%) and 36.3% (48.3% to 24.4%), respectively, and generally persisted over the 3-hour observation period. Similar effects were seen in the PDS. The majority of adverse events were mild; most frequently reported were headache (n=3/38; 7.9%), decreased oxygen saturation and fatigue (n=2/38; 5.3% each). No safety-relevant changes were seen in systemic vascular resistance or blood pressure. Mosliciguat demonstrated a favourable safety profile and sustained, clinically meaningful reductions in PVR in participants with PH. NCT03754660.
2026-08-31 | Dapagliflozin in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: The DAPAH randomized controlled trial.
SGLT2 inhibitors (SGLT2i) reduce mortality in left heart failure. In pulmonary arterial hypertension (PAH), preclinical data suggest SGLT2i improve right ventricular function through metabolic modulation and inhibition of vascular remodeling via smooth muscle cell pathways. The DAPAH trial evaluated whether the potential benefits of SGLT2 inhibition translate into clinical efficacy for symptomatic patients on background vasodilator therapy with either PAH or chronic thromboembolic pulmonary hypertension. In this single-center, double-blind trial, 52 patients were randomized (1:1) to dapagliflozin 10 mg daily or placebo for 12 weeks. The primary endpoint was change in Peak VO2. Secondary endpoints included invasive hemodynamics, NT-proBNP, 6-minute walk distance (6MWD) and REVEAL Lite 2 scores. Baseline characteristics were balanced (n=52; mean age 66.5 years; 63% female; n=40 PAH, n=12 CTEPH). Fifty-one patients had complete data on Peak VO2. At 12 weeks, there was no significant difference in Peak VO2 (Adjusted Mean Difference: -0.67 mL/kg/min; 95% CI [-1.67, 0.33]; p=0.187). No significant treatment effects were observed for pulmonary vascular resistance (p=0.255), 6MWD (p=0.22), or NT-proBNP trajectory (interaction p=0.681). REVEAL Lite 2 scores showed a small reduction with dapagliflozin (-0.66; 95% CI [-1.25, -0.06]; p=0.031). Metabolic target engagement was evident from a significant reduction in serum urate (P-interaction < 0.001). Dapagliflozin was safe and well-tolerated. This randomized study of SGLT2i in pre-capillary PH showed that 12 weeks of dapagliflozin did not significantly improve exercise capacity, hemodynamics, or functional status compared to placebo. gov (NCT05179356).
2026-08-08 | STOP-RIO study: protocol for a randomised, controlled, open-label non-inferiority trial to test the safety of discontinuation of riociguat after balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension.
Balloon pulmonary angioplasty (BPA) improves haemodynamics and outcomes in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Riociguat is frequently initiated before BPA to reduce procedural risks. However, evidence supporting continuation after successful BPA is lacking and current guidelines provide no criteria for treatment discontinuation. Consequently, many patients remain on long-term riociguat despite uncertain benefit, potential adverse effects and high costs. STOP-RIO is a multicentre, open-label, randomised, non-inferiority (NI) trial conducted in the two Dutch CTEPH expert centres. Seventy-four adult CTEPH patients treated with riociguat monotherapy with a mean pulmonary artery pressure (mPAP) <30 mmHg post-BPA will be randomised (1:1) to stop or continue the medication. The primary endpoint is the between-group difference in baseline-adjusted mPAP at rest measured by right heart catheterisation at 16 weeks. NI will be tested for the primary endpoint and for the two secondary endpoints highest in hierarchy N-terminal pro-B-type natriuretic peptide and 6-min walk distance. Additional secondary endpoints include haemodynamic parameters, safety outcomes, patient-reported outcomes and healthcare use. The primary analysis will be performed in a per-protocol population with secondary intention-to-treat and exploratory analyses. A prospective health economic evaluation will be conducted from a societal perspective. The study is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice and has received ethical approval. Written informed consent will be obtained from all participants. Results will be disseminated through peer-reviewed publication and shared with patient organisations and scientific congress. EU Clinical Trials Register: 2024-5 19 225-38-00.
cell therapies
2026-05-01 | D106-02 Upar+ Macrophages and Stromal Cells Drive Persistent Thromboembolic Remodeling in Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Mechanistic and Therapeutic Insights From Car-T Targeting
Abstract Purpose CTEPH is sustained by nonresolving thrombi enriched with inflammatory macrophages and fibrotic stromal populations. We hypothesized that targeting these cell subsets could remodel the thrombus niche and improve cardiopulmonary function. Methods scRNA-seq of human PTE clots and murine IVC wall and thrombi identified uPAR as a shared marker of pathogenic macrophages and fibroblasts. Murine T cells engineered with a uPAR-CAR were infused into IVC-ligated mice (n = 9/group). Outcomes included scRNA-seq validation, histology, cytokine assays, echocardiography, and flow analysis. Results scRNA-seq showed that uPAR+ macrophages expressed pro-inflammatory chemokines (Ccl6, Ccl8, Ccl12), while uPAR+ fibroblasts and vascular cells upregulated fibrogenic genes (Fn1, Timp1/2, Col15a1). In vivo, CAR-T treatment reduced thrombus weight by 41% (p = 0.004) and collagen content by 55% (p = 0.002) compared with untransduced controls. α-SMA+ myofibroblasts decreased ∼4-fold (p=0.001). Serum TNF-α, IL-1β, IL-6, and CCL2 were significantly reduced (p<0.05). Echocardiography revealed lower RV systolic pressure (-18%, p=0.03) and improved RV function (p=0.02). Respiratory testing under hypoxia/hypercapnia showed robust gains: minute ventilation +35% (p=0.0006), tidal volume +27% (p=0.0001), and peak inspiratory/expiratory flow +30% (p=0.0001). In human PTE clots, high uPAR+ burden correlated with residual pulmonary pressures post-surgery (p=0.01). Conclusion uPAR+ macrophages and stromal subsets drive persistent immune-fibrotic pathology in CTEPH. uPAR CAR-T therapy effectively depletes these populations, reduces fibrosis, lowers inflammation, and restores vascular and cardiopulmonary function. These results highlight a new therapeutic strategy for immune-fibrotic remodeling in pulmonary vascular disease. This abstract is funded by: None
2026-05-01 | Chronic Thromboembolic Pulmonary Hypertension in Patients With Thoracic Outlet Syndrome-Association With Younger Age and More Distal Disease.
We aimed to elucidate the potential role for thoracic outlet syndrome (TOS) and upper extremity deep venous thrombosis in the development of chronic thromboembolic pulmonary hypertension (CTEPH). Charts from 64 consecutive patients with CTEPH who underwent pulmonary endarterectomy in Helsinki University Hospital between 2015 and 2023 were analysed for baseline characteristics, risk factors for thrombosis, treatments, and outcome at 1 year. We found that seven patients with CTEPH (11%) had TOS with subclavian vein stenosis, impaired flow, and collaterals in provocation contrast venography. These patients with TOS CTEPH were younger (median 23 vs 59 years, p<0.001) and had more often distal (segmental 100% vs 38,6%, p<0.01) disease than other patients with CTEPH and had fewer risk factors for thrombosis (p<0.05). Functional class, N-terminal pro-B-type natriuretic peptide (NT-proBNP), 6-minute walk test and pulmonary vascular resistance (PVR) at baseline were similar. At 1 year postoperatively, there was a similar improvement in PVR (-45% vs -56%), NT-proBNP (-70.0% vs -71.8%), and functional class (improvement in 85.7% vs 91.5%) whereas 6-minute walk test increased more (247 vs 100 m, p<0.05) in patients with TOS. Patients with TOS were more often treated with balloon pulmonary angioplasty postoperatively (57.0 vs 10.5%, p<0.01). Treatment with pulmonary vasodilators did not differ significantly (42.9% vs 15.1%). TOS was later treated with thoracoscopic first-rib resection in three patients (43%). CTEPH with upper extremity deep venous thrombosis and TOS represents a unique subgroup of patients who benefit from interventional therapies.
2026-04-30 | Balloon Pulmonary Angioplasty for Treatment of Chronic Thromboembolic Pulmonary Hypertension: Statement From the BPA-CTEPH Alliance.
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by fibrothrombotic pulmonary vascular obstruction and associated small-vessel vasculopathy resulting in a progressive increase in pulmonary vascular resistance and right heart failure. Pulmonary thromboendarterectomy is the first-line treatment for surgically accessible disease. However, many patients are ineligible because of surgically inaccessible distal disease, medical comorbidities, or symptomatic residual disease after pulmonary thromboendarterectomy. Balloon pulmonary angioplasty (BPA) has emerged as a very effective therapeutic option in these patients. This statement from the BPA-CTEPH Alliance reviews the role of BPA in CTEPH, describing patient selection, procedural techniques, periprocedural management, complications, and training requirements. This U.S.-focused document provides practical guidance for establishing a BPA program within a multidisciplinary CTEPH center. Technical refinement and improved patient selection have significantly enhanced the safety and efficacy of BPA. Contemporary evidence suggests that BPA is associated with significant improvements in pulmonary vascular resistance, mean pulmonary artery pressure, functional class, and quality of life. There is a considerable learning curve associated with BPA, and complication rates, once prohibitive, have substantially decreased with operator experience and with adjunct medical therapy. BPA has become a critical component of multimodality management of CTEPH, with durable hemodynamic and clinical benefits. Continued research, with a particular focus on randomized controlled trials in the United States, is crucial to defining long-term outcomes and expanding access to this lifesaving therapy.
2026-04-01 | Balloon Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension: Identifying and Managing Complications for the Operator.
Balloon pulmonary angioplasty (BPA) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension who cannot receive pulmonary thromboendarterectomy or who have residual pulmonary hypertension after pulmonary thromboendarterectomy. As BPA volume and expertise have increased, significant strides in refining this technique have improved success and minimized complications; yet, minimal literature exists on appropriate complication management. This review summarizes how interventionalists can prevent, recognize, and manage BPA complications effectively. Operators must first focus on appropriate patient and vessel selection. Lower lung zones coupled with ring-like stenoses and web lesions are more favorable. Increased patient age, tortuous or subtotal lesions, and elevated pulmonary vascular resistance (>6 Wood units) portend a higher risk for complications. Vascular perforation can be treated with balloon tamponade, embolization (gelfoam and/or coils), and covered stents. Massive hemoptysis is managed with intubation and single lung ventilation if needed. As shock is predominantly hemorrhagic and/or cardiogenic, first-line therapies include vasopressors, inodilators, pulmonary vasodilators, and volume resuscitation, whereas mechanical support devices are second-line. Although reperfusion lung injury (RLI) is uncommon, it is generally well tolerated and managed with positive pressure ventilation, high-flow oxygen therapy, and diuresis. Acute kidney injury can be reduced by dilution of contrast dye, use of extension catheters, and procedural planning. Utilization of standard, angle-minimizing techniques, avoidance of high-dose cinefluoroscopy, and digital subtraction angiography minimizes radiation dose. In conclusion, most complications can be avoided or managed effectively without major morbidity or mortality by optimal preparation, patient selection, and commitment to a comprehensive BPA program.
2026-02-07 | Temporal Trends in Age Profile and Safety of Balloon Pulmonary Angioplasty for CTEPH.
Balloon pulmonary angioplasty (BPA) techniques have been refined and increasingly adopted for chronic thromboembolic pulmonary hypertension. This study aimed to evaluate the temporal trends in BPA safety, with a focus on outcomes in older patients. Using the Japanese Cardiovascular Disease All-Case Registry (2013-2022), we retrospectively analyzed 14,429 BPA procedures performed on 3,700 patients (median age, 68 years). The study period was divided into early (2013-2017) and late (2018-2022) periods. Patient characteristics and major complication rates were evaluated for each period. Complications were defined as a composite of major adverse events occurring within 30 days: death, mechanical ventilation, extracorporeal membrane oxygenation, continuous hemodiafiltration, transfusion, cardiac tamponade, or surgery. Patients treated in the late period were older (P < 0.001). The complication rate decreased from 7.8% in the early period to 4.2% in the late period (P < 0.001). In multivariable analysis, the adjusted OR of complications was lower in the late period (OR: 0.411; 95% CI: 0.247-0.675). The adjusted complication risk decreased across all age categories in the late period. An age-dependent increase in the adjusted complication risk was observed across all periods (trend P = 0.002), significant in the early (trend P = 0.015) but not in the late (trend P = 0.085) period. BPA safety has improved over time. Despite higher complication risks in older patients, the narrowing gap with younger patients in recent years suggests that BPA is a safe and feasible option for this population.
antibodies
2026-06-26 | Hemodynamic improvement but worsening hypoxemia after balloon pulmonary angioplasty: severe eosinophilic asthma unmasked in CTEPH.
We report a patient with peripheral-type chronic thromboembolic pulmonary hypertension (CTEPH) in whom exertional hypoxemia and dyspnea worsened despite substantial hemodynamic improvement after repeated balloon pulmonary angioplasty (BPA), prompting reassessment for a competing ventilatory limitation. Optimization of concomitant severe eosinophilic asthma with benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, and sinus surgery improved airflow obstruction and oxygenation and was accompanied over time by a further reduction in pulmonary arterial pressure. These changes suggest that a superimposed hypoxia-related pulmonary vascular component, compatible with group 3 physiology, may have been attenuated.
2025-11-16 | Characteristics of ferritinophagy-related genes in chronic thromboembolic pulmonary hypertension, a study based on bioinformatics with machine learning model.
Ferritinophagy plays a significant role in the development of cardiovascular diseases. The characteristics of ferritinophagy in chronic thromboembolic pulmonary hypertension (CTEPH) pathogenesis remains unknown. This study aims to identify ferritinophagy-related genes (FRGs) in CTEPH based on bioinformatics with machine learning model. The gene expression data of CTEPH and list of FRGs were downloaded from the Gene Expression Omnibus(GEO)database and GeneCards. CTEPH samples were stratified into distinct subtypes based on the expression levels of FRGs. Differences in immune characteristics and functional enrichment across different CTEPH subtypes were analyzed. Weighted gene co-expression network analysis (WGCNA) and machine learning algorithms were employed to identify hub genes among different subtypes, followed by the diagnostic model's construction based on the hub genes. Based on FRGs, two distinct CTEPH subtypes were revealed, cluster A and cluster B, with significant disparities in pathway enrichment and immune microenvironment between two clusters. Notably, 24 differentially expressed genes were found between two clusters. Based on WGCNA and machine learning algorithms, seven genes were identified as hub genes. Finally, the diagnostic model based on these seven genes was established, which can distinguish the two subtypes well. This study underscores two FRG-based CTEPH subtypes characterized by unique immune profiles, offering a promising avenue for the development of subtype-specific, personalized therapeutic strategies for CTEPH patients.
2025-07-10 | The Activin Pathway in Chronic Thromboembolic Pulmonary Hypertension: A Potential Biomarker for Residual Pulmonary Hypertension After Endarterectomy
Background Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by persistent pulmonary vascular obstruction due to unresolved thromboembolic lesions and distal pulmonary vascular remodeling. Despite the recognized role of the activin pathway in pulmonary vascular remodeling, its involvement in CTEPH remains insufficiently explored. This study aimed to investigate the presence of activin pathway components in CTEPH-related microvasculopathy and evaluate their potential as biomarkers. Methods Plasma levels of activin pathway biomarkers and key inflammatory mediators were assessed in controls and operable CTEPH patients pre- and post-surgery. The study enrolled 69 patients (mean age 62±13 years, 51% male), among whom 29 exhibited residual pulmonary hypertension (PH) after surgery, and 2 died following post-endarterectomy (PEA). Results CTEPH patients demonstrated elevated levels of activin-A, activin-B, FSTL3, C-X-C motif chemokine ligand 9 (CXCL9), beta-nerve growth factor (ß-NGF), C-reactive protein (CRP), and pro-brain natriuretic peptide (pro-BNP) compared to controls. Preoperative activin-A levels were associated with an increased risk of residual PH or mortality post-surgery (Odds ratio, 2.469 [95% CI, 1.011–5.487]; p=0.027), following adjustments for age, mean pulmonary arterial pressure before PEA (mPAP), and CRP. Histological analysis of lung specimens from CTEPH patients revealed nuclear accumulation of phosphorylated Smad 2 and upregulation of inhibin-βA, inhibin-βB, activin receptor type IIB (ACTRIIB), and FSTL3 in muscularized pulmonary arterioles. Conclusions These findings suggest a potential role for activin-A as a predictive biomarker for residual PH following pulmonary endarterectomy in CTEPH. Further investigation into the activin pathway may uncover therapeutic targets for managing CTEPH-associated vascular remodeling.
2025-07-05 | Transcriptional changes of the extracellular matrix in chronic thromboembolic pulmonary hypertension govern right ventricle remodeling and recovery.
Chronic thromboembolic pulmonary hypertension (CTEPH) leads to progressive right ventricular (RV) dysfunction. Pulmonary endarterectomy (PEA) is an established treatment for these patients; however, the molecular mechanisms underlying RV remodeling and recovery remain poorly understood. Here we show that RNA sequencing and histological analysis of RV free wall and septal biopsies from patients with CTEPH reveal extracellular matrix enrichment and cytoskeletal remodeling before PEA. These changes were consistent across an exploratory and confirmatory cohort. Post-PEA samples showed reversal of both histological and transcriptional abnormalities. Key signaling molecules-ANKRD1, IL7R and SERPINE1-were implicated in fibrotic and proliferative pathways, as confirmed in human tissues and experimental models. Our findings identify a reversible gene expression and structural remodeling signature in the RV, linking hemodynamic unloading with molecular recovery. These insights suggest potential therapeutic targets to modulate maladaptive RV remodeling in CTEPH and improve outcomes beyond surgical intervention.
2025-02-19 | Single-cell transcriptomic analysis reveals distinct plasma cell populations in chronic thromboembolic pulmonary hypertension.
Chronic thromboembolic pulmonary hypertension (CTEPH) presents challenges due to its complex pathobiology. Although numerous studies have reported heterogeneous cell types by single-cell RNA sequencing, the atlas and characteristics of plasma cells remain poorly understood. To identify the altered phenotype and differentiation patterns of plasma cells in CTEPH. We performed single-cell RNA sequencing on pulmonary endarterectomy tissue from 5 patients and 6 normal pulmonary arteries. Serum immunoglobulins (Igs) were measured using protein electrophoresis among 273 CTEPH patients, 259 idiopathic pulmonary arterial hypertension (IPAH) patients, and 251 healthy controls. The percentage of plasma cells was significantly increased from less than 1% in healthy controls to 15% in CTEPH patients. We identified 1 B cell cluster and 5 distinct mature plasma cell clusters, including IGHG1, HSPA1A, AHNAK, IGLC3, and IGKV4. Notably, the AHNAK and IGLC3 subclusters are newly identified. GeneSwitches analysis indicated early activation of IGHG1 and early deactivation of HLA-DPA1. The trajectory of AHNAK cluster was earlier than that of IGLC3 cluster, with an enrichment for pathways responsive to lipopolysaccharide. The IGLC3 cluster revealed lower differentiation potential and was predominantly associated with Ig production. Furthermore, Igα2 levels in CTEPH patients were lower than in controls but higher than in IPAH patients. Significantly, Igγ levels were markedly elevated in CTEPH patients compared with IPAH patients and controls, better distinguishing CTEPH patients from controls and IPAH patients. Plasma cells of CTEPH had a distinctive landscape and heterogeneity. The newly identified clusters represented excessive Ig production but lacked immune response function. These findings highlight that targeted plasma cells can be used to develop novel CTEPH treatments.
other
2025-02-27 | Rare variants inSTAB2in patients with chronic thromboembolic pulmonary hypertension
The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is poorly understood. Study of genetic risk factors for CTEPH is likely to improve our understanding of CTEPH pathogenesis, and may lead to novel treatment and prevention strategies. Genetic analysis focused on shared gene variants in high-risk disease pedigrees can aid in the identification of rare variants with a strong effect on disease risk. We identified 13 CTEPH high-risk pedigrees and performed whole exome sequencing in 22 CTEPH from these pedigrees cases, focusing on rare and deleterious variants that were shared between related CTEPH cases. We validated CTEPH candidate gene variants in two independent CTEPH cohorts, one from Utah (n=78) and one from University of California San Diego (n=238), and compared to controls from the UK Biobank. A rare and predicted deleterious missense variant in STAB2 was identified in two related CTEPH cases. Qualifying STAB2 variant alleles were observed more frequently in bothCTEPH cohorts (pooled allele frequency 4.6%) than in subjects from the UK Biobank with a history of PE (allele frequency 2.2%, p=0.0002) or without a history of PE (allele frequency 1.9%, p<0.0001). CTEPH subjects with qualifying STAB2 variants had elevated levels of plasma von Willebrand Factor (vWF) and Factor VIII, consistent with the known role of STAB2 as a genetic regulator of circulating vWF levels. Rare variants in STAB2 are identified in a CTEPH high-risk pedigree, and are over-represented in non-relatedCTEPH cases compared to controls with PE. These data suggest that STAB2 is a CTEPH risk gene.
2022-05-02 | LncRNA-GAS5/miR-382-3p axis inhibits pulmonary artery remodeling and promotes autophagy in chronic thromboembolic pulmonary hypertension.
We have clarified the role of miR-382-3p in chronic thromboembolic pulmonary hypertension (CTEPH), but what is less clear lies in its upstream regulatory mechanism. To explore the regulation mechanism of GAS5/miR-382-3p axis on CTEPH. In vitro, we constructed cell models by treating Pulmonary Artery Smooth Muscle Cells (PASMCs) with platelet-derived growth factor-BB (PDGF-BB). The effects of different concentrations of PDGF-BB on the activity of PASMCs were tested by cell counting kit-8 (CCK-8). The upstream lncRNA of miR-382-3p was screened and confirmed through bioinformatics analysis, RNA pull-down, quantitative reverse transcription polymerase chain reaction (qRT-PCR), dual luciferase reporter gene and RNA immunoprecipitation assays. The effects of GAS5/miR-382-3p axis on the viability, migration, and expressions of autophagy- and angiogenesis-related proteins were confirmed by rescue experiments (CCK-8, wound healing and western blot). In vivo, animal models by perfusing autologous blood vessels, the effects of GAS5 overexpression or silencing on the expressions of miR-382-3p, angiogenesis- and autophagy-related genes, mean pulmonary arterial pressure (mPAP) and pulmonary artery wall were determined by biological signal acquisition system, hematoxylin-eosin staining, qRT-PCR and western blot. PDGF-BB dose-dependently promoted PASMCs viability. XIST and GAS5 expressions in PASMCs were affected by the concentration of PDGF-BB, but only GAS5 can be pulled down by miR-382-3p probe. GAS5 targeted miR-382-3p to inhibit the viability and migration of PAMSCs, mPAP in CTEPH rats, pulmonary artery wall thickening and angiogenesis, and promote autophagy. GAS5/miR-382-3p axis is involved in the regulation of pulmonary artery remodeling and autophagy in CTEPH.
2022-04-04 | Epigenetic Modification of the von Willebrand Factor Promoter Drives Platelet Aggregation on the Pulmonary Endothelium in Chronic Thromboembolic Pulmonary Hypertension.
Rationale: von Willebrand factor (vWF) mediates platelet adhesion during thrombosis. While chronic thromboembolic pulmonary hypertension (CTEPH) is associated with increased plasma levels of vWF, the role of this protein in CTEPH has remained enigmatic. Objectives: To identify the role of vWF in CTEPH. Methods: CTEPH-specific patient plasma and pulmonary endarterectomy material from patients with CTEPH were used to study the relationship between inflammation, vWF expression, and pulmonary thrombosis. Cell culture findings were validated in human tissue, and proteomics and chromatin immunoprecipitation were used to investigate the underlying mechanism of CTEPH. Measurements and Main Results: vWF is increased in plasma and the pulmonary endothelium of CTEPH patients. In vitro, the increase in vWF gene expression and the higher release of vWF protein upon endothelial activation resulted in elevated platelet adhesion to CTEPH endothelium. Proteomic analysis revealed that nuclear factor (NF)-κB2 was significantly increased in CTEPH. We demonstrate reduced histone tri-methylation and increased histone acetylation of the vWF promoter in CTEPH endothelium, facilitating binding of NF-κB2 to the vWF promoter and driving vWF transcription. Genetic interference of NFκB2 normalized the high vWF RNA expression levels and reversed the prothrombotic phenotype observed in CTEPH-pulmonary artery endothelial cells. Conclusions: Epigenetic regulation of the vWF promoter contributes to the creation of a local environment that favors in situ thrombosis in the pulmonary arteries. It reveals a direct molecular link between inflammatory pathways and platelet adhesion in the pulmonary vascular wall, emphasizing a possible role of in situ thrombosis in the development or progression of CTEPH.
2019-07-30 | miRNA-PDGFRB/HIF1A-lncRNA CTEPHA1 Network Plays Important Roles in the Mechanism of Chronic Thromboembolic Pulmonary Hypertension
Our previous studies have revealed that long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and genes were abnormally expressed in the pulmonary artery tissues of the chronic thromboembolic pulmonary hypertension (CTEPH) patients. We aim to establish the CTEPH-related miRNA-gene-lncRNA network for finding the core genes and associated miRNA and lncRNA in CTEPH patients.Firstly, the target genes of differential miRNAs were predicted by searching TargetScan databases, and the predicted target genes were intersected with the mRNAs from the gene chip. Secondly, the intersective genes were analyzed by the Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway software for obtaining differential intersective genes and then establish the miRNA-gene networks. Thirdly, the possible genes regulated by the differential lncRNAs from the gene chip were intersected with the above-screened mRNA to build the lncRNA-mRNA networks. Subsequently, the miRNA-gene-lncRNA networks were constructed according to the two networks above (miRNA-gene networks and lncRNA-mRNA networks). Finally, the core genes of the networks in the experimental group were screened according to Diffk > 0.6 and used to construct the miRNA-core gene-lncRNA networks of CTEPH.The pathway network, miRNA-mRNA network, lncRNA-mRNA networks, and miRNA-gene-lncRNA networks were successfully constructed. The core genes of the miRNA-gene-lncRNA networks (Diffk > 0.6) were the human Beta-type platelet-derived growth factor receptor (PDGFRB) and hypoxia-inducible factor-1a (HIF-1A), the miRNAs-PDGFRB-lncRNAs and miRNAs-HIF1A-lncRNAs networks were constructed. Finally, miRNA-149-5p-PDGFRB-TCONS_l2_00020587-XLOC_l2_010723 and miRNA-338-5p/miRNA-199b-5p-HIF1A- TCONS_l2_00020587-XLOC_l2_010723 were found in the analysis of the network.miRNA-149-5p-PDGFRB-lncRNA CTEPH-associated 1 (CTEPHA1) (TCONS_l2_00020587-XLOC_l2_010723) and miRNA-338-5p/miRNA-199b-5p-HIF1A-lncRNA CTEPHA1 are related to the development of CTEPH.
2019-03-11 | Long non-coding RNA CASC2 suppresses pulmonary artery smooth muscle cell proliferation and phenotypic switch in hypoxia-induced pulmonary hypertension
In this study, we aimed to investigate whether and how lncRNA CASC2 was involved in hypoxia-induced pulmonary hypertension (PH)-related vascular remodeling. The expression of lncRNAs or mRNAs was detected by qRT-PCR, and western blot analysis or immunochemistry was employed for detecting the protein expression. Cell number assay and EdU (5-ethynyl-2′-deoxyuridine) staining were performed to assess cell proliferation. Besides, flow cytometry and wound healing assay were employed for assessments of cell apoptosis and cell migration, respectively. Rat model of hypoxic PH was established and the hemodynamic measurements were performed. Hematoxylin and eosin (HE) and Masson′s trichrome staining were carried out for pulmonary artery morphometric analysis. The expression of lncRNA CASC2 was decreased in hypoxia-induced rat pulmonary arterial tissues and pulmonary artery smooth muscle cells (PASMCs). Up-regulation of lncRNA CASC2 inhibited cell proliferation, migration yet enhanced apoptosis in vitro and in vivo in hypoxia-induced PH. Western blot analysis and immunochemistry showed that up-regulation of lncRNA CASC2 greatly decreased the expression of phenotype switch-related marker α-SMA in hypoxia-induced PH. Furthermore, it was indicated by the pulmonary artery morphometric analysis that lncRNA CASC2 suppressed vascular remodeling of hypoxia-induced rat pulmonary arterial tissues. LncRNA CASC2 inhibited cell proliferation, migration and phenotypic switch of PASMCs to inhibit the vascular remodeling in hypoxia-induced PH.
proteins
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.
2026-04-29 | Personalised viscoelastometry-guided systemic thrombolysis for high- and intermediate-high-risk acute pulmonary embolism in the ICU: a single-centre randomised controlled interventional feasibility trial.
Systemic thrombolysis is recommended for high-risk pulmonary embolism, but is associated with a substantial bleeding risk due to thrombolysis-induced coagulopathy. However, recent advances in precision and personalised care offer the potential to reduce mortality as well as the incidence of chronic thromboembolic pulmonary hypertension and post-pulmonary embolism impairment, thereby improving long-term outcomes. Our primary objective was to evaluate the feasibility of a viscoelastic testing-guided, low-dose, prolonged systemic thrombolysis protocol in acute pulmonary embolism. Exploratory secondary objectives included assessment of the safety and efficacy of the protocol using an individualised approach tailored to each patient's coagulation profile. This single-centre, prospective, randomised interventional feasibility trial was conducted at Semmelweis University (Budapest, Hungary). Adult pulmonary embolism patients were randomly assigned to a control group (CG) receiving the ESC-recommended 100 mg/2 h dose of rtPA or a viscoelastometry-guided group (VGG), in which the rtPA dose and duration were adjusted based on viscoelastic tests. Transthoracic echocardiography (TTE) was performed every two hours to monitor right ventricular (RV) function and determine cessation of systemic thrombolysis in VGG. The primary outcome was feasibility; the secondary outcome was safety and efficacy. Among 33 enrolled patients, 19 were included in the analysis (CG: 7; VGG: 12). Patients in the VGG received significantly lower doses of rtPA (median 32.00 mg [IQR 20.95-42.75 mg]) despite longer infusion duration (median 8.5 h [IQR 6.6-10.0]) and showed no coagulopathy. RV dysfunction persisted in two CG patients, whereas in the VGG it resolved in all patients. Major bleeding occurred in two patients in the CG and in one patient in the VGG. Viscoelastometry-guided, individualised, low-dose systemic thrombolysis is feasible and supports a personalised approach to thrombolysis in the management of pulmonary embolism.
2025-12-11 | Overexpression of PRDX2 alleviates chronic thromboembolic pulmonary hypertension by modulating inflammation and mitophagy.
Chronic thromboembolic pulmonary hypertension (CTEPH) results from thrombi-induced endothelial injury, inflammation, and oxidative stress in pulmonary vessels, leading to vascular remodelling, increased resistance, and elevated pulmonary arterial pressure. Peroxiredoxin 2 (PRDX2) is an antioxidant enzyme involved in regulating cellular redox balance and inflammation, its role in CTEPH is not yet fully understood. The aim is to investigate the expression and functional role of PRDX2 in CTEPH and explore its potential mechanisms in modulating inflammation and mitochondrial autophagy. Proteomics was used to analyse peripheral blood samples from patients with CTEPH and healthy controls to identify differentially expressed proteins. A rat model of CTEPH was developed through the intravenous injection of amino-crosslinked polystyrene microspheres. PRDX2 expression was assessed in lung tissues and primary pulmonary artery endothelial cells (PAECs) using immunohistochemistry, Western blotting, and qRT-PCR. The effects of PRDX2 overexpression and silencing on inflammation and mitochondrial autophagy were evaluated using ELISA, Western blotting, and transmission electron microscopy. The expression of PRDX2 was significantly increased in the peripheral blood of patients with CTEPH and in the pulmonary vasculature of rats with CTEPH.Overexpression of PRDX2 in PAECs attenuated the inflammatory response by NF-κB signaling pathway. Additionally, overexpression of PRDX2 regulated the expression of mitophagy-related proteins (LC3II/I, Beclin-1, and p62) and restored mitochondrial morphology. Further verification in rats showed that PRDX2 overexpression significantly improved haemodynamic parameters and pulmonary vascular remodelling in CTEPH. Overexpression of PRDX2 alleviates pulmonary vascular remodeling in CTEPH by reducing inflammation and Modulating mitophagy, suggesting its protective role and potential as a therapeutic target for the disease.
2025-11-17 | American Lung Association Pulmonary Hypertension Roundtable: Executive Summary.
The American Lung Association and Pulmonary Hypertension Association convened a scientific roundtable of pulmonary hypertension experts to discuss the latest recommendations from the European Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension (PH) and from the 7th World Symposium on Pulmonary Hypertension (WSPH). The aim of the roundtable was to discuss changes that were made compared to earlier recommendations and guidelines set out by the European Society of Cardiology and the European Respiratory Society in 2015, the 6th World Symposium on Pulmonary Hypertension in 2018, and the CHEST Guideline on Therapy for Pulmonary Arterial Hypertension in 2019. The overall objectives were to: 1) Create an educational resource for providers that summarizes currently available PAH guidelines, 2) Provide an expert critique of current guidelines, outlining strengths and weaknesses and resolving differences where guidelines do not agree. 3) Provide guidance for the incorporation of the recently approved drug, sotatercept into current guidelines. An executive summary was drafted following the roundtable meeting on April 8, 2024, and revised by the panel in September 2024, following publication of the proceedings from the 7th WSPH held in Barcelona June 29-July 1, 2024. The Executive Summary reviews changes to the hemodynamic criteria for defining pre- and post-capillary PH, exercise-induced PH, and PH associated with lung disease. Recommendations are given for proper diagnosis and clinical classifications of the various forms of PH. The role of screening for PH in high-risk populations and the use of risk scores for disease stratification are discussed. Finally, treatment algorithms for managing pulmonary arterial hypertension, PH associated with lung disease, and chronic thromboembolic pulmonary hypertension are presented.
2025-07-18 | Fluid management of cardiopulmonary bypass during pulmonary endarterectomy for CTEPH patients impacts perioperative outcome.
Pulmonary endarterectomy (PEA) using deep hypothermic circulatory arrest (DHCA) and cardiopulmonary bypass (CPB) is the preferred treatment for chronic thromboembolic pulmonary hypertension (CTEPH). Crystalloid priming solutions cause hemodilution with disadvantages, and no standard exists for PEA. This study evaluates CTEPH patient outcomes after adding 5% human albumin (HA) to the CPB-prime and hemodilution solution during PEA. The effect of the CPB-protocol change was evaluated by comparing patients operated under the old and new protocols in a 1:1 propensity score match based on age, sex, and preoperative peripheral vascular resistance (PVR). Matching resulted in 56 patients (28 per group) between July 1, 2010, and May 31, 2020. The new protocol group had a lower intraoperative fluid balance (1.85 vs 6.76 liters, p < 0.001), vasoactive-inotropic score (VIS) (8.7 vs 17.7, p = 0.04), shorter operative- (407 vs 451 min, p = 0.03), and hospitalization time (LOS) (18 vs 27 days, p = 0.008). Morbidity and mortality at 30- and 90-days were similar in both groups. The new protocol was associated with reduced intraoperative fluid balance after adjustment for operative time (-3.7 liters [95% CI -5.2, -2.1], p < 0.0001). Lower intraoperative fluid balance was associated with shorter hospitalization in the intensive care unit, intubation time, LOS, and lower VIS (p = 0.0011, 0.0013, 0.008, <0.0001, respectively). The protocol change shortened LOS, independent of operative time, by 27% [95% CI, 44%, 6%], p = 0.02. Priming and maintenance protocol for CPB with the addition of 5% HA had a beneficial effect on intraoperative fluid balance and improved outcome after PEA for patients with CTEPH.
small molecules
2026-09-18 | Riociguat as inpatient rescue therapy for acute decompensation of inoperable chronic thromboembolic pulmonary hypertension.
A man in his 70s, a retired coal miner with prior asbestos exposure and no smoking history, presented with syncope and progressive exertional dyspnoea. Initial CT pulmonary angiogram (CTPA) revealed bilateral lobar pulmonary emboli, and transthoracic echocardiography (TTE) showed evidence of pulmonary hypertension. He was discharged on rivaroxaban and referred to the heart failure and respiratory clinic. At the respiratory clinic follow-up, he reported worsening breathlessness and was initiated on long-term oxygen therapy (LTOT). Outpatient investigations were arranged, including a ventilation/perfusion (V/Q) scan, which demonstrated extensive mismatched perfusion defects consistent with chronic thromboembolic pulmonary hypertension (CTEPH). He was also referred for right heart catheterisation (RHC) and to the Irish National Pulmonary Hypertension Unit.Before he was reviewed in the pulmonary hypertension unit, he re-presented to the emergency department with worsening dyspnoea, haemoptysis and bilateral lower limb oedema, with clinical signs of right heart failure. Repeat imaging with TTE and CTPA confirmed persistent findings of chronic embolic disease. Despite optimal diuresis and anticoagulation, his symptoms remained refractory and required high-flow oxygen without decreasing requirements after 14 days. Riociguat was initiated and titrated inpatient, resulting in rapid clinical improvement and reduced oxygen requirement within 72 hours. Subsequent right heart catheterisation confirmed inoperable CTEPH. He was reviewed at the National Pulmonary Hypertension Clinic, and following multidisciplinary discussion, given insufficient surgically accessible thromboembolic burden and coexisting left ventricular dysfunction, the decision was made to continue riociguat as long-term medical therapy.
2026-09-18 | Endothelial Cell Transcriptomics Reveal Activation of Ribosomal-related Pathways in Chronic Thromboembolic Pulmonary Hypertension.
Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are rare, severe forms of pulmonary hypertension (PH) characterized by elevated mean pulmonary arterial pressure (mPAP) and ∼20% mortality at 3 years. PAH is defined by progressive obliterative vasculopathy, whereas CTEPH results from persistent pulmonary artery obstruction by fibrotic thrombotic material, leading to vascular remodelling, right ventricular hypertrophy, and heart failure. Endothelial colony-forming cells (ECFCs) derived from PAH and CTEPH patients and healthy-controls were analysed to identify disease-specific molecular and functional alterations. Transcriptomic profiling was integrated with functional assays, including global protein synthesis, mitochondrial bioenergetics, intracellular Ca2+ dynamics, and cellular ultrastructural assessment by transmission electron microscopy (TEM). The effects of riociguat, the approved therapy for inoperable or persistent post-surgical CTEPH, were also evaluated. Significant differences in gene expression profiles were observed among PAH-ECFCs, CTEPH-ECFCs, and control-ECFCs. CTEPH-ECFCs, exhibited a unique upregulation of ribosomal and translation-related genes, accompanied by increased global protein synthesis. Network analysis revealed a highly connected ribosomal-translational hub within CTEPH transcriptome signature. CTEPH-ECFCs also exhibited mitochondrial remodelling, increased endoplasmic reticulum-mitochondria contacts, altered intracellular Ca2+ handling, and reduced maximal respiratory capacity. Riociguat did not reverse these abnormalities. Dysregulated protein biosynthesis is a characteristic feature of CTEPH, distinguishing them from PAH. Our findings highlight a coordinated translation-mitochondria-MAM axis potentially involved in endothelial dysfunction and vascular remodelling, supporting the need for therapies targeting disease-specific molecular pathways beyond soluble guanylate cyclase stimulation.
2026-09-11 | Phase 1b ATMOS trial of the inhaled sGC activator mosliciguat in patients with PAH/CTEPH.
Mosliciguat, a soluble guanylate cyclase (sGC) activator, is designed for lung-targeted delivery via dry powder inhalation. Nitric oxide (NO) binds sGC's prosthetic heme group, catalysing cyclic guanosine monophosphate (cGMP) production, resulting in increased vasodilation, reduced inflammation/apoptosis, reverse vascular remodelling and antifibrotic effects. sGC is redox sensitive, losing heme in pulmonary hypertension (PH) oxidative stress conditions. Mosliciguat's novel 'activator' mechanism directly binds the sGC heme-binding pocket to induce cGMP, allowing it to target NO-insensitive heme-free sGC, potentially rescuing additional enzymatic activity. A Proof-of-Concept Trial of Inhaled Mosliciguat, a First-in-Class Soluble Guanylate Cyclase Activator (ATMOS; non-randomised, open-label phase 1b trial) assessed single-dose escalation of mosliciguat in participants with pulmonary arterial hypertension or chronic thromboembolic PH. 38 participants received mosliciguat. The per protocol set (PPS, n=20) included NO-non-responsive participants with baseline pulmonary vascular resistance (PVR) ≥5 Wood units (n=4/dose). The pharmacodynamic set (PDS, n=37) included NO-responsive participants. Five PPS participants underwent a ≥24-hour washout from background therapy. In the PPS, doses of 0.24, 0.48, 1.0, 2.0 and 4.0 mg resulted in mean peak per cent PVR reductions from baseline (95% CI) of 21.0% (31.6% to 10.4%), 16.1% (32.8% to -0.7%), 25.9% (60.3% to -8.4%), 38.1% (55.9% to 20.3%) and 36.3% (48.3% to 24.4%), respectively, and generally persisted over the 3-hour observation period. Similar effects were seen in the PDS. The majority of adverse events were mild; most frequently reported were headache (n=3/38; 7.9%), decreased oxygen saturation and fatigue (n=2/38; 5.3% each). No safety-relevant changes were seen in systemic vascular resistance or blood pressure. Mosliciguat demonstrated a favourable safety profile and sustained, clinically meaningful reductions in PVR in participants with PH. NCT03754660.
2026-08-31 | Dapagliflozin in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: The DAPAH randomized controlled trial.
SGLT2 inhibitors (SGLT2i) reduce mortality in left heart failure. In pulmonary arterial hypertension (PAH), preclinical data suggest SGLT2i improve right ventricular function through metabolic modulation and inhibition of vascular remodeling via smooth muscle cell pathways. The DAPAH trial evaluated whether the potential benefits of SGLT2 inhibition translate into clinical efficacy for symptomatic patients on background vasodilator therapy with either PAH or chronic thromboembolic pulmonary hypertension. In this single-center, double-blind trial, 52 patients were randomized (1:1) to dapagliflozin 10 mg daily or placebo for 12 weeks. The primary endpoint was change in Peak VO2. Secondary endpoints included invasive hemodynamics, NT-proBNP, 6-minute walk distance (6MWD) and REVEAL Lite 2 scores. Baseline characteristics were balanced (n=52; mean age 66.5 years; 63% female; n=40 PAH, n=12 CTEPH). Fifty-one patients had complete data on Peak VO2. At 12 weeks, there was no significant difference in Peak VO2 (Adjusted Mean Difference: -0.67 mL/kg/min; 95% CI [-1.67, 0.33]; p=0.187). No significant treatment effects were observed for pulmonary vascular resistance (p=0.255), 6MWD (p=0.22), or NT-proBNP trajectory (interaction p=0.681). REVEAL Lite 2 scores showed a small reduction with dapagliflozin (-0.66; 95% CI [-1.25, -0.06]; p=0.031). Metabolic target engagement was evident from a significant reduction in serum urate (P-interaction < 0.001). Dapagliflozin was safe and well-tolerated. This randomized study of SGLT2i in pre-capillary PH showed that 12 weeks of dapagliflozin did not significantly improve exercise capacity, hemodynamics, or functional status compared to placebo. gov (NCT05179356).
2026-08-08 | STOP-RIO study: protocol for a randomised, controlled, open-label non-inferiority trial to test the safety of discontinuation of riociguat after balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension.
Balloon pulmonary angioplasty (BPA) improves haemodynamics and outcomes in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Riociguat is frequently initiated before BPA to reduce procedural risks. However, evidence supporting continuation after successful BPA is lacking and current guidelines provide no criteria for treatment discontinuation. Consequently, many patients remain on long-term riociguat despite uncertain benefit, potential adverse effects and high costs. STOP-RIO is a multicentre, open-label, randomised, non-inferiority (NI) trial conducted in the two Dutch CTEPH expert centres. Seventy-four adult CTEPH patients treated with riociguat monotherapy with a mean pulmonary artery pressure (mPAP) <30 mmHg post-BPA will be randomised (1:1) to stop or continue the medication. The primary endpoint is the between-group difference in baseline-adjusted mPAP at rest measured by right heart catheterisation at 16 weeks. NI will be tested for the primary endpoint and for the two secondary endpoints highest in hierarchy N-terminal pro-B-type natriuretic peptide and 6-min walk distance. Additional secondary endpoints include haemodynamic parameters, safety outcomes, patient-reported outcomes and healthcare use. The primary analysis will be performed in a per-protocol population with secondary intention-to-treat and exploratory analyses. A prospective health economic evaluation will be conducted from a societal perspective. The study is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice and has received ethical approval. Written informed consent will be obtained from all participants. Results will be disseminated through peer-reviewed publication and shared with patient organisations and scientific congress. EU Clinical Trials Register: 2024-5 19 225-38-00.
cell therapies
2026-05-01 | D106-02 Upar+ Macrophages and Stromal Cells Drive Persistent Thromboembolic Remodeling in Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Mechanistic and Therapeutic Insights From Car-T Targeting
Abstract Purpose CTEPH is sustained by nonresolving thrombi enriched with inflammatory macrophages and fibrotic stromal populations. We hypothesized that targeting these cell subsets could remodel the thrombus niche and improve cardiopulmonary function. Methods scRNA-seq of human PTE clots and murine IVC wall and thrombi identified uPAR as a shared marker of pathogenic macrophages and fibroblasts. Murine T cells engineered with a uPAR-CAR were infused into IVC-ligated mice (n = 9/group). Outcomes included scRNA-seq validation, histology, cytokine assays, echocardiography, and flow analysis. Results scRNA-seq showed that uPAR+ macrophages expressed pro-inflammatory chemokines (Ccl6, Ccl8, Ccl12), while uPAR+ fibroblasts and vascular cells upregulated fibrogenic genes (Fn1, Timp1/2, Col15a1). In vivo, CAR-T treatment reduced thrombus weight by 41% (p = 0.004) and collagen content by 55% (p = 0.002) compared with untransduced controls. α-SMA+ myofibroblasts decreased ∼4-fold (p=0.001). Serum TNF-α, IL-1β, IL-6, and CCL2 were significantly reduced (p<0.05). Echocardiography revealed lower RV systolic pressure (-18%, p=0.03) and improved RV function (p=0.02). Respiratory testing under hypoxia/hypercapnia showed robust gains: minute ventilation +35% (p=0.0006), tidal volume +27% (p=0.0001), and peak inspiratory/expiratory flow +30% (p=0.0001). In human PTE clots, high uPAR+ burden correlated with residual pulmonary pressures post-surgery (p=0.01). Conclusion uPAR+ macrophages and stromal subsets drive persistent immune-fibrotic pathology in CTEPH. uPAR CAR-T therapy effectively depletes these populations, reduces fibrosis, lowers inflammation, and restores vascular and cardiopulmonary function. These results highlight a new therapeutic strategy for immune-fibrotic remodeling in pulmonary vascular disease. This abstract is funded by: None
2026-05-01 | Chronic Thromboembolic Pulmonary Hypertension in Patients With Thoracic Outlet Syndrome-Association With Younger Age and More Distal Disease.
We aimed to elucidate the potential role for thoracic outlet syndrome (TOS) and upper extremity deep venous thrombosis in the development of chronic thromboembolic pulmonary hypertension (CTEPH). Charts from 64 consecutive patients with CTEPH who underwent pulmonary endarterectomy in Helsinki University Hospital between 2015 and 2023 were analysed for baseline characteristics, risk factors for thrombosis, treatments, and outcome at 1 year. We found that seven patients with CTEPH (11%) had TOS with subclavian vein stenosis, impaired flow, and collaterals in provocation contrast venography. These patients with TOS CTEPH were younger (median 23 vs 59 years, p<0.001) and had more often distal (segmental 100% vs 38,6%, p<0.01) disease than other patients with CTEPH and had fewer risk factors for thrombosis (p<0.05). Functional class, N-terminal pro-B-type natriuretic peptide (NT-proBNP), 6-minute walk test and pulmonary vascular resistance (PVR) at baseline were similar. At 1 year postoperatively, there was a similar improvement in PVR (-45% vs -56%), NT-proBNP (-70.0% vs -71.8%), and functional class (improvement in 85.7% vs 91.5%) whereas 6-minute walk test increased more (247 vs 100 m, p<0.05) in patients with TOS. Patients with TOS were more often treated with balloon pulmonary angioplasty postoperatively (57.0 vs 10.5%, p<0.01). Treatment with pulmonary vasodilators did not differ significantly (42.9% vs 15.1%). TOS was later treated with thoracoscopic first-rib resection in three patients (43%). CTEPH with upper extremity deep venous thrombosis and TOS represents a unique subgroup of patients who benefit from interventional therapies.
2026-04-30 | Balloon Pulmonary Angioplasty for Treatment of Chronic Thromboembolic Pulmonary Hypertension: Statement From the BPA-CTEPH Alliance.
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by fibrothrombotic pulmonary vascular obstruction and associated small-vessel vasculopathy resulting in a progressive increase in pulmonary vascular resistance and right heart failure. Pulmonary thromboendarterectomy is the first-line treatment for surgically accessible disease. However, many patients are ineligible because of surgically inaccessible distal disease, medical comorbidities, or symptomatic residual disease after pulmonary thromboendarterectomy. Balloon pulmonary angioplasty (BPA) has emerged as a very effective therapeutic option in these patients. This statement from the BPA-CTEPH Alliance reviews the role of BPA in CTEPH, describing patient selection, procedural techniques, periprocedural management, complications, and training requirements. This U.S.-focused document provides practical guidance for establishing a BPA program within a multidisciplinary CTEPH center. Technical refinement and improved patient selection have significantly enhanced the safety and efficacy of BPA. Contemporary evidence suggests that BPA is associated with significant improvements in pulmonary vascular resistance, mean pulmonary artery pressure, functional class, and quality of life. There is a considerable learning curve associated with BPA, and complication rates, once prohibitive, have substantially decreased with operator experience and with adjunct medical therapy. BPA has become a critical component of multimodality management of CTEPH, with durable hemodynamic and clinical benefits. Continued research, with a particular focus on randomized controlled trials in the United States, is crucial to defining long-term outcomes and expanding access to this lifesaving therapy.
2026-04-01 | Balloon Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension: Identifying and Managing Complications for the Operator.
Balloon pulmonary angioplasty (BPA) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension who cannot receive pulmonary thromboendarterectomy or who have residual pulmonary hypertension after pulmonary thromboendarterectomy. As BPA volume and expertise have increased, significant strides in refining this technique have improved success and minimized complications; yet, minimal literature exists on appropriate complication management. This review summarizes how interventionalists can prevent, recognize, and manage BPA complications effectively. Operators must first focus on appropriate patient and vessel selection. Lower lung zones coupled with ring-like stenoses and web lesions are more favorable. Increased patient age, tortuous or subtotal lesions, and elevated pulmonary vascular resistance (>6 Wood units) portend a higher risk for complications. Vascular perforation can be treated with balloon tamponade, embolization (gelfoam and/or coils), and covered stents. Massive hemoptysis is managed with intubation and single lung ventilation if needed. As shock is predominantly hemorrhagic and/or cardiogenic, first-line therapies include vasopressors, inodilators, pulmonary vasodilators, and volume resuscitation, whereas mechanical support devices are second-line. Although reperfusion lung injury (RLI) is uncommon, it is generally well tolerated and managed with positive pressure ventilation, high-flow oxygen therapy, and diuresis. Acute kidney injury can be reduced by dilution of contrast dye, use of extension catheters, and procedural planning. Utilization of standard, angle-minimizing techniques, avoidance of high-dose cinefluoroscopy, and digital subtraction angiography minimizes radiation dose. In conclusion, most complications can be avoided or managed effectively without major morbidity or mortality by optimal preparation, patient selection, and commitment to a comprehensive BPA program.
2026-02-07 | Temporal Trends in Age Profile and Safety of Balloon Pulmonary Angioplasty for CTEPH.
Balloon pulmonary angioplasty (BPA) techniques have been refined and increasingly adopted for chronic thromboembolic pulmonary hypertension. This study aimed to evaluate the temporal trends in BPA safety, with a focus on outcomes in older patients. Using the Japanese Cardiovascular Disease All-Case Registry (2013-2022), we retrospectively analyzed 14,429 BPA procedures performed on 3,700 patients (median age, 68 years). The study period was divided into early (2013-2017) and late (2018-2022) periods. Patient characteristics and major complication rates were evaluated for each period. Complications were defined as a composite of major adverse events occurring within 30 days: death, mechanical ventilation, extracorporeal membrane oxygenation, continuous hemodiafiltration, transfusion, cardiac tamponade, or surgery. Patients treated in the late period were older (P < 0.001). The complication rate decreased from 7.8% in the early period to 4.2% in the late period (P < 0.001). In multivariable analysis, the adjusted OR of complications was lower in the late period (OR: 0.411; 95% CI: 0.247-0.675). The adjusted complication risk decreased across all age categories in the late period. An age-dependent increase in the adjusted complication risk was observed across all periods (trend P = 0.002), significant in the early (trend P = 0.015) but not in the late (trend P = 0.085) period. BPA safety has improved over time. Despite higher complication risks in older patients, the narrowing gap with younger patients in recent years suggests that BPA is a safe and feasible option for this population.
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2026-06-26 | Hemodynamic improvement but worsening hypoxemia after balloon pulmonary angioplasty: severe eosinophilic asthma unmasked in CTEPH.
We report a patient with peripheral-type chronic thromboembolic pulmonary hypertension (CTEPH) in whom exertional hypoxemia and dyspnea worsened despite substantial hemodynamic improvement after repeated balloon pulmonary angioplasty (BPA), prompting reassessment for a competing ventilatory limitation. Optimization of concomitant severe eosinophilic asthma with benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, and sinus surgery improved airflow obstruction and oxygenation and was accompanied over time by a further reduction in pulmonary arterial pressure. These changes suggest that a superimposed hypoxia-related pulmonary vascular component, compatible with group 3 physiology, may have been attenuated.
2025-11-16 | Characteristics of ferritinophagy-related genes in chronic thromboembolic pulmonary hypertension, a study based on bioinformatics with machine learning model.
Ferritinophagy plays a significant role in the development of cardiovascular diseases. The characteristics of ferritinophagy in chronic thromboembolic pulmonary hypertension (CTEPH) pathogenesis remains unknown. This study aims to identify ferritinophagy-related genes (FRGs) in CTEPH based on bioinformatics with machine learning model. The gene expression data of CTEPH and list of FRGs were downloaded from the Gene Expression Omnibus(GEO)database and GeneCards. CTEPH samples were stratified into distinct subtypes based on the expression levels of FRGs. Differences in immune characteristics and functional enrichment across different CTEPH subtypes were analyzed. Weighted gene co-expression network analysis (WGCNA) and machine learning algorithms were employed to identify hub genes among different subtypes, followed by the diagnostic model's construction based on the hub genes. Based on FRGs, two distinct CTEPH subtypes were revealed, cluster A and cluster B, with significant disparities in pathway enrichment and immune microenvironment between two clusters. Notably, 24 differentially expressed genes were found between two clusters. Based on WGCNA and machine learning algorithms, seven genes were identified as hub genes. Finally, the diagnostic model based on these seven genes was established, which can distinguish the two subtypes well. This study underscores two FRG-based CTEPH subtypes characterized by unique immune profiles, offering a promising avenue for the development of subtype-specific, personalized therapeutic strategies for CTEPH patients.
2025-07-10 | The Activin Pathway in Chronic Thromboembolic Pulmonary Hypertension: A Potential Biomarker for Residual Pulmonary Hypertension After Endarterectomy
Background Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by persistent pulmonary vascular obstruction due to unresolved thromboembolic lesions and distal pulmonary vascular remodeling. Despite the recognized role of the activin pathway in pulmonary vascular remodeling, its involvement in CTEPH remains insufficiently explored. This study aimed to investigate the presence of activin pathway components in CTEPH-related microvasculopathy and evaluate their potential as biomarkers. Methods Plasma levels of activin pathway biomarkers and key inflammatory mediators were assessed in controls and operable CTEPH patients pre- and post-surgery. The study enrolled 69 patients (mean age 62±13 years, 51% male), among whom 29 exhibited residual pulmonary hypertension (PH) after surgery, and 2 died following post-endarterectomy (PEA). Results CTEPH patients demonstrated elevated levels of activin-A, activin-B, FSTL3, C-X-C motif chemokine ligand 9 (CXCL9), beta-nerve growth factor (ß-NGF), C-reactive protein (CRP), and pro-brain natriuretic peptide (pro-BNP) compared to controls. Preoperative activin-A levels were associated with an increased risk of residual PH or mortality post-surgery (Odds ratio, 2.469 [95% CI, 1.011–5.487]; p=0.027), following adjustments for age, mean pulmonary arterial pressure before PEA (mPAP), and CRP. Histological analysis of lung specimens from CTEPH patients revealed nuclear accumulation of phosphorylated Smad 2 and upregulation of inhibin-βA, inhibin-βB, activin receptor type IIB (ACTRIIB), and FSTL3 in muscularized pulmonary arterioles. Conclusions These findings suggest a potential role for activin-A as a predictive biomarker for residual PH following pulmonary endarterectomy in CTEPH. Further investigation into the activin pathway may uncover therapeutic targets for managing CTEPH-associated vascular remodeling.
2025-07-05 | Transcriptional changes of the extracellular matrix in chronic thromboembolic pulmonary hypertension govern right ventricle remodeling and recovery.
Chronic thromboembolic pulmonary hypertension (CTEPH) leads to progressive right ventricular (RV) dysfunction. Pulmonary endarterectomy (PEA) is an established treatment for these patients; however, the molecular mechanisms underlying RV remodeling and recovery remain poorly understood. Here we show that RNA sequencing and histological analysis of RV free wall and septal biopsies from patients with CTEPH reveal extracellular matrix enrichment and cytoskeletal remodeling before PEA. These changes were consistent across an exploratory and confirmatory cohort. Post-PEA samples showed reversal of both histological and transcriptional abnormalities. Key signaling molecules-ANKRD1, IL7R and SERPINE1-were implicated in fibrotic and proliferative pathways, as confirmed in human tissues and experimental models. Our findings identify a reversible gene expression and structural remodeling signature in the RV, linking hemodynamic unloading with molecular recovery. These insights suggest potential therapeutic targets to modulate maladaptive RV remodeling in CTEPH and improve outcomes beyond surgical intervention.
2025-02-19 | Single-cell transcriptomic analysis reveals distinct plasma cell populations in chronic thromboembolic pulmonary hypertension.
Chronic thromboembolic pulmonary hypertension (CTEPH) presents challenges due to its complex pathobiology. Although numerous studies have reported heterogeneous cell types by single-cell RNA sequencing, the atlas and characteristics of plasma cells remain poorly understood. To identify the altered phenotype and differentiation patterns of plasma cells in CTEPH. We performed single-cell RNA sequencing on pulmonary endarterectomy tissue from 5 patients and 6 normal pulmonary arteries. Serum immunoglobulins (Igs) were measured using protein electrophoresis among 273 CTEPH patients, 259 idiopathic pulmonary arterial hypertension (IPAH) patients, and 251 healthy controls. The percentage of plasma cells was significantly increased from less than 1% in healthy controls to 15% in CTEPH patients. We identified 1 B cell cluster and 5 distinct mature plasma cell clusters, including IGHG1, HSPA1A, AHNAK, IGLC3, and IGKV4. Notably, the AHNAK and IGLC3 subclusters are newly identified. GeneSwitches analysis indicated early activation of IGHG1 and early deactivation of HLA-DPA1. The trajectory of AHNAK cluster was earlier than that of IGLC3 cluster, with an enrichment for pathways responsive to lipopolysaccharide. The IGLC3 cluster revealed lower differentiation potential and was predominantly associated with Ig production. Furthermore, Igα2 levels in CTEPH patients were lower than in controls but higher than in IPAH patients. Significantly, Igγ levels were markedly elevated in CTEPH patients compared with IPAH patients and controls, better distinguishing CTEPH patients from controls and IPAH patients. Plasma cells of CTEPH had a distinctive landscape and heterogeneity. The newly identified clusters represented excessive Ig production but lacked immune response function. These findings highlight that targeted plasma cells can be used to develop novel CTEPH treatments.
other
2025-02-27 | Rare variants inSTAB2in patients with chronic thromboembolic pulmonary hypertension
The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is poorly understood. Study of genetic risk factors for CTEPH is likely to improve our understanding of CTEPH pathogenesis, and may lead to novel treatment and prevention strategies. Genetic analysis focused on shared gene variants in high-risk disease pedigrees can aid in the identification of rare variants with a strong effect on disease risk. We identified 13 CTEPH high-risk pedigrees and performed whole exome sequencing in 22 CTEPH from these pedigrees cases, focusing on rare and deleterious variants that were shared between related CTEPH cases. We validated CTEPH candidate gene variants in two independent CTEPH cohorts, one from Utah (n=78) and one from University of California San Diego (n=238), and compared to controls from the UK Biobank. A rare and predicted deleterious missense variant in STAB2 was identified in two related CTEPH cases. Qualifying STAB2 variant alleles were observed more frequently in bothCTEPH cohorts (pooled allele frequency 4.6%) than in subjects from the UK Biobank with a history of PE (allele frequency 2.2%, p=0.0002) or without a history of PE (allele frequency 1.9%, p<0.0001). CTEPH subjects with qualifying STAB2 variants had elevated levels of plasma von Willebrand Factor (vWF) and Factor VIII, consistent with the known role of STAB2 as a genetic regulator of circulating vWF levels. Rare variants in STAB2 are identified in a CTEPH high-risk pedigree, and are over-represented in non-relatedCTEPH cases compared to controls with PE. These data suggest that STAB2 is a CTEPH risk gene.
2022-05-02 | LncRNA-GAS5/miR-382-3p axis inhibits pulmonary artery remodeling and promotes autophagy in chronic thromboembolic pulmonary hypertension.
We have clarified the role of miR-382-3p in chronic thromboembolic pulmonary hypertension (CTEPH), but what is less clear lies in its upstream regulatory mechanism. To explore the regulation mechanism of GAS5/miR-382-3p axis on CTEPH. In vitro, we constructed cell models by treating Pulmonary Artery Smooth Muscle Cells (PASMCs) with platelet-derived growth factor-BB (PDGF-BB). The effects of different concentrations of PDGF-BB on the activity of PASMCs were tested by cell counting kit-8 (CCK-8). The upstream lncRNA of miR-382-3p was screened and confirmed through bioinformatics analysis, RNA pull-down, quantitative reverse transcription polymerase chain reaction (qRT-PCR), dual luciferase reporter gene and RNA immunoprecipitation assays. The effects of GAS5/miR-382-3p axis on the viability, migration, and expressions of autophagy- and angiogenesis-related proteins were confirmed by rescue experiments (CCK-8, wound healing and western blot). In vivo, animal models by perfusing autologous blood vessels, the effects of GAS5 overexpression or silencing on the expressions of miR-382-3p, angiogenesis- and autophagy-related genes, mean pulmonary arterial pressure (mPAP) and pulmonary artery wall were determined by biological signal acquisition system, hematoxylin-eosin staining, qRT-PCR and western blot. PDGF-BB dose-dependently promoted PASMCs viability. XIST and GAS5 expressions in PASMCs were affected by the concentration of PDGF-BB, but only GAS5 can be pulled down by miR-382-3p probe. GAS5 targeted miR-382-3p to inhibit the viability and migration of PAMSCs, mPAP in CTEPH rats, pulmonary artery wall thickening and angiogenesis, and promote autophagy. GAS5/miR-382-3p axis is involved in the regulation of pulmonary artery remodeling and autophagy in CTEPH.
2022-04-04 | Epigenetic Modification of the von Willebrand Factor Promoter Drives Platelet Aggregation on the Pulmonary Endothelium in Chronic Thromboembolic Pulmonary Hypertension.
Rationale: von Willebrand factor (vWF) mediates platelet adhesion during thrombosis. While chronic thromboembolic pulmonary hypertension (CTEPH) is associated with increased plasma levels of vWF, the role of this protein in CTEPH has remained enigmatic. Objectives: To identify the role of vWF in CTEPH. Methods: CTEPH-specific patient plasma and pulmonary endarterectomy material from patients with CTEPH were used to study the relationship between inflammation, vWF expression, and pulmonary thrombosis. Cell culture findings were validated in human tissue, and proteomics and chromatin immunoprecipitation were used to investigate the underlying mechanism of CTEPH. Measurements and Main Results: vWF is increased in plasma and the pulmonary endothelium of CTEPH patients. In vitro, the increase in vWF gene expression and the higher release of vWF protein upon endothelial activation resulted in elevated platelet adhesion to CTEPH endothelium. Proteomic analysis revealed that nuclear factor (NF)-κB2 was significantly increased in CTEPH. We demonstrate reduced histone tri-methylation and increased histone acetylation of the vWF promoter in CTEPH endothelium, facilitating binding of NF-κB2 to the vWF promoter and driving vWF transcription. Genetic interference of NFκB2 normalized the high vWF RNA expression levels and reversed the prothrombotic phenotype observed in CTEPH-pulmonary artery endothelial cells. Conclusions: Epigenetic regulation of the vWF promoter contributes to the creation of a local environment that favors in situ thrombosis in the pulmonary arteries. It reveals a direct molecular link between inflammatory pathways and platelet adhesion in the pulmonary vascular wall, emphasizing a possible role of in situ thrombosis in the development or progression of CTEPH.
2019-07-30 | miRNA-PDGFRB/HIF1A-lncRNA CTEPHA1 Network Plays Important Roles in the Mechanism of Chronic Thromboembolic Pulmonary Hypertension
Our previous studies have revealed that long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and genes were abnormally expressed in the pulmonary artery tissues of the chronic thromboembolic pulmonary hypertension (CTEPH) patients. We aim to establish the CTEPH-related miRNA-gene-lncRNA network for finding the core genes and associated miRNA and lncRNA in CTEPH patients.Firstly, the target genes of differential miRNAs were predicted by searching TargetScan databases, and the predicted target genes were intersected with the mRNAs from the gene chip. Secondly, the intersective genes were analyzed by the Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway software for obtaining differential intersective genes and then establish the miRNA-gene networks. Thirdly, the possible genes regulated by the differential lncRNAs from the gene chip were intersected with the above-screened mRNA to build the lncRNA-mRNA networks. Subsequently, the miRNA-gene-lncRNA networks were constructed according to the two networks above (miRNA-gene networks and lncRNA-mRNA networks). Finally, the core genes of the networks in the experimental group were screened according to Diffk > 0.6 and used to construct the miRNA-core gene-lncRNA networks of CTEPH.The pathway network, miRNA-mRNA network, lncRNA-mRNA networks, and miRNA-gene-lncRNA networks were successfully constructed. The core genes of the miRNA-gene-lncRNA networks (Diffk > 0.6) were the human Beta-type platelet-derived growth factor receptor (PDGFRB) and hypoxia-inducible factor-1a (HIF-1A), the miRNAs-PDGFRB-lncRNAs and miRNAs-HIF1A-lncRNAs networks were constructed. Finally, miRNA-149-5p-PDGFRB-TCONS_l2_00020587-XLOC_l2_010723 and miRNA-338-5p/miRNA-199b-5p-HIF1A- TCONS_l2_00020587-XLOC_l2_010723 were found in the analysis of the network.miRNA-149-5p-PDGFRB-lncRNA CTEPH-associated 1 (CTEPHA1) (TCONS_l2_00020587-XLOC_l2_010723) and miRNA-338-5p/miRNA-199b-5p-HIF1A-lncRNA CTEPHA1 are related to the development of CTEPH.
2019-03-11 | Long non-coding RNA CASC2 suppresses pulmonary artery smooth muscle cell proliferation and phenotypic switch in hypoxia-induced pulmonary hypertension
In this study, we aimed to investigate whether and how lncRNA CASC2 was involved in hypoxia-induced pulmonary hypertension (PH)-related vascular remodeling. The expression of lncRNAs or mRNAs was detected by qRT-PCR, and western blot analysis or immunochemistry was employed for detecting the protein expression. Cell number assay and EdU (5-ethynyl-2′-deoxyuridine) staining were performed to assess cell proliferation. Besides, flow cytometry and wound healing assay were employed for assessments of cell apoptosis and cell migration, respectively. Rat model of hypoxic PH was established and the hemodynamic measurements were performed. Hematoxylin and eosin (HE) and Masson′s trichrome staining were carried out for pulmonary artery morphometric analysis. The expression of lncRNA CASC2 was decreased in hypoxia-induced rat pulmonary arterial tissues and pulmonary artery smooth muscle cells (PASMCs). Up-regulation of lncRNA CASC2 inhibited cell proliferation, migration yet enhanced apoptosis in vitro and in vivo in hypoxia-induced PH. Western blot analysis and immunochemistry showed that up-regulation of lncRNA CASC2 greatly decreased the expression of phenotype switch-related marker α-SMA in hypoxia-induced PH. Furthermore, it was indicated by the pulmonary artery morphometric analysis that lncRNA CASC2 suppressed vascular remodeling of hypoxia-induced rat pulmonary arterial tissues. LncRNA CASC2 inhibited cell proliferation, migration and phenotypic switch of PASMCs to inhibit the vascular remodeling in hypoxia-induced PH.
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Drug Discovery Landscape
17 orphan drug designations for Chronic thromboembolic pulmonary hypertension, including 2 approved therapies.
17 orphan drug designations for Chronic thromboembolic pulmonary hypertension, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Macitentan [Opsumit] | small molecules | EMA | Janssen Cilag International | |
selexipag | small molecules | FDA | Janssen Research & Development LLC | |
macitentan | small molecules | FDA | Actelion Pharmaceuticals Ltd. (a Janssen Pharmaceutical Company of Johnson and Johnson) | |
riociguat [Adempas] | small molecules | FDA | Approved | Bayer HealthCare Pharmaceuticals, Inc. |
Treprostinil sodium [Trepulmix] | small molecules | EMA | Approved | SciPharm Sàrl |
Lisuride hydrogen maleate | small molecules | EMA | Sinoxa Pharma GmbH | |
Riociguat [Adempas] | small molecules | EMA | Bayer AG | |
Treprostinil diethanolamine (oral use) | small molecules | EMA | Ferrer Internacional S.A. | |
Selexipag [Uptravi] | small molecules | EMA | [INACTIVE] Actelion Registration Limited | |
Ambrisentan [Volibris] | small molecules | EMA | [INACTIVE] Glaxo Group Limited | |
Sitaxentan sodium [Thelin] | small molecules | EMA | Pfizer Limited | |
Treprostinil sodium (inhalation use) | small molecules | EMA | United Therapeutics Ireland Limited | |
Sildenafil citrate [Revatio] | small molecules | EMA | Pfizer Limited | |
Beraprost sodium [Beradrak] | small molecules | EMA | Laboratoire Aventis | |
Bosentan monohydrate [Tracleer] | small molecules | EMA | [INACTIVE] Actelion Registration Limited | |
Iloprost [Ventavis] | small molecules | EMA | [INACTIVE] Bayer Pharma AG | |
Neutrophil-endothelial interaction inhibitor | small molecules | FDA | — | Cytel Corporation |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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