The Occult Cascade That Leads to CTEPH

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, progressive form of pre-capillary pulmonary hypertension characterized by persistent, organized thromboemboli in the pulmonary vasculature, leading to vascular remodeling, elevated pulmonary artery pressures, right heart failure, and significant morbidity and mortality if untreated. Despite advances, CTEPH remains underdiagnosed due to nonspecific symptoms and overlapping features with other forms of pulmonary hypertension. Basic Methodology: This review synthesizes data from large international registries, epidemiologic studies, translational research, and multicenter clinical trials. Key methodologies include analysis of registry data to assess incidence and risk factors, histopathological examination of lung specimens, and molecular studies investigating endothelial dysfunction and inflammatory pathways. Diagnostic modalities and treatment outcomes are evaluated through observational studies and randomized controlled trials. Recent Advances and Affected Population: Research has elucidated that CTEPH arises from incomplete resolution of pulmonary emboli, with subsequent fibrotic transformation mediated by dysregulated TGF-β/TGFBI signaling, endothelial dysfunction, and chronic inflammation. Affected populations are typically older adults, often with prior venous thromboembolism, splenectomy, or prothrombotic conditions, though up to 25% have no history of acute PE. The disease burden is substantial, with delayed diagnosis contributing to worse outcomes and higher societal costs. Microvascular arteriopathy and PAH-like lesions in non-occluded vessels further complicate the clinical picture. Conclusions: CTEPH is now recognized as a treatable disease, with multimodal therapies—surgical endarterectomy, balloon pulmonary angioplasty, and targeted pharmacotherapy—significantly improving survival and quality of life. Ongoing research into molecular mechanisms and biomarker-driven diagnostics promises earlier identification and more personalized management. Multidisciplinary care and continued translational investigation are essential to further reduce mortality and optimize outcomes for this complex patient population.

1. Introduction

Pulmonary hypertension (PH) is diagnosed in patients who have a mean pulmonary arterial pressure (mPAP) > 20 mmHg at rest, according to the proceedings of the sixth World Symposium on Pulmonary Hypertension, and affects approximately one percent of the population globally.

Pre-capillary PH is differentiated from post-capillary PH based on a PAWP (pulmonary artery wedge pressure) ≤ 15 mmHg and PVR (pulmonary vascular resistance) > 3 Woods Units. Pulmonary hypertension (PH) is classified into five clinical groups based on etiology and pathophysiology, as updated by the 2022 ESC/ERS guidelines. Group 1 [1]), pulmonary arterial hypertension (PAH), includes idiopathic, heritable, drug-induced, and connective tissue disease-associated forms, with a prevalence of 1–15 cases per 100,000 [1,2]. Group 2 PH occurs due to left heart disease and is the most common, accounting for up to 68% of PH cases. Group 3 is associated with lung diseases or hypoxemia (e.g., COPD, interstitial lung disease), comprising about 47% of cases. Group 4, chronic thromboembolic pulmonary hypertension (CTEPH), results in part from recurrent and unresolved pulmonary emboli leading to chronic vascular remodeling and occurs in 0.5–3% of PE survivors, but is often underdiagnosed due to nonspecific symptoms and a lack of utilization of standard diagnostics. Group 5 includes multifactorial or unclear causes such as hematologic or systemic disorders. The ESC/ERS 2022 update lowered the mean pulmonary arterial pressure threshold to ≥20 mm Hg and revised pulmonary vascular resistance criteria, emphasizing earlier diagnosis and nuanced risk stratification. Underdiagnosis is particularly problematic in CTEPH, where unlike other forms of PH, curative surgery is possible in these patients, underscoring the need for heightened clinical suspicion and improved screening for patients with CTEPH. CTEPH is a rare form of pre-capillary PH characterized by progressive pulmonary arteriopathy similar to other forms of pre-capillary PH, but uniquely characterized by pulmonary arteriolar obstruction from organized thrombi and a progressive vascular remodeling process and distal small vessel arteriopathy. CTEPH is driven by the combined mechanisms of inflammation, abnormal fibrinolysis, and endothelial dysfunction [3]. Without treatment, CTEPH, similar to other forms of pulmonary hypertension (PH), can lead to right heart failure and death. Recent translational and epidemiologic advances have reshaped our understanding of its mechanisms, risk factors, and therapeutic outcomes.

2. Epidemiology of CTEPH

CTEPH affects between three and thirty individuals per million globally, with 0.4–14.7% of acute pulmonary embolism (PE) survivors developing the disease. This broad diagnostic incidence can be attributed to several factors in the challenges in diagnostic accuracy. More than half of patients with CTEPH have no history of clinically apparent acute PE, and there is overlap with other conditions that resemble CTEPH symptoms including dyspnea and fatigue, which lead to delayed diagnosis of CTEPH. An additional challenge in the accurate description of CTEPH prevalence stems from the variability of the cohorts from which CTEPH incidence has been reported, since the included patient populations vary in the diagnostic methods used to define CTEPH as well as the heterogenous comorbidities of the index cohort (acute PE, race, cardiopulmonary disease, cancer, etc.) Registry data suggest that the prevalence of CTEPH is approximately equal in men and women, with an average age of onset in the sixth decade of life. Although CTEPH is thought to be only a direct sequela of chronic thromboembolic disease, a subset of patients diagnosed with CTEPH do not have a history or diagnosis of PE. In past registries, 25% of patients diagnosed with CTEPH did not have a formal diagnosis of acute PE [4,5,6]. In countries (France, Germany, Italy, Spain, the UK, the USA, and Japan) is expected to reach 37,009 cases, though only 28% may be diagnosed [7]). Underdiagnosis remains a critical issue, with a median diagnostic delay of 14 months from symptom onset. Delays in diagnosis can lead to the progression of the vessel remodeling and distal arteriopathy with worsening right heart dysfunction as a result of elevated pulmonary artery pressure (PAP). Historically, three-year mortality rates as high as 90% have been reported in patients with PAP > 50 mmHg [8,9].

One proposed reason for the underdiagnosis of CTEPH is the geographic differences in CTEPH populations, more specifically due to differences in healthcare systems [10]. For instance, in the United Kingdom, PH care is centralized, and patients must seek care at one of the eight certified PH centers. Once patients are established at one of the eight accredited centers, they are automatically entered into a national PH patient database. In countries where registries are not mandatory, national registries may not be fully representative and are likely underestimating patients. An international physician survey of CTEPH management practice reported that a relatively higher proportion of European patients than in the USA (43% versus 12%, respectively) were diagnosed with CTEPH in expert pulmonary hypertension centers [7]). Further, routine clinical practice between countries may influence the reported prevalence. Right heart catheterization (RHC) remains a gold-standard method for diagnosing and classifying PH. Ventilation/perfusion (V/Q) scans are the preferred initial radiologic test for CTEPH. However, in some countries, RHC or V/Q scans are unavailable or not systematically utilized, leading to misdiagnosis and underdiagnosis [11,12]. Other causes behind the underdiagnosis of CTEPH include a lack of clinical suspicion/underrecognition, a lack of an identifiable causative event and/or a lack of attribution of symptoms to CTEPH [7]. In 2015, the full annual incidence of CTEPH in France, Germany, Italy, Spain, the UK, the US, and Japan was estimated to be 32,636 cases; it was calculated that only 5334 (16%) of these cases were diagnosed. Another challenge is that CTPEH can be misdiagnosed as Group 1 pulmonary arterial hypertension (PAH) due to overlapping symptoms [4,13].

Nevertheless, as underdiagnosed as CTEPH is estimated to be, it is still associated with large societal costs. Societal costs were higher for CTEPH patients when compared to age, sex, and geographic area-matched control groups, which is thought to be most likely due to an overall productivity loss in the CTEPH patient population after diagnosis [14]. Additionally, the main cost drivers were prescribed drugs and hospitalizations for patients. Efforts are being made to reduce diagnostic delays when CTEPH is considered as part of a patient’s differential.

3. Affected Populations and Risk Factors

In general, there is a higher prevalence in patients aged 60–70 years, though idiopathic cases occur in younger populations [4,15]. Further, as previously mentioned, CTEPH disproportionately impacts individuals with acute pulmonary embolism (PE), with an estimated prevalence of 0.8–3.8% 2 years after the occurrence of acute PE. Even the symptoms present during the initial presentation of PE have been linked to the development of CTEPH, specifically right ventricular strain manifesting as elevated pulmonary artery systolic pressure. Recurrent events increase the risk of CTEPH 3-fold [6,8]. Other risk factors for the development of CTEPH include splenectomy, infected pacemakers, and ventriculoarterial shunts. Although PE is the primary cause of CTEPH, up to 62% of patients with proximal disease and 49% of those with distal disease have no history of acute PE, which can delay diagnosis in some cases [8,16]. See Figure 1 as a descriptive image of the above-discussed varied factors that lead to the development of CTEPH.

Pedigree analyses have identified families with multiple CTEPH cases, supporting the idea of a dominant inheritance pattern with incomplete penetrance [17]. These findings suggest that, while CTEPH is not a purely Mendelian disorder, genetic predisposition plays a significant role, and ongoing research is focused on identifying specific gene variants and inheritance patterns that contribute to CTEPH risk [18]. Typical hereditary risk factors for acute PE, such as Protein C deficiency, Protein S deficiency, and antithrombin deficiency, were found to be in higher prevalence in CTEPH patients (according to a CTEPH registry in the United States that examined 552 subjects) [19]. Antiphospholipid antibody syndrome, increased von Willebrand factor, and elevated factor VIII levels are known risk factors for developing CTEPH [1,19]. Finally, established comorbidities include chronic inflammatory states, splenectomy, hypothyroidism, thrombolytic therapy, and delayed diagnosis of PE [4,20].

The most recent epidemiologic data do not support the idea that general lifestyle factors such as diet and exercise increase the risk for chronic thromboembolic pulmonary hypertension (CTEPH). Instead, the evidence shows that certain lifestyle-related conditions—such as prolonged immobility during travel, hospitalization, or illness, obesity and tobacco usage—are established risk factors because they increase the risk of venous thromboembolism (VTE) [12], which can subsequently lead to CTEPH if a pulmonary embolism (PE) is not fully resolved.

4. Pathophysiologic and Molecular Mechanisms

Although the precise pathogenesis of CTEPH is not fully understood, it is thought to be a complication of acute (PE), when there is an incomplete resolution of pulmonary emboli, which then become organized into obstructive fibrotic material with an associated small vessel vasculopathy [1,2,20]. In the diseased vessel, there is an imbalance between clot formation and clot degradation, which initiates a cascade of macrovascular changes and ultimately alters the organization of the thrombus in the patient’s pulmonary vasculature. The non-resolved thrombi undergo endothelial-mediated fibrosis via TGF-β/TGFBI signaling, impairing fibrinolysis [13,21]. This remaining fibrotic material leads to systemic dysfunction of the vascular endothelium, increasing PVR with pulmonary vascular remodeling, and a permanent increase in pulmonary artery pressure, eventually leading to right heart failure [1,2,20]. Global dysfunction is also observed in the endothelial cells (ECs) in CTEPH which exhibit dysregulated angiogenesis, promoting aberrant vascular repair [13].

From a microvascular standpoint, a secondary arteriopathy develops in non-occluded vessels, resembling PAH-like changes. Specifically, there is medial hypertrophy of the muscularis layer of the pulmonary arterioles, concentric laminal internal fibroelastosis, and plexiform lesions. This observation of arteriopathy in the non-occluded vessels highlights two crucial points. First, it emphasizes the likelihood that there are some fundamental similarities between PAH and CTEPH on a mechanistic level. Second, the presence of vascular lesions in regions of the lung not affected by thrombotic disease suggests that systemic vascular mediators could provoke the development of these [4,21]. One proposed mechanism is that inflammation itself could affect the normal process of fibrinolysis as levels of C-reactive protein (CRP) and cytokines, such as interleukin-6 (IL-6), are elevated in CTEPH patients. The presence of inflammatory mediators such as CRP and IL-6 drives endothelial dysfunction and smooth muscle proliferation, affecting the process of angiogenesis [4]. A recent single-cell RNA sequencing analysis performed on surgically extracted clots from patients who had undergone pulmonary thrombendarterectomy (PTE) revealed and identified multiple cell types, including macrophages, T cells, and smooth muscle cells (SMCs), that constitute CTEPH thrombus. The identified macrophages were split into two categories, with the larger group characterized by an upregulation of inflammatory signaling through CD4+ and CD8+ T cells. This analysis presents CTEPH as a chronic inflammatory process promoted by the macrophages and T cells that drive smooth muscle cell-mediated vascular remodeling [22]. Historically, genetic or familial connections in CTEPH have not been established. The latest limited research indicates that familial CTEPH has a partially heritable, polygenic basis estimated at a frequency—defined as more than one case in a family—of about 2.2% [17], though this requires confirmation in larger cohorts. Classic hereditary thrombophilias such as Factor V Leiden and Prothrombin G20210A are less common in CTEPH patients than in those with acute PE, indicating that CTEPH may have some distinct genetic underpinnings that differentiate it from acute pulmonary embolism (PE) and deep vein thrombosis (DVT). Recent large-scale genome-wide association studies (GWAS) have identified multiple genetic loci associated with CTEPH, including ABO, FGG, F11, MYH7B, HLA-DRA, F2, TSPAN15, SLC44A2, and F5 [18]. Despite these genetic associations, CTEPH’s familial causes currently have a limited role in diagnostics and therefore have not translated to screening practices or clinical predictive algorithms.

While some BMPR2 mutations are found in CTEPH, these mutations are typically associated with PAH [4]. One study has demonstrated that patients with CTEPH had a higher frequency of mutations of known PAH-associated genes [23]. Additionally, only one familial case of CTEPH has been reported, suggesting that distinct pathways lead to the development of CTEPH [24].

5. Current Treatment Paradigm with Advances and Future Directions

Upon diagnosis, all patients with CTEPH should undergo a multidisciplinary review with a team comprised of a surgeon experienced in the CTEPH surgical procedures, a pulmonary hypertension specialist, an interventional cardiologist, and a radiologist to decide the optimal treatment strategy for the patient.

Surgical Evaluation pulmonary thrombendarterectomy (PTE) is the first-line treatment for CTEPH. Per current European Society of Cardiology (ESC) guidelines, pulmonary thrombendarterectomy (PTE) is the overall treatment of choice when a patient is an operable candidate. A crucial consideration for surgery is whether the disease burden can be effectively cleared by surgery. The procedure requires a cardiopulmonary bypass to redirect blood flow from the heart and systemic cooling at 20 °C. The pulmonary arteries are then opened and removed to allow for the complete visualization of the thrombotic material. Next, there is systemic rewarming, and the patient is taken off bypass and is sent to the intensive care unit for post-operative recovery. Currently, in CTEPH-certified centers, perioperative mortality rates are <2.5%. Post-operative pulmonary hypertension is seen in 25% of patients, but overall survival rates and long-term outcomes are favorable. PEA is curative for proximal disease, with 70.6% 10-year survival vs. 41.7% in inoperable cases [15,25].

Balloon Pulmonary Angioplasty (BPA) is an equivalent alternative to surgical treatment in non-operable CTEPH. ESC Guidelines state that balloon pulmonary angioplasty (BPA) is the selected treatment choice when patients are not operable candidates, or when patients have persistent or recurrent PH after PEA [1]. This procedure uses a balloon to open and dilate blood vessels with chronic blockages or narrowing due to embolic burden from CTEPH. Balloon dilation aims to restore adequate pulmonary blood flow and improve hemodynamics in distal disease, achieving 85% 3-year survival [12,26]. While BPA is a surgically less invasive procedure compared to a PEA, it has been associated with more severe post-procedure complications, including hypoxia due to lung injury (18 of 52 patients) and severe hypotension (two of 53 patients) [27]. Overall, BPA offers equivalent survival compared to surgical PTE, and superior functional gains based on six-minute walk testing compared to medical therapy alone. Of note, multiple sessions of BPA are often required to achieve maximal efficacy.

Medical Management of CTEPH: When patients are not eligible for surgical intervention, which occurs in approximately 40% of patients with CTEPH due to unattainable vascular obstruction, disproportionate morphological lesions, and significant comorbidities, medical therapy is the only alternative for the treatment of CTEPH patients [1,28]. In healthy patients, nitric oxide (NO) binds to soluble guanyl-cyclase (sGC), which then results in the production of cyclic guanosine monophosphate (cGMP), which promotes adequate pulmonary blood flow. In patients with PH, endothelial dysfunction impairs NO production and leads to pulmonary vasoconstriction. Riociguat is an oral medication and pulmonary vasodilator that increases the production of sGC and, ultimately, cGMP. cGMP then leads to vasodilation and improves pulmonary circulation [29]. While other pulmonary vasodilators are used in CTEPH management, riociguat is unique due to its FDA approval and demonstrated efficacy in improving exercise capacity and hemodynamics in CTEPH patients [30]. The other concurrent non-surgical management is lifelong anticoagulation, including non-vitamin K antagonist oral anticoagulation (NOACs) or vitamin K antagonists (VKAs) [11]. Additional therapies include supplemental oxygen, diuretics, and pulmonary rehabilitation as part of a strategy to improve functional class and reduce time to clinical worsening [31].

Recent meta-analyses and registry data (2021–2024) reveal significant differences in survival, hemodynamic outcomes, and safety profiles for CTEPH treatments. Among the options of PTE, BPA, and medical management discussed previously, surgical treatment with PTE offers the highest long-term survival (89% at 3 years) but carries surgical risks, especially in low-volume centers (24.4% composite complications vs. 12.1% in high-volume centers) [32]. BPA offers a near-equivalent survival to PTE with lower perioperative mortality [12,33]. Medical therapy alone offered no survival benefit and should be used primarily for inoperable patients or as an adjunctive therapy [12]. Recent studies have shown an overall improvement in survival rates due to multimodal therapies, resulting in a 93% 5-year survival in the current era versus a 68% 5-year survival pre-2000 [28]. Further, combination therapies of sequential PTE/BPA with riociguat reduce residual PH severity [11,26,28]. In general, earlier diagnosis and implementation of these multimodal therapies have reduced the number of late-stage presentations of CTEPH patients. For example, 63% of patients were diagnosed with CTEPH at the New York Heart Association Functioning Class (NYHA FC) III/IV at diagnosis in 2025, versus 72% of patients in 2015 [7,26]. In summary, PTE remains curative for operable CTEPH, while BPA offers comparable long-term survival in selective patients with fewer procedural risks for distal disease. Medical therapy provides palliative benefits with some hemodynamic improvements, but lacks disease-modifying efficacy. Treatment selection must be individualized through multidisciplinary assessment, prioritizing center expertise and anatomic suitability.

6. Recent Research and Future Pathways for Treatment

Biomarker research is underway, evaluating the transforming growth factor–beta induced (TGFBI) protein in distinguishing CTEPH from other types of PH that present with similar clinical features. One study identified endothelial cell phenotype alterations and the induction of TGF-b signaling as a mechanistic contribution to thrombus non-resolution and fibrosis, and identified TGFBI as a specifically up-regulated endothelial marker and a possible causal factor in the pathogenesis of CTEPH [13]. New strategies are currently underway to target known pathways implicated in CTEPH. Single-cell RNA analysis has new approaches for pharmacologically targeting CTEPH as an inflammatory process (similar to atherosclerosis) modulated through macrophage and T cell-driven vascular remodeling [22]. Another pathway suggested by preclinical models is through TGFBI inhibition, which enhances thrombus resolution and helps to decrease CTEPH [13]. This study is promising in that creating biomarker-guided screening, specifically for plasma TGFBI, fibrinogen variants, and microRNA profiles, may enable early diagnosis [4,13].

7. Conclusions

CTEPH has fully evolved from a previously fatal prognosis to a treatable condition, with survival now exceeding 90% at 5 years. Multimodal therapies—surgical endarterectomy, balloon pulmonary angioplasty, and targeted pharmacotherapy—have significantly improved survival and quality of life. Ongoing research into molecular mechanisms and biomarker-driven diagnostics promises earlier identification and more personalized management. Translational research highlights TGF-β/TGFBI as pivotal therapeutic targets, while epidemiologic data underscore the urgency of early detection initiatives. Multidisciplinary care and continued translational investigation are essential to further reduce mortality and optimize outcomes for this complex patient population. Future breakthroughs will hinge on unraveling the molecular drivers of thrombus persistence, and expanding access to multidisciplinary care networks, particularly in underserved populations.