Global research trends on chronic thromboembolic pulmonary hypertension: a bibliometric analysis (January 2000–January 2024)

Introduction

Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease characterized by organized thrombus obstruction in the major pulmonary arteries along with peripheral microvasculopathy in non-occluded areas, which can lead to decompensation of the right heart and death (1). Survival among untreated patients remains poor when the mean pulmonary arterial pressure (mPAP) is >40 mmHg, and the 5-year mortality rate is as high as 70% (2,3). Over the last two decades, remarkable improvements in survival among patients with CTEPH have been observed because of the introduction of novel treatment strategies, including pulmonary endarterectomy (PEA), pulmonary arterial hypertension (PAH)-targeted medicine, and balloon pulmonary angioplasty (BPA). PEA is considered a definitive and potentially curative therapy for CTEPH. Recent advancements in surgical techniques and instruments allow distal endarterectomy, making surgery the treatment of choice, even for patients with segmental or distal diseases. For patients who are ineligible for PEA or have residual pulmonary hypertension (PH) after PEA, BPA (4) the alternative interventional treatment, and PAH-targeted medicine (5) serve as the treatment of choice, with increasing supportive evidence. With the rapid evolution of medicine, techniques, and instruments, and the setting of more international prospective registered studies, the exploration of the uncertainties in the pathogenesis of CTEPH is essential to track the development and evolution of knowledge in CTEPH and guide clinical practice and future research. To date, there is a lack of research examining research hotspots and future trends in the field of CTEPH. To explore major areas and promising research directions, we aimed to perform a bibliometric study on CTEPH over the past two decades and provide an overview of studies on CTEPH.

Methods

Literature search

The Science Citation Index (SCI) Expanded and Social Sciences Citation Index (SSCI) database of Web of Science Core Collection (WoSCC) was used to retrieve data. Literature retrieval was performed on a single day (February 14, 2024) to avoid deviations and changes in citations due to rapid database renewal. The period for publications used in the current study was set from January 1, 2000, to January 31, 2024. The search terms were as follows: TS = “chronic thromboembolic pulmonary hypertension”. In terms of the publication type, only original articles and reviews written in English were included.

Data collection and cleaning

Two researchers independently conducted the primary data search and discussed potential discrepancies. Extraction of publishing characteristics from the database was performed comprehensively, including the number of papers and citations, H-index, year of publication, country/region, affiliations, authors, journal name, references, and keywords. Subsequently, we excluded duplicate studies, authors, and spelling errors. The original data were independently checked by two reviewers for duplications and potential errors to avoid inaccuracies due to varied citation versions.

Statistical analysis

Bibliometric indicators include the number of papers and citations that are frequently used to represent bibliographic material. The number of publications (Np) used to measure productivity and the number of citations without self-citations (Nc) used to represent the study impact were the two main indicators for evaluating the level of research. The H-index incorporates both productivity and impact by identifying the threshold connecting Np and Nc. The impact factor (IF) derived from the latest version of Journal Citation Reports (JCR) is widely viewed as a crucial metric of the quality and impact of medical journals. Bibliometric maps were generated using VOSviewer to obtain comprehensive information on co-authorship, co-occurrence, and co-citation analysis as previously described (6). CiteSpace 6.3.1 extracted the citation burst analysis of co-cited keywords. Additionally, R-bibliometrix was used for keyword extraction and historical citation graph analysis.

Results

Bibliometric analysis of publications on CTEPH

Overall, 3,856 publications were identified by searching the WoSCC. The titles, abstracts, and keywords of the articles were manually screened and filtered. Full texts were checked, if necessary. Finally, 2,264 publications were analyzed in our bibliometric analysis, with 1,592 literatures excluded. The detailed screening procedure is shown in Figure 1.

Figure 1 Flowchart of the screening process.

After screening the original article and review publications, the final number of CTEPH-related research documents published from January 1, 2000, to January 31, 2024, was 2,264. The total Nc for the retrieved articles was 56,067, and the mean Nc per article was 36.14. The H-index of all the publications was 118.

Historical overview

Figure 2 shows the annual Np from 2000 to 2024. The number of annual publications increased drastically from 14 in 2000 to 199 in 2023, with a peak in 2022.

Figure 2 Curve fitting of the total annual growth trend of publications (R²=0.6188). Np, number of publications.

Contributions of countries/regions and institutions to global publications

The top 10 countries with the most publications are listed in Table 1. The top five countries/regions with the highest Np were the USA, Germany, Japan, England, and China; the USA and Germany also had the highest H-index and Nc. The country collaboration network of CTEPH is illustrated in Figure 3. Consistent with the United States having the greatest publication contribution, it cooperated the most with other countries/regions, predominantly European countries/regions, including Germany, England, and France. Recently, China has been actively engaged in various research collaborations with many countries.

Figure 3 Overlay visualization of country/region cooperation analysis according to the average time of appearance. The circles indicate different countries/regions, the color represents the average year, the area of the circle represents the number of citations in each country or region, the distance indicates the correlation between each country/region, and the thickness of the connecting line indicates the strength of co-authorship cooperation. Countries/regions in yellow appeared later than that in blue.

The top 10 institutions with the highest yields are listed in Table 2. The University of California System had the most publications [166] and the highest H-index [52]. Assistance Publique-Hopitaux de Paris had the highest Nc [19,549] despite a fourth Np and third H-index ranking. Among the top 10 highest-yield affiliations, 40% were from France, 20% from the USA, and 20% from Germany.

Analysis of authors

Table 3 presents the top 10 authors with the most publications. Mayer (Kerckhoff Clinic, Bad Nauheim, University of Giessen, Germany) had the highest Np and H-index. Ghofrani HA (Justus Liebig University of Giessen, Germany) had the highest Nc (15,351) despite a relatively low Np (ranking 8^th).

Figure 4 depicts the collaborations among the authors, illustrating several leading research groups. Consistent with the ranking of the top 10 prolific authors, these researchers led major research groups, including Mayer et al., Pepke-Zaba et al., and Tanabe et al. European researchers collaborated closely with each other; however, they had little cooperation with Japanese researchers, who also led one of the most influential research groups.

Figure 4 Mapping author co-authorship on CTEPH publications. The size of the circles represents the co-authorship frequency of authors. The line between the two circles represents established the collaboration between the two authors. The thickening of the line represents the collaboration degree between the two authors. CTEPH, chronic thromboembolic pulmonary hypertension.

Analysis of journals

Table 4 lists the top 10 journals with the largest Np. Approximately 14.4% of the papers (325 publications) were published in the top 10 academic journals relating to respirology. Approximately 4.90% of the papers (111 publications) were published in the top 10 academic journals relating to cardiology. In total, 24.4% (553 publications) were published in top academic journals. Pulmonary Circulation ranked first in terms of the Np, whereas the Nc [1,296] and H-index were relatively low, ranking 3^rd along with the lowest IF in the top 10 [2.2]. The European Respiratory Journal ranked second in terms of the Np [75], with the highest H-index, Nc [7,543], and IF [24.9]. The Chest had the third-highest Np [56] and the second-highest H-index, IF [10.1], and Nc [6,236].

Highly cited papers and historical evolution of CTEPH research

Table 5 presented the top 10 papers in the field of CTEPH with citations ranging from 5,338 (2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension) to 656 (pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives).

Of the top 10 highly cited papers, half were articles, and half were reviews. Of the top 10 cited reviews, 2 focused on venous thromboembolic disease, which is an essential risk factor for CTEPH, and 3 summarized the pathophysiology, diagnosis, treatment, and prognosis of CTEPH. The three most cited articles were published in the New England Journal of Medicine, with over 1,000 citations. Two of the most cited articles were concerned with the treatment of CTEPH. The remaining studies focused on the development of CTEPH after venous thromboembolism (2 articles) and the clinical characteristics of CTEPH (1 article).

We further analyzed the historiography of CTEPH research to understand the publications that were important in the history of the discipline (Figure 5), which are shown in Table 6; we found that significant papers in the field were published from 2011–2019.

Figure 5 Historiography of CTEPH publications. Each node represents a paper, and the size of each node corresponds to the total number of citations. The edge between the two nodes indicates that the new paper directly cites the earlier paper. CTEPH, chronic thromboembolic pulmonary hypertension.

In 2001, an influential review was published by the New England Journal of Medicine (7). This study focused on PEA procedures and postoperative complications. Subsequently, in 2004, Dartevelle et al. (8) elaborated on the four stages of PEA and emphasized that PEA was a viable option for operable patients. Additionally, a prospective long-term follow-up study published in 2004 reported the incidence of CTEPH, suggesting that CTEPH was common after pulmonary embolism (PE) (9).

In 2006, the review written by Hoeper et al. (10) pointed out that pulmonary vascular remodeling is an important part of the pathophysiological mechanism of CTEPH and suggested that randomized controlled trials (RCTs) should be conducted to determine the role of medical therapies targeting small-vessel arteriopathy. Based on this review, a double-blind, randomized, placebo-controlled study published in 2008 found that the medication, bosentan, improved hemodynamics but did not improve the exercise capacity of patients with inoperable CTEPH or persistent/recurrent PH after PEA (11). In 2008, another study found that PEA had a good long-term prognosis for patients with CTEPH and that disease-modifying therapy improved the prognosis of inoperable patients (12).

Several studies reported the clinical features of CTEPH in 2009 and 2011. One study examined the risk factors of CTEPH and found that thyroid replacement therapy and a history of malignancy were associated with new medical conditions (13). Pepke-Zaba et al. (14) delved into the characteristics of CTEPH, noting that thrombophilic disorders were more prevalent among operable patients, while splenectomy and cancer were more prevalent among inoperable patients.

Since 2011, more influential papers in this field have been published than in the previous decade. Two studies (15,16) on the outcomes of CTEPH were published in 2011 and 2012, respectively, further indicating that PEA can significantly improve the prognosis of patients with CTEPH and that preoperative exercise capacity and postoperative pulmonary vascular resistance (PVR) are correlated with a 1-year mortality rate. Three studies conducted by Japanese researchers on the use of BPA for CTEPH were published in 2012 (17-19). Kataoka et al. (17) suggested that BPA could treat narrow distal lesions that cannot be reached by PEA with tolerable complications. Sugimura et al. (18) further improved the BPA technique using optical coherence tomography (OCT) and adopted a phased treatment strategy for pulmonary vascular lesions, which significantly improved hemodynamics in patients with CTEPH. The refined BPA technique proposed by Mizoguchi et al. (19) significantly improved hemodynamics and reduced the occurrence of pulmonary perfusion injury by using intravascular ultrasound (IVUS) to evaluate the diameter of the target pulmonary artery in a staged fashion over multiple separate procedures. In addition, in 2013, a review offered an exhaustive summary of the diagnosis and treatment modalities, primarily focusing on PEA and (PAH)-targeted medicine, pertinent to CTEPH (20).

Since 2013, significant progress has been made in our understanding of CTEPH pathophysiology. Pulmonary vascular remodeling is due to infection, immune phenomena, inflammation, circulation, and vasculature during CTEPH development (21). This improved understanding has fostered a substantial increase in research directed towards the development of novel PAH-targeted therapies for CTEPH. An influential RCT study called CHEST-1 was published in the New England Journal of Medicine and revealed that riociguat resulted in a significant improvement in exercise capacity and PVR in patients with CTEPH (22). Based on this study, riociguat became the first-line therapy for inoperable CTEPH and residual disease after PEA.

The most cited paper in this field (23), titled “2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension”, was published in 2016 in the European Heart Journal and ranked first with 5,338 citations. This review comprehensively summarizes relevant content on the diagnosis and treatment of CTEPH, provides an extremely important reference value for experts and scholars in the field, and further promotes the development and progress of CTEPH. Subsequently, in 2016, two studies (24,25) on the long-term prognosis of CTEPH were published, highlighting favorable outcomes in patients treated with PEA. Furthermore, these studies revealed that a significant proportion of both surgical and non-surgical patients with CTEPH were prescribed PH-targeted therapies. Additionally, a review published in 2017 suggested that small vessel abnormalities play a vital role in the pathophysiology of CTEPH (26). Based on previous studies, novel treatment algorithms have been developed, including the criteria for PEA, BPA, and new PAH-targeted drugs. In 2019, a review highlighted that this novel algorithm facilitated fluidity between these therapeutic modalities as information and expertise were progressively obtained (1).

Analysis of research hotspots

Figure 6 depicts the keywords extracted from the titles and abstracts of 2,264 papers analyzed using VOSviewer. The 107 keywords, which occurred more than 24 times among 5,158 keywords, were divided into 6 clusters (Figure 6A): PE development to CTEPH (yellow), diagnosis (green), PEA and BPA (light blue), pathophysiology (purple), medical treatment (blue), and right ventricular function (red). Figure 6B shows the visualization of keywords according to the average publication year. Recent hotspots with relatively a relatively high frequency of occurrences include riociguat, BPA, dual-energy computed tomography (DECT), and right ventricular function. Figure 6C shows the evolution of the keywords studied over time. In the last 5 years, vasoconstriction associated mechanisms of CTEPH in various pathways such as vasoconstrictor endothelin-1 (ET-1), and vasodilators, such as nitric oxide (NO) and its downstream mediators, cyclic guanosine monophosphate (cGMP), and prostacyclin (PGI₂) have received considerable attention. In addition, novel diagnostic imaging methods and therapy measures (BPA and riociguat) were studied. Future research is likely to focus on investigating specific mechanisms of pulmonary microvascular remodeling in CTEPH, novel and highly accurate diagnostic methods, and related novel treatments. Figure 7 shows the top 50 keywords. During the first 10 years of the study period, the hotspots were PEA, angiography, and medical treatments using epoprostenol, iloprost, bosentan, and sildenafil.

Figure 6 Distribution of keywords. (A) Clustering map of keywords. (B) Clustering map of keywords according to the average time of appearance. Keywords in yellow appeared later than that in blue. (C) Trend of keywords over time and duration of study. The square size reflects the co-occurrence frequencies; the link indicates the co-occurrence relationship; the thickness of the connecting line indicates the strength of the keywords co-occurrence link.

Figure 7 Top 50 keywords with the strongest citation bursts. The blue bars mean the reference had been published; the red bars represent citation burstness. Created with Figdraw (www.figdraw.com) and biorender.com (https://biorender.com/).

Discussion

In this bibliometric study, we summarized study trends, top institutions, leading researchers, influential studies, research trends, and hotspots in the field of CTEPH to provide researchers with an overview of CTEPH and guide future studies. According to the trend-fitting curve, the annual publication volume generally showed an upward trend, especially after 2016, and annual publications presented a significantly increased production slope over time, indicating an increasing amount of attention being paid to this area.

In the last two decades, the number of studies on CTEPH increased 10 times, indicating an increased awareness of the screening and diagnosis of CTEPH. Given the essential causal relationship between thrombosis and CTEPH, two of the most cited studies focused on the development and prevention of CTEPH after venous thromboembolism (9,27). In addition, we found a relatively high percentage of publications in top academic journals, especially in respirology and cardiology journals. Parallel to increased detection, the survival of patients with CTEPH has also improved significantly due to the introduction of PEA, PAH-targeted medicine, and BPA. The application of these innovations has created a new era in CTEPH management, which also accounts for the growth of high-quality studies on CTEPH (28).

The USA was the most prolific country in publications on CTEPH research, and it also had the most influential institutions in the field of CTEPH, including the University of California System and the University of California San Diego. The University of California San Diego, which is the pioneer of PEA, developed and refined the surgery over the last few decades (16,24,29), making CTEPH potentially curable and improving its 10-year survival to 72% (15). Since then, an increasing number of countries have engaged in learning and performing PEA from the University of California San Diego, making the USA the most frequently collaborating country in the world, and promoting a boom in research on PEA during the last two decades.

Japanese researchers also played an essential role in the treatment of CTEPH by refining BPA and establishing safer and more effective treatment strategies (19,30). The introduction of refined BPA reduced perioperative complications and improved the 3-year survival rate to 94.5% (30), encouraging both doctors and patients who are not suitable for PEA or have residual PH after PEA. Since then, BPA has become a novel hotspot of CTEPH and has contributed to the bloom of research on CTEPH.

Keyword co-occurrence analysis was used to identify and classify current and future research trends pertaining to CTEPH. This analysis identified six primary clusters of studies on these topics, which is briefly shown in Figure 8.

Figure 8 An overview of the six clusters of keyword analysis. The keyword analysis identified six primary clusters: risk factors of CTEPH after acute PE (cluster 1), pathophysiology of CTEPH (cluster 2), imaging diagnosis and evaluation of CTEPH (cluster 3), treatments of CTEPH (clusters 4 and 5), and right ventricular function in CTEPH (cluster 6). CTEPH, chronic thromboembolic pulmonary hypertension; PE, pulmonary embolism; PEA, pulmonary endarterectomy; BPA, balloon pulmonary angioplasty; PAH, pulmonary arterial hypertension.

Cluster 1: risk factors of CTEPH after acute PE

Several studies have revealed the risk factors and diseases associated with CTEPH. Circulating factor VIII, antiphospholipid antibodies, and lupus anticoagulants are elevated in patients with CTEPH (31-33). Alternatively, old age, non-O blood groups, thyroid replacement, malignancy, antiphospholipid syndrome, and splenectomy are common in patients with CTEPH (32,33). Although there is some understanding of the risk factors of CTEPH in this area, the depth of research is insufficient to fully reveal the risk factors of CTEPH. Based on current knowledge, the occurrence of CTEPH is likely not caused by a single risk factor but by a combination of factors (34). A majority of the current studies are small-sample retrospective studies, rendering their evaluation of effectiveness vulnerable. Hence, further prospective large-scale cohort studies are required to identify the risk factors for CTEPH.

Recently, proteomics has emerged as a popular topic in medical research (35), which plays a crucial role in elucidating disease-associated protein alterations and providing essential biomarkers for diagnostic and prognostic applications (36). Given their broad application in the study of biomarkers for various diseases, proteomic methodologies are expected to explore novel biomarkers associated with CTEPH.

Cluster 2: pathophysiology of CTEPH

Our understanding of the pathophysiological mechanisms underlying CTEPH remains limited. The underlying pathogenesis is primarily attributed to incomplete thrombus dissolution and pulmonary microvascular remodeling (34).

Through chronological analysis, it was found that inflammation has recently drawn more attention. Chronic inflammation plays a critical role in the pathogenesis of CTEPH (37). Multiple inflammatory factors are involved in the process. Plasma and thrombotic tissue samples obtained from patients with CTEPH show signs of inflammation (38,39). Elevated levels of various inflammatory mediators such as C-reactive protein (CRP), interleukin-6 (IL-6), interferon-gamma-inducible protein 10 (IP-10), C-C motif chemokine ligand 5 (CCL5), matrix metalloproteinase-9 (MMP-9), have been detected in the plasma of these patients (38). Furthermore, inflammatory cells, such as macrophages, T lymphocytes, and neutrophils, have been observed predominantly in atherosclerotic and thrombotic lesions (39). Endothelial cells promote vasodilation, fibrin dissolution, and anticoagulation by inhibiting white blood cells (WBCs) and platelet activities. After thrombosis, WBCs stimulate the fibrinolytic system and angiogenesis. Inflammation induces abnormal vasoconstriction and accelerates vascular remodeling. An in-depth exploration of the role of chronic inflammation in CTEPH will augment our understanding of its pathogenesis and subsequently provide novel approaches and therapeutic strategies for the management of this disease.

Based on the trend analysis of keywords, vasoconstriction, vasoconstrictor and mediators, all of which are closely associated with pulmonary endothelial cells, have become the recent research focus. While the determinants of pulmonary microangiopathy in CTEPH remain undetermined, an expanding corpus of research indicates that dysregulated pathways linked to endothelial dysfunction may be critically involved (40). Alterations in the structural and functional integrity of pulmonary vascular endothelial cells (PVECs) result in the decreased secretion of endogenous vasodilators, such as NO and its downstream mediators, cGMP, and PGI₂. In contrast, the release of ET-1 and thromboxane A2 (TXA₂) is often enhanced. ET-1, secreted by PVECs, functions as a potent vasoconstrictor peptide and a mitogen for smooth muscle cells. It exerts a substantial influence on the microangiopathy-induced smooth muscle cell hyperproliferative phenotype (41). NO functions as a vasodilator in conjunction with ET-1 to maintain normal vascular tone. NO and its second messenger, cGMP, also play significant roles in reducing leukocyte aggregation and activation (42), platelet adhesion and aggregation, as well as the proliferation and migration of vascular smooth muscle cells (43). Additionally, PGI₂, synthesized by PVECs, serves as another critical vasodilator and is among the most potent endogenous inhibitors of platelet aggregation (40). Building on the findings of this study, subsequent research on the mechanisms underlying CTEPH will increasingly focus on elucidating the role and potential molecular pathways of the pulmonary endothelium in the development of pulmonary microvasculopathy.

Cluster 3: imaging diagnosis and evaluation of CTEPH (green)

Interventional pulmonary angiography is traditionally considered the gold standard for CTEPH diagnosis, as it can accurately identify the presence, location, and degree of embolisms (44). Right heart catheterization (RHC) is the reference standard for hemodynamic diagnosis of CTEPH. Angiography also facilitates the immediate measurement of RHC hemodynamic parameters, aiding in the evaluation of PEA feasibility and BPA treatment outcomes (45). Nevertheless, the invasive nature of interventional pulmonary angiography may lead to potential complications, which significantly restricts its clinical application and limits its suitability for long-term clinical follow-up evaluation.

Ventilation/perfusion (V/Q) scintigraphy is currently the preferred method for the initial screening of CTEPH (45). However, positive V/Q findings alone do not provide sufficient diagnostic accuracy, necessitating the corroboration of additional cross-sectional imaging to accurately diagnose and delineate the anatomical extent of the disease (46). Recently, the integration of V/Q scintigraphy and single-photon emission computed tomography (SPECT) has gained traction for CTEPH diagnosis and evaluation (47). This technique incorporates the lung perfusion plane image into the anatomical image generated through computed tomography (CT) to significantly depict the anatomical structure, augment the precision in localizing the perfusion area, and identify additional sub-segmentation and peripheral PE. Although V/Q SPECT can detect a greater number of segmental or subsegmental filling defects, it also presents a certain probability of false positives, potentially because the tomography images generated by SPECT represent local sections rather than comprehensive sections, and its accuracy can be influenced by defects in the pulmonary interlobular fissure and other potential variables (48). The diagnostic efficacy of V/Q SPECT requires substantial validation in large-scale prospective studies.

Computed tomography pulmonary angiography (CTPA) is pivotal for the diagnosis of CTEPH. However, pulmonary thrombosis below the lung segment may not be discernible, potentially leading to a missed diagnosis (45). DECT is a relatively novel technology that addresses this issue and enhances the diagnostic potential of CTPA for CTEPH. DECT is an innovative technique that combines angiography and pulmonary perfusion information within a single scan (45,49). This technology can provide the material decay characteristics of multiple single energies and calculate the pulmonary perfusion blood volume through the iodine distribution map of the lung parenchyma, thereby evaluating pulmonary blood perfusion in individuals with CTEPH (49). Additionally, DECT can significantly improve the detection rate of chronic peripheral pulmonary emboli and can serve as a reliable tool for assessing pulmonary blood perfusion (45).

Molecular imaging (MI) is a recent discipline that has emerged with the rapid advancements in the life sciences. This field integrates medical imaging and molecular biology technologies, using diverse molecular probes within the forefront of science to achieve noninvasive visualization of specific or even single cells and molecules through several imaging modalities, including magnetic resonance imaging, CT, nuclide imaging, positron emission tomography, ultrasonic imaging, and optical imaging (50). The primary advantage of MI is its potential to detect diseases in their earliest stages before any morphological alterations, which holds significant potential for understanding the occurrence, progression, and outcome of diseases and for evaluating the efficacy of therapeutic agents (51). A phase II clinical trial involving molecular SPECT of the pulmonary vascular endothelium using ⁹⁹mTc-PulmoBind in patients with PH has recently been completed (52). The findings from this trial highlight the favorable safety profile of the imaging technique and its potential value in diagnosing PE and revealing the pathological changes associated with pulmonary vascular disease (52). Previous studies have provided valuable insights into the potential utility of MI by employing ⁶⁸Ga-labeled fibroblast activation protein inhibitors in patients with CTEPH (53,54). With advancements in science and technology, the use of MI holds significant potential for advancing CTEPH research.

Clusters 4 and 5: treatments of CTEPH

The primary interventions for CTEPH are PEA, BPA, and PAH-targeted medicine. Through chronological analysis, BPA and a novel medicine similar to soluble guanylate cyclase, riociguat, has drawn more attention recently, while PEA was the hotspot of the first decade of the 20^th century. PEA is the only feasible therapeutic approach with the potential to induce a definitive cure for patients with CTEPH. It is important to evaluate the feasibility of PEA in expert centers to maintain a postoperative mortality rate below 5% (23,55). Nevertheless, up to 51% of patients experience persistent or recurrent PH after PEA (24). For these patients, sequential BPA or a combination of PAH-targeted medicines may offer promising treatment options.

BPA is an interventional catheterization technique guided by angiography. This technique was first studied and described in 1988 (56). However, its application in CTEPH is hindered by the high incidence of postoperative reperfusion pulmonary edema (57). Notwithstanding, significant progress has been achieved over the past decade. In 2012, Japanese experts introduced a modified BPA methodology employing smaller balloons to perform fractionated expansion stages in succession (17-19). The use of pressure guidewires and OCT has enabled more precise guidance for BPA treatment, leading to a reduction in the rate of postoperative pulmonary edema to 2% (18). This has led to the widespread global adoption of BPA in clinical settings. In 2015, the ESC/ERS recommended BPA as a potential treatment option for patients not eligible for PEA (23). In 2022, The Lancet Respiratory Medicine published the findings of two multicenter RCTs that directly compared BPA and riociguat (58,59). These studies have demonstrated that the most common complication of modified BPA is pulmonary artery injury. Consequently, BPA is endorsed for performance in centers with extensive experience. The ESC has recently released a new consensus and statement on BPA, providing insights into patient selection, surgical planning, techniques, treatment outcomes, complications, management, and follow-up. The new consensus and statement is expected to help clinicians and researchers in making informed decisions about BPA treatment (60).

Medications specifically designed for the treatment of PAH have gradually transitioned into the integral aspect of CTEPH therapy. Currently, the use of PAH-targeted medicine for CTEPH is limited to inoperable patients and those experiencing persistent or recurrent PH postoperatively. Riociguat, a representative drug in the guanylate cyclase agonist family, is the only agent approved for the treatment of CTEPH. It functions independently of NO levels, directly stimulating guanylate cyclase to enhance the production of cyclic guanosine phosphate within smooth muscle cells, thereby manifesting anti-fibrotic, vasodilation, anti-proliferative, and anti-inflammatory properties. The pivotal multicenter, randomized, double-blind phase III trial, known as CHEST-1, demonstrated notable improvements in the 6-minute walk distance (6MWD), PVR, N-terminal pro-brain natriuretic peptide, and World Health Organization functional class in patients treated with riociguat compared to those receiving placebo (22). CHEST-2, a subsequent open-label extension clinical trial, further recruited CHEST-1 participants to evaluate the safety and efficacy of long-term riociguat use (61). RCTs that assess the combination of targeted drugs from different pathways and head-to-head comparisons of targeted drugs from diverse pathways are yet to be conducted. However, these areas require further investigation.

Interdisciplinary team collaboration and the comprehensive application of multiple treatment methodologies are expected to emerge as a novel trend in the forthcoming era of research.

Bridge therapy before PEA

Previous studies have established a significant correlation between preoperative hemodynamic parameters of preoperative pulmonary artery pressure and PVR and postoperative mortality in patients with CTEPH. However, the use of bridging PAH-targeted medicine before PEA is usually evaluated in patients with relatively severe disease. In this context, it is possible to delay surgery in these patients (62). Moreover, PAH-targeted drugs may alter thrombus properties, such as augmentation of the vascular wall and thrombo-fragility (25). These factors have potentially resulted in failed studies investigating the benefits of bridging targeted drugs in patients prior to surgery and increased mortality rates (25).

Bridge therapy before or after BPA

The findings of the study conducted by Wiedenroth et al. demonstrated that sequential BPA with riociguat treatment was more effective in improving cardiac function, PVR, and 6MWD compared to 12 weeks of riociguat monotherapy (63). Aoki et al. conducted a study that revealed that sequential BPA treatment with riociguat resulted in significant improvements in cardiac output and PVR compared with BPA monotherapy (64).

Additionally, a new cutoff of mPAP >20 mmHg has been proposed for the diagnosis of PH (65). However, a consensus has not been reached regarding the management of individuals with mPAP between 21 and 24 mmHg. Therefore, the management of patients with CTEPH and mildly elevated mPAP requires further research.

Cluster 6: right ventricular function in CTEPH

Right ventricular function is closely related to the severity and prognosis of patients with PH. The right ventricle (RV) can exhibit a similar injury response to the left ventricle, wherein elevated pressure and volume overload of the RV significantly augment wall stress, leading to the thickening of the RV wall and increased cardiomyocyte volume. This compensatory response, referred to as adaptive remodeling, enhances the contractility of the RV (66). However, in patients with CTEPH, the adaptive remodeling process is imperfect, and severe structural changes can occur in the late stages of the disease that are often ignored in the early stages. The mechanism of decreased adaptive remodeling of the right ventricular function in CTEPH remains unclear. Cardiac fibrosis plays an important role in decreasing adaptive remodeling (67). Hypoxia, inflammation, and oxidative stress are all involved in this process (68). PAH-targeted drugs can improve right ventricular function by reducing afterload; however, drugs that directly target right ventricular remodeling are still lacking. The development and implementation of therapeutic interventions specifically targeting the right ventricular function in the future would significantly enhance the long-term outcomes of patients with CTEPH.

In summary, over the past 20 years, significant research advances have been made in the field of CTEPH. Based on a high-quality literature review published recently, we anticipate that future research in this area will focus on the role of pulmonary endothelium in microvasculopathy of CTEPH, the mechanism and intervention for right ventricular dysfunction, clinical studies aiming at enhancing the diagnostic accuracy of imaging techniques, and treatment strategies for the selection of different therapies and combinations of therapies currently available.

Limitation

There are some limitations in this review. First, we only analyzed research on CTEPH during the last 20 years rather than from the origin of the field. Second, the WoSCC database is constantly updated; hence, some observations in the study are contemporary and may change in the future. Third, only publications in English were included in the current study, which may not wholly represent the actual research in the field.

Conclusions

The number of publications on CTEPH has increased in the past two decades. The USA is the most prolific country with the most influential institutions in the field of CTEPH. The diagnosis and treatment of CTEPH are significant topics in the field. Future research in this field will continue to focus on identifying pathophysiological mechanisms (especially the role of pulmonary endothelium in microvasculopathy), enhancing diagnostic accuracy and novel imaging techniques, combining therapies currently available, and treating right ventricular dysfunction.

Acknowledgments

The authors would like to express their appreciation to Professor CM Chen who invented CiteSpace, which is free to use.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-954/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-954/coif). The authors have no conflicts of interest to declare.

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References

1. Kim NH, Delcroix M, Jais X, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2019;53:1801915. [Crossref] [PubMed]
2. Riedel M, Stanek V, Widimsky J, et al. Longterm follow-up of patients with pulmonary thromboembolism. Late prognosis and evolution of hemodynamic and respiratory data. Chest 1982;81:151-8. [Crossref] [PubMed]
3. Fedullo P, Kerr KM, Kim NH, et al. Chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2011;183:1605-13. [Crossref] [PubMed]
4. Jin Q, Zhao ZH, Luo Q, et al. Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension: State of the art. World J Clin Cases 2020;8:2679-702. [Crossref] [PubMed]
5. Zhang Y, Yu X, Jin Q, et al. Advances in targeted therapy for chronic thromboembolic pulmonary hypertension. Heart Fail Rev 2019;24:949-65. [Crossref] [PubMed]
6. Wang S, Zhou H, Zheng L, et al. Global Trends in Research of Macrophages Associated With Acute Lung Injury Over Past 10 Years: A Bibliometric Analysis. Front Immunol 2021;12:669539. [Crossref] [PubMed]
7. Fedullo PF, Auger WR, Kerr KM, et al. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001;345:1465-72. [Crossref] [PubMed]
8. Dartevelle P, Fadel E, Mussot S, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2004;23:637-48. [Crossref] [PubMed]
9. Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257-64. [Crossref] [PubMed]
10. Hoeper MM, Mayer E, Simonneau G, et al. Chronic thromboembolic pulmonary hypertension. Circulation 2006;113:2011-20. [Crossref] [PubMed]
11. Jaïs X, D'Armini AM, Jansa P, et al. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol 2008;52:2127-34. [Crossref] [PubMed]
12. Condliffe R, Kiely DG, Gibbs JS, et al. Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2008;177:1122-7. [Crossref] [PubMed]
13. Bonderman D, Wilkens H, Wakounig S, et al. Risk factors for chronic thromboembolic pulmonary hypertension. Eur Respir J 2009;33:325-31. [Crossref] [PubMed]
14. Pepke-Zaba J, Delcroix M, Lang I, et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation 2011;124:1973-81. [Crossref] [PubMed]
15. Mayer E, Jenkins D, Lindner J, et al. Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. J Thorac Cardiovasc Surg 2011;141:702-10. [Crossref] [PubMed]
16. Madani MM, Auger WR, Pretorius V, et al. Pulmonary endarterectomy: recent changes in a single institution's experience of more than 2,700 patients. Ann Thorac Surg 2012;94:97-103; discussion 103. [Crossref] [PubMed]
17. Kataoka M, Inami T, Hayashida K, et al. Percutaneous transluminal pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv 2012;5:756-62. [Crossref] [PubMed]
18. Sugimura K, Fukumoto Y, Satoh K, et al. Percutaneous transluminal pulmonary angioplasty markedly improves pulmonary hemodynamics and long-term prognosis in patients with chronic thromboembolic pulmonary hypertension. Circ J 2012;76:485-8. [Crossref] [PubMed]
19. Mizoguchi H, Ogawa A, Munemasa M, et al. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv 2012;5:748-55. [Crossref] [PubMed]
20. Kim NH, Delcroix M, Jenkins DP, et al. Chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol 2013;62:D92-9. [Crossref] [PubMed]
21. Lang IM, Pesavento R, Bonderman D, et al. Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding. Eur Respir J 2013;41:462-8. [Crossref] [PubMed]
22. Ghofrani HA, D'Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013;369:319-29. [Crossref] [PubMed]
23. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67-119. [Crossref] [PubMed]
24. Cannon JE, Su L, Kiely DG, et al. Dynamic Risk Stratification of Patient Long-Term Outcome After Pulmonary Endarterectomy: Results From the United Kingdom National Cohort. Circulation 2016;133:1761-71. [Crossref] [PubMed]
25. Delcroix M, Lang I, Pepke-Zaba J, et al. Long-Term Outcome of Patients With Chronic Thromboembolic Pulmonary Hypertension: Results From an International Prospective Registry. Circulation 2016;133:859-71. [Crossref] [PubMed]
26. Simonneau G, Torbicki A, Dorfmüller P, et al. The pathophysiology of chronic thromboembolic pulmonary hypertension. Eur Respir Rev 2017;26:160112. [Crossref] [PubMed]
27. Cohen AT, Agnelli G, Anderson FA, et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007;98:756-64. [Crossref] [PubMed]
28. Jamieson SW, Kapelanski DP, Sakakibara N, et al. Pulmonary endarterectomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg 2003;76:1457-62; discussion 1462-4. [Crossref] [PubMed]
29. Moser KM, Braunwald NS. Successful surgical intervention in severe chronic thromboembolic pulmonary hypertension. Chest 1973;64:29-35. [Crossref] [PubMed]
30. Ogawa A, Satoh T, Fukuda T, et al. Balloon Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension: Results of a Multicenter Registry. Circ Cardiovasc Qual Outcomes 2017;10:e004029. [Crossref] [PubMed]
31. Guérin L, Couturaud F, Parent F, et al. Prevalence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. Prevalence of CTEPH after pulmonary embolism. Thromb Haemost 2014;112:598-605. [Crossref] [PubMed]
32. Cheng CY, Zhang YX, Denas G, et al. Prevalence of antiphospholipid (aPL) antibodies among patients with chronic thromboembolic pulmonary hypertension: a systematic review and meta-analysis. Intern Emerg Med 2019;14:521-7. [Crossref] [PubMed]
33. Delcroix M, Kerr K, Fedullo P. Chronic Thromboembolic Pulmonary Hypertension. Epidemiology and Risk Factors. Ann Am Thorac Soc 2016;13:S201-6. [Crossref] [PubMed]
34. Yan L, Li X, Liu Z, et al. Research progress on the pathogenesis of CTEPH. Heart Fail Rev 2019;24:1031-40. [Crossref] [PubMed]
35. Yuan H, Jiang B, Zhao B, et al. Recent Advances in Multidimensional Separation for Proteome Analysis. Anal Chem 2019;91:264-76. [Crossref] [PubMed]
36. Frantzi M, Latosinska A, Kontostathi G, et al. Clinical Proteomics: Closing the Gap from Discovery to Implementation. Proteomics 2018;18:e1700463. [Crossref] [PubMed]
37. Bernard J, Yi ES. Pulmonary thromboendarterectomy: a clinicopathologic study of 200 consecutive pulmonary thromboendarterectomy cases in one institution. Hum Pathol 2007;38:871-7. [Crossref] [PubMed]
38. Zabini D, Heinemann A, Foris V, et al. Comprehensive analysis of inflammatory markers in chronic thromboembolic pulmonary hypertension patients. Eur Respir J 2014;44:951-62. [Crossref] [PubMed]
39. Quarck R, Wynants M, Verbeken E, et al. Contribution of inflammation and impaired angiogenesis to the pathobiology of chronic thromboembolic pulmonary hypertension. Eur Respir J 2015;46:431-43. [Crossref] [PubMed]
40. Simonneau G, Dorfmüller P, Guignabert C, et al. Chronic thromboembolic pulmonary hypertension: the magic of pathophysiology. Ann Cardiothorac Surg 2022;11:106-19. [Crossref] [PubMed]
41. Southwood M, MacKenzie Ross RV, Kuc RE, et al. Endothelin ETA receptors predominate in chronic thromboembolic pulmonary hypertension. Life Sci 2016;159:104-10. [Crossref] [PubMed]
42. Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 1991;88:4651-5. [Crossref] [PubMed]
43. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989;83:1774-7. [Crossref] [PubMed]
44. Ranka S, Mohananey D, Agarwal N, et al. Chronic Thromboembolic Pulmonary Hypertension-Management Strategies and Outcomes. J Cardiothorac Vasc Anesth 2020;34:2513-23. [Crossref] [PubMed]
45. Gopalan D, Delcroix M, Held M. Diagnosis of chronic thromboembolic pulmonary hypertension. Eur Respir Rev 2017;26:160108. [Crossref] [PubMed]
46. Verbelen T, Godinas L, Maleux G, et al. Chronic thromboembolic pulmonary hypertension: diagnosis, operability assessment and patient selection for pulmonary endarterectomy. Ann Cardiothorac Surg 2022;11:82-97. [Crossref] [PubMed]
47. Moradi F, Morris TA, Hoh CK. Perfusion Scintigraphy in Diagnosis and Management of Thromboembolic Pulmonary Hypertension. Radiographics 2019;39:169-85. [Crossref] [PubMed]
48. Wang M, Wu D, Ma R, et al. Comparison of V/Q SPECT and CT Angiography for the Diagnosis of Chronic Thromboembolic Pulmonary Hypertension. Radiology 2020;296:420-9. [Crossref] [PubMed]
49. Dournes G, Verdier D, Montaudon M, et al. Dual-energy CT perfusion and angiography in chronic thromboembolic pulmonary hypertension: diagnostic accuracy and concordance with radionuclide scintigraphy. Eur Radiol 2014;24:42-51. [Crossref] [PubMed]
50. Landini L. The Future of Medical Imaging. Curr Pharm Des 2018;24:5487-8. [Crossref] [PubMed]
51. Dilsizian V, Chandrashekhar Y. Molecular Imaging: New Promises. JACC Cardiovasc Imaging 2022;15:2019-21. [Crossref] [PubMed]
52. Harel F, Langleben D, Provencher S, et al. Molecular imaging of the human pulmonary vascular endothelium in pulmonary hypertension: a phase II safety and proof of principle trial. Eur J Nucl Med Mol Imaging 2017;44:1136-44. [Crossref] [PubMed]
53. Gong JN, Chen BX, Xing HQ, et al. Pulmonary artery imaging with (68) Ga-FAPI-04 in patients with chronic thromboembolic pulmonary hypertension. J Nucl Cardiol 2023;30:1166-72. [Crossref] [PubMed]
54. Chen BX, Xing HQ, Gong JN, et al. Imaging of cardiac fibroblast activation in patients with chronic thromboembolic pulmonary hypertension. Eur J Nucl Med Mol Imaging 2022;49:1211-22. [Crossref] [PubMed]
55. Yang J, Madani MM, Mahmud E, et al. Evaluation and Management of Chronic Thromboembolic Pulmonary Hypertension. Chest 2023;164:490-502. [Crossref] [PubMed]
56. Voorburg JA, Cats VM, Buis B, et al. Balloon angioplasty in the treatment of pulmonary hypertension caused by pulmonary embolism. Chest 1988;94:1249-53. [Crossref] [PubMed]
57. Feinstein JA, Goldhaber SZ, Lock JE, et al. Balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension. Circulation 2001;103:10-3. [Crossref] [PubMed]
58. Jaïs X, Brenot P, Bouvaist H, et al. Balloon pulmonary angioplasty versus riociguat for the treatment of inoperable chronic thromboembolic pulmonary hypertension (RACE): a multicentre, phase 3, open-label, randomised controlled trial and ancillary follow-up study. Lancet Respir Med 2022;10:961-71. [Crossref] [PubMed]
59. Kawakami T, Matsubara H, Shinke T, et al. Balloon pulmonary angioplasty versus riociguat in inoperable chronic thromboembolic pulmonary hypertension (MR BPA): an open-label, randomised controlled trial. Lancet Respir Med 2022;10:949-60. [Crossref] [PubMed]
60. Lang IM, Andreassen AK, Andersen A, et al. Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension: a clinical consensus statement of the ESC working group on pulmonary circulation and right ventricular function. Eur Heart J 2023;44:2659-71. [Crossref] [PubMed]
61. Simonneau G, D'Armini AM, Ghofrani HA, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2). Eur Respir J 2015;45:1293-302. [Crossref] [PubMed]
62. Jensen KW, Kerr KM, Fedullo PF, et al. Pulmonary hypertensive medical therapy in chronic thromboembolic pulmonary hypertension before pulmonary thromboendarterectomy. Circulation 2009;120:1248-54. [Crossref] [PubMed]
63. Wiedenroth CB, Ghofrani HA, Adameit MSD, et al. Sequential treatment with riociguat and balloon pulmonary angioplasty for patients with inoperable chronic thromboembolic pulmonary hypertension. Pulm Circ 2018;8:2045894018783996. [Crossref] [PubMed]
64. Aoki T, Sugimura K, Terui Y, et al. Beneficial effects of riociguat on hemodynamic responses to exercise in CTEPH patients after balloon pulmonary angioplasty - A randomized controlled study. Int J Cardiol Heart Vasc 2020;29:100579. [Crossref] [PubMed]
65. Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2022;43:3618-731. [Crossref] [PubMed]
66. McCabe C, White PA, Hoole SP, et al. Right ventricular dysfunction in chronic thromboembolic obstruction of the pulmonary artery: a pressure-volume study using the conductance catheter. J Appl Physiol (1985) 2014;116:355-63. [Crossref] [PubMed]
67. Asano R, Ogo T, Ohta-Ogo K, et al. Prolonged QRS duration as a predictor of right ventricular dysfunction after balloon pulmonary angioplasty. Int J Cardiol 2019;280:176-81. [Crossref] [PubMed]
68. Stam K, Cai Z, van der Velde N, et al. Cardiac remodelling in a swine model of chronic thromboembolic pulmonary hypertension: comparison of right vs. left ventricle. J Physiol 2019;597:4465-80. [Crossref] [PubMed]