Shared and Distinct Genomics of Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Embolism.

RATIONALE: Chronic Thromboembolic Pulmonary Hypertension involves formation and non-resolution of thrombus, dysregulated inflammation, angiogenesis and the development of a small vessel vasculopathy. OBJECTIVES: We aimed to establish the genetic basis of chronic thromboembolic pulmonary hypertension to gain insight into its pathophysiological contributors. METHODS: We conducted a genome-wide association study on 1907 European cases and 10363 European controls. We co-analysed our results with existing results from genome-wide association studies on deep vein thrombosis, pulmonary embolism and idiopathic pulmonary arterial hypertension. MEASUREMENTS AND MAIN RESULTS: Our primary association study revealed genetic associations at the ABO, FGG, F11, MYH7B, and HLA-DRA loci. Through our co-analysis we demonstrate further associations with chronic thromboembolic pulmonary hypertension at the F2, TSPAN15, SLC44A2 and F5 loci but find no statistically significant associations shared with idiopathic pulmonary arterial hypertension. CONCLUSIONS: Chronic thromboembolic pulmonary hypertension is a partially heritable polygenic disease, with related though distinct genetic associations to pulmonary embolism and to deep vein thrombosis.

Angiogenesis in Chronic Thromboembolic Pulmonary Hypertension: A Janus-Faced Player?

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare form of pulmonary hypertension characterized by the presence of organized thrombi that obstruct pulmonary arteries, ultimately leading to right heart failure and death. Among others, impaired angiogenesis and inflammatory thrombosis have been shown to contribute to the progression of CTEPH. In this review, we summarize the 2-faced nature of angiogenesis in both thrombus formation and resolution in the context of CTEPH and highlight the dual role of angiogenesis and neovascularization in resolving venous thrombi. Furthermore, we discuss relevant in vitro and in vivo models that support the benefits or drawbacks of angiogenesis in CTEPH progression. We discuss the key pathways involved in modulating angiogenesis, particularly the underexplored role of TGFß (transforming growth factor-beta) signaling in driving fibrosis as an integral element of CTEPH pathogenesis. We finally explore innovative treatment strategies that target angiogenic pathways. These strategies have the potential to pioneer preventive, inventive, or alternative therapeutic options for patients with CTEPH who may not qualify for surgical interventions. Moreover, they could be used synergistically with established treatments such as pulmonary endarterectomy or balloon pulmonary angioplasty. In summary, this review emphasizes the crucial role of angiogenesis in the development of in fibrothrombotic tissue, a major pathological characteristic of CTEPH.

Treatment strategies and survival of patients with connective tissue disease and pulmonary arterial hypertension: a COMPERA analysis.

OBJECTIVES: Pulmonary arterial hypertension (PAH) occurs in various connective tissue diseases (CTDs). We sought to assess contemporary treatment patterns and survival of patients with various forms of CTD-PAH. METHODS: We analysed data from COMPERA, a European pulmonary hypertension registry, to describe treatment strategies and survival in patients with newly diagnosed PAH associated with SSc, SLE, MCTD, UCTD and other types of CTD. All-cause mortality was analysed according to the underlying CTD. For patients with SSc-PAH, we also assessed survival according to initial therapy with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5is) or a combination of these two drug classes. RESULTS: This analysis included 607 patients with CTD-PAH. Survival estimates at 1, 3 and 5 years for SSc-PAH (n = 390) were 85%, 59% and 42%; for SLE-PAH (n = 34) they were 97%, 77% and 61%; for MCTD-PAH (n = 33) they were 97%, 70% and 59%; for UCTD-PAH (n = 60) they were 88%, 67% and 52%; and for other CTD-PAH (n = 90) they were 92%, 69% and 55%, respectively. After multivariable adjustment, the survival of patients with SSc-PAH was significantly worse compared with the other conditions (P = 0.001). In these patients, the survival estimates were significantly better with initial ERA-PDE5i combination therapy than with initial ERA or PDE5i monotherapy (P = 0.016 and P = 0.012, respectively). CONCLUSIONS: Mortality remains high in patients with CTD-PAH, especially for patients with SSc-PAH. However, for patients with SSc-PAH, our results suggest that long-term survival may be improved with initial ERA-PDE5i combination therapy compared with initial monotherapy.

Clinical-radiological-pathological correlation in chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and potentially life-threatening complication of acute pulmonary embolism. It is characterised by persistent fibro-thrombotic pulmonary vascular obstructions and elevated pulmonary artery pressure leading to right heart failure. The diagnosis is based on two steps, as follows: 1) suspicion based on symptoms, echocardiography and ventilation/perfusion scan and 2) confirmation with right heart catheterisation, computed tomography pulmonary angiography and, in most cases, digital subtraction angiography. The management of CTEPH requires a multimodal approach, involving medical therapy, interventional procedures and surgical intervention. This clinical-radiological-pathological correlation paper illustrates the diagnostic and therapeutic management of two patients. The first had chronic thromboembolic pulmonary disease without pulmonary hypertension at rest but with significant physical limitation and was successfully treated with pulmonary endarterectomy. The second patient had CTEPH associated with splenectomy and was considered unsuitable for surgery because of exclusive subsegmental lesions combined with severe pulmonary hypertension. The patient benefited from multimodal treatment involving medical therapy followed by multiple sessions of balloon pulmonary angioplasty. Both patients had normalised functional capacity and pulmonary haemodynamics 3-6 months after the interventional treatment. These two examples show that chronic thromboembolic pulmonary diseases are curable if diagnosed promptly and referred to CTEPH centres for specialist treatment.

Pulmonary arterial hypertension drugs can partially restore altered angiogenic capacities in bmpr2-silenced human lung microvascular endothelial cells.

Mutations in the bone morphogenetic protein receptor type 2 (bmpr2) gene and signaling pathway impairment are observed in heritable and idiopathic pulmonary arterial hypertension (PAH). In PAH, endothelial dysfunction is currently handled by drugs targeting the endothelin-1 (ET-1), nitric oxide (NO), and prostacyclin (PGI2) pathways. The role of angiogenesis in the disease process and the effect of PAH therapies on dysregulated angiogenesis remain inconclusive. We aim to investigate in vitro whether (i) bmpr2 silencing can impair angiogenic capacity of human lung microvascular endothelial cells (HLMVECs) and (ii) PAH therapies can restore them. The effects of macitentan (ET-1), tadalafil (NO), and selexipag (PGI2), on BMPRII pathway activation, endothelial barrier function, and angiogenesis were investigated in bmpr2-silenced HLMVECs. Stable bmpr2 silencing resulted in impaired migration and tube formation in vitro capacity. Inhibition of ET-1 pathway was able to partially restore tube formation in bmpr2-silenced HLMVECs, whereas none of the therapies was able to restore endothelial barrier function, no deleterious effects were observed. Our findings highlight the potential role of BMPRII signaling pathway in driving pulmonary endothelial cell angiogenesis. In addition, PAH drugs display limited effects on endothelial function when BMPRII is impaired, suggesting that innovative therapeutic strategies targeting BMPRII signaling are needed to better rescue endothelial dysfunction in PAH.

Preexisting Chronic Thromboembolic Pulmonary Hypertension in Acute Pulmonary Embolism? A Case Report and Discussion.

A 61-year-old male presented with New York Heart Association class II breathlessness. Three years earlier, he had presented with a swollen leg, had received a diagnosis of deep vein thrombosis on ultrasound and of low-risk acute pulmonary embolism, and had been discharged on a direct oral anticoagulant after 8 hours. The patient also had a history of thyroidectomy and was on levothyroxine substitution. The case illustrates a patient with acute pulmonary embolism who developed chronic thrombotic pulmonary vascular lesions within 3 years after acute pulmonary embolism in the presence of typical risk factors.

Machine learning to differentiate pulmonary hypertension due to left heart disease from pulmonary arterial hypertension.

Background and aims: Pulmonary hypertension due to left heart disease (PH-LHD) is the most frequent form of PH. As differential diagnosis with pulmonary arterial hypertension (PAH) has therapeutic implications, it is important to accurately and noninvasively differentiate PH-LHD from PAH before referral to PH centres. The aim was to develop and validate a machine learning (ML) model to improve prediction of PH-LHD in a population of PAH and PH-LHD patients. Methods: Noninvasive PH-LHD predictors from 172 PAH and 172 PH-LHD patients from the PH centre database at the University Hospitals of Leuven (Leuven, Belgium) were used to develop an ML model. The Jacobs score was used as performance benchmark. The dataset was split into a training and test set (70:30) and the best model was selected after 10-fold cross-validation on the training dataset (n=240). The final model was externally validated using 165 patients (91 PAH, 74 PH-LHD) from Erasme Hospital (Brussels, Belgium). Results: In the internal test dataset (n=104), a random forest-based model correctly diagnosed 70% of PH-LHD patients (sensitivity: n=35/50), with 100% positive predicted value, 78% negative predicted value and 100% specificity. The model outperformed the Jacobs score, which identified 18% (n=9/50) of the patients with PH-LHD without false positives. In external validation, the model had 64% sensitivity at 100% specificity, while the Jacobs score had a sensitivity of 3% for no false positives. Conclusions: ML significantly improves the sensitivity of PH-LHD prediction at 100% specificity. Such a model may substantially reduce the number of patients referred for invasive diagnostics without missing PAH diagnoses.

Monographic Issue on Pulmonary Hypertension: Medical and Interventional Treatment for Chronic Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism. The reasons why clots do not resorb are incompletely understood, but the result is partial or complete fibrothrombotic obstruction of pulmonary arteries. A secondary microvasculopathy aggravates the pulmonary hypertension (PH) as a consequence of high flow and shear stress in the nonoccluded arteries. The treatment of CTEPH has long been purely surgical, but many patients were inoperable because of inaccessible lesions or severe comorbidities. Alternatives were developed, including medical therapy and more recently balloon pulmonary angioplasty (BPA). Depending on the generation of the obstructed vessels, the treatment will be surgical, up to the (sub)segmental level, or by BPA for more distal vessels. PH drugs are used to treat the microvasculopathy. The current paper describes the therapeutic management of inoperable patients: the medical approach with PH drugs used in mono- or combination therapy; the proper use of anticoagulants in CTEPH; the technique, indications, and results at short- and long-term of BPA; the multimodal approach for inoperable patients combining PH drugs and BPA; and the effects of rehabilitation. It shows the importance of a multidisciplinary approach to the disease.

Chronic thromboembolic pulmonary hypertension: realising the potential of multimodal management.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism. Important advances have enabled better understanding, characterisation, and treatment of this condition. Guidelines recommending systematic follow-up after acute pulmonary embolism, and the insight that CTEPH can mimic acute pulmonary embolism on initial presentation, have led to the definition of CTEPH imaging characteristics, the introduction of artificial intelligence diagnosis pathways, and thus the prospect of easier and earlier CTEPH diagnosis. In this Series paper, we show how the understanding of CTEPH as a sequela of inflammatory thrombosis has driven successful multidisciplinary management that integrates surgical, interventional, and medical treatments. We provide imaging examples of classical major vessel targets, describe microvascular targets, define available tools, and depict an algorithm facilitating the initial treatment strategy in people with newly diagnosed CTEPH based on a multidisciplinary team discussion at a CTEPH centre. Further work is needed to optimise the use and combination of multimodal therapeutic options in CTEPH to improve long-term outcomes for patients.

Anthracofibrosis mimicking chronic thromboembolic pulmonary hypertension.

We present the case of a 78-year-old female undergoing pulmonary endarterectomy (PEA) because of suspected chronic thromboembolic pulmonary hypertension (CTEPH). During surgery firm black masses were encountered in the aortopulmonary window and on the cranial part of the right pulmonary artery (PA). After PA arteriotomy we visualized intraluminal black firm stenosing plaques at the orifices of the three right and of the left lingular and lower lobar branches. Since no dissection plane could be obtained the procedure was discontinued. Subsequent bronchoscopy visualized a submucosal dark black-blue discoloration in both main bronchi. Pathological analysis revealed anthracofibrosis, which could be explained by biomass smoke exposure in the past. We are the first to provide intravascular pictures and pathologic images of this very rare entity. Moreover, we report stenoses at the orifices of the three right-sided lobar and of the left-sided lingular and lower lobe arteries, in contrast to three previous reports that report on single locations caused by extrinsic PA compression from lymphadenopathy. Our case, however, suggests extension of fibrosis with anthracotic pigment into the PA wall. We conclude that in the absence of a clear history of exposure to carbon smoke and with consequently no diagnostic bronchoscopy, anthracofibrosis of the lungs may mimic CTEPH not only by external compression but also by extension into pulmonary vascular structures. PEA-surgery should not be attempted in these cases.

Impairment of Angiogenesis-Driven Clot Resolution Is a Key Event in the Progression to Chronic Thromboembolic Pulmonary Hypertension: Validation in a Novel Rabbit Model.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition and rare complication of acute pulmonary embolism. Mechanisms underlying impaired clot resolution and in sustained fibrothrombotic obstruction of the pulmonary arterial bed remain poorly understood. Since defective angiogenesis correlated to defective clot resolution based on observations in surgical material from patients with CTEPH, we aimed to validate its crucial pathogenic role by intrathrombus inhibition of angiogenesis in a novel CTEPH rabbit model. METHODS: We aimed to compare whether intrathrombus administration of an antifibrinolytic agent, tranexamic acid, or an inhibitor of angiogenesis, SU5416, would contribute to CTEPH progression. Both products were administered on a weekly basis by autologous clot embolization in rabbits. Right ventricular pressure was monitored by telemetry, right ventricular function by transthoracic echocardiography, and a complete pulmonary hemodynamic evaluation was obtained through right heart catheterization. Markers of inflammation, endothelial dysfunction, heart failure, and fibrinolysis were measured in plasma. Pulmonary vessel remodeling was analyzed by immunohistochemistry. RESULTS: Impairing intrathrombus angiogenesis by repeatedly embolizing autologous blood clots containing SU5416 resulted in elevated mean pulmonary arterial pressure (38 mm Hg), increased indexed pulmonary vascular resistance, and enhanced right ventricular hypertrophy (80%, 1.9-fold, 36%, respectively, compared with rabbits embolized with clots containing an antifibrinolytic agent). This was caused by both obstruction of large pulmonary arteries with fibrothrombotic material and muscularization of pulmonary microvessels, and accompanied by inflammatory cell infiltration and increased circulating endothelin-1. CONCLUSIONS: The key role of angiogenesis-driven clot resolution was validated in a reliable small-animal model reproducing the major pathophysiological hallmarks of CTEPH.

European Society of Cardiology quality indicators for the care and outcomes of adults with pulmonary arterial hypertension. Developed in collaboration with the Heart Failure Association of the European Society of Cardiology.

AIMS: To develop a suite of quality indicators (QIs) for the evaluation of the care and outcomes for adults with pulmonary arterial hypertension (PAH). METHODS AND RESULTS: We followed the European Society of Cardiology (ESC) methodology for the development of QIs. This included (i) the identification of key domains of care for the management of PAH, (ii) the proposal of candidate QIs following systematic review of the literature, and (iii) the selection of a set of QIs using a modified Delphi method. The process was undertaken in parallel with the writing of the 2022 ESC/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension and involved the Task Force chairs, experts in PAH, Heart Failure Association (HFA) members and patient representatives. We identified five domains of care for patients with PAH: structural framework, diagnosis and risk stratification, initial treatment, follow-up, and outcomes. In total, 23 main and one secondary QIs for PAH were selected. CONCLUSION: This document presents the ESC QIs for PAH, describes their development process and offers scientific rationale for their selection. The indicators may be used to quantify and improve adherence to guideline-recommended clinical practice and improve patient outcomes.

Highlights from the International Chronic Thromboembolic Pulmonary Hypertension Congress 2021.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism. It is caused by persistent obstruction of pulmonary arteries by chronic organised fibrotic clots, despite adequate anticoagulation. The pulmonary hypertension is also caused by concomitant microvasculopathy which may progress without timely treatment. Timely and accurate diagnosis requires the combination of imaging and haemodynamic assessment. Optimal therapy should be individualised to each case and determined by an experienced multidisciplinary CTEPH team with the ability to offer all current treatment modalities. This report summarises current knowledge and presents key messages from the International CTEPH Conference, Bad Nauheim, Germany, 2021. Sessions were dedicated to 1) disease definition; 2) pathophysiology, including the impact of the hypertrophied bronchial circulation, right ventricle (dys)function, genetics and inflammation; 3) diagnosis, early after acute pulmonary embolism, using computed tomography and perfusion techniques, and supporting the selection of appropriate therapies; 4) surgical treatment, pulmonary endarterectomy for proximal and distal disease, and peri-operative management; 5) percutaneous approach or balloon pulmonary angioplasty, techniques and complications; and 6) medical treatment, including anticoagulation and pulmonary hypertension drugs, and in combination with interventional treatments. Chronic thromboembolic pulmonary disease without pulmonary hypertension is also discussed in terms of its diagnostic and therapeutic aspects.

Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression.

BACKGROUND: Senescent cells (SCs) are involved in proliferative disorders, but their role in pulmonary hypertension remains undefined. We investigated SCs in patients with pulmonary arterial hypertension and the role of SCs in animal pulmonary hypertension models. METHODS: We investigated senescence (p16, p21) and DNA damage (γ-H2AX, 53BP1) markers in patients with pulmonary arterial hypertension and murine models. We monitored p16 activation by luminescence imaging in p16-luciferase (p16LUC/+) knock-in mice. SC clearance was obtained by a suicide gene (p16 promoter-driven killer gene construct in p16-ATTAC mice), senolytic drugs (ABT263 and cell-permeable FOXO4-p53 interfering peptide [FOXO4-DRI]), and p16 inactivation in p16LUC/LUC mice. We investigated pulmonary hypertension in mice exposed to normoxia, chronic hypoxia, or hypoxia+Sugen, mice overexpressing the serotonin transporter (SM22-5-HTT+), and rats given monocrotaline. RESULTS: Patients with pulmonary arterial hypertension compared with controls exhibited high lung p16, p21, and γ-H2AX protein levels, with abundant vascular cells costained for p16, γ-H2AX, and 53BP1. Hypoxia increased thoracic bioluminescence in p16LUC/+ mice. In wild-type mice, hypoxia increased lung levels of senescence and DNA-damage markers, senescence-associated secretory phenotype components, and p16 staining of pulmonary endothelial cells (P-ECs, 30% of lung SCs in normoxia), and pulmonary artery smooth muscle cells. SC elimination by suicide gene or ABT263 increased the right ventricular systolic pressure and hypertrophy index, increased vessel remodeling (higher dividing proliferating cell nuclear antigen-stained vascular cell counts during both normoxia and hypoxia), and markedly decreased lung P-ECs. Pulmonary hemodynamic alterations and lung P-EC loss occurred in older p16LUC/LUC mice, wild-type mice exposed to Sugen or hypoxia+Sugen, and SM22-5-HTT+ mice given either ABT263 or FOXO4-DRI, compared with relevant controls. The severity of monocrotaline-induced pulmonary hypertension in rats was decreased slightly by ABT263 for 1 week but was aggravated at 3 weeks, with loss of P-ECs. CONCLUSIONS: Elimination of senescent P-ECs by senolytic interventions may worsen pulmonary hemodynamics. These results invite consideration of the potential impact on pulmonary vessels of strategies aimed at controlling cell senescence in various contexts.

Risk stratification and response to therapy in patients with pulmonary arterial hypertension and comorbidities: A COMPERA analysis.

BACKGROUND: A diagnosis of idiopathic pulmonary arterial hypertension (IPAH) is frequently made in elderly patients who present with comorbidities, especially hypertension, coronary heart disease, diabetes mellitus, and obesity. It is unknown to what extent the presence of these comorbidities affects the response to PAH therapies and whether risk stratification predicts outcome in patients with comorbidities. METHODS: We assessed the database of COMPERA, a European pulmonary hypertension registry, to determine changes after initiation of PAH therapy in WHO functional class (FC), 6-minute walking distance (6MWD), brain natriuretic peptide (BNP) or N-terminal fragment of probrain natriuretic peptide (NT-pro-BNP), and mortality risk assessed by a 4-strata model in patients with IPAH and no comorbidities, 1-2 comorbidities and 3-4 comorbidities. RESULTS: The analysis was based on 1,120 IPAH patients (n = 208 [19%] without comorbidities, n = 641 [57%] with 1-2 comorbidities, and n = 271 [24%] with 3-4 comorbidities). Improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk from baseline to first follow-up were significantly larger in patients with no comorbidities than in patients with comorbidities, while they were not significantly different in patients with 1-2 and 3-4 comorbidities. The 4-strata risk tool predicted survival in patients without comorbidities as well as in patients with 1-2 or 3-4 comorbidities. CONCLUSIONS: Our data suggest that patients with IPAH and comorbidities benefit from PAH medication with improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk, albeit to a lesser extent than patients without comorbidities. The 4-strata risk tool predicted outcome in patients with IPAH irrespective of the presence of comorbidities.