Search

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., Competing Interests: M.D. reports research grants from Janssen, speaker and consultant fees from Altavant, Acceleron, AOP, Daiichi Sankyo, Bayer, Ferrer, Gossamer, MSD outside the submitted work, and all paid to her institution. She is holder of the Janssen Chair for Pulmonary Hypertension at the KU Leuven. L.G. reports consultant fees and travel fees from Janssen and MSD outside the submitted work. C.B. reports speaker fees, fees for participation at Advisory Boards, and support for attending meetings and/or travel from Janssen and MSD, outside the submitted work, and all paid to her institution. G.M. reports no conflict of interest., (Thieme. All rights reserved.)

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 (PGI 2 ) 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 (PGI 2 ), 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., Competing Interests: Marion Delcroix is holder of the Actelion chair for Pulmonary Hypertension at the KU Leuven ‐ University of Leuven., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

The present study aimed to evaluate whether titration of fixed continuous positive airway pressure at home using telemonitoring produces patient outcomes equal to auto-adjusting positive airway pressure titration at home for patients with moderate obstructive sleep apnea. Patients were randomized with a 1:1 allocation ratio to receive either auto-adjusting positive airway pressure titration based on the median of the 95th percentile pressure across seven nights or fixed continuous positive airway pressure titration based on a fixed calculated pressure and specific adaptations after telemonitoring of device data after 3 and 7 nights. The results of the ambulatory titration were evaluated with in-laboratory polysomnography after 2 weeks. We hypothesized that fixed continuous positive airway pressure titration would be non-inferior to auto-adjusting positive airway pressure titration in respect to continuous positive airway pressure adherence at a 3-month follow-up. A non-inferiority margin of -0.75 hr was prespecified. One-hundred and four patients were randomly allocated to fixed continuous positive airway pressure (n = 52) and auto-adjusting positive airway pressure (n = 52) titration. The mean difference and the 95% confidence intervals in continuous positive airway pressure adherence after 3 months between the two arms were 0.80 (-0.08, 1.69) hr. The non-inferiority hypothesis was confirmed as the lower one-sided 97.5% confidence interval for the mean difference was above the prespecified margin. Patients in the fixed continuous positive airway pressure titration arm were titrated at significantly lower pressure level and had a significantly lower amount of average leaks compared with auto-adjusting positive airway pressure-titrated patients, while there was no difference in residual obstructive apnea-hypopnea index on polysomnography. Telemonitoring enables ambulatory continuous positive airway pressure titration with fixed pressure that is non-inferior to ambulatory titration with auto-adjusting pressure in patients with moderate obstructive sleep apnea., (© 2023 European Sleep Research Society.)

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., Competing Interests: Conflict of interest: M. De Vos received funding from the AI in Flanders project. M. Topalovic is CEO and co-founder of Artiq but received no payments related to the manuscript. G. Claessen received a KOOR grant from his institution. C. Belge reports personal fees from Actelion/Janssen and MSD/Bayer, outside the submitted work. J-L. Vachiery received grants from Actelion/Janssen. W. Janssens is supported as senior clinical researcher of the Flemish Research Foundation, and received grants from AstraZeneca and Chiesi, and obtained fees from AstraZeneca, Chiesi and GlaxoSmithKline. He is chairman of Board of Flemish Society for TBC prevention and board member of Artiq. M. Delcroix received funding from Actelion/Janssen and consulting fees from MSD, Acceleron, Actelion/Janssen, AOP, Ferrer and Gossamer BIO. She also participates on a data safety monitoring or advisory board for Actelion/Janssen. K. Swinnen, K. Verstraete, C. Baratto, L. Hardy and R. Quarck have nothing to disclose., (Copyright ©The authors 2023.)

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., Competing Interests: Disclosures M. Delcroix is holder of the Actelion/Johnson & Johnson chair for Pulmonary Hypertension at the University of Leuven and received financial support from the Belgian Pulmonary Hypertension Patient Association. The other authors report no conflicts.

Background: We aimed to explore the prevalence of prolonged symptoms, pulmonary impairments and residual disease on chest tomography (CT) in COVID-19 patients at 6 months after acute illness. Methods: In this prospective, single-center study, hospitalized patients with radiologically and laboratory-confirmed COVID-19 were included. Results: A high proportion of the 116 patients reported persistent symptoms (n = 54; 46.6%). On follow-up CT, 33 patients (28.4%) demonstrated residual disease. Multivariate analyses revealed that only neutrophil-to-lymphocyte ratio was an independent predictor for residual disease. Conclusion: Hospitalized patients with mild/moderate COVID-19 still had persistent symptoms and were prone to develop long-term pulmonary sequelae on chest CT. However, it did not have a significant effect on long-term pulmonary functions.

Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, BMPR2 (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered., Competing Interests: Conflict of interest: C.A. Eichstaedt reports lecture fees from MSD, outside the submitted work; and has a patent “Gene panel specific for pulmonary hypertension and its uses” (European Patent ID: EP3507380) issued. C. Belge reports consulting fees, participation on advisory boards and lecture honoraria from Janssen and MSD/Bayer; travel support from MSD/Bayer, outside the submitted work. W.K. Chung reports scientific advisory board participation with Regeneron Genetics Center, outside the submitted work. E. Grünig reports grants from Actelion, Bayer, GSK, United Therapeutics, Novartis, Bellerophon, OMT, Pfizer and REATA; lecture fees and consultancy fees from Actelion, Bayer/MSD and GSK; travel support from Janssen; advisory board participation with MSD and Ferrer, outside the submitted work; has a patent “Gene panel specific for pulmonary hypertension and its uses” (European Patent ID: EP3507380) issued; and has also served in leadership roles for ADue and pH e.V., outside the submitted work. D. Montani reports grants from Acceleron, Janssen and Merck; consulting fees from Acceleron; lecture honoraria from Bayer, Janssen and Merck, outside the submitted work. R.C. Trembath reports lecture fees from Clinical Cases, outside the submitted work. N.W. Morrell reports employment and stock/stock options from Centessa Pharmaceuticals. All other authors have nothing to disclose., (Copyright ©The authors 2023.)

Study Objectives: To evaluate (determinants of) treatment success of mandibular advancement device application in a selected phenotype of patients with obstructive sleep apnea (OSA)., Methods: Ninety nonobese patients with moderate OSA (obstructive apnea-hypopnea index [OAHI] ≥ 15 and < 30 events/h) without comorbidities were prospectively included. Polysomnography was performed at baseline and with a mandibular advancement device. A drug-induced sleep endoscopy with jaw thrust was performed in 83%., Results: OAHI reduction ≥ 50% was observed in 73%, OAHI reduction ≥ 50% with OAHI < 10 events/h in 70%, and complete OSA resolution (OAHI < 5 events/h) in 40%. Patients with nonpositional OSA showed a significantly higher rate of complete OSA resolution: Posttest probability increased to 67%. In patients with total disappearance of collapse at velum level and at all levels during drug-induced sleep endoscopy with jaw thrust, the drop in OAHI was impressive with an infinitively high positive likelihood ratio. However, the proportion of patients having nonpositional OSA or the drug-induced sleep endoscopy characteristics as described above was < 20%. The change in snoring disturbance based on a visual analog scale was 76% (interquartile range 40-89%, P < .001) and a statistically significant amelioration in Epworth Sleepiness Scale (especially in somnolent subjects) was observed. High adherence was reported., Conclusions: In this predefined OSA phenotype, a mandibular advancement device was effective in reduction of OAHI and in amelioration of symptoms. Stratification by nonpositional OSA and findings on drug-induced sleep endoscopy with jaw thrust increased treatment success defined as reduction in OAHI. However, the clinical relevance can be questioned because only a small number of patients demonstrated these characteristics., Citation: Buyse B, Nguyen PAH, Leemans J, et al. Short-term positive effects of a mandibular advancement device in a selected phenotype of patients with moderate obstructive sleep apnea: a prospective study. J Clin Sleep Med . 2023;19(1):5-16., (© 2023 American Academy of Sleep Medicine.)

Purpose: Obstructive sleep apnea (OSA) is a prevalent and multifaceted disease. To date, the presence and severity of objectively identified comorbidities and their association with specific OSA phenotypes, CPAP adherence, and survival remain to be elucidated. The aim of this study is to cluster patients with OSA based on 10 clinically important objectively identified comorbidities, and to characterize the comorbidity clusters in terms of clinical and polysomnographic characteristics, CPAP adherence, and survival., Study Design and Methods: Seven hundred ten consecutive patients starting CPAP for moderate-to-severe OSA were included. Comorbidities were based on generally accepted cutoffs identified in the peer-reviewed literature. Self-organizing maps were used to order patients based on presence and severity of their comorbidities and to generate clusters., Results: The majority of patients were men (80%). They were generally middle-aged (52 years) and obese (BMI: 31.5 kg/m 2 ). Mean apnea-hypopnea index (AHI) was 41 ± 20 per h of sleep. More than 94% of the patients had one or more comorbidities with arterial hypertension, dyslipidemia, and obesity being the most prevalent. Nine comorbidity clusters were identified. The clinical relevance of these comorbidity clusters was highlighted by the difference in symptoms, PSG parameters, and cardiovascular risk. Also, differences in CPAP adherence, improvements in ESS, and long-term survival were present between the clusters., Conclusion: Comorbidity prevalence in patients with OSA is high, and different comorbidity clusters, demonstrating differences in cardiovascular risk, CPAP adherence, and survival, can be identified. These results further substantiate the need for a comprehensive assessment of patients with OSA beyond the AHI., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Healthcare providers outside pulmonary hypertension (PH) centers having misinformation or insufficient education, and a general lack of treatment awareness contribute to a massive underdiagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), diagnostic delay and refusal of surgery by patients. Together with the subjective operability assessment, this leads to too few patients undergoing pulmonary endarterectomy (PEA); even though this surgery results in improved survival and exercise capacity. Acute pulmonary embolism (PE) survivors should undergo a CTEPH screening strategy. Patients screened positive and those with CTEPH symptoms (with or without history of PE), should undergo transthoracic echocardiography (TTE) to determine the probability of PH. High PH probability patients should undergo a ventilation/perfusion (V/Q) scan. A negative scan rules out CTEPH. Patients with a positive V/Q scan, but also patients with findings suggestive for CTEPH on computed tomography pulmonary angiography (CTPA) to diagnose acute PE, should be referred to a CTEPH center. Further diagnostic work-up currently consists of catheter based pulmonary angiography, CTPA and right heart catheterization. However, new imaging technologies might replace them in the near future, with one single imaging tool to screen, diagnose and assess operability as the ultimate goal. Operability assessment should be performed by a multidisciplinary CTEPH team. PEA surgery should be organized in a single center per country or for each forty to fifty million inhabitants in order to offer the highest level of expertise. Informing patients about PEA should preferably be done by the treating surgeon. Based on the estimated incidence of CTEPH and with a better education of patients and healthcare providers, despite the advent of new interventional and medical therapies for CTEPH, the number of PEA surgeries performed should still have the potential to grow significantly., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2022 Annals of Cardiothoracic Surgery. All rights reserved.)

Background: Right heart failure (RHF) in pulmonary hypertension (PH) patients is manifested by increased right atrial (RA) pressure. We hypothesized liver relaxation times measured at cardiovascular magnetic resonance (CMR) can be used to noninvasively assess increased right-sided filling pressure., Methods: Forty-five consecutive patients, that is, 37 PH patients and 8 chronic thromboembolic pulmonary disease patients without PH underwent right heart catheterization and CMR. CMR findings were compared to 40 control subjects. Native T1, T2, and extracellular volume (ECV) liver values were measured on the cardiac maps., Results: Patients with increased RA pressure (i.e.,≥8 mm Hg)(n = 19, RA+ group) showed higher NT-proBNP and CRP values, lower LVEF, MAPSE values, larger atrial size, and higher native T1 and T2 values of the myocardium than patients with normal RA pressure (RA- group, n = 26). Liver T1, T2 and ECV was significantly higher in RA+ than RA- patients and controls, that is, T1: 684 ± 129 ms vs 563 ± 72 ms and 540 ± 34 ms; T2: 60 ± 10 ms vs 49 ± 6 ms and 46 ± 4 ms; ECV: 36 ± 8% vs 29 ± 4% and 30 ± 3%. A positive correlation was found between liver T1, T2 and ECV and RA pressure, that is, r 2 of 0.61, 0.82, and 0.58, respectively (p < 0.001). ROC analysis to depict increased RA pressure showed an AUC of 0.847, 0.904, 0.816, and 0.645 for liver T1, T2, NT-proNBP and gamma-glutamyl transpeptidase, respectively. Excellent intra- and inter-observer agreement was found for assessment of T1/T2/ECV liver values., Conclusions: Assessment of liver relaxation times as part of a comprehensive CMR exam in PH patients may provide valuable information with regard to the presence of passive liver congestion., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a devastating condition affecting the pulmonary microvascular wall and endothelium, resulting in their partial or total obstruction. Despite a combination of expensive vasodilatory therapies, mortality remains high. Personalized therapeutic approaches, based on access to patient material to unravel patient specificities, could move the field forward. An innovative technique involving harvesting pulmonary arterial endothelial cells (PAECs) at the time of diagnosis was recently described. The aim of the present study was to fine-tune the initial technique and to phenotype the evolution of PAECs in vitro subcultures. PAECs were harvested from Swan-Ganz pulmonary arterial catheters during routine diagnostic or follow up right heart catheterization. Collected PAECs were phenotyped by flow cytometry and immunofluorescence focusing on endothelial-specific markers. We highlight the ability to harvest patients' PAECs and to maintain them for up to 7-12 subcultures. By tracking the endothelial phenotype, we observed that PAECs could maintain an endothelial phenotype for several weeks in culture. The present study highlights the unique opportunity to obtain homogeneous subcultures of primary PAECs from patients at diagnosis and follow-up. In addition, it opens promising perspectives regarding tailored precision medicine for patients suffering from rare pulmonary vascular diseases.