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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. ispartof: J Clin Sleep Med vol:19 issue:1 pages:5-16 ispartof: location:United States status: published

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.

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/m2). 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. ispartof: SLEEP AND BREATHING vol:26 issue:1 pages:195-204 ispartof: location:Germany status: published

ispartof: EUROPEAN RESPIRATORY JOURNAL vol:60 issue:1 ispartof: location:England status: published

According to the US Centers for Disease Control and Prevention (CDC), patients with underlying health conditions, including all types of lung and cardiovascular diseases, have an increased risk of developing serious disease when infected by SARS-CoV-2 [1]. Based on prior publications on the effects of acute right heart failure superimposed on systemic infection [2–5], Ryan et al. [6] suggested that right heart failure and concomitant COVID-19 infection may result in increased mortality in pulmonary arterial hypertension (PAH) patients. Surprisingly, the number of hospitalised PAH-COVID-19 patients remained rather low in Italy and the USA so far [7]. In late March 2020, experts from over 32 US PH expert centres answered a query endorsed by the US Pulmonary Hypertension Association. COVID-19 infection was reported in 13 PAH patients, among whom three required intubation and one died. This is consequently raising the question whether and why PAH patients appear to be at lower risk of developing severe COVID-19 [7]., This international survey highlights that a limited number of PAH and CTEPH patients suffered from severe #COVID19 infection https://bit.ly/3jGuBQq

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. ispartof: ANNALS OF CARDIOTHORACIC SURGERY vol:11 issue:2 pages:82-97 ispartof: location:China status: published

Background:Exertional intolerance is a limiting and often crippling symptom in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Traditionally the pathogenesis has been attributed to central factors, including ventilation/perfusion mismatch, increased pulmonary vascular resistance, and right heart dysfunction and uncoupling. Pulmonary endarterectomy and balloon pulmonary angioplasty provide substantial improvement of functional status and hemodynamics. However, despite normalization of pulmonary hemodynamics, exercise capacity often does not return to age-predicted levels. By systematically evaluating the oxygen pathway, we aimed to elucidate the causes of functional limitations in patients with CTEPH before and after pulmonary vascular intervention.Methods:Using exercise cardiac magnetic resonance imaging with simultaneous invasive hemodynamic monitoring, we sought to quantify the steps of the O2transport cascade from the mouth to the mitochondria in patients with CTEPH (n=20) as compared with healthy participants (n=10). Furthermore, we evaluated the effect of pulmonary vascular intervention (pulmonary endarterectomy or balloon angioplasty) on the individual components of the cascade (n=10).Results:Peak Vo2(oxygen uptake) was significantly reduced in patients with CTEPH relative to controls (56±17 versus 112±20% of predicted;P2cascade, including O2delivery (product of cardiac output and arterial O2content), skeletal muscle diffusion capacity, and pulmonary diffusion. The total O2extracted in the periphery (ie, ΔAVo2[arteriovenous O2content difference]) was not different. After pulmonary vascular intervention, peak Vo2increased significantly (from 12.5±4.0 to 17.8±7.5 mL/[kg·min];P=0.036) but remained below age-predicted levels (70±11%). The O2delivery was improved owing to an increase in peak cardiac output and lung diffusion capacity. However, peak exercise ΔAVo2was unchanged, as was skeletal muscle diffusion capacity.Conclusions:We demonstrated that patients with CTEPH have significant impairment of all steps in the O2use cascade, resulting in markedly impaired exercise capacity. Pulmonary vascular intervention increased peak Vo2by partly correcting O2delivery but had no effect on abnormalities in peripheral O2extraction. This suggests that current interventions only partially address patients’ limitations and that additional therapies may improve functional capacity.

Background During the COVID-19 pandemic, most of the health care systems suspended their non-urgent activities. This included the cancellation of consultations for patients with rare diseases, such as severe pulmonary hypertension (PH), resulting in potential medication shortage and loss of follow-up. Thus, the aim of the study was to evaluate PH patient health status evolution, access to health care and mental health experience during the early phase of the pandemic. Methods We conducted an online patient survey, available in 16 languages, between 22/05/2020 and 28/06/2020. The survey included questions corresponding to demographic, COVID-19 and PH related information. Results 1073 patients (or relatives, 27%) from 52 countries all over the world participated in the survey. Seventy-seven percent (77%) of responders reported a diagnosis of pulmonary arterial hypertension and 15% of chronic thromboembolic PH. The COVID-19 related events were few: only 1% of all responders reported a diagnosis of COVID-19. However, 8% of patients reported health deterioration possibly related to PH, and 4% hospitalization for PH. Besides, 11% of the patients reported difficulties to access their PH expert centre, and 3% interruption of treatment due to shortage of medication. Anxiety or depression was reported by 67% of the participants. Conclusion Although COVID-19 incidence in PH patients was low, PH related problems occurred frequently as the pandemic progressed, including difficulties to have access to specialized care. The importance of primary health care was emphasized. Further studies are needed to evaluate the long-term consequences of COVID-related PH care disruption.

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, r2 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.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition and a rare complication of pulmonary embolism (PE) [1]. It is characterised by increased pulmonary vascular resistance (PVR), due to unresolved fibro-thrombotic material obstructing large pulmonary arteries, and secondary microvasculopathy. Various factors are suspected to be involved in the pathogenesis and progression of CTEPH, including inflammatory thrombosis, dysregulated fibrinolysis and deficient angiogenesis [2]. The gold standard therapy is a surgical approach, namely pulmonary endarterectomy (PEA), consisting of removal of obstructing fibro-thrombotic material. Although long-term exposure to air pollution might influence several factors potentially contributing to the pathogenesis of CTEPH, including pulmonary and systemic inflammation, pro-thrombotic changes, oxidative stress, endothelial dysfunction and vasoconstriction [3, 4], no study has so far investigated the relationship between air pollution and CTEPH. Interestingly, epidemiologic and translational data supports the plausibility of a link between air pollution exposure, right ventricle failure and pulmonary hypertension (PH) [5–7]. Moreover, exposure to traffic-related air pollution was recently demonstrated being associated with disease severity and impaired survival in pulmonary arterial hypertension (PAH), characterised by progressive occlusion of precapillary arteries [8]. Eventually, a potential role of air pollution as a risk factor for developing venous thromboembolism has been suggested [9]. We consequently hypothesised that exposure to common air pollutants including particles with an aerodynamic diameter less than 2.5 or 10 µm (PM2.5, PM10), nitrogen dioxide (NO2), black carbon (BC) and traffic-related air pollution could influence the progression of CTEPH and interfere with disease outcomes. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Swinnen has nothing to disclose. Conflict of interest: Dr. Bijnens has nothing to disclose. Conflict of interest: Dr. Casas reports grants from Research Foundation Flanders (FWO), outside the submitted work. Conflict of interest: Dr. Nawrot has nothing to disclose. Conflict of interest: Dr. Delcroix reports grants and personal fees from Actelion/J&J, personal fees from Bayer, personal fees from MSD, personal fees from Reata, personal fees from Bellerophon, personal fees from Acceleron, outside the submitted work. Conflict of interest: Dr. Quarck has nothing to disclose. Conflict of interest: Dr. Belge reports personal fees from Actelion/Janssen, personal fees from MSD/Bayer, outside the submitted work.

Data concerning sleep-disordered breathing (SDB) after lung transplantation (LTX) are scarce. This study aims to analyze prevalence, associated factors, and impact on survival of moderate to severe SDB in a large cohort of consecutive LTX patients (n = 219). Patients underwent a diagnostic polysomnography 1 year after LTX. Moderate to severe SDB was present in 57.5% of patients, with the highest prevalence in chronic obstructive pulmonary disease/emphysema (71.1%) and pulmonary fibrosis (65.1%). SDB patients were older, mostly male, and had higher body mass index and neck circumference. Nocturnal diastolic and 24-hour blood pressures were higher in SDB patients. In 45 patients, polysomnography was also performed pre-LTX. Compared to pre-LTX, mean apnea/hypopnea index (AHI) increased significantly after LTX. A significant correlation was seen between lung function parameters and AHI, suggesting a role of decreased caudal traction on the pharynx. Presence of SDB had no impact on mortality or prevalence of chronic lung allograft dysfunction. However, survival was better in continuous positive airway pressure (CPAP) compliant SDB patients compared to SDB patients without CPAP treatment. These findings may be pertinent for systematic screening of SDB after LTX. ispartof: AMERICAN JOURNAL OF TRANSPLANTATION vol:21 issue:1 pages:281-290 ispartof: location:United States status: published

Rationale: Cardiovascular comorbidities are prevalent in patients after lung transplantation (LTX). While sleep apnea is known to be associated with cardiovascular problems, data concerning sleep apnea (SA) after LTX are scarce. The aim of this study is to analyze prevalence, associated factors and impact on survival of moderate to severe SA in a large cohort of consecutive LTX patients. Methods: Patients (n=219, 50,2% females) transplanted between February 2013 and March 2017 underwent a diagnostic polysomnography 1 year after LTX. Results: Moderate to severe SA was present in 57.5% of patients. SA patients were older, mostly male (57.9%) and had a higher BMI and neck circumference. The prevalence of moderate to severe SA was highest in COPD/emphysema patients (86/121; 71.1%) and pulmonary fibrosis (28/43; 65.1%). Nighttime diastolic and 24-hour blood pressures were higher in SA patients. Compared to pre-LTX, mean apnoea/hypopnoea index (AHI) increased significantly after LTX. A significant correlation was seen between lung function parameters and AHI. Presence of SA had no significant impact on mortality or prevalence of chronic lung allograft dysfunction. However, survival was significantly better in CPAP compliant SA patients compared to SA patients without CPAP treatment. Conclusion: The prevalence of SA one year after LTX was high, especially in patients with pre-LTX emphysema and pulmonary fibrosis. SA after LTX was associated with anthropometric, lung function parameters and higher blood pressure. CPAP compliant patients had a better survival than SA patients without CPAP treatment. These findings may ask for systemic screening of SA after LTX.

Intravascular leiomyomatosis (IVL) is a very rare condition. It is characterized by the proliferation of benign smooth muscle cells within vascular structures without invasion of these tissues. Symptoms depend on the site of origin and the extent of invasion. Rarely, this neoplasm is located in the inferior vena cava or in the pulmonary vasculature potentially causing symptoms of dyspnea, chest pain, or syncope. We report the case of a 53-year-old woman who was referred to our hospital with extensive pulmonary embolism comprising of a subtotal occlusion of the right pulmonary artery with extension into the left pulmonary artery. Due to persistent dyspnea (New York Heart Association class II) despite anticoagulation, after a six-week period, imaging was repeated and showed stable findings. As she was not responding to adequate anticoagulant therapy, intima sarcoma of the pulmonary artery was suspected, and a pulmonary endarterectomy (PEA) was performed. A smooth, white, intravascular mass was easily and completely removed. Analysis demonstrated a lesion consisting of cells without atypia, showing expression of alpha-smooth muscle actin (alpha SMA) and desmin with partial expression of estrogen receptor (ER) and progesterone receptor (PR), leading to the diagnosis of intravascular leiomyomatosis. The patient fully recovered. Complete surgical removal of the intravascular tumor is recommended to relieve symptoms and prevent possible complications. Clinicians have to be aware that in unresolved pulmonary embolism, nonthrombotic and rare causes, like an intima sarcoma or intravascular leiomyomatosis, should be considered. ispartof: Case Reports in Vascular Medicine vol:2020 pages:6084061- ispartof: location:United States status: published

Objectives:: Last years, vibrating devices were introduced to treat positional sleep apnoea (POSA). However, few data exist on determinants of effectiveness and adherence in clinical settin...

In the last decade significant research has focused on the relationship between physical activity (PA), exercise and obstructive sleep apnea (OSA). The purpose of this study is to provide an overview and interpretation of different studies regarding this subject.PubMed, Embase and Cochrane Library databases were searched for English articles published before August 21, 2017. Search terms were 'Sleep Apnea, Obstructive' and 'Exercise'.Low levels of PA are associated with higher odds of OSA. A negative correlation between PA level and OSA severity is shown, even after adjusting for baseline differences. OSA also impairs the aerobic exercise capacity significantly. OSA patients have a poor hemodynamic response to exercise, which is related to OSA severity. Findings on the influence of continuous positive airway pressure (CPAP) on PA in OSA are inconsistent in terms of statistical significance. A regular and predominantly aerobic exercise training significantly reduces OSA severity, even without a significant decrease in body weight.The available evidence suggests that further research is necessary to explore the relationships between PA, exercise and OSA and to examine the efficacy of exercise as alternative or additional treatment for OSA.

Background and objective Non-invasive ventilation (NIV) improves survival, quality of life and sleep in patients with amyotrophic lateral sclerosis (ALS). Nevertheless, NIV titration is conducted in different ways. We aim to provide more insight into NIV titration by comparing the effects of a spontaneous (S) and spontaneous-timed (ST) modes on gas exchange, sleep architecture and patient-ventilator asynchronies (PVAs). Methods After an initial night of NIV titration, patients were randomized to S or ST mode in a cross-over design. NIV was titrated using polysomnography, oximetry (oxygen saturation, SpO2 %) and transcutaneous carbon dioxide (PtcCO2 ) measurement. PVAs were analysed breath-by-breath. Results Thirteen patients were analysed after inclusion. ST mode showed better results in gas exchange (minimal SpO2 %: 83 (80–89)% vs 87 (84–89)%; oxygen desaturation index: 15 (5–28)/h sleep vs 7 (3–9)/h sleep; PtcCO2 >55 mm Hg: 20 (0–59)% vs 0 (0–27)% total sleep time for S and ST mode, respectively, all P

Pulmonary arterial hypertension is a rare and incurable chronic disease characterised by a progressive increase in pulmonary vascular resistance and right heart failure. Patient registries collecting observational data can be of great value in the understanding of clinical problems. While clinical trials provide data in selected patient populations, registries better depict real-life practice. This review aims to reflect the input of patient registries in the general knowledge of the disease. Advances in epidemiology of the different subgroups, including data on incidence and/or prevalence, increasing age at presentation and stagnating diagnostic delay are reported. The importance of haemodynamic definition criteria and cardiac comorbidities are underscored. The review also shows the major transformation that pulmonary arterial hypertension therapeutic management has undergone, with still insufficient use of combination therapies; consecutive improvement in outcome; upcoming evidence in disfavour of anticoagulation; and validity of the available risk-stratification tools derived from large registries. Product registries are also briefly presented. Finally, the benefits of registries and methodological aspects are discussed, including immortal time bias, registry data quality and recommendations from EU organisations (EUCERD and PARENT). ispartof: EUROPEAN RESPIRATORY REVIEW vol:28 issue:154 ispartof: location:England status: published

The bone morphogenetic protein receptor II (BMPRII) signaling pathway is impaired in pulmonary arterial hypertension and mutations in the BMPR2 gene have been observed in both heritable and idiopathic pulmonary arterial hypertension. However, all BMPR2 mutation carriers do not develop pulmonary arterial hypertension, and inflammation could trigger the development of the disease in BMPR2 mutation carriers. Circulating levels and/or lung tissue expression of cytokines such as tumor necrosis factor-α or interleukin-18 are elevated in patients with pulmonary arterial hypertension and could be involved in the pathogenesis of pulmonary arterial hypertension. We consequently hypothesized that cytokines could trigger endothelial dysfunction in addition to impaired BMPRII signaling. Our aim was to determine whether impairment of BMPRII signaling might affect endothelium barrier function and adhesiveness to monocytes, in response to cytokines. BMPR2 was silenced in human lung microvascular endothelial cells (HLMVECs) using lentiviral vectors encoding microRNA-based hairpins. Effects of tumor necrosis factor-α and interleukin-18 on HLMVEC adhesiveness to the human monocyte cell line THP-1, adhesion molecule expression, endothelial barrier function and activation of P38MAPK were investigated in vitro. Stable BMPR2 silencing in HLMVECs resulted in impaired endothelial barrier function and constitutive activation of P38MAPK. Adhesiveness of BMPR2-silenced HLMVECs to THP-1 cells was enhanced by tumor necrosis factor-α and interleukin-18 through ICAM-1 adhesion molecule. Interestingly, tumor necrosis factor-α induced activation of P38MAPK and disrupted endothelial barrier function in BMPR2-silenced HLMVECs. Altogether, our findings showed that stable BMPR2 silencing resulted in impaired endothelial barrier function and activation of P38MAPK in HLMVECs. In BMPR2-silenced HLMVECs, cytokines enhanced adhesiveness capacities, activation of P38MAPK and impaired endothelial barrier function suggesting that cytokines could trigger the development of pulmonary arterial hypertension in a context of impaired BMPRII signaling pathway. ispartof: PULMONARY CIRCULATION vol:9 issue:4 ispartof: location:United States status: published

Pulmonary arterial hypertension (PAH) is a severe condition characterised by remodelling of precapillary pulmonary arteries sometimes associated with mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene. Even in the absence of BMPR2 mutations, increased transforming growth factor (TGF)β receptor signalling and decreased BMPRII signalling have been shown to contribute to PAH pathogenesis. In this Keynote, we review the potential mechanisms by which the imbalance of BMP/TGFβ signalling contributes to endothelial dysfunction, vascular remodelling, inflammation and disordered angiogenesis in PAH. Additionally, we highlight how currently used drugs can influence BMP/TGFβ signalling. Finally, we browse the newly developed therapeutic approaches targeting BMPRII and TGFβ signalling pathways by focusing on preclinical studies and clinical trials and put them into perspectives. ispartof: DRUG DISCOVERY TODAY vol:24 issue:3 pages:703-716 ispartof: location:England status: published

INTRODUCTION Continuous positive airway pressure (CPAP)-therapy is the first-line treatment for moderate to severe obstructive sleep apnoea (OSA). A significant limitation of CPAP treatment is the poor therapy adherence, compromising the beneficial effects. OBJECTIVE This study evaluates three different educational approaches and their effect on therapy adherence. METHOD This single-center, retrospective study compared three groups of 100 consecutive, CPAP-naive patients with moderate to severe OSA who were started on CPAP therapy. Group 1 and 2 received the same individual structured education on two consecutive days with an extra phone call 7 to 10 days after CPAP start in group 2. Group 3 received individual structured education on the first day and participated in a group education using a slide presentation open for discussion on the second day. Re-evaluation was performed after 24 weeks. RESULTS Baseline characteristics did not differ significantly between groups. During the 24 weeks follow-up there was a drop-out rate of 16% (group 1), 12% (group 2) and 5% (group 3). In the patients still on CPAP after 24 weeks, the mean nightly CPAP usage was, respectively, 4.7 ± 1.8, 5.2 ± 2.3 and 5.7 ± 2.1 h/night. In group 3 both the drop-out rate and mean CPAP usage were significantly different (P values, respectively, P

Little is known about the effects of noninvasive ventilation (NIV) on sleep quality in amyotrophic lateral sclerosis (ALS). We aim to evaluate the long-term effects of NIV on sleep quality and quality of life in patients with ALS.In this prospective observational study, 13 ALS patients were followed for one year after initiating NIV. We evaluated sleep quality, quality of life and functional status with several questionnaires: Epworth sleepiness Scale (ESS), Pittsburg sleep quality index (PSQI), Short Form 36 Health Questionnaire (SF-36), McGill Quality of Life questionnaire (McGillQoL) and revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores (ALSFRS-R).Median and interquartile range (IQR) at the start of NIV was 59 (53-65) years. The ALSFRS-R at start was 30 (24-37) (median, IQR), with three patients having severe bulbar impairment (ALSFRS-R-bulbar ≤ 9). The PWe conclude that accurately titrated NIV in ALS patients can stabilize sleep quality and quality of life for at least one year, despite significant disease progression.

PURPOSE: To evaluate the safety and efficacy of balloon pulmonary angioplasty (BPA) for nonoperable chronic thromboembolic pulmonary hypertension (CTEPH) patients during the initial experience of a single center. METHODS: A total of 18 CTEPH patients (5 with residual pulmonary hypertension after pulmonary endarterectomy) were treated with BPA during the period 2014-2018 and were retrospectively reviewed. Mean age was 61 ± 19 years; 55% were female; mean pulmonary artery pressure was 44 ± 12 mmHg; cardiac output was 4.3 ± 1.0 l/min; and pulmonary vascular resistance was 8.4 ± 3.6 WU. Patients were evaluated by New York Heart Association functional class, 6-minute walk distance, N-terminal pro b-type natriuretic peptide, echocardiography, right heart catheterization, and before and after completions of BPA. RESULTS: A total of 91 procedures were performed, with a median number of 4 BPA sessions per patient (range, 2-8). There were no deaths or major complications requiring extracorporeal support or (non)invasive ventilation. The most common complication was self-limiting hemoptysis (3%). According to Society of Interventional Radiology classification, 4 mild, 4 moderate, and 1 severe adverse events were noted. Invasive hemodynamics significantly improved, with a cardiac index increase of 15% (P = .0333), decrease of mean pulmonary artery pressure of 30% (P = .0013), and decrease of pulmonary vascular resistance of 45% (P = .0048). Stroke volume index (P = .0171) and pulmonary arterial compliance (P = .0004) were also significantly enhanced. CONCLUSIONS: BPA significantly improves cardiopulmonary hemodynamics with an acceptable safety profile. Further studies assessing the long-term efficacy of BPA are required. ispartof: JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY vol:30 issue:8 pages:1265-1272 ispartof: location:United States status: published

Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe disease characterized by unresolved and organized thrombi obstructing the pulmonary arterial bed, resulting in PH and right ventricular (RV) failure. We previously found that repeated embolization and fibrinolysis inhibition induced CTEPH in rabbits. Neovascularization may play a role in resolving venous thrombi. We hypothesized that inhibition of angiogenesis may prevent clot resolution and promote CTEPH progression. We aimed to investigate whether repeated embolization with blood clots containing an inhibitor of angiogenesis may induce CTEPH in rabbits. Adult male New Zealand rabbits were weekly embolized (x 7) with autologous blood clots containing Sugen, an inhibitor of VEGF receptor, or not. Right heart catheterization was performed 8 weeks after the last embolization. RV function was assessed by transthoracic echocardiography at baseline, after the last embolization and before sacrifice. RV hypertrophy and lung vessel morphometry were analyzed. Repeated embolization with clots containing Sugen resulted in a 44% increase in mean pulmonary arterial pressure, a 2-fold increase in pulmonary vascular resistance index without any change in cardiac output and a 37 % increase in RV diameter compared to baseline; it also induced fibro-thrombotic lesions in large proximal pulmonary arteries and remodeling of distal pulmonary arteries. Embolization with autologous blood clots containing Sugen promoted CTEPH development in rabbits. Obstruction of large proximal pulmonary arteries by fibro-thrombotic lesions highlights the similarity with the human pathology of CTEPH.

Bone morphogenetic protein receptor II (BMPRII) signaling pathway is impaired in pulmonary arterial hypertension (PAH) and mutations in the BMPR2 gene are associated with both heritable and idiopathic PAH. Endothelial dysfunction is a key process in initiation and progression of PAH pathogenesis. We aimed to investigate whether loss of BMPRII could affect endothelial function, including endothelial integrity and angiogenesis of pulmonary lung microvascular endothelial cells (HLMVEC). BMPR2 knockdown was performed in HLMVEC using lentiviral vectors encoding microRNA-based hairpins against BMPR2. HLMVEC lines were established and phenotyped. BMPRII protein expression and activation of BMPRII downstream effectors, SMAD and p38MAPK, were investigated by Western blotting. Effects of BMPR2 knockdown on endothelial integrity using a permeability assay and angiogenic capacities were further evaluated in vitro using migration and tube formation assays. Stable BMPR2 silencing did not affect HLMVEC phenotype, resulted in i) a 87% decrease in BMPRII protein expression, ii) a 50% decrease in SMAD protein activation and iii) a 48% increase in p38 MAPK phosphorylation. Interestingly, loss of BMPRII resulted in a 24% significant decrease in barrier function and a 29% decrease in migration capacity and impaired 3D-angiogenesis in vitro. Stable BMPR2 silencing in HLMVECs results in a shift in attenuated activation of the canonical SMAD signaling into enhanced activation of the non-canonical p38 MAPK signaling. In addition, impaired BMPRII signaling induced a loss of barrier function and decreased angiogenic capacities indicating the involvement of BMPRII in endothelial dysfunction in PAH.

Transplant type for end-stage pulmonary vascular disease remains debatable. We compared recipient outcome after heart-lung (HLT) versus double-lung (DLT) transplantation. Single-center analysis (38 HLT-30 DLT; 1991-2014) for different causes of precapillary pulmonary hypertension (PH): idiopathic (22); heritable (two); drug-induced (nine); hepato-portal (one); connective tissue disease (four); congenital heart disease (CHD) (24); chronic thromboembolic PH (six). HLT decreased from 91.7% [1991-1995] to 21.4% [2010-2014]. Re-intervention for bleeding was higher after HLT; (P = 0.06) while primary graft dysfunction grades 2 and 3 occurred more after DLT; (P

Pulmonary arterial hypertension is a severe disease with a 1-year mortality of over 10%. Since it is a rare disease, it is usually managed in expert centres. However, life-threatening complications can occur at any moment and place and should be adequately taken care of to prevent avoidable deaths. Therefore, based on an analysis of the causes of death, this chapter describes the most important complications and their management: right heart failure, arrhythmias, haemoptysis, pericardial effusion, pulmonary arterial dilation with as a consequence left main coronary artery compression, and pulmonary artery dissection, as well as treatment-related adverse events.

OBJECTIVES: This study was a comprehensive evaluation of cardiopulmonary function in patients with chronic thromboembolic (pulmonary vascular) disease (CTED) during exercise. BACKGROUND: Exertional dyspnea is frequent following pulmonary embolism, but only a minority of patients eventually develops chronic thromboembolic pulmonary hypertension (CTEPH). Better understanding of the factors that limit exercise capacity in patients with persistent pulmonary artery obstruction could help to further define the entity of CTED. METHODS: Fifty-two subjects (13 healthy control subjects, 14 CTED patients, and 25 CTEPH patients) underwent cardiopulmonary exercise testing and exercise cardiac magnetic resonance with simultaneous invasive pressure registration. Pulmonary vascular function and right ventricular contractile reserve were assessed through combined invasive pressure measurements and magnetic resonance imaging volume measures. RESULTS: Exercise capacity was reduced by 29% and 57% in patients with CTED and CTEPH respectively, compared with control subjects. Both CTED (3.48 [interquartile range: 2.24 to 4.36] mm Hg × l-1 × min-1) and CTEPH patients (8.85 [interquartile range: 7.18 to 10.4] mm Hg × l-1 × min-1) had abnormal total pulmonary vascular resistance. Right ventricular contractile reserve was reduced in CTED patients compared with control subjects (2.23 ± 0.55 vs. 3.72 ± 0.94), but was still higher than that in CTEPH patients (1.34 ± 0.24; p < 0.001). As opposed to patients with CTEPH in whom right ventricular ejection fraction declined with exercise, right ventricular ejection fraction still increased in patients with CTED, albeit to a lesser extent than in healthy control subjects (interaction p < 0.001), which illustrated the distinct patterns of ventricular-arterial coupling. CONCLUSIONS: CTED represents an intermediate clinical phenotype. Exercise imaging unmasks cardiovascular dysfunction not evident at rest and identifies hemodynamically significant disease that results from reduced contractile reserve or increased vascular load. ispartof: JACC-Cardiovascular Imaging vol:12 issue:8 pages:1-3 ispartof: location:United States status: Published online

Pulmonary Arterial Hypertension (PAH) imposes a substantial burden on individuals with the disease. The symptoms of PAH are unspecific and of varying severities; breathlessness, fatigue, edema of the lower limbs, dizziness and syncope. The importance of measuring the associated impact on health-related quality of life (HRQoL) is increasingly recognized and new instruments are available. This article reviews the validation and use of recently published questionnaires to evaluate HRQoL in PAH, the economic burden of PAH and new evidence in non-pharmacological supportive treatments. ispartof: General Internal Medicine and Clinical Innovations vol:3 issue:3 pages:1-4 status: published

Background: There is a high prevalence of poor sleep quality in patients with pulmonary arterial hypertension (PAH). However, the impact of insomnia on exercise capacity and quality of life (QOL) in these patients is unclear. Moreover, there is a lack of data on the use of sleep medication and the effects of cognitive behavioural therapy for insomnia (CBTI) in PAH. Methods: Patients who visited the outpatient clinic of a tertiary centre from September 2015 to March 2016 were asked to complete the Pittsburgh Sleep Quality Index, the Insomnia Severity Index, the Epworth Sleepiness Scale, the Depression Anxiety Stress Scales and the 36-Item Short Form Survey. Exercise capacity was assessed by six-minute walk distance (6MWD). Results: Seventy-two PAH patients (median age 60y, 75% female) were enrolled. More than half (52%) of the patients had a poor sleep quality, 13% had clinical insomnia. Patients with poor sleep quality had a significant lower 6MWD (479 vs 368 m, p=0.003). A significantly higher Borg score was found in patients with insomnia (5 vs 7, p=0.019). Insomnia patients were significantly more depressed, had a worse NYHA class and a lower QOL. Benzodiazepines, z-drugs and antidepressants use was twice as high for insomnia patients. A total of 40% of all PAH patients used psychotropics. Only 5% of the patients with poor sleep quality agreed to follow CBTI. In these patients an improvement in NYHA class and the 6MWD was seen after three months. Conclusion: The high prevalence of poor sleep quality and insomnia in patients with PAH warrants regular screening and appropriate treatment. Treating sleep problems may contribute to improve the QOL and exercise capacity in PAH.

Alkylating agents can induce pulmonary veno-occlusive disease (PVOD) in animals and human. Mitomycin, used to treat anal and renal cancer, can induce PVOD in rats and human. The aim of the study was to investigate the effects of mitomycin on pulmonary hemodynamics and vessel remodeling in rabbits. Mitomycin (n=14) or saline (controls; n=5) was injected intraperitoneally in female rabbits twice at one-week interval in the presence or not of an antiemetic (maropitant citrate or metoclopramide). Animals underwent right heart catheterization (RHC) 5 weeks after the second injection; lungs and heart were collected. Fulton index was calculated to evaluate right ventricular hypertrophy. Sections of pulmonary tissue were stained with trichrome-Masson and immunohistochemistry against α-smooth muscle actin was performed. RHC was performed in 8 animals; lungs and heart were collected from 11 animals. Mean pulmonary arterial pressure (mPAP) was significantly increased in mitomycin-treated rabbits compared to controls animals (35 vs. 14 mmHg). mPAP was significantly correlated with Fulton index in mitomycin treated animals (r=0.71, p=0.009). Remodeling (muscularization, media thickening) of pulmonary arteries and fibrosis of pulmonary veins were observed. Mortality decreased from 75% to 28% in the presence of an antiemetic. In animals which did not receive any antiemetic, infiltration of inflammatory cells (macrophages and lymphocytes) was found. To conclude, mitomycin-treated female rabbits developed signs of pulmonary hypertension characterized by an elevated mPAP and distal arteriopathy, and of PVOD as indicated by venous fibrosis, suggesting that this animal model could serve as a model of PVOD.

We report the case of a 50-year-old woman with anorexigen-induced pulmonary arterial hypertension treated with epoprostenol, who presented with Trousseau's sign, leading to the diagnosis of severe hypocalcemia for which substitution was started (initially orally, followed by intravenous substitution). After further analysis, we assume that epoprostenol-induced diarrhea caused malabsorption (as other reasons were excluded), leading to nutritional osteomalacia with secondary hyperparathyroidism. We discovered that even more severe hypocalcemia was induced by the treatment with the anti-osteoporotic drug denosumab, which was started after the diagnosis of osteoporosis on bone densitometry. In our opinion, clinicians have to be aware that in patients with malabsorption, antiresorptive therapy can induce dangerous and even life-threatening hypocalcemia, even in patients with normal renal function. ispartof: Respiration vol:95 issue:2 pages:139-142 ispartof: location:Switzerland status: published