Pulmonary Arterial Hypertension Therapy Research Articles

Selonsertib in adults with pulmonary arterial hypertension (ARROW): a randomised, double-blind, placebo-controlled, phase 2 trial

Data obtained in human lung tissue and preclinical models suggest that oxidative stress and increased apoptosis signal-regulating kinase 1 (ASK1) activity might have a prominent role in the pathobiology of pulmonary arterial hypertension (PAH). The purpose of this study was to determine the efficacy, safety, and tolerability of the ASK1 inhibitor selonsertib compared with placebo in patients with PAH. We did a randomised, double-blind, placebo-controlled, phase 2 trial at 46 centres located in Canada, France, Germany, Italy, the Netherlands, Spain, the UK, and the USA. Participants were aged 18-75 years and had an established diagnosis of idiopathic or hereditary PAH, or PAH associated with connective tissue disease, drugs or toxins, human immunodeficiency virus, or repaired congenital heart defects. Patients were stratified by PAH aetiology and background therapy, and randomly assigned (1:1:1:1) using an interactive voice-response or web-response system to placebo or selonsertib 2 mg, 6 mg, or 18 mg administered orally once daily. Both placebo and selonsertib were in tablet form. The primary efficacy endpoint was change in pulmonary vascular resistance, measured by right heart catheterisation, from baseline to week 24 in the full analysis set. Pair-wise comparisons between each of the selonsertib groups and the placebo group were made with a stratified Wilcoxon (van Elteren) rank sum test for participants without major protocol deviations who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02234141. Between Dec 3, 2014, and Nov 13, 2015, 151 patients were enrolled and randomly assigned. Of 150 participants who received selonsertib or placebo, 134 (89%) completed 24 weeks of the randomly assigned treatment; all were on background PAH therapy (138 [92%] on combination therapy). 90 (60%) patients were in functional class II and 60 (40%) in functional class III. Mean baseline pulmonary vascular resistance was 772 (SD 334) dyn·s/cm5. Change in pulmonary vascular resistance was 6·0 dyn·s/cm5 (SD 28·0; n=31) for placebo, and 35·0 (35·4) dyn·s/cm5 (n=35; p=0·21 vs placebo) for 2 mg selonsertib, -28·0 (30·2) dyn·s/cm5 (n=34; p=0·27 vs placebo) for 6 mg selonsertib, and -21·0 (37·9) dyn·s/cm5 (n=36; p=0·60 vs placebo) for 18 mg selonsertib. The most frequent adverse events were headache (17 [15%]), abnormal dreams (eight [7%]), nausea (seven [6%]), and diarrhoea (seven [6%]) in the selonsertib groups, and headache (six [16%]), nausea (five [14%]), and diarrhoea (two [5%]) in the placebo group. Serious adverse events occurred in 23 (20%) of 113 selonsertib-treated patients and seven (19%) of 37 patients who received placebo. Selonsertib once daily for 24 weeks did not lead to a significant reduction in pulmonary vascular resistance or to clinical improvement in patients with PAH, but appeared to be safe and well tolerated. Although these data do not support the clinical use of selonsertib in PAH, further study of the potential of targeting the ASK1-p38 pathway in PAH is warranted. Gilead Sciences.

Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells.

Excessive pulmonary artery (PA) smooth muscle cell (PASMC) proliferation and migration are implicated in the development of pathogenic pulmonary vascular remodeling characterized by concentric arterial wall thickening and arteriole muscularization in patients with pulmonary arterial hypertension (PAH). Pulmonary artery smooth muscle cell contractile-to-proliferative phenotypical transition is a process that promotes pulmonary vascular remodeling. A rise in cytosolic Ca2+ concentration [(Ca2+)cyt] in PASMCs is a trigger for pulmonary vasoconstriction and a stimulus for pulmonary vascular remodeling. Here, we report that the calcium homeostasis modulator (CALHM), a Ca2+ (and ATP) channel that is allosterically regulated by voltage and extracellular Ca2+, is upregulated during the PASMC contractile-to-proliferative phenotypical transition. Protein expression of CALHM1/2 in primary cultured PASMCs in media containing serum and growth factors (proliferative PASMC) was significantly greater than in freshly isolated PA (contractile PASMC) from the same rat. Upregulated CALHM1/2 in proliferative PASMCs were associated with an increased ratio of pAKT/AKT and pmTOR/mTOR and an increased expression of the cell proliferation marker PCNA, whereas serum starvation and rapamycin significantly downregulated CALHM1/2. Furthermore, CALHM1/2 were upregulated in freshly isolated PA from rats with monocrotaline (MCT)-induced PH and in primary cultured PASMC from patients with PAH in comparison to normal controls. Intraperitoneal injection of CGP 37157 (0.6 mg/kg, q8H), a non-selective blocker of CALHM channels, partially reversed established experimental PH. These data suggest that CALHM upregulation is involved in PASMC contractile-to-proliferative phenotypical transition. Ca2+ influx through upregulated CALHM1/2 may play an important role in the transition of sustained vasoconstriction to excessive vascular remodeling in PAH or precapillary PH. Calcium homeostasis modulator could potentially be a target to develop novel therapies for PAH.

Novel Experimental Therapies for Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive and devastating disease characterized by pulmonary artery vasoconstriction and vascular remodeling leading to vascular rarefaction with elevation of pulmonary arterial pressures and pulmonary vascular resistance. Often PAH will cause death from right heart failure. Current PAH-targeted therapies improve functional capacity, pulmonary hemodynamics and reduce hospitalization. Nevertheless, today PAH still remains incurable and is often refractory to medical therapy, underscoring the need for further research. Over the last three decades, PAH has evolved from a disease of unknown pathogenesis devoid of effective therapy to a condition whose cellular, genetic and molecular underpinnings are unfolding. This article provides an update on current knowledge and summarizes the progression in recent advances in pharmacological therapy in PAH.

Quality of life of patients with pulmonary arterial hypertension: a meta-analysis.

Pulmonary arterial hypertension (PAH) is a rare condition, with an incidence of 15-50 cases per million annually. Available studies demonstrate that despite the longer survival of PAH patients, their quality of life (QoL) deteriorates as the condition progresses. Consequently, the goals of PAH therapy have expanded from increasing survival to improving health-related quality of life. The objective of this systematic review and meta-analysis was to summarize the available evidence about the level of QoL in patients with PAH. A systematic search was performed using the Cochrane guidelines for conducting meta-analysis following the PRISMA statement. The meta-analysis includes findings from 11 studies evaluating the QoL of PAH patients at baseline and at follow-up (12 weeks) using the Short Form (36) Health Survey (SF-36), the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR). The mean physical component score (SF-36) for the group was 37.2 points (95% CI: 33.24-41.16) and the heterogeneity coefficient was I²=97.71% (p < 0.001). The mean mental component score (SF-36) was 46.38 (95% CI: 44.21-48.56) and the heterogeneity coefficient was I²=87.92% (p < 0.001). The result indicates improved QoL 12 weeks after the intervention, though three papers did not fully confirm this. The greatest improvement in QoL was found in patients treated with bosentan and iloprost and the smallest improvement in QoL was found in patients treated with epoprostenol sodium. The heterogeneity coefficient was I²=91.36%, p < 0.001 for CAMPHOR and I²=97.65%, p < 0.001 for MLHFQ. PAH patients tend to have a poor QoL, mainly in the physical functioning domain, less so in the psychological functioning domain. QoL may be improved by therapeutic interventions, mainly pharmaceutical ones. Patients with PAH also tend to suffer from depression, anxiety, stress, or sleep disorders. All these factors are significantly correlated with poorer QoL.

A randomized, double-blind, placebo-controlled study to evaluate sildenafil, ambrisentan combination therapy in pulmonary hypertension, particularly of Eisenmenger syndrome

Pulmonary arterial hypertension (PAH) - a complex and progressive disease that carries significant morbidity and mortality despite optimal medical treatment. Combination therapy for PAH can be more effective than monotherapy. The present randomized trial compared the safety and efficacy of sildenafil ambrisentan combination therapy with sildenafil monotherapy. Twenty-two patients of Eisenmenger syndrome and five patients of idiopathic PAH were randomized to two arms. There was a significant improvement in NYHA functional class and mean pulmonary artery pressure, while an insignificant improving trend was observed for 6-min walk distance and oxygen saturation, following the 12 weeks of combination therapy. An upfront combination therapy was found to be safe and effective in the management of PAH patients.

Pulmonary Arterial Hypertension and Intraductal Papillary Mucinous Neoplasms of the Pancreas: A Novel Association?

Pulmonary arterial hypertension (PAH) is a rare, proliferative disease of the precapillary pulmonary vasculature, characterized by elevated pulmonary vascular resistance and resultant right ventricular failure.1 Although new PAH therapies have resulted in substantially improved patient survival,2 increased longevity has been accompanied by a growing incidence of other medical comorbidities. We herein report a possible association between two seemingly unrelated, rare conditions, PAH and intraductal papillary mucinous neoplasm (IPMN) of the pancreas.

Pressure-based estimation of right ventricular ejection fraction: Validation as a clinically relevant target for drug development in a rodent model of pulmonary hypertension

Depressed right ventricular ejection fraction (RVEF) has clear prognostic significance in patients with pulmonary arterial hypertension (PAH). Accordingly, improvements in RVEF represent a desirable end-point in the development of PAH therapies. However, current methods for determination of RVEF require measurement of RV volume and are relatively complex and costly. Here, we validate a novel method for quantitative estimation of RVEF in rats based entirely upon analysis of readily available RV pressure waveforms that eliminates the need for simultaneous volume measurement and can be rapidly applied.Right ventricular pressure and volume (conductance catheter) measurements acquired from 15 rats (7 controls, 8 sugen/hypoxia PAH; 220–250 g) were used for the study. Over the same 10 beat interval, RVEF was directly measured from the volume signal and estimated from the pressure signal. Simultaneous measures were compared by linear regression and Bland-Altman analysis to define bias (accuracy) and precision.Measured RVEF ranged from 0.19 to 0.60 (mean 0.44 ± 0.10) and estimated from 0.19 to 0.52 (mean 0.42 ± 0.09). Across the dataset there was strong correlation (r2 = 0.813), with minimal bias (0.01) and an overall error of 20% consistent with acceptable accuracy and precision.Study results support the potential utility of a method based entirely upon analysis of the RV pressure waveform for assessing drug effects on RVEF in rat models of PAH.

Current strategies for managing chronic thromboembolic pulmonary hypertension: results of the worldwide prospective CTEPH Registry.

BackgroundPulmonary endarterectomy (PEA), pulmonary arterial hypertension (PAH) therapy and balloon pulmonary angioplasty (BPA) are currently accepted therapies for chronic thromboembolic pulmonary hypertension (CTEPH). This international CTEPH Registry identifies clinical characteristics of patients, diagnostic algorithms and treatment decisions in a global context.Methods1010 newly diagnosed consecutive patients were included in the registry between February 2015 and September 2016. Diagnosis was confirmed by right heart catheterisation, ventilation–perfusion lung scan, computerised pulmonary angiography and/or invasive pulmonary angiography after at least 3 months on anticoagulation.ResultsOverall, 649 patients (64.3%) were considered for PEA, 193 (19.1%) for BPA, 20 (2.0%) for both PEA and BPA, and 148 (14.7%) for PAH therapy only. Reasons for PEA inoperability were technical inaccessibility (n=235), comorbidities (n=63) and patient refusal (n=44). In Europe and America and other countries (AAO), 72% of patients were deemed suitable for PEA, whereas in Japan, 70% of patients were offered BPA as first choice. Sex was evenly balanced, except in Japan where 75% of patients were female. A history of acute pulmonary embolism was reported for 65.6% of patients. At least one PAH therapy was initiated in 35.8% of patients (26.2% of PEA candidates, 54.5% of BPA candidates and 54.1% of those not eligible for either PEA or BPA). At the time of analysis, 39 patients (3.9%) had died of pulmonary hypertension-related causes (3.5% after PEA and 1.8% after BPA).ConclusionsThe registry revealed noticeable differences in patient characteristics (rates of pulmonary embolism and sex) and therapeutic approaches in Japan compared with Europe and AAO.

Parenteral Prostanoids in Pediatric Pulmonary Arterial Hypertension: Start Early, Dose High, Combine.

RationaleThere are currently no data supporting specific dosing and weaning strategies for parenteral prostanoid therapy in children with pulmonary arterial hypertension (PAH).ObjectivesTo describe the clinical practice of intravenous (IV) or subcutaneous (SC) prostanoid therapy in pediatric PAH and identify dosing strategies associated with favorable outcome.MethodsFrom an international multicenter cohort of 275 children with PAH, 98 patients who received IV/SC prostanoid therapy were retrospectively analyzed.ResultsIV/SC prostanoids were given as monotherapy (20%) or combined with other PAH-targeted drugs as dual (46%) or triple therapy (34%). The median time-averaged dose was 37 ng/kg/min, ranging 2–136 ng/kg/min. During follow-up, IV/SC prostanoids were discontinued and transitioned to oral or inhaled PAH-targeted therapies in 29 patients. Time-dependent receiver operating characteristic analyses showed specific hemodynamic criteria at discontinuation of IV/SC prostanoids (mean pulmonary arterial pressure < 35 mm Hg and/or pulmonary vascular resistance index < 4.4 Wood units [WU]⋅m2) identified children with favorable long-term outcome after IV/SC prostanoid discontinuation, compared with patients who do not meet those criteria (P = 0.027). In the children who continued IV/SC prostanoids until the end of follow-up, higher dose (>25 ng/kg/min), early start after diagnosis, and combination with other PAH-targeted drugs were associated with better transplant-free survival.ConclusionsEarly initiation of IV/SC prostanoids, higher doses of IV/SC prostanoids, and combination with additional PAH-targeted therapy were associated with favorable outcome. Transition from IV/SC prostanoid therapy to oral or inhaled therapies is safe in the long term in selected children, identified by reaching hemodynamic criteria for durable IV/SC prostanoid discontinuation while on IV/SC prostanoid therapy.

Severe Pulmonary Arterial Hypertension Is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency

BackgroundPreclinical evidence implicates neutrophil elastase (NE) in pulmonary arterial hypertension (PAH) pathogenesis, and the NE inhibitor elafin is under early therapeutic investigation.Research QuestionAre circulating NE and elafin levels abnormal in PAH and are they associated with clinical severity?Study Design and MethodsIn an observational Stanford University PAH cohort (n = 249), plasma NE and elafin levels were measured in comparison with those of healthy control participants (n = 106). NE and elafin measurements were then related to PAH clinical features and relevant ancillary biomarkers. Cox regression models were fitted with cubic spline functions to associate NE and elafin levels with survival. To validate prognostic relationships, we analyzed two United Kingdom cohorts (n = 75 and n = 357). Mixed-effects models evaluated NE and elafin changes during disease progression. Finally, we studied effects of NE-elafin balance on pulmonary artery endothelial cells (PAECs) from patients with PAH.ResultsRelative to control participants, patients with PAH were found to have increased NE levels (205.1 ng/mL [interquartile range (IQR), 123.6-387.3 ng/mL] vs 97.6 ng/mL [IQR, 74.4-126.6 ng/mL]; P < .0001) and decreased elafin levels (32.0 ng/mL [IQR, 15.3-59.1 ng/mL] vs 45.5 ng/mL [IQR, 28.1-92.8 ng/mL]; P < .0001) independent of PAH subtype, illness duration, and therapies. Higher NE levels were associated with worse symptom severity, shorter 6-min walk distance, higher N-terminal pro-type brain natriuretic peptide levels, greater right ventricular dysfunction, worse hemodynamics, increased circulating neutrophil levels, elevated cytokine levels, and lower blood BMPR2 expression. In Stanford patients, NE levels of > 168.5 ng/mL portended increased mortality risk after adjustment for known clinical predictors (hazard ratio [HR], 2.52; CI, 1.36-4.65, P = .003) or prognostic cytokines (HR, 2.63; CI, 1.42-4.87; P = .001), and the NE level added incremental value to established PAH risk scores. Similar prognostic thresholds were identified in validation cohorts. Longitudinal NE changes tracked with clinical trends and outcomes. PAH PAECs exhibited increased apoptosis and attenuated angiogenesis when exposed to NE at the level observed in patients’ blood. Elafin rescued PAEC homeostasis, yet the required dose exceeded levels found in patients.InterpretationBlood levels of NE are increased while elafin levels are deficient across PAH subtypes. Higher NE levels are associated with worse clinical disease severity and outcomes, and this target-specific biomarker could facilitate therapeutic development of elafin.

Impact of SARS-CoV-2-Pandemic on Mental Disorders and Quality of Life in Patients With Pulmonary Arterial Hypertension.

Background/Objective: Covid-19 pandemic may affect mental health and quality of life (QoL) in patients with pulmonary arterial hypertension (PAH). We assessed changes in anxiety and depression, quality of life (QoL) and self-described impact of Covid-19 in patients with PAH during the Covid-19 pandemic.Methods: This study included 152 patients with PAH from two German referral centers. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS-A and HADS-D) at two different timepoints before and during the Covid-19 pandemic with a median of 232 days between baseline and follow-up. QoL was assessed using EQ-5D and emPHasis-10. Perceived impact of Covid-19 and related regulations and measures were assessed using a set of specific questions and statements.Results: More than two thirds of patients had an unsuspicious HADS-A and HADS-D. Median scores did not differ from baseline for both HADS-A and HADS-D (p = 0.202; p = 0.621). Overall, no significant changes in HADS-A or HADS-D categories from baseline to follow up were observed (p = 0.07; p = 0.13). QoL did not change between baseline and follow-up. The Covid-19 pandemic had little impact on access to medical care and established PAH therapy. Patients were in agreement with governmental measures and regulations and felt sufficiently safe.Conclusion: First waves of Covid-19 pandemic had little impact on anxiety, depression and QoL in patient with PAH. Established PAH therapy and access to medical care were not affected. Further studies on the impact of prolonged duration of the ongoing Covid-19 pandemic are needed.

Metabolics of PH - an update.

While there has been a longstanding interest in metabolic disease in pulmonary hypertension, publications in the last several years have translated basic science findings to human disease and even led to recently published studies of metabolic therapy in pulmonary arterial hypertension that are discussed here. Progress has been made in four key areas including mechanisms of insulin resistance in pulmonary arterial hypertension, the role of obesity in pulmonary vascular disease, novel clinical trials targeting metabolism in pulmonary hypertension, and the role of metabolism in chronic thromboembolic pulmonary hypertension. : Insulin resistance in pulmonary arterial hypertension is primarily in the lipid axis. There are systemic manifestations of insulin resistance including right ventricular lipotoxicity. Obesity is associated with elevation of right ventricular systolic pressure even in a healthy population and therapies in pulmonary arterial hypertension that target metabolism hold promise for improving exercise, right ventricular function, and visceral adiposity. Finally, there are emerging data that chronic thromboembolic pulmonary hypertension is similarly characterized by metabolic alterations, though the specific metabolites may be different from pulmonary arterial hypertension.

Newer insights into the pathobiological and pharmacological basis of the sex disparity in patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) affects more women than men, although affected females tend to survive longer than affected males. This sex disparity in PAH is postulated to stem from the diverse roles of sex hormones in disease etiology. In animal models, estrogens appear to be implicated not only in pathologic remodeling of pulmonary arteries, but also in protection against right ventricular (RV) hypertrophy. In contrast, the male sex hormone testosterone is associated with reduced survival in male animals, where it is associated with increased RV mass, volume, and fibrosis. However, it also has a vasodilatory effect on pulmonary arteries. Furthermore, patients of both sexes show varying degrees of response to current therapies for PAH. As such, there are many gaps and contradictions regarding PAH development, progression, and therapeutic interventions in male versus female patients. Many of these questions remain unanswered, which may be due in part to lack of effective experimental models that can consistently reproduce PAH pulmonary microenvironments in their sex-specific forms. This review article summarizes the roles of estrogens and related sex hormones, immunological and genetical differences, and the benefits and limitations of existing experimental tools to fill in gaps in our understanding of the sex-based variation in PAH development and progression. Finally, we highlight the potential of a new tissue chip-based model mimicking PAH-afflicted male and female pulmonary arteries to study the sex-based differences in PAH and to develop personalized therapies based on patient sex and responsiveness to existing and new drugs.

PRO18 A Systematic Literature Review of the Economic Burden and Cost Drivers in Pulmonary Arterial Hypertension

The aim of this study was to identify cost drivers in Pulmonary Arterial Hypertension (PAH) in the US through a systematic literature review of economic and humanistic burden. A systematic literature review was conducted adhering to methodology published by the Cochrane Collaboration and the National Institute for Health and Clinical Excellence (NICE) in the UK. Population, Intervention & Comparators, Outcomes and Study Design (PICOS) criteria were used to identify resource utilization and economic burden studies in PAH published from credible databases (EMBASE, MEDLINE, MEDLINE In-Process) over the last 10 years. A total of 170 publications were extracted with most publications from the US. Total all-cause costs per patient per month (PPPM) in the US (all costs reported in 2019 $USD) were found to range from $2,494 to $11,037, driven primarily by medical costs. Medical costs accounted for a larger portion of total costs than pharmacy costs within both all-cause ($2,113 to $7,625 PPPM) and PAH-related ($293 to $5,086 PPPM) health care costs; among all-cause medical cost components, inpatient admission costs ($1,115 to $2,146 PPPM) contributed the highest costs, followed by outpatient costs ($954 to $1,944 PPPM). Although total costs increased after initiation of PAH therapies, increased pharmacy costs were partially offset by reduced medical costs ($1,506 to $57,409 decreased annual medical costs from baseline). Management of PAH carries a considerable economic burden with the major cost drivers consisting of primarily medical costs. All-cause costs vary widely in current literature, which may be due to heterogeneity in study population and cost components.

PULMONARY ARTERIAL HYPERTENSION: REGIONAL HEALTH CARE OPPORTUNITIES

Over the past few decades, there have been significant changes in approaches to the management of patients with pulmonary arterial hypertension (PAH). From the moment when the classification of this disease was first published, new diagnostic capabilities and new drugs have appeared that have improved the quality of life and survival of patients. The article is devoted to the issues of rapid diagnosis of PAH in the case of its high probability. Particular attention is paid to the rapid referral of such patients to an expert center, where it is possible to perform catheterization of the right heart. The importance of risk stratification of patients is also noted, which allows prescribing combination specific therapy at an early stage, which can significantly improve the quality of life and reduce the risk of adverse outcomes. Risk assessment is indicated for all patients at both regional and expert level by determining the risk of 1-year mortality in PAH. The article also discusses the issues of dispensary observation of such patients and dose titration when prescribing specific therapy by an expert center. Recommendations are given for non-specific therapy for PAH, the use of oxygen support, anticoagulants, and other drugs. It is emphasized that ACE inhibitors, angiotensin receptor blockers, betablockers, and ivabradine are generally not used to treat PAH, and their use may limit the possibilities of specific therapy. Occasionally, patients with PH at the regional level require dose titration of PAH-specific therapy, as well as regular follow-up, which requires specialized knowledge. This dictates the need to create pulmonary hypertension rooms in each region or manage this group of patients in high-risk rooms, where medical workers will have the necessary knowledge and will regularly undergo training in expert centers. The described clinical case demonstrates the effectiveness of combination therapy of pulmonary arterial hypertension using an innovative selective agonist of prostacyclin receptors for oral administration – Selexipag. Practical recommendations are given for dose titration and its use in patients with PAH.

Notoginsenoside R1 improves monocrotaline-induced pulmonary arterial hypertension via modulation NF-κB signaling in rats

Purpose: To investigate the potentials of notoginsenoside R1 (NGR1) in ameliorating inflammation and pulmonary vascular remodeling in rats with pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT), and to examine the mechanisms underlying such effects.&#x0D; Methods: Eight-week-old male Sprague Dawley rats were randomly divided into groups: control, MCT, MCT+5mg/kg NGR1, MCT+12.5mg/kg NGR1, and MCT + 25 mg/kg NGR1. Right cardiac catheterization was used to measure pulmonary hemodynamics. Pulmonary morphology was evaluated with the aid of H &amp; E staining. Serum levels of inflammatory cytokines were measured using ELISA, while levels of inflammation-associated factors in the lung were measured using RT-PCR. NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and IκBα (nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha) protein levels were determined by western blot.&#x0D; Results: Pulmonary hemodynamics and pulmonary morphology worsened following MCT injection and were accompanied by NF-κB pathway activation and elevated levels of inflammation-associated factors. In contrast, MCT treatment followed by NGR1 treatment ameliorated MCT-induced PAH by improving pulmonary hemodynamics and pulmonary vascular remodeling while reducing NF-κB activation and levels of inflammation-associated factors.&#x0D; Conclusion: NGR1 exerts ameliorative effects on MCT-induced PAH by inhibiting NF-κB pathway. Therefore, NGR1 may be a new potential therapy for PAH.

Significance of BMPR2 mutations in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a debilitating disease that results from progressive remodeling and inflammation of pulmonary arteries. PAH develops gradually, is difficult to diagnose, and has a high mortality rate. Although mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene has been identified as the main genetic cause of PAH, the underlying pathways involving the pathophysiology of PAH are complex and still not fully understood. Endothelial dysfunction has been observed in PAH development that results in a multitude of disturbances in the cellular processes in pulmonary vessels. Changes in the pulmonary vasculature caused by the disruption of BMPR2 signaling are observed in three main vascular components; endothelial cells, smooth muscle cells, and fibroblasts. BMPR2 also has a prominent role in maintenance of the immune system. The disruption of BMPR2 signaling pathway causes an increased degree of inflammation and decreases the ability of the immune system to resolve it. Inflammatory processes and changes in pulmonary vasculature interact with one another, resulting in the progression of chronic PAH. In this review, we highlight the various components of vascular remodeling and immune response that are caused by disruption of BMPR2 signaling, including the clinical evidence and the prospects of these components as a potential target for PAH therapy. Indeed, development of drugs to target the pathogenic pathways involved in PAH may complement existing treatment regimens and improve patient prognosis.

Haemodynamic effects of PAH-targeted therapies in pulmonary hypertension due to lung disease: A systematic review and meta-analysis

BackgroundPulmonary hypertension (PH) is a negative predictor in patients with lung disease and/or hypoxia (group 3 PH). Current guidelines do not endorse the use of targeted therapies for pulmonary arterial hypertension (PAH) in patients with group 3 PH, due to lack of strong evidence. However, a variety of studies have examined the effect of PAH-targeted therapies in group 3 PH with mixed methods and conflicting results. ObjectiveTo evaluate the effect of PAH-targeted therapies on haemodynamic parameters as assessed by right heart catheterization in patients with group 3 PH. MethodsSearch strategy included PubMed and CENTRAL databases for randomized controlled trials from inception until Jan 30, 2020. We hand searched review articles, clinical trial registries and reference lists of retrieved articles. The primary outcome was the effect of PAH-targeted therapies on haemodynamic parameters [mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index (CI) and right atrial pressure (RAP)] in patients with group 3 PH, while secondary outcomes were 6-min walking distance (6MWD), brain natriuretic peptide (BNP) and quality of life (QoL). ResultsFive studies with a total of 140 patients were included. PAH-targeted therapies improved significantly mPAP [mean difference (MD) −4.02 mmHg, 95% CI -7.95;-0.09], and PVR [standardized mean difference (SMD) −0.29, 95% CI -0.50;-0.07], but not CI (SMD 0.23, 95% CI -0.23; 0.70) or RAP (MD 0.26 mmHg, 95% CI -18.75; 19.27). PAH-targeted therapies significantly increased the 6MWD by 38.5 m (95% CI 17.6; 59.4), while they did not manage to improve QoL (SMD -3.42, 95% CI -14.74; 7.91) or BNP values. There was no effect of oxygenation by the PAH-targeted therapies compared to placebo. ConclusionPAH-targeted therapies slightly improved mPAP and PVR in group 3 PH, without affecting CI. Larger RCTs targeted in specific subpopulations are needed to extract more robust conclusions. Protocol registrationOpen Science Framework 10.17605/OSF.IO/56FDW.

846 Pulmonary Arterial Hypertension as a Sequela of Untreated Obstructive Sleep Apnea in a Patient with Prader-Willi Syndrome

Abstract Introduction Prader-Willi Syndrome (PWS) is a complex neurogenetic disorder characterized by hypotonia, behavioral problems, endocrinopathies, sleep and respiratory abnormalities. Morbidity and mortality in the PWS population is attributable to obesity, cardiovascular problems, and sleep apnea. We report a patient with PWS presenting with pulmonary arterial hypertension (PAH) due to untreated obstructive sleep apnea (OSA). Report of case(s) Our patient is a 17-year-old female with a past medical history of PWS, scoliosis, obesity (BMI 52.46), hypogonadotropic hypogonadism, and type II diabetes. Baseline echocardiogram (ECHO) performed at age 9 revealed an estimated right ventricular systolic pressure (eRVSP) of 32mmHg above right atrial pressure (RAP), tricuspid regurgitation (TR) at 2.8 m/sec with no interventricular septal flattening (IVSF) and right ventricle (RV) systolic dysfunction suggestive of mild PAH. Given significant scoliosis the patient did not qualify for growth hormone therapy. She underwent a polysomnogram (PSG) at age 14 showing severe obstructive sleep apnea; apnea-hypopnea index (AHI) of 22.6 (oAHI 22.6). Patient was subsequently lost to follow up until presenting in acute respiratory failure at age 17. She required endotracheal intubation and was extubated to bilevel PAP (BPAP) with inability to wean off BPAP. At that time an ECHO revealed eRVSP of 55 mmHg above RAP, IVSF, TR at 3.7 m/sec, and RV systolic dysfunction suggestive of moderate to severe PAH and developing right sided heart failure. A PAP titration PSG during this admission revealed hypoxemia with oxygen saturation less than 90% (O2 nadir 70%) 12.6% of total sleep time (TST) and hypoventilation (transcutaneous CO2 max of 57 mmHg with an elevation above 50 mmHg for 100% of TST). Using an inspiratory PAP (IPAP) of 24 cmH2O and expiratory PAP (EPAP) of 14 cmH20 with supplemental O2 of 4LPM the respiratory events and hypoxemia resolved but there was persistence of hypoventilation. Tadalafil was initiated for PAH and BPAP therapy for OSA. Follow up visits 4- and 8-weeks post discharge shows improving PAH (TR 3.6 m/sec, eRSVP 52 mmHg, and mild IVSF) due to BPAP and tadalafil therapies. Conclusion This case highlights the importance of treating OSA in patients with PWS to prevent cardiorespiratory complications and reduce morbidity and mortality. Support (if any) None

Sotatercept therapy for PAH.

Sotatercept, a ligand trap for multiple members of the transforming growth factor-β superfamily, reduces pulmonary vascular resistance in patients with pulmonary arterial hypertension (PAH) receiving background therapy for PAH, according to findings from the multicentre, phase II PULSAR trial.