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Background: INCREASE was a multicenter, randomized, double-blind, placebo-controlled, 16-week study that evaluated the safety and efficacy of inhaled treprostinil in patients with interstitial lung disease and associated pulmonary hypertension (PH-ILD). The study met its primary endpoint of change in peak 6-minute walk distance at Week 16. Methods: Pulmonary function testing and exacerbations of underlying lung disease were conducted as safety assessments. This current analysis assessed the effects of inhaled treprostinil on the forced vital capacity (FVC). Findings: 326 patients were randomized to inhaled treprostinil or placebo. Inhaled treprostinil was associated with placebo-corrected improvements in the FVC of 28·5 mL (95% CI -30·8-87.7, p=0·345) and 44·4 mL (95% CI -25·3-114·1, p=0·211) at Weeks 8 and 16, respectively. The associated percent predicted FVC improvements at Weeks 8 and 16 were 1·79% (95% CI 0·37-3·21, p=0·014) and 1·80% (95% CI 0·20-3·39, p=0·028), respectively. Patients with idiopathic interstitial pneumonia (IIP) demonstrated FVC improvements of 46·5 mL (n=129, 95% CI -32·55-125·5, p=0·247) and 108·2 mL (n=115, 95% CI 15·3-201·1, p=0·023) at Weeks 8 and 16, respectively. Patients with idiopathic pulmonary fibrosis (IPF) demonstrated FVC improvements of 84·5 mL (n=78, 95% CI -20·4-189·5, p=0·113) and 168·5 mL (n=70, 95% CI 40·1-297·0, p=0·011) at Weeks 8 and 16, respectively. Interpretation: In patients with PH-ILD, inhaled treprostinil resulted in improvements in FVC compared to placebo. This difference was most evident in patients with IIP and in particular, IPF. Inhaled treprostinil appears to be a promising therapy for IPF that warrants further prospective clinical study. Trial Registration: The INCREASE study (NCT02630316) is registered with ClinicalTrials.gov. Funding Statement: The INCREASE study was funded by United Therapeutics Corporation. Declaration of Interests: SDN has received research funding and consulting fees from United Therapeutics. He has received consulting fees from Boehringer-Ingelheim, Roche-Genentech and Galapagos. He is also on the speakers bureau for Boehringer-Ingelheim and Roche-Genentech. AW reports grants from United Therapeutics Corporation, during the conduct of the study. SR reports grants from United Therapeutics Corporation, during the conduct of the study; grants and personal fees from United Therapeutics, grants and personal fees from Janssen Pharmaceuticals, personal fees from Altavant Sciences, personal fees from Liquidia Technologies, Inc., personal fees from Insmed, Inc., personal fees from Bayer Pharmaceuticals, outside the submitted work. AC reports grants from United Therapeutics Corporation, during the conduct of the study. SJ reports grants from United Therapeutics Corporation, during the conduct of the study; grants and personal fees from Bayer Pharmaceuticals, grants from Bellerophon Therapeutics, grants and personal fees from Janssen Research and Development, outside the submitted work. HD reports grants from United Therapeutics Corporation during the conduct of the study; grants and personal fees from Actelion Pharmaceuticals, outside the submitted work. DZ reports grants from United Therapeutics Corporation, during the conduct of the study. SS reports grants from United Therapeutics Corporation, during the conduct of the study; personal fees and non-financial support from Bayer Pharmaceuticals, personal fees and non-financial support from United Therapeutics, personal fees and non-financial support from Actelion Pharmaceuticals, personal fees from Liquidia, personal fees from Altavant Sciences, from GSK, grants from ACCP CHEST ILD Research Grant, personal fees from Boehringer Ingelheim, outside the submitted work. CK reports grants from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics, personal fees from Actelion, personal fees from Boehringer Ingelheim Pharmaceuticals, personal fees from Genentech, outside the submitted work. LMG reports grants and personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, personal fees from Janssen and Janssen Pharmaceuticals, personal fees from Bayer Pharmaceuticals, outside the submitted work. PS reports personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, outside the submitted work. ES reports personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, outside the submitted work. LDE reports personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, outside the submitted work. AN reports personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, outside the submitted work. VFT reports grants from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics, outside the submitted work. Ethics Approval Statement: The study protocol was approved by the institutional review board at each participating site. The study was monitored by an independent data and safety monitoring committee and was conducted in accordance with the principles of Good Clinical Practice.

Introduction: PAH is characterized by a loss of pulmonary vascular complexity. In this study, total, arterial, and venous vasculatures of patients with PAH and with ePAH were analyzed using fractal analysis and compared against controls Methods: Data from 1514 consecutive right heart catheterizations from 4/27/2011 to 10/2/2018 representing subjects referred to our dyspnea center were searched for availability of imaging. 388 CT angiography (CTA) scans were identified (used given retrospective availability of thin slice reconstructions). Three initial cohorts (no overlap) were identified from individuals in this set. Control patients had normal resting and exercise hemodynamics and no history of cardiopulmonary disease. The second group met the current definition of PAH (resting mean pulmonary arterial pressure >20mmHg, pulmonary vascular resistance >3 Wood Units, pulmonary capillary wedge pressure Results: Venous fractal dimensions of controls (2.10±0.07) were higher than those of PAH (2.03±0.08; p=3e-6) and of ePAH (2.04±0.13; p=0.008). Total fractal dimension also yielded higher values for controls (2.30±0.05) compared against PAH (2.28±0.07; p=0.009) and ePAH (2.26±0.10; p=0.04). No significant differences were found between arterial fractal dimensions of controls (2.17±0.04) against those of PAH (2.16±0.07; p=0.15) and of ePAH (2.15±0.10; p=0.14). Conclusions: Fractal dimension allows for non-invasive characterization of pulmonary vascular complexity. Using this method, patients with PAH or ePAH were found to have lower total and venous vascular complexities than controls without PAH or ePAH.

Introduction: Increased vascular tortuosity has been proposed as a marker of pulmonary arterial hypertension (PAH). In this analysis, we compared arterial and venous vascular tortuosity between controls and subjects with resting PAH. Furthermore, we examined if abnormalities could be detected in exercise PAH (EPAH), thought to be an early form of PAH. Methods: From an institutional registry, 388 patients with both right heart catheterization and computed tomography angiography (CTA) data were selected. Within this cohort, three distinct groups were identified: 1) controls, who had no cardiopulmonary disease and normal resting and exercise hemodynamics; 2) EPAH, with normal resting hemodynamics but age-adjusted pre-capillary pulmonary hypertension on exertion, and 3) PAH, defined as resting mPAP >20mmHg, pulmonary vascular resistance >3 Wood Units, and pulmonary capillary wedge pressure 10% was defined as the number of arterial segments with tortuosity >10% divided by the same venous measure. Analysis was performed with Wilcoxon rank sum tests in R 3.5. Results: There were 99 patients in the final cohort, including 47 (47.4%) with PAH, 12 (12.1%) with EPAH, and 40 (40.4%) without disease. Compared to controls, median arterial tortuosity was increased in PAH (3.3 ± 0.1% vs. 3.4 ± 0.1%, p=0.0009; Figure 1) but not in EPAH (3.3 ± 0.1%, p=0.82). Median venous tortuosity did not differ between groups. AV>10% was increased in EPAH (vs. controls, 1.86 ± 0.38 vs. 1.56 ± 0.44, p=0.03) and resting PAH (2.0 ± 1.2 p=2e-6). Conclusions: Increased arterial tortuosity on CTA is a biomarker of resting PAH. When corrected for venous tortuosity, arterial tortuosity also appears to be abnormal in EPAH. Figure 1 . Arterial vessels in PAH, EPAH, and control subjects. Red segments have tortuosity > 10%.

More than 200,000 individuals are hospitalized with an acute pulmonary embolism in the United States annually. Despite advances in diagnosis and treatment, pulmonary embolism accounts for nearly 1% of all cardiovascular-related deaths each year in the United States alone. Those who survive an acute episode remain at a risk of recurrent events as well as ongoing dyspnea, reduced quality of life, and chronic thromboembolic pulmonary hypertension. Recognized risk factors for pulmonary embolism include advanced age, obesity, smoking, malignancy, immobilization from any cause, pregnancy and the postpartum period, oral contraceptives, and hormone replacement therapy. Numerous heritable and acquired thrombophilias increase the risk of pulmonary embolism. Additionally, inflammation and autoimmune disorders are increasingly recognized as potent risk factors for pulmonary embolism. This review contains 3 figures, 6 tables, 54 references. Key Words: anticoagulation, deep vein thrombosis, epidemiology, genetics, inflammation, malignancy, pulmonary embolism, thrombosis, venous thromboembolism

Background Right ventricular (RV) dysfunction is associated with poorer outcomes in heart failure with preserved ejection fraction (HFpEF). Although female subjects are more likely to have HFpEF, male subjects have worse prognosis and resting RV function. The contribution of dynamic RV-pulmonary arterial (RV-PA) coupling between sex and its impact on peak exercise capacity (VO2) in HFpEF is not known. Research Question The goal of this study was to investigate the differential effects of sex on RV-PA coupling during maximum incremental exercise in patients with HFpEF. Study Design and Methods This study examined rest and exercise invasive pulmonary hemodynamics in 22 male patients with HFpEF and 27 female patients with HFpEF. To further investigate the discrepancy in RV-PA response between sex, 26 age-matched control subjects (11 male subjects and 15 female subjects) were included. Single beat analysis of RV pressure waveforms was used to determine the end-systolic elastance (Ees) and pulmonary arterial elastance. RV-PA coupling was determined as the ratio of end-systolic elastance/PA elastance. Results Both HFpEF groups experienced decreased peak VO2 (% predicted). However, male patients with HFpEF experienced a greater decrement in peak VO2 compared with female patients (58 ± 16% vs 70 ± 15%; P Interpretation Male patients with HFpEF were more compromised regarding dynamic RV-PA uncoupling and reduced peak VO2 compared with female patients. This finding was driven by both RV contractile impairment and afterload mismatch. In contrast, female patients with HFpEF had preserved RV-PA coupling during exercise and better peak exercise VO2 compared with male patients with HFpEF.

Introduction: Increasing evidence suggests that borderline and exercise pulmonary hypertension (PH), bPH and ePH respectively, are associated with increased mortality. bPH and ePH may represent early stages of PH. Micro-RNAs (miRNAs) have been shown to play a key role in the pathophysiology of PH. We sought to identify miRNA signatures for early detection of PH, bPH and ePH. Methods: 245 plasma samples were collected at rest from PH (mPAP >25 mmHg, n=75), bPH (mPAP 21-24 mmHg, n=27), ePH (mPAP 30mmHg with exercise, n=39) and non-PH dyspnea patients (DC, n=104)) and assayed for N-terminal pro b-type natriuretic peptide (NTproBNP) and 600 miRNAs. Samples were randomly partitioned into training and validation sets. MiRNA signatures were generated with or without NTproBNP from the training set for distinguishing DC from PH, bPH, “bPH+ePH”, and “PH+bPH+ePH” and tested on a naive (split-sample) validation set. Results: The average Area Under the Curve (AUC) for miRNA vs. NTproBNP was 0.71 vs. 0.59, 0.60 vs. 0.56, 0.75 vs. 0.70, and 0.74 vs. 0.81 for distinguishing “DC” from “bPH+ePH”, “bPH”, “PH+bPH+ePH”, and “PH”, respectively. Conclusion: miRNA signatures can discriminate early stage disease (bPH and ePH) from DC better than NTproBNP, suggesting that miRNA signatures are capable of identifying the pulmonary vascular disease phenotype before disease progression to PH with significant RV dysfunction.

Introduction: Patients with pulmonary arterial hypertension (PAH) have exertional intolerance; however, the biological mediators relevant for PAH that are affected by this phenomenon remain incompletely characterized. Aim: To examine the transpulmonary gradient of proteins in PAH and how these are perturbed by an exercise challenge. Methods: Twelve patients with PAH and 12 age- and sex-matched patients with unexplained dyspnea underwent level 3 cardiopulmonary exercise testing with blood sampling from the pulmonary artery and pulmonary capillary wedge compartments at rest, peak exercise, and post-exercise. Proteomics were performed on plasma samples using an aptamer-based technology. Pathway and functional enrichment analyses were used to cluster proteins. Results: Patients with PAH (mPAP 39±6, PVR 376±189 dyn‑s-cm-5) had a cardiac output similar to patients with unexplained dyspnea, but exercised to a lower workload and had lower peak lactate levels (5±2 vs. 8±2 mmol/L, p Conclusions: Patients with PAH have a differentiated transpulmonary profile of proteins following an exercise challenge. Changes in the transpulmonary gradient of these proteins suggest that they might play a role in the pathophysiology of PAH and serve as a biomarker of exercise intolerance in the disease.

Introduction: Inhalation profiles to support use of DPIs for drug delivery in PAH subjects have not been reported. Objective: Evaluate the inspiratory flow pattern associated with low and medium flow resistance DPI devices (RS01L, RS01M, respectively) in subjects with PAH. Methods: This single center study enrolled subjects with PAH associated with connective tissue disease (aPAH, n=10) and idiopathic PAH (iPAH, n=10) to measure the following inhalation parameters: inspiratory effort (kPa), peak inspiratory flow rate (L/min), inhaled volume (L), and flow increase rate (L/s2) using the two devices. Results: On average, peak inspiratory flow rate was higher with RS01L vs. RS01M (84 ± 19.73 L/min vs. 70.47 ± 13.26 L/min; p=0.015). In the overall group, no differences between RS01L and RS01M were observed for inhaled volume, inspiratory effort, or flow increase rate. Inhaled volume with RS01L was higher in aPAH vs iPAH subjects: 1.67 ± 0.43L vs. 1.31 ± 0.26L; p=0.042. For the RS01L, inhaled volume correlated with forced expiratory volume in one second (r=0.460, p=0.030) and forced vital capacity (r=0.507, p=0.015). In subjects with aPAH using RSO1L, inspiratory effort was highly correlated with pulmonary vascular compliance (PVC) (r=0.903), and flow increase rate with PVC (r=0.906). For RSO1M, inspiratory effort was highly correlated with PVC (r=0.81). Conclusions: Use of RS01L and RS01M DPI devices allowed adequate inspiratory flow in PAH subjects. The correlation between flow increase rate and PVC in aPAH deserves further investigation.

Pulmonary hypertension is a progressive disease whose survival is linked to adequate right ventricle adaptation to its afterload. In the current study, we performed an in-depth characterization of right ventricle function during maximum incremental exercise in patients with pulmonary hypertension and how it relates to exercise capacity. A total of 377 pulmonary hypertension patients who completed a maximum symptom-limited invasive cardiopulmonary exercise testing were evaluated to identify 45 patients with heart failure with preserved ejection fraction, 48 with exercise pulmonary hypertension, and 47 with established pulmonary arterial hypertension. These patients were compared to 17 age- and gender-matched normal controls. Load-adjusted right ventricle function was quantified as the ratio of right ventricle stroke work index to pulmonary arterial elastance. All patients with pulmonary hypertension had reduced peak VO 2 %predicted compared to controls. Right ventricle function deteriorated for all pulmonary hypertension groups by 50% of peak VO 2 . Worsening of right ventricle function during freewheeling exercise was associated with greater reduction in peak VO 2 compared to those whose right ventricle function deteriorated at later exercise stages (i.e. min 1, 2, and 3). On multivariate analysis, reduced ratio of right ventricle stroke work index to arterial elastance was an independent predictor of peak VO 2 %predicted (β-Coefficient –5.46, 95% CI: –9.47 to –1.47, p = 0.01). Right ventricle function deteriorates early during incremental exercise in pulmonary hypertension, occurring by 50% of peak oxygen uptake. The current study demonstrates that right ventricle dysfunction is an early phenomenon during incremental exercise in pulmonary hypertension, occurring by 50% of peak oxygen uptake. The threshold at which right ventricle function is compromised during incremental exercise in pulmonary hypertension influences aerobic capacity and may help guide exercise strategies to mitigate dynamic worsening of right ventricle function during exercise training.

Purpose of review Despite worse outcomes associated with the development of pulmonary hypertension in chronic lung disease, there are no approved treatments for this population. The present review summarizes the recent clinical trials in World Symposium on Pulmonary Hypertension (WSPH) Group 3 pulmonary hypertension, with a particular focus on the study of pulmonary arterial hypertension (PAH)-targeted therapy. Recent findings Multiple recent randomized controlled trials have studied a host of PAH-specific medications in the treatment of WSPH Group 3 pulmonary hypertension, including endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins. In pulmonary hypertension associated with chronic obstructive lung disease (PH-COPD) and with interstitial lung disease (PH-ILD), most trials have shown conflicting or negative results, although they have been limited by variable patient populations and small sample sizes. Recent large-scale trial data demonstrate that inhaled treprostinil is associated with improved outcomes in the PH-ILD population. Summary Although most PAH medications have not shown consistent benefit in the WSPH Group 3 population, recent work suggests that inhaled treprostinil has an important role in the treatment of PH-ILD. Efforts are ongoing to evaluate the efficacy of other medications, identify optimal treatment candidates, and define clinically meaningful endpoints in WSPH Group 3 pulmonary hypertension.

A major outcome determinant in patients with precapillary pulmonary hypertension (PH) is right ventricular (RV) function. We studied the effect of ranolazine on RV function over 6 months using cardiovascular magnetic resonance (CMR) imaging in patients with precapillary PH (groups I, III, and IV).We enrolled patients with PH and RV dysfunction (CMR imaging ejection fraction [EF] of45%) in a longitudinal, randomized, double-blinded, placebo controlled, multicenter study of ranolazine treatment. All enrolled patients were on stable PH-specific therapy. Enrolled patients were assessed using CMR imaging, New York Heart Association functional class, N-terminal pro brain natriuretic peptide, 6-minute walk test, and quality of life health outcomes at baseline and repeated at the end of treatment. The primary outcome was change in RVEF after 6 months of treatment. Analysis of covariance was used to analyze the longitudinal changes taking into account baseline values, age, and sex, based on per protocol population. Twenty-two patients were enrolled, and 9 patients completed follow-up CMR imaging after ranolazine treatment and 6 completed placebo treatment. There was significant increase in RVEF at end of treatment compared with baseline in the ranolazine group adjusted for baseline values, age, and sex. There were no statistically significant changes in secondary outcomes such as changes in New York Heart Association functional class, 6-minute walk distance, N-terminal pro brain natriuretic peptide, or quality of life measures. Ranolazine treated patients experienced a higher number of adverse events, but only one was discontinued owing to side effects.Ranolazine may improve RV function in patients with precapillary PH. Larger studies are needed to confirm the beneficial effects of ranolazine.

Aims Dyspnoea is common in heart failure (HF) but non-specific. Lung ultrasound (LUS) could represent a non-invasive tool to detect subclinical pulmonary congestion in patients with undifferentiated dyspnoea. Methods and results We assessed the feasibility of an abbreviated LUS protocol (eight and two zones) in a prospective pilot study of 25 ambulatory patients with undifferentiated dyspnoea undergoing clinically indicated invasive cardiopulmonary exercise testing (iCPET) at rest (LUS 1) and after peak exercise (LUS 2). We also related LUS findings (B-lines) to invasive haemodynamics stratified by supine pulmonary capillary wedge pressure (PCWP) (Congestion, >15 mmHg; Control, ≤15 mmHg). All enrolled patients (median age 68, 60% women, 32% prior HF, median ejection fraction 59%) had interpretable LUS 1 images in eight zones, and 20 (80%) had adequate LUS 2 images. LUS images were adequate in two posterior zones in 24 patients (96%) for LUS 1 and 18 (72%) for LUS 2. Although B-line number was numerically higher in the Congestion group at rest and after peak exercise, this difference did not reach statistical significance. In the entire cohort, there was an association between B-lines and rest systolic pulmonary artery pressure (r = 0.46, P = 0.02) and PCWP (r = 0.54, P = 0.005). There was an inverse relationship between B-lines and peak VO2 (r = -0.65, P = 0.002). Conclusions Among ambulatory patients with undifferentiated dyspnoea, an abbreviated LUS protocol before and after iCPET is feasible in the majority of patients. B-line number at rest was associated with invasively measured markers of haemodynamic congestion and was inversely related with peak VO2 .

Background Right ventricular (RV) dysfunction and heart failure with preserved ejection fraction may contribute to exercise intolerance in obesity. To further define RV exercise responses, we investigated RV–arterial coupling in obesity with and without development of exercise pulmonary venous hypertension (ePVH). Methods RV–arterial coupling defined as RV end-systolic elastance/pulmonary artery elastance (Ees/Ea) was calculated from invasive cardiopulmonary exercise test data in 6 controls, 8 obese patients without ePVH (Obese−ePVH) and 8 obese patients with ePVH (Obese+ePVH) within a larger series. ePVH was defined as a resting pulmonary arterial wedge pressure

Rationale: Current methods assessing clinical risk because of exercise intolerance in patients with cardiopulmonary disease rely on a small subset of traditional variables. Alternative strategies incorporating the spectrum of factors underlying prognosis in at-risk patients may be useful clinically, but are lacking. Objective: Use unbiased analyses to identify variables that correspond to clinical risk in patients with exercise intolerance. Methods and Results: Data from 738 consecutive patients referred for invasive cardiopulmonary exercise testing at a single center (2011–2015) were analyzed retrospectively (derivation cohort). A correlation network of invasive cardiopulmonary exercise testing parameters was assembled using |r|>0.5. From an exercise network of 39 variables (ie, nodes) and 98 correlations (ie, edges) corresponding to P −46 for each correlation, we focused on a subnetwork containing peak volume of oxygen consumption (pV o 2 ) and 9 linked nodes. K-mean clustering based on these 10 variables identified 4 novel patient clusters characterized by significant differences in 44 of 45 exercise measurements ( P o 2 and pV o 2 itself, the network model was less redundant and identified clusters that were more distinct. Cluster assignment from the network model was predictive of subsequent clinical events. For example, a 4.3-fold ( P P =0.0018; 95% CI, 1.5–5.2) increase in hazard for age- and pV o 2 -adjusted all-cause 3-year hospitalization, respectively, were observed between the highest versus lowest risk clusters. Using these data, we developed the first risk-stratification calculator for patients with exercise intolerance. When applying the risk calculator to patients in 2 independent invasive cardiopulmonary exercise testing cohorts (Boston and Graz, Austria), we observed a clinical risk profile that paralleled the derivation cohort. Conclusions: Network analyses were used to identify novel exercise groups and develop a point-of-care risk calculator. These data expand the range of useful clinical variables beyond pV o 2 that predict hospitalization in patients with exercise intolerance.

Ambrisentan in 22 patients with pulmonary hypertension diagnosed during exercise (ePH) improved pulmonary hemodynamics; however, there was only a trend toward increased maximum oxygen uptake (VO 2 max) secondary to decreased maximum exercise systemic oxygen extraction (Ca-vO 2 ). We speculate that improved pulmonary hemodynamics at maximum exercise “unmasked” a pre-existing skeletal muscle abnormality.

BACKGROUND: We aim to develop a four-tier severity classification system of main pulmonary artery diameter (mPA) and its ratio to the ascending aorta diameter (ratio PA) for the diagnosis and prognosis of pulmonary hypertension (PH) on computed tomography (CT) scans. METHODS: In 228 patients (136 with PH) undergoing right heart catheterization (RHC) and CT for dyspnea, we measured mPA and ratio PA. In a derivation cohort (n=114), we determined the four-tier cutpoints to maximize sensitivity and specificity, and validated it in a separate cohort (n=114). Cutpoints for mPA were defined with the Framingham sex-specific normative values of ≤27mm(F) and ≤29mm(M) as the normal reference range; mild as >27 to 29 to 34 mm. Cutpoints for ratio PA were defined as normal ≤0.9; mild>0.9 to 1.0; moderate>1.0 to 1.1; and severe>1.1. RESULTS: Sensitivities for normal tier were 99% for mPA and 93% for ratio PA; while specificities for severe tier were 98% for mPA>34mm and 100% for ratio PA>1.1. C-statistics for four-tier mPA and ratio PA were both 0.90 (derivation) and both 0.85 (validation). Severity of mPA and ratio PA corresponded to hemodynamics by RHC and echocardiography (both p1.1 had worse survival than normal values (all p≤0.01). CONCLUSION: Four-tier severity classification of mPA and ratio PA on CT has high accuracy for PH diagnosis with increase mortality in patients with moderate-severe mPA and ratio PA values supporting its use clinically on chest and cardiac CT reports.

Studies assessing the quality of anticoagulation therapy in patients with pulmonary arterial hypertension (PAH) have not been conducted.To assess the quality of anticoagulation management, the rate of anticoagulation-related complications in patients with PAH, and to identify risk factors for poor anticoagulation.This observational, retrospective cohort study included patients with confirmed PAH taking a regimen of oral anticoagulants from two centers: Brigham and Women's Hospital in Boston, and Hospital Universitario La Paz in Madrid from January 2009 to August 2015. Efficacy of anticoagulation management and time spent within therapeutic range of study participants were assessed.There were a total of 121 patients with PAH taking oral anticoagulants. Time spent within range (TTR) of those taking vitamin K antagonists (VKAs) was 57.0%. Forty-seven patients (38.8%) had a total of 105 anticoagulation-related events. The odds ratio of having an event in patients with a TTR60% was 2.43 (CI 95%, 1.01-5.83; p=0.046). Possible factors that affected the quality of the anticoagulation were the age, sex, functional capacity, atrial fibrillation and certain pulmonary arterial hypertension specific medications.The quality of targeted anticoagulation in patients with PAH was low. Patients with low TTR were at a higher risk of experiencing anticoagulation-related complications. Specialized anticoagulation centers showed better management of oral anticoagulants.

Background aims In this study, we demonstrate long-term persistence of human mesenchymal stromal cells (hMSCs) after intracoronary injection in a large animal model of pulmonary hypertension (PH). Methods Commercially available placenta-derived hMSCs were used. Experiments were conducted on 14 female Yorkshire swine. Four animals served as controls, and 10 underwent pulmonary vein (PV) banding. After 12 ± 2 weeks, PH and PV dysfunction were confirmed by right heart catheterization and cardiac magnetic resonance imaging. hMSCs were injected in the marginal branch of the right coronary artery. Tissues were harvested 6, 9 or 24 days after infusion. Results After 12 ± 2 weeks after PV banding, all subjects had increased mean pulmonary artery pressure (13.6 ± 3.6 versus 30.8 ± 4.5 mm Hg, P P = 0.003). Intracoronary injection of hMSCs was well tolerated. Up to 24 days after hMSC injection, immunohistochemistry revealed extravascular viable human CD105 + mononuclear cells in the right ventricle (RV) that were Ki67 + . This was confirmed by fluorescence in situ hybridization. CD45 + porcine inflammatory cells were identified, commonly seen adjacent to areas of healing microscopic infarction that likely dated to the time of the original hMSC injection. Anti-CD31 staining produced strong signals in areas of injected hMSCs. Immunohistochemistry staining for vascular cell adhesion molecule-1 showed upregulation in the clusters, where mononuclear cells were located. Conclusions hMSCs injected via intracoronary infusion survived up to 24 days and demonstrated proliferative capacity. hMSCs can persist long term in the RV and are potential cell source for tissue repair in RV dysfunction.

Background: Invasive hemodynamic evaluation through right heart catheterization plays an essential role in the diagnosis, categorization, and risk stratification of patients with pulmonary hypertension. Methods: Subjects enrolled in the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) program undergo an extensive invasive hemodynamic evaluation that includes repeated measurements at rest and during several provocative physiological challenges. It is a National Institutes of Health/National Heart, Lung, and Blood Institute initiative to reclassify pulmonary hypertension groups based on clustered phenotypic and phenomic characteristics. At a subset of centers, participants also undergo an invasive cardiopulmonary exercise test to assess changes in hemodynamics and gas exchange during exercise. Conclusions: When coupled with other physiological testing and blood -omic analyses involved in the PVDOMICS study, the comprehensive right heart catheterization protocol described here holds promise to clarify the diagnosis and clustering of pulmonary hypertension patients into cohorts beyond the traditional 5 World Symposium on Pulmonary Hypertension groups. This article will describe the methods applied for invasive hemodynamic characterization in the PVDOMICS program. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02980887.

Pulmonary hypertension is a disease caused by a multitude of medical conditions which leads to vascular remodeling and increased resistance of the pulmonary circulation. This increased pulmonary vascular resistance and loss of vascular distensibility causes increased afterload for the right ventricle to pump against. Despite adaptive changes to increase contractility, the right ventricle eventually uncouples from the pulmonary circulation, dilates, and goes into failure. Signs of right heart failure may be subtle at first and only detected on imaging and right heart catheterization. However, evolution to right ventricular failure from pulmonary hypertension can be a challenging condition to treat in the intensive care unit with a focus on improving right ventricular contractility, preventing ischemia, and utilizing vasodilator therapy to target afterload reduction. There is a high mortality for those who rapidly progress or fail to respond to medical therapy and the use of extra corporeal membrane oxygenation (ECMO) and lung transplantation is a developing field for only a subset of patients.

Background: Novel therapies are needed to attenuate the progression of PAH. Disruptions in transforming growth-factor (TGF)-β and bone morphogenetic protein (BMP) signaling are associated with the development of PAH. Sotatercept (ACE-011) is a first-in-class fusion protein consisting of the extracellular domain of activin receptor IIa (ActRIIa) attached to the Fc portion of human IgG1 that sequesters TGF-β superfamily ligands such as activin A and B and growth differentiation factor (GDF)-11 to suppress TGF-β signaling and rebalance deficient BMPR2 signaling. Aims: To determine the efficacy and safety of sotatercept versus placebo when administered with SOC in adults with PAH. Methods: Eligible participants (pts) have World Health Organization (WHO) Group 1 functional class II-III PAH; age ≥18 years; baseline pulmonary vascular resistance (PVR) of ≥5 Wood units; 6-minute walk distance (6MWD) of 150–550m; and stable PAH SOC therapy. One hundred pts will be randomized 3:3:4 to placebo, 0.3 mg/kg sotatercept, or 0.7 mg/kg sotatercept administered SC every 21 days plus SOC for 24 weeks. The primary endpoint is change from baseline in PVR at 24 weeks. An 18-month extension period follows. Results and Conclusions: Primary analysis results for PULSAR (NCT03496207) are expected in the first half of 2020. A related study (SPECTRA; NCT03738150) will evaluate the effects of sotatercept on cardiopulmonary hemodynamics and functional capacity in pts with PAH.

Despite recent advances, the prognosis of pulmonary hypertension (PH) remains poor. While the initial insult in PH implicates the pulmonary vasculature, the functional state, exercise capacity, and survival of such patients are closely linked to right ventricular (RV) function. In the current study, we sought to investigate the effects of maximum incremental exercise on the matching of RV contractility and afterload (i.e. right ventricular–pulmonary arterial [RV–PA] coupling) in patients with exercise PH (ePH) and pulmonary arterial hypertension (PAH). End-systolic elastance (Ees), pulmonary arterial elastance (Ea), and RV–PA coupling (Ees/Ea) were determined using single-beat pressure-volume loop analysis in 40 patients that underwent maximum invasive cardiopulmonary exercise testing. Eleven patients had ePH, nine had PAH, and 20 were age-matched controls. During exercise, the impaired exertional contractile reserve in PAH was associated with blunted stroke volume index (SVI) augmentation and reduced peak oxygen consumption (peak VO 2 %predicted). Compared to PAH, ePH demonstrated increased RV contractility in response to increasing RV afterload during exercise; however, this was insufficient and resulted in reduced peak RV–PA coupling. The dynamic RV–PA uncoupling in ePH was associated with similarly blunted SVI augmentation and peak VO 2 as PAH. In conclusion, dynamic rest-to-peak exercise RV–PA uncoupling during maximum exercise blunts SV increase and reduces exercise capacity in exercise PH and PAH. In ePH, the insufficient increase in RV contractility to compensate for increasing RV afterload during maximum exercise leads to deterioration of RV–PA coupling. These data provide evidence that even in the early stages of PH, RV function is compromised.

Background: Deficiencies of iron-sulfur (Fe-S) clusters, metal complexes that control redox state and mitochondrial metabolism, have been linked to pulmonary hypertension (PH), a deadly vascular disease with poorly defined molecular origins. BOLA3 (BolA Family Member 3) regulates Fe-S biogenesis, and mutations in BOLA3 result in multiple mitochondrial dysfunction syndrome, a fatal disorder associated with PH. The mechanistic role of BOLA3 in PH remains undefined. Methods: In vitro assessment of BOLA3 regulation and gain- and loss-of-function assays were performed in human pulmonary artery endothelial cells using siRNA and lentiviral vectors expressing the mitochondrial isoform of BOLA3. Polymeric nanoparticle 7C1 was used for lung endothelium-specific delivery of BOLA3 siRNA oligonucleotides in mice. Overexpression of pulmonary vascular BOLA3 was performed by orotracheal transgene delivery of adeno-associated virus in mouse models of PH. Results: In cultured hypoxic pulmonary artery endothelial cells, lung from human patients with Group 1 and 3 PH, and multiple rodent models of PH, endothelial BOLA3 expression was downregulated, which involved hypoxia inducible factor-2-dependent transcriptional repression via histone deacetylase 1-mediated histone deacetylation. In vitro gain- and loss-of-function studies demonstrated that BOLA3 regulated Fe-S integrity, thus modulating lipoate-containing 2-oxoacid dehydrogenases with consequent control over glycolysis and mitochondrial respiration. In contexts of siRNA knockdown and naturally occurring human genetic mutation, cellular BOLA3 deficiency downregulated the glycine cleavage system protein H, thus bolstering intracellular glycine content. In the setting of these alterations of oxidative metabolism and glycine levels, BOLA3 deficiency increased endothelial proliferation, survival, and vasoconstriction while decreasing angiogenic potential. In vivo, pharmacological knockdown of endothelial BOLA3 and targeted overexpression of BOLA3 in mice demonstrated that BOLA3 deficiency promotes histological and hemodynamic manifestations of PH. Notably, the therapeutic effects of BOLA3 expression were reversed by exogenous glycine supplementation. Conclusions: BOLA3 acts as a crucial lynchpin connecting Fe-S-dependent oxidative respiration and glycine homeostasis with endothelial metabolic reprogramming critical to PH pathogenesis. These results provide a molecular explanation for the clinical associations linking PH with hyperglycinemic syndromes and mitochondrial disorders. These findings also identify novel metabolic targets, including those involved in epigenetics, Fe-S biogenesis, and glycine biology, for diagnostic and therapeutic development., National Institutes of Health (U.S.) (Grant R01 HL124021), National Institutes of Health (U.S.) (Grant HL 122596), National Institutes of Health (U.S.) (Grant HL 138437), National Institutes of Health (U.S.) (Grant UH2 TR002073)

Aims Impaired left ventricular (LV) deformation despite preserved LV ejection fraction (LVEF) is common and predicts outcomes in heart failure with preserved LVEF. We hypothesized that impaired LV deformation at rest is a marker of impaired cardiac systolic and diastolic reserve, and aimed to determine whether resting longitudinal (LS) and circumferential strain (CS) are associated with invasively measured haemodynamic response to exercise in patients with dyspnoea and a normal LVEF. Methods and results We studied 85 patients with LVEF ≥50% and free of significant valvular disease who were referred for evaluation of dyspnoea. All patients underwent rest echocardiography followed by right heart catheterization and cardiopulmonary exercise testing with concomitant invasive haemodynamic monitoring. The LS, CS and CS/LS ratio were measured by two-dimensional speckle-tracking echocardiography at rest. Lower absolute LS at rest was associated with greater increase in pulmonary arterial wedge pressure (PAWP) from rest to peak exercise (r = 0.23, P = 0.034). In contrast, higher absolute CS at rest predicted a greater increase in PAWP (r = - 0.27, P = 0.032) and greater stroke volume augmentation with exercise (r = - 0.26, P = 0.021). Higher CS/LS ratio was most predictive of elevation in PAWP with exercise (r = 0.30, P = 0.015). Of the measures of LV systolic and diastolic function assessed, the CS/LS ratio resulted in the highest area under the curve and specificity for the presence of rest- or exercise-induced pulmonary venous hypertension. Conclusion Left ventricular deformation at rest predicts exercise-induced rise in PAWP among patients with dyspnoea and a preserved LVEF. A pattern of rest deformation characterized by worse LS and exaggerated CS is most strongly associated with exercise-induced rise in PAWP.

Group 2 Pulmonary hypertension (PH) is associated with left heart disease (LHD;Group 2 PH) and is the most common form of PH. Group 2 PH represents an important subgroup of patients with LHD where the development of PH leads to a significant increase in morbidity and mortality. Early diagnosis may provide an opportunity to intervene and significantly delay progression. In addition to clinical suspicion, several approaches including hemodynamic assessment, exercise testing, and imaging techniques play an important role in better disease characterization and management. Here, we review the role of physiologic based hemodynamic and exercise assessments of Group 2 PH patients.

Background The use of systemic prostanoids in severe pulmonary arterial hypertension (PAH) is often limited by patient/physician dissatisfaction with the delivery methods. Complications associated with external pump-delivered continuous therapy include IV catheter-related bloodstream infections and subcutaneous infusion site pain. We therefore investigated a fully implantable intravascular delivery system for treprostinil infusion. Methods A multicenter, prospective, single-arm, clinical trial (DelIVery for Pulmonary Arterial Hypertension) was conducted by using an implantable intravascular delivery system. The implanted pumps were refilled percutaneously at least every 12 weeks. The primary end point was the rate of catheter-related complications using the new model 10642 catheter compared with a predefined objective performance criterion of 2.5 per 1,000 patient-days based on the literature. Results Patients (n = 60) with severe PAH (World Health Organization group 1) receiving a stable dose of IV treprostinil for at least 4 weeks received an implant device and were followed up for 12.1 ± 4.4 months. Six catheter-related complications occurred, corresponding to a complication rate of 0.27 per 1,000 patient-days. The 97.5% upper one-sided confidence bound of 0.59 was less than the predefined criterion of 2.5 per 1,000 patient-days ( P r = 0.91; P P Conclusions The implantable intravascular delivery system delivered treprostinil to patients with PAH with a low rate of catheter-related complications and a high rate of patient satisfaction. Trial Registry ClinicalTrials.gov; No.: NCT01321073; URL: www.clinicaltrials.gov

Exercise intolerance in pulmonary hypertension (PH) is a major factor affecting activities of daily living and quality of life. Evaluation strategies (i.e., non-invasive and invasive tests) are integral to providing a comprehensive assessment of clinical and functional status. Despite a growing body of literature on the clinical consequences of PH, there are limited studies discussing the contribution of various physiological systems to exercise intolerance in this patient population.This review, through a search of various databases, describes the physiological basis for exercise intolerance across the various PH etiologies, highlights the various exercise evaluation methods and discusses the rationale for exercise training amongst those diagnosed with PH. Expert commentary: With the growing importance of evaluating exercise capacity in PH (class 1, Level C recommendation), understanding why exercise performance is altered in PH is crucial. Thus, the further study is required for better quality evidence in this area.

Schistosomiasis is a prevalent cause of pulmonary arterial hypertension (PAH) currently classified as Group 1 pulmonary hypertension (PH) [1]. In comparison to other etiologies of PAH such as idiopathic PAH, Schistosomiasis-associated PAH (Sch-PAH) has not been extensively studied. Potential mechanisms of PAH development in schistosomiasis include systemic and localised lung inflammation, involvement of other organs such as the liver and spleen, and direct blockage of precapillary vessels from parasite egg embolisation. Currently, the diagnosis of Sch-PAH relies on hemodynamics assessment using right heart catheterisation. In several etiologies of PH, loss of visualised distal vascular volume has been quantified from pulmonary angiography [2, 3] and computed tomography (CT) of the lungs [4–6]. Additionally, loss of distal vascular volume has been shown to be associated with loss of vascular cross-sectional area histologically [7]. In this pilot study we hypothesised that relative loss of arterial pulmonary vascular volume differentially correlates with hemodynamics in Sch-PAH patients, compared to a group of control subjects. 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. Funke-Chambour reports grants from roche, grants and personal fees from Boehringer Ingelheim, outside the submitted work;. Dr. Funke-Chambour reports grants from roche, grants and personal fees from Boehringer Ingelheim, outside the submitted work;. Conflict of interest: Dr. Rahaghi reports grants from NHLBI/NIH, during the conduct of the study. Conflict of interest: Dr. Hilton has nothing to disclose. Conflict of interest: Dr. Correa has nothing to disclose. Conflict of interest: Dr. Loureiro has nothing to disclose. Conflict of interest: Dr. Ota-Arakaki has nothing to disclose. Conflict of interest: Dr. Verrastro has nothing to disclose. Conflict of interest: Dr. Lee reports other from NANO X IMAGING LTD (NNOX), outside the submitted work. Conflict of interest: Dr. Mickael has nothing to disclose. Conflict of interest: Dr. Nardelli has nothing to disclose. Conflict of interest: Dr. Systrom has nothing to disclose. Conflict of interest: Dr. Waxman has nothing to disclose. Conflict of interest: Dr. Washko reports grants from NIH, grants and other from Boehringer Ingelheim, other from Quantitative Imaging Solutions, other from PulmonX, grants and other from Janssen Pharmaceuticals, other from GlaxoSmithKline, other from Novartis, other from Vertex, other from CSL Behring, outside the submitted work; and Dr. Washko's spouse works for Biogen . Conflict of interest: Dr. San Jose Estepar reports grants from NIH-NHLBI, during the conduct of the study; personal fees from LeukoLabs, grants and personal fees from Boehringer Ingelheim, personal fees from Chiesi, from null, outside the submitted work; and he is also a founder and co-owner of Quantitative Imaging Solutions which is a company that provides image based consulting and develops software to enable data sharing. Conflict of interest: Dr. Graham reports grants from NIH, during the conduct of the study. Conflict of interest: Dr. Oliveira has nothing to disclose.

Background Exercise stress testing of the pulmonary circulation may uncover decreased pulmonary vascular (PV) distensibility as a cause of impaired aerobic exercise capacity and right ventricular (RV)-pulmonary arterial (PA) uncoupling. As such, it may help in the differential diagnosis of unexplained dyspnea, including pulmonary hypertension (PH) and/or heart failure with preserved ejection fraction (HFpEF). We investigated rest and exercise invasive pulmonary hemodynamics, ventilation, and gas exchange in patients with unexplained dyspnea, including 44 patients with HFpEF (of whom 20 had a normal pulmonary vascular resistance [PVR] during exercise [ie, passive HFpEF] and 24 had a higher than normal exercise PVR), 22 patients with exercise PH, 19 patients with pulmonary arterial hypertension (PAH), and 24 age- and sex-matched normal control subjects. Methods A PV distensibility coefficient α (%/mm Hg) was determined from multipoint PV pressure-flow plots. RV-PA coupling was quantified from the analysis of RV pressure curves to determine ratios of end-systolic to arterial elastances (Ees/Ea). Aerobic exercise capacity was estimated by peak oxygen consumption. Results The α coefficient decreased from 1.35 ± 0.58%/mm Hg in control subjects and 1.1 ± 0.48%/mm Hg in patients with passive HFpEF to 0.62 ± 0.32%/mm Hg in exercise PH, 0.54 ± 0.27%/mm Hg in HFpEF with high exercise PVR, and 0.18 ± 0.16%/mm Hg in PAH. On multivariate analysis, PV distensibility was associated with decreased Ees/Ea and maximal volume of oxygen consumed. Conclusions PV distensibility is an early and sensitive hemodynamic marker of PV disease that is associated with RV-PA uncoupling and decreased aerobic exercise capacity.

Right ventricular (RV) dysfunction is associated with shortened life expectancy in heart failure with preserved ejection fraction (HFpEF). The contribution of pulmonary vascular dysfunction to RV dysfunction in HFpEF is not well understood.We investigated rest and exercise invasive pulmonary hemodynamics, ventilation, and gas exchange in 67 patients with HFpEF (of whom 28 had an abnormal pulmonary vascular response during exercise referred to as HFpEF+PVR group and 39 had a normal pulmonary vascular response during exercise referred to as HFpEF group) and in 21 matched control subjects.Both groups of patients with HFpEF had a markedly decreased peak oxygen consumption (VoWe conclude that RV-PA uncoupling is common in HFpEF and is caused by both intrinsic RV contractile impairment and afterload mismatch. Resting and dynamic RV-PA uncoupling in HFpEF is driven by an increase in RV pulsatile rather than resistive afterload. However, with the additive effects of increased RV resistive afterload, RV-PA uncoupling worsens dynamically during exercise.

The medical management of pulmonary arterial hypertension (PAH) has advanced considerably over the years. Once the diagnosis of PAH is made, the medical management includes both conventional and PAH-pathway specific therapies. Five different classes of drugs are now available targeting the endothelin, prostacyclin, and nitric oxide pathways (i.e. endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, prostacyclin analogues, and prostacyclin receptor agonists). These targeted therapies are approved for treatment of patients with PAH and chronic thromboembolic pulmonary hypertension (CTEPH) only. Long-term and event-driven studies of novel drugs have led to further improvement in the medical management of PAH and CTEPH. In this review, we will focus on the medical management of patients with PAH and CTEPH. This review contains 4 figures, 6 Tables and 30 references Keywords: Pulmonary arterial hypertension, Chronic thromboembolic pulmonary hypertension, Medical management, Pulmonary vasodilators, Phosphodiesterase inhibitor, Soluble guanylate cyclase stimulator, Endothelin receptor antagonist, Prostacyclin receptor agonist

It is unclear if ultrasound-assisted catheter-directed thrombolysis (UACDT) confers benefit over anticoagulation (AC) alone in the management of intermediate-risk (“submassive”) pulmonary embolism (PE), defined by evidence of right ventricular (RV) dysfunction in hemodynamically stable patients. This study sought to evaluate any lasting advantage of UACDT on mortality and resolution of RV dysfunction in intermediate-risk PE at a large academic medical center. Adults aged ≤ 86 years admitted with intermediate-risk PE from 2011 to 2016 were retrospectively identified. Patients were excluded if there was a history of cancer, pre-existing pulmonary hypertension, pregnancy or postpartum status, contraindication to AC, or treatment with systemic thrombolysis. Baseline Pulmonary Embolism Severity Index (PESI) scores were computed. Outcomes including length of stay (LOS), bleeding complications, resolution of RV dysfunction, and mortality were compared between patients who received UACDT and those managed with AC alone. A total of 104 patients met inclusion criteria, 65 of whom underwent UACDT. The cohorts had similar PESI scores ( P = 0.45) and no clearly imbalanced confounding variables. There was no significant difference in LOS ( P = 0.11). UACDT was associated with more bleeding complications (exact P = 0.04). Follow-up transthoracic echocardiograms performed in 54 UACDT and 24 AC patients demonstrated similar rates of resolution of RV dysfunction (61% in UACDT patients versus 75% in AC patients, P = 0.25). Overall one-year mortality was approximately 5% in both groups (exact P > 0.99). In this limited retrospective analysis of intermediate-risk PE patients, UACDT treatment was not associated with mortality benefit or increased resolution of RV dysfunction.

Dyspnea is a common, distressing symptom of cardiopulmonary and neuromuscular disease. In a consensus statement, the American Thoracic Society defined dyspnea as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity.” Dyspnea is a nonspecific complaint and is one of the most frequent patient complaints. This review discusses the definition, epidemiology, etiology, pathophysiology, peripheral mechanisms, and evaluation of dyspnea. Figures depict cellular metabolism and exercise physiology, and an invasive cardiopulmonary exercise testing (iCPET) flow diagram. Tables list the common causes of dyspnea, invasive cardiopulmonary exercise testing (iCPET) diagnosis, and iCPET characteristics of pulmonary hypertension. This review contains 2 highly rendered figures, 3 tables, and 51 references.

Germline mutations involving small mothers against decapentaplegic-transforming growth factor-β (SMAD-TGF-β) signaling are an important but rare cause of pulmonary arterial hypertension (PAH), which is a disease characterized, in part, by vascular fibrosis and hyperaldosteronism (ALDO). Here, we developed and analyzed a fibrosis protein-protein network (fibrosome) in silico, which predicted that the SMAD3 target neural precursor cell expressed developmentally down-regulated 9 (NEDD9) is a critical ALDO-regulated node underpinning pathogenic vascular fibrosis. Bioinformatics and microscale thermophoresis demonstrated that oxidation of Cys18 in the SMAD3 docking region of NEDD9 impairs SMAD3-NEDD9 protein-protein interactions in vitro. This effect was reproduced by ALDO-induced oxidant stress in cultured human pulmonary artery endothelial cells (HPAECs), resulting in impaired NEDD9 proteolytic degradation, increased NEDD9 complex formation with Nk2 homeobox 5 (NKX2–5), and increased NKX2–5 binding to COL3A1. Upregulation of NEDD9-dependent collagen III expression corresponded to changes in cell stiffness measured by atomic force microscopy. HPAEC-derived exosomal signaling targeted NEDD9 to increase collagen I/III expression in human pulmonary artery smooth muscle cells, identifying a second endothelial mechanism regulating vascular fibrosis. ALDO-NEDD9 signaling was not affected by treatment with a TGF-β ligand trap, and, thus, was not contingent on TGF-β-signaling. Colocalization of NEDD9 with collagen III in HPAECs was observed in fibrotic pulmonary arterioles from PAH patients. Furthermore, NEDD9 ablation or inhibition prevented fibrotic vascular remodeling and pulmonary hypertension in animal models of PAH in vivo. These data identify a critical TGF-β-independent post-translational modification that impairs SMAD3-NEDD9 binding in HPAECs to modulate vascular fibrosis and promote PAH.

Acute pulmonary embolism (PE) can be fatal and requires prompt medical attention. This chapter reviews the treatment of acute PE, including a detailed report of the acute- and long-term management of high-risk (“massive”), medium-risk (“submassive”), and low-risk thrombi. It summarizes the reperfusion therapies available in hemodynamically unstable patients with massive PEs such as thrombolysis, embolectomy, and percutaneous catheter-directed treatment. There is further in-depth examination of the various anticoagulants available including parenteral therapies, vitamin K antagonists, and direct oral anticoagulants. Recommendations on the treatment duration are discussed. Other considerations are described, including how management changes in the pregnant patient with acute PE, when venous filters should be considered and whether to initiate treatment before confirming a diagnosis. Overall this chapter serves as an excellent evidenced-based guide to better manage the various presentations of acute PE. This review contains 3 figures, 5 tables and 47 references Key Words: anticoagulation, embolectomy, PE, pulmonary embolism, reperfusion therapy, thrombolysis, treatment