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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.

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.

EiPAH, defined by: mPAP>30mmHg at peak exercise, PVRmax>80 dynes sec cm-5, and PCWPmax Methods: Single-center, open-label 6-month study to evaluate the effects of ambrisentan on exercise capacity utilizing invasive cardiopulmonary exercise testing (iCPET) in EiPAH. Patients were recruited after a clinically indicated ICPET for evaluation of unexplained exertional dyspnea. After 6-months of treatment patients underwent repeat iCPET, and exercise capacity, symptoms and hemodynamics were assessed. We compared change from baseline in peak exercise values of VO2, mPAP, PAWP, PVR, and CO. Results: To date 5 patients (4/5 male, age 58.2±7.0 years) have completed the 6-month treatment phase and undergone repeat ICPET. Baseline resting hemodynamics were mPAP=18.4±4.2mmHg, PAWP=9.4±4.3mmHg, CO=4.3±1.3l/min and PVR=141.2±70.8 dynes sec cm-5; peak values were mPAP=37.6±5.2, PAWP=14.0±4.1, CO=9.8±2.0 and PVR=176.4±63.7 dynes sec cm-5. After 6 months of treatment there was an increase in peak CO (+3.4±2.4l/min), with a decline in peak mPAP (-7.6±3.5, range -2 to -11; p=0.008) and PVR (-94.8±59.2, range -35 to -176; p=0.02). Neither peak PCWP (+0.8±8.2, p=0.84) nor peak VO2 (+48.4mL/min, p=0.29) changed significantly. Conclusions: These preliminary findings suggest that treatment of EiPAH with ambrisentan results in improved hemodynamics over a 6-month period. Further study of EiPAH and early treatment is warranted.

We hypothesized that hemodynamic recovery patterns in exercise induced pulmonary hypertension (eiPH) and pulmonary venous hypertension (eiPVH) would differ. 442 consecutive invasive cardiopulmonary exercise tests at our center from 2012-2014 were reviewed. Recovery hemodynamics were available in 245. 36 eiPH, 28 eiPVH and 31 age matched normal controls (NC) were identified at peak exercise. eiPVH had significantly lower HRmax vs. NC (72±13 vs. 87±11% predicted, p eiPVH decays quickly in recovery while markers of eiPH including resistance and compliance persist. The data suggest more fixed pulmonary vascular remodeling in eiPH than in eiPVH.