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Objective Exercise intolerance is a common clinical manifestation of CTD. Frequently, CTD patients have associated cardio-pulmonary disease, including pulmonary hypertension or heart failure that impairs aerobic exercise capacity (pVO2). The contribution of the systemic micro-vasculature to reduced exercise capacity in CTD patients without cardiopulmonary disease has not been fully described. In this study, we sought to examine the role of systemic vascular distensibility, α in reducing exercise capacity (i.e. pVO2) in CTD patients. Methods Systemic and pulmonary vascular distensibility, α (%/mmHg) was determined from multipoint systemic pressure-flow plots during invasive cardiopulmonary exercise testing with pulmonary and radial arterial catheters in place in 42 CTD patients without cardiopulmonary disease and compared with 24 age and gender matched normal controls. Results During exercise, systemic vascular distensibility, α was reduced in CTD patients compared with controls (0.20 ± 0.12%/mmHg vs 0.30 ± 0.13%/mmHg, P =0.01). The reduced systemic vascular distensibility α, was associated with impaired stroke volume augmentation. On multivariate analysis, systemic vascular distensibility, α was associated with a decreased exercise capacity (pVO2) and decreased systemic oxygen extraction. Conclusion Systemic vascular distensibility, α is associated with impaired systemic oxygen extraction and decreased aerobic capacity in patients with CTD without cardiopulmonary disease.

Pulmonary arterial hypertension (PAH) is a highly morbid disease characterized by elevated pulmonary vascular resistance (PVR) and pathogenic right ventricular remodeling. Endothelial expression of the prometastatic protein NEDD9 is increased in fibrotic PAH arterioles, and NEDD9 inhibition decreases PVR in experimental PAH. We hypothesized that circulating NEDD9 is increased in PAH and informs the clinical profile of patients.Clinical data and plasma samples were analyzed retrospectively for 242 patients from 5 referral centers (2010-2017): PAH (n = 139; female 82%, 58 [48-67] years), non-PAH pulmonary hypertension (PH) (n = 54; female 56%, 63.4 ± 12.2 years), and dyspnea non-PH controls (n = 36; female 75%, 54.2 ± 14.0 years).Compared with controls, NEDD9 was increased in PAH by 1.82-fold (p0.0001). Elevated NEDD9 correlated with PVR in idiopathic PAH (ρ = 0.42, p0.0001, n = 54), connective tissue disease (CTD)-PAH (ρ = 0.53, p0.0001, n = 53), and congenital heart disease-PAH (ρ = 0.68, p0.0001, n = 10). In CTD-PAH, NEDD9 correlated with 6-minute walk distance (ρ = -0.35, p = 0.028, n = 39). In contrast to the PAH biomarker N-terminal pro-brain natriuretic peptide (n = 38), NEDD9 correlated inversely with exercise pulmonary artery wedge pressure and more strongly with right ventricular ejection fraction (ρ = -0.41, p = 0.006, n = 45) in a mixed population. The adjusted hazard ratio for lung transplant-free survival was 1.12 (95% confidence interval [CI], 1.02-1.22, p = 0.01) and 1.75 (95% CI, 1.12-2.73, p = 0.01) per 1 ng/ml and 5 ng/ml increase in plasma NEDD9, respectively, by Cox proportional hazard model.In PAH, plasma NEDD9 is increased and associates with key prognostic variables. Prospective studies that include hard end points are warranted to validate NEDD9 as a novel PAH biomarker.

Mechanisms underlying pulmonary arterial hypertension (PAH) remain elusive. Pulmonary arterial hypertension and exercise PH share similar physiologic consequences; it is debated whether they share biologic mechanisms and if exercise PH represents an early phase of pulmonary arterial hypertension. We conducted an observational study to test if there is a graded metabolic disturbance along the severity of PH, which may indicate shared or disparate pathophysiology. Individuals referred to an academic medical dyspnea center with unexplained exertional intolerance underwent invasive cardiopulmonary exercise testing. We identified controls with no hemodynamic exercise limitation, individuals with exercise PH (mean pulmonary arterial pressure (mPAP) 25 mmHg at rest without pulmonary venous hypertension) ( n = 26 in each group). Unbiased metabolomics with chromatography mass spectrometry was performed on pulmonary arterial blood at rest and peak exercise. Random forest analysis and hierarchical clustering were used to quantify metabolite prediction of group membership and rank metabolites which were significantly different between groups. Compared to controls, pulmonary arterial hypertension subjects exhibited perturbations in pathways involving glycolysis, TCA cycle, fatty acid and complex lipid oxidation, collagen deposition and fibrosis, nucleotide metabolism, and others. The metabolic signature of exercise PH was uniquely between that of control and pulmonary arterial hypertension subjects. Accuracy predicting control, exercise PH, and pulmonary arterial hypertension group was 96%, 90%, and 88%, respectively, using paired rest-exercise metabolic changes. Our data suggest the metabolic profile of exercise PH is between that of controls and patients with pulmonary arterial hypertension.

The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE). We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO2)/[Hb] ≤ 0.8 and VO2max 0.8, VO2max ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO2

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.

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

Background: Exercise pulmonary hypertension (ePH) is associated with reduced aerobic capacity and is believed to represent an early stage of pulmonary vascular disease. However, the prognostic impact of ePH is not completely understood. Objectives: To evaluate the prognostic impact of ePH in patients with unexplained exertional intolerance. Methods: 707 invasive cardiopulmonary exercise tests performed between 2011-2015 at the Brigham and Women’s Hospital due to unexplained exertional intolerance were analyzed. 27 patients with ePH and 108 patients with normal resting/exercise hemodynamics (non-PH) were identified. ePH was defined by age-specific exercise pulmonary hemodynamic criteria. All-cause mortality and all-cause hospitalization rates were accessed. Results: Median follow-up was 758 days [IQR 479-1,107 days]. Mean age was 56±18 years for ePH and 56±14 years for non-PH (p=0.969). During the study period, death was reported in only 2 patients (1.5%): one with ePH (3.7%) and one with non-PH (0.9%). Inpatient hospitalization occurred in 20 patients (14.8%): seven with ePH (25.9%) and 13 with non-PH (12.0%). The Kaplan-Meier analysis of the probability of all-cause hospitalization revealed a tendency of ePH in having more hospitalizations (log rank p value = 0.079). By cox proportional analysis, the ePH hazard ratio for all-cause hospitalization was 2.2 (95%CI 0.9-5.6, p=0.087). Conclusions: In this preliminary study, with a relatively short-term follow-up, we identified that ePH might impact patients’ prognosis. This finding suggests a potential link between early pathophysiology and long-term outcome. Further studies with extended follow-up are necessary to determine the long-term prognostic impact of ePH.

Pulmonary hypertension (PH) in the setting of parenchymal lung disease adversely affects quality of life and survival. However, PH-specific drugs may result in ventilation/perfusion imbalance and currently, there are no approved PH treatments for this patient population. In the present retrospective study, data from 22 patients with PH associated with lung disease treated with inhaled treprostinil (iTre) and followed up clinically for at least 3 months are presented. PH was defined by resting right heart catheterization as a mean pulmonary artery pressure (mPAP) ≥ 35 mmHg, or mPAP ≥ 25 mmHg associated with pulmonary vascular resistance ≥ 4 Woods Units. Follow-up evaluation was performed at the discretion of the attending physician. From baseline to follow-up, we observed significant improvement in functional class (n = 22, functional class III-IV 82 vs. 59%, p = 0.041) and 6-min walk distance (n = 11, 243 ± 106 vs. 308 ± 109; p = 0.022), without a deleterious effect on resting peripheral oxygen saturation (n = 22, 92 ± 6 vs. 94 ± 4; p = 0.014). Most of the patients (86%, n = 19/22) were using long-term nasal supplemental oxygen at baseline. During follow-up, only one patient had increased supplemental oxygen requirement. The most common adverse events were cough, headache, and diarrhea. No severe adverse event was reported. The results suggest that iTre is safe in patients with Group 3 PH and evidence of pulmonary vascular remodeling in terms of functional class, gas exchange, and exercise capacity. Additionally, iTre was well tolerated. The potential role of PH-specific drugs in Group 3 PH should be further assessed in larger prospective studies.

Borderline resting mean pulmonary arterial pressure (mPAP) is associated with adverse outcomes and affects the exercise pulmonary vascular response. However, the pathophysiological mechanisms underlying exertional intolerance in borderline mPAP remain incompletely characterized. In the current study, we sought to evaluate the prevalence and functional impact of exercise pulmonary hypertension (ePH) across a spectrum of resting mPAP’s in consecutive patients with contemporary resting right heart catheterization (RHC) and invasive cardiopulmonary exercise testing. Patients with resting mPAP 0.05) and similar underlying mechanisms of exercise intolerance compared with non-PH (peak oxygen delivery 1868 ± 599 mL/min versus 1756 ± 720 mL/min versus 2482 ± 875 mL/min, respectively; P