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Background: Patients with COPD frequently demonstrate pulmonary hypertension (PH). Severe PH in patients with COPD, identified by pulmonary vascular resistance (PVR) of > 5 Wood units (WU), is closely linked to impaired transplant-free survival. The impact of PH-targeting pharmacotherapy in this context remains unclear., Research Question: Is PH-targeted therapy associated with improved transplant-free survival in patients with COPD and PH?, Study Design and Methods: This study included Pulmonary Vascular Research Institute GoDeep meta-registry patients with COPD and PH and available right heart catheterization at diagnosis. We investigated PH-targeted therapy prevalence and its association with transplant-free survival using diverse statistical methods, including Cox regression and subgroup analyses based on PH severity, comorbidities, and pulmonary function test results. Immortal time bias was addressed through a landmark approach., Results: As of December 2023, the GoDeep meta-registry included 26,981 patients (28% in PH group 1, 13% in PH group 2, 12% in PH group 3, 10% in PH group 4, 2% in PH group 5, 26% undefined, and 9% control participants). Of these, 836 patients had a diagnosis of COPD with PH and were included in this analysis, with median age of 66 years (59-73 years), FEV 1 of 51% predicted (34%-69% predicted), mPAP of 35 mm Hg (28-44 mm Hg), PVR of 5 WU (4-8 WU), cardiac index of 2.5 L/min/m 2 (2.0-2.9 L/min/m 2 ), and mostly World Health Organization functional class III were included. Five-year transplant-free survival was 42%, significantly worse than in group 1 PH. A multivariable Cox proportional hazards model identified PVR, but not FEV 1 , as a major predictor of outcome. Four hundred eighteen patients (50%) received phosphodiesterase 5 inhibitor (PDE5i) therapy, which was associated with significantly reduced mortality: hazard ratio of 0.65 (0.57-0.75) for the entire cohort of patients with COPD and PH and of 0.83 (0.74-0.94) when performing landmark analysis. This PDE5i effect was reproduced robustly when performing subgroup analyses for patients with moderate to severe PH, various comorbidities, and supplemental oxygen requirement and when assessing the impact of unobserved confounders., Interpretation: Patients with COPD and PH exhibit poor transplant-free survival, with PVR being a predictor of mortality. In this meta-registry, PDE5i therapy was associated with a significant reduction in mortality across all tested models., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: K. T. has received personal fees from Bayer, AstraZeneca, and Gossamer. A. Y. has received personal fees from MSD and support for scientific meetings from AOP. D. G. K. reports support from the Sheffield Biomedical Research Centre and consulting fees and other payments from Jansen Pharmaceuticals, Ferrer, Altavant, MSD, and United therapeutics. H. O. reports grants or contracts from Actelion, Bayer, Boehringer-Ingelheim, Janssen, MSD, IQVIA, and Pfizer; consulting fees from Bayer and IQVIA; speaker fees from Actelion, Bayer, Boehringer-Ingelheim, MSD, and Pfizer; support for scientific meetings from Astra Zeneca, Boehringer-Ingelheim, Menarini, and MSD; and participation on data safety board or advisory board for Bayer and IQVIA. G. K. reports consulting and speaker fees from Boehringer-Ingelheim, Janssen, MSD, Astra Zeneca, Chiesi, AOP, and Ferrer and support for scientific meetings from AOP, Vitalaire, MSD, and Boehringer-Ingelheim. P. M. H. reports personal fees from Merck Co. M. R. W. reports personal fees from MorphogenIX, Janssen, Chiesi, and Aerami; grants from British Heart Foundation and NIHR; and personal fees from MSD, Benevolent AI, and Tiakis Biotech outside the submitted work. L. H. reports personal fees and nonfinancial support from Janssen and personal fees from MSD, Gossamer, and Altavant. M. R. has received support from Janssen Pharmaceutica and Bayer Pharma AG, and speaker fees from Janssen Pharmaceutica and OMT. H.-A. G. has received fees from Actelion, AstraZeneca, Bayer, GSK, Janssen-Cilag, Lilly, Novartis, OMT, Pfizer, and United Therapeutics. W. S. has received consultancy fees from United Therapeutics, Tiakis Biotech AG, Liquidia, Pieris Pharmaceuticals, Abivax, Pfizer, and Medspray BV. None declared (R. W. M., A. L., E. B., J. S. A., A. B., Z. K., A. J. S., R. T. Z., A. A., G. G., H. R. C., R. F., P. G. W., M. Frauendorf, K. M., T. A., M. Feunerich, F. G., J. W.)., (Copyright © 2024. Published by Elsevier Inc.)

Background: Pulmonary hypertension (PH) is a heterogeneous disease with a poor prognosis. Accurate risk stratification is essential for guiding treatment decisions in pulmonary arterial hypertension (PAH). Although various risk models have been developed for PAH, their comparative prognostic potential requires further exploration. Additionally, the applicability of risk scores in PH groups beyond group 1 remains to be investigated., Research Question: Are risk scores originally developed for PAH predictive in PH groups 1 through 4?, Study Design and Methods: We conducted a comprehensive analysis of outcomes among patients with incident PH enrolled in the multicenter worldwide Pulmonary Vascular Research Institute GoDeep meta-registry. Analyses were performed across PH groups 1 through 4 and further subgroups to evaluate the predictive value of PAH risk scores, including the Registry to Evaluate Early and Long-Term PAH Disease Mangement (REVEAL) Lite 2, REVEAL 2.0, European Society of Cardiology/European Respiratory Society 2022, Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) 3-strata, and COMPERA 4-strata., Results: Eight thousand five hundred sixty-five patients were included in the study, of whom 3,537 patients were assigned to group 1 PH, whereas 1,807 patients, 1,635 patients, and 1,586 patients were assigned to group 2 PH, group 3 PH, and group 4 PH, respectively. Pulmonary hemodynamics were impaired with median mean pulmonary arterial pressure of 42 mm Hg (interquartile range, 33-52 mm Hg) and pulmonary vascular resistance of 7 Wood units (WU) (interquartile range, 4-11 WU). All risk scores were prognostic in the entire PH population and in each of the PH groups 1 through 4. The REVEAL scores, when used as continuous prediction models, demonstrated the highest statistical prognostic power and granularity; the COMPERA 4-strata risk score provided subdifferentiation of the intermediate-risk group. Similar results were obtained when separately analyzing various subgroups (PH subgroups 1.1, 1.4.1, and 1.4.4; PH subgroups 3.1 and 3.2; group 2 with isolated postcapillary PH vs combined precapillary and postcapillary PH; patients of all groups with concomitant cardiac comorbidities; and severe [> 5 WU] vs nonsevere PH)., Interpretation: This comprehensive study with real-world data from 15 PH centers showed that PAH-designed risk scores possess predictive power in a large PH cohort, whether considered as common to the group or calculated separately for each PH group (1-4) and various subgroups., Trial Registry: ClinicalTrials.gov; No.: NCT05329714; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: A. Y. has received personal fees from MSD. H. G. has received personal fees from Actelion, AstraZeneca, Bayer, BMS, GossamerBio, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. M. R. W. reports personal fees from MorphogenIX, Janssen, Chiesi, and Aerami; grants from British Heart Foundation and NIHR; and personal fees from MSD, Benevolent AI, and Tiakis Biotech, outside the submitted work. L. H. reports personal fees and nonfinancial support from Janssen and personal fees from MSD, Gossamer, and Altavant. D. G. K. reports support for the present manuscript from the Sheffield Biomedical Research Centre and consulting fees and other payments from Jansen Pharmaceuticals, Ferrer, Altavant, MSD, and United therapeutics. P. M. H. reports personal fees from Merck Co. S. Y. C. reports personal fees from Janssen, Bayer, Pfizer, United Therapeutics, and Acceleron Pharma and is a director, officer, and shareholder of Synhale Therapeutics. S. O. reports personal fees from MSD, Janssen, and Gallenica-Ferrer. H. A. G. has received fees from Actelion, AstraZeneca, Bayer, GSK, Janssen-Cilag, Lilly, Novartis, OMT, Pfizer, and United Therapeutics. M. J. R. has received support from Janssen Pharmaceutica and Bayer Pharma AG and speaker fees from Janssen Pharmaceutica and OMT. S. S. reports personal fees from Gossamer Bio, Merck, Keros, Janssen, United Therapeutics, and Liquidia. K. T. has received personal fees from Bayer, AstraZeneca, and Gossamer. W. S. has received consultancy fees from United Therapeutics, Tiakis Biotech AG, Liquidia, Pieris Pharmaceuticals, Abivax, Pfitzer, and Medspray BV. None declared (M. Fünderich, A.L., Y. S., O. T., A. J. S., R. T. Z., P. G. W., M. Frauendorf, A. Arvanitaki, G. G., K. S., H. R. C., R. F., I. A. G., E. B., J. S. A., A. P., S. G., A. Anthi, R. W. M., J. W., F. G.), (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Health-related quality of life (HRQOL) is frequently impaired in pulmonary arterial hypertension. However, little is known about HRQOL in other forms of pulmonary hypertension (PH)., Research Question: Does HRQOL vary across groups of the World Symposium on Pulmonary Hypertension (WSPH) classification system?, Study Design and Methods: This cross-sectional study included patients with PH from the Pulmonary Vascular Disease Phenomics (PVDOMICS) cohort study. HRQOL was assessed by using emPHasis-10 (e-10), the 36-item Medical Outcomes Study Short Form survey (physical component score [PCS] and mental component score), and the Minnesota Living with Heart Failure Questionnaire. Pearson correlations between HRQOL and demographic, physiologic, and imaging characteristics within each WSPH group were tested. Multivariable linear regressions compared HRQOL across WSPH groups, adjusting for demographic characteristics, disease prevalence, functional class, and hemodynamics. Cox proportional hazards models were used to assess associations between HRQOL and survival across WSPH groups., Results: Among 691 patients with PH, HRQOL correlated with functional class and 6-min walk distance but not hemodynamics. HRQOL was severely depressed across WSPH groups for all measures except the 36-item Medical Outcomes Study Short Form survey mental component score. Compared with Group 1 participants, Group 2 participants had significantly worse HRQOL (e-10 score, 29 vs 24 [P = .001]; PCS, 32.9 ± 8 vs 38.4 ± 10 [P < .0001]; and Minnesota Living with Heart Failure Questionnaire score, 50 vs 38 [P = .003]). Group 3 participants similarly had a worse e-10 score (31 vs 24; P < .0001) and PCS (33.3 ± 9 vs 38.4 ± 10; P < .0001) compared with Group 1 participants, which persisted in multivariable models (P < .05). HRQOL was associated in adjusted models with survival across Groups 1, 2, and 3., Interpretation: HRQOL was depressed in PH and particularly in Groups 2 and 3 despite less severe hemodynamics. HRQOL is associated with functional capacity, but the severity of hemodynamic disease poorly estimates the impact of PH on patients' lives. Further studies are needed to better identify predictors and treatments to improve HRQOL across the spectrum of PH., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: H. M. D. has received grant funding from Bayer Pharmaceuticals, has served on advisory boards for Janssen Pharmaceuticals and has received consulting fees from Janssen Pharmaceuticals. N. S. H. serves on a clinical trial steering committee for Aerovate, advisory board for Gossamer, DSMB for Merch, and consultant for Liquidia and United Therapeutics. R.M. has received an honorarium from the American Academy of Sleep Medicine; funds for service on the American Board of Internal Medicine and as associate editor of the American Journal of Respiratory and Critical Care Medicine; has received National Institutes of Health funding; and has received royalties from UpToDate. A. R. H. has served as a consultant for Bayer, GossamerBio, Janssen, Merck, Tenax, and United Therapeutics. She owns stock in Tenax. P. M. H. has served on a steering committee for Merck and as consultant ARIA-CVS. S. C. M. has served as a consultant for Acceleron, Janssen, Merck, and United Therapeutics. None declared (A. B., A. B. L., E. M. H., M. S. J., J. A. L., M. K. R., S. C. E., E. B. R., R. P. F., F. P. R., G. J. B.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Detecting right heart failure post left ventricular assist device (LVAD) is challenging. Sensitive pressure-volume loop assessments of right ventricle (RV) contractility may improve our appreciation of post-LVAD RV dysfunction., Methods: Thirteen LVAD patients and 20 reference (non-LVAD) subjects underwent comparison of echocardiographic, right heart cath hemodynamic, and pressure-volume loop-derived assessments of RV contractility using end-systolic elastance (Ees), RV afterload by effective arterial elastance (Ea), and RV-pulmonary arterial coupling (ratio of Ees/Ea)., Results: LVAD patients had lower RV Ees (0.20 ± 0.08 vs 0.30 ± 0.15 mm Hg/ml, p = 0.01) and lower RV Ees/Ea (0.37 ± 0.14 vs 1.20 ± 0.54, p < 0.001) versus reference subjects. Low RV Ees correlated with reduced RV septal strain, an indicator of septal contractility, in both the entire cohort (r = 0.68, p = 0.004) as well as the LVAD cohort itself (r = 0.78, p = 0.02). LVAD recipients with low RV Ees/Ea (below the median value) demonstrated more clinical heart failure (71% vs 17%, p = 0.048), driven by an inability to augment RV Ees (0.22 ± 0.11 vs 0.19 ± 0.02 mm Hg/ml, p = 0.95) to accommodate higher RV Ea (0.82 ± 0.38 vs 0.39 ± 0.08 mm Hg/ml, p = 0.002). Pulmonary artery pulsatility index (PAPi) best identified low baseline RV Ees/Ea (≤0.35) in LVAD patients ((area under the curve) AUC = 0.80); during the ramp study, change in PAPi also correlated with change in RV Ees/Ea (r = 0.58, p = 0.04)., Conclusions: LVAD patients demonstrate occult intrinsic RV dysfunction. In the setting of excess RV afterload, LVAD patients lack the RV contractile reserve to maintain ventriculo-vascular coupling. Depression in RV contractility may be related to LVAD left ventricular unloading, which reduces septal contractility., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Right ventricular (RV) contractile reserve shows promise as an indicator of occult RV dysfunction in pulmonary vascular disease. We investigated which measure of RV contractile reserve during exercise best predicts occult RV dysfunction and clinical outcomes., Methods: We prospectively studied RV contractile reserve in 35 human subjects referred for right heart catheterization for known or suspected pulmonary hypertension. All underwent cardiac magnetic resonance imaging, echocardiography, and supine invasive cardiopulmonary exercise testing with concomitant RV pressure-volume catheterization. Event-free survival was prospectively adjudicated from time of right heart catheterization for a 4-year follow-up period., Results: RV contractile reserve during exercise, as measured by a positive change in end-systolic elastance (Ees) during exertion, was associated with elevation in pulmonary pressures but preservation of RV volumes. Lack of RV reserve, on the other hand, was tightly coupled with acute RV dilation during exertion (R 2  = 0.76, p< 0.001). RV Ees and dilation changes each predicted resting RV-PA dysfunction. RV ejection fraction during exercise, which captured exertional changes in both RV Ees and RV dilation, proved to be a robust surrogate for RV contractile reserve. Reduced exercise RV ejection fraction best predicted occult RV dysfunction among a variety of resting and exercise RV measures, and was also associated with clinical worsening., Conclusions: RV ejection fraction during exercise, as an index of RV contractile reserve, allows for excellent identification of occult RV dysfunction, more so than resting measures of RV function, and may predict clinical outcomes as well., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with COPD who experience pulmonary hypertension (PH) have worse mortality than those with COPD alone. Predictors of poor outcomes in COPD-PH are not well-described. Diffusing capacity of the lung (Dlco) assesses the integrity of the alveolar-capillary interface and thus may be a useful prognostic tool among those with COPD-PH., Research Question: Using a single center registry, we sought to evaluate Dlco as a predictor of mortality in a cohort of patients with COPD-PH., Study Design and Methods: This retrospective cohort study analyzed 71 COPD-PH patients from the Johns Hopkins Pulmonary Hypertension Registry with right-sided heart catheterization (RHC)-proven PH and pulmonary function testing data within one year of diagnostic RHC. Transplant-free survival was calculated from index RHC. Adjusted transplant-free survival was modelled using Cox proportional hazard methods; age, pulmonary vascular resistance, FEV 1 , oxygen use, and N-terminal pro-brain natriuretic peptide were included as covariates., Results: Overall unadjusted transplant-free 1-, 3-, and 5-year survivals were 87%, 60%, and 51%, respectively. Survival was associated with reduced Dlco across the observed range of pulmonary artery pressures and pulmonary vascular resistance. Severe Dlco impairment was associated with poorer survival (log-rank χ 2 13.07) (P < .001); adjusting for covariates, for every percent predicted decrease in Dlco, mortality rates increased by 4% (hazard ratio, 1.04; 95% CI, 1.01-1.07)., Interpretation: Among patients with COPD-PH, severe gas transfer impairment is associated with higher mortality, even with adjustment for airflow obstruction and hemodynamics, which suggests that Dlco may be a useful prognostic marker in this population. Future studies are needed to further investigate the association between Dlco and morbidity and to determine the utility of Dlco as a biomarker for disease risk and severity in COPD-PH., (Copyright © 2020. Published by Elsevier Inc.)

Background: Three biomarkers, soluble suppression of tumorigenicity 2 (ST2), galectin 3 (Gal3), and N-terminal brain natriuretic peptide prohormone (NT-proBNP), are approved for noninvasive risk assessment in left-sided heart failure, and small observational studies have shown their prognostic usefulness in heterogeneous pulmonary hypertension cohorts. We examined associations between these biomarkers and disease severity and survival in a large cohort of patients with pulmonary arterial hypertension (PAH) (ie, group 1 pulmonary hypertension). We hypothesized that additive use of biomarkers in combination would improve the prognostic value of survival models., Methods: Biomarker measurements and clinical data were obtained from 2,017 adults with group 1 PAH. Associations among biomarker levels and clinical variables, including survival times, were examined with multivariable regression models. Likelihood ratio tests and the Akaike information criterion were used to compare survival models., Results: Higher ST2 and NT-proBNP were associated with higher pulmonary pressures and vascular resistance and lower 6-min walk distance. Higher ST2 and NT-proBNP levels were associated with increased risk of death (hazard ratios: 2.79; 95% CI, 2.21-3.53; P < .001 and 1.84; 95% CI, 1.62-2.10; P < .001, respectively). The addition of ST2 to survival models composed of other predictors of survival, including NT-proBNP, significantly improved model fit and predictive capacity., Conclusions: ST2 and NT-proBNP are strong, noninvasive prognostic biomarkers in PAH. Despite its prognostic value in left-sided heart failure, Gal3 was not predictive in PAH. Adding ST2 to survival models significantly improves model predictive capacity. Future studies are needed to develop multimarker assays that improve noninvasive risk stratification in PAH., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: 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., Methods: 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)., Results: Compared with controls, NEDD9 was increased in PAH by 1.82-fold (p < 0.0001). Elevated NEDD9 correlated with PVR in idiopathic PAH (ρ = 0.42, p < 0.0001, n = 54), connective tissue disease (CTD)-PAH (ρ = 0.53, p < 0.0001, n = 53), and congenital heart disease-PAH (ρ = 0.68, p < 0.0001, 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., Conclusions: 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., (Published by Elsevier Inc.)

Background: Ischemia-reperfusion injury is characterized by an increase in oxidative stress and leads to significant morbidity and death. The tyrosine kinase c-Abl is activated by oxidative stress and mediates processes that affect endothelial barrier function. We hypothesized treatment with the c-Abl inhibitor imatinib would be protective against ischemia-reperfusion injury in our ex vivo rabbit model., Methods: Heart-lung blocs were harvested from rabbits and stored in cold in Perfadex (Vitrolife, Englewood, CO) for 18 hours. Blocs were reperfused for 2 hours in an ex vivo circuit with donor rabbit blood alone (untreated group, n = 7) or donor rabbit blood and 4 mg imatinib (treatment group, n = 10). Serial clinical variables measured every 15 minutes (arterial oxygen and carbon dioxide tension and mean pulmonary artery pressures) and biochemistry of tissue samples before and after reperfusion were assessed., Results: Compared with untreated lungs, imatinib treatment improved physiologic parameters, including oxygen, carbon dioxide, and pulmonary artery pressures. Imatinib-treated lungs had less vascular barrier dysfunction as quantified by wet-to-dry weight ratios and bronchoalveolar lavage protein concentrations. Treated lungs showed less inflammation as measured by bronchoalveolar lavage myeloperoxidase assay, less mitochondrial reactive oxygen species production, and increased antioxidant catalase levels. Finally, imatinib protected lungs from DNA damage and p53 upregulation., Conclusions: Imatinib treatment significantly improved the physiologic performance of reperfused lungs and biochemical indicators associated with reperfusion injury in this ex vivo model. Further study is necessary to elucidate the mechanism of tyrosine kinase inhibition in lungs exposed to ischemia and reperfusion., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary arterial hypertension (PAH) is a progressive, fatal disease. Current prognostic models are not ideal, and identifying more accurate prognostic variables is needed. The objective of this study was to evaluate the relative prognostic value of the right atrial pressure/pulmonary artery wedge pressure (RAP/PAWP) ratio in PAH patients. We hypothesized that the RAP/PAWP ratio is more predictive of survival than any of the other measured or calculated hemodynamic variables., Methods: We performed a secondary analysis of a PAH cohort (Cohort 1) and validated our results in a separate cohort (Cohort 2). Cohort 1 included primarily patients enrolled in prospective, short-term, randomized clinical trials and subsequently followed long term. Cohort 2 included patients prospectively enrolled in a PAH registry at a tertiary PAH referral center., Results: Cohort 1 (n = 847) and Cohort 2 (n = 697) had a mean age of 47 and 54 years, respectively. Most were female (78% and 73%, respectively), Caucasian (83% and 82%), with advanced functional class disease status (New York Heart Association Functional Class III/IV 85% and 68%) and with significantly elevated hemodynamics (mean RAP/PAWP ratio: 1.2 and 1.0; pulmonary vascular resistance: 13.5 and 9.4 Wood units). RAP/PAWP ratio indicated a 1-year hazard ratio of 1.44 (p = 0.0001) and 1.35, respectively (p < 0.0001), and was the most consistently predictive hemodynamic variable across the 2 cohorts. These results remain valid even when adjusted for other covariables in multivariable regression models., Conclusions: The RAP/PAWP ratio is a more specific predictor of survival than any other hemodynamic variable, and we recommend that it be used in clinical prognostication and PAH predictive models., (Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Imatinib is an oral inhibitor of several protein kinases implicated in the pathophysiology of pulmonary hypertension. Treatment with imatinib resulted in improved hemodynamics and exercise capacity in a controlled trial (Imatinib [QTI571] in Pulmonary Arterial Hypertension, a Randomized Efficacy Study [IMPRES]), among pulmonary arterial hypertension (PAH) patients inadequately responsive to 2 to 3 PAH-specific therapies., Methods: The long-term (up to 204 weeks) safety and efficacy of imatinib in this open-label extension study were reviewed until early study termination on April 16, 2014. Of 202 IMPRES-enrolled patients, 66 imatinib and 78 placebo recipients entered the extension., Results: Overall, 93.8% (135 of 144) of patients discontinued the extension study; administrative issues (i.e., sponsor termination; 32.6%) and adverse events (31.3%) were the primary reasons for discontinuation. Nine patients completed the extension study before it was terminated. Serious and unexpected adverse events were frequent. These included 6 subdural hematomas in the extension study and 17 deaths during or within 30 days of study end. Although the patients who tolerated imatinib and remained in the extension for a longer duration did experience an improvement in functional class and walk distance, most discontinued the drug and the study., Conclusions: Severe adverse events, significant side effects, and a high discontinuation rate limit the utility of imatinib in the treatment of PAH. These risks outweigh any possible improvements in hemodynamics and walk distance seen in those patients able to remain on drug. The off-label use of this compound in PAH is discouraged., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Pixel-based multimodality tissue tracking (MTT) is a new noninvasive method for the quantification of cardiac deformation from cine image of MRI. The aim of this study is to validate bi-ventricular strain measurement by MTT compared to strain-encoding (SENC) MRI and harmonic phase (HARP) MRI in pulmonary hypertension (PH) patients., Methods: In 45 subjects (30 PH patients and 15 normal subjects), RV and LV peak global longitudinal strains (Ell) were measured from long axis 4 chamber view using MTT. LV peak global circumferential strains (Ecc) by MTT were measured from short axis. For validation, RV and LV Ell by MTT were compared to measures by SENC-MRI from short axis, and LV Ecc by MTT was compared to measures by short axis tagged MRI analysis (HARP). Reproducibility of MTT was also determined., Results: MTT quantified RV Ell correlated closely to those of SENC (r=0.72, p<0.001), with good limits of agreement. LV Ell quantified by MTT showed moderate correlation with SENC (r=0.57, p=0.001), and LV Ecc by MTT also showed moderate correlation with HARP (-16.9±4.1 vs -14.3±3.5, p<0.001 for all, r=0.60, p<0.001). RV Ell negatively correlated with RVEF (r=-0.53, p=0.001) and also positively correlated with mean PAP in PH patients (r=0.60, p=0.001). Strain measurement by MTT showed high reproducibility., Conclusions: We demonstrate that MTT is a reproducible tool for quantification of cardiac deformation using cine images in PH patients. Hence, it could serve as a new rapid and comprehensive technique for clinical assessment of regional cardiac function., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Pulmonary arterial hypertension (PAH) is a progressive disease with high rates of morbidity and mortality. Current therapies improve symptoms, functional capacity, and, in select cases, survival. Little is known about patient factors that may predict the likelihood of patient-important, clinically relevant responses to therapy such as the 6-min walk distance (6MWD) and health-related quality of life (HRQoL)., Methods: Data from the randomized clinical trial of tadalafil in PAH were used. Adjusted logistic regression models were created to examine the relationship between baseline characteristics and odds of achieving the minimal important difference (MID) in three parameters, defined as either a > 33-m increase in 6MWD, a > 5-unit increase in physical component summary score of the Medical Outcomes Study Short Form-36 (SF-36), or a > 5-unit increase in mental component summary score of the SF-36., Results: The study included 405 subjects. Younger age, male sex, lower baseline 6MWD, and disease etiology were associated with greater odds of achieving the MID for the 6-min walk test. Active treatment, younger age, and male sex were associated with greater odds of achieving the MID for the physical component summary score. Male sex was associated with greater odds of achieving the MID for the mental component summary score., Conclusions: Age, sex, baseline functional capacity, and disease etiology are variably associated with the likelihood of achieving clinically relevant responses in patient-important outcomes to PAH-specific therapy such as 6MWD and HRQoL. The increased likelihood of response in men compared with women is a novel finding and may reflect pathophysiologic differences between sexes.

Background: Patients with pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc-APAH) experience higher mortality rates than patients with idiopathic disease and those with other connective tissue diseases (CTD-APAH). We sought to identify unique predictors of mortality associated with SSc-APAH in the CTD-APAH population., Methods: The Registry to Evaluate Early and Long-Term PAH Management (REVEAL Registry) is a multicenter, prospective US-based registry of patients with previously and newly diagnosed (enrollment within 90 days of diagnostic right-sided heart catheterization) PAH. Cox regression models evaluated all previously identified candidate predictors of mortality in the overall REVEAL Registry population to identify significant predictors of mortality in the SSc-APAH (n = 500) vs non-SSc-CTD-APAH (n = 304) populations., Results: Three-year survival rates in the previously diagnosed and newly diagnosed SSc-APAH group were 61.4% ± 2.7% and 51.2% ± 4.0%, respectively, compared with 80.9% ± 2.7% and 76.4% ± 4.6%, respectively, in the non-SSc-CTD-APAH group (P < .001). In multivariate analyses, men aged > 60 years, systolic BP (SBP) ≤ 110 mm Hg, 6-min walk distance (6MWD) < 165 m, mean right atrial pressure (mRAP) > 20 mm Hg within 1 year, and pulmonary vascular resistance (PVR) > 32 Wood units remained unique predictors of mortality in the SSc-APAH group; 6MWD ≥ 440 m was protective in the non-SSc-CTD-APAH group, but not the SSc-APAH group., Conclusions: Patients with SSc-APAH have higher mortality rates than patients with non-SSc-CTD-APAH. Identifying patients with SSc-APAH who are at a particularly high risk of death, including elderly men and patients with low baseline SBP or 6MWD, or markedly elevated mRAP or PVR, will enable physicians to identify patients who may benefit from closer monitoring and more aggressive treatment., Trial Registry: ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Background: Although the transpulmonary gradient (TPG) and pulmonary vascular resistance (PVR) are commonly used to differentiate heart failure patients with pulmonary vascular disease from those with passive pulmonary hypertension (PH), elevations in TPG and PVR may not always reflect pre-capillary PH. Recently, it has been suggested an elevated diastolic pulmonary artery pressure-to-pulmonary capillary wedge pressure gradient (DPG) may be a better indicator of pulmonary vascular remodeling, and therefore, may be of added prognostic value in patients with PH being considered for cardiac transplantation., Methods: Using the United Network for Organ Sharing (UNOS) database, we retrospectively reviewed all primary adult (age > 17 years) orthotropic heart transplant recipients between 1998 and 2011. All patients with available pre-transplant hemodynamic data and PH (mean pulmonary artery pressure ≥ 25 mm Hg) were included (n = 16,811). We assessed the prognostic value of DPG on post-transplant survival in patients with PH and an elevated TPG and PVR., Results: In patients with PH and a TPG > 12 mm Hg (n = 5,827), there was no difference in survival at up to 5 years post-transplant between high DPG (defined as ≥3, ≥5, ≥7, or ≥10 mm Hg) and low DPG (<3, <5, <7, or <10 mm Hg) groups. Similarly, there was no difference in survival between high and low DPG groups in those with a PVR > 3 Wood units (n = 6,270). Defining an elevated TPG as > 15 mm Hg (n = 3,065) or an elevated PVR > 5 (n = 1,783) yielded similar results., Conclusions: This large analysis investigating the prognostic value of DPG found an elevated DPG had no effect on post-transplant survival in patients with PH and an elevated TPG and PVR., (© 2013 International Society for Heart and Lung Transplantation Published by International Society for the Heart and Lung Transplantation All rights reserved.)

Pulmonary arterial hypertension (PAH) is the leading cause of death in systemic sclerosis (SSc) and affects up to 12% of all patients with SSc, with a 50% mortality rate within 3 years of PAH diagnosis. Compared with the idiopathic form of PAH (IPAH), patients with SSc-associated PAH (SSc-PAH) have a threefold increased risk of death and may receive a diagnosis late in the course of disease because of insidious onset and the high prevalence of cardiac, musculoskeletal, and pulmonary parenchymal comorbidities. Treatment with conventional forms of PAH therapy often yield poor results compared with IPAH cohorts; unfortunately, the exact reasons behind this remain poorly understood but likely include variations in the pathologic mechanisms, differences in cardiovascular response to increasing afterload, and inadequate strategies to detect and treat SSc-PAH early in its course. Current methods for screening and longitudinal evaluation of SSc-PAH, such as the 6-min walk test, transthoracic echocardiography, and MRI, each have notable advantages and disadvantages. We provide an up-to-date, focused review of SSc-PAH and how it differs from IPAH, including pathogenesis, appropriate screening for disease onset, and new approaches to treatment and longitudinal assessment of this disease.

Right ventricular (RV) dysfunction arises in chronic lung disease when chronic hypoxemia and disruption of pulmonary vascular beds increase ventricular afterload. RV dysfunction is defined by hypertrophy with preserved myocardial contractility and cardiac output. RV hypertrophy seems to be a common complication of chronic and advanced lung disease. RV failure is rare, except during acute exacerbations of chronic lung disease or when multiple comorbidities are present. Treatment is targeted at correcting hypoxia and improving pulmonary gas exchange and mechanics. There are no data supporting the use of pulmonary hypertension-specific therapies for patients with RV dysfunction secondary to chronic lung disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: REVEAL (the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) is the largest US cohort of patients with pulmonary arterial hypertension (PAH) confirmed by right-sided heart catheterization (RHC), providing a more comprehensive subgroup characterization than previously possible. We used REVEAL to analyze the clinical features of patients with connective tissue disease-associated PAH (CTD-APAH)., Methods: All newly and previously diagnosed patients with World Health Organization (WHO) group 1 PAH meeting RHC criteria at 54 US centers were consecutively enrolled. Cross-sectional and 1-year mortality and hospitalization analyses from time of enrollment compared CTD-APAH to idiopathic disease and systemic sclerosis (SSc) to systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and rheumatoid arthritis (RA)., Results: Compared with patients with idiopathic disease (n = 1,251), patients with CTD-APAH (n = 641) had better hemodynamics and favorable right ventricular echocardiographic findings but a higher prevalence of pericardial effusions, lower 6-min walk distance (300.5 ± 118.0 vs 329.4 ± 134.7 m, P = .01), higher B-type natriuretic peptide (BNP) levels (432.8 ± 789.1 vs 245.6 ± 427.2 pg/mL, P < .0001), and lower diffusing capacity of carbon monoxide (Dlco) (44.9% ± 18.0% vs 63.6% ± 22.1% predicted, P < .0001). One-year survival and freedom from hospitalization were lower in the CTD-APAH group (86% vs 93%, P < .0001; 67% vs 73%, P = .03). Compared with patients with SSc-APAH (n = 399), those with other CTDs (SLE, n = 110; MCTD, n = 52; RA, n = 28) had similar hemodynamics; however, patients with SSc-APAH had the highest BNP levels (552.2 ± 977.8 pg/mL), lowest Dlco (41.2% ± 16.3% predicted), and poorest 1-year survival (82% vs 94% in SLE-APAH, 88% in MCTD-APAH, and 96% in RA-APAH)., Conclusions: Patients with SSc-APAH demonstrate a unique phenotype with the highest BNP levels, lowest Dlco, and poorest survival of all CTD-APAH subgroups., Trial Registry: ClinicalTrials.gov; No.: NCT00370214; URL: clinicaltrials.gov.

The mechanisms underlying schistosomiasis-induced pulmonary hypertension (PH), one of the most common causes of PH worldwide, remain unclear. We sought to determine whether Schistosoma mansoni causes experimental PH associated with pulmonary vascular remodeling in an interleukin (IL)-13-dependent manner. IL-13Ralpha1 is the canonical IL-13 signaling receptor, whereas IL-13Ralpha2 is a competitive nonsignaling decoy receptor. Wild-type, IL-13Ralpha1(-/-), and IL-13Ralpha2(-/-) C57BL/6J mice were percutaneously infected with S. mansoni cercariae, followed by i.v. injection of eggs. We assessed PH with right ventricular catheterization, histological evaluation of pulmonary vascular remodeling, and detection of IL-13 and transforming growth factor-beta signaling. Infected mice developed pulmonary peri-egg granulomas and arterial remodeling involving predominantly the vascular media. In addition, gain-of-function IL-13Ralpha2(-/-) mice had exacerbated vascular remodeling and PH. Mice with loss of IL-13Ralpha1 function did not develop PH and had reduced pulmonary vascular remodeling. Moreover, the expression of resistin-like molecule-alpha, a target of IL-13 signaling, was increased in infected wild-type and IL-13Ralpha2(-/-) but not IL-13Ralpha1(-/-) mice. Phosphorylated Smad2/3, a target of transforming growth factor-beta signaling, was increased in both infected mice and humans with the disease. Our data indicate that experimental schistosomiasis causes PH and potentially relies on up-regulated IL-13 signaling.

Background: Pulmonary hypertension (PH) is a common complication of sarcoidosis that is associated with increased mortality. The pathogenesis of PH in sarcoidosis is uncertain, and the role of pulmonary arterial hypertension (PAH)-specific therapies remains to be determined., Methods: We conducted a retrospective study of patients with sarcoidosis and PH at two referral centers. New York Heart Association (NYHA) functional class, exercise capacity, hemodynamic data, pulmonary function tests, and survival were collected and analyzed., Results: Twenty-two sarcoidosis patients treated with PAH-specific therapies were identified. After a median of 11 months of follow-up, NYHA class was improved in nine subjects. Mean 6-min walk distance (n = 18) increased by 59 m (p = 0.032). Patients with a higher FVC experienced a greater increment in exercise capacity. Among 12 patients with follow-up hemodynamic data, mean pulmonary artery pressure was reduced from 48.5 +/- 4.3 to 39.4 +/- 2.8 mm Hg (p = 0.008). The 1- and 3-year transplant-free survival rates were 90% and 74%, respectively., Conclusions: PAH-specific therapy may improve functional class, exercise capacity, and hemodynamics in PH associated with sarcoidosis. Prospective, controlled trials of PAH therapies for sarcoidosis are warranted to verify this apparent benefit. Mortality among the study population was high, highlighting the need for urgent evaluation at a lung transplant center.

Mechanical ventilation (MV) is used as therapy to support critically ill patients; however, the mechanisms by which MV induces lung injury and inflammation remain unclear. Epidermal growth factor receptor (EGFR)-mediated signaling plays a key role in various physiologic and pathologic processes, which include those modulated by mechanical and shear forces, in various cell types. We hypothesized that EGFR-activated signaling plays a key role in ventilator-induced lung injury and inflammation (VILI). To test this hypothesis, we assessed lung vascular and alveolar permeability as well as inflammation, which are cardinal features of VILI, in mice treated with the EGFR inhibitor AG1478. Inhibition of EGFR activity greatly diminished MV-induced lung alveolar permeability and neutrophil accumulation in the bronchoalveolar lavage (BAL) fluid, as compared with vehicle-treated controls. Similarly, AG1478 inhibition diminished lung vascular leak (as assessed by Evans blue extravasation), but it did not affect interstitial neutrophil accumulation. Inhibition of the EGFR pathway also blocked expression of genes induced by MV. However, intratracheal instillation of EGF alone failed to induce lung injury. Collectively, our findings suggest that EGFR-activated signaling is necessary but not sufficient to produce acute lung injury in mice.

We hypothesize that pulmonary arterial hypertension (PAH)-associated genes identified by expression profiling of peripheral blood mononuclear cells (PBMCs) from patients with idiopathic pulmonary arterial hypertension (IPAH) can also be identified in PBMCs from scleroderma patients with PAH (PAH-SSc). Gene expression profiles of PBMCs collected from IPAH (n = 9), PAH-SSc (n = 10) patients, and healthy controls (n = 5) were generated using HG&#95;U133A&#95;2.0 GeneChips and were processed by the RMA/GCOS&#95;1.4/SAM&#95;1.21 data analysis pipeline. Disease severity in consecutive patients was assessed by functional status and hemodynamic measurements. The expression profiles were analyzed using PAH severity-stratification, and identified candidate genes were validated with real-time polymerase chain reaction (PCR). Transcriptomics of PBMCs from IPAH patients was highly comparable with that of PMBCs from PAH-SSc patients. The PBMC gene expression patterns significantly correlate with right atrium pressure (RA) and cardiac index (CI), which are known predictors of survival in PAH. Array stratification by RA and CI identified 364 PAH-associated candidate genes. Gene ontology (GO) analysis revealed significant (Z(score) > 1.96) alterations in angiogenesis genes according to PAH severity: matrix metalloproteinase 9 (MMP9) and vascular endothelial growth factor (VEGF) were significantly upregulated in mild as compared with severe PAH and healthy controls, as confirmed by real-time PCR. These data demonstrate that PBMCs from patients with PAH-SSc carry distinct transcriptional expression. Furthermore, our findings suggest an association between angiogenesis-related gene expression and severity of PAH in PAH-SSc patients. Deciphering the role of genes involved in vascular remodeling and PAH development may reveal new treatment targets for this devastating disorder.

Background: Bosentan improves clinical outcomes in pulmonary arterial hypertension (PAH), particularly in the idiopathic (IPAH) subset. Scant data are available regarding PAH associated with the scleroderma spectrum of diseases (APAH-SSD). Here we review our experience with bosentan in these 2 groups., Methods: Included were all patients at our center with either IPAH or APAH-SSD in whom bosentan was the first-line, single-agent therapy with at least 6 months of follow-up. Changes in the World Health Organization (WHO) functional class from baseline to the most recent follow-up on monotherapy were compared between the 2 groups, as well as overall survival and time to a composite end point of hepatotoxicity requiring discontinuation, use of additional therapy, or death., Results: Nineteen IPAH and 17 APAH-SSD subjects with similar baseline clinical characteristics and a median follow-up 9 months (range, 6-44) were analyzed. In IPAH subjects, WHO class improved from 3.1 +/- 0.5 at baseline to 2.4 +/- 0.8 (p = 0.005). No change occurred in the APAH-SSD group: 2.9 +/- 0.3 vs. 2.8 +/- 0.8; p = 0.5. Hepatotoxicity requiring discontinuation developed in 6 patients (17%). Seven (37%) IPAH and 8 SSD patients (47%) reached the composite end point (p = NS). Overall survival at 1 and 2 years was 100% and 100% vs 87% and 79% for IPAH and APAH-SSD patients, respectively (p = 0.075)., Conclusions: First-line bosentan monotherapy is associated with long-term improvement in functional class and good overall survival in patients with WHO class III IPAH. Most APAH-SSD patients experienced stability or decline in functional class and tended to have a higher mortality.

Pulmonary involvement is common in patients with portal hypertension and can manifest in diverse manners. Changes in pulmonary arterial resistance, manifesting either as the hepatopulmonary syndrome or portopulmonary hypertension (PPHTN), have been increasingly recognized in these patients in recent years. This review summarizes the clinicopathologic features, diagnostic criteria, as well as the latest concepts in the pathogenesis and management of PPHTN, which is defined as an elevated pulmonary artery pressure in the setting of an increased pulmonary vascular resistance and a normal wedge pressure in a patient with portal hypertension.