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Physicians who specialize in pulmonary arterial hypertension (PAH) care for patients facing a serious, life-limiting illness. Palliative care is underutilized in patients with PAH, and little is known about how best to provide palliative care to this patient population.Using a qualitative approach, assess physicians' perspectives on barriers and facilitators to the use of palliative care in PAH.Participants were board-certified pulmonologists and cardiologists recruited from the Pulmonary Hypertension Association's list of physician specialists and academic center websites. We performed one-on-one semi-structured interviews that were recorded, transcribed, and analyzed using thematic analysis.Twelve physicians participated in the study, with a median age of 48.5 years and 20.5 years of clinical experience caring for patients with PAH. We identified the following themes and associated barriers and facilitators to effective implementation of palliative care for patients with PAH: a tailored approach to the individual patient; a PAH-specialist-led culture of care; effective collaboration with palliative care clinicians; and limitations imposed by health systems.PAH physicians are open to palliative care for their patients and are willing to partner with palliative care clinicians to implement this effectively and in the right setting. Areas for targeted improvement in enhancing palliative care for patients with PAH exist, especially enhancing collaboration between PAH physicians and palliative care specialists and navigating barriers in health systems.

Von Willebrand factor (VWF) is classically associated with primary hemostasis and platelet-rich arterial thromboses, but recently has also been implicated in fibrin clotting and venous thrombosis. Direct interaction between fibrin and VWF may mediate these processes, although prior reports are conflicting.We combined two complementary platforms to characterize VWF-fibrin(ogen) interactions and identify their potential physiologic significance.Engineered microvessels were lined with human endothelial cells, cultured under flow, and activated to release VWF and form transluminal VWF fibers. Fibrinogen, fibrin monomers, or polymerizing fibrin were then perfused, and interactions with VWF evaluated. Thrombin and fibrinogen were perfused into living versus paraformeldahyde-fixed microvessels and the pressure drop across microvessels monitored. Separately, protein binding to tethered VWF was assessed on a single-molecule level using total internal reflection fluorescence (TIRF) microscopy.Within microvessels, VWF fibers colocalized with polymerizing fibrin, but not fibrinogen. TIRF microscopy showed no colocalization between VWF and fibrinogen or fibrin monomers in a microfluidic flow chamber across a range of shear rates and protein concentrations. Thrombin-mediated fibrin polymerization within living microvessels triggered endothelial VWF release, increasing the rate and amount of microvessel obstruction compared to fixed vessels with an inert endothelium.We did not identify specific binding between fibrin(ogen) and VWF at a single-molecule level. Despite this, our results suggest that rapid release of endothelial VWF during clotting may provide a physical support for fibrin polymerization and accelerate thrombosis. This interaction may be of fundamental importance for the understanding and treatment of human thrombotic disease.

BACKGROUND: Soluble Fms-like tyrosine kinase 1 (sFlt-1) may inhibit angiogenesis. Higher levels of sFlt-1 are associated with worse prognosis in prevalent heart failure patients. The aim of this study was to better understand the role of sFlt-1 in heart failure pathogenesis by characterizing relationships between sFlt-1, cardiac morphology, and the composite outcome of incident heart failure or cardiovascular (CV) death in in a multi-ethnic cohort free of CV disease at baseline. METHODS: sFlt-1 was measured in 1381 participants in the Multi-Ethnic Study of Atherosclerosis Angiogenesis sub-study. Linear regression was used to estimate the association between sFlt-1 and cardiac morphology and Cox proportional hazard regression was used to estimate association with incident heart failure or CV mortality. RESULTS: over a median follow-up of 13.1 years, higher sFlt-1 levels were associated with incident heart failure or CV mortality regardless of CV risk factors or NT-proBNP levels (HR 1.17, 95% CI 1.10–1.26, p < 0.001). Higher sFlt-1 levels were also associated with both greater baseline left ventricular (LV) mass by cardiac MRI and increased loss of LV mass over the 10 years following the baseline exam (p-value 0.02 for each), but this association was no longer statistically significant after adjustment for baseline NT-proBNP (p= 0.11 and 0.10 respectively). CONCLUSIONS: baseline sFlt-1 levels are associated with incident heart failure and cardiovascular mortality independent of traditional CV risk factors or NT-proBNP. An association was also found with cardiac mass but was no longer significant after adjustment for NT-proBNP.

Background: Pulmonary arterial hypertension (PAH) is a complex disease characterized by progressive right ventricular (RV) failure leading to significant morbidity and mortality. Investigating metabolic features and pathways associated with RV dilation, mortality, and measures of disease severity can provide insight into molecular mechanisms, identify subphenotypes, and suggest potential therapeutic targets. Methods: We collected data from a prospective cohort of PAH participants and performed untargeted metabolomic profiling on 1045 metabolites from circulating blood. Analyses were intended to identify metabolomic differences across a range of common metrics in PAH (eg, dilated versus nondilated RV). Partial least squares discriminant analysis was first applied to assess the distinguishability of relevant outcomes. Significantly altered metabolites were then identified using linear regression, and Cox regression models (as appropriate for the specific outcome) with adjustments for age, sex, body mass index, and PAH cause. Models exploring RV maladaptation were further adjusted for pulmonary vascular resistance. Pathway enrichment analysis was performed to identify significantly dysregulated processes. Results: A total of 117 participants with PAH were included. Partial least squares discriminant analysis showed cluster differentiation between participants with dilated versus nondilated RVs, survivors versus nonsurvivors, and across a range of NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, REVEAL 2.0 composite scores, and 6-minute-walk distances. Polyamine and histidine pathways were associated with differences in RV dilation, mortality, NT-proBNP, REVEAL score, and 6-minute walk distance. Acylcarnitine pathways were associated with NT-proBNP, REVEAL score, and 6-minute walk distance. Sphingomyelin pathways were associated with RV dilation and NT-proBNP after adjustment for pulmonary vascular resistance. Conclusions: Distinct plasma metabolomic profiles are associated with RV dilation, mortality, and measures of disease severity in PAH. Polyamine, histidine, and sphingomyelin metabolic pathways represent promising candidates for identifying patients at high risk for poor outcomes and investigation into their roles as markers or mediators of disease progression and RV adaptation.

One of the most dreaded complications of end stage liver disease is hepatorenal syndrome AKI (HRS-AKI; formally known as hepatorenal syndrome 1 [HRS-1]). HRS-AKI carries a high mortality, and treatment options are limited. Guidelines recommend terlipressin as the first-line treatment of HRS-AKI

Rationale Pulmonary hypertension (PH) is associated with significant perioperative morbidity and mortality. We hypothesised that pulmonary arterial hypertension (PAH) composite risk assessment scores could estimate perioperative risk for PH patients when adjusted for inherent procedural risk. Methods We identified patients in the Johns Hopkins PH Center Registry that had noncardiac surgery (including endoscopies) between September 2015 and January 2020. We collected information on preoperative patient-level and procedural variables and used logistic regression to evaluate associations with a composite outcome of death within 30 days or serious postoperative complication. We generated composite patient-level risk assessment scores for each subject and used logistic regression to estimate the association with adverse surgical outcomes. We adjusted multivariable models for inherent procedural risk of major cardiovascular events and used these models to generate a numerical PH perioperative risk (PHPR) score. Results Among 150 subjects, 19 (12.7%) reached the primary outcome, including 7 deaths (4.7%). Individual patient-level and procedural variables were associated with the primary outcome (all p10%) risk of reaching the primary outcome. Conclusion Composite PAH risk assessment scores can predict perioperative risk for PH patients after accounting for inherent procedural risk. Validation of the PHPR score in a multicentre, prospective cohort is warranted., For patients with pulmonary hypertension undergoing noncardiac surgery, perioperative risk can be estimated using a model that combines inherent procedural risk with composite PAH risk assessment scores https://bit.ly/3uTCibP

Background The renin-angiotensin-aldosterone system (RAAS) contributes to pulmonary hypertension (PH) pathogenesis. Although animal data suggest that RAAS inhibition attenuates PH, it is unknown if RAAS inhibition is beneficial in PH patients. Research Question Is RAAS inhibitor use associated with lower mortality in a large cohort of patients with hemodynamically confirmed PH? Study Design and Methods We used the Department of Veterans Affairs Clinical Assessment Reporting and Tracking Database to study retrospectively relationships between RAAS inhibitors (angiotensin converting enzyme inhibitors [ACEIs], angiotensin receptor blockers [ARBs], and aldosterone antagonists [AAs]) and mortality in 24,221 patients with hemodynamically confirmed PH. We evaluated relationships in the full and in propensity-matched cohorts. Analyses were adjusted for demographics, socioeconomic status, comorbidities, disease severity, and comedication use in staged models. Results ACEI and ARB use was associated with improved survival in unadjusted Kaplan-Meier survival analyses in the full cohort and the propensity-matched cohort. This relationship was insensitive to adjustment, independent of pulmonary artery wedge pressure, and also was observed in a cohort restricted to individuals with precapillary PH. AA use was associated with worse survival in unadjusted Kaplan-Meier survival analyses in the full cohort; however, AA use was associated less robustly with mortality in the propensity-matched cohort and was not associated with worse survival after adjustment for disease severity, indicating that AAs in real-world practice are used preferentially in sicker patients and that the unadjusted association with increased mortality may be an artifice of confounding by indication of severity. Interpretation ACEI and ARB use is associated with lower mortality in veterans with PH. AA use is a marker of disease severity in PH. ACEIs and ARBs may represent a novel treatment strategy for diverse PH phenotypes.

Purpose Pacing to increase resting heart rate (HR) is commonly employed in order to improve hemodynamics and cardiac output (CO), particularly in post-operative setting when right ventricle (RV) dysfunction is present. We tested if right atrial (RA) pacing improves RV hemodynamics acutely, and if the degree of baseline RV dysfunction modifies this relationship. Methods We prospectively enrolled adult subjects with known or suspected pulmonary arterial hypertension (PAH) who underwent elective right heart catheterization between January 2013 and April 2016. RV pressure-volume (PV) analysis was performed with conductance catheters. RV volumes were calibrated by cardiac MRI same day. After measuring baseline PV data, a bipolar pacing wire was positioned in the RA and rate set to 80 to 90 beats per minute (bpm). Rate was increased in steps of 20 bpm. PV loops were recorded at end-expiration after 1 minute in each group: 80-99, 100-119, and 120-139 bpm. Parametric data were analyzed by Repeated Measures ANOVA, and non-parametric data were analyzed by Friedman Test. Baseline hemodynamic predictors of CO were analyzed by Repeated Measures simple linear regression. Results Twenty-three subjects were included in this analysis. Baseline mean RA pressure was 7 ± 3 mmHg with pulmonary vascular resistance of 5.2 ± 4.1 wood units. As HR increased with RA pacing, stroke volume (SV) declined in each pacing group (68±22, 61±19, 54±21 mL, respectively; p Conclusion As heart rate increases with RA pacing, RV contractility and CO increase modestly at the expense of cardiac efficiency.

Subtypes of pulmonary arterial hypertension (PAH) differ in both fundamental disease features and clinical outcomes. Angiogenesis and inflammation represent disease features that may differ across subtypes and are of special interest in connective tissue disease-associated PAH (CTD-PAH). We compared inflammatory and angiogenic biomarker profiles across different etiologies of PAH and related them to clinical outcomes.Participants with idiopathic PAH, CTD-PAH, toxin-associated PAH (tox-PAH), or congenital heart disease-associated PAH (CHD-PAH) were enrolled into a prospective observational cohort. Baseline serum concentrations of 33 biomarkers were related to 3-year mortality, echocardiogram, REVEAL score, and 6-minute walk distance (6MWD). Findings were validated using plasma proteomic data from the UK PAH Cohort Study.One hundred twelve patients were enrolled: 45 idiopathic, 27 CTD-PAH, 20 tox-PAH, and 20 CHD-PAH. Angiogenic and inflammatory biomarkers were distinctly elevated within the CTD-PAH cohort. Six biomarkers were associated with mortality within the entire PAH cohort: interleukin-6 (IL-6, HR:1.6, 95% CI:1.18-2.18), soluble fms-like tyrosine kinase 1 (sFlt-1, HR:1.35, 95% CI:1.02-1.80), placental growth factor (PlGF, HR:1.55, 95% CI:1.07-2.25), interferon gamma-induced protein 10 (IP-10, HR:1.44, 95% CI:1.04-1.99), tumor necrosis factor-beta (TNF-β, HR:1.81, 95% CI:1.11-2.95), and NT-proBNP (HR:2.19, 95% CI:1.52-3.14). Only IL-6 and NT-proBNP remained significant after controlling for multiple comparisons. IL-6, IP-10, and sFlt-1 significantly associated with mortality in CTD-PAH, but not non-CTD-PAH subgroups. In the UK cohort, IP-10, PlGF, TNF-β, and NT-proBNP significantly associated with 5-year survival.Levels of angiogenic and inflammatory biomarkers are elevated in CTD-PAH, compared with other etiologies of PAH, and may correlate with clinical outcomes including mortality.

BACKGROUND The age of patients with pulmonary arterial hypertension (PAH) has increased, with registries now reporting mean ages of 50 to 65 years old. Limited data exist on age-related differences in hemodynamic and functional assessments in PAH. METHODS Adults with PAH in the Pulmonary Hypertension Association Registry were divided into 3 groups (18–50, 51–65, and >65 years old). Analysis of variance and chi-square testing were used to assess for baseline differences. Linear regression was used to examine the association of age with continuous hemodynamic and functional variables. RESULTS A total of 769 patients with mean age of 56 ± 16 years were included. Older patients had more connective tissue disease–associated PAH and less drug-associated PAH. In linear regression models, each year of increased age was associated with shorter 6-minute walk distance (−3.37 meters; 95% CI, −3.97 to −2.76), lower mean pulmonary arterial pressure (−0.21 mm Hg; 95% CI, −0.27 to −0.15), and lower pulmonary vascular resistance (−0.06 Wood units; 95% CI, −0.09 to −0.04). Pulmonary arterial compliance, cardiac index, right ventricular stroke work index, and percent predicted 6-minute walk distance were unrelated to age; resistance-compliance time was negatively related to age (−3 milliseconds per year; 95% CI, −4 to −2). CONCLUSIONS Relative to their pulmonary vascular resistance, older patients have lower pulmonary artery compliance and worse right ventricular performance. Based on these findings, we suspect that age influences right ventricular loading conditions and the response of the right ventricle to increased afterload.

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.

Background Prior studies suggested lower risk of heart failure (HF) in individuals taking H 2 receptor antagonists (H2RA) compared with H2RA nonusers in relatively small studies. We evaluated the association of H2RA use and incident HF in postmenopausal women in the large‐scale WHI (Women’s Health Initiative) study. Methods and Results This study included postmenopausal women from the WHI without a history of HF at baseline. HF was defined as first incident hospitalization for HF and physician adjudicated. Multivariable Cox proportional hazards regression models evaluated the association of H2RA use as a time‐varying exposure with HF risk, after adjustment for demographic, lifestyle, and medical history variables. Sensitivity analyses examined (1) risk of HF stratified by the ARIC (Atherosclerosis Risk in Communities) score, (2) propensity score matching on H2RA use, (3) use of proton pump inhibitors rather than H2RA nonuse as the referent, and (4) exclusion of those taking diuretics at baseline. The primary analysis included 158 854 women after exclusion criteria, of whom 9757 (6.1%) were H2RA users. During median 8.2 years of follow‐up, 376 H2RA users (4.9 events/1000 person‐years) and 3206 nonusers (2.7 events/1000 person‐years) developed incident HF. After multivariable adjustment, there was no association between H2RA use and HF in the primary analysis (hazard ratio, 1.07; 95% CI, 0.94–1.22; P =0.31) or in any of the sensitivity analyses. Conclusions Clinical H2RA use was not associated with incident HF among postmenopausal women. Future studies are needed to evaluate potential effect modification by sex, HF severity, or patterns of use on H2RA exposure and HF risk. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00000611.

Background Prior studies suggested lower risk of heart failure (HF) in individuals taking H

This study aims to describe the safety and efficacy of revascularizing chronic total occlusions (CTOs) of the pulmonary arteries with balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH).BPA has emerged as an effective treatment for CTEPH patients when surgical treatment is not possible. Experience to date has suggested treating CTOs may be associated with excess risk and less procedural success relative to other lesion types.This study is a retrospective case series of all BPAs on CTOs for individuals with CTEPH at a single institution. Procedural approach, complications, and success rate over a 6-month period are described.During the study period, 6 individuals with 15 CTOs were identified and intervened upon during 21 interventions. Success rate for revascularization was 62% per attempt and 87% per lesion. Techniques used for successful intervention include true to true lumen wiring (n = 7) and subintimal dissection re-entry with subintimal tracking and re-entry (n = 3), Stingray balloon (Boston Scientific) assisted re-entry (n = 2), and direct wire re-entry (n = 1). Wire perforations were relatively common and occurred in 62% of interventions, but rarely resulted in a change in clinical status.Although important barriers to routine intervention on CTOs in CTEPH remain, the current series suggests a higher success rate than previously reported experiences using CTO revascularization techniques including subintimal tracking and re-entry and Stingray balloon-assisted re-entry. Although the frequency of wire perforation was relatively high, the clinical ramifications of these complications were mild.

Background At the recent 6th World Symposium on Pulmonary Hypertension (PH), the definition of PH was redefined to include lower pulmonary artery pressures in the setting of elevated pulmonary vascular resistance (PVR). However, the relevance of this change to subjects with PH due to left-heart disease as well as the preoperative assessment of heart transplant (HT) recipients is unknown. Methods The United Network for Organ Sharing database was queried to identify adult recipients who underwent primary HT from 1996 to 2015. Recipients were subdivided into those with mean pulmonary artery pressure (mPAP) Results Over the study period, 32,465 patients underwent HT, including 12,257 (38%) with mPAP Conclusions Elevated PVR remains associated with a significant increase in the hazard for 30-day mortality after cardiac transplantation, even in the setting of lower pulmonary artery pressures. These data support the validity of the new definition of pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is characterized by increased resistance in the pulmonary arterioles as a result of remodeled blood vessels. We sought all available epidemiologic data on population-based prevalence, incidence, and 1-year survival of PAH as part of the Global Burden of Disease Study. We performed a systematic review searching Global Index Medicus (GIM) for keywords related to PAH between 1980 and 2021 and identified population-representative sources of prevalence, incidence, and mortality for clinically diagnosed PAH. Of 6772 articles identified we found 65 with population-level data: 17 for prevalence, 17 for incidence, and 58 reporting case fatality. Reported prevalence ranged from 0.37 cases/100,000 persons in a referral center of French children to 15 cases/100,000 persons in an Australian study. Reported incidence ranged from 0.008 cases/100,000 person-years in Finland, to 1.4 cases/100,000 person-years in a retrospective chart review at a clinic in Utah, United States. Reported 1-year survival ranged from 67% to 99%. All studies with sex-specific estimates of prevalence or incidence reported higher levels in females than males. Studies varied in their size, study design, diagnostic criteria, and sampling procedures. Reported PAH prevalence, incidence, and mortality varied by location and study. Prevalence ranged from 0.4 to 1.4 per 100,000 persons. Harmonization of methods for PAH registries would improve efforts at disease surveillance. Results of this search contribute to ongoing efforts to quantify the global burden of PAH.

Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure and frequently is associated with pulmonary hypertension (PH). HFpEF associated with PH may be difficult to distinguish from precapillary forms of PH, although this distinction is crucial because therapeutic pathways are divergent for the two conditions. A comprehensive and systematic approach using history, clinical examination, and noninvasive and invasive evaluation with and without provocative testing may be necessary for accurate diagnosis and phenotyping. After diagnosis, HFpEF associated with PH can be subdivided into isolated postcapillary pulmonary hypertension (IpcPH) and combined postcapillary and precapillary pulmonary hypertension (CpcPH) based on the presence or absence of elevated pulmonary vascular resistance. CpcPH portends a worse prognosis than IpcPH. Despite its association with reduced functional capacity and quality of life, heart failure hospitalizations, and higher mortality, therapeutic options focused on PH for HFpEF associated with PH remain limited. In this review, we aim to provide an updated overview on clinical definitions and hemodynamically characterized phenotypes of PH, pathophysiologic features, therapeutic strategies, and ongoing challenges in this patient population.

IntroductionPulmonary arterial hypertension (PAH) remains a serious and life-threatening illness. Thyroid dysfunction is relatively understudied in individuals with PAH but is known to affect cardiac function and vascular tone in other diseases. The aim of this observational study was to evaluate the association between thyroid-stimulating hormone (TSH), mortal and non-mortal outcomes in individuals with PAH.MethodsThe Seattle Right Ventricle Translational Science (Servetus) Study is an observational cohort that enrolled participants with PAH between 2014 and 2016 and then followed them for 3 years. TSH was measured irrespective of a clinical suspicion of thyroid disease for all participants in the cohort. Linear regression was used to estimate the relationships between TSH and right ventricular basal diameter, tricuspid annular plane systolic excursion and 6-minute walk distance. Logistic regression was used to estimate the relationship with New York Heart Association Functional Class, and Cox proportional hazards were used to estimate the relationship with mortality. Staged models included unadjusted models and models accounting for age, sex at birth and aetiology of pulmonary hypertension with or without further adjustment for N-terminal-pro hormone brain natriuretic peptide.ResultsAmong 112 participants with PAH, TSH was strongly associated with mortality irrespective of adjustment. There was no clear consistent association between TSH and other markers of severity in a cohort with PAH.DiscussionThis report reinforces the important observation that TSH is associated with survival in patients with PAH, and future study of thyroid dysfunction as a potential remediable contributor to mortality in PAH is warranted.

BACKGROUND: Angiopoietin-1 and 2 (Ang1, Ang2) are important mediators of angiogenesis. Angiopoietin levels are perturbed in cardiovascular disease, but it is unclear whether angiopoietin signaling is causative, an adaptive response, or merely epiphenomenon of disease activity. METHODS AND RESULTS: In a cohort free of cardiovascular disease at baseline (MESA), relationships between angiopoietins, cardiac morphology, and subsequent incidence of heart failure or cardiovascular death were evaluated. In cohorts with pulmonary arterial hypertension (PAH) or left heart disease (LHD), associations between angiopoietins, invasive hemodynamics, and adverse clinical outcomes were evaluated. In MESA, Ang2 was associated with a higher incidence of heart failure or cardiovascular death (HR 1.21 per standard deviation, P

The renin-angiotensin-aldosterone system (RAAS) contributes to pulmonary hypertension (PH) pathogenesis. Although animal data suggest that RAAS inhibition attenuates PH, it is unknown if RAAS inhibition is beneficial in PH patients.Is RAAS inhibitor use associated with lower mortality in a large cohort of patients with hemodynamically confirmed PH?We used the Department of Veterans Affairs Clinical Assessment Reporting and Tracking Database to study retrospectively relationships between RAAS inhibitors (angiotensin converting enzyme inhibitors [ACEIs], angiotensin receptor blockers [ARBs], and aldosterone antagonists [AAs]) and mortality in 24,221 patients with hemodynamically confirmed PH. We evaluated relationships in the full and in propensity-matched cohorts. Analyses were adjusted for demographics, socioeconomic status, comorbidities, disease severity, and comedication use in staged models.ACEI and ARB use was associated with improved survival in unadjusted Kaplan-Meier survival analyses in the full cohort and the propensity-matched cohort. This relationship was insensitive to adjustment, independent of pulmonary artery wedge pressure, and also was observed in a cohort restricted to individuals with precapillary PH. AA use was associated with worse survival in unadjusted Kaplan-Meier survival analyses in the full cohort; however, AA use was associated less robustly with mortality in the propensity-matched cohort and was not associated with worse survival after adjustment for disease severity, indicating that AAs in real-world practice are used preferentially in sicker patients and that the unadjusted association with increased mortality may be an artifice of confounding by indication of severity.ACEI and ARB use is associated with lower mortality in veterans with PH. AA use is a marker of disease severity in PH. ACEIs and ARBs may represent a novel treatment strategy for diverse PH phenotypes.

Treprostinil, a prostacyclin analogue used in the treatment of pulmonary arterial hypertension (PAH), is available for administration by parenteral, oral, or inhaled routes. Transitioning between routes may be beneficial for appropriate patients; however, there is little published data on transitions between oral and inhaled treprostinil. We used a modified Delphi process to develop expert consensus recommendations on transitions between these formulations. Three questionnaires were used to develop statements about relevant aspects of transition management, which the panelists rated, using a Likert scale, from -5 (strongly disagree) to +5 (strongly agree). Eleven physicians with expertise in PAH treatment modalities, participated in the panel. Of the 492 statements evaluated, consensus was reached on 215 (43.7%). Key consensus recommendations included (1) accurately defining successful transition, as stable or improved PAH with good tolerability and adherence, and (2) patients with stable, low-risk PAH showing insufficient response or tolerability to their existing treprostinil therapy (and due to restrictions in up titration of dosing), as appropriate candidates for transitions between treprostinil formulations. Panelists did not reach consensus for an overall strategy for performing these transitions, mainly because of variability in their practice parameters. Consensus was also achieved on recommendations for adverse event management, including reassurance, administration of oral treprostinil 3 times daily with food, and dosing inhaled treprostinil at intervals ≥3 hours apart. The Delphi process aided in developing expert consensus recommendations that may provide clinically useful guidance for transitioning between treprostinil formulations. However, additional data from centers with high volumes of PAH patients undergoing treprostinil transitions would be optimal for defining more complete and robust strategies to facilitate successful transition.

Rationale: New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach that complements traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation and inflammation may ultimately prolong the time to Pa recurrence. Objectives: To test the hypothesis that the addition of azithromycin to TIS in children with cystic fibrosis and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence. Methods: The OPTIMIZE (Optimizing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis) trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF, 6 months to 18 years of age, with early Pa. Azithromycin or placebo was given 3× weekly with standardized TIS. Measurements and Main Results: The primary endpoint was the time to pulmonary exacerbation requiring antibiotics and the secondary endpoint was the time to Pa recurrence, in addition to other clinical and safety outcomes. A total of 221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrollment was stopped early by the NHLBI because the trial had reached the prespecified interim boundary for efficacy. The risk of pulmonary exacerbation was reduced by 44% in the azithromycin group as compared with the placebo group (hazard ratio, 0.56; 95% confidence interval, 0.37–0.83; P = 0.004). Weight increased by 1.27 kg in the azithromycin group compared with the placebo group (95% confidence interval, 0.01–2.52; P = 0.046). No significant differences were seen in microbiological or other clinical or safety endpoints. Conclusions: Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and a sustained improvement in weight, but had no impact on microbiological outcomes in children with early Pa. Clinical trial registered with clinicaltrials.gov (NCT02054156).

Background: Pulmonary arterial hypertension (PAH) is characterized by increased resistance in the pulmonary arterioles as a result of remodeled blood vessels. We sought to establish the baseline level of PAH by assembling all available epidemiologic data on population-based prevalence, incidence, and one-year survival of PAH as part of the Global Burden of Disease Study. Methods: We performed a systematic review searching Global Index Medicus (GIM) for key words related to PAH between 1980 and 2021, and identified population-representative sources of prevalence, incidence, and mortality for clinically diagnosed PAH. Results: Of 6,772 identified we found 65 with population-level data: 17 for prevalence, 17 for incidence, and 58 reporting case fatality. Reported prevalence ranged from 0.37 cases/100,000 persons in a referral center of French children to 150 cases/100,000 persons in an Australian echocardiography study. Reported incidence ranged from 0.008 cases/100,000 person-years in a study of hospital discharge records in Finland, to 1.4 cases/100,000 person-years in a retrospective chart review at a clinic in Utah, USA. Reported one-year survival ranged from 67% to 99%. All studies with sex-specific estimates reported higher levels in females than males. Studies varied in their size, study design, diagnostic criteria, and sampling procedures. Conclusions: Reported PAH prevalence, incidence, and mortality varied by location and study. Prevalence ranged from 0.4 to 1.4 per 100,000 persons. Harmonization of methods for PAH registries would improve efforts at disease surveillance. Results of this search contribute to ongoing efforts to quantify the global burden of PAH.

Myocardial H 2 receptor activation contributes to heart failure (HF) in preclinical models, and H 2 receptor antagonists are associated with decreased HF incidence. This study evaluated whether H 2 histamine receptor (HRH2) single nucleotide polymorphisms (SNPs) are associated with HF incidence and whether myocardial transcript abundance is associated with HF recovery. The association of SNPs in HRH2 with incident HF was characterized using Cox proportional hazards regression among participants in the Multi-Ethnic Study of Atherosclerosis. Differences in myocardial HRH2 transcripts were characterized in participants with dilated cardiomyopathy comparing 6 “super-responders” with 6 nonresponders to β blockade in the Beta-Blocker Effect on Remodeling and Gene Expression Trial. In MESA, no candidate SNP was associated with HF in black, Hispanic, or white participants. The rs2241562 minor allele was present only in Chinese participants and the adjusted HF hazard among those with 1 or more copies of this allele was 3.7, 95% confidence interval 1.0 to 13.4. In BORG, super-responders to β blockade had higher levels of myocardial HRH2 transcript at baseline compared with nonresponders (fragments per kilobase per transcript per million mapped reads: Variant 2, 5.5 ± 1.1 compared with 3.2 ± 0.8 in nonresponders, p = 0.002; Variant 1 + 2, 32.1 ± 7.4 compared with 23.3 ± 4.2 in nonresponders, p = 0.04). In conclusion, t he presence of a minor allele at rs2241562 was associated with increased HF incidence in Chinese participants. Differences in myocardial HRH2 transcript abundance were seen in participants with dilated cardiomyopathy who responded to β blockade. These observations support the hypothesis that HRH2 is involved in the pathogenesis of HF.

Background Adverse drug events (ADEs) with pulmonary vasodilator use in pulmonary arterial hypertension (PAH) are common. ADEs may contribute to worse quality of life; however, their relationship to prognosis is unknown. The objective of this study was to determine whether common ADEs after initiating subcutaneous treprostinil were associated with prognosis in PAH. Methods We assembled a retrospective cohort of participants from four clinical trials of treprostinil for PAH, including 908 participants who received subcutaneous treprostinil and 243 who received placebo at the time ADEs were ascertained. The occurrences of four common early ADEs (infusion reactions, headaches, jaw pain, or gastrointestinal side effects) were assessed during the eight weeks after starting the infusion. We used Cox proportional hazards to estimate associations between ADEs and mortality. Results No ADEs related to placebo were associated with mortality. In participants who received treprostinil, infusion reactions, headaches, and jaw pain were not associated with mortality. Gastrointestinal side effects occurring during the first eight weeks following treprostinil infusion were associated with a 57% increase in the hazard of mortality (95% CI: 14–118%). This relationship was unchanged after adjusting for demographic differences and differences in baseline PAH severity. Conclusions Gastrointestinal ADEs after starting subcutaneous treprostinil were associated with an increased risk for mortality. Increased mortality was not observed with other early ADEs or with gastrointestinal symptoms in participants who were not receiving treprostinil at the time. This hypothesis-generating association suggests ADEs may identify different phenotypes in PAH.

Introduction The OPsumit® Historical USers cohort (OrPHeUS) is a multicentre, US, retrospective medical chart review conducted to supplement the OPsumit® USers (OPUS) Registry to fulfil the FDA request to characterise the safety of macitentan in clinical practice. Purpose To describe patient characteristics, treatment patterns, hepatic safety and survival in patients with pulmonary hypertension (PH) newly treated with macitentan. Methods OrPHeUS (NCT03197688) aimed to include 2200 new users of macitentan, between October 2013 and March 2017, who were not enrolled in OPUS. Here we present patients with follow-up data, including characteristics and treatment patterns at macitentan initiation, hepatic adverse events (HAEs) identified using preferred terms in chart entries and pharmacovigilance reporting, hospitalisations and survival. Results OrPHeUS included 2982 patients newly treated with macitentan and with follow-up data; the reason for macitentan prescription was pulmonary arterial hypertension (PAH) in 2362 (79.3%) patients, other PH aetiologies in 612 (20.6%) patients and 8 patients with other/unknown reasons. At macitentan initiation, the median (Q1, Q3) age of the patients was 62 (51, 72) years and 73.9% were female. WHO functional class (FC) was documented in 654 (21.9%) patients, 35.6% of patients were in FC I/II and 64.4% in FC III/IV; median (Q1, Q3) 6-minute walk distance, documented in 411 (13.8%) patients, was 293 (200, 383) metres. At macitentan initiation, 41.5% (n=1239) of patients were not receiving PAH therapy, 46.3% (n=1382) were already receiving one PAH therapy and 11.9% (n=356) were already receiving two PAH therapies. The median (Q1, Q3) exposure to macitentan was 14.9 (5.6, 27.1) months; 57% and 43% of patients had exposures of >12 and >18 months. During the exposure period, 933 (31.3%) patients discontinued treatment, including 474 (15.9%) patients who discontinued due to an adverse event (AE), 6 (0.2%) due to a HAE, 449 (15.1%) for reasons other than an AE/HAE, and 4 (0.1%) for unknown reasons. There were 275 (9.2%) patients who experienced ≥1 HAE (incidence rate [IR]: 0.07 [95% CI, 0.06, 0.08] per 1 person-year); alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3x upper limit of normal (ULN) were experienced by 113 (3.8%) patients (IR: 0.028 [95% CI, 0.023, 0.033] per 1 person-year); ALT/AST ≥x3 ULN and bilirubin ≥2x ULN was experienced by 33 (1.1%) patients (IR: 0.008 [95% CI, 0.006, 0.011] per 1 person-year). There were 1148 (38.5%) patients who experienced at least one hospitalisation (IR: 0.36 [95% CI, 0.34, 0.39] per 1 person-year). The 12-month Kaplan-Meier survival estimate was 92% (95% CI, 91, 93). Conclusion OrPHeUS provides additional real-world evidence in patients newly treated with macitentan, confirming the hepatic safety profile of macitentan. Acknowledgement/Funding Actelion Pharmaceuticals Ltd

BACKGROUND Circulating levels of endothelin-1 (ET1) are elevated in heart failure and predict poor prognosis. However, it is not clear whether ET1 elevation is an adaptive response, maladaptive response, or an epiphenomenon of heart failure. In this study, we evaluated the relationships between ET1, cardiac morphology, and incident heart failure or cardiovascular death in participants with no evidence of clinical cardiovascular disease at the time ET1 was measured. METHODS AND RESULTS ET1 was measured in 1,361 participants in the Multi-Ethnic Study of Atherosclerosis Angiogenesis Sub-Study. As suggested by linear regression , participants with lower circulating ET1 levels tended to be older, non-white, more likely to have smoked heavily, and less likely to report intentional exercise. Participants with higher ET1 levels had smaller left ventricular end-diastolic volumes (8.9 ml smaller per log increase in ET1, 95% confidence interval 17.1–0.7, p = 0.03) with an increased left ventricular ejection fraction (2.8% per log increase in ET1, 95% confidence interval 0.5%–5.2%, p = 0.02). As suggested by Cox Proportional Hazards estimates, participants with higher ET1 levels had a lower risk for the composite outcome of heart failure or cardiovascular death in models that were unadjusted or had limited adjustment (p = 0.03 and p = 0.05, respectively). Lower risk for heart failure with higher ET1 levels could not be clearly shown in a model including health behaviors. CONCLUSIONS These results suggest, but do not confirm, that elevated levels of circulating ET1 are associated with a more favorable cardiac phenotype. The relationship between ET1 and outcomes was not fully independent of one or more covariates.

At the recent 6th World Symposium on Pulmonary Hypertension (PH), the definition of PH was redefined to include lower pulmonary artery pressures in the setting of elevated pulmonary vascular resistance (PVR). However, the relevance of this change to subjects with PH due to left-heart disease as well as the preoperative assessment of heart transplant (HT) recipients is unknown.The United Network for Organ Sharing database was queried to identify adult recipients who underwent primary HT from 1996 to 2015. Recipients were subdivided into those with mean pulmonary artery pressure (mPAP) 25 mm Hg and ≥ 25 mm Hg. Exploratory univariable analysis was undertaken to identify candidate risk factors associated with 30-day and 1-year survival (conditional on 30-day survival) in recipients with mPAP 25 mm Hg, and subsequently, parsimonious multivariable Cox proportional hazards models were constructed to assess the independent association with PVR.Over the study period, 32,465 patients underwent HT, including 12,257 (38%) with mPAP 25 mm Hg. The median age was 55 years (interquartile range, 47-62) and the median PVR was 1.5 Wood units (WU) (interquartile range, 1-2.2) in recipients with mPAP 25 mm Hg. After controlling for confounders, PVR was independently associated with increased risk for 30-day mortality (hazard ratio, 1.16; 95% CI, 1.05-1.27; P .01), but not conditional 1-year mortality (hazard ratio, 1.03; 95% CI, 0.94-1.12; P = .55). PVR ≥ 3 WU was associated with an absolute 1.9% increase in 30-day mortality in those with mPAP 25 mm Hg, a similar risk to recipients with PVR ≥ 3 WU and mPAP ≥ 25 mm Hg.Elevated PVR remains associated with a significant increase in the hazard for 30-day mortality after cardiac transplantation, even in the setting of lower pulmonary artery pressures. These data support the validity of the new definition of pulmonary hypertension.

Background: Myocardial H2 receptor activation may promote cardiac fibrosis and apoptosis in pre-clinical models and histamine H2 receptor antagonist (H2RA) use may improve symptoms in parti...

IntroductionWhile the performance of the emPHasis-10 (e10) score has been evaluated against limited patient characteristics within the United Kingdom, there is an unmet need for exploring the performance of the e10 score among pulmonary arterial hypertension (PAH) patients in the United States.MethodsUsing the Pulmonary Hypertension Association Registry, we evaluated relationships between the e10 score and demographic, functional, haemodynamic and additional clinical characteristics at baseline and over time. Furthermore, we derived a minimally important difference (MID) estimate for the e10 score.ResultsWe analysed data from 565 PAH (75% female) adults aged mean±sd 55.6±16.0 years. At baseline, the e10 score had notable correlation with factors expected to impact quality of life in the general population, including age, education level, income, smoking status and body mass index. Clinically important parameters including 6-min walk distance and B-type natriuretic peptide (BNP)/N-terminal proBNP were also significantly associated with e10 score at baseline and over time. We generated a MID estimate for the e10 score of −6.0 points (range −5.0–−7.6 points).ConclusionsThe e10 score was associated with demographic and clinical patient characteristics, suggesting that health-related quality of life in PAH is influenced by both social factors and indicators of disease severity. Future studies are needed to demonstrate the impact of the e10 score on clinical decision-making and its potential utility for assessing clinically important interventions.

Background: Acute right heart failure (RHF) after left ventricular assist device implantation remains a major source of morbidity and mortality, yet the definition of RHF and the preimplant variables that predict RHF remain controversial. This study evaluated the ability of (1) INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) RHF classification to predict post-left ventricular assist device survival and (2) preoperative characteristics and hemodynamic parameters to predict severe and severe acute RHF. Methods and Results: An international, multicenter study at 4 large academic centers was conducted between 2008 and 2016. All subjects with hemodynamics measured by right heart catheterization within 30 days before left ventricular assist device implantation were included. RHF was defined using the INTERMACS definition for RHF. In total, 375 subjects were included (mean age, 57.4±13.2 years, 54% bridge-to-transplant). Mild RHF was most common (34%), followed by moderate RHF (16%), severe RHF (13%), and severe acute RHF (9%). Estimated on-device survival rates at 2 years were 72%, 71%, and 55% in the patients with none, mild-to-moderate, and severe-to-severe acute RHF, respectively ( P =0.004). In addition, the independent hazard ratio for mortality was only increased in the patients with severe-to-severe acute RHF (hazard ratio, 3.95; 95% CI, 2.16–7.23; P Conclusions: The INTERMACS RHF classification correctly identifies patients at risk for mortality, though this risk is only increased in patients with severe-to-severe acute RHF. Several predictors for RHF were identified, of which ratio of systolic pulmonary artery pressure to stroke volume was the strongest hemodynamic predictor. Coupling ratio of systolic pulmonary artery pressure to stroke volume with right atrial pressure may be most helpful in identifying patients at risk for severe-to-severe acute RHF.

Disease-specific metabolomic signatures have been associated with mortality in pulmonary arterial hypertension (PAH). We explore whether this reflects right ventricular (RV) dysfunction. We analyzed quantitative targeted profiling of over 300 metabolites from a prospective cohort of PAH patients.

Background: Patients with combined post- and precapillary pulmonary hypertension due to left heart disease have a worse prognosis compared with isolated postcapillary. However, it remains unclear whether increased mortality in combined post- and precapillary pulmonary hypertension is simply a result of higher total right ventricular load. Pulmonary effective arterial elastance (Ea) is a measure of total right ventricular afterload, reflecting both resistive and pulsatile components. We aimed to test whether pulmonary Ea discriminates survivors from nonsurvivors in patients with pulmonary hypertension due to left heart disease and if it does so better than other hemodynamic parameters associated with combined post- and precapillary pulmonary hypertension. Methods and Results: We combined 3 large heart failure patient cohorts (n=1036) from academic hospitals, including patients with pulmonary hypertension due to heart failure with preserved ejection fraction (n=232), reduced ejection fraction (n=335), and a mixed population (n=469). In unadjusted and 2 adjusted models, pulmonary Ea more robustly predicted mortality than pulmonary vascular resistance and the transpulmonary gradient. Along with pulmonary arterial compliance, pulmonary Ea remained predictive of survival in patients with normal pulmonary vascular resistance. The diastolic pulmonary gradient did not predict mortality. In addition, in a subset of patients with echocardiographic data, Ea and pulmonary arterial compliance were better discriminators of right ventricular dysfunction than the other parameters. Conclusions: Pulmonary Ea and pulmonary arterial compliance more consistently predicted mortality than pulmonary vascular resistance or transpulmonary gradient across a spectrum of left heart disease with pulmonary hypertension, including patients with heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, and pulmonary hypertension with a normal pulmonary vascular resistance.

Patients with adult congenital heart disease have an increased risk of developing pulmonary hypertension. There are several mechanisms of pulmonary hypertension in patients with adult congenital heart disease, and understanding them requires a systematic approach to define the patient's hemodynamics and physiology. This article reviews the updated classification of pulmonary hypertension in patients with adult congenital heart disease with a focus on pathophysiology, diagnostics, and the evaluation of pulmonary hypertension in special adult congenital heart disease populations.

Objectives: This study sought to evaluate if diastolic pulmonary gradient (DPG) can predict survival in patients with pulmonary hypertension due to left heart disease (PH-LHD).Background: P...