Inhaled treprostinil in patients with pulmonary hypertension associated with interstitial lung disease with less severe haemodynamics: a post hoc analysis of the INCREASE study.

BACKGROUND: Inhaled treprostinil (iTre) is the only treatment approved for pulmonary hypertension due to interstitial lung disease (PH-ILD) to improve exercise capacity. This post hoc analysis evaluated clinical worsening and PH-ILD exacerbations from the 16-week INCREASE study and change in 6-minute walking distance (6MWD) in the INCREASE open-label extension (OLE) in patients with less severe haemodynamics. METHODS: Patients were stratified by baseline pulmonary vascular resistance (PVR) of <4 Wood units (WU) versus ≥4 WU and <5 WU versus ≥5 WU. Exacerbations of underlying lung disease, clinical worsening and change in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in INCREASE were evaluated. For the OLE, patients previously assigned to placebo were considered to have a 16-week treatment delay. 6MWD and clinical events in the OLE were evaluated by PVR subgroup. RESULTS: Of the 326 patients enrolled in INCREASE, patients with less severe haemodynamics receiving iTre had fewer exacerbations of underlying lung disease and clinical worsening events. This was supported by the Bayesian analysis of the risk of disease progression (HR<1), and significant decreases in NT-proBNP levels. In the OLE, patients without a treatment delay had improved exercise capacity after 1-year compared with those with a 16-week treatment delay (22.1 m vs -10.3 m). Patients with a PVR of ≤5 WU without a treatment delay had a change of 5.5 m compared with -8.2 m for those with a treatment delay. Patients without a treatment delay had a prolonged time to hospitalisation, lung disease exacerbation and death. CONCLUSION: Treatment with iTre led to consistent benefits in clinical outcomes in patients with PH-ILD and less severe haemodynamics. Earlier treatment in less severe PH-ILD may lead to better exercise capacity long-term, however, the subgroup analyses in this post hoc study were underpowered and confirmation of these findings is needed.

Sleep disturbances in chronic liver disease.

Sleep disturbances are common in chronic liver disease and significantly impact patient outcomes and quality of life. The severity and nature of sleep disturbances vary by liver disease etiology and severity. While there is ongoing research into the association between liver disease and sleep-wake dysfunction, the underlying pathophysiology varies and, in many cases, is poorly understood. Liver disease is associated with alterations in thermoregulation, inflammation, and physical activity, and is associated with disease-specific complications, such as HE, that may directly affect sleep. In this article, we review the relevant pathophysiologic processes, disease-specific sleep-wake disturbances, and clinical management of CLD-associated sleep-wake disturbances.

Health-Related Quality of Life Across the Spectrum of Pulmonary Hypertension.

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.

Using PAH-SYMPACT to assess quality of life in patients with pulmonary hypertension associated with chronic lung disease.

Chronic lung disease (CLD) is the second leading cause of pulmonary hypertension (PH) and is associated with significant morbidity and mortality. Although PH associated with CLD (PH-CLD) leads to impaired health-related quality of life (HRQOL), there are no validated tools to assess HRQOL in PH-CLD. The Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire (PAH-SYMPACT) is an HRQOL instrument aimed at assessing the symptoms and impact of PH on overall function and well-being. We performed a single-center prospective cohort study using PAH-SYMPACT scores to compare symptoms, exercise capacity and HRQOL in patients with PAH and PH-CLD. One hundred and twenty-five patients (99 patients with idiopathic/heritable PAH and 26 with PH-CLD) completed the PAH-SYMPACT questionnaire which consists of 22 questions that assess HRQOL across four domains: cardiopulmonary (CP) symptoms, cardiovascular (CV) symptoms, physical impact (PI), and cognitive/emotional (CE) impact. Higher scores indicate worse HRQOL. We compared patients with PAH and PH-CLD using a Wilcoxon rank sum or chi-squared test as appropriate. Multivariate linear regression analysis was used to assess the relationship between PH classification and SYMPACT scores. Compared to PAH, patients with PH-CLD were older, more likely to use oxygen and had worse functional class and exercise capacity. While there was no significant difference between the two groups in CP, CV, or CE domain scores, patients with PH-CLD had significantly worse PI scores by univariate (1.79 vs. 1.13, p < 0.001) and multivariate analysis (1.61 vs. 1.17, p = 0.02) and overall worse SYMPACT scores (1.19 vs. 0.91, p = 0.03). In conclusion, patients with PH-CLD have worse HRQOL as assessed by the PAH-SYMPACT questionnaire versus patients with PAH. Although PAH-SYMPACT has not been validated in PH-CLD, the results of this study can guide clinicians in understanding the symptoms and impact of PH-CLD relative to PAH.

Hemodynamic response to inhaled nitric oxide in patients with pulmonary hypertension and chronic kidney disease: A retrospective cohort study.

Pulmonary hypertension (PH) associated with chronic kidney disease (CKD) (PH-CKD) affects approximately 20%-40% of CKD patients and is associated with increased morbidity and mortality. PH and CKD are both pathophysiologically associated with nitric oxide (NO) deficiency. The NO pathway, an important therapeutic domain in pulmonary arterial hypertension (PAH), is an intriguing but unexplored target in PH-CKD. We sought to improve understanding of the clinical significance of the NO pathway in patients with PH-CKD by assessing the hemodynamic response to inhaled NO (iNO) during right heart catheterization (RHC). In this retrospective cohort study, patients with diagnosis codes of PH and stage IV/V CKD or end-stage renal disease and estimated glomerular filtration rate < 60 mL/min/body surface area who underwent RHC and hemodynamic drug study between July 2011 and June 2021 were eligible. Patients with mean pulmonary artery pressure (mPAP) > 20 mmHg and pulmonary vascular resistance (PVR) > 3 Wood units were included. The final cohort included 37 patients (45.9% female, mean age 72.5 ± 9.7 years). A total of 56.7% of the cohort (21/37) had precapillary PH, while 43.2% (16/37) had combined precapillary postcapillary PH (Cpc-PH). Median survival was 3.1 years after RHC. iNO was associated with a significant decrease in both mPAP and PVR. Hemodynamic changes in mPAP and PVR were similar in precapillary and Cpc-PH groups. Among a small subset (n = 14) who were subsequently treated with PAH-targeted therapy, treatment response was mixed and did not reveal significant benefit. Further studies are warranted to better define the potential role of PAH therapy in PH-CKD.

Pulmonary hypertension patient perspectives toward pulmonary rehabilitation.

Pulmonary rehabilitation (PR) is a supervised exercise program for patients with chronic lung disease. Among patients with pulmonary hypertension (PH), PR has been shown to improve both quality of life and exercise capacity. The purpose of this study was to assess the prevalence of PR participation among PH patients, patient perspectives regarding PR, and to identify potential barriers to PR participation. We performed a cross-sectional survey of patients with self-reported PH who attended the Pulmonary Hypertension Association (PHA) conference in June 2022 in Atlanta, Georgia, and patients within the PHA listserv. A total of 429 participants completed the survey and were enrolled in the study. The average age of participants was 61 ± 14 years with 83% of participants identifying as female, 51% of patients self-reported as having group 1 PH. Among patients who completed the survey, 41% had previously attended a PR program. Of those who had completed a PR program, 83% reported being satisfied or very satisfied with the program and 86% reported that they would recommend PR to other PH patients. After completion of a PR program, 76% of patients reported an improvement in their quality of life and 88% reported improvement in exercise capacity. Among the patients who had not previously participated in PR (n = 254), 63% reported an interest in participation while 64% cited a lack of discussion from their treatment team as the primary reason for the lack of PR participation. Limitations of the study include sampling and response bias. According to this cross-sectional survey, the majority of PH patients who have participated in PR report improvement in both quality of life and exercise capacity and would recommend PR to other PH patients. The majority of PH patients who have not participated in PR were interested in participation and cited a lack of discussion with their treatment team as one of the primary reasons for the lack of participation. PR is associated with self-reported improvements in quality of life and exercise capacity but remains underutilized among patients with PH.

Safety of Macitentan for the Treatment of Portopulmonary Hypertension: Real-World Evidence from the Combined OPUS/OrPHeUS Studies.

INTRODUCTION: Portopulmonary hypertension (PoPH) carries a worse prognosis than other forms of pulmonary arterial hypertension (PAH). Data regarding use of PAH-specific therapies in patients with PoPH are sparse as they are usually excluded from clinical trials. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles in patients with PoPH newly initiating macitentan in the USA using the OPUS/OrPHeUS combined dataset. METHODS: OPUS was a prospective, US, multicenter, observational drug registry (April 2014-June 2020); OrPHeUS was a retrospective, US, multicenter chart review (October 2013-March 2017). Additional information regarding patients' liver disease was retrospectively collected for patients with PoPH in OPUS. RESULTS: The OPUS/OrPHeUS dataset included 206 patients with PoPH (median age 58 years; 52.4% female), with baseline cirrhosis and liver test abnormalities reported in 72.8% and 31.6% of patients respectively. Macitentan was initiated as combination therapy in 74.8% of patients and median (Q1, Q3) exposure to macitentan was 11.9 (3.1, 26.0) months. One-year Kaplan-Meier estimates (95% confidence limit, CL) of patients free from all-cause hospitalization and survival were 48.6% (40.7, 56.0) and 82.2% (75.1, 87.4). Of the 96 patients with PoPH in OPUS, 29.2% were classified as in need of liver transplant due to underlying liver disease during the study; transplant waitlist registration was precluded because of PAH severity for 32.1% and 17.9% were transplanted. Hepatic adverse events (HAE) were experienced by 49.0% of patients; the most common being increased bilirubin (16.0%), ascites (7.3%), and hepatic encephalopathy (5.8%); 1.5% and 21.8% of patients discontinued macitentan as a result of HAE and non-hepatic adverse events. CONCLUSION: There were no unexpected safety findings in patients with PoPH treated with macitentan. These data add to the evidence supporting the safety and tolerability of macitentan in patients with PoPH. A graphical abstract is available with this article. TRIAL REGISTRATION: OPsumit® Users Registry (OPUS): NCT02126943; OPsumit® Historical Users cohort (OrPHeUS): NCT03197688; www. CLINICALTRIALS: gov .

Economic Burden of Delayed Diagnosis in Patients with Pulmonary Arterial Hypertension (PAH).

BACKGROUND: The aim of this study was to assess health care resource utilization (HRU) and costs associated with delayed pulmonary arterial hypertension (PAH) diagnosis in the United States. METHODS: Eligible adults with newly diagnosed PAH from Optum's de-identified Clinformatics® Data Mart Database (2016-2021) were assigned to mutually exclusive cohorts based on time between first PAH-related symptom and first PAH diagnosis (i.e., ≤12 months' delay, >12 to ≤24 months' delay, >24 months' delay). All-cause HRU and health care costs per patient per month (PPPM) were assessed during the first year following diagnosis and compared across cohorts using regression analysis adjusted for baseline covariates. Sensitivity analyses were conducted to assess outcomes during all available follow-up post-diagnosis. RESULTS: Among 538 patients (mean age: 65.6 years; 60.6% female), 60.8% had ≤12 months' delay, 23.4% had a delay of >12 to ≤24 months, and 15.8% had >24 months' delay. Compared with ≤12 months, delays of >12 to ≤24 months and >24 months were associated with increased hospitalizations (incidence rate ratio [95% confidence interval]: 1.40 [1.11-1.71] vs 1.71 [1.29-2.12]) and outpatient visits (1.17 [1.06-1.30] vs 1.26 [1.08-1.41]). Longer delays were also associated with more intensive care unit (ICU) stays and 30-day readmissions. Diagnosis delays translated into excess costs PPPM of US$3986 [1439-6436] for >12 to ≤24 months and US$5366 [2107-8524] for >24 months compared with ≤12 months' delay; increased hospitalization costs (US$3248 [1108-5135] and US$4048 [1401-6342], respectively) being the driver. Sensitivity analyses yielded similar trends. CONCLUSIONS: Delayed PAH diagnosis is associated with significant incremental economic burden post-diagnosis, driven by hospitalizations including ICU stays and 30-day readmissions, highlighting the need for increased awareness and a potential benefit of earlier screening.

Characteristics and Outcomes of Critically Ill Patients With Pulmonary Hypertension Who Undergo Endotracheal Intubation and Mechanical Ventilation.

Background: Patients with pulmonary hypertension (PH) who undergo endotracheal intubation have an increased risk of adverse outcomes, but little is known regarding prognostic factors and there is limited evidence to guide management. We sought to define characteristics, prognostic factors, and outcomes of critically ill patients with PH who underwent intubation. Study Design: We performed a single-center retrospective cohort study of critically ill patients with group 1, 3 or 4 PH who underwent intubation. Results: Eighty-one patients were included. Patients had a median age of 56 years (interquartile range 44-65) and were predominantly female (n = 53, 65%) and Caucasian (n = 71, 88%). Forty-five (56%) had group 1 PH while 25 (31%) had group 3 PH and 11 (14%) had group 4 PH. Patients were admitted to the hospital for right ventricular failure (n = 21, 25.6%), sepsis (n = 18, 22.2%), and respiratory failure (n = 19, 23.1%). Hypoxemic respiratory failure (n = 54, 66.7%) was the most common indication for intubation. In-hospital mortality was 30.9% and 1-year mortality was 48.2%. All patients (11 of 11, 100%) intubated electively for intensive care unit procedures survived to hospital discharge while only 1 of 6 (16.7%) intubated in the setting of a cardiac arrest survived. After adjusting for right ventricular systolic pressure, pre-intubation PaO2 (odds ratio [OR] = 0.99, 95% confidence interval [CI] 0.97-1.00, P = .02) and postintubation PaO2 (OR = 0.97 per 1mm Hg, 95% CI 0.95 to 0.99, P = .003), pH (OR = 0.49 per 0.1 increase, 95% CI 0.29 to 0.80, P = .005) and PaCO2 (OR = 1.08 per 1mm Hg, 95% CI 1.02 to 1.14, P = .005) were significantly associated with in-hospital mortality. Results were similar when we excluded patients intubated electively or in the setting of cardiac arrest. Conclusions: Intubation in critically ill patients with PH is associated with significant in-hospital mortality and nearly 50% 1-year mortality. Potentially modifiable factors, such as peri-intubation gas exchange, are associated with an increased risk of death while other demographic and hemodynamic variables are not.

Pulmonary hypertension in ANCA-associated vasculitis: a retrospective analysis.

BACKGROUND: Little is known about pulmonary hypertension (PH) in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). OBJECTIVES: The aims of this retrospective study, in which echocardiography was used for detection of PH, were to identify the potential causes of PH in AAV and to analyze the risk factors for mortality. METHODS: We performed a retrospective descriptive review of 97 patients who had AAV with PH at our institution from January 1, 1997, through December 31, 2015. These patients with PH were compared with 558 patients who had AAV without PH. Demographic and clinical data were abstracted from electronic health records. RESULTS: Among the patients who had PH, 61% were men; mean (SD) age was 70.5 (14.1) years at the time of PH diagnosis. The majority of patients with PH (73.2%) had more than 1 potential cause of PH, with left heart disease and chronic lung disease being the most common causes. Older age, male sex, smoking history, and kidney involvement were associated with the presence of PH. PH was associated with an increased risk of death (hazard ratio, 3.15; 95% CI, 2.37-4.18). On multivariate analysis, PH, age, smoking status, and kidney involvement were independent risk factors for death. Median survival after the diagnosis of PH was 25.9 months (95% CI, 12.2-49.9). CONCLUSIONS: PH in AAV is often multifactorial, is commonly associated with left heart disease, and is associated with a poor prognosis.

Effects of inhaled nitric oxide on Fontan hemodynamics in adults.

The pulmonary vasculature plays a pivotal role in the nonpulsatile systemic venous return post-Fontan palliation. Elevated pulmonary vascular resistance index (PVRi) carries a worse prognosis post-Fontan, but the benefits of pulmonary vasodilators remain controversial. Moreover, the potential for worsening ventricular filling pressures with pulmonary vasodilation has been highlighted. We reviewed our experience with inhaled nitric oxide (iNO) administration during cardiac catheterization in 30 adults (age 32.7 ± 8.5 years) post-Fontan. The main findings of the study are: (1) iNO decreased pulmonary artery pressures, transpulmonary gradient, and PVRi without increasing pulmonary artery wedge pressure, (2) cardiac index was unchanged with iNO, and (3) different from acquired left heart disease, iNO did not result in further elevations in pulmonary artery wedge pressure in those with elevated ventricular filling pressures. iNO administration in adults post-Fontan was safe; whether baseline PVRi and response to iNO could be used to predict response to pulmonary vasodilators post-Fontan requires further investigation.

Cardiac index and hepatopulmonary syndrome in liver transplantation candidates: The pulmonary vascular complications of liver disease study.

BACKGROUND AND AIMS: Hepatopulmonary syndrome (HPS) and a hyperdynamic circulation are common complications of advanced liver disease, but the relationship between HPS and cardiac index (CI) is poorly understood. We sought to compare CI in patients with and without HPS and to assess the relationship between CI and symptoms, quality of life, gas exchange, and exercise capacity among liver transplantation (LT) candidates. We performed a cross-sectional analysis within the Pulmonary Vascular Complications of Liver Disease 2 study, a multicenter prospective cohort study of patients being evaluated for LT. We excluded patients with obstructive or restrictive lung disease, intracardiac shunting, and portopulmonary hypertension. We included 214 patients (81 with HPS and 133 controls without HPS). Compared with controls, patients with HPS had a higher CI (least square mean 3.2 L/min/m 2 , 95% CI 3.1-3.4 vs. 2.8 L/min/m 2 , 95% CI 2.7-3.0, p < 0.001) after adjustment for age, sex, Model for End-stage Liver Disease-Sodium (MELD-Na) score and beta-blocker use, and a lower systemic vascular resistance. Among all LT candidates, CI was correlated with oxygenation (Alveolar-arterial oxygen gradient r =0.27, p < 0.001), intrapulmonary vasodilatation severity ( p < 0.001), and biomarkers of angiogenesis. Higher CI was independently associated with dyspnea and worse functional class and physical quality of life after adjusting for age, sex, MELD-Na, beta-blocker use, and HPS status. HPS was associated with a higher CI among LT candidates. Independent of HPS, higher CI was associated with increased dyspnea and worse functional class, quality of life, and arterial oxygenation.

Portopulmonary Hypertension: Management and Liver Transplantation Evaluation.

Portopulmonary hypertension (POPH) affects 5% to 6% of patients with advanced liver disease and accounts for 5% to 15% of pulmonary arterial hypertension (PAH) cases. Compared with idiopathic PAH, POPH is associated with significantly worse survival. Recent studies have improved our understanding of the role of both PAH therapy and liver transplantation (LT) in the management of POPH and their impact on overall prognosis. We performed a review of the published literature to summarize the available evidence and guidelines regarding the diagnosis and management of POPH. POPH is defined by the presence of precapillary pulmonary hypertension in the context of portal hypertension. POPH is associated with increased perioperative risk at the time of LT, which can be stratified by mean pulmonary arterial pressure and pulmonary vascular resistance. Screening with echocardiography is recommended in all LT candidates to facilitate detection and treatment of POPH. Despite a paucity of evidence, POPH is treated similarly to idiopathic PAH with PAH therapy. These therapies are associated with improved pulmonary hemodynamics and facilitation of safe LT. LT can result in improvement or resolution of POPH in one-half of patients and has been associated with improved survival in highly selected patients. In summary, the prognosis in POPH is poor and is impacted by the severity of both pulmonary hypertension and liver disease. Management with a combination of PAH therapy and LT in selected patients has been associated with improved pulmonary hemodynamics and survival.

Six-Minute walk distance predicts outcomes in liver transplant candidates.

A 6-minute walk test is a simple tool for assessing submaximal exercise capacity. We sought to determine whether a 6-minute walk distance (6MWD) predicts outcomes in patients with cirrhosis. The Pulmonary Vascular Complications of Liver Disease 2 study is a multicenter, prospective cohort study that enrolled adults with portal hypertension during liver transplantation evaluation. We excluded subjects with an incident or prevalent portopulmonary hypertension. The 6-minute walk test was performed using standardized methods. Cox proportional hazards modeling and multivariable linear regression analysis were performed to determine the relationship between baseline 6MWD and outcomes. The study sample included 352 subjects. The mean 6MWD was 391±101 m. For each 50-meter decrease in 6MWD, there was a 25% increase in the risk of death (HR 1.25, 95% CI [1.11, 1.41], p < 0.001) after adjustment for age, gender, body mass index, MELD-Na, and liver transplant as a time-varying covariate. In a multistate model, each 50-meter decrease in 6MWD was associated with an increased risk of death before the liver transplant ( p < 0.001) but not after the transplant. 6MWD was similar to MELD-Na in discriminating mortality. Each 50-meter decrease in 6MWD was associated with an increase in all-cause ( p < 0.001) and transplant-free hospitalizations ( p < 0.001) in multivariable models for time-to-recurrent events. Shorter 6MWD was associated with worse Short Form-36 physical ( p < 0.001) and mental component scores ( p = 0.05). In conclusion, shorter 6MWD is associated with an increased risk of death, hospitalizations, and worse quality of life in patients evaluated for liver transplantation. The 6-minute walk distance may be a useful adjunct for risk assessment in patients undergoing liver transplant evaluation.

Histologic and proteomic remodeling of the pulmonary veins and arteries in a porcine model of chronic pulmonary venous hypertension.

AIMS: In heart failure (HF), pulmonary venous hypertension (PVH) produces pulmonary hypertension (PH) with remodeling of pulmonary veins (PV) and arteries (PA). In a porcine PVH model, we performed proteomic-based bioinformatics to investigate unique pathophysiologic mechanisms mediating PA and PV remodeling. METHODS AND RESULTS: Large PV were banded (PVH, n = 10) or not (Sham, n = 9) in piglets. At sacrifice, PV and PA were perfusion labelled for vessel-specific histology and proteomics. The PA and PV were separately sampled with laser-capture micro-dissection for mass spectrometry. Pulmonary vascular resistance [Wood Units; 8.6 (95% confidence interval: 6.3, 12.3) vs. 2.0 (1.7, 2.3)] and PA [19.9 (standard error of mean, 1.1) vs. 10.3 (1.1)] and PV [14.2 (1.2) vs. 7.6 (1.1)] wall thickness/external diameter (%) were increased in PVH (P < 0.05 for all). Similar numbers of proteins were identified in PA (2093) and PV (2085) with 94% overlap, but biological processes differed. There were more differentially expressed proteins (287 vs. 161), altered canonical pathways (17 vs. 3), and predicted upstream regulators (PUSR; 22 vs. 6) in PV than PA. In PA and PV, bioinformatics indicated activation of the integrated stress response and mammalian target of rapamycin signalling with dysregulated growth. In PV, there was also activation of Rho/Rho-kinase signalling with decreased actin cytoskeletal signalling and altered tight and adherens junctions, ephrin B, and caveolae-mediated endocytosis signalling; all indicating disrupted endothelial barrier function. Indeed, protein biomarkers and the top PUSR in PV (transforming growth factor-beta) suggested endothelial to mesenchymal transition in PV. Findings were similar in human autopsy specimens. CONCLUSION: These findings provide new therapeutic targets to oppose pulmonary vascular remodeling in HF-related PH.

Inhaled Treprostinil Dosage in Pulmonary Hypertension Associated With Interstitial Lung Disease and Its Effects on Clinical Outcomes.

BACKGROUND: Pulmonary hypertension (PH) complicates the course of many patients with fibrotic interstitial lung disease (ILD). Inhaled treprostinil (iTre) has been shown to improve functional ability and to delay clinical worsening in patients with PH resulting from ILD. RESEARCH QUESTION: Do higher dosages of iTre have greater benefits in preventing clinical worsening and achieving clinical improvement? STUDY DESIGN AND METHODS: Post hoc analysis of the INCREASE study, a 16-week double-blind, randomized, placebo-controlled trial of iTre in patients with PH resulting from ILD. Four groups were identified based on the number of breaths per session (bps; < 9 and ≥ 9 bps) of active drug or placebo attained at 4 weeks. Patients were evaluated for clinical worsening (15% decrease in 6-min walkdistance, cardiopulmonary hospitalization, lung transplantation, or death) or clinical improvement (15% increase in the six-minute walk distance with a concomitant 30% reduction in N-terminal prohormone of brain natriuretic peptide without any clinical worsening event). RESULTS: At 4 weeks, 70 patients were at a dose of ≥ 9 bps (high-dosage group) and 79 patients were at a dose of < 9 bps (low-dosage group) in the iTre arm vs 86 patients in the high-dose group and 67 patients in the low-dose group in the placebo arm. Between weeks 4 and 16, 17.1% of patients in the high-dose treprostinil group and 22.8% in the low-dose treatment group experienced a clinical worsening event vs 33.7% and 34.3% of patients in the two placebo arms, respectively (P = .006). By week 16, 15.7% and 12.7% of patients in the high- and low-dose iTre groups, respectively, demonstrated clinical improvement vs 7% and 1.5% patients in the placebo arms (P = .003) INTERPRETATION: Higher dosages of iTre overall show greater benefit in terms of preventing clinical worsening and achieving clinical improvement. These data support the early initiation and uptitration of therapy to a dosage of at least 9 bps four times daily in patients with PH resulting from ILD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02630316; URL: www. CLINICALTRIALS: gov.

Erratum: Health disparities and treatment approaches in portopulmonary hypertension and idiopathic pulmonary arterial hypertension: An analysis of the Pulmonary Hypertension Association Registry.

[This corrects the article DOI: 10.1177/20458940211020913.].

Temporal Trends in Portopulmonary Hypertension Model for End-stage Liver Disease Exceptions and Outcomes.

Model for end-stage liver disease (MELD) exception criteria for portopulmonary hypertension (POPH) were created to prioritize patients for liver transplant before POPH progression. Little is known about trends in POPH exception frequency, disease severity, pulmonary hypertension treatment patterns, or outcomes since the POPH MELD exception began. Methods: Using data from the Organ Procurement and Transplantation Network database, we describe the frequency of POPH MELD exceptions between 2006 and 2019, compare baseline patient characteristics, and characterize trends in liver disease and POPH severity' as well as POPH treatment and outcomes' over time. To facilitate comparison, we divided this 14-y period into 3 "eras" (2006-2010, 2011-2015, and 2016-2019). Results: Between 2006 and 2019, 504 unique POPH MELD exceptions were granted. Both liver disease severity and patient age have increased over time (P = 0.04 and P = 0.006, respectively). Posttreatment hemodynamic values (mean pulmonary arterial pressure and pulmonary vascular resistance) have significantly improved (P < 0.001 and P = 0.008, respectively). Treatment with endothelin receptor antagonists has become more prevalent, whereas use of parenteral therapy and monotherapy regimens has decreased (P < 0.001). Neither waitlist nor liver transplant mortality outcomes have significantly changed over the eras analyzed. Conclusions: In conclusion, 504 patients have received POPH MELD exceptions between 2006 and 2019. Since 2010, nearly all patients granted POPH MELD exceptions have met hemodynamic criteria for POPH. Over time, there has been a trend toward older age and higher MELD scores with significant changes in pulmonary arterial hypertension treatment patterns and an improvement in posttreatment hemodynamics without major change in outcomes.

Bezold-Jarisch reflex mediated syncope in pulmonary arterial hypertension: An illustrative case series.

We present a novel description of Bezold-Jarisch Reflex (BJR) during cardiopulmonary exercise testing (CPET) in three young female patients with Group 1 pulmonary arterial hypertension (PAH). These three cases presented within 26 months, representing only 0.8% of 11,387 tests on patients with PAH undergoing CPET during this time frame.

Portopulmonary Hypertension in Nontransplanted Patients: Results of the Largest US Single-Institution Registry.

OBJECTIVE: To explore clinical characteristics, risk profiles, and outcomes of patients with portopulmonary hypertension (PoPH) who have contraindications to liver transplant (LT). METHODS: From the largest US single-institution registry of patients with PoPH, we analyzed 160 patients who did not receive LT between 1988 to 2019. Pulmonary arterial hypertension (PAH)-pertinent characteristics, hemodynamic features, treatments, and risk stratification were compared at baseline, first follow-up visit, and censor/death time. RESULTS: Median survival for the entire cohort was 27.5 months from the diagnosis of PoPH. Overall survival was 89%, 77%, 51%, and 38% at 6 months, 1 year, 3 years, and 5 years, respectively. Survival was significantly affected by the severity of liver disease (P<.001). Most patients received PAH-specific therapies (136 [85%]), predominantly monotherapy (123 [77%)]. With treatment, significant improvements were noted in World Health Organization functional class (P=.04), 6-minute walk distance (P<.001), right ventricular function (P<.001), pulmonary vascular resistance (P<.001), and Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) Lite 2 score (P=.02) univariately. Per European Society of Cardiology risk stratification, no patient met full criteria for low risk at baseline or at follow-up. In a multivariate Cox risk model, 6-minute walk distance, right atrial pressure, pulmonary capillary wedge pressure, bilirubin level, and Model for End-Stage Liver Disease-sodium score of 15 or higher were associated with increased risk of death. CONCLUSION: Patients with PoPH who did not undergo LT had a poor prognosis. This persisted despite use of PAH-specific therapies and significant improvements in hemodynamics, echocardiography parameters of right ventricle function, 6-minute walk distance, and World Health Organization functional class.