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Aims: The clinical utility of pulmonary hypertension (PH) risk scores in non-group 1 PH with pulmonary vascular disease (PVD) remains unresolved., Methods and Results: We utilized the prospective multicenter PVDOMICS cohort with group 2, 3, 4 or 5 PH-related PVD and calculated group 1 PH risk scores (REVEAL 2.0, REVEAL Lite 2, French registry score and COMPERA 2). The c-statistic to predict death was compared separately in (i) pre-capillary PH groups 3/4/5, and (ii) combined post- and pre-capillary PH group 2. Exercise right heart catheterization reserve, ventricular interdependence and right ventricular-pulmonary artery (RV-PA) coupling were compared across risk categories. Among 449 individuals with group 3/4/5 PH, the REVEAL 2.0 risk score had the highest c-statistic for predicting death (0.699, 95% confidence interval [CI] 0.660-0.737, p < 0.0001) with comparable performance using the simpler REVEAL Lite 2 score (0.695, 95% CI 0.656-0.734, p < 0.0001). The French and COMPERA 2 risk scores were also predictive of mortality, but performance of both was statistically inferior to REVEAL 2.0 (c-statistic difference -0.072, 95% CI -0.123 to -0.020, p = 0.006, and -0.043, 95% CI -0.067 to -0.018, p = 0.0007, respectively). RV function and RV-PA coupling measures were prognostic in isolation, but did not add incremental value to REVEAL (p > 0.50 for all). Findings were similar in patients with group 2 PH (n = 239). Stratification by the REVEAL Lite 2 score non-invasively identified non-group 1 PH with more advanced PVD with worse exercise capacity, RV-PA uncoupling, ventricular interdependence and impaired cardiac output reserve (p < 0.05 for all)., Conclusions: Non-invasive REVEAL risk predicts mortality in non-group 1 PH without incremental prognostic value from detailed RV function or RV-PA coupling assessment. Baseline REVEAL Lite 2 risk stratification non-invasively identifies greater pulmonary vascular dysfunction and right heart-related exercise limitation, which may help guide patient selection for targeted pulmonary vascular therapies in non-group 1 PH., (© 2024 European Society of Cardiology.)

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., (Copyright © 2024 American Association for the Study of Liver Diseases.)

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 ., (© 2024. The Author(s).)

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.

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., (Copyright © 2023 American Association for the Study of Liver Diseases.)

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., (Copyright © 2022 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

We present an unusual case of a woman in her 30s who was admitted for diabetic ketoacidosis (DKA) in the setting of newly diagnosed but late COVID-19 infection with associated Klebsiella pneumoniae infection. Her altered mental status, out of proportion with her metabolic decompensation, revealed a superimposed cerebral venous sinus thrombosis (CVST) with fulminant cerebral oedema and ultimately brain death. This unusual and fulminant case of cerebral oedema in the setting of COVID-19 infection with bacterial infection, DKA and CVST was the perfect storm with multiple interwoven factors. It offered diagnostic and treatment challenges with an unfortunate outcome. This unique case is a reminder that it is important to consider a broad neurological differential in patients with COVID-19 with unexplained neurological manifestations, which may require specific neurointensive care management., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: There are limited data regarding hospital and intensive care unit (ICU) outcomes in patients with hepatopulmonary syndrome (HPS) following liver transplantation (LT)., Methods: Data were retrospectively collected from consecutive HPS adult patients who underwent LT and were immediately admitted to the ICU at three transplant centers with shared management protocols, from 2002 to 2018. Demographic, clinical, surgical, laboratory, and outcome data were extracted., Results: We identified 137 patients (74 male, 54%), with a median age at LT of 58 years (IQR: 52-63). One hundred and 31 (95.6%) patients were admitted to the ICU on invasive mechanical ventilation (MV). The median time on invasive MV in the ICU was 12 hours (IQR: 5-28) and 97 patients (74%) were extubated within 24 hours of ICU admission. The median highest positive end expiratory pressure and fraction of inspired oxygen (FiO 2 ) were 7 (IQR: 5-8) and 0.6 (IQR: 0.5-0.7), respectively. 7 patients (5%) developed severe post-transplant hypoxemia. Of all patients, 42 (30.4%) required vasopressors and the median ICU and hospital length of stay (LOS) were 3 (IQR: 1-5) and 10 (IQR: 7-20) days, respectively. The in-hospital mortality rate was 3.6% (5/137). HPS severity was not associated with hospital mortality., Conclusion: Most HPS patients have short durations of MV, ICU, and hospital LOS post-LT. HPS severity does not impact hospital mortality., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: INCREASE was a randomised, placebo-controlled, phase 3 trial that evaluated inhaled treprostinil in patients with interstitial lung disease (ILD) and associated pulmonary hypertension. Treprostinil improved exercise capacity from baseline to week 16, assessed with the use of a 6-min walk test, compared with placebo. Improvements in forced vital capacity (FVC) were also reported. The aim of this post-hoc analysis was to further characterise the effects of inhaled treprostinil on FVC in the overall study population and in various subgroups of interest., Methods: In this post-hoc analysis, we evaluated FVC changes in the overall study population and in various subgroups defined by cause of disease or baseline clinical parameters. The study population included patients aged 18 years and older who had a diagnosis of ILD based on evidence of diffuse parenchymal lung disease on chest CT done within 6 months before random assignment (not centrally adjudicated). All analyses were done on the intention-to-treat population, defined as individuals who were randomly assigned and received at least one dose of study drug. The INCREASE study is registered with ClinicalTrials.gov, NCT02630316., Findings: Between Feb 3, 2017, and Aug 30, 2019, 326 patients were enrolled in the INCREASE trial. Inhaled treprostinil was associated with a placebo-corrected least squares mean improvement in FVC of 28·5 mL (SE 30·1; 95% CI -30·8 to 87·7; p=0·35) at week 8 and 44·4 mL (35·4; -25·2 to 114·0; p=0·21) at week 16, with associated percentage of predicted FVC improvements of 1·8% (0·7; 0·4 to 3·2; p=0·014) and 1·8% (0·8; 0·2 to 3·4; p=0·028). Subgroup analysis of patients with idiopathic interstitial pneumonia showed FVC differences of 46·5 mL (SE 39·9; 95% CI -32·5 to 125·5; p=0·25) at week 8 and 108·2 mL (46·9; 15·3 to 201·1; p=0·023) at week 16. Analysis of patients with idiopathic pulmonary fibrosis showed FVC differences of 84·5 mL (52·7; -20·4 to 189·5; p=0·11) at week 8 and 168·5 mL (64·5; 40·1 to 297·0; p=0·011) at week 16. The most frequent adverse events included cough, headache, dyspnoea, dizziness, nausea, fatigue, and diarrhoea., Interpretation: In patients with ILD and associated pulmonary hypertension, inhaled treprostinil was associated with improvements in FVC versus placebo at 16 weeks. This difference was most evident in patients with idiopathic interstitial pneumonia, particularly idiopathic pulmonary fibrosis. Inhaled treprostinil appears to be a promising therapy for idiopathic pulmonary fibrosis that warrants further investigation in a prospective, randomised, placebo-controlled study., Funding: United Therapeutics Corporation., Competing Interests: Declaration of interests SDN has received research funding and consulting fees from United Therapeutics, and consulting fees from Boehringer Ingelheim, Roche-Genentech, and Galapagos; he is on the speaker's bureau for Boehringer Ingelheim and Roche-Genentech. AW reports grants from United Therapeutics, during the conduct of the study. SR reports grants from United Therapeutics, during the conduct of the study; grants and personal fees from United Therapeutics and Janssen Pharmaceuticals; and personal fees from Altavant Sciences, Liquidia Technologies, Insmed, and Bayer Pharmaceuticals, outside the submitted work. AC reports grants from United Therapeutics, during the conduct of the study. SJ reports grants from United Therapeutics, during the conduct of the study; grants and personal fees from Bayer Pharmaceuticals and Janssen Research & Development; and grants from Bellerophon Therapeutics, outside the submitted work. HD reports grants from United Therapeutics, during the conduct of the study; and grants and personal fees from Actelion Pharmaceuticals, outside the submitted work. DJDLZ reports grants from United Therapeutics, during the conduct of the study. SS reports grants from United Therapeutics, during the conduct of the study; personal fees and non-financial support from Bayer Pharmaceuticals, United Therapeutics, and Actelion Pharmaceuticals; personal fees from Liquidia, Altavant Sciences, GSK, and Boehringer Ingelheim; and grants from ACCP CHEST ILD, outside the submitted work. CK reports grants from United Therapeutics, during the conduct of the study; and personal fees from United Therapeutics, Actelion, Boehringer Ingelheim, and Genentech, outside the submitted work. LM-G reports grants and personal fees from United Therapeutics, during the conduct of the study; and personal fees from United Therapeutics, Janssen Pharmaceuticals, and Bayer Pharmaceuticals, outside the submitted work. PS, ES, LDE, and AN report personal fees from United Therapeutics, during the conduct of the study; and personal fees from United Therapeutics, outside the submitted work. VFT reports grants from United Therapeutics, during the conduct of the study; and personal fees from United Therapeutics, outside the submitted work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Portopulmonary hypertension (POPH) is the presence of pulmonary arterial (PA) hypertension in patients with portal hypertension and is associated with significant morbidity and mortality. In a cohort of POPH patients, we describe the clinical outcomes of POPH patients who underwent liver transplantation (LT)., Methods: Retrospectively collected data from a prospectively assembled cohort of all consecutive POPH adults evaluated in 3 transplant centers from 1996 to 2019., Results: From a cohort of 228 POPH patients, 50 patients underwent LT. Significant hemodynamic improvement after PA-targeted therapy was observed, with 58% receiving only monotherapy pretransplant. After LT, 21 (42%) patients were able to discontinue and remained off PA-targeted therapy. The 1-, 3-, and 5-y unadjusted survival rates after LT were 72%, 63%, and 60%, respectively. An elevated pulmonary vascular resistance (PVR) before LT was associated with worse survival rate (HR, 1.91; 95% CI, 1.07-3.74, P = 0.04). No survival difference was observed in those granted MELD exception or transplants performed before or after the year 2010., Conclusions: Significant number of POPH patients discontinued PA-targeted therapy after LT. Higher PVR before LT was associated with worse survival, as was monotherapy use. Despite effective PA-targeted therapies, POPH survival outcomes after LT in our cohort were modest and may reflect the need for more aggressive therapy., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To assess the health care costs and utilization in patients with hereditary hemorrhagic telangiectasia (HHT) in the United States., Patients and Methods: Retrospective analysis of patients with HHT diagnosed between 2007 and 2017 was performed using deidentified administrative claims data from the OptumLabs Data Warehouse. Adult patients with new (incident) diagnosis of HHT between January 1, 2007, and December 31, 2017, were included. Comparisons were made using the Wilcoxon rank sum test., Results: Three thousand nine hundred seventy-seven patients with a first diagnosis of HHT between 2007 and 2017 were identified, of which 3590 were matched 1:1 to non-HHT patients with similar baseline characteristics and comorbidities. These 3590 patients with HHT were 63.1% female and 83.9% white with a mean age of 51.1 ± 18.5 years, and a mean follow-up period of 3.2 ± 2.2 years (range, 1.0-11.7 years). Compared with the control group, the cumulative 5-year median total health care cost for patients with HHT was 41.4% higher ($21,118 vs $14,929; P < .001) in those with private commercial insurance and 31.7% higher ($35,462 vs $26,925; P < .001) in those with Medicare Advantage coverage. The median annual health care costs were significantly higher in patients with HHT with commercial insurance and Medicare Advantage in the first year after diagnosis ($4,333 vs $1,804; P < .001), and ($7,322 vs $5,245; P < .001), respectively, and remained higher throughout the duration of follow-up. Further analysis showed that outpatient clinic visits, hospital admission, imaging rates, invasive procedures, iron infusions, and blood transfusions were all significantly higher in the HHT group., Conclusion: Patients with HHT have significantly higher health care costs compared with a matched control group. A better understanding of the reasons underlying these cost differences will provide opportunities for patients, providers, and other stakeholders to better manage this rare condition., (© 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.)

Objective: To evaluate the safety and efficacy of balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) seen at a US medical center., Patients and Methods: Patients with inoperable or residual postendarterectomy CTEPH who underwent BPA at Mayo Clinic in Rochester, Minnesota, between August 11, 2014, and May 17, 2018, were included. Invasive hemodynamic, clinical, laboratory, and echocardiographic data were collected and analyzed retrospectively., Results: We identified 31 patients (26 with inoperable CTEPH and 5 with residual postendarterectomy CTEPH) who underwent 75 BPA procedures performed in a staged manner to reduce complications. The median number of sessions was 2 (interquartile range [IQR], 1-3) per patient, and the number of vessels treated per session was 3 (IQR, 2-3). Of the 31 patients, 24 (77.4%) were taking pulmonary vasodilators and 22 (71.0%) were taking riociguat. The mean pulmonary arterial pressure decreased from 40 mm Hg (IQR, 29-48 mm Hg) to 29 mm Hg (IQR, 25-37 mm Hg; P <.001); pulmonary vascular resistance decreased from 5.5 Wood units (WU) (IQR, 3.0-7.6 WU) to 3.3 WU (2.2-5.2 WU; P <.001). The follow-up 6-minute walk test was performed in 13 patients and improved from 402 m (IQR, 311-439 m) to 439 m (366-510 m; P =.001). Of the 31 patients, 19 (61.3%) had improvement in New York Heart Association functional class. The mean ± SD nadir of minute ventilation/carbon dioxide production decreased by 3.4±5.5 ( P =.03), reflecting improved ventilatory efficiency. Complications included hemoptysis requiring overnight intensive care unit observation (n=1) and cardiac tamponade requiring pericardiocentesis (n=1). One patient had reperfusion injury requiring intubation, recovered, and was dismissed to home but died unexpectedly within less than 30 days of the procedure. Serious complications occurred in 3 of the 75 BPA procedures (4.0%)., Conclusion: Our experience with BPA revealed that this procedure has acceptable risk and improves hemodynamics, functional class, and exercise tolerance in patients with inoperable or residual CTEPH.