Search

Disclaimer: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time., Purpose: A case of successful transition from high-dose epoprostenol to high-dose subcutaneous treprostinil for treatment of pulmonary arterial hypertension (PAH) is reported., Summary: PAH is a chronically progressive disease characterized by pulmonary artery luminal narrowing that causes increased pulmonary artery pressures leading to right ventricular failure. Parenteral prostacyclin analogues, such as epoprostenol and treprostinil, are direct vasodilators and are cornerstones of therapy for patients with severe disease that have been proven to reduce mortality and increase exercise tolerance. These agents must be administered continuously via intravenous or subcutaneous devices and are high-risk medications due to their potent vasodilatory actions. Chronic use of these medications requires constant attention from both providers and patients because of potential complications including central venous catheter infection, thromboembolism, therapy interruptions, and other undesirable consequences. This case report describes management of a 35-year-old male patient on high-dose outpatient intravenous epoprostenol (101 ng/kg/min; dosing weight, 47 kg) for treatment of PAH who was admitted to the hospital with a malfunctioning central venous catheter. Surrounding manipulation of the central catheter, the patient experienced an ischemic stroke that led to cognitive disability resulting in a lack of ability to manage his previously used home infusion device. The patient was successfully transitioned from intravenous epoprostenol to subcutaneous treprostinil (discharge dose, 200 ng/kg/min) over 5 days by infusing both medications simultaneously and adjusting doses based upon patient-reported symptoms., Conclusion: This successful transition from high-dose epoprostenol to high-dose subcutaneous treprostinil demonstrates the importance in considering patient-specific factors during high-risk medication transitions, the value of a patient-directed flexible prostacyclin transition plan, and the benefit of institutional training and education in ensuring the safe use of parenteral prostacyclin analogues., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Pulmonary hypertension (PH) frequently complicates the evaluation of kidney transplantation (KT) candidates, and is associated with increased adverse outcomes [mortality, delayed graft function (DGF), and major adverse cardiovascular event] following KT., Research Question: What is the relationship between cardiopulmonary hemodynamics and post-KT outcomes?, Study Design and Methods: We conducted a multicenter retrospective cohort study of adults undergoing KT between October 1, 2011 and October 1, 2021, who underwent right heart catheterization (RHC) to assess cardiopulmonary hemodynamics within 1 year of transplantation. Frailty models and logistic regression models were used to evaluate the association between cardiopulmonary hemodynamics and outcomes (mortality, DGF, major adverse cardiovascular event) following KT., Results: A total of 117 patients were included in the final analysis, predominantly male (72%), with a median age of 57 years. PH, defined as mean pulmonary artery pressure (mPAP) > 20 mm Hg, was present in most of the cohort (n = 93; 79%). The cohort was monitored for a median of 29.9 months post-KT, during which about one-fourth experienced mortality (23%) or DGF (25%) events, and approximately one-third (34%) experienced major adverse cardiovascular event. Although echocardiographic measures of pulmonary artery pressure failed to identify post-KT outcomes, a mPAP of ≥ 30 mm Hg on RHC was associated with post-KT major adverse cardiovascular event (hazard ratio, 2.60; 95% CI, 1.10-6.10) and more prevalent in those experiencing post-KT mortality (63% vs 32%; P = .001). Precapillary pulmonary hypertension was also associated with post-KT mortality (hazard ratio, 3.71; 95% CI, 1.07-12.90)., Interpretation: Precapillary pulmonary hypertension and an mPAP of ≥ 30 mm Hg on RHC, but not echocardiographic evidence of PH, was associated with mortality and major adverse cardiovascular event following KT. These data suggest that RHC hemodynamics are superior to echocardiographic measures of PH in association with outcomes following KT, and RHC-derived mPAP in particular may have value in predicting major adverse cardiovascular event and mortality post-KT., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: A. J. reports investigator-initiated research supported by United Therapeutics. S. S. K. has received research grant support from Edwards Life Sciences, Hemosonics, and PCORI. R. G. A. has received research grant support and served on the consultant or advisory board of United Therapeutics. N. M. B. is the site principal investigator for a clinical trial sponsored by Rednvia. J. M. E. has received research grant support from Janssen, United Therapeutics, Liquidia, Phase Bio, Gossamer Bio, Bayer, Merck, Altavant, Aerovate, Tenax, and Pharmosa, and serves on the consultant or advisory board of United Therapeutics, Altavant, Aerovate, Bayer, Gossamer Bio, Liquidia, Merck, and Janssen. None declared (L. G., S. H. F., A. S. F., D. S., M. V., N. J. D., A. P., C. J.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Portopulmonary hypertension (PoPH), associated with increased mortality, can limit treatment options for liver diseases. Data on the continuum of clinical risk related to cardiopulmonary hemodynamics in PoPH are lacking., Methods and Results: As part of the United States national Veterans Affairs Clinical Assessment, Reporting, and Tracking database, we performed a retrospective cohort study of adults with cirrhosis undergoing right heart catheterization between October 1, 2017, and September 30, 2022. Pulmonary hypertension (mean pulmonary arterial pressure [mPAP] >20 mm Hg without PoPH) and PoPH (mPAP >20 mm Hg+pulmonary artery wedge pressure ≤15 mm Hg+pulmonary vascular resistance ≥3 WU) were defined by right heart catheterization hemodynamics. Multivariable Cox proportional hazards using natural splines for hemodynamic variables were used to evaluate the association between cardiopulmonary hemodynamics and mortality following right heart catheterization. A total of 4409 patients were included in the final analysis, predominantly men (96.3%), with a mean age of 68.5 years. Pulmonary hypertension and PoPH were observed in 71.6% and 10.2% of the cohort, respectively. Compared with a reference cardiac index of 2.5 L/min per m 2 , the hazard for mortality increased progressively with decreasing cardiac index, even after adjustment for mPAP and pulmonary vascular resistance. The minority of patients with PoPH (N=65, 14.5%) were prescribed pulmonary vasodilator therapy., Conclusions: These data suggest that pulmonary hypertension and PoPH are prevalent in veterans with chronic liver disease, but low use of targeted PoPH therapy persists. Cardiac function discriminated mortality risk across a wide range of mPAP and pulmonary vascular resistance values and may diagnose and clarify prognosis in this patient population.

Rationale: Oral treprostinil slows disease progression and improves exercise capacity in pulmonary arterial hypertension; however, titration can be prolonged. Published data suggests prostacyclin-naïve patients achieve total daily oral treprostinil doses of about 6 mg by Week 16, while those on prior parenteral treprostinil reach higher doses at the same timepoint., Objectives: EXPEDITE (NCT03497689), a single-arm, multicenter study, assessed the efficacy of rapid parenteral treprostinil induction to quickly reach higher doses of oral treprostinil for the treatment of pulmonary arterial hypertension., Methods: Parenteral treprostinil was titrated for 2-8 weeks, followed by cross-titration of oral treprostinil. The primary endpoint was percentage of patients reaching ≥12 mg daily of oral treprostinil at Week 16. Secondary endpoints included clinical changes from baseline to Week 16., Results: Twenty-nine prostacyclin-naïve patients were included in efficacy analyses. At Week 16, the mean daily oral treprostinil dose was 16.4 mg; 79% of patients met the primary endpoint. From baseline to Week 16, median REVEAL Lite 2 score improved (decreased) from 6 to 3.5 (p = 0.0006). Statistically significant improvements were also seen in World Health Organization Functional Class, N-terminal-pro brain natriuretic peptide levels, 6-minute walk distance, right atrial area, Borg Dyspnea Score, and emPHasis-10 score. Favorable trends were seen in risk stratification, echocardiography parameters, disease symptoms, and treatment satisfaction., Conclusion: Short-course parenteral treprostinil induction resulted in oral treprostinil doses over twice those reported in de novo initiations and may be a useful approach to quickly achieve the therapeutic benefits of oral treprostinil., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CEM – United Therapeutics Corporation (research, consulting, speakers bureau, advisory board), Janssen (research, speakers bureau, advisory board), Insmed (research), Bayer (advisory board, steering committee); VF – United Therapeutics Corporation (research), Merck (research), Acceleron (research), Johnson & Johnson (research), Respira (research), Aerovate (research), Cereno (research), Abbott (research); JSS – United Therapeutics Corporation (research, speakers bureau), Bayer (research, speakers bureau); VB – United Therapeutics Corporation (consulting); JK – United Therapeutics Corporation (research, consulting, speakers bureau, advisory board), Janssen (research, consulting, speakers bureau, advisory board), Acceleron (research), Gossamer (research), Bayer (consulting, speakers bureau, advisory board); RZ – United Therapeutics Corporation (consulting), Bayer (consulting), Janssen (consulting), Johnson & Johnson (consulting); LMG – United Therapeutics Corporation (research, consulting, advisory board), Janssen (research, consulting), Gossamer bio (research, consulting), Merch (research, consulting), Bayer (research, consulting); JH – Acceleron (research), CardiolRx (research), Aaadi Bioscience (research), Astra Zeneca (spouse); JME – United Therapeutics Corporation (research, consulting), Janssen (research), Liquidia (research, consulting), Phase Bio (research), Gossamer Bio (research, consulting), Bayer (research, consulting), Acceleron (research), Altavant (research, consulting), Aerovate (research consulting), Tenax (research), Pharmosa (research), Merck (consulting); AR – United Therapeutics Corporation (consulting), Bayer (consulting), Actelion (consulting); DC, ES, SS, CMT, MB – United Therapeutics Corporation (employee); RJO – United Therapeutics Corporation (research, consulting), Janssen (research, consulting), Merck (research, consulting), Gossamer Bio (research), Insmed (research)., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Portopulmonary hypertension (PoPH) is a type of pulmonary vascular disease due to portal hypertension that exhibits high morbidity and mortality. The mechanisms driving disease are unknown, and transcriptional characteristics unique to the PoPH liver remain unexplored. Here, we apply single nuclear RNA sequencing to compare cirrhotic livers from patients with and without PoPH. We identify characteristics unique to PoPH in cells surrounding the central hepatic vein, including increased growth differentiation factor signaling, enrichment of the arginine biosynthesis pathway, and differential expression of the bone morphogenic protein type II receptor and estrogen receptor type I genes. These results provide insight into the transcriptomic characteristics of the PoPH liver and mechanisms by which PoPH cellular dysfunction might contribute to pulmonary vascular remodeling., (© 2023. Springer Nature Limited.)

Treprostinil is a prostacyclin analogue that targets multiple cellular receptors to treat pulmonary arterial hypertension (PAH). In certain scenarios, patients may require aggressive treprostinil titration. Several studies have demonstrated that higher doses of treprostinil lead to greater clinical benefit. Data supports successful transitions from parenteral to oral treprostinil; however, administration routes, transition duration, and transition setting vary in the real-world. The EXPEDITE clinical trial (NCT03497689) prospectively studied whether rapid parenteral treprostinil induction can be used to achieve high doses of oral treprostinil (total daily dose: ≥12 mg) in prostacyclin naïve PAH patients. Parenteral prostacyclin induction may be more appropriate for patients who need to reach therapeutic dosing more urgently than longer titration durations reported with conventional de novo oral treprostinil initiation. This summary provides strategies utilized in EXPEDITE. Parenteral treprostinil was initiated at 2 ng/kg/min intravenously or subcutaneously; clinicians determined the frequency and dose increment of up-titration. Two distinct transition schedules from parenteral to oral treprostinil were employed: rapid cross-titration in an inpatient setting (median: 2 days) or gradual cross-titration in an outpatient setting (median: 5 days). Patient status was closely monitored after transition; oral treprostinil dose was titrated to clinical effect and tolerability. Factors considered when individualizing dosing strategies included parenteral and oral treprostinil target doses, nursing support, patient education, medication counseling and adverse events management. EXPEDITE demonstrated the time to a therapeutic dose of oral treprostinil is significantly shorter when utilizing a short-term parenteral induction strategy and may be suitable for patients requiring aggressive titration of oral treprostinil., Competing Interests: J. F. Kingrey is part of the speaker bureau for United Therapeutics, Bayer pharmaceuticals, and Janssen Pharmaceuticals, attends advisory boards for United Therapeutics, Bayer, and Janssen, consults for United Therapeutics, Bayer, Janssen, and conducts research for United Therapeutics, Janssen, Acceleron, Gossamer Bio. C. E. Miller is part of the speaker bureau for United Therapeutics, Janssen, and Bayer, attends advisory boards for United Therapeutics and Janssen, consults for United Therapeutics, and conducts clinical research for United Therapeutics, Janssen, Bayer, and Insmed. J. S. Smith serves as a speaker for and has received research funds from Bayer and United Therapeutics. V. Franco has served on advisory boards for United Therapeutics and has supported research for United Therapeutics, Merck, Acceleron, Johnson and Johnson, Respira, Aerovate, Cereno, and Abbott. R. Zolty has received payments for consulting on behalf of United Therapeutics, Bayer, and Janssen/Johnson and Johnson. R. J. Oudiz has received grants from Acceleron/Merck, Gossamer Bio, Insmed, Janssen, and United Therapeutics and honoraria/speaker fees from Merck, Janssen, and United Therapeutics. J. M. Elwing consults for United Therapeutics, Altavant, Aerovate, Bayer, Gossamer Bio, Liquida, and Merck and has received research support and grants from Janssen, United Therapeutics, Liquidia, Phase Bio, Gossamer Bio, Bayer, Acceleron, Altavant, Aerovate, Tenax, and Pharmosa. J. H. Huston has conducted clinical trials for Acceleron, CardiolRx, and Aadi Bioscience. L. Melendres‐Groves has received honoraria and/or fees for consultancy and advisory committees for United Therapeutics Corporation outside of submitted works. A. Ravichandran reports personal fees from United Therapeutics, Bayer, and Actelion outside the submitted work. V. Balasubramanian serves as a consultant for United Therapeutics. B. Wu, S. Hwang, S. Seaman, and M. Broderick are paid employees of United Therapeutics. F. F. Rahaghi has consulted for United Therapeutics, Janssen PH, Merck, and Altavant; served as a speaker for United Therapeutics, Janssen PH, and Bayer; and received research funding from Janssen, Bayer, Merck, Gossamer, and Bellerophon., (© 2023 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Right heart (RH) structure and function are major determinants of symptoms and prognosis in pulmonary arterial hypertension (PAH). RH imaging provides detailed information, but evidence and guidelines on the use of RH imaging in treatment decisions are limited. We conducted a Delphi study to gather expert opinion on the role of RH imaging in decision-making for treatment escalation in PAH. A panel of 17 physicians with expertise in PAH and RH imaging used three surveys in a modified Delphi process to reach consensus on the role of RH imaging in PAH. Survey 1 used open-ended questions to gather information. Survey 2 contained Likert scale and other questions intended to identify consensus on topics identified in Survey 1. Survey 3 contained Likert scale questions derived from Survey 2 and summary information on the results of Survey 2. The Delphi panel reached consensus that RH imaging is likely to improve the current risk stratification algorithms and help differentiate risk levels in patients at intermediate risk. Tricuspid annular plane systolic excursion, right ventricular fractional area change, right atrial area, tricuspid regurgitation, inferior venae cavae diameter, and pericardial effusion should be part of routine echocardiography in PAH. Cardiac magnetic resonance imaging is valuable but limited by cost and access. A pattern of abnormal RH imaging results should prompt consideration of hemodynamic evaluation and possible treatment escalation. RH imaging is an important tool for decisions about treatment escalation in PAH, but systematically collected evidence is needed to clarify its role., Competing Interests: Paul Forfia has served on a speaker's bureau and consulted for Bayer, Janssen, and United Therapeutics. Raymond Benza has received consulting fees from Bayer, Janssen, United Therapeutics, Acceleron, CERENO, Abbott, and Gossamer; and advisory board fees from Acceleron. Michele D'Alto has received consulting fees from Janssen, MSD, Dompè, Ferrer, and AOP. Teresa De Marco has received research funding from Acceleron; and has served as a consultant for Action/Janssen, United Therapeutics, BIAL, Merck, NXT, Aerovate, and Pulnovo. Jean M. Elwing has served as a consultant for United Therapeutics, Altavant, Aerovate, Bayer, Gossamer Bio, Acceleron, Janssen, Liquid, and Insmed; and has participated in clinical research funded by Janssen, United Therapeutics, Liquidia, Phase Bio, Gossamer Bio, Bayer, Acceleron, Altavant, and Aerovate. Robert Frantz has received consulting fees from Altavant, Gossamer Bio, Insmed, Liquidia, ShouTi, and Tenax; serves on DSMB for IQVIA; and has received research grants from Bayer and United Therapeutics. Francois Haddad has received research funding from Janssen. Ronald Oudiz has received research funding, advisory board honoraria, and speaker fees from United Therapeutics. Ioana R. Preston has received research funding from Acceleron/Merck, Janssen, United Therapeutics, and PhaseBio; and consulting fees from Acceleron/Merck, Janssen, United Therapeutics, Aerovate, Gossamer Bio, and Respira. Stephan Rosenkranz has received fees for lectures and/or consultations from Abbott, Acceleron, Actelion, Aerovate, Altavant, AOP Orphan, AstraZeneca, Bayer, Boehringer Ingelheim, Edwards, Ferrer, Gossamer, Janssen, MSD, United Therapeutics, and Vifor; and his institution has received research grants from Actelion, AstraZeneca, Bayer, and Janssen. John Ryan has received consulting fees and payment or honoraria from lectures, presentations, speakers' bureaus, manuscript writing, or education events from Bayer, Merck, United Therapeutics, Kiniksa, and Janssen PH. Robert Schilz has received research funding from Acceleron/Merck, United Therapeutics, Respira, and Bellerophon; consulting fees from Janssen, United Therapeutics, and Acceleron; and currently serves on speakers' bureaus for Bayer, Janssen, and United Therapeutics. Oksana A. Shlobin has received consulting fees from United Therapeutics and Janssen; has received honoraria from Medscape, Total CME, and Bayer; and has participated in a Data Safety Monitoring Board or Advisory Board for Janssen and Altavant. Jean‐Luc Vachiery has received consulting fees from Acceleron, Actelion Pharmaceuticals (now Janssen), Altavant, Bayer HealthCare, Boehringer Ingelheim, GlaxoSmithKline, Gossamer Bio, MSD, Novartis, and Shouti. Carmine Dario Vizza has received consulting fees from Acceleron, Janssen, Altavant, Bayer HealthCare, Ferrer, GlaxoSmithKline, Gossamer Bio, and MSD. Anton Vonk Noordegraaf has served as a member of the scientific advisory board of Morphogen‐X, Ferrer, Gosamer Bio, and Johnson & Johnson. The institute of Anton Vonk Noordegraaf has received consulting fees from a speakers' bureau for Johnson & Johnson, MSD, Actelion, Bayer, and Ferrer. Margaret R. Sketch and Meredith Broderick are employees and shareholders of United Therapeutics Corporation. Vallerie McLaughlin has received research funding from Acceleron, Janssen, Sonovie, and United Therapeutics; and consulting fees from Acceleron, Aerovate, Altavant, Bayer, Caremark LLC, CiVi Biopharma Inc., Corvista, Gossamer Bio, Janssen, Merck, and United Therapeutics., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Portopulmonary hypertension (POPH) is a type of pulmonary arterial hypertension occurring exclusively in those with portal hypertensive liver disease. Liver transplantation (LT) can significantly improve outcomes. Current guidelines counsel against immediate adjustments to targeted therapy after LT and suggest routine echocardiography as sufficiently informative to guide therapeutic adjustments. Current practice patterns for adjusting targeted therapy after LT in POPH, and how they compare with guidelines, are not well established. To answer this question, we performed an institutional review board-approved, cross-sectional mixed-methods survey-based study of US POPH providers. Anonymized requests to complete the survey were sent through professional networks between January 20, 2022, and April 20, 2022. Responses were compared between cardiologists and pulmonologists using Fisher's exact tests, at a significance of 0.05. A total of 85 POPH physicians were included in the final analysis (66% pulmonologists and 34% cardiologists). Following LT, the majority of respondents routinely used a combination of standard cardiopulmonary assessment modalities to guide adjustment of targeted therapy following LT. Most respondents (69%) started by adjusting parenteral prostacyclins with small titrations and frequent reassessments within 3 months of LT, but some (19.7%) adjusted targeted therapy immediately after LT. Our results showed that the majority of respondents favored serial integrated cardiopulmonary testing (including routine right heart catheterization) to guide the adjustment of targeted therapy in POPH after LT, and almost one-fifth of respondents weaned therapy immediately after LT. Our study demonstrates heterogeneity in POPH practice patterns after LT, highlights differences between current practice patterns and the most recent guidelines, emphasizes the need for additional research, and supports a team-based approach to standardize care for these high-risk patients and optimize post-LT outcomes., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Interhospital transfer (IHT) of patients with acute life-threatening pulmonary embolism (PE) is necessary to facilitate specialized care and access to advanced therapies. Our goal was to understand what barriers and facilitators may exist during this transfer process from the perspective of both receiving and referring physicians., Methods: This qualitative descriptive study explored physician experience taking care of patients with life threatening PE. Subject matter expert physicians across several different specialties from academic and community United States hospitals participated in qualitative semi-structured interviews. Interview transcripts were subsequently analyzed using inductive qualitative description approach., Results: Four major themes were identified as barriers that impede IHT among patients with life threatening PE. Inefficient communication which mainly pertained to difficulty when multiple points of contact were required to complete a transfer. Subjectivity in the indication for transfer which highlighted the importance of physicians understanding how to use standardized risk stratification tools and to properly triage these patients. Delays in data acquisition were identified in regards to both obtaining clinical information and imaging in a timely fashion. Operation barriers which included difficulty finding available beds for transfer and poor weather conditions inhibiting transportation. In contrast, two main facilitators to transfer were identified: good communication and reliance on colleagues and dedicated team for transferring and treating PE patients ., Conclusion: The most prominent themes identified as barriers to IHT for patients with acute life-threatening PE were: (1) inefficient communication, (2) subjectivity in the indication for transfer, (3) delays in data acquisition (imaging or clinical), and (4) operational barriers. Themes identified as facilitators that enable the transfer of patients were: (1) good communication and (2) a dedicated transfer team. The themes presented in our study are useful in identifying opportunities to optimize the IHT of patients with acute PE and improve patient care. These opportunities include instituting educational programs, streamlining the transfer process, and formulating a consensus statement to serve as a guideline regarding IHT of patients with acute PE., Competing Interests: CK is consultant for BMS and Abbott, and provided by a grant from Grifols and Diagnostica Stago. RR is consultant for Abbott, BMS, Dova, Janseen, Inari Medical, and Penumbra, and provided by a grant from Janssen and BMS. OF is consultant for Inari Medical. BR-L is consultant for Inari Medical and Johnson & Johnson, and provided by a grant from Johnson & Johnson. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 DeBerry, Rali, McDaniel, Kabrhel, Rosovsky, Melamed, Friedman, Elwing, Balasubramanian, Sahay, Bossone, Farmer, Klein, Hamm, Ross and Rivera-Lebron.)

Background: Patients suffering from pulmonary arterial hypertension (PAH) demand frequent assessment to keep pace with a dynamic and sometimes rapidly progressive disease course. To improve our understanding of patient monitoring, we conducted a survey of pulmonary hypertension (PH) providers to establish real-world practice patterns., Objective: To evaluate the type and frequency of patient assessment methods employed by expert PH providers following PAH diagnosis METHODS: A descriptive cross-sectional survey of PH providers across the United States was utilized to assess provider practices. Between September 14, 2017 to October 17, 2017, a survey was distributed electronically to PH experts assessing follow-up frequency and testing evaluation of patients with PAH., Results: 40 (11.4%) providers completed the survey, representing cardiologists, pulmonologists, and advanced practice providers at centers who cared for an average of 95 patients per year with PAH. Follow-up testing and clinic evaluation was influenced by severity of patient illness. Frequency of re-assessment of clinic follow-up, six-minute walk test, echocardiogram, brain natriuretic peptide, and right heart catheterization in various clinical scenarios all reflected disparate practice., Conclusions: Current clinical practice patterns in the monitoring of patients with PAH are variable and do not necessarily reflect guideline-based practices, suggesting the need for further research and improved guidelines on the frequency of follow up and repeat testing., (Copyright © 2022. Published by Elsevier Inc.)

Background Diagnosis of pulmonary hypertension (PH) is often delayed or missed, leading to disease progression and missed treatment opportunities. In this study, we measured variation in care provided by board-certified cardiologists and pulmonologists in simulated patients with potentially undiagnosed PH. Methods and Results In a cross-sectional study (https://www.clinicaltrials.gov, NCT04693793), 219 US practicing cardiologists and pulmonologists cared for simulated patients presenting with symptoms of chronic dyspnea and associated signs of potential PH. We scored the clinical quality-of-care decisions made in a clinical encounter against predetermined evidence-based criteria. Overall, quality-of-care scores ranged from 18% to 74%, averaging 43.2%±11.5%. PH, when present, was correctly suspected 49.1% of the time. Conversely, physicians incorrectly identified PH in 53.7% of non-PH cases. Physicians ordered 2-dimensional echocardiography in just 64.3% of cases overall. Physicians who ordered 2-dimensional echocardiography in the PH cases were significantly more likely to get the presumptive diagnosis (61.9% versus 30.7%; P <0.001). Ordering other diagnostic work-up items showed similar results for ventilation/perfusion scan (81.5% versus 51.4%; P =0.005) and high-resolution computed tomography (60.4% versus 43.2%; P =0.001). Physicians who correctly identified PH were significantly more likely to order confirmatory right heart catheterization or refer to PH center (67.3% versus 15.8%; P <0.001). Conclusions A wide range of care in the clinical practice among simulated patients presenting with possible PH was found, specifically in the evaluation and plan for definitive diagnosis of patients with PH. The delay or misdiagnosis of PH is likely attributed to a low clinical suspicion, nonspecific symptoms, and underuse of key diagnostic tests. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04693793.

Portopulmonary hypertension (PoPH) is a progressive, ultimately fatal cardiopulmonary disease that occurs exclusively in patients with underlying portal hypertensive liver disease. PoPH outcomes are driven by both the severity of underlying liver disease and the degree of cardiac adaptation to elevated pulmonary pressures. The mainstay of treatment in PoPH is targeted pulmonary vascular therapy. Liver transplantation (LT) can be beneficial in some patients, but is associated with considerable risks in the PoPH population, and outcomes are variable. The optimal management strategy for PoPH, LT, or medical therapy alone, is unclear, and further research is needed to help guide clinical decision-making., Competing Interests: Disclosure The authors have no commercial or financial conflicts of interest pertaining to the contents of this article. A. Jose receives funding from the National Institutes of Health (2UL1RT00424, 2KL2TR001426), the Parker B. Francis Foundation, and the United Therapeutics Corporation through an investigator-sponsored grant. C.R. Jones has no funding disclosures. J.M. Elwing receives funding from United Therapeutics, Altavant, Aerovate, Bayer, and Gossamer Bio and serves as a consultant for Janssen, United Therapeutics, Liquidia, Phase Bio, Gossamer Bio, Bayer, Acceleron, and Altavant., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The coronavirus of 2019 (COVID-19) disrupted delivery of healthcare. Patients with pulmonary hypertension (PH), especially pulmonary arterial hypertension (PAH), require significant resources for both diagnosis and management and are at high risk for decompensation due to disruption in their care. A survey consisting of 47 questions related to the care of patients with PH was designed by the American College of Chest Physicians 2020-2021 Pulmonary Vascular Disease (PVD) NetWork Steering Committee and sent to all members of the PVD NetWork, as well as the multiple other professional networks for PH. Participation was voluntary and anonymous. Responses were collected from November 2020 through February 2021. Ninety-five providers responded to this survey. The majority (93%) believe that care of PH patients has been affected by the pandemic. Sixty-seven percent observed decreased referrals for PH evaluation. Prior to the pandemic, only 15% used telemedicine for management of PH patients compared to 84% during the pandemic. Telemedicine was used most for follow up of selected low-risk patients (49%). While 22% respondents were completely willing to prescribe new PAH therapy via telemedicine, 11% respondents were completely unwilling. Comfort levels differed based on type of medication being prescribed. Over 90% of providers experienced disruptions in obtaining testing and 31% experienced disruptions in renewal or approval of medications. Overall, providers perceived that the COVID-19 pandemic caused significant disruption of care for PH patients. Telemedicine utilization increased but was used mostly in low-risk patients. Some providers had a decreased level of comfort prescribing PAH therapy via telemedicine encounters., Competing Interests: Declaration of competing interest None of the authors have conflicts of interest to disclose on the topic of this pulmonary hypertension survey., (Copyright © 2022. Published by Elsevier Ltd.)

Background: The clinical significance of incidentally found RV abnormalities on low-risk SPECT studies is not well-defined. The objective of this study was to determine the predictive value of incidental right ventricular (RV) abnormalities identified on single photon emission computed tomography (SPECT) scans for mortality and pulmonary hypertension (PH)., Methods: We retrospectively analyzed all low-risk SPECT studies in patients without known coronary artery or pulmonary vascular disease, performed at our institution, from 2007-2020. Adjusted Cox proportional hazards models were used to evaluate the association between incidental RV abnormalities on low-risk SPECT studies and outcomes., Results: Of the 4761 patients included in the analysis, mortality events were present in 494, and echocardiographic PH was present in 619. Incidental RV abnormalities on low-risk SPECT studies were significantly and independently associated with all-cause mortality (HR = 1.41, CI [1.07-1.86], P = 0.0152) and echocardiographic PH (HR = 2.06, CI [1.64-2.60], P < 0.0001)., Conclusions: These data suggest incidental RV abnormalities found on low-risk SPECT imaging studies are significantly and independently associated with increased mortality and risk of developing echocardiographic PH, and could identify high-risk patients for closer monitoring and additional diagnostic testing., (© 2021. American Society of Nuclear Cardiology.)

Social determinants of health (SDoH) can impact the vulnerable pulmonary arterial hypertension (PAH) population, especially during the COVID-19 pandemic. Providers' understanding of SDoH at the point of care and their impact is unknown. We conducted semi-structured virtual interviews with US clinicians at 17 pulmonary hypertension (PH) centers and one patient advocate from the Pulmonary Hypertension Association. We sought participants' perspective on SDoH in PAH and their impact. Transcripts were developed and analyzed for key themes to assess potential policy implications. Participants served a large PAH population and demonstrated high awareness of SDoH and its impact on treatment and outcomes. They reported that patients' SDoH, including socioeconomic status, health insurance, access to health care, education levels, health literacy, employment status, and insecurities associated with housing, food, transportation, and family support, impacted health and well-being. COVID-19-related social isolation, mental health, and substance abuse contributed to significant inequities in care provision and outcomes. While telemedicine helped clinicians manage patients remotely during the pandemic, there was a concern for patients with limited access to this medium. Participants reported no formal screening for SDoH at the point of care. With the recognition and the desire to act upon health inequities associated with SDoH, participants felt that it was vital for their centers to have a dedicated PH social worker and support staff to optimize care and outcomes. An approach that integrates SDoH in PAH care management, streamlined through institutional policy, could address health disparities leading to improved healthcare access, outcomes, and quality of care., Competing Interests: Vijay R. Nadipelli is a Master of Science Health Policy Candidate at Thomas Jefferson University's College of Population Health. Portions of this study were previously presented at the Pulmonary Hypertension Association Scientific Conference, Atlanta, Georgia, June 9–12, 2022. The culminating study has been submitted in fulfillment of Vijay R. Nadipelli's institutional academic degree requirements. The other authors declare no conflict of interest., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Pulmonary arterial hypertension (PAH) is a chronically progressive fatal disease. A goal-oriented approach to achieve low risk status has been associated with improved survival. A variety of risk stratification tools are available, but use is low. We conducted a survey to assess potential reasons for under-utilization. We conducted a survey-based study of global PAH disease specialists with a goal of assessing risk assessment utilization and identifying modifiable barriers to use. The survey was designed by the American College of Chest Physicians' Pulmonary Vascular Diseases (PVD) NetWork. Respondents were global members of the PVD NetWork and Pulmonary Hypertension Association. Survey invitations were sent electronically to all members. Participation was anonymous and no provider or patient level data was collected. Participants from four countries responded with the majority (84%) being from the United States. Our survey found suboptimal use of any risk stratification tool with 71/112 (63%) reporting use. A total of 85% of the respondents had more than 5 years of experience in managing PAH. REVEAL 2.0 and European Society of Cardiology/European Respiratory Society risk tools were the most commonly used. A total of 44 (65%) surveyed felt that use of risk tools led to change in PAH therapies. Only 6 (9%) felt they prompted additional testing or changed the frequency of follow-up. A total of 5 (7%) reported they prompted goals of care/palliative care discussions and 2 (3%) that they triggered lung transplant referral. The vast majority indicated that incorporation of risk tools into electronic medical records (EMR) would improve utilization. PAH risk assessment tools remain under-utilized. Most respondents were experienced PAH clinicians. More than one-third were not routinely using risk tools. Most felt that risk tools led to PAH therapy changes but few reported impacts on other aspects of care. The most commonly identified barriers to use were time constraints and lack of integration with EMR., Competing Interests: Sandeep Sahay: Consultant for United Therapeutics, Acceleron, Actelion, Bayer Pharmaceuticals. Advisor and speaker for United Therapeutics, Actelion and Bayer. Research grant support from ACCP CHEST and United Therapeutics. Clinical Trial site PI for United Therapeutics, Actelion, Merck, Liquidia Altavant Sciences, and Gossamer Bio. Vijay Balasubramanian: Research support—United Therapeutics, Speaker bureau—Bayer, Boehringer Ingelheim, Consultant—Bayer, United Therapeutics. Lana Melendres‐Groves: Consultant, speaker and advisor—Bayer, United Therapeutics, Janssen. Stephen C Mathai: Consultant: Actelion, Bayer, Acceleron, United Therapeutics, Funding: NHLBI, DOD. Oksana Shlobin: Speaker & Consultant for United Therapeutics, J&J, and Bayer. Jean M Elwing: Consultant/advisor for Janssen/Actelion, United Therapeutics, Acceleron, Liquidia, Altavant, Aerovate, Gossamer Bio, and participated in clinical trials with Actelion, Acceleron, Altavant, Aerovate, Reata, United Therapeutics, Liquidia, Phase Bio, Gossamer Bio, Bayer, LungLLC. All other authors declare no conflict of interests., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Dual combination therapy with a phosphodiesterase-5 inhibitor (PDE5i) and endothelin receptor antagonist is recommended for most patients with intermediate-risk pulmonary arterial hypertension (PAH). The RESPITE and REPLACE studies suggest that switching from a PDE5i to a soluble guanylate cyclase (sGC) activator may provide clinical improvement in this situation. The optimal approach to escalation or transition of therapy in this or other scenarios is not well defined. We developed an expert consensus statement on the transition to sGC and other treatment escalations and transitions in PAH using a modified Delphi process. The Delphi process used a panel of 20 physicians with expertise in PAH. Panelists answered three questionnaires on the management of treatment escalations and transitions in PAH. The initial questionnaire included open-ended questions. Later questionnaires consolidated the responses into statements that panelists rated on a Likert scale from -5 ( strongly disagree ) to +5 ( strongly agree ) to determine consensus. The Delphi process produced several consensus recommendations. Escalation should be considered for patients who are at high risk or not achieving treatment goals, by adding an agent from a new class, switching from oral to parenteral prostacyclins, or increasing the dose. Switching to a new class or within a class should be considered if tolerability or other considerations unrelated to efficacy are affecting adherence. Switching from a PDE5i to an SGC activator may benefit patients with intermediate risk who are not improving on their present therapy. These consensus-based recommendations may be helpful to clinicians and beneficial for patients when evidence-based guidance is unavailable., Competing Interests: Franck F. Rahaghi reports consultation, research, and speakership honoraria from Bayer and Janssen, consultation and speakership from United Therapeutics, and consultation fees from Acceleron. Vijay P. Balasubramanian reports a research grant from United Therapeutics and serves on a speakers bureau for Bayer. Robert C. Bourge reports research grant support to my institution from United Therapeutics and Bayer, and service on a Scientific Advisory Board at United Therapeutics. Murali M. Chakinala reports grants or contracts from Actelion/Janssen, Bayer, Medtronic, NIH, Reata, Liquidia, Phase Bio, Complexa, United Therapeutics, Altavant, Trio Health Analytics, Reata, Acceleron, Arena, and Gossamer; consulting fees from Altavant, Vaderis Therapeutics, Aerovate, Reata, VWave, and Arena; honoraria from Bayer, Gilead, Simply Speaking, WebMD, and United Therapeutics; support for attending meetings and/or travel from Actelion/Janssen, United Therapeutics, Bayer, Acceleron, Reata, and Gilead; participation on a Data Safety Monitoring Board or Advisory Board for Actelion/Janssen, Express Scripts, Phase Bio, Altavant, Gossamer, United Therapeutics, Bayer, Acceleron, and Liquidia; and leadership or a fiduciary role in the Pulmonary Hypertension Association and the Cure HHT Global Research and Medical Advisory Board. Michael S. Eggert reports research contracts with United Therapeutics (BREEZE and ADVANCE Outcomes), Acceleron, and Actelion. Jean M. Elwing reports grants from Actelion, Acceleron, Reata, United Therapeutics, Liquidia, Phase Bio, Complexa, Gossamer Bio, Bayer, Arena, Eiger, Akros, Bellerophon, and Lung LLC and consulting fees from United Therapeutics, Acceleron, Liquidia, Altavant, Bayer, Gossamer Bio, Actelion, Bayer. Jeremy Feldman reports consulting and giving talks for Bayer, United Therapeutics, and Jansen. Christopher King reports personal fees from Actelion, personal fees from Genentech, United Therapeutics, and Boehringer Ingelheim; has served on advisory boards for and is on the Speakers’ Bureau of Actelion, Boehringer‐Ingelheim Pharmaceuticals, and United Therapeutics. James R. Klinger reports that his institution receives research funding from United Technologies, service on a Steering Committee and a Clinical Outcomes Committee for Bayer, and a leadership role in the Pulmonary Hypertension Association. Stephen C. Mathai reports personal fees from United Therapeutics; participation on a data safety monitoring board or advisory board from United Therapeutics, Actelion, and Bayer, and leadership or a fiduciary role in the PCORI Rare Disease Advisory Panel and the World Symposium on Pulmonary Hypertension. John Wesley McConnell reports consulting fees from Actelion, Bayer, Gossamer, Altavant, and Liquidia; honoraria from Actelion, Bayer, Simply Speaking, Impact PH, and Reata, and participation on a data safety monitoring board or advisory board for Actelion, Liquidia, Gossamer, and Altavant. Harold I. Palevsky reports honoraria for serving on scientific advisory boards for Acceleron, Actelion/Janssen, PhaseBio and United Therapeutics, and serving on a DSMB for United Therapeutics. Ricardo Restrepo‐Jaramillo reports serving on speaker's bureau for United Therapeutics, Bayer, and Actelion. Zeenat Safdar reports serving on a speakers bureau, consultation and advisory boards for Actelion, United Therapeutics, Boehringer Ingelheim, Bayer, and Roche. Jeffrey S. Sager reports personal fees from Bayer pharmaceuticals, grants and personal fees from United Therapeutics, grants and personal fees from Janssen (J and J), and grants from Reata outside the submitted work. Namita Sood reports a speaking fee from Bayer. Roxana Sulica reports research grants from Bayer, United Therapeutics, Complexa, and Reata, and serves on advisory boards for Actelion, Bayer, United Therapeutics, and Reata. R. James White reports research grants from United Therapeutics, Reata, Bayer, Merck, and Janssen and consulting fees from Merck and Bayer. Nicholas S. Hill reports honoraria from Axon Research for this study; grants to his institution from Actelion, Bayer, Gilead, and United Therapeutics; consulting fees from United Therapeutics; and participation in Data Safety Monitoring Boards for United Therapeutics and Pfizer. All authors had access to the Delphi questionnaire analysis and data and participated in the review, revision, and approval of the content of the manuscript for submission. Charles D. Burger reports no disclosures or conflicts of interest., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Pulmonary arterial hypertension (PAH) is a progressive, ultimately fatal cardiopulmonary disease associated with a number of physiologic changes, which is believed to result in imbalances in the intestinal microbiota. To date, comprehensive investigational analysis of the intestinal microbiota in human subjects is still limited. To address this, we performed a pilot study of the intestinal microbiome in 20 PAH and 20 non-PAH healthy control subjects, recruited from a single center, with each PAH subject recruited simultaneously with a cohabitating non-PAH control subject. Shotgun metagenomic sequencing was used to analyze the microbiome profiles. There were no differences between PAH and non-PAH subjects across several measures of microbial abundance and diversity (Alpha Diversity, Beta Diversity, F/B ratio). The relative abundance of Lachnospiraceae bacterium GAM79 was lower in PAH stool samples as compared to non-PAH control subject' stool. There was no strong or reproducible association between PAH disease severity and global microbial abundance, but several bacterial species (a relative abundance of Anaerostipes rhamnosivorans and a relative deficiency of Amedibacterium intestinale , Ruminococcus bicirculans , and Ruminococcus albus species were associated with disease severity (most proximal right heart catheterization hemodynamics and six-minute walk test distance) in PAH subjects. Our results support further investigation into the presence, significance, and potential physiologic effects of a PAH-specific intestinal microbiome., Competing Interests: The authors declare that there are no conflict of interests., (© 2022 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Hepatopulmonary syndrome (HPS) is a type of pulmonary vascular disease occurring exclusively in those with underlying liver disease, associated with significant mortality in patients awaiting liver transplantation (LT). LT is curative in HPS, and these patients are granted Model for End Stage Liver Disease (MELD) exception points to expedite LT. The purpose of this study is to use multivariable competing risk Accelerated Failure Time models and propensity matching to examine the relationship between pre-LT hypoxemia and post-LT outcomes in HPS. We performed a retrospective cohort study of UNOS/OPTN database of all adult patients undergoing LT between January 1, 2006 and January 12, 2020. Pre-LT PaO 2 was significantly associated with post-LT mortality in HPS, with each 1 mmHg increase in PaO 2 significantly decreasing the risk of post-LT mortality (coefficient 0.039, HR = 0.95, p = 0.001). HPS patients with a pre-LT PaO 2 < 54 mmHg demonstrated increased mortality following LT as compared to matched non-HPS cirrhotic patients. We conclude that HPS patients with a PaO 2 , 54 mmHg are at increased risk of post-LT mortality and may identify high-risk patients who would benefit from additional resources during LT, and that the effects of HPS MELD exception points to optimize post-LT outcomes should be continuously re-evaluated., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Portopulmonary hypertension (POPH) is a pulmonary vascular disease associated with significant morbidity and mortality in those with liver disease, conferring a higher mortality in patients awaiting liver transplantation (LT). Although not a transplant indication, patients with POPH can experience significant clinical improvement following LT, and those maintaining a mean pulmonary artery pressure (MPAP) <35mm Hg and a pulmonary vascular resistance (PVR) <5 Woods units (WU) are granted additional listing points to expedite LT. The effect of POPH on posttransplant outcomes such as mortality and graft failure, however, is not well defined. We performed a retrospective cohort study of the US Organ Procurement and Transplantation Network database of all adult patients who underwent LT between January 1, 2006, and December 1, 2020. Using adjusted accelerated failure time models, we examined the relationship between a diagnosis of POPH and outcomes following LT and the relationship between pre-LT hemodynamics and post-LT survival (alive with a functioning graft) in patients with POPH. Compared with those undergoing transplants without exception points, patients with POPH had comparable post-LT survival rates but were significantly more likely to have graft failure. Both pre-LT MPAP and PVR predicted post-LT survival in POPH, with a pre-LT PVR of ≥1.6 WU, more than doubling the hazard for mortality (death or a nonfunctioning graft; coefficient, 2.01; standard error, 0.85; hazard ratio, 2.21; P = 0.02). POPH may confer a significantly higher risk of post-LT graft failure compared with patients with cirrhosis without POPH, and a pre-LT PVR of ≥1.6 WU may predict post-LT survival. Further investigation into the relationship between pre-LT hemodynamics, right ventricular function, and post-LT outcomes of mortality and graft failure in POPH is needed., (Copyright © 2021 by the American Association for the Study of Liver Diseases.)

Acute pulmonary embolism (PE) is associated with significant morbidity and mortality. The management paradigm for acute PE has evolved in recent years with wider availability of advanced treatment modalities ranging from catheter-directed reperfusion therapies to mechanical circulatory support. This evolution has coincided with the development and implementation of institutional pulmonary embolism response teams (PERT) nationwide and internationally. Because most institutions are not equipped or staffed for advanced PE care, patients often require transfer to centers with more comprehensive resources, including PERT expertise. One of the unmet needs in current PE care is an organized approach to the process of interhospital transfer (IHT) of critically ill PE patients. In this review, we discuss medical optimization and support of patients before and during transfer, transfer checklists, defined roles of emergency medical services, and the roles and responsibilities of referring and receiving centers involved in the IHT of acute PE patients., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, morbid, potentially curable subtype of pulmonary hypertension that negatively impacts health-related quality of life (HRQoL). Little is known about differences in HRQoL and hospitalization between CTEPH patients and idiopathic pulmonary arterial hypertension (IPAH) patients. Using multivariable linear regression and mixed effects models, we examined differences in HRQoL assessed by emPHasis-10 (E10) and SF-12 between CTEPH and IPAH patients in the Pulmonary Hypertension Association Registry, a prospective multicenter cohort of patients newly evaluated at a Pulmonary Hypertension Care Center. Multivariable negative binomial regression models were used to estimate incidence rate ratios (IRR) for hospitalization amongst the two groups. We included 461 IPAH patients and 169 CTEPH patients. Twenty-one percent of CTEPH patients underwent pulmonary thromboendarterectomy (PTE) before the end of follow-up. At baseline, patients with CTEPH had significantly worse HRQoL (higher E10 scores) (ß 2.83, SE 1.11, p = 0.01); however, differences did not persist over time. CTEPH patients had higher rates of hospitalization (excluding the hospitalization for PTE) compared to IPAH patients after adjusting for age, sex, body mass index, WHO functional class and six-minute walk distance (IRR 1.66, 95%CI 1.04-2.65, p = 0.03). CTEPH patients who underwent PTE had improved HRQoL as compared to those who were medically managed, but patients who underwent PTE were younger, had higher cardiac outputs and greater six-minute walk distances. In this large, prospective, multicenter cohort, CTEPH patients had significantly worse baseline HRQoL and higher rates of hospitalizations than those with IPAH. CTEPH patients who underwent PTE had significant improvements in HRQoL., (© The Author(s) 2021.)

Compared to idiopathic pulmonary arterial hypertension (IPAH), patients with portopulmonary hypertension (POPH) have worse survival. Health disparities may contribute to these differences but have not been studied. We sought to compare socioeconomic factors in patients with POPH and IPAH and to determine whether socioeconomic status and/or POPH diagnosis were associated with treatment and health-care utilization. We performed a cross-sectional study of adults enrolled in the Pulmonary Hypertension Association Registry. Patients with IPAH (n = 344) and POPH (n = 57) were compared. Compared with IPAH, patients with POPH were less likely to be college graduates (19.6% vs. 34.9%, p = 0.02) and more likely to be unemployed (54.7% vs. 30.5%, p < 0.001) and have an annual household income below poverty level (45.7% vs. 19.0%, p < 0.001). Patients with POPH had similar functional class, quality of life, 6-min walk distance, and mean pulmonary arterial pressure with a higher cardiac index. Compared with IPAH, patients with POPH were less likely to receive combination therapy (46.4% vs. 62.2%, p = 0.03) and endothelin receptor antagonists (28.6% vs. 55.1%, p < 0.001) at enrollment with similar treatment at follow-up. Patients with POPH had more emergency department visits (1.7 ± 2.1 vs. 0.9 ± 1.2, p = 0.009) and hospitalizations in the six months preceding enrollment (1.5 ± 2.1 vs. 0.8 ± 1.1, p = 0.02). Both POPH diagnosis and lower education level were independently associated with a higher number of emergency department visits. Compared to IPAH, patients with POPH have lower socioeconomic status, are less likely to receive initial combination therapy and endothelin receptor antagonists but have similar treatment at follow-up, and have increased health-care utilization., (© The Author(s) 2021.)

Rationale: Single-center studies demonstrated that methamphetamine use is associated with pulmonary arterial hypertension (Meth-APAH). We used the Pulmonary Hypertension Association Registry to evaluate the national distribution of Meth-APAH and to compare its impact on patient-reported and clinical outcomes relative to idiopathic PAH. Objectives: To determine if patients with Meth-APAH differ from those with idiopathic PAH in demographics, regional distribution in the United States, hemodynamics, health-related quality of life, PAH-specific treatment, and health care use. Methods: The Pulmonary Hypertension Association Registry is a U.S.-based prospective cohort of patients new to care at a Pulmonary Hypertension Care Center. The registry collects baseline demographics, clinical parameters, and repeated measures of health-related quality of life, World Health Organization functional class, 6-minute walk distance, therapy, and health care use. Repeated measures of functional class, health-related quality of life, type of therapy, emergency department visits, and hospitalizations were compared using generalized estimating equations. Results: Of 541 participants included, 118 had Meth-APAH; 83% of Meth-APAH arose in the western United States. The Meth-APAH group was younger and had a poorer socioeconomic status and lower cardiac index than the idiopathic PAH group, despite no difference in mean pulmonary artery pressure or pulmonary vascular resistance. The Meth-APAH group had a more advanced functional class in longitudinal models (0.22 points greater; 95% confidence interval [CI], 0.07 to 0.37) and worse PAH-specific (emPHasis-10) health-related quality of life (-5.4; 95% CI, -8.1 to -2.8). There was no difference in dual combination therapy; however, participants with Meth-APAH were less likely to be initiated on triple therapy (odds ratio [OR], 0.43; 95% CI, 0.24 to 0.77) or parenteral therapy (OR, 0.10; 95% CI, 0.04 to 0.24). Participants with Meth-APAH were more likely to seek care in the emergency department (incidence rate ratio, 2.30; 95% CI, 1.71 to 3.11) and more likely to be hospitalized (incidence rate ratio, 1.42; 95% CI, 1.10 to 1.83). Conclusions: Meth-APAH represents a unique clinical phenotype of PAH, most common in the western United States. It accounts for a notable proportion of PAH in expert centers. Assessment for methamphetamine use is necessary in patients with PAH.

Background: Pulmonary arterial hypertension is a life-limiting complication in patients with systemic sclerosis. Current recommendations suggest a minimum screening of an annual transthoracic echocardiogram and pulmonary function test. We hypothesize that modifiable provider-level hurdles contribute to inadequate screening and can be alleviated., Methods and Results: We performed a longitudinal study over 23 months of all systemic sclerosis patients seen in pulmonary and/or rheumatology clinics. Pulmonary arterial hypertension screening was measured monthly as percentage of patients with up-to-date transthoracic echocardiogram and pulmonary function test out of the total systemic sclerosis patients with an outpatient encounter that month. Tests were considered "up-to-date" if they were performed 12 months prior or within the next 6 months post-encounter. Baseline adherence to PAH screening was assessed using a 9-month preproject period. Physicians in rheumatology and pulmonary clinics were surveyed for knowledge and perceived as barriers to screening. Interventions focused on provider-level hurdles to improve the screening rate to >90%. Adherence to systemic sclerosis-associated pulmonary arterial hypertension was compared between baseline and post-intervention phases as a continuous variable using nonparametric Mann-Whitney-Wilcoxon test and as categorical variable using chi-square test for overall adherence rate. A total of 18 providers were surveyed, of which 67% knew minimal screening recommendations and 44% identified "difficulty ordering tests" as a barrier. Our interventions were as follows: (1) didactic education and literature dissemination and (2) best practice alert in the electronic medical record to facilitate just-in-time ordering of screening. Adherence was measured for 23 months, comprising 166 systemic sclerosis patients. Monthly adherence to pulmonary arterial hypertension screening increased by 10.4% (69.2%-79.6%, p  = 0.01 with chi-square and p  = 0.09 with Mann-Whitney-Wilcoxon test), with an increase in transthoracic echocardiogram by 7.5% and pulmonary function test by 4.9%., Conclusion: Provider-level hurdles contribute to sub-optimal systemic sclerosis-associated pulmonary arterial hypertension screening. Lack of knowledge and difficulty in ordering tests were major barriers. Structured education and decision-support aids improve screening. These interventions, however, were insufficient to improve screening to a goal target of >90%., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

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., (Published by Elsevier Inc.)

Purpose: Targeted treatment for pulmonary arterial hypertension (PAH), diagnosed via right heart catheterization (RHC), has been shown to improve morbidity and mortality. Identifying characteristics that predict clinical worsening has been challenging. We sought to evaluate the role of cardiac Magnetic Resonance Imaging (CMR) as a predictor of clinical worsening in a cohort of treatment-naïve pulmonary hypertension (PH) patients., Methods: We performed a retrospective single center analysis of all adults with newly diagnosed treatment-naïve PH between January 1st 2013 and January 1st 2019. Patients with World Health Organization (WHO)-Group I PAH or WHO-Group II/III PH disease, who underwent both CMR (Signa Horizon 1.5 T, General Electric, Milwaukee, WI and Siemens Espree 1.5 T, Munich, Germany) and RHC testing prior to targeted PAH treatment, were included for analysis. Cox proportional hazards models were constructed., Results: A total of 38 patients, of which 12 (32 %) experienced the primary outcome of clinical worsening. were included in the final analysis, Patients with clinical worsening were significantly more likely to have RV dysfunction by CMR (including lower RV ejection fraction (HR 0.93, p = 0.007) and more RV dilation (HR 1.02, p = 0.005-0.021)) and RHC (including worse pulmonary vascular resistance (HR 1.32, p < 0.001)), even after adjustment for disease severity. Both CMR and RHC measures of RV dysfunction were found to be equally effective in predicting clinical worsening, regardless of PH etiology., Conclusions: In treatment-naïve PH patients, including those with WHO-Group II/III disease, both CMR and RHC measures independently and significantly predicted clinical worsening, even after adjustment for disease severity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Systemic anticoagulation may be beneficial in pulmonary arterial hypertension, but there is no randomized clinical trial data to guide therapeutic decision making, and current guidelines do not account for patient preferences or quality of life. Decision analytic models to evaluate the potential risks and benefits of systemic anticoagulation in pulmonary arterial hypertension patients, focusing on the benefit in quality-adjusted life years, may be helpful in clarifying this uncertainty. We constructed a 31-state Markov decision analytic model to explore anticoagulation and no anticoagulation strategies. Modeled patient characteristics included gender, use of central catheter-based pulmonary arterial hypertension therapy, type of pulmonary arterial hypertension (idiopathic, idiopathic pulmonary arterial hypertension, or connective-tissue associated, connective tissue disease-pulmonary arterial hypertension), and use of oral contraceptive medication by females. Modeled events included mortality, thromboembolic complications, atrial fibrillation, stroke, and anticoagulation bleeding. Deterministic and probabilistic sensitivity analyses were performed. Anticoagulation was favored in all idiopathic pulmonary arterial hypertension cases, with a gain of 0.43-0.51 quality-adjusted life years, and detrimental in all connective tissue disease-pulmonary arterial hypertension cases, with a loss of 0.66-1.89 quality-adjusted life years. Anticoagulation would need to demonstrate a hazard ratio for pulmonary arterial hypertension mortality of 0.95 or better to be favored. In our model, idiopathic pulmonary arterial hypertension patients benefit from anticoagulation in terms of quality-adjusted life years, and connective tissue disease-pulmonary arterial hypertension patients were harmed, with a hazard ratio for pulmonary arterial hypertension mortality of 0.95 or better being required to favorably impact quality-adjusted life years. These results suggest that anticoagulation significantly improves quality adjusted life years and should be offered to all idiopathic pulmonary arterial hypertension patients. Shared decision models based on these results may help clarify therapeutic decision-making uncertainty in pulmonary arterial hypertension patients., (© The Author(s) 2019.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive pulmonary vascular disease with significant morbidity. It is a result of an alternate natural history in which there is limited resolution of thromboemboli with pulmonary artery obstruction leading to pulmonary hypertension (PH). CTEPH requires a thorough clinical assessment including pulmonary hemodynamics and radiologic evaluation in addition to consultation with an expert center. Surgical intervention remains the optimal management strategy. Select patients may be candidates for catheter-based intervention with balloon pulmonary angioplasty in centers with clinical expertise. Inoperable patients or those with post-intervention PH are treated with pulmonary hypertension-targeted medical therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Oral treprostinil was recently labeled for treatment of pulmonary arterial hypertension. Similar to the period immediately after parenteral treprostinil was approved, there is a significant knowledge gap for practicing physicians who might prescribe oral treprostinil. Despite its oral route of delivery, use of the drug is challenging because of the requirement for careful titration and management of drug-related adverse effects. We aimed to create a consensus document combining available evidence with expert opinion to provide guidance for use of oral treprostinil. Following a methodology commonly used in business and social sciences (the 'Delphi Process'), two investigators from the oral treprostinil (Freedom) studies created a series of statements based on available evidence and the package insert. The set of 'best practice' statements was circulated to nine other Freedom trial investigators. Their comments were incorporated into the document as new line items for further vote and comment. The subsequent document was put to vote line by line (scale of -5 to +5) and a final statement was drafted. Consensus recommendations include initial therapy with 0.125 mg for treatment naÿ patients, three times daily dosing, aggressive use of antidiarrheal medication, and a strong preference for use of the drug in combination with other approved PAH therapies. This process was particularly valuable in providing guidance for the management of adverse events (where essentially no data is available). The Delphi process was useful to codify investigator experience and subsequently develop investigator consensus about practical issues for physicians who may wish to prescribe oral treprostinil.

Background: Pulmonary hypertension (PH) is associated with increased morbidity across the cardiopulmonary disease spectrum. Based primarily on expert consensus opinion, PH is defined by a mean pulmonary artery pressure (mPAP) ≥25 mm Hg. Although mPAP levels below this threshold are common among populations at risk for PH, the relevance of mPAP <25 mm Hg to clinical outcome is unknown., Methods and Results: We analyzed retrospectively all US veterans undergoing right heart catheterization (2007-2012) in the Veterans Affairs healthcare system (n=21,727; 908-day median follow-up). Cox proportional hazards models were used to evaluate the association between mPAP and outcomes of all-cause mortality and hospitalization, adjusted for clinical covariates. When treating mPAP as a continuous variable, the mortality hazard increased beginning at 19 mm Hg (hazard ratio [HR]=1.183; 95% confidence interval [CI], 1.004-1.393) relative to 10 mm Hg. Therefore, patients were stratified into 3 groups: (1) referent (≤18 mm Hg; n=4,207); (2) borderline PH (19-24 mm Hg; n=5,030); and (3) PH (≥25 mm Hg; n=12,490). The adjusted mortality hazard was increased for borderline PH (HR=1.23; 95% CI, 1.12-1.36; P<0.0001) and PH (HR=2.16; 95% CI, 1.96-2.38; P<0.0001) compared with the referent group. The adjusted hazard for hospitalization was also increased in borderline PH (HR=1.07; 95% CI, 1.01-1.12; P=0.0149) and PH (HR=1.15; 95% CI, 1.09-1.22; P<0.0001). The borderline PH cohort remained at increased risk for mortality after excluding the following high-risk subgroups: (1) patients with pulmonary artery wedge pressure >15 mm Hg; (2) pulmonary vascular resistance ≥3.0 Wood units; or (3) inpatient status at the time of right heart catheterization., Conclusions: These data illustrate a continuum of risk according to mPAP level and that borderline PH is associated with increased mortality and hospitalization. Future investigations are needed to test the generalizability of our findings to other populations and study the effect of treatment on outcome in borderline PH., (© 2016 American Heart Association, Inc.)

Systemic sclerosis is a rare autoimmune disorder with a wide spectrum of clinical manifestations and a multitude of autoantibodies that are associated with it. In the past several years, advances in serologic testing have led to research indicating important prognostic and phenotypic associations with certain subsets of autoantibodies. In particular, anti-RNA polymerase III (anti-RNAP III) has been associated with diffuse cutaneous disease, scleroderma renal crisis, a temporal relationship with malignancy, myositis, synovitis, joint contractures, and gastric antral vascular ectasia. However, anti-RNAP III has not been associated with systemic sclerosis sine scleroderma. We describe a patient with an atypical presentation of anti-RNAP III positive systemic sclerosis sine scleroderma who presented without the typical features of anti-RNAP III disease. Instead, she presented with critical digital ischemia, pulmonary arterial hypertension, gastroesophageal reflux disease, interstitial lung disease, and no clinically detectable sclerodactyly.

PH occurs alone or in association with many disorders. Many patients with transthoracic echocardiography (TTE) findings suggesting PH never receive additional evaluation. Patient characteristics and echocardiographic data associated with increased recognition of PH have not been fully evaluated. We evaluated TTE reports at the Cincinnati Veterans Affairs Medical Center from 2005 to 2006 retrospectively for findings highly indicative of PH: Estimated systolic pulmonary artery pressure (sPAP) ≥40 mmHg, increased right atrial or right ventricular (RV) size, or reduced RV function. Only patients with left ventricular ejection fraction (LVEF) ≥50% and no known diagnosis of PH were included. Patient characteristics, TTE findings, provider recognition rates, and subsequent referral for additional evaluation were assessed. A total of 227 of 3,960 (5.7%) TTE reports revealed findings indicating possible PH. Providers acknowledged possible PH in 53 (23.4%) reports. Recognized PH was predicted by increased RV size (odds ratio (OR) = 5.07, P < 0.001), increased right atrial dimension (OR = 6.45, P < 0.001), decreased RV function (OR = 8.86, P < 0.001), and increased PAP (OR = 1.04 corresponding to each unit increase of PAP, P < 0.01). Patients with comorbid obstructive sleep apnea (OSA), interstitial lung disease, and dyspnea were also more likely to be recognized (OR = 3.63, P = 0.021; OR = 10.98, P = 0.004; OR = 2.39, P = 0.007, respectively). The 12-month mortality rate for recognized patients, 11.3% (7/53), was lower than for unrecognized patients, 25.3% (44/174; P = 0.03). Providers recognized less than one in four patients with echocardiographic evidence suggesting PH. Echocardiography reports revealing higher PAP and right heart dilation and dysfunction are associated with increased acknowledgement of possible PH.

Dynamic appearance of intrapulmonary arteriovenous fistula (AVF) during exercise may be associated with unexplained exertional dyspnea (UED) and can be diagnosed with an agitated saline contrast study during exercise echocardiography. However, the occurrence of AVF during exercise in patients with UED has not been well described. Thus, the frequency of exercise-induced intrapulmonary AVF in the outpatients with UED was retrospectively analyzed. Thirty-nine outpatients (age: 53 ± 12, 33 female) with UED underwent symptom-limited supine bicycle exercise echocardiography. Ten patients (26%) developed exercise-induced intrapulmonary AVF. Patients with and without AVF showed the similar peak exercise heart rate, systolic blood pressure, and rate-pressure product. The patients with AVF demonstrated a small but significant decrease in arterial oxygen saturation with exercise as compare to baseline (95.6 ± 2.8% at peak, vs. 97.5 ± 2.5% at baseline, P < 0.05 with a paired Student t-test). Our study suggests that exercise-induced intrapulmonary AVF is relatively common in the outpatients with UED and associated with mild exercise desaturation; however, the mechanism of desaturation could not be determined by this study. Further investigation to characterize and determine the clinical significance of AVF is warranted., (© 2010, Wiley Periodicals, Inc.)

Although most late complications after lung transplantation are related to chronic rejection, airway anastomotic disease cannot be overlooked as a substantial contributor to morbidity and mortality. A rare, but nearly universally fatal example of anastomotic disease is fistula formation with the vascular system. Reports of fistula formation between the respiratory tree and the vascular system are not uncommon, but in the lung transplant population, specifically, only scattered case reports exist. Here we describe 3 cases of bronchovascular fistula formation after lung transplantation, with a review of the literature and exploration of possible risk factors, diagnostic techniques, and treatment modalities.

Background: Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling., Methods: We conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed tomography of lung cysts, and pulmonary-function tests were performed., Results: Of the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean (+/-SD) angiomyolipoma volume at 12 months was 53.2+/-26.6% of the baseline value (P<0.001) and at 24 months was 85.9+/-28.5% of the baseline value (P=0.005). At 24 months, five patients had a persistent reduction in the angiomyolipoma volume of 30% or more. During the period of sirolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 second (FEV1) increased by 118+/-330 ml (P=0.06), the forced vital capacity (FVC) increased by 390+/-570 ml (P<0.001), and the residual volume decreased by 439+/-493 ml (P=0.02), as compared with baseline values. One year after sirolimus was discontinued, the FEV1 was 62+/-411 ml above the baseline value, the FVC was 346+/-712 ml above the baseline value, and the residual volume was 333+/-570 ml below the baseline value; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections., Conclusions: Angiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after the therapy was stopped. Some patients with lymphangioleiomyomatosis had improvement in spirometric measurements and gas trapping that persisted after treatment. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808.), (2008 Massachusetts Medical Society)

Receptor-mediated airway smooth muscle (ASM) contraction via G(alphaq), and relaxation via G(alphas), underlie the bronchospastic features of asthma and its treatment. Asthma models show increased ASM G(alphai) expression, considered the basis for the proasthmatic phenotypes of enhanced bronchial hyperreactivity to contraction mediated by M(3)-muscarinic receptors and diminished relaxation mediated by beta(2)-adrenergic receptors (beta(2)ARs). A causal effect between G(i) expression and phenotype has not been established, nor have mechanisms whereby G(i) modulates G(q)/G(s) signaling. To delineate isolated effects of altered G(i), transgenic mice were generated overexpressing G(alphai2) or a G(alphai2) peptide inhibitor in ASM. Unexpectedly, G(alphai2) overexpression decreased contractility to methacholine, while G(alphai2) inhibition enhanced contraction. These opposite phenotypes resulted from different crosstalk loci within the G(q) signaling network: decreased phospholipase C and increased PKCalpha, respectively. G(alphai2) overexpression decreased beta(2)AR-mediated airway relaxation, while G(alphai2) inhibition increased this response, consistent with physiologically relevant coupling of this receptor to both G(s) and G(i). IL-13 transgenic mice (a model of asthma), which developed increased ASM G(alphai), displayed marked increases in airway hyperresponsiveness when G(alphai) function was inhibited. Increased G(alphai) in asthma is therefore a double-edged sword: a compensatory event mitigating against bronchial hyperreactivity, but a mechanism that evokes beta-agonist resistance. By selective intervention within these multipronged signaling modules, advantageous G(s)/G(q) activities could provide new asthma therapies.