PHA 2022 International Pulmonary Hypertension Conference Abstracts

Lily M. Landry

Department of Pediatrics, Division of Pediatric Cardiology University of Mississippi Medical Center, Jackson, MS, USA

Andrew C. Burks

School of Medicine, University of Mississippi Medical Center, Jackson, MS, USA

Onyekachukwu Osakwe

Department of Pediatrics, Division of Pediatric Cardiology, University of Mississippi Medical Center, Jackson, MS, USA

Jarrod D. Knudson

Department of Pediatrics, Division of Pediatric Critical Care, University of Mississippi Medical Center, Jackson, MS, USA

Christopher L. Jenks

Department of Pediatrics, Division of Pediatric Critical Care, University of Mississippi Medical Center, Jackson, MS, USA

Category: Clinical Science

Selected Areas: Pediatrics, Therapeutic Strategies

Background: Pulmonary hypertension (PH) is a rare and potentially fatal disease in children if left untreated. Emerging therapies, including bosentan, a dual endothelin receptor antagonist (ERA), have shown significant benefits in the adult PH population; however, few studies have assessed the efficacy and safety of ERAs in infants and young children.

Methods: Our study was a single-center retrospective analysis of patients <2 years of age with a confirmed diagnosis of PH and started on bosentan therapy between 2017 and 2020. Twelve cases met eligibility criteria. Demographic (Table 1), laboratory, echocardiographic, and cardiac catheterization data were analyzed (Tables 2–4).

Results: With treatment, there was a statistically significant decrease in mean right ventricular systolic pressure estimated by the tricuspid regurgitation jet (79 ± 23 mm Hg reduced to 52 ± 25 mm Hg; P value <0.001) and pro-brain natriuretic peptide levels (21 071 reduced to 2037; P < 0.001). Additionally, improvement and eventual normalization of right ventricular function and septal geometry was seen within the first 4 months of therapy (Figure). Patients who underwent cardiac catheterization after therapy initiation (n = 4) demonstrated hemodynamic improvements; however, only the decrease in diastolic pulmonary pressure was statistically significant (P value = 0.018). No significant difference in hemoglobin, platelet count, or liver function tests was observed between groups.

Conclusions: In conclusion, these data suggest that bosentan may be an effective and relatively safe treatment option for children <2 years of age with PH. Further long-term randomized control studies are necessary to validate the potential clinical benefit of using this drug therapy in young children.

Essam Ibrahim

Janssen Inc., Toronto, Ontario, Canada

Assem Al-Akabawi

Janssen Inc., Toronto, Ontario, Canada

Moses Dawodu

Janssen Inc., Toronto, Ontario, Canada

Juejing Ling

IQVIA Solutions Canada Inc., Kirkland, Quebec, Canada

Irene Wang

IQVIA Solutions Canada Inc., Kirkland, Quebec, Canada

Brad Millson

IQVIA Solutions Canada Inc., Kirkland, Quebec, Canada

Category: Clinical Science

Selected Areas: Databases and Registries

Background: The current standard of care for pulmonary arterial hypertension (PAH) is combination therapy, which imposes pill burden on PAH patients who live with multiple comorbidities. This study aims to understand the concomitant medication use in treatment journey of Canadian PAH patients.

Methods: Patients initiating PAH therapy (index) from September 1, 2016, to August 31, 2019, were selected in the Ontario Drug Benefits (ODB), Régie de l’assurance maladie du Québec (RAMQ), and IQVIA Canadian Private Drug Plan (PDP) databases. Medication prescriptions 5-year prior and 1-year postindex were tracked. Concomitant medication analysis used ODB and PDP; prescriber specialty analysis used PDP database.

Results: A total of 1019 patients were included from ODB (N = 481), PDP (N = 422), and RAMQ (N = 116). Tadalafil (61%) and sildenafil (22%) were most prescribed at index. One year prior to index, 75% and 30% of patients with concomitant medications (N = 828) were on 5+ and 10+ concomitant medication classes, respectively. From 5 years prior to the 1-year postindex, the proportion of cardiovascular medications use declined (16% versus 13%), while that of diuretics use increased (10% versus 16%). Compared with the year prior, prescriptions of rescue treatment decreased 1 year postindex (926 versus 763). Here, 72% of patients (N = 300) were prescribed by general practitioner (GP) before index, while prescribers of cardiovascular and respiratory medications shifted from GP to specialist postindex. Among the top 3 prescribers, females had a significant reduction in the number of concomitant medications postindex, while males trended the opposite way.

Conclusions: This study shows the complex treatment journey of Canadian PAH patients and highlights the need to reduce pill burden and improve disease management.

Essam Ibrahim

Janssen Inc., Toronto, Ontario, Canada

Assem Al-Akabawi

Janssen Inc., Toronto, Ontario, Canada

Moses Dawodu

Janssen Inc., Toronto, Ontario, Canada

Juejing Ling

IQVIA Solutions Canada Inc., Kirkland, Quebec, Canada

Jillian Murray

IQVIA Solutions Canada Inc., Kirkland, Quebec, Canada

Brad Millson

IQVIA Solutions Canada Inc., Kirkland, Quebec, Canada

Category: Clinical Science

Selected Areas: Databases and Registries

Background: Treatment guidelines for pulmonary arterial hypertension (PAH) recommend combination therapy in most patients. This study evaluated retention of PAH drugs and time-to-initiation of combination drug therapy with macitentan and selexipag in Canada.

Methods: Patients claiming PAH drugs from January 2017 to March 2021 were identified in the Ontario Drug Benefits (ODB), Régie de l’assurance maladie du Québec (RAMQ), and IQVIA Canadian Private Drug Plan (PDP) databases. Drug retention was calculated for patients submitting claims 12 months following treatment index (March 2019 to February 2020 [PDP, ODB]; January to December 2019 [RAMQ]). Treatment was considered first line if patients were treatment naïve with >180 days of claims history. Time-to-initiation of combination therapy was calculated for macitentan+PDE5i and selexipag-containing therapies.

Results: Around 2150 patients claimed PAH drugs annually, with averages of 1000 (PDP), 900 (ODB), and 250 (RAMQ). Most patients were female (65%–77%) and aged 45+ years (69%–85%). The 12-month retention was greatest for macitentan in PDP (67%) and RAMQ (88%), and tadalafil (78%) in ODB. Of patients on macitentan or selexipag, approximately 79% and 95% were on combination therapy (2+ drugs) in 2020, respectively. In 2020, 12%–17% of patients were on macitentan combination therapy (3+ drugs), and 43%–69% were on selexipag combination therapy (3+ drugs). In 2020, mean time-to-initiation was 4–5 months for macitentan+PDE5i and 17–23 months for selexipag-containing therapies (Table).

Conclusions: Real-world data from Canada shows that most PAH patients on macitentan or selexipag are on combination therapies. Time-to-initiation was 4–5 months for macitentan+PDE5i, and 17–23 months for selexipag-containing combination therapies. This study shows the complex treatment journey of Canadian PAH patients and highlights the need to reduce pill burden and improve disease management.

Roxana Sulica

Pulmonary Critical Care and Sleep Division, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA

Stacy Mandras

AdventHealth Transplant Institute, Orlando, FL, USA

Chad Miller

Piedmont Physicians, Pulmonary Hypertension/Pulmonary Critical Care Medicine, Piedmont Healthcare, Austell, GA, USA

R. James White

University of Rochester Medical Center, Rochester, NY, USA

Nick H. Kim

Division of Pulmonary and Critical Care Medicine, University of California San Diego, La Jolla, CA, USA

Sameer Bansilal

Bayer US, LLC, Whippany, NJ, USA

Vicki Poon

Bayer US, LLC, Whippany, NJ, USA

Daniel Johnson

Bayer US, LLC, Whippany, NJ, USA

Valerie Carvajal

Bayer US, LLC, Whippany, NJ, USA

Murali Chakinala

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University at Barnes-Jewish, St. Louis, MO, USA

Category: Clinical Science

Selected Areas: Databases and Registries, Quality of Life, Therapeutic Strategies

Background: Initial pulmonary arterial hypertension (PAH) treatment has evolved from monotherapy to combinations of approved drug classes. Riociguat was approved for PAH based on the PATENT study, which studied it as monotherapy or in sequential combination with an endothelin receptor antagonist (ERA) or nonparenteral prostanoid. PATENT and REPLACE gave substantial data on riociguat combinations, but there are no US-based registry data on riociguat.

Methods: ROAR (NCT04813926; funder: Bayer US, LLC) is a US-based, multicenter, prospective, observational registry of adults with PAH who are riociguat-naïve or who initiated riociguat 90 days previously. Data will be collected at standard-of-care visits (usually every 3–6 months) for 24 months or until 30 days after discontinuing riociguat. Planned enrollment: 500 patients (~50 sites). The primary objective is to study safety and effectiveness of riociguat as first-line therapy or combined with an ERA and/or prostanoid. Secondary objectives include safety and effectiveness of first-line riociguat versus transition from a phosphodiesterase-5 inhibitor, and the importance of treatment sequence. Effectiveness outcomes include change from baseline to months 6 and 12 in 6-minute walk distance, biomarkers, clinical PAH risk scores, hemodynamics (right heart catheterization), echocardiography, laboratory tests, and New York Heart Association and World Health Organization functional class. Patient-reported outcomes will be assessed at baseline, month 6, and month 12. Primary safety endpoints are incidence of selected adverse events and serious adverse events through 24 months. ROAR began recruitment in July 2021.

Results: By January 13, 2022, 35 patients were enrolled.

Conclusions: Interim baseline data will be presented.

Sandeep Sahay

Houston Methodist Hospital, Houston, TX, USA

Elizabeth Aselage

Gossamer Bio, Inc., San Diego, CA, USA

David F. Harris

Insight & Measurement, LLC, Durham, NC, USA

Marie Mascia-Rand

Project Breathless, Princeton, NJ, USA

Rob Roscigno

Gossamer Bio, Inc., San Diego, CA, USA

Erin Elman

Gossamer Bio, Inc., San Diego, CA, USA

Stephen C. Mathai

Johns Hopkins University School of Medicine, Baltimore, MD, USA

Category: Clinical Science

Selected Areas: Databases and Registries

Background: Ongoing trials of therapies targeting drivers of disease are key to improving outcomes in patients with pulmonary arterial hypertension (PAH), but enrollment is challenging. Factors affecting enrollment in PAH trials are not well characterized. We conducted a survey to identify factors that encourage or discourage trial participation by PAH patients.

Methods: A survey was administered through Rare Patient Voice, an online platform used by >100 000 patients and caregivers, to gather demographics, trial considerations, and preferences for health care provider (HCP) communication. Eligible participants were >21 years old, treated with 1 PAH medication, had a self-reported PAH diagnosis for 6 months, and had never participated in a clinical trial. The protocol was approved by a central institutional review board, and participants provided informed consent.

Results: One hundred two patients completed the survey. Average age was 51.4 years, average time from PAH diagnosis was 8.3 years, and 69% reported stable disease. Fifty-three percent and 37% of respondents were very interested and somewhat interested in trial participation, respectively, yet 75% reported not having a discussion about trial participation with HCPs. Over 90% reported they would welcome such a discussion. Factors encouraging trial participation are summarized (Figure).

Conclusions: While PAH patients are interested in clinical trial enrollment, awareness regarding trial opportunities is lacking. Other barriers to participation include concerns regarding maintenance of current therapy and providers and a desire to continue study drug after trial completion. Further education is needed for patients and clinicians to encourage trial participation.

Janice E. Heffernan

Rush University College of Nursing, Northwestern Memorial Hospital Pulmonary Department, Chicago, IL, USA

Jacquelynne Messinger

Formerly Bluhm Cardiovascular Institute, Pulmonary Vascular Disease Program, Chicago, IL, USA

Michael J. Cuttica

Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

Ruben Mylvaganam

Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

David Pugh

Pulmonary Vascular Disease Program, Northwestern Medicine, Chicago, IL, USA

Yasmin Raza

Bluhm Cardiovascular Institute, Feinberg School of Medicine, Northwestern University, Feinberg School of Medicine, Northwestern Medicine, Chicago, IL, USA

Ambalavanan Arunachalam

Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

Category: Clinical Science

Selected Areas: Therapeutic Strategies

Background: The most recent pulmonary arterial hypertension (PAH) guidelines stress the importance of multiparameter risk assessments to classify disease severity and guide management decisions. However, formal risk assessment tools are often underused in clinical practice, leading to missed opportunities to escalate pharmacotherapy and other supportive measures, which may prevent clinical deterioration.

Methods: A retrospective chart review was conducted to understand the frequency of risk assessment documentation at a large pulmonary hypertension (PH) specialty clinic. Electronic medical record (EMR) modifications, including a REVEAL 2.0 flowsheet and quick text, were implemented to support provider use of a formal risk assessment tool. An education session for providers focused on the new EMR features and the collection of key variables necessary for accurate risk assessments. A separate training for medical assistants reviewed the organization’s 6-minute walk test (6MWT) protocol. Throughout the project period, audit and feedback cycles were used to measure and communicate progress toward outcome objectives.

Results: During the 4-month implementation period, documentation of risk assessments improved from 22% to 88%. The percent of patients with a 6MWT documented in the previous 6 months increased from 26% to 67%. The collection of brain natriuretic peptide values and pulmonary fitness tests also improved (Figures 1 and 2).

Conclusions: EMR integration of a preferred risk assessment tool paired with evidence-based quality improvement methods is an effective strategy to increase provider use of PAH risk assessments in a real-world setting. More research is needed to understand how this increased collection of risk assessments affects management decisions. The effects of risk stratification on the selection and timing of pharmacotherapy is of particular interest.

Anam Pyakurel, MBBS

Pulmonary Hypertension Association Nepal, Urlabari, Nepal Civil Service Hospital, Kathmandu, Nepal

Sahadev Bidari, MBBS

Pulmonary Hypertension Association Nepal, Urlabari, Nepal Greencity Hospital, Kathmandu, Nepal

Prasansha Thapa, MBBS

Pulmonary Hypertension Association Nepal, Urlabari, Nepal Birat Nursing Home, Biratnagar, Nepal

George Bush Jung Katwal, MBBS

Pulmonary Hypertension Association Nepal, Urlabari, Nepal Annapurna Neurological Institute And Allied Sciences, Kathmandu, Nepal

Chooda M. Khanal, PhD

Pulmonary Hypertension Association Nepal, Miami, FL Florida International University, Miami, FL

Lava Timsina, PhD

Pulmonary Hypertension Association Nepal, Miami, FL Indiana University, Indianapolis, IN

Roshan Khatiwada, MBBS

Pulmonary Hypertension Association Nepal, Miami, FL Himal Hospital, Kathmandu, Nepal

Category: Case Report

Selected Areas: Diagnosis or Screening and Physiologic Studies; Diseases and Conditions Associated with PH; Quality of Life

Background: Congenital heart defects (CHDs) are the most common types of birth defects (1% of births per year in the United States). Among babies with CHD, 1 in 4 presents critical CHD with a need for surgery in infancy. In this study, we highlight the importance of screening camp and early intervention in pulmonary arterial hypertension (PAH) cases secondary to CHDs in rural settings of Nepal.

Methods: Series of comprehensive cardiac screening camps were conducted in different parts of rural Nepal. In this paper, we present clinical symptoms, diagnosis, surgical management, and follow-up outcomes of 2 PAH cases secondary to CHD who were screened at one of the cardiac camps and referred to and reevaluated in tertiary cardiac centers.

Results: The first case of an 11-year-old female who was referred from the screening camp was managed surgically in 37 days of screening, had a favorable outcome, and was doing well during follow-up, whereas the second case of a 22-year-old male managed surgically after 9 months of screening had an unfavorable outcome of death on the first postoperative day. The difference in time to surgical management in both cases was attributed to several factors: patient’s age, awareness and their socioeconomic factors, and clinical heterogeneity in consensus recommendation and practices in government facilities in Nepal.

Conclusions: Cardiac screening camp in rural settings of developing countries like Nepal may help in early diagnosis and prevention of cardiac related morbidity and mortality. Early diagnosis and hence management of CHD facilitated through cardiac screening camp can save many more lives of children living with CHDs if conducted effectively with continuity of care at regular follow-up intervals.

Jack Li

Gossamer Bio, Inc., San Diego, CA, USA

Matt Cravets

Gossamer Bio, Inc., San Diego, CA, USA

Emanuel DeNoia

ICON Clinical Research, LLC, Gaithersburg, MD, USA

Debbie Slee

Gossamer Bio, Inc., San Diego, CA, USA

Lawrence S. Zisman

Gossamer Bio, Inc., San Diego, CA, USA

Category: Clinical Science

Selected Areas: Therapeutic Strategies

Background: Seralutinib is an inhaled small-molecule kinase inhibitor specifically developed for the treatment of pulmonary arterial hypertension (PAH), with an optimized kinase specificity profile that targets PDGFRa/β, CSF1R, and c-KIT, and modulates BMPR2. Targeting these pathways may reverse pulmonary vascular inflammation, cellular proliferation, and fibrosis. In addition, by directly targeting the diseased lung, inhaled seralutinib limits systemic exposure. Based on in vitro predictions and given that multi-agent regimens are often required in treating PAH, we evaluated the potential for drug-drug interactions (DDIs) with inhaled seralutinib.

Methods: Twenty-four healthy adults received a cocktail of probe substrates: caffeine (CYP1A2), montelukast (CYP2C8), flurbiprofen (CYP2C9), midazolam (CYP3A), digoxin (P-gp), and pravastatin (OATP1B1/1B3) with or without seralutinib. Pharmacokinetics and safety were evaluated.

Results: Geometric least square mean ratios for Cmax and AUC of probe substrates with and without seralutinib are shown. Seralutinib is a moderate CYP3A inhibitor per the effect on midazolam (Figure).

Conclusions: Based on the moderate effect, seralutinib is not expected to cause clinically relevant DDIs with most PAH drugs that are CYP3A substrates (tadalafil, riociguat, bosentan, and macitentan); these drugs may be co-administered without dose modification. In the case of sildenafil, dose adjustments should be considered based on risk-benefit assessment. In addition, clinically relevant DDIs with substrates of CYP1A2, CYP2C8, CYP2C9, CYP2C19, P-gp (except for digoxin), or OATP1B1/1B3 are not anticipated. Seralutinib was well tolerated with or without co-administered agents.

Robin Osterhout

Gossamer Bio, Inc., San Diego, CA, USA

Kristin B. Highland

Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA

Robert P. Frantz

Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA

David Nickle

Gossamer Bio, Inc., San Diego, CA, USA

John McConnell

Norton Pulmonary Specialists, Louisville, KY, USA

Charles D. Burger

Division of Pulmonary, Allergy, and Sleep Medicine, Mayo Clinic, Jacksonville, FL, USA

Robert F. Roscigno

Gossamer Bio, Inc., San Diego, CA, USA

Matt Cravets

Gossamer Bio, Inc., San Diego, CA, USA

Ramona McCaffrey

Gossamer Bio, Inc., San Diego, CA, USA

Jack Li

Gossamer Bio, Inc., San Diego, CA, USA

Lawrence S. Zisman

Gossamer Bio, Inc., San Diego, CA, USA

Jean-Marie Bruey

Gossamer Bio, Inc., San Diego, CA, USA

Luke S. Howard

Imperial College Healthcare NHS Trust, London, UK

Category: Clinical Science

Selected Areas: Therapeutic Strategies

Background: Seralutinib is an inhaled small-molecule kinase inhibitor which selectively targets PDGFRa/β, CSF1R, and c-KIT signaling implicated in pulmonary arterial hypertension (PAH) pathobiology. An approximately 30× higher lung than plasma exposure and extended lung target engagement (TE) in preclinical studies suggest that pharmacodynamic activity in the human lung is expected at the dose levels studied. We evaluated changes in exploratory peripheral biomarkers of TE and mechanism of action in PAH subjects.

Methods: In a phase 1b multicenter, randomized, placebo-controlled study, subjects with PAH were randomized 3:1 to receive inhaled seralutinib up to 90 mg BID or placebo for 14 days. Whole blood and serum samples were collected at screening and day 14 for biomarker analysis: pretreatment, 5 minutes, and 2 hours posttreatment. A novel whole blood CSF1R internalization assay was developed to assess TE. Epi-genetic immunoprofiling assays and RNAseq were performed.

Results: Eight subjects received seralutinib (n = 6) or placebo (n = 2). Seralutinib was well tolerated at doses up to 90 mg BID. Seralutinib inhibited CSF1R internalization at 5 minutes but not 2 hours postinhalation relative to baseline, consistent with its short half-life in peripheral circulation. Transcriptomics data at day 14 identified treatment-associated shifts in 779 genes. An epigenetic signal suggestive of increasing FOXP3+ Tregs:CD4+ T cells following treatment was also observed.

Conclusions: Preliminary biomarker findings support TE and downstream effects in the periphery that suggest target modulation by seralutinib in PAH patients. Seralutinib is being evaluated as a new treatment for patients with PAH receiving standard of care (SOC) background therapies in a recruiting phase 2 study (NCT04456998).

Robert P. Frantz

Mayo Clinic, Rochester, MN, USA

Luke S. Howard

Imperial College Healthcare NHS Trust, London, UK

Vallerie V. McLaughlin

University of Michigan, Ann Arbor, MI, USA

Olivier Sitbon

Université Paris-Saclay, Le Kremlin-Bicêtre, France

Roham T. Zamanian

Stanford University, Menlo Park, CA, USA

Raymond L. Benza

Ohio State University, Columbus, OH, USA

Kelly Chin

UT Southwestern Medical Center, Dallas, TX, USA

Richard Channick

UCLA Medical Center, Los Angeles, CA, USA

Matt Cravets

Gossamer Bio, Inc., San Diego, CA, USA

Jean-Marie Bruey

Gossamer Bio, Inc., San Diego, CA, USA

Erin Elman

Gossamer Bio, Inc., San Diego, CA, USA

Robert Roscigno

Gossamer Bio, Inc., San Diego, CA, USA

David Mottola

Gossamer Bio, Inc., San Diego, CA, USA

Lawrence S. Zisman

Gossamer Bio, Inc., San Diego, CA, USA

Hossein-Ardeschir Ghofrani

Justus-Liebig University Giessen, Giessen, Germany

Category: Clinical Science

Selected Areas: Therapeutic Strategies

Background: Seralutinib is a potent, clinical-stage kinase inhibitor for treatment of patients with pulmonary arterial hypertension (PAH). It selectively targets PDGFRa/β, CSF1R, and c-KIT signaling implicated in PAH pathobiology, and modulates BMPR2. Seralutinib is delivered with a discreet, hand-held dry powder inhaler to directly target the diseased lung to limit systemic exposure and thereby potentially improve efficacy and tolerability. A phase 2 study is ongoing (TORREY; NCT04456998).

Methods: TORREY is a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of inhaled seralutinib in adult subjects with World Health Organization Group 1 pulmonary hypertension (PH). Patients with Functional Class II or III PAH on therapy with a pulmonary vascular resistance (PVR) ≥400 dyn·s/cm⁵ are eligible. The planned treatment period is 24 weeks, with a target enrollment of 80 patients. The primary endpoint is change in PVR measured by right heart catheterization from baseline to 24 weeks. The key secondary endpoint is change in 6-minute walk test (6MWT) from baseline to 24 weeks. Two substudies will explore novel endpoints. In the heart rate monitoring substudy, the effect of seralutinib on cardiac effort during 6MWT will be assessed. The computerized tomography substudy will examine the effect of seralutinib on pulmonary vascular remodeling by quantifying changes in pulmonary arterial blood volume. Exploratory biomarkers will be evaluated for target engagement and response to treatment.

Conclusions: This abstract was previously presented at the ISHLT2021 Annual Meeting and Scientific Sessions (Frantz et al., J Heart Lung Transplant. 2021;40(4 Suppl):S107. doi:10.1016/j.healun.2021.01.346).

Rosemarie Gadioma, ANP

New York Presbyterian Weill Cornell, New York City, NY, USA

Category: Case Report

Selected Areas: Diseases and Conditions Associated with PH

Background: Portopulmonary hypertension is pulmonary arterial hypertension (PAH) in portal hypertension. Pulmonary hypertension (PH) is classified in five groups: Group 1 is PAH with several etiologies including idiopathic, heritable PAH, collagen vascular disease, congenital heart disease, HIV, drugs, or portopulmonary hypertension. Group 2 is PH owing to left heart disease. Group 3 is PH owing to lung disease. Group 4 is chronic thromboembolic PH (CTEPH). Group 5 is miscellaneous cause of PH.

Methods: Portal hypertension develops in the setting of cirrhosis, extrahepatic portal vein thrombosis, or schistosomiasis. This results in the resistance to portal blood flow leading to complications such as ascites and variceal bleed. Portopulmonary hypertension affects up to 6% of patients with advanced liver disease.

Results: (Case) A 66-year-old woman with newly diagnosed PH World Symposia on Pulmonary Hypertension Group 1 with history of chronic Hepatitis C (HCV; status post Epclusa February through August 2020) and alcohol-related cirrhosis complicated by ascites and hepatopulmonary syndrome, hypertension, and diabetes type 2 was being evaluated for liver transplant. She had an echocardiogram which showed moderate PH. She was then referred after cardiac catheterization which showed systemic level PH. She was started on AMBITION medications with subsequent severe migraine headaches. She had gained fluid weight and was then admitted for further management.

Karim El-Kersh

University of Nebraska Medical Center, Omaha, NE, USA

Hilary DuBrock

Mayo Clinic, Rochester, MN, USA

Stephen Mathai

Johns Hopkins University School of Medicine, Baltimore, MD, USA

Melisa Wilson

AdventHealth, Orlando, FL, USA

Stephanie Hwang

University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC, USA

Scott Seaman

United Therapeutics Corporation, Research Triangle Park, NC, USA

Meredith Broderick

United Therapeutics Corporation, Research Triangle Park, NC, USA

Kristin Highland

Cleveland Clinic, Cleveland, OH, USA

Category: Clinical Science

Selected Areas: Databases and Registries, Diagnosis or Screening and Physiologic Studies, Diseases and Conditions Associated with PH

Background: The World Health Organization Functional Classification (WHO-FC) measures pulmonary arterial hypertension (PAH) symptom severity and activity limitations. The Pulmonary Hypertension Functional Classification Self-Report (PHFC-SR) is an adapted version of the WHO-FC for patient self-completion (Table 1). PH-FC-SR can provide longitudinal monitoring when collecting clinician-rated FC may not be feasible or practical. The study aimed to determine if patient-reported PHFC-SR agreed with clinician-assessed WHO-FC.

Methods: ADAPT is a real-world registry of PAH patients taking oral treprostinil. An optional substudy in ADAPT collected PH-FC-SR and WHO-FC at baseline, week 24, and week 52. Patient responses were blinded to study team members assessing WHO-FC. PH-FC-SR and WHOFC were matched if both patient and clinician completed the FC survey within 30 days of each other. Agreement between PH-FC-SR and WHOFC was assessed.

Results: There were 27 matched assessments from 18 unique patients at 9 sites. Baseline characteristics include socioeconomic and PAH disease statuses (Table 2). Twenty-four of 27 (89%) matched assessments were completed on the same day (Table 3). Twenty-three of 27 (85%) patient and clinician scores were the same. Two patients underreported and 2 patients overreported PH-FC-SRs compared with matched clinician assessments (unique patients, Table 3).

Conclusions: This is the first study assessing agreement between WHO-FC and PH-FC-SR. Patients from different sites with a range of PAH disease and socioeconomic statuses successfully matched clinician-assessed FC reports, supporting validity of use in clinical practice for longitudinal, at-home monitoring.

Raymond L. Benza

The Ohio State University Wexner Medical Center, Columbus, OH, USA

Veronica Franco

The Ohio State University Wexner Medical Center, Columbus, OH, USA

Mandar A. Aras

University of California San Francisco, San Francisco, CA, USA

Leslie Spikes

University of Kansas Medical Center, Kansas City, KS, USA

Daniel Grinnan

Virginia Commonwealth University School of Medicine, Richmond, VA, USA

Kevin Corkery

Respira Therapeutics Inc., Albuquerque, NM, USA

Carol Satler

Respira Therapeutics Inc., Albuquerque, NM, USA

Category: Clinical Science

Selected Areas: Therapeutic Strategies

Background: Pulmonary arterial hypertension (PAH) is currently managed using chronic, scheduled treatments to improve exercise capacity and delay clinical worsening. Availability of an as-needed (PRN) treatment may further enhance patient quality of life by rapidly resolving symptoms associated with physical activity. RT234 is a drug and device combination of vardenafil hydrochloride and the novel axial oscillating sphere dry powder inhaler that is suitable for PRN use and has the potential to improve exercise capacity, physical activity, and associated symptoms (ie, dyspnea).

Methods: The CL202 study (NCT04266197; Sept 2020–Dec 2023 [expected completion]) is a multicenter, open-label, dose-escalation, phase 2b study designed to evaluate the safety and efficacy of RT234 on exercise parameters assessed by cardiopulmonary exercise testing (CPET) and 6-minute walk distance (6MWD) in patients with PAH (Figure).

Results: Up to 40 adult patients with right heart catheterization—confirmed World Health Organization Group 1 PAH on stable oral PAH-specific (=2) and/or inhaled therapy are being enrolled in 2 successive dose cohorts (0.5 mg; 1.0 mg). A safety monitoring committee will decide whether to proceed with the 1.0 mg cohort or terminate the study. Safety measures include adverse events (at each of 2 single-dose treatment days and for 30-day follow-up) and acute physical and cardiac effects. Efficacy measures include changes in peak oxygen capacity (Vo₂; primary endpoint) and exertional symptoms from baseline (day 1) to 15 minutes postdose during CPET on day 8, and change in 6MWD from baseline (screening, day −28 to day −3) to 15 minutes postdose on day 15.

Conclusions: Exploratory endpoints include pharmacokinetics and exposure-response analyses. The results of the CL202 study are expected to inform the design of phase 3 trials of RT234.

Evan Carabelli MD

Temple University Hospital, Philadelphia, PA, USA

Philip Lavenburg DO

Temple University Hospital, Philadelphia, PA, USA

Riyaz Bashir

Temple University Hospital, Philadelphia, PA, USA

Paul Forfia

Temple University Hospital, Philadelphia, PA, USA

William Auger

Temple University Hospital, Philadelphia, PA, USA

Vladimir Lakhter

Temple University Hospital, Philadelphia, PA, USA

Frances A. Rogers

Temple University Hospital, Philadelphia, PA, USA

Lori Warren

Temple University Hospital, Philadelphia, PA, USA

Estefania Oliveros Soles

Temple University Hospital, Philadelphia, PA, USA

Anjali Vaidya

Temple University Hospital, Philadelphia, PA, USA

Category: Case Report

Selected Areas: Diseases and Conditions Associated with PH

Background: While pulmonary hypertension (PH) is often cured in chronic thromboembolic PH (CTEPH) after pulmonary thromboendarterectomy (PTE), there is a risk of recurrent PH after PTE in a minority of patients.

Methods: (Case) A 50-year-old female with hypertension and hysterectomy for fibroids presented with dyspnea, severe PH and right ventricular (RV) dysfunction. Ventilation-perfusion scan (Figure 1), computed tomography angiography (CTA), and pulmonary angiography (Figure 2) revealed multiple areas of severe thromboembolic disease. She underwent urgent PTE (Figure 3) with markedly improved hemodynamics, albeit warranting resumption of sildenafil early postop. Six months postop, she developed worsening dyspnea and was restarted on 3-drug PH therapy. One year postop she had severe PH despite high-dose combination PH therapy and underwent balloon pulmonary angioplasty (BPA). Ongoing fatigue and dyspnea prompted readmission 1 month later.

Results: (Decision making) Severe PH post-PTE and post-BPA should prompt consideration of PH etiologies beyond thromboembolic disease. She was noted to have persistent sinus tachycardia, bounding arterial pulses, hyperreflexia, and hyperdynamic findings on echo-Doppler (Figure 4). Thyroid studies revealed severe thyrotoxicosis leading to a diagnosis of Graves’ disease. She was treated with methimazole, iodine, and steroids followed by thyroidectomy with substantial improvement in symptoms and improved RV function by echo.

Conclusions: While PH after PTE is generally related to thromboembolic disease, it may not always be. Clinical assessment of PH after PTE should include careful consideration and evaluation for thyroid disease and the broad range of medical conditions known to be associated with PH.

Anne Keogh

St Vincent’s Hospital, Darlinghurst, NSW, Australia

Nathan Dwyer

Royal Hobart Hospital, Hobart, TAS, Australia

Eugene Kotlyar

St Vincent’s Hospital, Darlinghurst, NSW, Australia

David Kaye

The Alfred Hospital, Melbourne, VIC, Australia

Category: Clinical Science

Selected Areas: Quality of Life, Therapeutic Strategies

Background: RT234 is an inhaled formulation of phosphodiesterase type-5 inhibitor (PDE5i) vardenafil, in development for episodic symptoms of pulmonary arterial hypertension (PAH). This phase 2a escalating-dose trial evaluated acute changes in pulmonary vascular resistance (PVR) and other hemodynamic (HD) parameters in PAH patients on stable maintenance dual therapy.

Methods: Three cohorts received RT234 0.2, 0.6, or 1.2 mg during right heart catheterization.

Results: Of 14 subjects, age was 54 ± 14 years (79% female) and functional class was 2 (57%), 3 (36%), or 4 (7%). In the 0.2, 0.6, and 1.2 mg cohorts, respectively, mean PVR was 635 ± 344, 469 ± 431, and 579 ± 337 dyn·s/cm⁵ at baseline and decreased by −6.6% (−22.2 to 2.7), 23.7% (−44.7 to −18.6), and −16.0% (−22.7 to −10.5) postinhalation. With 0.6 and 1.2 mg, PVR fell >10% at 5 minutes, a reduction sustained for 60 minutes. PVR/systemic vascular resistance ratio changed by −8.0% (−27.1 to 14.1), −18.4% (−37.8 to 0.9), and −11.9% (−23.9 to −0.3) for the 0.2, 0.6, and 1.2 mg doses, indicating the 0.6 mg dose may offer the greatest pulmonary selectivity. No clinically significant changes in systemic blood pressure or heart rate were observed. Change in PaO₂ was +1.8% (−13.5 to 27.4), +8.1% (−13.5 to 22.6), and +4.3% (−1.4 to 9.9) for the 3 doses. Improvements in pulmonary HD with 0.6 mg RT234 were on par with 20 mg oral vardenafil, with less systemic hypotension and higher oxygenation. The only treatment-related adverse events (AEs) were mild headache and mild throat irritation, each in a single subject. No respiratory AEs occurred. RT234 produced rapid reduction in PVR, sustained for 60 minutes, and was well tolerated (Figure).

Conclusions: The optimally effective RT234 dose appears to be 0.6 mg. RT234 is suited for as-needed or preemptive PAH therapy.

Vijay R. Nadipelli

BPharm, MS, Thomas Jefferson University, Philadelphia, PA, USA

Karim El-Kersh, MD

University of Nebraska Medical Center, Omaha, NE, USA

Willie H. Oglesby, PhD, MBA

Thomas Jefferson University, Philadelphia, PA, USA

Jean M. Elwing, MD

University of Cincinnati, Cincinnati, OH, USA

Category: Clinical Science

Selected Areas: Diseases and Conditions Associated with PH, Effect of COVID and Telemedicine on PH Management, Quality of Life

Background: Social determinants of health (SDOH) can affect the vulnerable pulmonary arterial hypertension (PAH) population, especially during the COVID-19 pandemic. Providers’ understanding of SDOH at the point of care and their potential effect is unknown.

Methods: Semistructured virtual interviews of US health care providers (HCP) at pulmonary hypertension (PH) centers and an association were conducted ( January and February 2022). A trained interviewer sought participants’ perspectives of SDOH in PAH and its effect. Transcripts were developed and analyzed for key themes to assess potential policy implications.

Results: Participants served a large PAH population (Tables 1 and 2) and demonstrated high awareness of SDOH and its effect on treatment and outcomes. Patients’ socioeconomic status, health insurance, education, health literacy, employment, housing, food security, transportation, and family support were reported to affect health and well-being. Further complicated by COVID-19-related social isolation, mental health and substance abuse were cited as contributing to significant inequities in care provision and outcomes. While telemedicine helped HCPs manage patients remotely during the pandemic, there was a concern for patients with limited access to this medium. Participants reported not formally screening for SDOH. With the recognition and the desire to act upon health inequities afforded by SDOH, HCPs felt that it was vital for their centers to have a dedicated PH social worker and support staff to optimize care and outcomes.

Conclusions: Participants were highly aware of the importance of SDOH in PAH patients. An approach that integrates SDOH in care management, streamlined through institutional policy, could minimize disparities contributing to improved health care access, outcomes, and quality of care.

Fraz A. Ismat

Insmed Incorporated, Bridgewater, NJ, USA

Helen Usansky

Insmed Incorporated, Bridgewater, NJ, USA

Shilpa Dhar Murthy

Insmed Incorporated, Bridgewater, NJ, USA

Jun Zou

Insmed Incorporated, Bridgewater, NJ, USA

Ariel Teper

Insmed Incorporated, Bridgewater, NJ, USA

Category: Clinical Science

Selected Areas: Therapeutic Strategies

Background: Use of treprostinil (TRE) in pulmonary arterial hypertension (PAH) is limited by a short half-life (t_1/2) and dose-limiting treatment emergent adverse events (TEAEs). Treprostinil palmitil inhalation powder (TPIP) is a dry powder formulation of a TRE prodrug.

Rationale: To examine the safety, tolerability, and pharmacokinetics (PK) of single- and repeat-dose administration of once-daily (QD) TPIP.

Methods: Healthy adults received single doses of 112.5, 225, 450, or 675 mg (n = 6/dose) or placebo (n = 2) or multiple doses of 225 mg QD × 7 days (n = 6) or 112.5 mg QD × 4 days, then 225 mg QD × 3 days (n = 6), or placebo × 7 days (n = 4).

Results: Forty-one of 42 participants completed the study. Of single-dose participants, 70.8% (n = 17/24) experienced a TEAE versus 0% of placebo (0/2); cough (42.3%), dizziness (26.9%), throat irritation (19.2%), nausea (15.4%), and hypotension (15.4%) were most common. Of multiple-dose participants. 83.3% (n = 10/12) had a TEAE versus 50.0% of placebo (2/4); cough (58.3% TPIP versus 50.0% PLA), headache (50.0% versus 0%), nausea (33.3% versus 0%), and dizziness (25.0% versus 0%) were most common. TEAEs were mild in 69.0% (29/42) and moderate in 16.7% (7/42), with no severe or serious TEAEs. Titration of TPIP had fewer TEAEs in multiple QD dosing. TRE exposure was dose proportional, and steady-state accumulation was insignificant. Elimination t_1/2 was 8.7–11.6 hours after a single dose and 6.8–8.8 hours after multiple QD dosing (Figure).

Conclusions: TPIP was generally safe and well tolerated in healthy volunteers, with a PK profile that supports QD dosing. TEAEs were dose related and attenuated with titration.

Kelsey Cramer, MSN, DNP, AGACNP

Medical College of Wisconsin, Milwaukee, WI, USA

Linus Santo Tomas, MD

Pulmonary and Critical Care Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

David Ishizawar, MD

Cardiology, Advanced Heart Failure, Medical College of Wisconsin, Milwaukee, WI, USA

Category: Case Report

Selected Areas: Diagnosis or Screening and Physiologic Studies, Diseases and Conditions Associated with PH, Therapeutic Strategies

Background: (Case) A 49-year-old man with dyspnea and concerns for graft versus host disease after receiving a hematopoietic stem cell blood transplant for acute myeloid leukemia underwent a video-assisted thoracoscopic surgery (VATs) lung biopsy and was found to have pulmonary vascular remodeling, but preop right heart catheterization (RHC) had demonstrated normal hemodynamics. A repeat RHC with supine bicycle exercise study demonstrated exercise induced pulmonary hypertension (EiPH) with a mPA-CO slope of 3.1 mm Hg/L/min (Table 1). He was treated with riociguat and followed with cardiopulmonary exercise testing (CPET) which demonstrated gradual improvements even after he decided to wean off riociguat (Table 2). Repeat echocardiogram testing demonstrated still normal estimated pulmonary artery systolic pressure 23 mm Hg once weaned off riociguat.

Results: (Discussion) EiPH is felt to demonstrate an early spectrum of pulmonary vascular disease, but without consensus on exercise methodology and/or diagnostic criteria, it can be challenging to diagnose. Data on treatment of EiPH are even more limited. Our case demonstrated a mPA-CO slope > 3 mm Hg/L/min, felt to be an indicator of reduced pulmonary vascular distensibility. Furthermore, this case reinforces the importance of identifying and treating pulmonary vascular disease at its earlier disease spectrum (Figures 1–3).

Conclusions: Our case uniquely presents a histopathologic basis for EiPH demonstrating early pulmonary vascular changes on lung biopsy.

R. J. White

University of Rochester, Rochester, NY, USA

M. Broderick

United Therapeutics Corportation, Durham, NC, USA

C. Q. Deng

United Therapeutics Corportation, Durham, NC, USA

R. Grover

United Therapeutics Corportation, Durham, NC, USA

L. Holdstock

United Therapeutics Corportation, Durham, NC, USA

A. Khan

Oregon Health and Science University, Portland, OR, USA

G. Meyer

Complexo Hospitalar Santa Casa de Porto Alegre, Porto Alegre, Brazil

B. Ng

Nepean Hospital, Sydney, Australia

T. Pulido

Instituto Nacional de Cardiologia Ignacio Chavez, Mexico City, Mexico

Y. Rao

United Therapeutics Corportation, Durham, NC, USA

I. Saib

United Therapeutics Corportation, Durham, NC, USA

P. Sepulveda

Pontifica Universidad Catolica de Chile, Santiago, Chile

Category: Clinical Science

Selected Areas: Therapeutic Strategies

Background: Oral treprostinil (TRE) is approved to treat pulmonary arterial hypertension (PAH). FREEDOM-EV established 3 times daily (TID) TRE to delay disease progression when added to oral monotherapy. Data reported here are from subjects who transitioned to an open-label extension (OLE) study after experiencing a clinical worsening event (CWE) during the parent study or at parent study closure.

Methods: Subjects attended visits at baseline (start of OLE) and every 12 weeks until voluntary discontinuation or study closure. Efficacy measures included 6-minute walk distance (6MWD), World Health Organization Functional Class (FC), and plasma NT-pro-BNP level (week 48 only).

Results: Of 690 FREEDOM-EV subjects, 470 enrolled in the OLE: 258 previously assigned placebo (PBO) and 212 assigned TRE. Baseline characteristics, dosing, and key data are presented in the Table. Mean 6MWD increased significantly from baseline in subjects initially assigned PBO with a CWE in the parent study (85 ± 100 m). NT-pro-BNP decreased significantly in previous PBO subjects with CWE. FC improved in >40% of previous PBO subjects with CWE. Discontinuations from the study due to adverse events were most common in previous PBO patients with CWE (22%). No new safety signals were observed.

Conclusions: Subjects starting TRE after CWE had a significant increase in 6MWD, improved FC, and reduced NT-pro-BNP 48 weeks after starting TRE, whereas those without CWE had small improvements in all efficacy measures after initiating TRE. These data are consistent with the placebo-controlled FREEDOM-EV results and suggest that TRE was effective in a group of higher-risk PBO subjects who had just had a CWE.

Kristen Wallace

Department of Pediatric Pulmonology, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA

Nidhy Varghese

Department of Pediatric Pulmonology, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA

Category: Case Report

Selected Areas: Diseases and Conditions Associated with PH; Pediatrics

Background: Cantú syndrome has been associated with pulmonary hypertension (PH), but case reports describe it as an infantile condition, often in conjunction with a patent ductus arteriosus (PDA). Here, we present the case of an adolescent with new-onset PH in the setting of Cantú diagnosis.

Methods: (Case) An adolescent male presented after unwitnessed syncopal event and 1-month history of exertional dyspnea and orthopnea. Review of symptoms was remarkable only for nausea, emesis, fatigue, dry nighttime cough, and bilateral leg swelling for a few weeks. Of note, mother’s pregnancy was complicated by polyhydramnios requiring multiple amniocenteses and delivery at 36 weeks due to macrosomia. He had a 2-week neonatal intensive care unit admission for respiratory distress and underwent surgical closure of large PDA at 6 weeks of age. His medical history included hypotonia, short stature (recently started on growth hormone), diabetes, elevated body mass index, learning disability, and attention deficit hyperactivity disorder on methylphenidate. Chest x ray showed significant cardiomegaly and chest computed tomography scan had dilation of the pulmonary arteries. Echocardiogram revealed a large pericardial effusion with severe PH. Initial brain natriuretic peptide (BNP) level was elevated to 168 pg/mL. He was tachycardic, mildly hypertensive, and admitted to the intensive care unit for further evaluation and monitoring. Cardiac catheterization revealed mean pulmonary artery pressure 44 mm Hg, wedge pressure 18 mm Hg, and pulmonary vascular resistance 4.3 Wood units, on 50% FiO₂ and nitric oxide (iNO). He was carefully transitioned from iNO to sildenafil therapy and started on diuretics with improvement. As part of the workup for PH, a sleep study revealed moderate obstructive sleep apnea (oAHI: 8.26/hour), which improved with auto-positive airway pressure (PAP) therapy, 5–10 cm H₂O. Genetic studies were also sent, part of our protocol for idiopathic PAH, and supported by distinct facial features. A mutation in the ABCC9 gene resulted, confirming the diagnosis of Cantú Syndrome. He has since been transitioned to tadalafil as an outpatient, and most recent echocardiogram shows improvement in right ventricular function.

Results: (Discussion) Cantú syndrome, also known as hypertrichotic osteochondrodysplasia, is an autosomal dominant genetic condition associated with a gain of function mutation in the ABCC9 or KCNJ8 gene, which encode regulatory and pore forming subunits of ATP-sensitive potassium (K-ATP) channels, respectively. The mechanism of PH development in patients with Cantú syndrome is likely multifactorial, related to obesity effects, obstructive sleep apnea, and risk for effusions. Although K-ATP channelopathy has been associated with development of PH, typically decreased potassium channel activity causing vasoconstriction is seen. In Cantú syndrome, it is the converse: Increased channel activity leads to vasodilation of smooth muscle, compensatory cardiac hypertrophy, and increased cardiac output. The association of PH and Cantú-related channel disease is therefore not clear, and further mechanistic studies are needed. To our knowledge, this is the first noninfantile Cantú syndrome patient with PH. Cantú syndrome patients are reported to develop PH during infancy, perhaps related to PDA physiology, and there is improvement with resolution of the PDA. Although our patient did have a PDA, he did not have any evidence of PH on infantile or childhood studies. Therefore, we hypothesize that PH development in our patient was secondary to the cumulative effect of several risk factors, including Cantú syndrome, obstructive sleep apnea, exposure to methylphenidate therapy, and exposure to growth hormone. This case illustrates the importance of monitoring patients with this syndrome for the development of PH as they grow older and develop other comorbidities. We also highlight the potential for stabilization and improvement of PH with phosphodiesterase inhibitors.

Conclusions: PH should be considered when a patient Cantú syndrome presents with cardiopulmonary issues regardless of age. Further studies are warranted to examine the link between the 2 conditions.

Scott A. Helgeson, MD

Division of Pulmonary & Critical Care Medicine, Mayo Clinic, Jacksonville, FL, USA

Hollie Saunders, MD

Division of Pulmonary & Critical Care Medicine, Mayo Clinic, Jacksonville, FL, USA

Charles D. Burger, MD

Division of Pulmonary, Allergy & Sleep Medicine, Mayo Clinic, Jacksonville, FL, USA

John E. Moss, MD

Division of Pulmonary & Critical Care Medicine, Mayo Clinic, Jacksonville, FL, USA

Tonya K. Zeiger, RRT

Division of Pulmonary, Allergy & Sleep Medicine, Mayo Clinic, Jacksonville, FL, USA

Bryan J. Taylor, PhD

Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, USA

Category: Clinical Science

Selected Areas: Diagnosis or Screening and Physiologic Studies, Effect of COVID and Tele-medicine on PH Management

Background: Facemask wearing is a key control measure to prevent transmission of SARS-CoV-2. However, widespread face mask use has proven challenging. Frequently asserted reasons for noncompliance with facemask wearing include heightened breathlessness and carbon dioxide retention and/or hypoxemia, especially during exertion. Our objective was to evaluate whether facemask wearing affected distanced covered, rating of perceived exertion (RPE), and arterial oxygen saturation (SpO₂) during a 6-minute walk test (6MWT) in patients with pulmonary arterial hypertension (PAH).

Methods: Forty-five patients being treated for Group 1 PAH and who performed a 6MWT without (Test 1) and with (Test 2) a facemask between October 2019 and October 2020 (ie, before and after implementation of a facemask mandate) were included.

Results: At both time points, all patients also underwent a submaximal cardiopulmonary exercise test, echocardiogram, and blood laboratory tests, with a REVEAL Lite 2.0 score calculated (Table). The 6MWTs were performed 81 ± 51 days apart. All patients were clinically stable at both testing timepoints. 6MWT distance was not different between Test 1 versus Test 2 (405 ± 108 m versus 400 ± 103 m, P = 0.81; Figure). Similarly, both end-test RPE and lowest SpO₂ during the 6MWT were not different in Test 1 versus Test 2 (RPE: 2.5 ± 1.7 versus 2.5 ± 2.1, P = 0.91; SpO₂ nadir: 93 ± 3.4% versus 93.3 ± 3.3%, P = 0.55; Figure).

Conclusions: Wearing a facemask had no discernable effect on the arterial oxygen saturation and perceptual responses to exercise or exercise capacity in patients with moderate-to-severe PAH. Wearing a facemask appears to be safe in PAH patients, even during exercise.

Amy Chybowski, NP

UW Health, Madison, WI, USA

Debra Dalsing, RN, MSN, CNML

UW Health, Madison, WI, USA

Tracy Kussmaul, MSN, RN-BC

UW Health, Madison, WI, USA

Category: Clinical Science

Selected Areas: Therapeutic Strategies

Background: Pulmonary arterial hypertension (PAH) is a rare, incurable disease that leads to right heart failure. One treatment for PAH is continuous subcutaneous (SQ) or intravenous (IV) prostacyclin infusion. These specialized therapies are potent vasodilators, some with very short half-lives, such that any interruption in the infusion can lead to serious injury or death. Direct management by a pulmonary hypertension (PH) team in the ambulatory, emergency room, inpatient, and procedural areas is essential. The purpose of this quality improvement project was to improve patient safety through creation of a best practice advisory (BPA) alert within the electronic medical record (EMR) of patients with PAH receiving an infused prostacyclin.

Methods: Using FOCUS PDCA, the PH team identified the need to ensure all health care professionals (HCPs) are alerted when a patient they encounter is receiving an infused prostacyclin. This would mitigate erroneous manipulation of the infusion by untrained HCPs and ensure the PH team is involved in clinical management, regardless of how or why the patient is seeking access to care.

Results: In collaboration with Clinical Knowledge Management and Nursing Informatics, a BPA was created (Figure). It launches upon opening the EMR of an individual with an infused prostacyclin on their active medication list. The BPA states the patient is receiving a prostacyclin infusion, interrupting the infusion could cause serious injury or death, and the PH team must be contacted. The BPA must be acknowledged by the HCP prior to proceeding into the EMR. Education was provided by the PH team to HCPs working in the Access Center, Department of Emergency Medicine, and Anesthesia.

Conclusions: The BPA has enhanced patient safety and could be explored at other PH centers.

Charles Fauvel, MD

Internal Medicine Department, Division of Cardiovascular Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, USA

Amy Webb, PhD

Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA

Zilu Liu, MS

Department of Statistics, The Ohio State University, Columbus, OH, USA

Shili Lin, PhD

Department of Statistics, The Ohio State University, Columbus, OH, USA

Priscilla Correa-Jaque, BMS

Internal Medicine Department, Division of Cardiovascular Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, USA

Raymond Benza, MD

Internal Medicine Department, Division of Cardiovascular Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, USA

Category: Clinical Science

Selected Areas: Databases and Registries

Background: Accurate risk assessment is essential to making individualized treatment decision in pulmonary arterial hypertension (PAH) patients, yet existing probabilistic risk assessment models are insufficient since they do not include contemporary genomic and imaging biomarkers. We aimed to build a risk assessment genomic model using a Bayesian network (BN) for PAH patients.

Methods: After performing a whole genome sequencing on 325 samples, variants were filtered for quality, assigned to genes, and filtered for function and population frequency. Retaining PAH patients that survived past 7 years or died prior to 5 years left 221 samples for analysis (mean age = 54 years, 50% idiopathic PAH, 81% of female). Ingenuity pathways analysis was used to generate a list of pathways containing >1 mutated gene from our dataset.

Results: Thirty-one pathways which were significantly (Fisher exact test P < 0.05) associated with long-term (>7 years) versus short-term (<5 years) survival were retained. Finally, a BN model, showing interdependency (arrow direction) and association weight (arrow thickness) between the 31 selected pathways and length of survival was built. The 10-fold cross-validation area under the curve averaged 0.75. Using already published peer-reviewed articles, we were able to link each of the 31 pathways to the natural history of PAH including endothelial dysfunction, vascular smooth muscular cell proliferation, inflammation and dysimmunity, genetic and environmental factors, metabolism dysfunction, and right ventricular effect (Figures 1 and 2).

Conclusions: Using a BN, we were able to provide the first PAH risk assessment genomic model including 31 pathways that may be related to the natural PAH course.

Liu Zilu

Department of Statistics, The Ohio State University, Columbus, OH, USA

Fauvel Charles

Cardiovascular Medicine Division, Wexner Medical Center, The Ohio State University, Columbus, OH, USA

Lin Shili

Department of Statistics, The Ohio State University, Columbus, OH, USA

Correa-Jaque Priscilla

Cardiovascular Medicine Division, Wexner Medical Center, The Ohio State University, Columbus, OH, USA

Amy Webb

Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA

Raymond Benza

Cardiovascular Medicine Division, Wexner Medical Center, The Ohio State University, Columbus, OH, USA

Category: Clinical Science

Selected Areas: Diseases and Conditions Associated with PH

Background: Existing risk assessment models in pulmonary arterial hypertension (PAH) are powerful in predicating survival, yet they are limited in accounting for the internal relationships among variables since they typically assume the independence between variables and their linear association with outcomes. To break free of these limits, we aimed to build a clinical risk assessment model using machine learning methods.

Methods: We harmonized clinical data measured at baseline from 7 adult PAH trials: GRIPHON, SERAPHIN, EARLY, COMPASS-2, COMPASS-3, MAESTRO, and TRANSIT-1. The harmonized data comprised 2870 subjects (mean age = 43 years, 77% female, 50% idiopathic or familial PAH) and 125 clinical variables, with a mortality rate being 14%. We split the data into 80% as the training dataset and 20% as the test dataset.

Results: Using the training data, we studied variable importance in predicting time to mortality by implementing Random Forest. Sixteen variables with importance values >0.0015 were selected to construct a Bayesian network (BN; Figure) in predicting the 1-year survival status (primary outcome). The thresholds to discretize continuous variables were determined based on clinical knowledge. The BN obtained an area under the curve (AUC) of 0.85 validated using the test dataset. In 5-fold cross-validation, the average AUC was 0.77.

Conclusions: Machine learning provides new powerful methods to build PAH risk assessment models, taking the interdependence among variables into account.

Evangelia Sourounis, PharmD

CVS Health, Northbrook, IL, USA

Pavlo Kyrychenko, PhD

CVS Health, Northbrook, IL, USA

Elisea Avalos-Reyes, PhD

CVS Health, Northbrook, IL, USA

Denise Bagford, BSN, RN, CRNI

CVS Health, Northbrook, IL, USA

Rashmi Grover, PharmD

CVS Health, Northbrook, IL, USA

Lucia Feczko, RPh

CVS Health, Northbrook, IL, USA

Category: Clinical Science

Selected Areas: Databases and Registries, Therapeutic Strategies

Background: Therapies currently available to treat pulmonary arterial hypertension (PAH) patients do not reverse the disease; however, they improve pulmonary hemodynamics and offer symptomatic relief and lengthen the time to clinical worsening. These therapies do not come without their challenges, which include side effects and compliance with challenging titration regimens. Health care professionals (HCPs), particularly nurses, play a significant role in improving patient medication adherence. The purpose of this study is to determine the effect that in-home, face-to-face nursing visits have on optimal adherence to oral PAH therapies.

Methods: We identified patients who received an oral PAH drug (riociguat, selexipag, or treprostinil) supported by a nursing program (study group) and patients who received an oral PAH drug (bosentan, ambrisentan, or macitentan) not supported by a nursing program (control group) using CVS Health pharmacy data from January 1, 2018, to June 30, 2019. A logistic regression model examined demographic and medication factors associated with adherence (Table 1).

Results: From January 2018 to June 2019, we identified 107 patients in the study group and 213 patients in the control group. After 6 months, patients in the study group reported 0.6 more fill counts (5.1 versus 4.5; P < 0.01), an 11% higher medication possession ratio (MPR; 86.4% versus 75.0%; P < 0.01), and higher rates of persistence (72.0% versus 60.6%; P < 0.05) than those in the control group. First-fill discontinuation rate was 3% higher (2.7% versus 5.7%; P = 0.14) in the control group and more likely to discontinue therapy in the first 6 months following the index fill (HR = 1.52; P = 0.06; Table 2, Figure).

Conclusions: Patients supported by nursing had significantly higher adherence.

Prangthip Charoenpong, MD, MPH

Division of Pulmonary and Critical Care, Department of Medicine, Louisiana State University Health Science Center—Shreveport, Shreveport, LA, USA

Sonia Tindel, RN

Division of Pulmonary and Critical Care, Department of Medicine, Louisiana State University Health Science Center— Shreveport, Shreveport, LA, USA

Kevin Murnane, PhD

Department of Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Science Center—Shreveport, Shreveport, LA, USA

Nicholas Goeders, PhD

Department of Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Science Center—Shreveport, Shreveport, LA, USA

Robert Walter, MD, MPH

Division of Pulmonary and Critical Care, Department of Medicine, Louisiana State University Health Science Center—Shreveport, Shreveport, LA, USA

Category: Basic Science

Selected Areas: Diagnosis or Screening and Physiologic Studies

Background: Estrogen paradox describes the increased incidence of pulmonary arterial hypertension (PAH) while having better outcomes in women and female animals. There are limited data suggesting that effects of amphetamine may be modified by sex in several cardiovascular outcomes. We hypothesize the effects of methamphetamine (MA) on the pulmonary vasculature are modified by sex in the binge-crash model of MA administration.

Methods: Experimentally naïve male and female Wistar rats will be used in the study. During a 96-hour procedure of the binge-crash model of MA administration, they will be housed in experiment chamber and will be returned to temperature-and humidity-controlled animal facility for 72 hours. Rats will be trained to self-administer MA by pressing one of the response levers. At the end of the exposure period (8 weeks), the animals will be euthanized, and lungs and hearts collected for histological evaluation and right ventricular/left ventricular septum (RV/LVS) weight ratio measurements. The lungs will be inflated and fixed in formalin overnight. The left lung will be blocked and embedded in paraffin. All sections will be cut and stained with hematoxylin and eosin.

Results: Preliminary data showed that MA-exposed male rats had more inflammation—demonstrated by congestion—than control female and MA-exposed female rats. The arteriolar wall was found to be thinner in MA-exposed female rats than control female rats and MA-exposed male rats (Figure)

Conclusions: Preliminary data demonstrated congestion and arteriolar wall changes in MA-exposed rats, more prominent in male rats. This may suggest estrogen paradox phenomenon in MA-PAH from the binge-crash model.

Prangthip Charoenpong, MD, MPH

Division of Pulmonary and Critical Care, Department of Medicine, Louisiana State University Health Science Center—Shreveport, Shreveport, LA, USA

Sonia Tindel, RN

Division of Pulmonary and Critical Care, Department of Medicine, Louisiana State University Health Science Center—Shreveport, Shreveport, LA, USA

Robert Walter, MD, MPH

Division of Pulmonary and Critical Care, Department of Medicine, Louisiana State University Health Science Center—Shreveport, Shreveport, LA, USA

Category: Clinical Science

Selected Areas: Databases and Registries, Diseases and Conditions Associated with PH

Background: Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension. Most patients need lung transplantation (LTx) as a curative treatment. Previous authors showed that PVOD patients had higher waitlist mortality than pulmonary arterial hypertension (PAH) patients. However, there are no reports on outcomes of LTx in this population. We would like to compare LTx outcomes between PVOD and idiopathic PAH (IPAH) patients.

Methods: This is a retrospective observational study. Patients with a diagnosis of PVOD and PAH underwent LTx between 2005 and 2018 were identified from SRTR database. Numerical data were reported in mean ± SD. Categorical data were reported in count and percent. T-tests and χ² tests were performed to compare variables between 2 groups. Survival was compared using the Kaplan-Meier (K-M) method.

Results: Sixty-one PVOD patients and 970 PAH patients who underwent LTx were identified. Patients with PVOD had significant lower posttransplant systolic, diastolic, and mean pulmonary artery (PA) pressure and higher cardiac output. Lung allocation score (LAS) at matching were not significantly different. PVOD patients had shorter time on the waiting list (152.7 versus 337.6, P < 0.01). The proportion of patients requiring extracorporeal membrane oxygenator (ECMO) post-LTx were higher in the PVOD group (13.11% versus 4.23%, P < 0.01). The proportion of patients developing primary graft dysfunction (PGD) was lower in the PVOD group (37.5% versus 61.93%, P = 0.056). There was no difference of length of stay, FEV1, FVC, PCO₂ post-LTx, or acute rejection. Survivals were not different using the K-M method (P = 0.33; Figure).

Conclusions: PVOD patients had shorter waiting time than PAH patients, suggestive of higher disease severity in PVOD than IPAH. Though more PVOD patients required ECMO support postoperative, long-term outcomes were not different.

Naoya Inoue, MD

Department of Cardiology, Chutoen General Medical Center, 1-1 Shobugaike, Kakegawa city, Shizuoka prefecture, Japan

Shuji Morikawa, MD

Department of Cardiology, Chutoen General Medical Center, 1-1 Shobugaike, Kakegawa city, Shizuoka prefecture, Japan

Category: Case Report

Selected Areas: Diseases and Conditions Associated with PH

Background: Pulmonary hypertension is a rare complication of sarcoidosis. Herein, we present the case of a 63-year-old female with a diagnosis of ocular and cutaneous sarcoidosis who developed shortness of breath and was referred to our department to rule out cardiac sarcoidosis.

Methods: Swan-Ganz catheterization was performed, and she was diagnosed with pulmonary arterial hypertension and started on selexipag.

Results: A few days after starting treatment, she presented with hemiplegia and was diagnosed with cardiogenic cerebral embolism by magnetic resonance imaging. As there was no evidence of preexisting intracardiac thrombosis, we suspected unusual cerebral embolism. Echocardiography revealed a deep venous thrombus (DVT), and a bubble study showed a right-left shunt through a patent foramen ovale (PFO) (Figures 1–4).

Conclusions: Based on the above, we concluded that the initiation of selexipag improved pulmonary blood flow and caused unusual cerebral embolism. This report highlights the importance of confirming PFO and DVT before starting treatment for pulmonary hypertension.

Keith Babbs

Keros Therapeutics, Lexington, MA, USA

Chris Materna

Keros Therapeutics, Lexington, MA, USA

Elliott Fisher

Keros Therapeutics, Lexington, MA, USA

Jasbir Seehra

Keros Therapeutics, Lexington, MA, USA

Jennifer Lachey

Keros Therapeutics, Lexington, MA, USA

Category: Basic Science

Selected Areas: Therapeutic Strategies

Background: Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary vascular resistance resulting in impaired cardiac output and right ventricle (RV) overload. PAH is associated with imbalanced TGF-β signaling, including insufficient activation of SMAD1/5/9. In preclinical studies and clinical trials, rebalancing SMAD signaling with an activin receptor type IIB (ActRIIA) ligand trap has shown benefit but can also increase red blood cells (RBCs), a potentially dose-limiting effect for PAH. KER-012 is an investigational modified ActRIIB ligand trap designed to target ActRII signaling to favor SMAD1/5/9, potentially rebalancing signaling without affecting RBCs.

Methods: We evaluated a research form of KER-012 (RKER-012) to prevent pulmonary and RV dysfunction in a sugen-hypoxia (SH) rat model of PAH. On day 1, 2 groups of Sprague Dawley rats received a single subcutaneous (SQ) dose of SUGEN5416 and were placed in a hypoxic environment (10%–12% O₂). For 3 weeks, SH rats received either vehicle (VEH) or 10 mg/kg RKER-012 twice weekly SQ. A third group serving as healthy controls received VEH twice weekly and remained in a normoxic (NX) environment.

Results: Relative to NX rats, VEH-treated SH rats (VEH-SH) had significantly increased systolic pulmonary arterial pressure (sPAP) and Fulton index (FI; ps < 0.0001), and a trend for increased RBCs (P = 0.06), potentially a compensatory response to hypoxia. Relative to VEH-SH, RKER-012 treatment significantly reduced sPAP (−44.5%) and FI (−28.0%; ps < 0.001), with no observed additional change in RBCs.

Conclusions: These results demonstrate that RKER-012 prevented pulmonary and RV dysfunction without affecting RBCs in a rat PAH model. We believe these results provide early evidence that KER-012 has the potential to treat human PAH without a potentially dose-limiting RBC effect.

Kerry Mello-Parker, PharmD, MBA

Shields Health Solutions, Stoughton, MA, USA

Stacy Walton, RN, BSN

Shields Health Solutions, Stoughton, MA, USA

Category: Clinical Science

Selected Areas: Diseases and Conditions Associated with PH, Quality of Life, Therapeutic Strategies

Background: The integrated health system-owned specialty pharmacy provides an innovative approach to providing high touch service for patients living with rare disease and complex conditions. The physical presence of an in-clinic patient liaison promotes direct provider engagement, and the fully integrated patient management platform enables clinical pharmacists and nurses to follow a patient’s journey across the continuum of care.

Methods: The integrated health system-owned specialty pharmacy is uniquely positioned to clinically manage rare and complex disease states, such as pulmonary arterial hypertension (PAH). Patient liaisons, clinical pharmacists, and nurses play integral roles in onboarding PAH patients and monitoring progress across their clinical journey.

Results: Using standardized, validated assessment tools such as EmPHasis-10, clinical pharmacists and nurses review patient-reported outcomes specific to PAH and assess patient quality of life. Clinicians perform an individualized risk stratification for each patient and adjust the cadence of follow-up assessments based on disease severity. For patients who report the severest of symptoms, clinicians work directly with the provider and the care team to adjust medications and address potential medication nonadherence concerns.

Conclusions: Since several of the medications used in the treatment of PAH require Food and Drug Administration Risk Evaluation and Mitigation Strategy (REMS) with Elements to Assure Safe Use, the integrated pharmacy care model also encompasses manufacturer data reporting, REMS program compliance, and desktop audit support. For these medications, early results demonstrate 100% REMS audit compliance, attributed to a dedicated clinical team and full integration with the health system electronic medical record.

S. Gratsianskaya

Federal State Budget Organization “National Medical Research Center of Cardiology” of Ministry of Healthcare of the Russian Federation, Scientific Research Institute of Clinical Cardiology of A.L. Myasnikov, Department of Pulmonary hypertension and Heart Diseases, Moscow, Russia

Z. Valieva

Federal State Budget Organization “National Medical Research Center of Cardiology” of Ministry of Healthcare of the Russian Federation, Scientific Research Institute of Clinical Cardiology of A.L. Myasnikov, Department of Pulmonary hypertension and Heart Diseases, Moscow, Russia

T. Martynyuk

Federal State Budget Organization “National Medical Research Center of Cardiology” of Ministry of Healthcare of the Russian Federation, Scientific Research Institute of Clinical Cardiology of A.L. Myasnikov, Department of Pulmonary hypertension and Heart Diseases, Moscow, Russia

Category: Clinical Science

Selected Areas: Diseases and Conditions Associated with PH

Background: To assess clinical, functional, and hemodynamic characteristics of patients with pulmonary arterial hypertension (PAH) associated with congenital heart defect (CHD) and Eisenmenger syndrome (ES) in comparison with patients with PAH after defect closure.

Methods: Here, 56 patients (mean age = 39.1 ± 14.3 years, 46 women): 30 patients with PAH-CHD and ES and 26 patients with PAH after defect closure from the Russian National Registry of Patients with PAH (NCT03707561) were followed for 24 months. Clinical parameters, 6-minute walk test, echocardiogram, and right heart catheterization (RHC) were prospectively recorded.

Results: The age at the onset of symptoms in PAH-CHD and ES was 18.2 ± 15.1 years versus 32.9 ± 14.9 years in PAH after defect closure (P = 0.003). The mean time from the occurrence of complaints until the final diagnosis was 36 months for ES and 9 months for PAH after defect closure (P = 0.0006). The mean age of atrial septal defect correction was 50 years. Mean time to development of PAH was 4 years. The mean age of ventricular septal defect and patent ductus arteriosus correction was 5 years. Mean time to development of PAH was 20 years. The main complaints were dyspnea (95%) in both groups, but in the ES group, hemoptysis (13%, P = 0.03) and weakness (31%, P = 0.02) were significantly more frequent. According to echocardiogram, patients with ES had significantly greater right ventricular hypertrophy, higher mean pulmonary arterial pressure (PAP), and patients with PAH after defect closure had the lowest tricuspid annular plane systolic excursion (TAPSE) and the greatest dilatation of right atrium and vena cava inferior. According to RHC, mean PAP and pulmonary vascular resistance were significantly higher in patients with ES. The survival rate of patients with ES was better than with PAH after defect closure (80.5% and 47.9%, respectively).

Conclusions: Our data suggest that adults with ES have more favorable hemodynamic profiles which may result in better prognoses than adults with PAH after defect closure.

Krittika Teerapuncharoen

Biological Sciences Division, The University of Chicago, Chicago, IL, USA

Division of Respiratory Disease and Tuberculosis, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand

Kavitha Selvan

Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA

Remzi Bag

Biological Sciences Division, The University of Chicago, Chicago, IL, USA

Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA

Category: Clinical Science

Selected Areas: Diagnosis or Screening and Physiologic Studies

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening complication of pulmonary embolism (PE). Delay in diagnosis and treatment is associated with poor outcomes. CTEPH is underreported due to nonspecific signs and symptoms, underuse of ventilation-perfusion (VQ) scans, and underrecognition of CTEPH signs on computed tomography pulmonary angiogram (CTPA) and computed tomography (CT).

Methods: Using our image library, we will discuss findings and provide clinical correlation for our cohort of CTEPH patients.

Results: Signs of preexisting CTEPH include findings of chronic PE (eccentric filling defect, abrupt tapering, stenosis ± poststenotic dilatation, webs or bands, calcified thrombus, and dilated bronchial arteries) on CTPA and findings related to pulmonary hypertension (right ventricular hypertrophy, right atrial dilatation, flattening of the interventricular septum, pulmonary artery dilatation, and mosaic attenuation) on CT. If signs of CTEPH plus acute PE are visualized, acute-on-chronic events should be suspected. In situ pulmonary artery thrombosis, pulmonary artery sarcoma, tumor emboli, and pulmonary vasculitis are all CTPA CTEPH mimickers. A positive VQ scan for CTEPH differs from acute PE and includes at least 1 segmental or larger mismatched perfusion defect. As mismatched perfusion defects can be found in many other conditions altering pulmonary blood flow, further imaging correlation is necessary.

Conclusions: The presence of CT signs or a positive VQ scan should prompt a referral for CTEPH confirmation and evaluation for treatment, including pulmonary endarterectomy. The precise interpretation and early recognition of radiographic signs of CTEPH are essential to improve outcomes.

Sue Gu, MD

University of Colorado School of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, Aurora, CO, USA

National Jewish Health, Department of Pediatrics, Denver, CO, USA

Cardiovascular Pulmonary Research Laboratory, University of Colorado School of Medicine, Department of Pediatrics-Critical Care Medicine, Aurora, CO, USA

Claudia Mickael, PhD

University of Colorado School of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, Aurora, CO, USA

Linda Sanders, BS

University of Colorado School of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, Aurora, CO, USA

Ronald Vagnozzi, PhD

University of Colorado School of Medicine, Division of Cardiology, Aurora, CO, USA

Delaney Swindle, MS

Cardiovascular Pulmonary Research Laboratory, University of Colorado School of Medicine, Department of Pediatrics-Critical Care Medicine, Aurora, CO, USA

David Irwin, PhD

Cardiovascular Pulmonary Research Laboratory, University of Colorado School of Medicine, Department of Pediatrics-Critical Care Medicine, Aurora, CO, USA

Peter Henson, PhD

National Jewish Health, Department of Pediatrics, Denver, CO, USA

Kurt Stenmark, MD

Cardiovascular Pulmonary Research Laboratory, University of Colorado School of Medicine, Department of Pediatrics-Critical Care Medicine, Aurora, CO, USA

Category: Basic Science

Selected Areas: Diseases and Conditions Associated with PH

Background: Macrophages play critical roles in tissue homeostasis and response to disease and may provide novel therapeutic targets in right heart failure. We hypothesize that the right ventricle (RV) contains macrophage populations at steady state that orchestrate the RV adaptation to pulmonary hypertension.

Methods: C57BL/6J mice at 8–10 weeks were placed in hypobaric hypoxia at 18 000 feet or in normoxia at sea level for 4 or 21 days. We measured hemodynamics, resecting the RV and left ventricle (LV), and identified populations of CCR2+ and CCR2− macrophages using flow cytometry.

Results: The RV contained a higher proportion of CCR2+ macrophages than the LV at steady state (43% versus 9.3%, P < 0.0001), 4-day hypoxia (37% versus 12.6%, P = 0.0014), and 3-week hypoxia (54.5% versus 20%, P = 0.0007). After 3-week hypoxia, mice developed pulmonary hypertension with RV systolic pressure of 36 mm Hg versus 24 mm Hg in normoxic mice (P < 0.0001) and a trend toward RV hypertrophy with increased Fulton index (0.48 versus 0.32, P = 0.08). Three-week hypoxic mice had significantly increased RV macrophages per milligram tissue compared with normoxic mice (224.8 versus 63, P = 0.03), particularly in the CCR2+ subset of macrophages (132.5 versus 31.3, P = 0.03; Figure).

Conclusions: The RV in homeostasis and hypoxia contains a higher proportion of CCR2+ macrophages than the LV. Chronic hypoxic pulmonary hypertension results in an expansion of all macrophages, particularly CCR2+ macrophages, in the RV which we posit play a role in RV adaptation to pulmonary hypertension.

Ayedh K. Alamri

Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

Dominique Ingram

Division of Cardiovascular Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

Nathan D. Hatton

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Utah, Salt Lake City, UT, USA

Emily M. Beck

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Utah, Salt Lake City, UT, USA

Jennalyn D. Mayeux

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Utah, Salt Lake City, UT, USA

Dana Klanderud

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Utah, Salt Lake City, UT, USA

Christy L. Ma

Division of Cardiovascular Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

Ben Sadeh

Division of Cardiovascular Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

Brittany Penn

Division of Cardiovascular Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

John J. Ryan

Division of Cardiovascular Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

Category: Clinical Science

Selected Areas: Databases and Registries, Diseases and Conditions Associated with PH

Background: Methamphetamine prevalence has been increasing through the last decade and is associated with multiple cardiovascular complications, including pulmonary arterial hypertension (PAH). In this abstract, we are aiming to define methamphetamine-PAH to find out the rate of hospitalizations, mortality, and quality of life.

Methods: Investigators at the University of Utah Pulmonary Hypertension Program enrolled adults diagnosed with World Health Organization Group 1 PAH, toxin induced, who were seen between August 2020 and December 2021 in a program-specific registry. Their exposure histories were collected through structured interview and questionnaires, and their hemodynamic criteria were recorded. A total of 67 patients with methamphetamine-associated PAH were enrolled within the University of Utah Registry.

Results: Of the 67 patients enrolled, 50.7% were female, 91% were between the ages of 25 and 64. In 82.1% of patients, there was a history of methamphetamine use only (Table 1). The remaining 17.9% had a history of methamphetamine use and either cocaine or heroin. Most of the patients had Functional Class II–III (Figure). Hypertension was seen in 37.3%, hyperlipidemia in 25.4%, and 22.4% had a history of type 2 diabetes mellitus (Table 2).

Conclusions: In this United States Pulmonary Hypertension Association-accredited academic medical center, there are significant numbers of patients with methamphetamine-associated PAH. Published literature currently lacks large multicenter studies on methamphetamine-associated PAH and factors that affect the progression of this disease.

Dominique Ingram

Division of Cardiovascular Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

Ayedh K. Alamri

Division of Cardiovascular Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

Brittany Penn

Division of Cardiovascular Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

Jennalyn D. Mayeux

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Utah, Salt Lake City, UT, USA

Christy Ma

Division of Cardiovascular Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

Dana Klanderud

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Utah, Salt Lake City, UT, USA

Ben Sadeh

Division of Cardiovascular Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

Emily Beck

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Utah, Salt Lake City, UT, USA

Nathan D. Hatton

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Utah, Salt Lake City, UT, USA

John J. Ryan

Division of Cardiovascular Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

Category: Clinical Science

Selected Areas: Databases and Registries; Diagnosis or Screening and Physiologic Studies; Effect of COVID and Telemedicine on PH Management

Background: The phenotype of pulmonary arterial hypertension (PAH) continues to evolve. In this study, we report the characteristics of patients seen in an academic medical center for PAH from August 2020 through November 2021 and contrast those with nationally reported data.

Methods: Investigators at the University of Utah PAH center prospectively enrolled adults diagnosed with World Health Organization Group 1 PAH who were seen between August 2020 and November 2021 in a registry. A total of 251 patients were enrolled within the University of Utah PAH Registry (Table 1).

Results: Of the 251 patients enrolled, the most common etiology was associated-PAH (APAH), accounting for 72% of the population (Figure, Table 2, Table 3). The second largest etiology was idiopathic PAH (IPAH) at 26%. Of the total population with APAH, 36% of cases were noted as secondary to connective tissue disease, and 35% were toxin induced (26% and 25% of the total population, respectively). The remainder of patients were familial PAH and other subgroups of PAH. This contrasts significantly with the percentages reported by the United States Pulmonary Hypertension Registry, among others, where 51% are IPAH, and toxin-APAH accounts for only 18%. Of note, 8% of the patients enrolled in the University of Utah Registry were not on PAH-specific therapies. This contrasts with the published national registries, where nonadherence is <1%.

Conclusions: In a US academic medical center, the PAH population contrasts with traditional reported percentages of etiology of PAH. APAH, not IPAH, accounts for most cases. This may reflect regional variation or practice patterns. This study is limited by the lack of genotyping.

Adriana C. Mares, MS

Division of Cardiovascular Medicine; Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA

Jose B. Cruz, MD

Division of Cardiovascular Medicine; UC San Diego Health, San Diego, CA, USA

Anoop Ayyappan, MD

Radiology Department; Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA

Haider Alkhateeb, MD

Division of Cardiovascular Medicine; Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA

Hernando Garcia, MD

Division of Pulmonary and Critical Care Medicine; Mount Sinai Medical Center, Miami Beach, FL, USA

Category: Case Report

Selected Areas: Diseases and Conditions Associated with PH

Background: Pulmonary veno-occlusive disease (PVOD) is a rare cause of Group 1 pulmonary hypertension (PH) and difficult to distinguish clinically and hemodynamically from idiopathic pulmonary arterial hypertension. Therefore, we must rely on the thorax high-resolution computed tomography (THRCT) diagnostic triad and clinical cues to reach a correct diagnosis.

Methods: (Case) A 74-year-old female with history of limited scleroderma presented with dyspnea New York Heart Association (NYHA) Class IV and NT-pro-BNP of 350 pg/mL. Right heart catheterization showed: right atrial pressure = 3mmHG, pulmonary artery pressure = 78/33/48mmHG, pulmonary capillary wedge pressure = 10mmHG, cardiac index = 1.59L/min/m2, SVO₂ = 65%, and pulmonary vascular resistance = 15.9 WU. Shortly after epoprostenol infusion, chest x ray revealed pulmonary edema. THRCT showed the radiological diagnostic triad (Figure).

Results: (Decision making) Findings of pulmonary edema after epoprostenol infusion, triad THRCT features, and limited scleroderma strongly suggested diagnosis of PVOD. Therapy was initiated with low-dose up-titration of intravenous infusion epoprostenol with a target dose of 10–12 ng/kg/min in combination with endothelin receptor antagonist macitentan. After 8 months, NT-pro-BNP reduced to 57 pg/mL, and dyspnea improved to NYHA Class III, along with quality of life.

Conclusions: This case illustrates the sensitivity of radiological features, which led to the diagnosis of PVOD, the presumptive high prevalence of PVOD in limited scleroderma, and the possible treatment response with pulmonary arterial hypertension-specific therapy in patients who are not lung transplant candidates.

Raysa Morales-Demori

Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA

Jamil Ortoleva

Tufts University School of Medicine, Boston, MA, USA

Marc Anders

Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA

Category: Clinical Science

Selected Areas: Databases and Registries

Background: Extracorporeal membrane oxygenator (ECMO) support in adult patients diagnosed with COVID-19 infection has been widely used; however, the outcomes of this procedure in chronic pulmonary hypertension remain unknown.

Methods: A retrospective cohort study of all patients over 18 years old diagnosed with COVID-19 infection reported to the Extracorporeal Life Support Organization Registry from 2020 until 2021.

Results: A total of 7253 patients diagnosed with COVID-19 who underwent ECMO support were divided into patients without pulmonary hypertension (No-PH; 96%), patients with acute PH (acute-PH; 2%), and patients with chronic PH (chronic-PH; 2%). There were no differences on median age (No-PH = 49 years versus acute-PH = 48 years versus chronic-PH = 50 years). Chronic-PH patients had more comorbidities, such as acute renal failure (45% versus No-PH 29% versus acute-PH 29%, P < 0.001), liver disease (27% versus No-PH 3% versus acute-PH 4%, P < 0.001), and heart failure (25% versus No-PH 6% versus acute-PH 15%, P < 0.001). Chronic-PH patients had longer median hours on ECMO support (604 hours versus No-PH 425 hours versus acute-PH 409 hours, P < 0.001), and higher complications (84% versus No-PH 70% versus acute-PH 81%, P < 0.001). Inpatient mortality was higher in chronic-PH patients (64% versus No-PH 53% versus acute-PH 51%, P = 0.04). When comparing mortality cases between groups, chronic-PH patients had more liver disease (No-PH 4% versus chronic-PH 33%, P < 0.001, odds ratio [OR] = 12.4 [7.7–20.0]), chronic lung disease (No-PH 5% versus chronic-PH 10%, OR = 2.3 [1.1–4.6]), and heart failure (No-PH 8% versus chronic-PH 26%, P < 0.001, OR = 4.3 [2.6–7.1]); however, liver disease was the only factor associated with increased mortality (P = 0.03, OR = 2.6 [1.1–6.3]).

Conclusions: Chronic-PH patients diagnosed with COVID-19 infection undergoing ECMO support have higher comorbidities and inpatient mortality than No-PH or acute-PH patients.

Martha Kingman

University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA

Savan Patel

Liquidia Technologies, Morrisville, NC, USA

Category: Clinical Science

Selected Areas: Quality of Life; Therapeutic Strategies

Background: Liquidia has developed LIQ861, a dry powder formulation of treprostinil by using PRINT Technology, designed to enhance deep-lung delivery and enable QID delivery of doses in 2 breaths per capsule via a convenient, palm-sized dry powder inhaler. PRINT Technology produces drug particles that are precise in size, shape, and composition.

Methods: The INSPIRE trial was a phase 3, open-label, multicenter trial (LTI-301) that enrolled patients with pulmonary arterial hypertension (PAH) over 18 years of age who transitioned to LIQ861 from nebulized treprostinil (Transition) or added LIQ861 to 2 nonprostacyclin oral therapies, prostacyclin naïve (Naïve). The Minnesota Living With Heart Failure Questionnaire (MLHFQ) survey was administered at baseline, 2 months, and 4 months during the trial.

Results: One hundred and twenty-one patients were enrolled in the trial, including 55 in the Transition group and 66 in the Naïve group. Most patients were female, white, and non-Hispanic, with a mean age of 54.2 years. Approximately two-thirds of the patients were New York Heart Association (NYHA) Functional Classification (FC) II, the remaining being NYHA FC III. Most patients received background PAH medications, with 71% receiving a combination of endothelin receptor antagonist and phosphodiesterase 5 inhibitor or soluble guanylate cyclase agonists.

By month 4 (N = 104), there was a clinically meaningful improvement in the total MLHFQ score for all patients from baseline. Overall, the mean score of 36.0 at baseline decreased to 25.8. At month 4, both physical and emotional dimension scores decreased from 16.2 to 11.8 and 7.8 to 5.2, respectively. Improvements were seen in both the Transition and Naïve patient groups.

Conclusions: Treatment with LIQ861 may help improve health-related quality of life, which has been shown to be impaired in PAH patients.

Alvin Rocha

Children’s Hospital Los Angeles, Los Angeles, CA, USA

Reem Itani

Children’s Hospital Los Angeles, Los Angeles, CA, USA

Jacqueline Szmuszkovicz

Children’s Hospital Los Angeles, Los Angeles, CA, USA

Lara C. Bishay

Children’s Hospital Los Angeles, Los Angeles, CA, USA

Category: Case Reports

Selected Areas: Diseases and Conditions Associated with PH; Pediatrics

Background: Scurvy is a rare and reversible cause of pulmonary hypertension in pediatrics with few case reports. Our case is unlike prior cases, as it also included hypothyroidism.

Methods: (Case) A 4-year-old male presented with 2 months of refusal to walk due to leg pain.

Results: Right femur magnetic resonance imaging (MRI) showed presumed osteomyelitis, yet oral antibiotics were ineffective, and thus, he underwent bone biopsy. Postoperatively, he developed acute respiratory distress and hypoxia. D-dimer was elevated, and computed tomography angiogram revealed possible pulmonary embolism or acute infection. Echocardiogram indicated severe pulmonary hypertension (tricuspid regurgitation gradient 119 Torr), presumably secondary to possible pulmonary embolism. Oxygen supplementation and anticoagulation started. Hypercoagulable workup was unremarkable. Whole-body MRI indicated osteopenia. Thyroid function tests revealed severe hypothyroidism without autoimmunity. Levothyroxine was started. Rheumatologic and infectious evaluations were unremarkable. Sildenafil was initiated with mild improvement in right ventricular (RV) pressures. Given history of limited diet of peanut butter sandwiches, vitamin C level was checked and returned undetectable. Intravenous vitamin C started. Within 3 days, RV pressure reduced to 32 Torr. Exome sequencing indicated a variant of uncertain significance in NKX2-1. He was discharged on oral vitamin C, sildenafil, levothyroxine, and oxygen. Echocardiogram normalized 4 weeks after discharge, and oxygen was weaned. He resumed ambulation. Follow-up echocardiogram 4 weeks after weaning sildenafil off remained normal.

Conclusions: (Discussion) Severe pulmonary hypertension and hypothyroidism were reversed with supplemental vitamin C. We are not aware of other case reports of scurvy with hypothyroidism. Exome findings could be relevant.

Brandon Croft

UCSF Fresno, Fresno, CA, USA

Coralee Koning

UCSF Fresno, Fresno, CA, USA

Marcus Cummins

UCSF School of Medicine, San Francisco, CA, USA

Vijay Balasubramanian

UCSF Fresno, Fresno, CA, USA

Category: Case Report

Selected Areas: Diagnosis or Screening and Physiologic Studies; Diseases and Conditions Associated with PH; Quality of Life

Background: Idiopathic pulmonary arterial hypertension (IPAH) is a rare entity that leads to right ventricular (RV) overload and death. Postpartum unmasking of IPAH is rarely reported in the literature but may suggest a new phenotype. We report a case of a young previously healthy female with new onset severe IPAH that was discovered 3 weeks after delivery.

Methods: (Case) A 24-year-old young mother of 4 children presented to our facility 3 weeks after uneventful vaginal delivery with severe dyspnea and syncope found to have a brain natriuretic peptide (BNP) of 2056 pg/mL and normal troponin.

Results: Echocardiogram revealed a severely dilated RV, severe tricuspid regurgitation, and septal flattening. Right heart catheterization confirmed World Health Organization (WHO) Group 1 PAH with high-risk features. Parenteral prostacyclin therapy was initiated immediately. Endothelin receptor antagonist (ERA) and tadalafil was added later sequentially at various times. Acute onset PAH was followed by rapid improvement as well. She was switched to oral treprostinil after 17 months of parenteral therapy. Currently, she remains in a low-risk status—WHO Functional Class 1 after >72 months of prescription (Table).

Conclusions: This case illustrates a phenotype of PAH characterized by acute onset followed by rapid improvement with aggressive upfront treatment measures.

Brandon J. Croft, MD

UCSF Fresno, Fresno, CA, USA

Marcus Cummins, BS

UCSF School of Medicine, San Francisco, CA, USA

Siri Kunchakarra, MD

UCSF Fresno, Fresno, CA, USA

Vaikom Mahadevan, MD

UCSF Division of Cardiology, San Francisco, CA, USA

Vijay Balasubramanian, MD

UCSF Fresno, Fresno, CA, USA

Category: Clinical Science

Selected Areas: Diagnosis or Screening and Physiologic Studies; Diseases and Conditions Associated with PH

Background: Atrial septal defect (ASD) with Eisenmenger’s physiology (EP) is classified as World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH). Pulmonary artery (PA) dilation in this setting can cause left main coronary artery (LMCA) compression and myocardial ischemia. We report a case of a 35-year-old female with ASD who had PAH decompensation secondary to myocardial infarction (MI) from LMCA compression.

Methods: (Case) A 35-year-old woman with WHO Group 1 PAH secondary to ASD and EP presented with abdominal pain and shortness of breath and was found to have acute sepsis from pelvic inflammatory disease on initial presentation.

Results: Troponin was 61 ng/mL with anterolateral T-wave inversion on electrocardiogram. Acute coronary syndrome was diagnosed, and therapeutic heparin was started. Brain natriuretic peptide was 2287 pg/mL with echocardiogram showing preserved ejection fraction, right ventricular systolic pressure of 70 mm Hg, and septal flattening. Computed tomography pulmonary angiogram showed external LMCA compression by the PA (Figure). Coronary angiogram confirmed 95% stenosis of the LMCA without angiographic evidence of atherosclerosis. Right heart catheterization revealed mean pulmonary artery pressure of 54 mm Hg, pulmonary arterial systolic pressure of 102 mm Hg, pulmonary capillary wedge pressure of 15 mm Hg, and pulmonary vascular resistance of 4.3 Wood units. Percutaneous intervention with stent placement resulted in resolution of stenosis.

Conclusions: Sepsis can increase myocardial demand which may worsen right heart function and result in PAH decompensation. Dilatation of main PA predisposes to LMCA compression causing myocardial ischemia. Prompt recognition and intervention resulted in a positive outcome.

Natalie W. Anderson

United Therapeutics Corp., RTP, NC, USA

Melissa Miceli

United Therapeutics Corp., RTP, NC, USA

Natalie E. Patzlaff

United Therapeutics Corp., RTP, NC, USA

Aaron B. Waxman

Brigham and Women’s Hospital, Boston, MA, USA

Category: Clinical Science

Selected Areas: Diseases and Conditions Associated with PH

Background: The goal of the INCREASE study was to see if inhaled treprostinil could help people with pulmonary hypertension and interstitial lung disease (PH-ILD). Before INCREASE, there was no Food and Drug Administration-approved drug for treating PH-ILD. The goal of this plain language summary is to explain the INCREASE trial so that nondoctors can understand the results.

Methods: This was a multicenter, randomized, double-blind, placebo-controlled clinical trial that lasted 16 weeks. A total of 326 people with PH-ILD took part in the study; 163 were given inhaled treprostinil (Tyvaso), and 163 were given a placebo that does not contain any medicine. Because PH-ILD causes breathing problems and tiredness, researchers wanted to test if taking inhaled treprostinil would help people with PH-ILD walk farther in 6 minutes than people with PH-ILD taking placebo.

Results: On average, after 16 weeks in the study, people taking inhaled treprostinil raised their 6-minute walking distance by 31 meters (about 102 feet) more than people in the placebo group (Figure 1). NT-pro-BNP is a protein measuring heart function. Participants taking inhaled treprostinil lowered (improved) their NT-pro-BNP levels from the study start by 42% versus placebo (Figure 2). Compared with placebo, participants taking inhaled treprostinil had a 39% reduced risk of their PH-ILD getting worse. Cough, headache, and throat pain were reported more often by people taking inhaled treprostinil than by people taking placebo (Figure 3; Table).

Conclusions: People with PH-ILD in this study who took inhaled treprostinil walked farther in 6 minutes than those who took placebo. Study participants who received inhaled treprostinil improved other important measures, including a reduced risk of their PH-ILD getting worse.

Cough, headache, and throat pain were reported more often by participants taking inhaled treprostinil than those taking the placebo.

Coralee Koning

UCSF Fresno, Fresno, CA, USA

Brandon Croft

UCSF Fresno, Fresno, CA, USA

Marcus Cummins

UCSF School of Medicine, San Francisco, CA, USA

Ibironke Adelaijaja

UCSF Fresno, Fresno, CA, USA

Vijay Balasubramanian

UCSF Fresno, Fresno, CA, USA

Category: Clinical Science

Selected Areas: Diagnosis or Screening and Physiologic Studies; Diseases and Conditions Associated with PH; Quality of Life

Background: Pulmonary arterial hypertension (PAH) is a devastating disease caused by remodeling of precapillary arterioles leading to a progressive increase in pulmonary vascular resistance, right heart failure, and death. Breast cancer also is a serious diagnosis associated with an adverse prognosis. We describe the case of a young woman who was diagnosed with both conditions in a brief time span. PAH was optimized with parenteral prostacyclin therapy, and she underwent successful surgical mastectomy.

Methods: (Case) A 35-year-old female was diagnosed with World Health Organization Group 1 idiopathic PAH (IPAH) with high-risk features (Table).

Results: Treatment regimen included treprostinil (SQ) and tadalafil. Shortly after, a right breast lump was detected. Evaluation revealed stage IIIb invasive ductal carcinoma with axillary lymph node (LN) involvement. Surgical mastectomy was rendered necessary despite her heightened mortality risk due to PAH. Following multidisciplinary (Surgical Oncology, Cardiac Anesthesiology, Palliative Care, and Pulmonary Hypertension teams) discussion of risks and benefits with the patient, surgery was planned. Preoperative optimization of PAH included increase in treprostinil dose and conversion to intravenous, aggressive diuresis, and pulmonary artery catheter placement. Mastectomy with axillary LN dissection was successfully completed without complication.

Conclusions: Against all odds, this young woman is fighting two serious disease processes associated with high mortality. The above case illustrates her first success. However, the road ahead is less known. A multidisciplinary approach, patient education, and hope are essential to maximize improved outcomes.

Usha Yendrapalli

Huntsville Hospital, Huntsville, AL, USA

Muhammad Mohsin Zafar

UAB, Huntsville Hospital, Huntsville, AL, USA

Abdulwahab Hritani

Cardiology, Huntsville Hospital, Huntsville, AL, USA

Category: Case Report

Selected Areas: Diseases and Conditions Associated with PH; Therapeutic Strategies

Background: Partial anomalous pulmonary venous return (PAPVR) is rare congenital condition that may present during late adulthood or can go undiagnosed for years. We present 3 patients with pulmonary arterial hypertension (PAH) secondary to PAPVR whose symptoms improved after treatment.

Methods: Retrospective chart review and case series.

Results: A 60-year-old male presented with dyspnea. Echo-cardiogram revealed ejection fraction (EF) of 45%–50% and pulmonary arterial systolic pressure (PASP) of 83 mm Hg. Right heart catheterization (RHC) revealed PAH with pulmonary arterial pressure (PAP) of 80/40 mm Hg, and pulmonary capillary wedge pressure (PCWP) of 18 mm Hg. Computed tomography (CT) angiogram of the heart showed anomalous pulmonary venous return from the right lung. Patient was initiated on PDE-5 inhibitor with improvement in his symptoms.

A 73-year-old male presented with dyspnea. Echocardiogram revealed EF of 60% and PASP of 90 mm Hg. RHC revealed severe PAH with mean PAP of 65 mm Hg and PCWP of 26 mm Hg. Serial O₂ saturation showed a significant increase in O₂ saturation, particularly at high right atrium (RA), and superior vena cava junction of 86%. CT angiogram of the heart showed anomalous return of the left upper pulmonary vein to the superior vena cava. Patient began PDE-5 inhibitor treatment with good symptomatic response.

A 75-year-old female presented with dyspnea. Echocardiogram revealed EF of 55% and PASP of 50 mm Hg. Bubble study was positive for a right to left shunt via both arm access with a shunt ratio of 4.7. CT angiogram of the heart showed anomalous drainage of the right-sided pulmonic veins into the RA. RHC revealed PAP of 76/17 mm Hg and PCWP of 18 with a pulmonary angiogram, which demonstrated right upper, middle pulmonary veins draining into RA. Patient began PDE-5 inhibitor with improvement in her symptoms.

Conclusions: Patients with unexplained PAH should have a high degree of suspicion for PAPVR. Awareness of PAPVR is important because untreated PAPVR can lead to PAH.

Jason Peng, MD

Loyola University Medical Center, Maywood, IL, USA

Phoebe Stracener, PharmD

Loyola University Medical Center, Maywood, IL, USA

Jenny Altobelli, RN, BSN

Loyola University Medical Center, Maywood, IL, USA

James Gagermeier, MD

Loyola University Medical Center, Maywood, IL, USA

Sana Quddus, MD

Loyola University Medical Center, Maywood, IL, USA

Category: Case Report

Selected Areas: Diseases and Conditions Associated with PH; Quality of Life; Therapeutic Strategies

Background: Parenteral prostacyclin therapy is well established for patients with World Health Organization Group 1 pulmonary arterial hypertension (PAH). However, difficulty tolerating long-term parenteral therapy due to line- and delivery-related complications is common, resulting in poor quality of life. While case series describing the transition from parenteral prostacyclin to selexipag exist, there is no standardized protocol. Furthermore, we sought to assess the change in quality of life associated with the transition.

Methods: This case series includes 3 transitions (2 inpatient and 1 outpatient) from parenteral prostacyclins to selexipag between February 2020 and November 2021. Protocols are shown in Figures 1–3. Quality of life was assessed using the emPHasis-10 score.

Results: Patient 1 is a 50-year-old female with PAH and sarcoidosis on macitentan and intravenous (IV) epoprostenol, who transitioned over 7 days as an inpatient for recurrent line infections. Patient 2 is a 22-year-old female with idiopathic PAH on macitentan, sildenafil, and IV treprostinil, who transitioned over 5 days as an inpatient for recurrent line infections. Patient 3 is a 71-year-old female with HIV-associated PAH on macitentan and SQ treprostinil who had a prolonged outpatient transition for severe site discomfort. This transition over 647 days was interrupted by the COVID-19 pandemic. Mean emPHasis-10 scores decreased from 28.3 (pretransition) to 15.3 (posttransition). Six-minute walk distance (6MWD) improved, while the New York Heart Association (NYHA) Functional Class remained stable pretransition and posttransition (Table).

Conclusions: Our case series provides a reference with time-lines for transitioning from low-dose parenteral prostacyclins to selexipag. Patients had significant improvements in quality of life and 6MWD.

Usha Yendrapalli

Huntsville Hospital, Huntsville, AL, USA

Muhammad Mohsin Zafar

UAB, Huntsville Hospital, Huntsville, AL, USA

Abdulwahab Hritani

Cardiology, Huntsville Hospital, Huntsville, AL, USA

James D Murphy

Cardiology, Huntsville Hospital, Huntsville, AL, USA

Category: Case Report

Selected Areas: Diseases and Conditions Associated with PH

Background: Cor triatriatum sinister is a rare congenital heart defect in which a fibromuscular membrane subdivides the left atrium (LA) into 2 chambers. We present a case report of pulmonary arterial hypertension (PAH) secondary to cor triatriatum.

Methods: Retrospective chart review and case report.

Results: A 43-year-old male presented for dyspnea on exertion. Echocardiogram showed ejection fraction of 60%, right ventricular pressure overload, pulmonary arterial systolic pressure of 80 mm Hg, and membrane separating LA chambers concerning cor triatriatum. Computed tomography (CT) angiogram of the heart showed dilated pulmonary artery (PA; 4 cm), enlarged and septated LA with evidence for cor triatriatum. Right heart catheterization (RHC) revealed severe PAH with pulmonary arterial pressure (PAP) of 95/65 mm Hg with mean of 75 mm Hg, transpulmonary gradient of 70, cardiac output was 4.65, cardiac input of 2.4. He underwent complete repair of the cor triatriatum with surgical resection of the membranes. Post-surgery repeat echocardiogram showed improved right-sided pressures, and RHC showed PAP of 62/37 with a mean of 47 mm Hg. Symptoms improved significantly after surgery.

Conclusions: Awareness of cor triatriatum is important because untreated cor triatriatum can lead to PAH. Identification of cor triatriatum sinister is increasing due to widespread use of advanced techniques, such as CT and angiography. Cor triatriatum is amenable to surgical repair with good outcomes when diagnosed early.

Sindhubarathi Murali

SUNY Upstate Medical University, Syracuse, NY, USA

Subrat Khanal

SUNY Upstate Medical University, Syracuse, NY, USA

Kartik Ramakrishna

SUNY Upstate Medical University, Syracuse, NY, USA

Category: Case Report

Selected Areas: Therapeutic Strategies

Background: After initiation of combination therapy, one must be careful about potential interruption in therapy resulting in rebound pulmonary arterial hypertension (PAH).

Methods: The first case involved a 41-year-old woman with heritable pulmonary hypertension (PH) on ambrisentan, tadalafil, and inhaled treprostinil. Given her acute cholecystitis, she was unable to tolerate her medications. The second case involved a 55-year-old woman with PAH on intravenous treprostinil and macitentan. She was without infusion for 50 minutes.

Results: Both patients experienced right heart failure and required aggressive diuresis. The first patient’s echocardio-gram showed a severely dilated right ventricle (RV) and right atrium (RA; 90.1 mL/m), moderate tricuspid regurgitation (TR V Max, 4.88 m/s; tricuspid annular plane systolic excursion (TAPSE), 1 cm) and RV systolic pressure of 110 mm Hg (Figure 1). The second patient’s computed tomography of the thorax showed a dilated pulmonary artery (PA; Figure 2). Right heart catheterization showed RA pressure of 6 mm Hg, RV pressure of 74/10, PA pressures of 73/25, pulmonary capillary wedge pressure of 10 mm Hg, cardiac output/cardiac input of 2.4/1.6, and pulmonary vascular resistance of 15 consistent with severe precapillary PH. She was started on tadalafil.

Conclusions: Despite the vast benefits PGI2 analogues provide, careful consideration should be taken before starting them given their difficulty to discontinue. Those with poor functional class or abnormal hemodynamics have greater difficulty discontinuing from a PGI2 analogue. If discontinuation of the medication is <4–5 half-lives of the last dose taken, then the medication should be taken at the last tolerated dose. If the time between doses is >4–5 half-lives, then a lower dose with rapid up-titration based on tolerance is required (Narechania S, Torbic H, Tonelli AR. Treatment discontinuation or interruption in pulmonary arterial hypertension. J Cardiovasc Pharmacol Ther. 2019;25(2): 131–141. https://doi.org/10.1177/107424841987740). These case reports highlight the importance and severity of abrupt discontinuation of PAH medication and in turn provide some guidance on how to manage such patients.

Nicholas Shelburne

Department of Medicine, Division of Allergy, Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN, USA

Hui Nian

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA

Chang Yu

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA

Anna Hemnes

Department of Medicine, Division of Allergy, Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN, USA

PVDOMICS Study Group

Category: Clinical Science

Selected Areas: Diagnosis or Screening and Physiologic Studies

Background: Sex-based differences are important factors in the development and progression of PH. We sought to use the deep phenotyping of the PVDOMICS project to test the hypothesis that males with pulmonary hypertension (PH) will have worse right ventricular (RV) function than females at similar elevations of pulmonary vascular resistance (PVR).

Methods: Subjects enrolled in PVDOMICS with PH were included. For this analysis, subjects were grouped based on PVR: 2.4–5 and >5 Wood units (WU), and differences in RV ejection fraction (EF) on cardiac magnetic resonance imaging between men and women were assessed using the Wilcoxon rank sum test. Effects of sex and RV function on transplant-free survival were assessed using Cox Proportional Hazards Model.

Results: A total of 750 patients with PH (62.8% female) were enrolled. World Symposia on Pulmonary Hypertension Group 1 patients were most predominantly female at 73.4%. Among the 349 PH patients (61.8% female) with measurements of both RVEF and PVR, RVEF was significantly lower in men (38.3 ± 10.2% versus 42.4 ± 11.8%, P < 0.001), while there was no significant difference in PVR (5.4 ± 3.4 versus 5.9 ± 3.8 WU, P = 0.3). In PH patients with mild elevation in PVR (2.4–5 WU; n = 148, 58.8% female), RVEF was reduced in men (41.0 ± 9.3% versus 46.8 ± 10.3%, P < 0.001); however, in patients with PVR >5 WU (n = 157, 64.3% female), the trend toward worsened RVEF in men was not significant (34.3 ± 9.8% versus 37.3 ± 11.5%, P = 0.09). In PH patients, female sex was associated with improved survival (heart rate = 0.61, 95% confidence interval = 0.46–0.82), and this difference was partially mediated by differences in RVEF (natural indirect effect: −0.14, P = 0.01; Figure).

Conclusions: Among PH patients with mild elevations in PVR, RV function is significantly worse in men. Women with PH have improved survival compared with men, and this difference is partially explained by differences in RV function.

Meghan Morrisette PharmD

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC, USA

Kristine Ritenour RN

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC, USA

Denise Sese MD

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC, USA

Rahul G. Argula MBBS, MPH

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC, USA

Category: Case Report

Selected Areas: Effect of COVID and Telemedicine on PH Management; Quality of Life; Therapeutic Strategies

Background: During the COVID-19 pandemic, there was a need for providers to continue providing quality care for pulmonary arterial hypertension (PAH) patients despite limitations in access to care. Safe transitions of PAH patients from intravenous (IV) prostacyclin therapy to PO selexipag therapy in the inpatient setting have previously been described in several case series with mixed results, but there is a dearth of experience with the outpatient setting.

Methods: In this case series, we describe the successful transition of 4 patients with World Health Organization (WHO) Group 1 PAH and WHO Functional Class (FC) 1 or 2 symptoms who were transitioned at home under supervision of the PAH team. We compared the differences in their baseline and follow-up functional class, 6-minute walk distance, echocardiograms, right heart catheterizations, and reported quality of life.

Results: Patients were all female (2 Caucasian, 2 African American) with an age range of 26–54 years. The primary reasons for transitioning patients to PO therapy were to improve quality of life and unmanageable IV prostacyclin side effects. The length of IV therapy prior to PO transition ranged from 3 to 100 months with an epoprostenol maintenance dose range of 9–29.5 ng/kg/min. Three out of the 4 patients were on triple PAH therapy. Patients were transitioned with an average decrement of epoprostenol of 0.62 ng/kg/min/day and an average weekly increase of selexipag of 172 mcg twice daily over a range of 17–57 days. There were no significant changes in FC nor significant complications related to PAH in the first 3 months following transition. All patients reported an improvement in their quality of life.

Conclusions: Home IV to PO therapy transitions can be done successfully in carefully selected patients with guidance from a multidisciplinary team.

Michelle Palacios

Altavanty Sciences Inc, Cary, NC, USA

Jill Denning

Altavanty Sciences Inc, Cary, NC, USA

Howard Lazarus

Altavanty Sciences Inc, Cary, NC, USA

Stephen Wring

Altavanty Sciences Inc, Cary, NC, USA

Category: Basic Science

Selected Areas: Diseases and Conditions Associated with PH

Background: Rodatristat (R), as rodatristat ethyl (RE) prod-rug, inhibits tryptophan hydroxylase (TPH) the rate-limiting enzyme in serotonin (5-HT) biosynthesis. In pulmonary arterial hypertension (PAH), elevated 5-HT in pulmonary endothelial cells drives vascular remodeling. Key to TPH therapy is avoiding reductions in brain 5-HT. Here, we leverage nonclinical disposition data, with mood and Columbia-Suicide Severity Rating Scale (C-SSRS) assessments in healthy subjects, to assess potential for central nervous system effects.

Methods: Potency for TPH inhibition, protein binding, and blood-brain barrier passage were measured in vitro. Tissue disposition was by quantitative whole-body autoradiography in rats receiving 14C-RE at the dose efficacious in rat PAH models. Rat brain 5-HT was measured after 21 days RE at 2× the efficacious dose. In healthy subjects, C-SSRS data were collected at baseline and after 14 days of either: 400 mg BID, 800 mg BID, 500 mg QD, or 800 mg QD RE.

Results: In vitro R potently inhibits nonneuronal TPH1 (IC50, 52 nM) and neuronal TPH2 (9 nM); however, exposure was barely detectable in rat brain consistent with in vitro data (>99% protein bound; permeability <25 nm/s). Brain 5-HT was unaffected in monocarboxylate transporter (MCT) + vehicle and MCT + RE animals. Free R levels in lung were ~3× the TPH1 IC50, yielding robust reductions in tissue 5-HT in MCT rats. Plasma concentration (Cmax) for R was ~2560 ng/mL. In healthy subjects, steady-state Cmax was 1370 ng/mL (800 mg BID RE) and 1260 ng/mL (600 mg BID, highest phase 2b dose). Plasma concentrations in humans are ~50% of rat where no changes in brain 5-HT were observed. In humans, there were no changes in mood or suicidal ideation in any subject across all dose groups (n = 36).

Conclusions: RE should not affect brain 5-HT nor mood in humans.

Kate Schole, MD

Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA

Guillermo Torres, MD

Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA

Jun Yang, PhD

Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA

Stephanie Brandal

Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA

Megan Griffiths, MD

Division of Pediatric Cardiology, Department of Pediatrics, Columbia University Medical Center, New York, NY, USA

Rachel Damico, MD, PhD

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA

Dhananjay Vaidya, MD, PhD

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

Division of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA

Catherine E. Simpson, MD, PhD

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA

Michael W. Pauciulo, PhD

Division of Human Genetics, Cincinnati Children’s Hospital Medical Center; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

William C. Nichols, PhD

Division of Human Genetics, Cincinnati Children’s Hospital Medical Center; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

David D. Ivy, MD

Department of Pediatric Cardiology, Children’s Hospital Colorado, Denver, CO, USA

Eric D. Austin, MD

Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA

Paul M. Hassoun, MD

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA

Allen D. Everett, MD

Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA

Category: Clinical Science

Selected Areas: Diagnosis or Screening and Physiologic Studies

Background: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vascular remodeling resulting in right ventricular pressure overload and right heart failure. Growth differentiation factor 15 (GDF-15), a member of the transforming growth factor-B cytokine superfamily, is a left heart failure biomarker with pilot evidence of elevation in patients with PAH.

Rationale: Determine diagnostic and prognostic utility of GDF-15 levels in PAH patients via correlation with deteriorating clinical severity and mortality rates.

Methods: Serum GDF-15 levels from the National Heart, Lung, and Blood Institute PAH Biobank were evaluated by enzyme-linked immunosorbent assay (ELISA). A total of 1932 subjects and 50 healthy controls was evaluated. Association of GDF-15 levels with PAH clinical variables were assessed via Spearman’s rank correlation test and Kruskal-Wallis test. Cox multivariable and Kaplan-Meier analyses were used to examine survival associations with GDF-15.

Results: Receiver operating characteristic (ROC) analysis evaluated GDF-15’s ability to distinguish between PAH and controls with area under the curve = 0.85. By PAH classification, connective tissue participants had highest overall GDF-15 levels (3.07 ± 2.5 ng/mL). Higher GDF-15 correlated with higher New York Heart Association Classification. Adjusted GDF-15 levels were associated with a 20 m decrease in 6-minute walk distance (95% confidence interval [CI] = −29.2 to −11.3, P < 0.001), and a 0.58 mm Hg increase in right atrial pressure (95% CI = 0.29–0.86, P < 0.001). Kaplan-Meier analyses showed a significant difference in survival curves and adjusted Cox proportional hazards showed a 1.88 greater risk of death (95% CI = 1.59–2.23, P < 0.001; Figure).

Conclusions: Measuring GDF-15 levels may offer additional prognostic value in the clinical evaluation of PAH.

Elise Whalen

Department of Pulmonary Medicine, Texas Children’s Hospital, Houston, TX, USA

Myra Baker

Department of Pulmonary Medicine, Texas Children’s Hospital, Houston, TX, USA

Amy Alonzo

Department of Pharmacy, Texas Children’s Hospital, Houston, TX, USA

Rozmeen Fombin

Department of Pulmonary Medicine, Texas Children’s Hospital, Houston, TX, USA

Erin Ely

Department of Pulmonary Medicine, Texas Children’s Hospital, Houston, TX, USA