Conference Guide for the Pulmonary Hypertension Association by KTD Creative

PHA 2018 SCIENTIFIC SESSIONS AND EDUCATION FOR

MEDICAL PROFESSIONALS THE PATH TO PRECISION MEDICINE IN PULMONARY VASCULAR DISEASE

June 29 to July 1, 2018

Orlando, Florida

Thank you for attending the PHA Scientific Sessions and PH Clinical Sessions: Continuing Education for Medical Professionals! Unlike the patient breakout sessions during Conference, the PHA Scientific Sessions and PH Clinical Sessions are dedicated to the exchange of information among health care professionals who work in the field of pulmonary hypertension. If you are not a health care professional, we ask that you refrain from asking questions during the presentations.

ERIKA S. BERMAN ROSENZWEIG, M.D.

Chair, PHA Scientific Leadership Council Professor of Pediatrics (in Medicine) Medical Director, Pulmonary Hypertension Comprehensive Care Center Columbia University Medical Center New York Presbyterian Hospital New York, N.Y.

2018 PHA SCIENTIFIC SESSIONS COMMITTEE

Dear Friends,

VINICIO A. DE JESUS PEREZ, M.D., FCCP, FAHA

Chair, PHA Scientific Sessions Committee Assistant Professor of Medicine and Staff Physician Stanford Adult Pulmonary Hypertension Clinic Comprehensive Care Center Stanford University Medical Center Stanford, Calif.

PULMONARY HYPERTENSION ASSOCIATION

PHA Scientific Sessions Agenda....3

Dear Colleagues, Welcome to PHA’s 2018 International PH Conference and Scientific Sessions: PHinding Your Hope, the largest international gathering of pulmonary hypertension (PH) community members in the world. This year’s theme unites the community to celebrate the achievements that have helped people with PH live longer, healthier lives while looking toward the future. During the Conference, people living with PH and their families and caregivers will feel empowered by learning more about the disease, meeting others who have stories similar to their own, discovering ways to be more involved in the community and participating in research that will help advance our knowledge, as health care professionals, of the disease. Aligned with PHinding Your Hope, this year’s PHA Scientific Sessions theme, The Path to Precision Medicine in Pulmonary Vascular Disease, focuses on care that is tailored to each patient’s needs. As we explore the path towards individualized treatments in the Scientific and Clinical Sessions and CME/CE-accredited poster hall, patients and their families will explore the path towards hope and living their best lives with PH. I hope that you take advantage of this opportunity to not only learn more about caring for your patients, but also to connect with them in this unique setting PHA has fostered. Thank you for joining us at PHA’s 13th Conference. I look forward to learning with you.

Welcome to PHA’s 2018 International PH Conference and Scientific Sessions! The PHA Scientific Sessions Committee has planned four days of thoughtprovoking and motivating medical education for you and your colleagues. On Thursday evening, join us in the poster hall to explore ongoing research in the field, hear lightning-round presentations from authors of the top submitted abstracts and – for the first time at Conference – earn three hours of CME/CE credit for attendance. Also new this year are the PH Clinical Sessions, which have replaced PH Fundamentals as a sequence of highly interactive sessions designed for health care professionals of all experience levels to enhance their skills and expertise in the diagnosis, treatment and management of patients with PH. During the PHA Scientific Sessions on Friday, we will explore topics aligned with the theme: The Path to Precision Medicine in Pulmonary Vascular Disease. These sessions were designed in blocks that will explore: 1) novel treatments and clinical trials, 2) the future of therapy development, 3) insights into genetics and genomics, 4) use of wearable devices for disease monitoring and 5) pediatric advancements. The planning committee has invited key opinion leaders in the field of PH, as well as prominent representatives from other disciplines in order to gain a unique perspective. Thanks for joining us, and welcome!

TABLE OF CONTENTS PH Clinical Sessions Agenda.......4 Hotel Floor Plans.........................5 Accreditation Information............7

Vinicio A. de Jesus Perez, M.D., FCCP, FAHA (Chair) Stanford University Medical Center Stanford, Calif.

Christine Archer-Chicko, M.S.N., CRNP University of Pennsylvania Philadelphia

Abstract Winners and Presentations..............................10 PHA Scientific Sessions..............12 PH Clinical Sessions..................16 Abstracts.................................... 18 PHA Resources........................126 PHA Grant Award Recipients....127 PHA Leadership.......................129

Evan Brittain, M.D., M.Sc. Vanderbilt University Medical Center Nashville, Tenn.

Jason Elinoff, M.D. NIH Clinical Center Bethesda, Md.

Rachel Hopper, M.D. Stanford University School of Medicine Palo Alto, Calif.

Laura Duvall, PharmD, BCPS OhioHealth Dublin, Ohio

Brian Graham, M.D., M.A. University of Colorado Anschutz Medical Campus Aurora, Colo.

Allyson Rupp, M.S.W., LCSW Stanford University Medical Center Stanford, Calif.

801 Roeder Road, Suite 1000 Silver Spring, MD, 20910 Ph: 301-565-3004 Fax: 301-565-3994 Patient-to-Patient Support Line: 800-748-7274

Thenappan Thenappan, M.D. University of Minnesota Minneapolis

Tonya Zeiger, R.R.T., CPFT Mayo Clinic Florida Jacksonville, Fla.

PHAssociation.org PHAOnlineUniv.org PHA@PHAssociation.org

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

Friday, June 29 (continued)

Thursday, June 28 Time

Session

Location

Omics and Wearables in Pulmonary Hypertension: Are We There Yet?

4:30 - 7:30 p.m.

Scientific Sessions Poster Hall

Atrium A (Lobby level)

4:10 - 4:35 p.m.

An Integrative Personal Omics Profile

Oceans Ballroom 9-12 (Lobby level)

7:30 - 9 p.m.

Fellow and Junior Faculty Reception All PHCR members welcome Sponsored by Actelion Pharmaceuticals

Upper Deck (2nd floor)

4:35 - 5 p.m.

The NHLBI PVDOMICS Initiative: An Introduction

Oceans Ballroom 9-12 (Lobby level)

PH Professional Network Reception Sponsored by Actelion Pharmaceuticals

5 - 5:25 p.m.

Oceans Ballroom 9-12 (Lobby level)

Crystal C (Lobby level)

The Role of Wearable Devices in PAH: The Case of CardioMEMS™

5:25 - 5:30 p.m.

Closing Remarks

Oceans Ballroom 9-12 (Lobby level)

7 - 8:30 p.m.

Medical Update Dinner General session

Oceans Ballroom 1-8 (Lobby level)

7:30 - 9 p.m.

Friday, June 29 PHA SCIENTIFIC SESSIONS 7 - 8 a.m.

Scientific Sessions Continental Breakfast

Oceans Ballroom Foyer (Lobby level)

8 - 8:15 a.m.

Scientific Sessions Welcome and Introduction

Oceans Ballroom 9-12 (Lobby level)

8:15 - 8:45 a.m.

Keynote Address: How Do You Envision Precision Medicine for PH?

Oceans Ballroom 9-12 (Lobby level)

Basic Science and Clinical Trials: Accelerating the Future 8:45 - 9:15 a.m.

Novel Therapies Targeting the Right Ventricle

Oceans Ballroom 9-12 (Lobby level)

9:15 - 9:45 a.m.

Novel Therapies Targeting the Pulmonary Vasculature

Oceans Ballroom 9-12 (Lobby level)

9:45 - 10:15 a.m.

Novel Clinical Trial Design and Endpoints

Oceans Ballroom 9-12 (Lobby level)

10:15 - 10:30 a.m.

Coffee Break Sponsored by Accredo

Oceans Ballroom Foyer (Lobby level)

Pathway to Developing Future PH Therapies: Road Work Ahead 10:30 - 11:15 a.m.

Limitations and Opportunities for the Pharmaceutical Industry in Developing New PH Therapies

Oceans Ballroom 9-12 (Lobby level)

11:15 to noon

What the FDA Wants for New PH Therapy Development and Approval

Oceans Ballroom 9-12 (Lobby level)

noon to 12:10 p.m. Lunch Pickup 12:10 - 12:55 p.m.

Academia, Industry and Patient Advocacy Foundations Working Together to Develop New Therapeutics

Oceans Ballroom 9-12 (Lobby level)

1 - 2 p.m.

Conference Opening General session

Oceans Ballroom 1-8 (Lobby level)

2:30 - 2:55 p.m.

PH in the Pediatric Population: Insights From the PPHNet Registry

Oceans Ballroom 9-12 (Lobby level)

2:55 - 3:20 p.m.

Lung Development and Origins of PH Associated With Chronic Lung Disease of Prematurity

Oceans Ballroom 9-12 (Lobby level)

3:20 - 3:40 p.m.

Congenital Heart Disease and PH: Novel Treatment Approaches

Oceans Ballroom 9-12 (Lobby level)

3:40 - 4 p.m.

Imaging the Right Ventricle in Children

Oceans Ballroom 9-12 (Lobby level)

4 - 4:10 p.m.

Coffee Break

Oceans Ballroom Foyer (Lobby level)

PULMONARY HYPERTENSION ASSOCIATION

PH CLINICAL SESSIONS 8 - 9 a.m.

Networking with a Medical Professional Breakfast General session Please use open seating

Oceans Ballroom 1-8 (Lobby level)

9:30 - 10:30 a.m.

Palliative Care and Navigating Difficult Discussions in Pulmonary Hypertension 2018 PHA Scientific Sessions

Oceans Ballroom 9-12 (Lobby level)

10:30 - 11 a.m.

and Education Coffee Break

Oceans Ballroom Foyer (Lobby level)

11 a.m. to noon

Pulmonary Rehabilitation and Oxygen Therapy

Oceans Ballroom 9-12 (Lobby level)

12:30 - 1:30 p.m.

Journeys Lunch General session

Oceans Ballroom 1-8 (Lobby level)

2 - 3 p.m.

Lung Transplantation: From Listing to Management

Oceans Ballroom 9-12 (Lobby level)

3 - 3:30 p.m.

Coffee Break

Oceans Ballroom Foyer (Lobby level)

3:30 - 4:30 p.m.

Pediatric PH Patients: New Guidelines and Differences From Adult Care

Oceans Ballroom 9-12 (Lobby level)

6 - 7 p.m.

Awards Dinner General session

Oceans Ballroom 1-6 (Lobby level)

7 - 8 a.m.

Coffee Break

Oceans Ballroom Foyer (Lobby level)

8 - 9 a.m.

Chronic Thromboembolic Pulmonary Hypertension: Oceans Ballroom 9-12 (Lobby level) Cases, Controversies, Challenges and Conundrums

9:30 - 10:30 a.m.

PAH Therapies: Insurance, Patient Assistance Programs and New Therapies on the Horizon

Oceans Ballroom 9-12 (Lobby level)

11 a.m. to noon

Closing Brunch General session

Oceans Ballroom 1-6 (Lobby level)

Oceans Ballroom Foyer (Lobby level)

Pediatrics: Fast Lane or the Scenic Route?

Saturday, June 30

for Medical

Professionals

Sunday, July 1

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

HOTEL FLOOR PLANS Lobby level

HOTEL FLOOR PLANS 2nd Floor

2018 PHA Scientific Sessions and Education for Medical Professionals

Exhibit Hall

PULMONARY HYPERTENSION ASSOCIATION

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

CONTINUING EDUCATION CREDIT Physicians

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the Joint Providership of Professional Education Services Group/AffinityCE and the Pulmonary Hypertension Association. Professional Education Services Group is accredited by the ACCME to provide continuing medical education for physicians. Professional Education Services Group designates this live CME activity for a maximum of 16.0 hours of AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Physician Assistants

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the Joint Providership of Professional Education Services Group/AffinityCE and the Pulmonary Hypertension Association. Professional Education Services Group is accredited by the ACCME to provide continuing medical education for physicians. Professional Education Services Group designates this live CME activity for a maximum of 16.0 hours of AMA PRA Category 1 Credit(s)™. Physician assistants should claim only the credit commensurate with the extent of their participation in the activity.

Nurses

This educational activity is provided through a collaboration between Professional Education Services Group and The Pulmonary Hypertension Association. Professional Education Services Group is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC). This activity provides a maximum of 16.0 contact hours of nurse CE credit.

Nurse Practitioners

This activity has been planned and implemented in accordance with the accreditation standards of the American Association of Nurse Practitioners (AANP) through the joint providership of Professional Education Services Group/AffinityCE and the Pulmonary Hypertension Association. Professional Education Services Group is accredited by the American Association of Nurse Practitioners as an approved provider of nurse practitioner continuing education. Provider number: 031105. This course is offered for 16.0 contact hours.

Respiratory Therapists

Professional Education Services Group is accredited as a provider of continuing education contact hours for respiratory therapists by the American Association for Respiratory Care. This Continuing Respiratory Care Education (CRCE) system of the American Association of Respiratory Care (AARC) grants approval for 16.0 hours for this course.

PULMONARY HYPERTENSION ASSOCIATION

Pharmacists and Pharmacy Technicians

Professional Education Services Group is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This knowledge-based activity is approved for up to 16.0 (1.60 CEUs) of pharmacy continuing education credit. UAN are provided for each session. Participant CE records will be electronically communicated to CPE Monitor. The cost for pharmacy CE activities are included in Conference registration fees.

Social Workers

This program is approved by the National Association of Social Workers for up to 13.0 Social Work continuing education contact hours.

Other Professionals

Other professionals participating in this activity may obtain a General Participation Certificate indicating their participation and the number of hours of continuing education credit. This certificate may be used as a record of continuing education participation to meet licensing requirements. Please consult your professional licensing organization for acceptance of this CE credit.

PLANNING COMMITTEE DISCLOSURES Vinicio A. de Jesus Perez, M.D., FCCP, FAHA is a selfmanaged stock shareholder in Actelion Pharmaceuticals Ltd., Gilead Sciences, Inc., Pfizer, Inc. and Eiger BioPharmaceuticals, Inc. Christine Archer-Chicko, M.S.N., CRNP has served as a consultant, advisory board member or steering committee member for Actelion Pharmaceuticals Ltd.

Rachel Hopper, M.D. has nothing to disclose. Allyson Rupp, M.S.W., LCSW has served as a consultant, advisory board member or steering committee member for Actelion Pharmaceuticals Ltd., has served on a speaker’s bureau for Actelion Pharmaceuticals Ltd., and is an active faculty member for “Beyond the Basics” through Guidemark Health, sponsored by Actelion Pharmaceuticals Ltd.

Laura Duvall, PharmD, BCPS has nothing to disclose.

Thenappan Thenappan, M.D. has served as a consultant, advisory board member or steering committee member for Actelion Pharmaceuticals Ltd. and Gilead Sciences, Inc. and has served on a speaker’s bureau for Medscape.

Jason Elinoff, M.D. has nothing to disclose.

Tonya Zeiger, R.R.T., CPFT has nothing to disclose.

Brian Graham, M.D., M.A. has received research or grant support from the National Institutes of Health.

PHA staff and PESG staff planners and reviewers have no relevant financial interest to disclose.

Evan Brittain, M.D., M.Sc. has received investigator initiated research support from Gilead Sciences, Inc.

FACULTY DISCLOSURES

Commercial Support:

No commercial support was provided for accredited activities.

Participation Costs:

The cost to participate in these CE sessions is included in the meeting registration cost.

CME Inquiries:

For all CME related inquiries, please contact cds_support+pha@ pesgce.com.

Additional Information:

Additional information about this activity can be found at: PHAssociation.org/Education-Programs/Conference

How to Claim CE Credit

1. Go to the following URL: https://pha.cds.pesgce.com 2. Select the activity: 2018 Scientific Conference 3. Enter an e-mail address and password to begin setting up your profile or log in to an existing account 4. Verify, correct or add your information 5. Proceed and complete the activity evaluation for each session you attended 6. Upon completing your evaluations, you can print your CE certificate; your CE record will also be stored here for later retrieval 7. Please note that you must also complete an overall activity evaluation before you can print your CE certificate 8. If you are a pharmacist or pharmacy technician, your records will be reported directly to CPE Monitor 9. The website is open for completing your evaluation for 45 days after the event 10. After the website has closed, you can come back to the site at any time to print your certificate, but you will not be able to add any evaluations Please send any customer service requests to cds_ support+pha@pesgce.com.

Steven H. Abman, M.D. has received research or grant support from United Therapeutics Corporation. Rana Awdish, M.D., FCCP has nothing to disclose. Raymond L. Benza, M.D., FACC has received research or grant support from Actelion Pharmaceuticals Ltd., United Therapeutics Corporation, Bellerophon Therapeutics and Abbott. Erika S. Berman Rosenzweig, M.D. has received research or grant support from Actelion Pharmaceuticals Ltd., Gilead Sciences, Inc., Bayer HealthCare Pharmaceuticals LLC, United Therapeutics Corporation and Lung Biotechnology PBC. Sangeeta M. Bhorade, M.D. has nothing to disclose. Harm Bogaard, M.D. has nothing to disclose. Gerilynn Connors, B.S., R.R.T., MAACVPR has nothing to disclose. Ramona Doyle, M.D., M.Sc. is a self-managed stock shareholder in Roche Pharma and Gilead Sciences, Inc. Greg Elliott, M.D., MACP has served as a consultant, advisory board member or steering committee member for Bayer HealthCare Pharmaceuticals LLC and Bellerophon Therapeutics, has received research or grant support from Intermountain Research & Medical Foundation/Intermountain Healthcare, and Actelion Pharmaceuticals Ltd.

David B. Frank, M.D., Ph.D. has nothing to disclose. Elena Goncharova, Ph.D. has received research or grant support from Regeneron Pharmaceuticals. Stephanie Siehr Handler, M.D. has nothing to disclose. Anna Hemnes, M.D. has served as a consultant, advisory board member or steering committee member for Acceleron Pharma, Inc., Actelion Pharmaceuticals Ltd., Bayer HealthCare Pharmaceuticals LLC and United Therapeutics Corporation, and has received corporation grants from the National Institutes of Health and The Cardiovascular Medical Research Fund. Dunbar Ivy, M.D. has served as a consultant, advisory board member or steering committee member for Actelion Pharmaceuticals Ltd., Bayer HealthCare Pharmaceuticals LLC, Eli Lilly and Company and United Therapeutics Corporation; has received research or grant support from Actelion Pharmaceuticals Ltd., United Therapeutics Corporation, Eli Lilly and Company, Bayer HealthCare Pharmaceuticals LLC, the National Institutes of Health and U.S. Food and Drug Administration; and is also a Board member of the Association for Pediatric Pulmonary Hypertension. Steven M. Kawut, M.D., M.S. has nothing to disclose.

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

FACULTY DISCLOSURES

ABSTRACT WINNERS AND PRESENTATIONS

(CONTINUED)

Tim Lahm, M.D. has served as a consultant, advisory board member or steering committee member for Actelion Pharmaceuticals Ltd. and Gilead Sciences, Inc., has served on a speaker’s bureau for Bayer HealthCare Pharmaceuticals LLC, and has received research or grant support from Eli Lilly and Company. Deborah J. Levine, M.D. has nothing to disclose. Sagar Lonial, M.D., FACP has served as a consultant, advisory board member or steering committee member for Amgen, Inc., Bristol-Myers Squibb, Celgene Corporation, GlaxoSmithKline, Janssen Pharmaceutica NV, Merck & Co., Inc., Novartis Pharmaceuticals and Takeda Pharmaceutical Company Ltd. Dana McGlothlin, M.D. has nothing to disclose. Mary P. Mullen, M.D., Ph.D. has nothing to disclose. Roxane Paulin, Ph.D. has nothing to disclose. Marlene Rabinovitch, M.D. has served as a consultant, advisory board member or steering committee member for Acceleron Pharma, Inc., Pfizer, Inc. and Calibr. Josanna Rodriguez-Lopez, M.D. has received research or grant support from Actelion Pharmaceuticals Ltd. Zeenat Safdar, M.D., M.S., FCCP has served as a consultant, advisory board member or steering committee member for Actelion Pharmaceuticals Ltd., Bayer HealthCare Pharmaceuticals LLC, Boehringer Ingelheim, Genentech, Inc., United Therapeutics Corporation and Gilead Sciences, Inc., and has served on a speaker’s bureau for Actelion Pharmaceuticals Ltd., Bayer HealthCare Pharmaceuticals LLC, Genentech, Inc., Boehringer Ingelheim, United Therapeutics Corporation and Gilead Sciences, Inc. Oksana A. Shlobin, M.D. has served as a consultant, advisory board member or steering committee member for Actelion Pharmaceuticals Ltd., Bayer HealthCare Pharmaceuticals LLC, United Therapeutics Corporation and Lung Rx, LLC and has served on a speaker’s bureau for Actelion Pharmaceuticals Ltd., Bayer HealthCare Pharmaceuticals LLC, Lung Rx, LLC and United Therapeutics Corporation.

Michael Snyder, Ph.D. has served as a consultant, advisory board member or steering committee member for Personalis, SensOmics, Qbio, January, Genapsys, Fitricine and Epinomics, has served on a speaker’s bureau for Illumina and Merck (pending), has received research or grant support from the National Institutes of Health, and is a co-founder of Personalis, SensOmics, Qbio, January and Fitricine.

PULMONARY HYPERTENSION ASSOCIATION

At the conclusion of this session, participants will be able to: • Understand the contribution of genetic mutations, protein expression and inflammation to PH pathogenesis and progression • Discuss the role and utility of novel diagnostic strategies in the diagnosis of PH • Understand the efficacy of PH-targeted therapies currently in early phase clinical trials and effectiveness of approved therapies through interpretation of data from post-marketing studies • Analyze interclass and intraclass treatment modality transitions in patients with pulmonary arterial hypertension

Thursday, June 28 4:30 – 7:30 p.m.

Namita Sood, M.D., FCCP has served on a speaker’s bureau for Gilead Sciences, Inc.

The following top ten abstracts will be presented during the Poster Hall Session. PHA congratulates the winners of the awards for best abstracts in basic and clinical science chosen by the 2018 PHA Scientific Sessions Committee.

Norman Stockbridge, M.D., Ph.D. has nothing to disclose.

Basic Science – Category Winner

Fernando Torres, M.D. has served as a consultant, advisory board member or steering committee member for Bayer HealthCare Pharmaceuticals LLC, Gilead Sciences, Inc., Actelion Pharmaceuticals Ltd., SteadyMed Therapeutics, Inc., Reata Pharmaceuticals, Inc. and Arena Pharmaceuticals, Inc., has served on a speaker’s bureau for Bayer HealthCare Pharmaceuticals LLC, Actelion Pharmaceuticals Ltd. and Reata Pharmaceuticals, Inc., and has received research or grant support from Gilead Sciences, Inc., United Therapeutics Corporation, Medtronic, GeNO, LLC, the National Institutes of Health, Eiger BioPharmaceuticals, Inc. and Bellerophon Therapeutics.

5:30 – 5:40 p.m. Presenting Author: Zhiyu Dai, Ph.D.

Northwestern University, Chicago, IL, USA

Basic Science – Runner-up 5:40 – 5:50 p.m. Presenting Author: Ekaterina Legchenko, Ph.D.

Roham T. Zamanian, M.D., FCCP has served as a consultant, advisory board member or steering committee member for Actelion Pharmaceuticals Ltd., Vivus and Eiger BioPharmaceuticals, Inc., has received research or grant support from Actelion Pharmaceuticals Ltd., United Therapeutics Corporation and Lung Rx, LLC, and is a self-managed stock shareholder in Selten Pharmaceuticals.

2018 PHA Scientific Sessions

1012 Education for Medical The PPARγand Agonist Pioglitazone Reverses Pulmonary Arterial Hypertension and Prevents Right Heart Failure Through Fatty Acid Oxidation Professionals Legchenko E1, Chouvarine P1, Borchert P1, Fernandez-Gonzalez A 2, Snay E3, Mägel L4, Mitsialis SA 2, Meier M5, Rog-Zielinska E6, Kourembanas S2, Jonigk D4, Hansmann G1 Department of Pediatric Cardiology and Critical Care, and Pulmonary Vascular Research Center (PVRC), Hannover Medical School, Germany, 2Division of Newborn Medicine, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA, 3 Division of Nuclear Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA, 4Institute of Pathology, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany; The German Center for Lung Research (Deutsches Zentrum für Lungenforschung DZL), 5Institute of Laboratory Animal Science, Hannover Medical School, Hannover, Germany, 6Institute for Experimental Cardiovascular Medicine, Freiburg, Germany, 7Actelion Pharmaceuticals US, Inc., South San Francisco, CA, USA, 8 Boston University School of Medicine, Boston, MA, USA

Corey E. Ventetuolo, M.D., M.S. has served as a consultant, advisory board member or steering committee member for Acceleron Pharma, Inc., Bayer HealthCare Pharmaceuticals LLC and United Therapeutics Corporation, has received research or grant support from Actelion Pharmaceuticals Ltd. and Eiger BioPharmaceuticals, Inc. and her spouse is an employee of CVS Health. Timothy L. Williamson, M.D. has received research or grant support from United Therapeutics Corporation, Reata Pharmaceuticals, Inc., Bayer HealthCare Pharmaceuticals LLC and Liquidia Technologies.

1004 Endothelial and Smooth Muscle Cell Interaction Via FoxM1 Mediates Vascular Remodeling and Pulmonary Arterial Hypertension Dai Z, Zhu MM, Peng Y, Jin H, Machireddy N, Qian Z, Zhang X, Zhao YY

Uyen T. Truong, M.D. has nothing to disclose.

For a full list of conflict of interest disclosures submitted and resolved for the 2018 PHA Scientific Sessions poster presenters, visit: PHAssociation.org/2018-Conference-Poster-Hall-Disclosures.

Poster Hall Session

Clinical Science – Category Winner 5:50 – 6 p.m. Presenting Author: Geoffrey A. Bocobo, B.Sc.

1031 Bone Morphogenetic Protein 9 is a Mechanistic Biomarker of Portopulmonary Hypertension Nikolic I1, Yung LM1, Yang P1, Malhotra R2, Paskin-Flerlage SD1, Dinter T1, Bocobo GA1, McNeil M1, Faugno AJ3, Lai CSC1, Upton PD4, Goumans MJ5, Zamanian RT6, Elliott G7, Morrell NW4, Chung RT8, Channick RW9, Roberts KE3, Yu PB1 Brigham and Women’s Hospital and Harvard Medical School, Division of Cardiovascular Medicine, Department of Medicine, Boston, MA, USA, 2Massachusetts General Hospital and Harvard Medical School, Division of Cardiology, Department of Medicine, Boston, MA, USA, 3 Tufts Medical Center, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Boston, MA, USA, 4University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, Division of Respiratory Medicine, Department of Medicine, Cambridge, United Kingdom, 5Leiden University Medical Centre, Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden, Netherlands, 6Stanford University Medical Center, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford, CA, USA, 7Intermountain Medical Center and University of Utah, Department of Medicine, Salt Lake City, UT, USA, 8Massachusetts General Hospital and Harvard Medical School, Gastrointestinal Unit and Liver Center, Department of Medicine, Boston, MA, USA, 9 Massachusetts General Hospital and Harvard Medical School, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston, MA, USA 1

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

Clinical Science – Runner-up 6 – 6:10 p.m. Presenting Author: Kara Goss, M.D.

1034 Early Pulmonary Vascular and Right Ventricular Dysfunction in Healthy Young Adults Born Prematurely Goss KN, Beshish A, Macdonald J, Barton GP, Mulchrone AM, Chesler NC, Francois C, Wieben O, Eldridge MW

Keynote Address: How Do You Envision Precision Medicine for PH? Friday, June 29 8:15 – 8:45 a.m.

University of Wisconsin, Madison, WI, USA

Additional Oral Presentations: 6:10 – 6:20 p.m. Presenting Author: Olga Rafikova, M.D., Ph.D.

PHA SCIENTIFIC SESSIONS

1005 Gender Difference on the Cellular Level: Distinct Stress Responses in Male and Female Endothelial Cells Isolated From Mouse Lungs

Speaker: Roham T. Zamanian, M.D., FCCP Stanford University Medical Center Stanford, Calif.

At the conclusion of this session, participants will be able to: • Define “precision medicine” in the context of pulmonary vascular disorders • Evaluate the goals and potential utility of current scientific studies which will become the foundation of deep phenotyping in pulmonary hypertension • Discuss the role of a precision medicine approach in future clinical trials in pulmonary hypertension

Rafikova O, Zemskova M, Kurdyukov S, Rafikov R University of Arizona, Tucson, AZ, USA 6:20 – 6:30 p.m. Presenting Author: Kazuyo Kegan, Ph.D.

Despite scientific advances in our understanding and treatment of pulmonary hypertension, this life-threatening disorder is still characterized by heterogeneity of pathobiology and treatment response. Recent consensus statements have called for molecular ‘deep phenotyping’ to address this heterogeneity paving a road to precision medicine. In this session, we will explore the definition of precision medicine within the context of pulmonary vascular disorders, review current scientific projects, which will likely set the roadmap and explore the utility of a precision approach for PH clinical trials of the future.

1008 Insulin Receptor Substrate 2 is Decreased in Clinical Pulmonary Hypertension and its Anti-Inflammatory Role in the Pulmonary Vasculature Under Hypoxic Conditions Yamaji-Kegan K, Johns RA The Johns Hopkins Medical Institutions, Baltimore, MD, USA

6:30 – 6:40 p.m. Presenting Author: Ruslan Rafikov, Ph.D.

Basic Science and Clinical Trials: Accelerating the Future

1011 The Role of Perivascular Edema and Endothelial Barrier Function in Pulmonary Arterial Hypertension

2018 PHA Scientific Sessions and Education for Medical Elena Goncharova, Ph.D. Evan Brittain, M.D., M.Sc. Professionals University of Pittsburgh Vanderbilt University Medical Center

Moderators:

Rafikov R1, Srivastava A1, Desai AA1, Simon M2, Rafikova O1 University of Arizona, Tucson, AZ, 2University of Pittsburgh, Pittsburgh, PA, USA

6:40 – 6:50 p.m. Presenting Author: Stephen J. Halliday, M.D.

1021 Clinical, Hemodynamic, and Genetic Associations With Parenteral Prostacyclin Response in Pulmonary Arterial Hypertension Halliday S, Faber-Eger E, Sheng Q, Xu M, Ye F, Pugh M, Robbins I, Assad T, Mosley J, West J, Brittain E, Hemnes A

Pittsburgh

Thenappan Thenappan, M.D. University of Minnesota Minneapolis

Corey E. Ventetuolo, M.D., M.S. Brown University Providence, R.I.

Novel Therapies Targeting the Right Ventricle

Vanderbilt University Medical Center, Nashville, TN, USA 6:50 – 7 p.m. Presenting Author: Harrison W. Farber, M.D.

Nashville, Tenn.

1038 Risk Assessment and Prognosis Based on ESC/ERS Guidelines in Patients With Chronic Thromboembolic Pulmonary Hypertension Receiving Riociguat Farber H1, Humbert M2, Hoeper MM3, Busse D4, Meier C5, Ghofrani HA6

Friday, June 29 8:45 – 9:15 a.m. Speaker: Harm Bogaard, M.D. VU University Medical Center Amsterdam, Netherlands

1044 Transition to Oral Treprostinil From Parenteral or Inhaled Treprostinil or as Add-On Therapy in Pediatric Subjects With Pulmonary Arterial Hypertension Ivy D , Feinstein J , Yung D , Mullen MP , Kirkpatrick E , Hirsch R , Austin ED , Fineman J8, Doran A9, Solum D9, Deng CQ9, Hopper RK10 1

Children’s Hospital of Colorado, Lucile Packard Children’s Hospital, Seattle Children’s Hospital, 4 Boston Children’s Hospital, 5Children’s Hospital of Wisconsin, 6 Cincinnati Children’s Hospital, 7Monroe Carell Jr. Children’s Hospital at Vanderbilt, 8University of California San Francisco, 9United Therapeutics, 10 Children’s Hospital of Philadelphia

PULMONARY HYPERTENSION ASSOCIATION

At the conclusion of this session, participants will be able to: • Discover the importance of right heart adaptation for patient survival and quality of life • Understand the main mechanisms of right heart failure

Boston University School of Medicine, Boston, MA, USA, 2Université Paris-Sud, Le Kremlin– Bicêtre, France, 3 Hannover Medical School, Hannover, Germany, member of the German Center for Lung Research (DZL), 4Chrestos Concept GmbH & Co. KG, Essen, Germany, 5 Bayer AG, Berlin, Germany, 6University of Giessen and Marburg Lung Center, Giessen, Germany, member of the German Center for Lung Research (DZL), Imperial College London, London, UK 1

7 – 7:10 p.m. Presenting Author: Dunbar Ivy, M.D.

This presentation will discuss the importance of right heart adaptation for the prognosis of PAH patients and describe the main mechanisms of right ventricular dysfunction and failure. It will also identify possible treatment targets and discuss state-of-the-art right heart-directed treatments in PAH.

• Understand potential treatment targets for direct treatment of the right heart

Novel Therapies Targeting the Pulmonary Vasculature Friday, June 29 9:15 – 9:45 a.m. Speaker: Marlene Rabinovitch, M.D. Stanford University School of Medicine Stanford, Calif.

This session will provide novel therapies targeting the pulmonary vasculature. At the conclusion of this session, participants will be able to: • Discuss advantages and limitations of using human cells including iPS cells and animal models to test promising new agents • Learn bioinformatic approaches to discover new therapies for PH • Explore the opportunities provided by new and emerging therapies for PH and identifying patients most likely to respond to a specific therapy

All participants seeking continuing education credit must record their attendance and complete an activity evaluation at http://pha.cds.pesgce.com. Please complete this process and print your CE certificate no later than August 15, 2018. 12

Novel Clinical Trial Design and Endpoints Friday, June 29 9:45 – 10:15 a.m. Speaker: Steven M. Kawut, M.D., M.S. Perelman School of Medicine at the University of Pennsylvania Philadelphia

This session will discuss available study designs and endpoints for clinical trials of novel therapies for pulmonary hypertension. At the conclusion of this session, participants will be able to: • Review alternative study designs for PH studies • Define and highlight various types of endpoints for PH studies • Identify appropriate study designs based on the drugs and populations under study

Pathway to Developing Future PH Therapies: Road Work Ahead Limitations and Opportunities for the Pharmaceutical Industry in Developing New PH Therapies Friday, June 29 10:30 – 11:15 a.m. Speaker: Ramona Doyle, M.D., M.Sc. University of California, San Francisco San Francisco

What the FDA Wants for New PH Therapy Development and Approval Friday, June 29 11:15 a.m. – noon Speaker: Norman Stockbridge, M.D., Ph.D. FDA/CDER/Division of Cardiovascular and Renal Products Silver Spring, Md.

Academia, Industry and Patient Advocacy Foundations Working Together to Develop New Therapeutics Friday, June 29 12:10 – 12:55 p.m. Speaker: Sagar Lonial, M.D., FACP Emory University Atlanta

The field of pulmonary hypertension has experienced tremendous progress since the disease was first recognized and treated. However, it is only since 1995, with the introduction of intravenous epoprostenol, that disease -specific targeted medical therapies for PAH have become available. In 2001, bosentan was the first oral therapy approved for the treatment of PAH; sildenafil citrate, an oral phosphodiesterase type 5 inhibitor, was approved in 2005. Since then new drugs and new formulations have added to the therapeutic options for patients and improved prognosis. However, the path from drug development and proof of efficacy to gaining regulatory approval has also changed and evolved. This session will provide a history of drug development in PAH and help delineate the path forward for more and better therapeutic options for patients. At the conclusion of this session, participants will be able to: • Understand the history of drug development in PAH • Understand basic principles of the drug development process • Learn about what endpoints in clinical trials are and why they are important • Understand the drug approval process and how it influences companies and insurers This session will provide a summary of the basis for approval of existing therapies for pulmonary arterial hypertension. The presenter will describe how future development programs might be different. To date, only one drug for PAH is approved in the US for use in pediatric patients with PAH. This problem will also be discussed. At the conclusion of this session, participants will be able to: • Review the principles applied to approval of drugs to treat pulmonary arterial hypertension • Understand the evolving need for new drugs to treat pulmonary arterial hypertension • Discover what PHA can do to facilitate new therapies in adults and children

Pediatrics: Fast Lane or the Scenic Route? Moderators:

Dunbar Ivy, M.D. Children's Hospital Colorado Aurora, Colo.

PH in the Pediatric Population: Insights From the PPHNet Registry Friday, June 29 2:30 – 2:55 p.m. Speaker: Steven H. Abman, M.D. University of Colorado School of Medicine Aurora, Colo.

Mary P. Mullen, M.D., Ph.D. Boston Children's Heart Foundation, Inc. Boston This session will provide an overview of pediatric pulmonary hypertension, highlighting unique features of diseases associated with PH in neonates, infants and children. The presenter will describe underlying developmental aspects of lung vascular disease that contribute to the etiology and physiology of PH, and will present information from the patient registry developed by the Pediatric Pulmonary Hypertension Network (PPHNet), a collaborative of multicenter institutions across North America. At the conclusion of this session, participants will be able to: • Demonstrate the diverse causes of pediatric pulmonary hypertension • Enhance understanding of features of disease and therapeutic issues that are unique to children with PH

Congenital Heart Disease and PH: Novel Treatment Approaches

This session will provide information on congenital heart disease and pulmonary hypertension, with a focus on novel treatment approaches. The presenter will describe the classification system of pulmonary Friday, June 29 hypertension 2018 PHA Scientificassociated Sessions with congenital heart disease, different 3:20 – 3:40 p.m. treatment strategies and insights into future application of pulmonary and Education for Medical hypertension specific therapies. Speaker: Stephanie Siehr Handler, M.D. Professionals At the conclusion of this session, participants will be able to: Children's Hospital of Wisconsin Milwaukee • Understand the association between congenital heart disease and pulmonary hypertension • Define several treatment strategies for pulmonary hypertension associated with congenital heart disease

Imaging the Right Ventricle in Children Friday, June 29 3:40 – 4 p.m.

This session will provide up-to-date knowledge of the use of MRI in evaluating children with PH, as well as future research directions. At the conclusion of this session, participants will be able to: • Understand role of MRI in evaluating children with PH

Speaker: Uyen T. Truong, M.D. Children's Hospital Colorado Aurora, Colo.

The landscape of drug development has rapidly changed over the past decade with increased opportunities, but a more fragmented approach. Unifying the constituents (patients, providers, advocacy groups, pharmaceutical companies, the National Institutes of Health) represents an important goal as we strive to improve outcomes for patients. Strategies to achieve this unification will be discussed. At the conclusion of this session, participants will be able to: • Understand the different stakeholders and their goals • Discuss strategies to unify goals among stakeholders • Learn how to maximize stakeholders’ engagements to advance drug development

Omics and Wearables in Pulmonary Hypertension: Are We There Yet? Moderators:

Tim Lahm, M.D. (Lead) Indiana University School of Medicine Indianapolis

Greg Elliott, M.D., MACP Intermountain Medical Center Murray, Utah

Palliative Care and Navigating Difficult Discussions in Pulmonary Hypertension

Roxane Paulin, Ph.D. Universite Laval, Quebec Heart and Lung Institute Quebec, Canada

Corey E. Ventetuolo, M.D., M.S. Brown University Providence, R.I.

Saturday, June 30 9:30 – 10:30 a.m.

An Integrative Personal Omics Profile Friday, June 29 4:10 – 4:35 p.m. Speaker: Michael Snyder, Ph.D. Stanford University Stanford, Calif.

Improving technologies, decreasing costs and advanced statistical modeling have allowed for a more detailed understanding of an individual and his or her disease. “Omics” profiling allows scientists to measure a vast amount of data, some of which does not change (e.g., genetics) and some of which can change greatly over time. A combined approach looking at genomic, epigenomic, transcriptomic, proteomic, metabolomic, and coagulomic data from patients has the ability to improve our understanding of disease pathogenesis and progression, as well as potentially illuminating novel therapeutic targets for that individual: the ultimate goal of personalized medicine. At the conclusion of this session, participants will be able to: • Understand how your genome sequence can help you • Explain how big data can inform health • Discover what can be learned from wearables

The NHLBI PVDOMICS Initiative: An Introduction Friday, June 29 4:35 – 5 p.m. Speaker: Anna Hemnes, M.D. Vanderbilt University Medical Center Nashville, Tenn.

The Role of Wearable Devices in PAH: The Case of CardioMEMS™ Friday, June 29 5 – 5:25 p.m. Speaker: Raymond L. Benza, M.D., FACC Allegheny General Hospital Pittsburgh

PH CLINICAL SESSIONS

This session will describe the National Heart, Lung, and Blood Institute’s (NHLBI) Pulmonary Vascular Disease Phenomics Program (PVDOMICS) study including funding, study structure and participating centers, study protocol and procedures and data collected. The presenter will discuss enrollment criteria including pulmonary hypertension groups eligible, disease comparators and healthy controls. Further, the presenter will discuss planned analyses, hypotheses of the study and emerging data on enrollee composition. At the conclusion of this session, participants will be able to: • Describe the goals of the PVDOMICS study • Describe groups of patients and controls to be enrolled in the PVDOMICS study

CardioMEMS™ HF System is a tool that has been FDA approved to assist in heart failure management. The system includes a small pressure-sensing device that is implanted in the pulmonary artery for wireless pulmonary artery pressure and heart rate measurement, which is transmitted directly to the healthcare team. Clinical studies have demonstrated a reduction of hospital admissions and improvement in quality of life in patients with heart failure. Studies are ongoing in the PH patient population.

Speaker: Rana Awdish, M.D., FCCP Henry Ford Health System Detroit

Pulmonary Rehabilitation and Oxygen Therapy Saturday, June 30 11 a.m. – noon Speaker: Gerilynn Connors, B.S., R.R.T., MAACVPR Inova Fairfax Hospital Falls Church, Va.

We all know the importance of palliative care in PH. But how do you actually incorporate palliative care into patient care? This session will provide strategies to give health care providers in the PH community the skills to have essential conversations with patients with PH. Through case studies, attendees will review approaches to these conversations and responding to challenges communicating with patients with chronic illness and their caregivers. Attendees will leave with a practical framework for holding these discussions. At the conclusion of this session, participants will be able to: • Recognize the importance of empathetic communication in healthcare settings • Describe an approach to responding to patient/family emotion with empathy • Describe five steps involved in a value-based goals of care discussion with a seriously ill patient • Recognize the importance of initiating goals of care discussions with PH patients

Attendees will learn why pulmonary rehabilitation is an adjunct therapy for the pulmonary hypertension patient. Understand that pulmonary rehabilitation is more than just an exercise program but includes a respiratory assessment, education, therapeutic exercise, psychosocial intervention and long-term adherence. Oxygen therapy is a medication that has specific prescription requirements that the patient and health care professional should understand. It will also be critical to understand limitations of oxygen delivery devices such as portable oxygen concentrators (POCs) and the types of oxygen delivery devices available. At the conclusion of this session, participants will be able to: • List the components of comprehensive pulmonary rehabilitation: assessment, education, therapeutic exercise, psychosocial intervention and long-term adherence • Understand how pulmonary rehabilitation is an adjunct therapy for the pulmonary hypertension patient • Know the guidelines for oxygen therapy based on oxygen saturation at rest, with exercise and also with sleep • Understand the limitations of portable oxygen concentrators • Know the oxygen delivery devices available and the liter flow the devices can deliver

At the conclusion of this session, participants will be able to: • Understand the technology underlying the CardioMEMS™ device • Understand the safety considerations when the device is deployed • Understand the utility of combined pressure and imaging data from MRI • Appreciate the feasibility of using the device to manage PAH patients

Lung Transplantation: From Listing to Management

This session will explore the entire spectrum of care for PAH patients who are candidates for lung transplantation, including indications for lung transplant, patient preparation and when to refer patients to an expert transplant center. Attendees will learn bridging strategies for PAH patients listed for transplantation, clinical management and recognition and treatment of progressive PAH and RV failure.

Saturday, June 30 2 - 3 p.m. Speakers: Deborah J. Levine, M.D. University Health System in San Antonio San Antonio

At the conclusion of this session, participants will be able to: • Recognize when to refer patients with PAH for transplantation • Know the barriers and how to prepare patients for lung transplantation • Know how the LAS score affects PAH patients listed for transplantation • Recognize progressive PAH and RV failure and know how to treat it • Understand bridging strategies for PAH patients listed for transplantation, including the early use of ECMO

Dana McGlothlin, M.D. Kaiser Permanente - California San Francisco

Moderators:

Sangeeta M. Bhorade, M.D. Northwestern University Chicago

Zeenat Safdar, M.D., M.S., FCCP Houston Methodist Hospital-Weill Cornell College Houston

Oksana A. Shlobin, M.D. Inova Fairfax Hospital Falls Church, Va.

Fernando Torres, M.D. UT Southwestern Medical Center Dallas

Pediatric PH Patients: New Guidelines and Differences From Adult Care Saturday, June 30 3:30 - 4:30 p.m. Speakers: Erika S. Berman Rosenzweig, M.D. Columbia University Medical Center New York, N.Y. Dunbar Ivy, M.D. Children's Hospital Colorado Aurora, Colo.

Chronic Thromboembolic Pulmonary Hypertension: Cases, Controversies, Challenges and Conundrums Sunday, July 1 8 - 9 a.m. Speakers: Josanna Rodriguez-Lopez, M.D. Massachusetts General Hospital Boston Timothy L. Williamson, M.D. Kansas University Hospital Kansas City, Kan.

PAH Therapies: Insurance, Patient Assistance Programs and New Therapies on the Horizon

Pediatric pulmonary hypertension (PH) is organized into a clinical classification system similar to adult PH. However, important differences in developmental mechanisms and physiology, leading to unique clinical phenotypic presentations, complicate simply applying adult PH guidelines to the pediatric population. At the conclusion of this session, participants will be able to: • Provide a general overview of the most recent pediatric guidelines for diagnosis and treatment of PAH • Highlight updates in the recommendations for management of pediatric PAH • Provide a review of the similarities and differences of pediatric pulmonary hypertension care with the care of adults with PAH This session will be a case-based interactive session focusing on interesting and complex CTEPH cases. We will discuss the diagnostic work up, operability evaluation, options for inoperable CTEPH and some mimics of CTEPH. At the conclusion of this session, participants will be able to: • Understand the diagnostic evaluation for a patient with suspected CTEPH • Review the different treatment options for CTEPH and inoperable CTEPH • Understand different imaging techniques used and how they can help to identify mimics of CTEPH

This session will very briefly review the current therapies available and the new therapies being developed. It will also discuss the insurance coverage process and the current patient assistance programs available.

At the conclusion of this session, participants will be able to: • Understand the current therapies for PAH • Discuss cost and insurance challenges Speaker: Namita Sood, M.D., FCCP • Increase awareness of patient assistance programs University of Texas Health Science Center at Houston • Review new therapies in the pipeline Houston Sunday, July 1 9:30 - 10:30 a.m.

BASIC SCIENCE ABSTRACTS Associated Diseases and Conditions 1001

A Novel Paradigm and New Drug for the Management of Ductus-Dependent Congenital Heart Disease Ye L, Li M, Ye X, Jiang C, Chen H, Zhang H, Liu J, Hong H, Yan X, Liu X

Databases and Registries 1002

Genetic Analysis of 2,592 WHO Group 1 PAH Patients Enrolled in the PAH Biobank Lutz K, Walsworth A, Pauciulo M, Martin L, He H, Nichols W

Mechanistic Studies 1003 1004 1005

Bardoxolone Methyl Improves Molecular and Cellular Parameters Associated With Pulmonary Arterial Hypertension Miller GA, Probst BL, Dulubova I, Trevino I, McCauley L, Ferguson DA, Wigley WC

1006

Heme-Induced Glycolytic Imbalance Contributes to Endothelial Cell Proliferation Rafikov R, Srivastava A, Eccles C, Rafikova O

1007

Inflammatory Macrophage Expansion in Pulmonary Hypertension Depends Upon Mobilization of Blood-Borne Monocytes Florentin J, Coppin E, Vasamsetti SB, Zhao J, Tai YY, Tang Y, Zhang Y, Watson A, Sembrat J, Rojas M, Vargas SO, Chan SY, Dutta P

1008

Insulin Receptor Substrate 2 is Decreased in Clinical Pulmonary Hypertension and its Anti-Inflammatory Role in the Pulmonary Vasculature Under Hypoxic Conditions Yamaji-Kegan K, Johns RA

1009

Salutary Effects of Estrogen Receptor (ER)-α on the Pulmonary Vasculature in Experimental Pulmonary Hypertension (PH) Frump AL, Yakubov B, Zeng L, Albrecht M, Essex A, Cook T, Fisher A, Martinez D, Phillips JL, Li R, Sun X, Chesler NC, Lahm T

1010

Stability of Treprostinil With Diluents and Medications Doran A, Borg E, Rollins K, Phares K

1011

The Role of Perivascular Edema and Endothelial Barrier Function in Pulmonary Arterial Hypertension Rafikov R, Srivastava A, Desai AA, Simon M, Rafikova O

Endothelial and Smooth Muscle Cell Interaction Via FoxM1 Mediates Vascular Remodeling and Pulmonary Arterial Hypertension Dai Z, Zhu MM, Peng Y, Jin H, Machireddy N, Qian Z, Zhang X, Zhao YY Gender Difference on the Cellular Level: Distinct Stress Responses in Male and Female Endothelial Cells Isolated From Mouse Lungs Rafikova O, Zemskova M, Kurdyukov S, Rafikov R

Therapeutic Strategies 1012

The PPARγ Agonist Pioglitazone Reverses Pulmonary Arterial Hypertension and Prevents Right Heart Failure Through Fatty Acid Oxidation Legchenko E, Chouvarine P, Borchert P, Fernandez-Gonzalez A, Snay E, Mägel L, Mitsialis SA, Meier M, Rog-Zielinska E, Kourembanas S, Jonigk D, Hansmann G

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

Treatment 1013

Therapeutic MAb Targeting Endothelin Receptor A for Pulmonary Arterial Hypertension Zhang C, Guo Y, Fan K, Jing S

CLINICAL SCIENCE ABSTRACTS Associated Diseases and Conditions 1014

A Retrospective Comparison of Pulmonary Arterial Hypertension (PAH) Patients With Myositis-Related Autoantibodies to Patients With Idiopathic PAH and PAH Associated With Systemic Sclerosis Si S, Weinmann S, Despotovic VN, McEvoy C, Chakinala MM

1015

Baseline Characteristics From a Pre-Specified Interim Analysis of a Phase IIb, Randomized, Double-Blind, Placebo-Controlled Trial of Sildenafil Added to Pirfenidone in Patients With Advanced Idiopathic Pulmonary Fibrosis and Risk of Pulmonary Hypertension Behr J, Nathan SD, Harari S, Wuyts W, Stauffer JL, Kirchgaessler KU, Bengus M, Gilberg F, Wells AU

1016

Myositis-Related Autoantibodies and Pulmonary Arterial Hypertension (PAH): Another Sub-Type of PAH Associated With Autoimmune Conditions Si S, Weinmann S, Despotovic VN, McEvoy C, Chakinala MM

1017

Risk of Pulmonary Hypertension in HIV Infected Patients - A Retrospective Analysis Pyarali F, Iordanov R, Zablah G, Haque T, Parmar R, Boulanger C, Jayaweera D, Hurwitz B, Kolber M, De La Zerda D, Martinez C

Databases and Registries 1018

Advance Care Planning Completion in Pulmonary Hypertension Care Center Rachu G, Whittenhall ME, Ventetuolo CE, Mullin CJ, Klinger JR, Allahua M, Ahearn M

1019

Baseline and Demographic Data on the First 250 Patients From SPHERE (Uptravi® [SelexiPag]: tHe usErs dRug rEgistry) McLaughlin V, Kim NH, Chin K, Highland KB, Hemnes A, Chakinala MM, Keating M, Zhao C, Colvin J, Farber H

1020

Clinical Classification and Prevalence of Pulmonary Hypertension in Rural Minnesota Mirfakhraie L, Dirks T, Ebnet S, Eckman P, Cabuay B, Garberich R, Reed S, Stokman P, Fenstad E

1021

Clinical, Hemodynamic, and Genetic Associations With Parenteral Prostacyclin Response in Pulmonary Arterial Hypertension Halliday S, Faber-Eger E, Sheng Q, Xu M, Ye F, Pugh M, Robbins I, Assad T, Mosley J, West J, Brittain E, Hemnes A

1022 1023 1024

Electronic Medical Record (EMR) Tool for Hospitalized Patients to Facilitate Safe Management of Pulmonary Arterial Hypertension Patients on Prostacyclin Therapy Driscoll T, Duncan M, Blakley A

Health Care Costs and Resource Utilization Prior to Initiation of a Prostacyclin Receptor Agonist for Pulmonary Arterial Hypertension in a Real-World Database Representing a Large US Health Plan Pruett J, Hull M, Elliott C, Tsang Y, Drake W Intersecting Identities and Patient Outcomes in Pulmonary Arterial Hypertension: Early Results in Derivation of a Model Using the Pulmonary Hypertension Association Registry (PHAR) Grinnan D, Kang L, DeWilde C, Johnson D, Sager J, Badesch D, Bull T, Chakinala MM, DeMarco T, Feldman J, Fineman J, Ford J, Klinger J, McConnell J, Berman Rosenzweig E, Shlobin O, Zamanian R, Bartolome S, Elwing J, Franz R, and 9 more

PULMONARY HYPERTENSION ASSOCIATION

1025

Medication Adherence and Risk of Hospitalization in Pulmonary Arterial Hypertension (PAH) Patients Treated With Endothelin Receptor Antagonists (ERAs) or Phosphodiesterase Type 5 Inhibitors (PDE5Is) Cole MR, Hill JW, Lickert C, Wade RL, Drake W

1026

National Trends of Hospitalization Characteristics in Patients With Pulmonary Hypertension Agarwal MA, Shah M, Patel B, Garg L, Khouzam RN

1027

Pulmonary Hypertension in Hereditary Hemorrhagic Telangiectasia Harder E, Fares W

1028

1029

1030

Treatment With Prostacyclins Reduces Hospital Readmissions Among Patients With Pulmonary Arterial Hypertension Blanchette C, Noone J, Howden R, Classi P, Gordon K, Nelsen A

Diagnosis, Screening and Assessment 1031

Bone Morphogenetic Protein 9 is a Mechanistic Biomarker of Portopulmonary Hypertension Nikolic I, Yung LM, Yang P, Malhotra R, Paskin-Flerlage SD, Dinter T, Bocobo GA, McNeil M, Faugno AJ, Lai CSC, Upton PD, Goumans MJ, Zamanian RT, Elliott G, Morrell NW, Chung RT, Channick RW, Roberts KE, Yu PB

1032 1033

Changes of Plasma Angiotensin-(1-7) in Patients With Pulmonary Arterial Hypertension Due to Congenital Heart Disease Before and After Intervention Closure Dai HL, Guang XF, Yin XL, Yang QF

1034

Early Pulmonary Vascular and Right Ventricular Dysfunction in Healthy Young Adults Born Prematurely Goss KN, Beshish A, Macdonald J, Barton GP, Mulchrone AM, Chesler NC, Francois C, Wieben O, Eldridge MW

1035 1036 1037

Non-Invasive Ultrasonographic Cardiac Output Measurement in Pulmonary Arterial Hypertension Matusov Y, Achamallah N, Sager JS

1038

Risk Assessment and Prognosis Based on ESC/ERS Guidelines in Patients With Chronic Thromboembolic Pulmonary Hypertension Receiving Riociguat Farber H, Humbert M, Hoeper MM, Busse D, Meier C, Ghofrani HA

1075

Risk Assessment and Prognosis Based on ESC/ERS Guidelines in Patients With Pulmonary Arterial Hypertension Receiving Riociguat Humbert M, Farber H, Ghofrani HA, Busse D, Meier C, Hoeper MM

Digital Subtraction Pulmonary Angiography: An Old Technique With Novel Role in Children With Pulmonary Hypertension Das BB, Mills J, Jadotte MM, Chan KC

Reliability of Systolic Pulmonary Artery Pressure by Doppler Echocardiography Compared to Right Heart Catheterization in Patients With Atrial Septal Defect: Analysis in a Large Patient Population Dai HL, Guang XF, Yin XL, Yang QF Right Ventricular Transient Exertional Dilation (TED) in Pulmonary Hypertension – Is There Diagnostic Utility? El-Yafawi R, Wirth J, Rancourt D, Hacobian M, Atherton D, Cohen M

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

1039

Serum Uric Acid as a Biomarker of Disease Severity in Scleroderma Patients With Pulmonary Arterial Hypertension Simpson C, Khair R, Kolb T, Hassoun PM, Damico R, Mathai SC

1040

Tissue Doppler Imaging on Transthoracic ECHO to Assess Prevalence of HIV-Associated Pulmonary Hypertension Singh N, Shah S, Ly V, Ojeda-Martinez H, Ajam MA

Mechanistic Studies 1041

Pediatrics

Male Gender Predisposes PAH Patients to Reductive Stress and Disease Progression Rafikova O, Desai AA, Rafikov R

1052

Evaluation of Pharmacist Discharge Counseling Process in Pulmonary Hypertension Patients Humphrey J, Miller A, Rechtien K, Hard M, Williamson T

1053

Novel Analysis of Treprostinil Dose-Response Relationship Using Weight-Normalized Dosing Ramani G, Shen E, Broderick M, Wasik A, Rao Y

1054

Pulsed Inhaled Nitric Oxide (iNO) Improves Exercise Tolerance in Severe Chronic Obstructive Pulmonary Disease (COPD) Patients With Pulmonary Hypertension (PH) Haijan B, Shivalkar B, Ferreir F, Van Holsbeke C, Vos W, De Backer J, Sartoris K, Warren DQ, Hulkens A, Parizel PM, Cluckers J, De Backer W

1055

Submaximal Exercise Testing (SET) in Idiopathic Pulmonary Arterial Hypertension (IPAH) Menon DP, Ray JC, Burger CD

Treatment

1042

Riociguat in Pediatric Pulmonary Arterial Hypertension: PATENT-CHILD Study Design and Rationale Beghetti M, Wirsching G, Bonnet D, Ivy DD, Moledina S, Lippert S, Ribeiro S

1043

Basic Pulmonary Hemodynamics Correlated to Pulmonary Vascular Resistance in Pulmonary Hypertension Related to Congenital Heart Disease in Children Benjapondsapun T, Momsila P, Patipanvat S, Limsuwan A

1044

Transition to Oral Treprostinil From Parenteral or Inhaled Treprostinil or as Add-on Therapy in Pediatric Subjects With Pulmonary Arterial Hypertension Ivy D, Feinstein J, Yung D, Mullen MP, Kirkpatrick E, Hirsch R, Austin ED, Fineman J, Doran A, Solum D, Deng CQ, Hopper RK

Quality of Life 1045

Financial Burden of Medical Therapy in Patients With Pulmonary Arterial Hypertension (PAH) Ghandour M, Helmi H, Burger CD

1046

Frequency of Palliative Care Referrals in Newly Diagnosed Pulmonary Arterial Hypertension (PAH): The Pulmonary Hypertension Association Registry Gray MP, Wright R, Khair RM, Badesch D, Bartolome S, Boyle K, Bull T, Chakinala M, De Marco T, Elwing J, Feldman J, Ford HJ, Frantz RP, Grinnan DC, Klinger JR, Lammi MR, McConnell JW, Berman Rosenzweig E, Runo JR, Sager JS, Shlobin OA, Thenappan T, Ventetuolo CE, White RJ, Williamson TL, Zamanian RT, Mathai SC

1047

Implantable System for Remodulin®: A Real-World Experience Study in Patients With Pulmonary Arterial Hypertension Bourge RC, Shapiro SM, Pozella P, Harris DF, Borg EH, Nelsen AC

1048

Manifestations of Depression in Patients Receiving Goal-Directed Treatment for Pulmonary Arterial Hypertension Swisher J, Overton-Barnes R, Clay S, Collins C

1049

Quality of Life and Needs for Support in Japanese Patients With Pulmonary Hypertension Sato N, Takemura N, Murakami N, Fukushima H

1056

Hemodynamic Effects of the Oral Prostacyclin (IP) Receptor Agonist Ralinepag in Pulmonary Arterial Hypertension (PAH) Torres F, Farber H, Ristic AD, McLaughlin V, Adams J, Turner S, Klassen P, Escribano-Subias P, Sood N, Keogh AM, Rubin L

1057

Phase 1 Study Results of LIQ861, an Inhaled Dry Powder Formulation of Treprostinil Roscigno R, Vaughn T, Wargin WW, Williams RL, Forsythe C, Hunt T

1058 1059

1060

Transitioning Prostanoid Therapy in Pulmonary Arterial Hypertension: Aggregate Cohort Data From One Specialty Pharmacy D'Albini L, Porco L, Hahn J

1061

Use of an Obese Population in Phase I to Evaluate the Pharmacology of Oral CXA-10, a Nitro-fatty Acid Cell Signaling Agent, as a Disease-Modifying Therapy in Pulmonary Arterial Hypertension Tarka E, Chieffo C, Botbyl J, Perry KT, Blok TM, Jorkasky DK

Results of the Prospective, Multicenter, Single-Arm, Open-Label, Phase 4 MOTION Study of Riociguat in Pulmonary Arterial Hypertension Sood N, Aranda A, Platt D, Kleinjung F, O’Brien G

Associated Diseases and Conditions 1062

A Case of HIV-Associated Pulmonary Arterial Hypertension in the Setting of Cardiomyopathy George MP, Dillingham J, Chanin J, Shafton A

1063

A Review of High Risk OB Patients with PAH Savage L, Pinson J, Grinnan D, Lester C

1064

Methamphetamine Associated Pulmonary Arterial Hypertension in Pregnancy Beutner M, Gill K, Balasubramanian V

Therapeutic Strategies

1065

Takayasu’s Arteritis in a Patient With Dasatinib-Induced PAH Samant M, McEvoy C

1066

Treatment of Pulmonary Hypertension in the Setting of Interstitial Lung Disease with Intravenous Prostacyclin Therapy Duncan M, Krishnan S, Driscoll T, Blakley A

1050 Implementing a Transcultural Nursing Care Model to Improve Pulmonary Hypertension Medication Compliance Salinero M, Hyman T, Matos M, Pallares M, Bouza E, Valdes J, Bello A, Sandoval E, Reyes C 1051 A Prospective Study to Describe Clinical and Tolerability Outcomes in Patients Transitioning From Bosentan or Ambrisentan to Macitentan McConnell JW, Robinson K, Royse M

PULMONARY HYPERTENSION ASSOCIATION

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

RESEARCH ABSTRACTS & CASE STUDIES Pediatrics 1067

Advanced Pulmonary Vasodilator Therapy for an Infant With Atypical Presentation of Alveolar Capillary Dysplasia Parker C, Colglazier E, Fineman J

Quality of Life 1068

Palliative Care Involvement in Pulmonary Arterial Hypertension Patient Care: Single-Center Experience Paulus S, Fowler J

1069

Ventavis to Selexipag Conversion Litton K, Curry K

CASE STUDIES Therapeutic Strategies 1070

Epoprostenol-Induced Colitis in a Patient With HIV Associated Pulmonary Arterial Hypertension: A Case Report Stevens G, Bains J, Giri P

1071

Fast Pass: How to Start Higher Doses of Oral Treprostinil by Using IV Epoprostenol Salinero M, Hyman T, Matos M, Pallares M, Jimenez J

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Outpatient Transition of Parenteral to Oral Prostacyclin in Pulmonary Arterial Hypertension Morris KL, Kelkhoff A, Schmit A, Ravichandran A

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Successful Transition From Subcutaneous Treprostinil to Oral Treprostinil in a Patient With Pulmonary Arterial Hypertension: A Case Study Fearon-Clarke J, Goldschmidt M, Hollasch K

1001 A Novel Paradigm and New Drug for the Management of Ductus-Dependent Congenital Heart Disease

Ye L, Li M, Ye X, Jiang C, Chen H, Zhang H, Liu J, Hong H, Yan X, Liu X Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China

Background: Proper management of ductus-dependent congenital heart disease (CHD) is always a great concern to pediatricians. Our previous study suggested MEK1/2 may play a role in the regulation of ductus arteriosus (DA) patent or constricted. Here, we present the mechanism’s study of MEK1/2 pathway on DA patency and that whether MEK1/2 inhibitor PD0325901 has therapy potentiality for keeping DA patency.

Results: Data indicated that MEK1/2 was differentially expressed between constricted and patent DA tissues. Post- or prenatal administration of PD0325901 maintained DA patency during the postnatal period. MEK1/2 inhibition may promote DA patency by reducing cytosolic calcium in DASMCs, which is associated with DA functional closure, and reducing the proliferation and migration of DASMCs, which is associated with DA anatomic closure.

Conclusions: MEK1/2 pathway may simultaneously Methods: MEK1/2 expression in patent and constricted regulate both functional and anatomic closure of DA. human DA tissues was measured and MEK1/2 pathway MEK1/2 inhibitor PD0325901 may hold therapeutic promise inhibition with respect to DA patency was tested in a to keep DA patency. mouse model via postnatal or prenatal administration of MEK1/2 inhibitor, PD0325901. Mechanisms of MEK1/2 inhibition and DA patency were explored in human DA 2018 PHA Scientific Sessions smooth muscle cells (DASMCs).

and Education for Medical Professionals

Treatment 1074

Successful Transition From Oral Selexipag to Subcutaneous Treprostinil George MP, Coons J, Kim D, Buckner JK, Mathier M

Figure 1: Expression of MEK1/2 and its phosphorylated MEK1/2(p-MEK1/2), in patent and constricted DAs

PULMONARY HYPERTENSION ASSOCIATION

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

RESEARCH ABSTRACTS & CASE STUDIES

Figure 2: The effectiveness of PD0325901 in maintaining DA patency

Figure 4: Schematic diagram of MEK1/2 signaling pathways and modulators regulating DASMC contraction, proliferation and migration

Figure 3: The mechanism of PD0325901-mediated DA patency 25

PULMONARY HYPERTENSION ASSOCIATION

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

RESEARCH ABSTRACTS & CASE STUDIES

1002

1003

Genetic Analysis of 2,592 WHO Group 1 PAH Patients Enrolled in the PAH Biobank Lutz K, Walsworth A, Pauciulo M, Martin L, He H, Nichols W Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Background: The National Biological Sample and Data Repository for PAH (PAH Biobank) was established with NHLBI funding to build a resource of biological specimens, clinical data and genetic data available to the PAH research community to further our understanding of the pathogenesis of this potentially fatal disease. Information on the resource and access to the samples/ data can be found at www. pahbiobank.org. To date, 2,851 patients have been enrolled from 38 Enrolling Centers. Methods: Blood samples are collected at the Enrolling Centers across the U.S and shipped overnight to the PAH Biobank. Blood is processed to store plasma and serum, extract DNA and RNA, and prepare immortalized cell lines. DNA sequencing is performed using the Illumina TruSeq Custom Amplicon system to interrogate the coding sequences/intron-exon junctions of BMPR2, ALK1, ENG, CAV1, SMAD9, KCNK3, EIF2AK4, ABCC8, GDF2, KCNK5, SMAD4 and TBX4. Genotyping of >4.3 million SNPs is done using the Illumina HumanOmni5 Beadchip. Multiplex ligation-dependent probe amplification is performed to identify exonic deletions/duplications of BMPR2, ALK1, and ENG.

PULMONARY HYPERTENSION ASSOCIATION

Results: Genetic analysis has been completed in 2,592 patients including 1130 IPAH, 1,231 APAH, 101 FPAH, and 116 Drugs and Toxins PAH. 695 distinct variants occurred 24,425 times. 294 distinct synonymous and intronic variants occurred 19,542 times. The remaining 401 coding variants were observed 4,883 times. This included 33 nonsense variants in 57 patients, 70 ins/dels in 504 patients, and 14 splice site variants in 18 patients. 284 missense variants occurred 4,304 times; some patients harbored more than one missense variant. Of the 401 distinct coding variants, 141 were in BMPR2. The remaining 260 coding variants were spread across ALK1 (35), ENG (34), CAV1 (9), SMAD9 (27), KCNK3 (9), EIF2AK4 (69), ABCC8 (18), GDF2 (22), KCNK5 (19) SMAD4 (4) and TBX4 (14). MLPA identified 21 exonic insertion/deletions in BMPR2 (19), ALK1 (1) and ENG (1) in 11 IPAH, 8 HPAH, and 2 APAH patients. Conclusions: The PAH Biobank is a powerful resource available to the PAH research community. This is the largest single cohort for which genetic analysis has been completed to date. While pathogenic/suspected pathogenic variants have been identified in several genes, BMPR2 remains the gene with the most pathogenic/suspected pathogenic variants. Stratification of the cohort based on these genetic analyses could enable the identification of additional, novel genes and/or modifier genes affecting disease severity/penetrance in those harboring pathogenic/ suspected pathogenic variants in previously identified genes.

Bardoxolone Methyl Improves Molecular and Cellular Parameters Associated With Pulmonary Arterial Hypertension Miller GA, Probst BL, Dulubova I, Trevino I, McCauley L, Ferguson DA, Wigley WC Reata Pharmaceuticals, Irving, TX, USA Background: Bardoxolone methyl (BARD) is an Nrf2 activator currently under investigation in the LARIAT and CATALYST clinical trials for the treatment of connective tissue disease associated pulmonary arterial hypertension (CTD-PAH). Vasoconstriction is an important feature of PAH and several drugs with vasodilatory activity have been approved for PAH treatment. However, alterations in other molecular and cellular processes –including inflammation, mitochondrial metabolism, oxidative stress, abnormal proliferation, and fibrosis–also play key roles in PAH and underlie tissue damage and remodeling. Nrf2 activation is known to promote the resolution of inflammation, improve mitochondrial function, and reduce oxidative stress. In this study, we asked whether the Nrf2 activator BARD improves the molecular and cellular parameters associated with PAH. Methods: THP-1 monocytes and RAW 264.7 macrophages were stimulated with IFNγ ± LPS to activate inflammatory signaling pathways. Mitochondrial function was assessed in RAW 264.7 macrophages and C2C12 skeletal muscle cells using Seahorse XF Technology. Reactive oxygen species were measured in H9c2 cardiomyocytes and C2C12 skeletal muscle cells using fluorescent molecular probes. Pulmonary arterial smooth muscle cells (PASMCs) were cultured under normoxic (21% O2) or hypoxic (2% O2) conditions and hypoxia-induced cell proliferation was assessed by BrdU incorporation. Pulmonary artery endothelial cells (PAECs)

were treated with TGFβ, IL-1β, and TNFα to induce endothelial to mesenchymal transition (EndMT) and fibrosis. Expression of Nrf2 target genes, pro-inflammatory cytokines, and markers of EndMT was measured by reverse transcription and quantitative PCR. Protein levels of pro-inflammatory cytokines were measured by ELISA or HTRF. Results: Treatment with BARD increased the expression of Nrf2 target genes in monocytes, macrophages, PAECs, PASMCs, cardiomyocytes, and skeletal muscle cells. At the same concentrations that increased Nrf2 activity, BARD suppressed the levels of pro-inflammatory cytokines in several cell types. BARD restored compromised mitochondrial function in activated macrophages and skeletal muscle cells. In addition, BARD reduced reactive oxygen species in skeletal muscle cells and cardiomyocytes. Treatment with BARD prevented hypoxia-induced proliferation in PASMCs without affecting their viability. Finally, BARD inhibited markers of EndMT and fibrosis in PAECs treated with TGFβ, IL-1β, and TNFα. Conclusions: Taken together, these results demonstrate that BARD may have the potential to improve multiple dysfunctional molecular and cellular parameters that are associated with pulmonary arterial hypertension.

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

RESEARCH ABSTRACTS & CASE STUDIES

1004

Endothelial and Smooth Muscle Cell Interaction Via FoxM1 Mediates Vascular Remodeling and Pulmonary Arterial Hypertension Dai Z, Zhu MM, Peng Y, Jin H, Machireddy N, Qian Z, Zhang X, Zhao YY Northwestern University, Chicago, IL, USA Background: SMC-specific FoxM1 or Cxcr4 knockout mice, EC-specific FoxM1 or Egln1 knockout mice, as well as EC-specific Egln1/Cxcl12 double knockout mice were used to assess the role of FoxM1 on SMC proliferation and pulmonary hypertension (PH). Lung tissues and cells from PAH patients were employed to validate clinical relevance. FoxM1 inhibitor Thiostrepton was used in Sugen 5416/ hypoxia- and monocrotaline-challenged rats. Methods: SMC-specific Foxm1 or Cxcr4 knockout mice, EC-specific Foxm1 or Egln1 knockout mice, as well as EC-specific Egln1/Cxcl12 double knockout mice were used to assess the role of FoxM1 on SMC proliferation and PH. Lung tissues and cells from PAH patients were employed to validate clinical relevance. FoxM1 inhibitor Thiostrepton was used in Sugen 5416/hypoxia- and monocrotalinechallenged rats.

Results: FoxM1 expression was markedly upregulated in lungs and pulmonary arterial SMCs of idiopathic PAH (IPAH) patients and 4 discrete PH rodent models. Mice with SMC- (but not EC-) specific deletion of FoxM1 were protected from hypoxia- or Sugen 5416/hypoxia-induced PH. The upregulation of FoxM1 in SMCs induced by multiple EC-derived factors (PDGF-B, Cxcl12, ET-1 and MIF) mediated SMC proliferation. Genetic deletion of endothelial Cxcl12 in Egln1Tie2Cre mice or loss of its cognate receptor Cxcr4 in SMCs in hypoxia-treated mice inhibited FoxM1 expression, SMC proliferation and PH. Accordingly, pharmacological inhibition of FoxM1 inhibited severe PH in both Sugen 5416/hypoxia and monocrotaline-challenged rats. Conclusions: Angiocrine factors derived from dysfunctional ECs induced expression of FoxM1 in SMCs and activated FoxM1-dependent SMC proliferation which contributes to pulmonary vascular remodeling and PH. Thus, targeting FoxM1 signaling represents a novel strategy for treatment of PAH.

Figure 2: Foxm1 disruption in SMCs inhibits SuHx-induced PH in mice

Figure 1: FoxM1 disruption in SMCs inhibits SuHx-induced PH in mice.

Figure 3: Endothelial and smooth muscle cell interaction mediate FoxM1 upregulation, SMC proliferation and PH

PULMONARY HYPERTENSION ASSOCIATION

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

RESEARCH ABSTRACTS & CASE STUDIES

1005

Gender Difference on the Cellular Level: Distinct Stress Responses in Male and Female Endothelial Cells Isolated From Mouse Lungs Rafikova O, Zemskova M, Kurdyukov S, Rafikov R University of Arizona, Tucson, AZ, USA

Background: Pulmonary arterial hypertension (PAH) is a disease with a well-established sexual dimorphism. While females generally being associated with higher susceptibility to PAH, males are showing lower survival rate and predisposition to develop RV failure. Sex hormones mediated gender difference is well described for many vascular diseases, including PAH. In this study, we investigated whether the contribution of gender goes beyond the effects of sex hormones by comparing the profile of pulmonary endothelial cells isolated from both genders. Methods: Mouse lung endothelial cells (MLEC) were obtained from male and female 8 wk old mice using positive selection with anti-PECAM-1 antibody conjugated to Dynabeads and cultured for 3 passages. After 3th passage, MLEC were additionally purified by a second positive selection using ICAM2 antibody and validated by FACS analysis with antiCD31-FITS antibody, which yields 98% pure population of MLEC. Gender difference in the MLEC omitted from effects of sex hormones was analyzed by evaluation of cell morphology, proliferation rate, mitochondrial function, and capability to tolerate the stress. Results: Male MLEC were found to be smaller in size and possessed about 2 times higher rate of proliferation comparing to female. The level of mitochondrial polarization was also higher in male cells, suggesting an increased

cellular energy and metabolic output associated with male gender that could be also responsible for the higher proliferative state. Exposure of cells to 2% hypoxia for 24 hours induced a strong apoptotic response in female but not male MLEC. In contrast, treatment with mitochondrial respiratory Complex III inhibitor Antimycin A (AA) mediated a severe necrosis specifically in male MLEC, while female cells responded again primarily by apoptosis. Taken together these results suggest that male cells appeared to be protected against the mild stress conditions, possibly due to an increased mitochondrial biogenesis. In contrast, female cells are protected against more damaging stimuli, such as mitochondrial dysfunction. Indeed, the apoptotic response to AA in females was similar to hypoxia. Besides, apoptosis as a controlled and immune silent type of cell death represents a more physiological response to stress compared to necrosis. Conclusions: This study revealed that isolated and cultured pulmonary endothelial cells retain a gender difference even in the absence of sex hormone stimulation, suggesting the importance of genetic mechanisms in gender dimorphism. The discovered difference in the ability to tolerate the stress is of a great importance for the PAH known to be closely associated with different types of stress conditions, including hypoxia and mitochondrial dysfunction.

Figure 4: Pharmacological inhibition of FoxM1 inhibits both SuHx and MCT-induced PH in rats

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2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

RESEARCH ABSTRACTS & CASE STUDIES

RESEARCH ABSTRACTS & CASE STUDIES 1007

1006

Heme-Induced Glycolytic Imbalance Contributes Towards Endothelial Cell Proliferation Rafikov R, Srivastava A, Eccles C, Rafikova O University of Arizona, Tucson, AZ, USA

Background: An increasing number of studies have implicated glycolytic switch in the pathology of pulmonary arterial hypertension (PAH). Although, this “Warburg-like” effect is well reported for PAH patients and is well characterized in pre-clinical studies, there are no mechanistic insights on why this metabolic switch occurs. Decreased mitochondrial respiration and activation of HIF signaling have been shown to be associated with the metabolic switching in PAH. We have found elevated free hemoglobin (Hb) levels in PAH patients and animal models of PAH. Interestingly; our data indicates that free heme, a degradation product of free Hb, can directly affect the glycolytic metabolism in endothelial cells (EC). Methods: Human lung microvascular endothelial cells (HLMVECs) were utilized to study heme-mediated effects on glycolytic pathway. We analyzed the glycolytic function using Seahorse Extracellular Flux analyzer and the glycolytic enzyme activities were measured using commercially available kits. Cell index measured by the xCELLigence system (Acea) was used for proliferation assays.

Results: Heme induced strong inhibition of glycolysis in HLMVEC after 1h of treatment (Figure 1A). Our data showed that on one hand activation of phosphofructokinase (PFK) (Figure 1C) and on the other inhibition of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (Figure 1D) after 1h of heme treatment. PFK catalyzed formation of fructose 1,6-bisphosphate is considered the rate-limiting step of glycolysis. Therefore, under the influence of heme, the glycolytic rate limiting step in endothelial cells is reassigned to GAPDH (Figure 1B). Further, our data indicates an increased activity of GAPDH after 24h of heme incubation. Thus, we believe that this could be the possible mechanism by which heme causes this shift in cellular metabolism toward glycolysis. Moreover, the rate of endothelial cell proliferation exhibited two-phase effect of the heme treatment, with growth inhibition in the acute phase (0-12h) and increased proliferation after 48h. Conclusions: Our results indicate involvement of free heme in the endothelial glycolytic pathway. Further studies on identifying the role of heme signaling on the glycolytic shift could potentially lead to identification of new targets for vascular remodeling in PAH.

Figure 1: Heme induced glycolytic imbalance in EC. A) heme induced glycolysis inhibition B) Bottle neck of glycolysis C) PFK activation D) GAPDH inhibition 33

PULMONARY HYPERTENSION ASSOCIATION

Inflammatory Macrophage Expansion in Pulmonary Hypertension Depends Upon Mobilization of Blood-Borne Monocytes

Florentin J1, Coppin E1, Vasamsetti SB1, Zhao J1, Tai YY1, Tang Y1, Zhang Y1, Watson A1, Sembrat J1, Rojas M1, Vargas SO2, Chan SY1, Dutta P1 1 University of Pittsburgh, Pittsburgh, PA, USA 2 Boston Children's Hospital, Boston, MA, USA

Background: Pulmonary inflammation, characterized by the presence of perivascular macrophages, has been proposed as a key pathogenic driver of pulmonary hypertension (PH), a vascular disease with increasing global significance. However, the mechanisms of expansion of lung macrophages and the role of bloodborne monocytes in PH are poorly understood. Methods: Using multicolor flow cytometric analysis of blood in mouse and rat models of PH and patients with PH, an increase in blood monocytes was observed. Results: In correlation, lung tissue displayed increased chemokine transcript expression, including those responsible for monocyte recruitment such as Ccl2 and Cx3cl1, accompanied by an expansion of interstitial lung macrophages. These data indicate that blood monocytes are recruited to lung perivascular spaces and differentiate into inflammatory macrophages. Correspondingly, parabiosis between congenically different hypoxic mice

demonstrated that most interstitial macrophages originated from blood monocytes. To define the actions of these cells in PH in vivo, we reduced blood monocyte numbers via genetic deficiency of cx3cr1 or ccr2 in chronically hypoxic male mice and by pharmacologic inhibition of Cx3cl1 in monocrotaline-exposed rats. Both models exhibited decreased inflammatory blood monocytes as well as interstitial macrophages, leading to a substantial decrease of arteriolar remodeling but with a less robust hemodynamic effect. Conclusions: This study defines a direct mechanism by which interstitial macrophages expand in PH. It also demonstrates a pathway for pulmonary vascular remodeling in PH that depends upon interstitial macrophage-dependent inflammation yet at least is partially dissociated from hemodynamic consequences, thus offering guidance on future anti-inflammatory therapeutic strategies in this disease.

Figure 1: Schematic diagram depicting monocyte recruitment to the lungs and expansion of interstitial macrophages in PH

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

RESEARCH ABSTRACTS & CASE STUDIES

1008

1009

Insulin Receptor Substrate 2 is Decreased in Clinical Pulmonary Hypertension and Its Anti-Inflammatory Role in the Pulmonary Vasculature Under Hypoxic Conditions The Johns Hopkins Medical Institutions, Baltimore, MD, USA

Background: Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. Recently, an important association between insulin resistance and PH has been identified. Both conditions occur in the presence of chronic inflammation and vascular dysfunction. We have found previously that insulin receptor substrate 2 (IRS2), one of the most critical molecules to insulin resistance and cellular energy homeostasis, plays a critical anti-inflammatory role in macrophage (MΦ) activation in Th2-skewed lung inflammation and pulmonary vascular remodeling. Here, we investigated the role of IRS2 in human PAH. We also analyzed the role of IRS2 in pulmonary vascular remodeling in mice under hypoxic conditions. Methods: We analyzed the IRS2 expression in the remodeling pulmonary vasculature in the patients with idiopathic PAH (IPAH). We compared the degree of hypoxia-induced pulmonary vascular remodeling between wild-type (IRS2 +/+) and IRS2 heterozygous-knockout (IRS2 +/-) mice in vivo.

PULMONARY HYPERTENSION ASSOCIATION

Results: We observed dysregulated IRS2 expression in the pulmonary vasculature of patients with IPAH as compared to healthy control subjects. In our preliminary studies, IRS2+/- mice showed dramatic increases in fully muscularized pulmonary vessels accompanied by accumulation of RELMα-expressing MΦ at day 4 of hypoxia stimulation. To our surprise, pulmonary vessels were fully muscularized in IRS2+/- mice at day 4 of hypoxia, whereas full muscularization usually requires 3 weeks in mice. We also observed that IRS2 knockdown resulted in exaggerated proliferative activities in the pulmonary vasculature as compared to IRS2+/+ mice in response to hypoxia. Conclusions: Our results suggest that IRS2 expression is dysregulated in clinical PAH. It also suggests that IRS2 possesses anti-inflammatory properties by regulating MΦ activation and recruitment which may limit vascular inflammation and a hyper-proliferative microenvironment that are seen in PAH pathology. Restoring IRS pathway in humans may be an effective immunosuppressive therapy for the treatment of PAH.

Salutary Effects of Estrogen Receptor (ER)-α on the Pulmonary Vasculature in Experimental Pulmonary Hypertension (PH)

Frump AL1, Yakubov B1, Zeng L1, Albrecht M1, Essex A1, Cook T1, Fisher A1, Martinez D2, Phillips JL 2, Li R2, Sun X 2, Chesler NC2, Lahm T1 1 Indiana University School of Medicine, Indianapolis, IN, USA 2 University of Wisconsin-Madison, Madison, WI, USA Background: Women are more prone to developing pulmonary arterial hypertension (PAH), but once affected also exhibit better survival. In the systemic vasculature, ERα exerts beneficial effects on endothelial cell function, while ERα loss-of-function mutations have been linked to cardiovascular disease. Effects of ERα on pulmonary artery endothelial cells (PAECs), on the other hand, are poorly defined. We hypothesize that ERα increases PAEC BMPR2 and apelin signaling, decreases PAEC apoptosis and attenuates pulmonary vascular remodeling. Methods: PAECs were treated with 17β-estradiol (E2) or ERα-agonists PPT or BTPα (0.1 nM-100 nM; 6-24hrs) and apelin, BMPR2, phospho-Smad 1/5/8, and Id1 expression were analyzed (western blot). E2 or ERα-agonist effects on pro-apoptotic signaling were assessed by caspase-3/7 activity assay in PAECs treated with staurosporine (50-500 nM). PAEC tube formation was assessed by matrigel assay. For prevention studies, male and female Sprague-Dawley rats with sugen/hypoxia (SuHx)-PH were treated with E2 or PPT and female ERα knockout rats (generated by CRISPR-Cas) were exposed to 3 weeks hypoxia to induce PH. Additionally, monocrotaline (MCT)-PH rats were treated with E2 or PPT two weeks post MCT injection (rescue approach). Animals were assessed for hemodynamic alterations, pulmonary vascular remodeling (Verhoff-van Giessen stain), apoptotic signaling (TUNEL, cleaved caspase 3), BMPR2 signaling and apelin expression (whole lungs, western blot). p<0.05 by ANOVA was significant.

Results: Treatment with E2, PPT or BTPα increased BMPR2, Id1 and apelin expression and Smad1/5/8 phosphorylation in PAECs (p<0.05). PPT and BTPα attenuated staurosporine-induced increases in caspase3/7 activity by 30% and E2 or PPT dose-dependently increased PAEC tube formation by 45% (p<0.05). In MCT rats treated with E2 or PPT, MCT-induced decreases in lung BMPR2 and apelin were rescued. PPT treatment attenuated SuHx-induced increases in lung cleaved caspase-3 at one week, and prevented pulmonary arterial remodeling at seven weeks (p<0.05). MCT rats treated with PPT exhibited a 58% decrease in total pulmonary resistance (TPR; surrogate for pulmonary vascular resistance; p<0.05), whereas availability of ERα in control female rats prevented the near doubling of arterial elastance and TPR with hypoxia observed in female ERα KO rats (p<0.05), suggesting increased RV afterload is attenuated by ERα. Conclusions: We identified a novel mechanism of action of ERα leading to attenuation of pro-apoptotic signaling and up-regulation of BMPR2 and apelin in cultured PAECs and in vivo. Compared to broadly targeting estrogen in PAH, selectively activating ERα signaling may allow for a more precise strategy to harness protective estrogenic effects, maximizing benefit while avoiding detriment.

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

RESEARCH ABSTRACTS & CASE STUDIES

RESEARCH ABSTRACTS & CASE STUDIES 1011

1010

Stability of Treprostinil With Diluents and Medications Doran A, Borg E, Rollins K, Phares K United Therapeutics Corporation, Research Triangle Park, NC, USA

Background: Parenteral treprostinil (TRE) is indicated for the treatment of pulmonary arterial hypertension (PAH) to diminish symptoms associated with exercise. Pivotal studies with subcutaneous TRE included 470 patients with New York Heart Association functional class II (11%), III (81%), or IV (7%) PAH, with a mean age of 45 (range: 9 to 75) years. A number of studies have evaluated the effects of parenteral TRE on functional status, hemodynamics, and survival in pediatric patients with pulmonary vascular disease. The safety and efficacy of intravenous (IV) TRE in neonates with persistent pulmonary hypertension is currently being evaluated in a randomized, placebo-controlled, Phase II study (NCT02261883). Lack of data demonstrating stability of TRE with diluents and IV medications commonly used in the adult, pediatric, and neonatal PAH inpatient populations complicates the ability of health care teams to make decisions. These high-risk populations may have central line access issues or caloric needs, necessitating co-administration of IV medications and use of dextrose solutions. The purpose of this study was to evaluate the chemical and physical stability of TRE over time, when diluted in 5/10% dextrose in water (D5/D10W), and when individually combined in normal saline (NS) with IV inotropes and other medications commonly used in the critical care setting. Methods: TRE was diluted to three concentrations (0.00025, 0.004, and 0.13 mg/mL) with D5/D10W and stored at 25°C/60% relative humidity. Samples were evaluated for stability at 24 and 54 hours (hr). TRE (0.4 mg/mL) was combined with heparin (20 units/mL) in NS and stored at ambient conditions (20 to 23°C). Samples were evaluated for stability at 24 and 52 hr. TRE was individually combined with eleven IV medications at lower and/or higher concentrations in NS and stored at ambient conditions. Samples were evaluated for stability at 18 and 24 hr. Physical stability was evaluated by visual assessment for appearance of precipitation or color change.

PULMONARY HYPERTENSION ASSOCIATION

Chemical stability was evaluated by assay comparison to initial medication concentration(s) using high-performance liquid chromatography. Results: • Three concentrations of TRE (0.00025, 0.004, and 0.13mg/mL) diluted in D5W or D10W were chemically and physically stable to 54 hr. • TRE (0.4 mg/mL) with heparin (20 units/mL) was chemically and physically stable to 52 hr in NS. • Lower-concentration TRE (0.4mg/ mL) was chemically and physically stable to 24 hr in NS with: dexmedetomidine (4 µg/mL), dobutamine (1 mg/mL), fentanyl (10 µg/mL), furosemide (1.5 mg/mL), midazolam (0.1 mg/mL), milrinone (0.2 mg/mL), morphine (5 mg/mL), norepinephrine (16 µg/mL), and vasopressin (2 units/mL). • Higher-concentration TRE (1 mg/mL) was chemically and physically stable to 24 hr in NS with: dexmedetomidine (4 µg/mL), dobutamine (8 mg/mL), fentanyl (50 µg/mL), furosemide (10 mg/mL), midazolam (5 mg/mL), milrinone (1 mg/mL), morphine (5 mg/mL), and norepinephrine (80 µg/ mL). • Lower-concentration TRE (0.4 mg/mL) with dopamine (1.6 mg/mL) was chemically and physically stable to 18 hr in NS. Higher-concentration TRE (1 mg/mL) with dopamine (40 mg/mL) was not physically or chemically stable. • TRE (0.4 and 1 mg/mL) and epinephrine (8 and 90 µg/mL) stability was inconclusive due to epinephrine standard degradation. Conclusions: TRE was chemically and physically stable to 52 hr at 25°C/60% relative humidity when diluted in D5W or D10W. TRE and eleven IV medications were chemically and physically stable to various time points at ambient conditions when combined in NS. The compatibility of TRE with epinephrine warrants further evaluation, due to inconclusive results from the reference standard.

The Role of Perivascular Edema and Endothelial Barrier Function in Pulmonary Arterial Hypertension Rafikov R1, Srivastava A1, Desai AA1, Simon M2, Rafikova O1 1 University of Arizona, Tucson, AZ, USA 2 University of Pittsburgh, Pittsburgh, PA, USA

Background: Pulmonary arterial hypertension (PAH) is a progressive condition, characterized by a continued increase in pulmonary pressure that ultimately leads to right heart failure and death. Although PAH is a rare disease with 10-15 cases per million for the general population (0.001%), patients with hemolytic anemias have a high frequency of PAH development of up to 80%. While the association between sickle cell disease (SCD), thalassemia and the risk of PAH development is wellestablished, other hemolytic conditions such as G6PD deficiency, spherocytosis and microangiopathic hemolytic anemia (MAHA) were also shown to be associated with PAH. Thus, chronic hemolytic conditions contribute significantly to PAH risk, but mechanisms hemolysis involvement in PAH development remain unclear. Apart from the ability of hemoglobin (Hb) to scavenge nitric oxide and to produce reactive oxygen species in circulation, no additional mechanistic studies exist on the role of free hemoglobin involvement in PAH. Methods: Plasma samples from patients with and without pulmonary arterial hypertension (both confirmed by right heart catheterization) were used to measure free Hb and its correlation with the severity of PAH. A sugen (50mg/kg) / hypoxia (3wks) /normoxia (2wks) and monocrotaline (60mg/ kg) 2wks rat models were used to elucidate the role of free Hb/heme pathways in PAH. Human lung microvascular endothelial cells (HLMVECs) were utilized to study heme-mediated endothelial barrier effects.

Results: Our data indicate that PAH patients have significantly, 5-fold, elevated free hemoglobin in plasma. Further analysis of clinical data indicated a strong correlation (r=0.78, p<0.0001) between levels of hemolysis and mean Pulmonary Arterial Pressure (mPAP). We also found a significant correlation (r=0.58, p<0.0003) between free Hb and Pulmonary Vascular Resistance (PVR). Free Hb also negatively correlated with Cardiac Index (CI) (r= -0.42, p<0.01). Using cell culture model we found that, in contrast to free Hb, its degradation product - free heme, induces intracellular pathways in endothelial cells (EC) leading to PAH development. We observed that free heme activates the p38/HSP27 pathway and redistributes tight junction from cell-cell contacts into the perinuclear region leading to EC barrier dysfunction with the formation of perivascular cuffs around pulmonary arteries in the animal model. The main features of perivascular edema such as decreased vaso-reactivity, increased stiffness, inflammatory cells infiltration and local hypoxia around the vessel may all contribute to pathologic vascular remodeling. Interestingly, in both animal PAH models, monocrotaline and Sugen/ Hypoxia, we found the formation of perivascular cuffs at the earlier stage of the PAH. Conclusions: Local hypoxia, stiffness and inflammation in the pulmonary circulation induced by perivascular fluids around vessels can explain remodeling activation and why patients develop PAH without being under hypoxic condition.

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

RESEARCH ABSTRACTS & CASE STUDIES

1013

1012

The PPARγ Agonist Pioglitazone Reverses Pulmonary Arterial Hypertension and Prevents Right Heart Failure Through Fatty Acid Oxidation

Therapeutic MAb Targeting Endothelin Receptor A for Pulmonary Arterial Hypertension

Legchenko E , Chouvarine P , Borchert P , Fernandez-Gonzalez A , Snay E , Mägel L , Mitsialis SA , Meier M , Rog-Zielinska E6, Kourembanas S2, Jonigk D4, Hansmann G1 1 Department of Pediatric Cardiology and Critical Care, and Pulmonary Vascular Research Center (PVRC), Hannover Medical School, Germany 2 Division of Newborn Medicine, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA 3 Division of Nuclear Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA 4 Institute of Pathology, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany; The German Center for Lung Research (Deutsches Zentrum für Lungenforschung DZL) 5 Institute of Laboratory Animal Science, Hannover Medical School, Hannover, Germany 6 Institute for Experimental Cardiovascular Medicine, Freiburg, Germany 1

Background: Pulmonary arterial hypertension (PAH) has a mortality rate of 25% to 60% within 5 years after diagnosis, with right ventricular (RV) failure being the leading cause of death. So far, no intervention could fully reverse PAH or even prevent pressure overload heart failure, in the well-established Sugen 5416/hypoxia (SuHx) rat model that closely resembles human disease. We hypothesized that the PPARγ agonist pioglitazone (Pio) reverses angio-obliterative PAH and prevents heart failure in RV pressure overloaded rats. Methods: We measured ventricular function and pulmonary artery acceleration time (PAAT) in mice with deletion of PPARγ in cardiomyocytes (cmPPARγ -/-) by magnetic resonance imaging (MRI) and echocardiogram (ECHO). In addition, SD rats were divided into 4 groups, injected either with no agent, vehicle (dimethyl sulfate, DMSO), or the VEGFR2 inhibitor SU5416: control normoxia (ConNx); control/hypoxia (ConHx, 1x subcutaneous [SC] DMSO, 3 weeks hypoxia, 6 weeks room air); SU5416/hypoxia (SuHx, SU5416 20 mg/kg/dose SC x1, 3 weeks Hx, 6 weeks Nx); SU5416/hypoxia treated with Pio (SuHx + Pio, SU5416 SC x1, 3 weeks Hx, 6 weeks Nx, including 5 weeks of Pio treatment 20 mg/ kg/day by mouth). Hemodynamics, RV/left ventricular (LV) mass and volumes were assessed by cardiac catheterization, MRI, ECHO, RV/ LV+S mass ratio. Mitochondrial integrity and lipid accumulation were assessed by 2D/3D electron microscopy and cardiac magnetic resonance spectroscopy. RNA expression studies (mRNASeq, single/array miRNA qPCR) were performed on rat RV and LV (N=3/group), and on laser-capture microdissected explanted heart and lung tissue of idiopathic PAH (IPAH) heart-lung transplantation (HLTx) patients and donors (N=7-10). We measured Pio-regulated mitochondrial function (FAO, ATP production) in rat neonatal ventricular cardiomyocytes (NRCM) by Seahorse.

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Results: cmPPARγ -/- mice developed biventricular systolic dysfunction vs. controls, in the absence of PAH (PAAT not significantly different). SuHx rats developed severe PAH and overt RV failure vs. ConNx and ConHx. PAH was fully reversed and RV failure prevented by Pio administration (SuHx+Pio): right ventricular systolic pressure (RVSP) (91.1 in SuHx vs. 28.8 vs. 32.2 vs. 34.2 mmHg). Electron ~ microscopy showed abnormal mitochondrial~ ~and = T-tubule/ SR couplon morphology, and large vacuoles (lipid vacuoles) in SuHx rats. Magnetic resonance spectroscopy unraveled inter- and intracellular lipid accumulation in failing RVs, which was not present in controls or SuHx+Pio rats. Consistently, Pio induced FAO and ATP production in cultured NRCM. RNASeq revealed 104 genes with differential expression in SuHx RVs, and 67 genes to be Pio-regulated. Several miRNAs were altered in SuHx RVs and regulated by Pio. Accordingly, altered miR expression was confirmed in human plexiform lesions vs. small pulmonary arteries, and RVs of HLTx IPAH patients.

Zhang C, Guo Y, Fan K, Jing S Gmax Biopharm, Hangzhou, Zhejiang Province, China

Background: Endothelin receptor A (ETa) is a G proteincoupled receptor and a major therapeutic target for pulmonary arterial hypertension (PAH). Approved small molecule endothelin receptor antagonists (ERAs) have been beneficial to PAH patients; however, low target specificity and chemical structure-based liver toxicity of the ERAs limited their ability to further improve patient’s quality of life and extend their survival. Methods: To overcome the shortcomings of the existing drugs, we developed an antagonistic monoclonal antibody (Getagozumab) against ETa. Cell-based binding and calcium influx assays were set up for in vitro studies of Getagozumab. Both acute hypoxia-induced and MCT-induced PAH monkey models were also established to assess the pharmacodynamic and pharmacokinetic characteristics of Getagozumab.

Results: Getagozumab displayed a Kd of 8.7 nM in vitro and an IC50 of 37.9 nM in the cell-based functional assay. Getagozumab could significantly lower pulmonary artery pressure in both hypoxia-induced and MCT-induced monkey models and further attenuate the pulmonary arterial wall thickness and right ventricular hypertrophy in MCT-induced PAH monkeys. The preclinical studies demonstrated that Getagozumab is safe, long-lasting and significantly more efficacious than Ambrisentan. A phase I clinical trial of Getagozumab to study safety and PK in healthy volunteers is on-going in Australia. Conclusions: Getagozumab could serve as a novel and best-in-class treatment option for PAH and may be able to further improve patient’s quality of life and extend their survival.

Conclusions: PPARγ deficiency in cardiomyocytes leads to biventricular systolic dysfunction in mice. PPARγ activation by Pio is the first intervention that fully reverses angio-obliterative PAH/pulmonary vascular disease and prevents heart failure in a robust animal model of PAH/RV failure, and as such is an attractive treatment option for clinical PAH that regulates lipid metabolism.

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A Retrospective Comparison of Pulmonary Arterial Hypertension (PAH) Patients With Myositis-Related Autoantibodies to Patients With Idiopathic PAH and PAH Associated With Systemic Sclerosis

Si S1, Weinmann S2, Despotovic VN2, McEvoy C2, Chakinala MM2 Washington University School of Medicine, Saint Louis, MO, USA 2 Duke University School of Medicine, Durham, NC, USA

Background: Pulmonary arterial hypertension (PAH) is a heterogeneous disorder that can arise from a number of causes. Distinct forms of PAH, most notably PAH related to connective tissue diseases or systemic sclerosis (SScPAH), have differing characteristics and are associated with worse outcomes relative to idiopathic PAH (IPAH). We are not aware of studies that have specifically investigated a group of patients with myositis autoantibodies and PAH (MA-PAH) in comparison to other cohorts of PAH patients. Methods: We carried out a single-center, retrospective cohort study to compare the phenotypic, laboratory, functional, hemodynamics, and outcomes of patients with myositis autoantibodies and PAH to IPAH and SSc-PAH patients. Individuals with PAH confirmed by cardiac catheterization were eligible for inclusion into the study, and patients were enrolled from August 2012 to January 2017. MyoMarker Panel 3 (RDL Reference Laboratories, Inc.) assay was used for myositis autoantibody testing. Patient characteristics were compared between groups using the Chi-square test and one-way ANOVA with Tukey post hoc test. Survival analysis was performed utilizing the Kaplan-Meier method and the log-rank test. Patient Variables Age, years Female sex, No. (%) Active Myositis, No. (%) Interstitial Lung Disease, No. (%) WHO Functional Class I, No. (%) WHO Functional Class II, No. (%) WHO Functional Class III, No. (%) WHO Functional Class IV, No. (%) 6-Minute Walk Test, Meters Antinuclear Antibody, No. (%) BNP, pg/mL FEV1, % Predicted FVC, % Predicted FEV1/FVC, % TLC, % Predicted DLCO, % Predicted TAPSE<1.6cm, No. (%) Pericardial Effusion, No. (%) mRAP, mmHg mPAP, mmHg mPCWP, mmHg 2 Cardiac Index, L/min/m PVR, Wood units Calcium Channel Blocker Endothelin Receptor Antagonist Phosphodiesterase Inhibitor Prostacyclin

Results: 37 MA-PAH patients were compared to 47 IPAH and 19 SSc-PAH patients. The median age of the subjects was 61 years (range 30 to 80 years) and 81 (79%) patients were female. MA-PAH patients did not differ with respect to any tested characteristic when compared to SSc-PAH patients. Of note, subjects with IPAH were significantly younger, had superior exercise capacity, and demonstrated better lung function relative to both MA-PAH patients and SSc-PAH patients. Hemodynamically, IPAH patients had more elevated mean pulmonary artery pressures (mPAP) and pulmonary vascular resistances (PVR) in comparison to MA-PAH patients and SSc-PAH patients. There were no significant differences in PAH-specific therapies between groups. Estimated survival from enrollment for the overall cohort was 94%, 89%, and 81% at one year, two years, and four years, respectively, with no differences in mortality between any of our three cohorts. Conclusions: Our results demonstrate that MA-PAH patients are clinically similar to SSc-PAH patients and significantly dissimilar to IPAH patients. Differences in response to treatment and long-term outcomes for this novel sub-group of PAH patients needs further investigation.

Myositis-Autoantibody Positive, N = 37 61 ± 13** 29 (78) 11 (30) 22 (59) 1 (3) 7 (19) 25 (68) 4 (11) 232 ± 118** 27/36 (75%) 518 ± 848 64 ± 20****(vs. IPAH) 71 ± 20**** 72 ± 11 77 ± 21**** 35 ± 15*** 17 (46) 10 (27) 9±6 44 ± 11** 10 ± 4 2.3 ± 0.5 9 ± 4* 2 (5) 11 (30) 28 (76) 10 (27)

Behr J1, Nathan SD2, Harari S3, Wuyts W4, Stauffer JL5, Kirchgaessler KU6, Bengus M6, Gilberg F6, Wells AU7 Department of Internal Medicine V, LMU and Asklepios Fachkliniken Gauting, Comprehensive Pneumology Center, Munich, Germany; Member of the German Center for Lung Research 2 Inova Heart and Vascular Institute, Inova Fairfax Hospital, Falls Church, VA, USA 3 U.O. di Pneumologia e Terapia Semi-Intensiva Respiratoria, Servizio di Fisiopatologia Respiratoria ed Emodinamica Polmonare, Ospedale San Giuseppe, MultiMedica IRCCS, Milan, Italy 4 Department of Pulmonary Medicine, Unit for Interstitial Lung Diseases, University of Leuven, Leuven, Belgium 5 Genentech, Inc., South San Francisco, CA, USA 6 F. Hoffmann-La Roche Ltd., Basel, Switzerland 7 Interstitial Lung Disease Unit, Royal Brompton Hospital, London, UK 2

IPAH N = 47 52 ± 13 36 (77) N/A 2 (4) 5 (11) 15 (32) 26 (55) 1 (2) 331 ± 133 5/39 (13%) 280 ± 342 84 ± 15 93 ± 16 74 ± 8 94 ± 13 50 ± 20 32 (68) 7 (15) 11 ± 6 52 ± 13 11 ± 4 2.2 ± 0.7 11 ± 5 6 (13) 16 (34) 29 (62) 16 (34)

SSc-PAH N = 19 67 ± 8*** 16 (84) N/A 10 (53) 1/17 (6%) 2/17 (12%) 12/17 (71%) 2/17 (12%) 224 ± 151** 18/19 (95%) 380 ± 437 74 ± 14 78 ± 17** 77 ± 7 75 ± 14*** 34 ± 15** 11 (58) 4 (21) 10 ± 9 44 ± 10* 10 ± 4 2.5 ± 0.7 8 ± 5* 0 (0) 8 (42) 12 (63) 6 (32)

p-value <0.0001 0.4694 <0.0001 0.3577 0.1691 0.3847 0.2059 0.0009 <0.0001 0.2037 <0.0001 <0.0001 0.1594 <0.0001 <0.0001 0.1595 0.3898 0.2637 0.0023 0.5157 0.4673 0.0165 0.1714 0.6514 0.3711 0.7872

Background: Pirfenidone is one of two treatments approved for idiopathic pulmonary fibrosis (IPF). Pulmonary vascular disease and pulmonary hypertension (PH) are common in patients with advanced IPF. Although the overall results of the STEP-IPF study were inconclusive, sildenafil had beneficial effects compared with placebo in patients with right ventricular systolic dysfunction, with no safety concerns (IPFCRN 2010). Combination treatment with sildenafil and pirfenidone may address unmet needs in patients with IPF and PH. MA29957 (NCT02951429) is an ongoing study assessing the efficacy, safety and tolerability of sildenafil (20 mg TID) or placebo in patients with advanced IPF and risk of PH who are tolerating pirfenidone at a stable dose (target enrollment=176 patients). The ongoing study is being monitored by an experienced independent data monitoring committee (iDMC). We report baseline characteristics from a scheduled, blinded interim analysis performed in September 2017 for the iDMC. Methods: Eligible patients with advanced IPF (% predicted diffusing capacity for carbon monoxide [%DLCO] ≤40%) and risk of Group 3 PH (mean pulmonary arterial pressure [mPAP] ≥20 mmHg with pulmonary arterial wedge pressure ≤15 mmHg on a previous right-heart catheterization [RHC], or intermediate/high probability Group 3 PH per the 2015 European Society of Cardiology/European Respiratory Society guidelines, i.e., peak tricuspid valve regurgitation velocity [TRV] ≥2.9 m/s). The composite primary endpoint is ≥15% decline in 6-minute walk distance (6MWD), respiratoryrelated non-elective hospitalization and all-cause mortality.

Results: A total of 101 patients provided signed informed consent of which 33 patients were in screening/run-in at the time of the analysis. Screening/run-in failure occurred in 20/101 patients (19.8%), mainly based on eligibility criteria related to advanced IPF and risk of PH. Forty-eight randomized patients were included in this analysis; mean age was 70.4 years, 69% were male and mean time from IPF diagnosis was 45.3 months (Table). Mean %DLCO and % forced vital capacity were 25.65% and 68.74%, respectively. Mean mPAP on RHC was 32.2 mmHg (n=6), peak TRV was 3.61 m/s and systolic pulmonary arterial pressure on ECHO was 61.8 mmHg (n=46). Mean 6MWD was 282.6 m. Updated baseline data will be presented. Conclusions: Some baseline characteristics (e.g., age, sex, WHO class, %DLCO) were comparable to those of patients from STEP-IPF (advanced IPF; %DLCO <35%) and RISE-IIP (idiopathic interstitial pneumonia and PH confirmed by RHC). The results of this study will allow the impact of pirfenidone/sildenafil combination treatment on outcomes in patients with IPF and risk of PH to be assessed.

Table 1: Baseline Clinical, Functional, and Hemodynamic Characteristics Chi-square test or one-way ANOVA with Tukey post hoc test. *P<.05, **P<.01, ***P<.001, ****P<.0001. 41

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1016 Table 1: Baseline Characteristics From an Interim Analysis of Patients Participating in the MA29957 Study (N = 48) Compared With Those Reported in the STEP-IPF and RISE-IIP Studies1,3 1

Characteristic Age, years Male, % Time since IPF diagnosis, months WHO Functional Class, % II III IV DLCO, % predicted FVC, % predicted FEV1/FVC mPAP, RHC, mmHg* Peak TRV, ECHO, m/s PAPs, ECHO, mmHg 6MWD, m

70.4 (5.29) 69

STEP-IPF (N = 180)2 Sildenafil Placebo (n = 89) (n = 91) 69.76 (8.71) 68.20 (9.25) 84 82

45.3 (36.38)

24.36 (23.28)

MA29957 (N = 48)

31.3 64.6 2.1 25.65 (9.558) 68.74 (18.343) 0.875 (0.0841) 32.2 (7.81) (n = 6) 3.61 (0.655) (n = 46)† 61.8 (21.01) (n = 46)† 282.6 (108.30)

RISE-IIP (N = 147)3 Riociguat Placebo (n = 73) (n = 74) 68 (8) 69 (8) 68 61

22.44 (23.16)

N/A

25.81 (6.03) 26.73 (6.16) 54.89 (14.00) 58.73 (14.12) N/A

22 68 10 32.0 (11.5) 76.3 (19.1) 0.8 (0.1)

30 61 9 30.5 (10.9) 74.3 (15.7) 0.8 (0.1)

N/A

33.2 (8.2)

33.5 (9.4)

N/A

246.93 (99.11)

267.71 (127.75)

307 (80)

324 (66)

6MWD, 6-minute walk distance; DLCO, diffusing capacity for carbon monoxide; ECHO, echocardiogram; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; PAP, pulmonary arterial pressure; RHC, right-heart catheterization; TRV, tricuspid valve regurgitation velocity; WHO, World Health Organization. Data are mean (SD) unless otherwise stated. * Six patients were eligible for study enrolment based on RHC criteria. † At the interim analysis, baseline ECHO data were missing for 2 patients. Disclaimer: The data presented in this abstract is a subset of the overall planned study population and is still subject to extensive data cleaning efforts. Therefore, any interpretation of the results presented should be treated with caution and may change in the future. 1 IPFCRN, et al. N Engl J Med. 2010. 2 Han, et al. Chest. 2013. 3 Nathan SD. Eur Respir J. 2017.

Myositis-Related Autoantibodies and Pulmonary Arterial Hypertension (PAH): Another Sub-Type of PAH Associated With Autoimmune Conditions Si S1, Weinmann S2, Despotovic VN1, McEvoy C1, Chakinala MM1 Washington University School of Medicine, Saint Louis, MO, USA 2 Duke University School of Medicine, Durham, NC, USA 1

Background: Patients being evaluated for PAH must be screened for underlying (autoimmune) connective tissue diseases (CTD). Available commercial assays identify myositis-related autoantibodies that are associated with autoimmune inflammatory myopathies or myositis overlapping with CTDs. However, little is known regarding the clinical characteristics of these autoimmune conditions with myositis-related autoantibodies and concomitant pulmonary arterial hypertension (PAH) or the implications of such testing on clinical practice. Methods: In this single-center, retrospective case series, we explored the phenotypic, laboratory, functional, hemodynamic, and treatment profile of 37 patients with PAH (mean PAP ≥ 25, normal LV filling pressures, PVR ≥ 3) and myositis autoantibodies evaluated between August 2012 to January 2017. Myositis autoantibody testing was carried out utilizing the MyoMarker Panel 3 (RDL Reference Laboratory, Inc.). Results: Median age of the cohort was 61 years (range 30 to 80) and 29 patients (78%) were female. 15 (41%) patients were determined to have two myositis autoantibodies and 3 (8%) patients had three unique myositis autoantibodies. The SSA-52 autoantibody was most common, present in

Autoantibody Mi-2 Jo-1* Pl-7* Pl-12* EJ* OJ* SRP P155/140 P140 Ku U1RNP PM-Scl U3 Fibrillarin SSA-52 U2 SNRNP

25 (68%) patients. Detection of myositis autoantibodies aided in either a novel CTD diagnosis or an alternative CTD diagnosis in 11 patients. 6 patients were diagnosed with antisynthetase syndrome. 22 (59%) patients had interstitial lung disease and 29 (78%) patients were NYHA Functional Class III or IV. The cohort’s mean (±SD) (% predicted) FEV1, FVC, and TLC was 64 ± 20%, 71 ± 20%, 77 ± 21%, respectively, while the 6-minute walk distance was 256 ± 128 meters. Mean pulmonary artery pressure (PAP) was 44 ± 11 mmHg and pulmonary vascular resistance (PVR) was 9 ± 4 Wood units, including 29 (78%) patients with mPAP >35 mmHg. At the time of myositis autoantibody positivity, 2 (5%) patients were being treated with a calcium-channel blocker, 11 (30%) with an endothelin receptor antagonist, 28 (76%) with a PDE5 inhibitor, and 10 (27%) with a prostacyclin analogue. Conclusions: In this novel cohort of myositis autoantibody positive patients diagnosed with PAH, there was a high prevalence of severely elevated mPAPs and PVR. During the evaluation of possible pulmonary arterial hypertension, testing for myositis autoantibodies should be considered and may be informative.

Number of Patients 7 2 3 1 0 0 0 0 4 4 7 1 2 25 2

Table 1: Distribution of myositis autoantibodies in 37 patients. *Antisynthetase antibodies.

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Background: The advent of highly active antiretroviral therapy (HAART) has substantially improved the survival of HIV-infected individuals, but this has been accompanied by an increase in the prevalence of cardiovascular disease and their complications, including pulmonary hypertension (PH). While this could be attributed to heightened inflammatory state and higher endothelin levels, data on PH and HIV is limited. This study aims to evaluate the risk of PH in HIV-infected adults in a single center in Miami. Methods: A retrospective chart review was conducted in patients seen at the University of Miami Adult HIV Clinic. Information on demographics, vital signs, lab results, lifestyle factors, and diagnostic studies were collected. Results from two-dimensional echocardiograms were evaluated for right ventricular systolic pressures (RVSP) and tricuspid regurgitant jet velocity (TRJV). Patients were deemed to have “high probability” of PH if the RVSP was greater than 50 mmHg or if the TRJV was greater than 3.4 m/s. Patients were defined as having “intermediate probability” of PH if the RVSP was greater than 35 mmHg or if the TRJV was greater than 2.8 m/s. Univariate logistic regressions were used to calculate odds ratios, and multivariate linear regression was used to identify predictors of RVSP. Results: A total of 267 patients with diagnosed HIV were reviewed, of which 44 (16.5%) had two-dimensional

echocardiograms. In the patients with echocardiograms, the average age was 55.1 years, and 56.8% were male. The average CD4 count was 594.6 (SD 394), and the average viral load was 8471.7 (SD 28,300). One patient (2.7%) of these patients was found to have high probability of PH, and eight patients (21.6%) were identified as having intermediate probability of PH. Being male (OR 2.44), having a history of smoking (OR 1.64), COPD (OR 4.00), diabetes (OR 3.17), and systolic heart failure (OR 9.33) were associated with an intermediate risk of PH. Patients with undetectable viral load were less likely to be classified as intermediate risk (OR 0.35). None of these variables were statistically significant, likely a result of the limited sample size of this study. Linear regression did not show a statistically significant relationship between these predictors and RVSP. Conclusions: A number of HIV patients that had echocardiograms have findings suggesting pulmonary hypertension, yet echocardiograms are not performed routinely in this population. Given this finding, providers treating HIV patients should be aware of the increased risk of PH in HIV patients compared to the general population, and should consider targeting questions addressing cardiopulmonary symptoms and, if clinically indicated, perform echocardiograms. Further studies evaluating the current epidemiology and risk factors of PH in HIV patients in the current HAART era are needed.

Advance Care Planning Completion in Pulmonary Hypertension Care Center Rachu G, Whittenhall ME, Ventetuolo CE, Mullin CJ, Klinger JR, Allahua M, Ahearn M The Warren Alpert Medical School of Brown University Division of Pulmonary, Critical Care and Sleep Medicine, Providence, RI, USA Purpose: To increase advance care planning (ACP) documentation for patients in the pulmonary hypertension care center. Background: Advance care planning involves an ongoing process between patients, family, and health care providers with the aim to clarify goals and alleviate debilitating symptoms. ACP has been shown to help patients express and control their values and health care goals, based on personal, cultural, and religious beliefs; thereby improving patient-defined quality of life and reducing anxiety/ depression associated with serious illness. Methods: Baseline advance care planning completion and documentation rates were obtained after programming the electronic medical record with concordant ICD-10 codes. Interventions including provider reminders in the EMR,

educational handouts for the patients regarding advance care planning, and provision of advance directive forms to the patients through dedicated office visits will be completed. After three months, ACP completion and documentation rates will be re-calculated with baseline and follow-up comparisons. Results: Results are pending at this time. Conclusions: We are expecting that this multi-interventional approach will facilitate and increase advance care planning completion and documentation for our patients with pulmonary hypertension. We are anticipating barriers to completion and documentation of advance care planning from previous studies and hope to overcome these limitations.

Figure 1: Histogram of Right Ventricular Systolic Pressures Based on 2-D Echo Predictors of Pulmonary Hypertension Risk 45

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Baseline and Demographic Data on the First 250 Patients From SPHERE (Uptravi® [SelexiPag]: tHe usErs dRug rEgistry) McLaughlin V1, Kim NH2, Chin K3, Highland KB4, Hemnes A5, Chakinala MM5, Keating M7, Zhao C7, Colvin J7, Farber H8 University of Michigan Medical Center, Ann Arbor, MI, USA 2 University of California San Diego, La Jolla, CA, USA 3 University of Texas, Southwestern Medical Center, Dallas, TX, USA 4 Cleveland Clinic, Cleveland, OH, USA 5 Vanderbilt University Medical Center, Nashville, TN, USA 6 Washington University School of Medicine, St. Louis, MO, USA 7 Actelion Pharmaceuticals US, Inc., South San Francisco, CA, USA 8 Boston University School of Medicine, Boston, MA, USA

Background: The selective oral IP receptor agonist selexipag is approved to delay disease progression and reduce the risk of hospitalization in pulmonary arterial hypertension (PAH) patients. SPHERE is a US drug registry of PAH patients designed to provide data on the real-world use of selexipag. The main objectives of SPHERE are to describe: 1) dosing regimens and titration schemes; 2) disease characteristics; and 3) the clinical course of patients being treated with selexipag. The aim of the present report from SPHERE is to describe the baseline characteristics of the first 250 patients enrolled. Methods: Enrollment began in November 2016 with the goal of enrolling 500 patients. Patients previously or newly initiated on selexipag are eligible for the registry, however previously initiated patients must have a documented titration regimen. Data are collected at routine clinic visits; patients are to be followed for 18 months. The baseline information was analyzed by the times of diagnosis, selexipag initiation, and enrollment into the registry. Results: At selexipag initiation, the median age of the patient population was 61.0 years, the median duration of PAH was 4.2 years, the majority were women and white (both 73%). Approximately 50% were WHO functional class (FC) III while 26% were FC II and the median 6MWD was

314m. The most common comorbidities were: hypertension (56%), sleep apnea (37%), obesity (29%), diabetes (28%) and hypothyroidism (24%). Fifty percent of the patients had idiopathic PAH and 36% had associated PAH (29% connective tissue disease, 5% congenital heart disease and 2.9% portal pulmonary hypertension). Ninety-two percent had initiated selexipag prior to enrollment with a median duration of 7.1 months. At the time of selexipag initiation, 28% of patients were receiving monotherapy (ERA or PDE5i or sGC) and 47% were receiving dual therapy (ERA +PDE5i or sGC). Sixty patients (26%) were transitioned from a prostanoid to selexipag (24 patients from an IV/SQ prostanoid and 36 from an oral/inhaled prostanoid). The median maintenance selexipag dose was 1200mcg BID (IQR=800-1600). The total duration of exposure to selexipag was 11.6 months. No new safety profiles were observed than during the Phase III GRIPHON trial.

Clinical Classification and Prevalence of Pulmonary Hypertension in Rural Minnesota

Mirfakhraie L1, Dirks T2, Ebnet S3, Eckman P1, Cabuay B1, Garberich R3, Reed S2, Stokman P2, Fenstad E2 1 Minneapolis Heart Institute, Minneapolis, MN, USA 2 Minneapolis Heart Institute, Baxter, MN, USA 3 Minneapolis Heart Institute Foundation, Minneapolis, MN, USA Background: Pulmonary hypertension (PH) is a progressive disease characterized by pulmonary vascular remodeling and subsequent right ventricular dysfunction. PH presentation and prevalence at major urban centers has been well described by national registries. PH identification and prevalence in rural communities has not been well described and may represent an opportunity for earlier patient diagnosis and treatment. Methods: Retrospective review of all patients with estimated right ventricular systolic pressure (RVSP) > 50 mmHg by echocardiography or PH referral seen at three clinics in rural northern Minnesota between 8/1/2015 and 6/14/2017. Only patients with right heart catheterizations were included in analysis. PH classification was based on standard Nice Criteria. To determine prevalence, population data from Crow Wing County and Aitkin County, Minnesota was recorded from the 2010 Census. All patients were classified by zip code.

Results: Of 72 patients with RVSP > 50 mmHg, 21 patients had pulmonary arterial hypertension (PAH), 44 patients had PH due to left sided heart disease, 3 patients had PH due to chronic lung disease, 1 patient had chronic thromboembolic pulmonary hypertension, and 3 patients had exercise-induced PH. Of 21 patients with PAH, 1 patient had connective tissue disease, 1 patient had portopulmonary hypertension, and 1 patient had toxin-induced PH while 18 patients had idiopathic PAH. Prevalence of PH and PAH were calculated for Crow Wing County, MN and Aitkin County, MN using 2010 Census data and patient zip codes. Prevalence of PAH in Crow Wing and Aitkin Counties was 128 cases/million and 185 cases/ million respectively. Conclusions: PAH prevalence in rural Minnesota appears to be 2.5-12.5 times higher than the estimated 15-50 cases/ million compared to national/international PAH registry data suggesting PH registries may not accurately reflect prevalence in rural communities. Review of echocardiogram outreach databases may provide an opportunity for earlier identification of PH patients.

Conclusions: Of the first 250 patients enrolled in SPHERE most were WHO FC III women with iPAH or CTD. Nearly 47% of patients were receiving combination therapy with an ERA, PDE5i and/or sGC, 50% were receiving a maintenance dose of selexipag ≥1200mcg BID and 26% had been transitioned from a prostanoid.

Table 1: Right heart catheterization hemodynamics for Group 1 and Non Group 1 Pulmonary Hypertension.

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Table 1: Characteristics of Parenteral Prostacyclin Responders and Non-Responders at Follow-up

Clinical, Hemodynamic, and Genetic Associations With Parenteral Prostacyclin Response in Pulmonary Arterial Hypertension

Halliday S, Faber-Eger E, Sheng Q, Xu M, Ye F, Pugh M, Robbins I, Assad T, Mosley J, West J, Brittain E, Hemnes A Vanderbilt University Medical Center, Nashville, TN, USA

Background: Pulmonary arterial hypertension (PAH) is a highly morbid disease, and despite recent advances in therapeutic options, parenteral prostacyclin therapy remains the most efficacious pharmacologic treatment. However, there is significant heterogeneity of response to parenteral prostacyclins in PAH, with some patients having tremendous improvements in functional class and survival, while others continue to deteriorate despite aggressive treatment. We sought to better characterize prostacyclin "responders" and "non-responders", and identify clinical, hemodynamic, and genetic associations with response to therapy. Methods: Patients were found in Vanderbilt's de-identified electronic medical record and the associated DNA biobank by exporting right heart catheterization (RHC) reports, cross-referencing these with references to epoprostenol and treprostinil, and manual chart review. Patients with confirmed PAH and a RHC in the 6 months prior to initiation of a parenteral prostacyclin were included. Responders were defined by attainment of World Health Organization (WHO) function class (FC) 2 or better at the time of repeat RHC within 2 years of initiation of parenteral prostacyclin. Non-responders were defined by WHO FC >2 at repeat RHC, or death within 2 years of drug initiation if there was no repeat RHC. Genotyping was performed on the Illumina MEGAEX chip. Single nucleotide variants (SNVs) with p < 0.01 were matched to the nearest gene by expression quantitative trait loci mapping.

Results: Of 129 patients identified, 54 met our criteria for "responders". These patients were younger, more likely to be male, and were less likely to have connective tissue disease related PAH (Table 1). At follow-up, responders had more favorable hemodynamics and 6-minute walk distance than non-responders (Table 1) and significantly improved long-term survival (Figure 1). In Cox proportional hazards models, the variables most associated with survival at baseline were younger age and higher pulmonary artery oxygen saturation (Figure 2). At follow-up, WHO FC was the variable most associated with survival (Figure 3). Among the 32 patients of white European ancestry with genotyping data, 1275 genes were different between the responders and non-responders. Gene ontology analysis using WebGestalt revealed highly statistically significant enrichment in genes related to cell development, cell adhesion, and circulatory system development. Significant pathways included aldosterone synthesis and secretion, calcium signaling, insulin secretion, cAMP signaling, and vascular smooth muscle contraction. Conclusions: Our study suggests that age at treatment initiation, WHO FC at short-term follow up, and PA O2% are associated with survival in this population. Exploratory genetic comparison between these groups yielded associations in biologically plausible pathways in the pathogenesis of PAH.

Patients Achieving WHO FC 2 or Better at Repeat RHC (n= 54) 42.2 ± 12.3 42 (78%) 1 (2%) 3 (6%) 0 50 (93%) 8 (15%) 24 (44%) 4 (7%)

Age at drug initiation Gender (female) Ethnicity Asian Black Hispanic White Etiology Heritable Idiopathic Congenital Heart Disease HIV Connective Tissue Disease Portopulmonary Anorexigen/Stimulant Six Minute Walk Distance (meters) at repeat RHC WHO Functional Class at repeat RHC 1 2 3 4 Dead (no repeat RHC) Heart Rate Right Atrial Pressure (mmHg) Mean PA Pressure (mmHg) Pulmonary Vascular Resistance (Wood's Units) Cardiac Index (L/min/m2) Pulmonary Artery Oxygen Saturation Additional Treatment after Prostanoid Therapy PDE5 inhibitors

Patients with WHO FC >2 or dead (n= 75)

P-value

51.1 ± 12.0 68 (91%) 0 6 (8%) 2 (3%) 67 (89%) 2 (3%) 30 (40%) 2 (3%)

<0.001 0.042 0.371 0.04

2 (4%) 11 (20%)

2 (3%) 33 (44%)

4 (7%) 1 (2%) 421 ± 92

4 (5%) 2 (3%) 319 ± 105

0.002

12 (22%) 42 (78%) 0 0 0 79.4 ± 12.6 6.2 ± 4.3 47.7 ± 13.4 9.02 ± 5.5

0 0 44 (59%) 3 (4%) 28 (37%) 82.3 ± 13.5 9.1 ± 6.0 48.5 ± 11.3 9.18 ± 4.1

0.29 0.015 0.62 0.45

2.6 ± 0.6 67.7 ± 7.6

2.5 ± 0.8 63.3 ± 8.0

0.072 0.023

9 (17%)

12 (26%)

0.27

Values are mean ± SD or (%). Hemodynamic variables and medications are from follow-up RHC. WHO = World Health Organization; FC = Functional class; RHC = Right heart catheterization; HIV = Human immunodeficiency virus; PDE5 = phosphodiesterase type 5; ERA = endothelin receptor antagonist

PULMONARY HYPERTENSION ASSOCIATION

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

RESEARCH ABSTRACTS & CASE STUDIES

RESEARCH ABSTRACTS & CASE STUDIES 1022

Electronic Medical Record (EMR) Tool for Hospitalized Patients to Facilitate Safe Management of Pulmonary Arterial Hypertension Patients on Prostacyclin Therapy Driscoll T, Duncan M, Blakley A Indiana University Health Pulmonary Hypertension Clinic, Indianapolis, IN, USA

Figure 1: Survival in Prostacyclin Responders vs. Non-responders Unadjusted survival between parenteral prostacyclin responders and non-responders (p < 0.0001 by log-rank test)

Background: Prostacyclin therapy, specifically epoprostenol, has been identified by the Institute for Safe Medication Practices (ISMP) as high alert medication in the acute care setting.1 In a survey of pulmonary hypertension (PH) health care providers, 68-94% reported serious errors occurred with these medications.2 The purpose of this Electronic Medical Record (EMR) tool was to develop and implement a tool for hospitalized patients to facilitate safe management of pulmonary arterial hypertension (PAH) patients on prostacyclin therapy. This tool was developed to alert PAH providers of patients admitted on prostacyclin therapy to decrease medication errors, enhance communication in the health system, and facilitate transitions of care.

of care from the outpatient setting to the inpatient setting.

Methods: A tool was developed to query the EMR database for patients hospitalized with active orders for prostacyclin therapy (epoprostenol and treprostinil, all dosage forms) in a single tertiary/quaternary 800 bed hospital within a large, state-wide hospital system. When a new medication order for prostacyclin therapy is ordered inpatient, a secure message is sent to notify the pulmonary hypertension team (PH physician, PH clinical nurse coordinator, and PH clinical pharmacist). The PH team then reviews the patient and therapy for appropriateness and accuracy to ensure continuity

Conclusions: This process improvement utilizing a newly developed EMR tool to identify hospitalized PAH patients on prostacyclin therapy resulted in increased communication with the PH team and improved safety for patients while ensuring continuity of care.

Results: Prior to implementation of this EMR tool, there was a lack of a systematic approach to notifying the PH team of patients on prostacyclin therapy when admitted to the hospital. From March 2017 to February 2018, six PAH patients on prostacyclin therapy were admitted inpatient without notification of the PH team. Since implementation of this EMR tool, the PH team has been successfully notified of PAH patients on prostacyclin therapy. This has enhanced interprofessional communication between inpatient specialty teams and outpatient specialty clinics to improve transitions of care and ensure patient safety.

Figure 2: Variables Measured at RHC Prior to Starting Prostanoid IPAH = idiopathic pulmonary arterial hypertension, HPAH = Heritable PAH, APAH = associated PAH, BPM = beats per minute, mRAP = mean right atrial pressure, PA O2 sat % = pulmonary artery oxygen % saturation.

Figure 3: Variables Measured at RHC After Starting Prostanoid See Table 1 and Figure 2 for acronym definitions. 51

PULMONARY HYPERTENSION ASSOCIATION

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

RESEARCH ABSTRACTS & CASE STUDIES

1023

1024

Health Care Costs and Resource Utilization Prior to Initiation of a Prostacyclin Receptor Agonist for Pulmonary Arterial Hypertension in a Real-World Database Representing a Large US Health Plan Pruett J1, Hull M2, Elliott C2, Tsang Y1, Drake W1 1 Actelion Pharmaceuticals, US, Inc., South San Francisco, CA, USA 2 Optum, Eden Prairie, MN, USA Purpose: This study examined the health care resource utilization (HCRU) and costs among patients with PAH in the year prior to the addition of selexipag, an oral selective IP prostacyclin receptor agonist agent, to the treatment regimen. Background: Pulmonary arterial hypertension (PAH) is a chronic and progressive disease characterized by abnormally high pressure in the pulmonary arterioles, with increased pulmonary vascular resistance that may result in right heart failure and premature death. Studies have demonstrated that medications that act on the prostacyclin pathway are effective therapies for PAH. As new PAH specific medications targeting the prostacyclin pathway are introduced, treatment patterns and HCRU must be considered by providers and payers. The real-world treatment patterns of selexipag, an oral selective IP prostacyclin receptor agonist agent, remain largely unexplored. Methods: Patients with a diagnosis code for pulmonary hypertension and a prescription fill for selexipag identified by pharmacy claims between January 2016 and May 2017 were included. Patients were ≥18 years old with continuous enrollment in a large US health plan with medical and pharmacy coverage for 1 year (baseline period) before initiation of selexipag. Diagnosis, pharmacy, and medical codes were used to identify baseline comorbidities and medications. HCRU and costs were examined during the baseline period and the 6 months after selexipag initiation.

Results: The study included 95 patients, mostly female (70.5%) with mean (+SD) age 61.8±13.8 years, Charlson score 3.6±2.3, and 67.4% enrolled in Medicare Advantage plans. Common comorbidities included hypertension (81.1%), heart failure (64.2%), sleep apnea (41.1%), and type 2 diabetes mellitus (26.3%). Baseline inpatient admissions occurred in 41.9% and 51.6% of commercial and MAPD enrollees, respectively. Mean all-cause baseline medical costs were $46,024 for commercial enrollees and $57,581 for MAPD enrollees, and increased 266.8% and 26.7%, respectively, from the first to the last quarter prior to selexipag initiation. In 42 patients with six months of follow-up after initiation of selexipag, mean all-cause medical costs were $17,215 and $23,976 for commercial and MAPD enrollees, respectively. Conclusions: Patients with PAH presented with complex comorbidity profiles, and a high percentage were admitted for inpatient stays in the year prior to initiation of selexipag. In the six months prior to selexipag initiation, mean all-cause baseline medical costs substantially increased over time, particularly among commercial enrollees. For 44% of enrolled patients, mean all-cause medical costs six months after selexipag initiation were available and showed an all-cause medical costs decrease of 62% and 58% for commercial and MAPD enrollees, respectively.

Intersecting Identities and Patient Outcomes in Pulmonary Arterial Hypertension: Early Results in Derivation of a Model Using the Pulmonary Hypertension Association Registry (PHAR)

Grinnan D1, Kang L1, DeWilde C1, Johnson D1, Sager J2, Badesch D3, Bull T3, Chakinala MM4, DeMarco T5, Feldman J6, Fineman J5, Ford J7, Klinger J8, McConnell J9, Berman Rosenzweig E10, Shlobin O11, Zamanian R12, Bartolome S13, Elwing J14, Franz R15 and 9 more 1 VCU Health, Richmond, VA, USA 2 Cottage Health, Santa Barbara, CA, USA 3 University of Colorado, Denver, CO, USA 4 Barnes-Jewish Hospital, St Louis, MO, USA 5 UCSF, San Francisco, CA, USA 6 Arizona Pulmonary Specialists, Phoenix AZ, USA 7 UNC, Chapel Hill, NC, USA 8 Brown University, Riverside, RI, USA 9 Kentuckiana Pulmonary Associates, Louisville, KY, USA 10 Columbia University, New York, NY, USA 11 INOVA Fairfax, Fairfax, VA, USA 12 Stanford University, Stanford, CA, USA 13 UT Southwestern Medical Center, Dallas, TX, USA 14 University of Cincinnati, Cincinnati, OH, USA 15 Mayo Clinic, Rochester, MN, USA Background: Existing guidelines for pulmonary arterial hypertension (PAH) yield vastly differing results between patients, even when meticulously implemented. This may be explained through intersectionality. Intersectionality refers to the overlapping of identities, experiences, and characteristics including race, ethnicity, gender, genderidentity, and class, which combine to make a person uniquely who they are and place the individual along a continuum of disadvantage to advantage. We believe intersecting identities may have an additive effect on health outcomes such that disadvantaged patients are at risk for poor outcomes. Using data from the Pulmonary Hypertension Association Registry (PHAR), we will derive a model (the PHAR Evaluation or PHARE) to assess the impact of intersecting identities on PAH patients for future validation. As a preliminary to deriving this model, we provide data from three medically important outcomes to serve as a framework for assessing intersectionality in PAH. Methods: PHAR data collected at initial and follow-up visits (every 6 months) from participating patients is used. Independent variables include age, race, sex born, level of education, income, household number, marital status, drug use, and type of insurance. The dependent variables include the number of Emergency Department (ED) visits, number of hospitalizations, and days of hospitalizations. Mortality was excluded in this initial dataset due to the short duration of follow-up and resultant events. Analysis was performed

PULMONARY HYPERTENSION ASSOCIATION

using repeated measures Poisson regression models for the outcome count data. For inclusion in the regression model, a p-value of 0.2 was used. Results: Data from the initial 362 patients is being used in the Poisson regression analyses. 172 patients had data from one follow-up visit and 68 patients had data from two or more follow-up visits (Table 1). Lower income, lower education, and divorced or ‘never married’ were positively associated with more ED visits while having private health insurance was negatively associated with fewer ED visits. Lower income, lower education, drug use, and divorced or never married were positively associated with more hospitalizations while being uninsured or underinsured was negatively associated with fewer hospitalizations. Conclusions: Early analyses of the PHAR data shows positive associations between income and education level on ED visits and a negative association between private insurance and ED visits. That under/no insurance is associated with fewer hospitalizations may indicate these patients have difficulty being admitted to a hospital. As further longitudinal data from this cohort strengthens these associations, we plan to derive and validate a model that will explore their intersectionality.

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

RESEARCH ABSTRACTS & CASE STUDIES

1025 Early Outcomes from the PHARE Pa#ent Characteris#c

Log of Number of ED Visits Es#mate

Standard Error

Race (Black)

0.1966

0.1828

-0.1618

Race (other)

0.2283

0.2287

-0.2199

-0.3439

0.4058

Race (White)

95% Conﬁdence Limits

Log of Number of Nights in Hospital Z

Pvalue

Es#mate

Standard Error

0.5550

1.08

0.2823

-0.0857

0.2338

-0.5439

0.3725

-0.37

0.7140

-0.1314

0.1311

-0.3884

0.6765

1.00

0.3181

0.2179

0.2873

-0.3453

0.7811

0.76

0.4483

0.1007

0.1715

-0.2354

-0.85

0.3967

0.0782

0.2027

0.39

0.6996

-0.0124

0.1531

Reference for Race

Sex Born (Male) Sex Born (Female)

-1.1393

0.4515

95% Conﬁdence Limits

Log of Number of Hospitaliza#ons

PEs#mate value

Standard Error

Reference for Race

Reference for Sex

-0.3191

0.4755

Pvalue

0.1256

-1.00

0.3162

0.4368

0.59

0.5570

-0.08

0.9357

95% Conﬁdence

Reference for Race

Reference for Sex

-0.3125

0.2878

-0.0895

0.0317

-0.1516

-0.0274

-2.82

0.0048

-0.0929

0.0392

-0.1698

-0.0161

-2.37

0.0178

-0.0632

0.0344

-0.1306

0.0042

-1.84

0.0660

Household Income

-0.0032

0.0022

-0.0075

0.0011

-1.46

0.1447

-0.0039

0.0030

-0.0097

0.0020

-1.30

0.1919

-0.0024

0.0019

-0.0061

0.0014

-1.25

0.2123

Number in Household

-0.0115

0.0531

-0.1157

0.0926

-0.22

0.8280

0.0542

0.0584

-0.0603

0.1688

0.93

0.3535

-0.0388

0.0345

-0.1063

0.0287

-1.13

0.2602

Marital Status (Married)

1.1081

0.8319

-0.5225

2.7387

1.33

0.1829

-0.6419

0.6913

-1.9968

0.7129

-0.93

0.3531

0.4677

0.1302

0.2124

0.7229

3.59

0.0003

Marital Status (Widowed)

1.1349

0.8785

-0.5869

2.8566

1.29

0.1964

-0.6004

0.8367

-2.2404

1.0395

-0.72

0.4730

0.4600

0.2833

-0.0953

1.0153

1.62

0.1045

Marital Status (Divorced)

1.6707

0.8408

0.0228

3.3187

1.99

0.0469

-0.7148

0.6967

-2.0803

0.6506

-1.03

0.3049

0.5253

0.2490

0.0372

1.0134

2.11

0.0349

Mar#al Status (Separated)

1.7041

0.8541

0.0301

3.3781

2.00

0.0460

-1.1808

0.8441

-2.8352

0.4735

-1.40

0.5107

0.3277

-0.1315

1.1529

1.56

0.1191

Marital Status (Never Married)

1.4478

0.8344

-0.1877

3.0832

1.74

0.0827

-0.6351

0.6729

-1.9539

0.6837

-0.94

0.1618

0.5195

0.1626

0.2008

0.8381

3.20

0.0014

Marital Status (Lives with Partner)

1.5516

0.8621

-0.1380

3.2412

1.80

0.0719

-0.3427

0.7240

-1.7618

1.0763

-0.47

0.3452

0.4135

0.2279

-0.0331

0.8602

1.81

0.0696

0.1410

Reference for Marital Status

Drug Use

0.1493

0.1830

-0.2093

0.5078

0.82

0.4146

-0.1148

0.2793

-0.6622

0.4325

-0.41

0.6809

0.2688

0.1825

-0.0890

0.6265

1.47

Insurance (Government)

0.3105

0.4697

-0.6101

1.2312

0.66

0.5086

0.6784

0.4406

-0.1851

1.5419

1.54

0.1236

0.7040

0.3038

0.1087

1.2994

2.32

0.0205

Insurance (Private)

-0.3150

0.2756

-0.8552

0.2252

-1.14

0.2531

-0.0412

0.2886

-0.6068

0.5244

-0.14

0.8865

0.7126

0.2821

0.1597

1.2654

2.53

0.0115

Insurance (Public)

-0.-388

0.2783

-0.5844

0.5067

-0.14

0.8890

0.2988

0.2710

-0.2325

0.8300

1.10

0.2703

0.9127

0.3004

0.3239

1.5015

3.04

0.0024

-1.31

0.1909

Insurance (Under/Uninsured) Age

Reference for Insurance -0.0072

0.0050

-0.0169

0.0025

Reference for Insurance -1.45

0.1480

-0.0003

0.0062

-0.0124

Cole MR1, Hill JW2, Lickert C1, Wade RL 2, Drake W1 Actelion Pharmaceuticals, South San Francisco, CA, USA 2 IQVIA, Plymouth Meeting, PA, USA

Reference for Sex

Level of Educa#on Completed

Marital Status (Don’t Know)

Medication Adherence and Risk of Hospitalization in Pulmonary Arterial Hypertension (PAH) Patients Treated With Endothelin Receptor Antagonists (ERAs) or Phosphodiesterase Type 5 Inhibitors (PDE5Is)

0.0119

Reference for Insurance -0.04

0.9660

-0.0045

0.0034

-0.0112

0.0022

Figure 1: Association of patient characteristics with number of ED visits, number of nights in the hospital, and number of hospitalizations. Level of education, household income, number in household, drug use, and age are continuous variables. All categorical variables have a reference value (eg. “white” for race and “female” for gender.

Purpose: To evaluate the relationship between adherence and risk of hospitalization in PAH patients treated with ERAs or PDE5Is. Background: Pulmonary arterial hypertension (PAH) is a rare, progressive disease characterized by increasing pulmonary vascular resistance and pressure. There are 13 approved PAH-specific medications in the United States (US) targeting three distinct pathways. In addition to clinical trials, real world evidence provides information on adherence and outcomes of PAH treatments. Methods: The PharMetrics Plus claims database consisting of medical and pharmacy claims for more than 150 million patients in the US was used to identify PAH patients between 1/1/2009-6/30/2015 (first Rx claim = index date). Inclusion required one inpatient or ≥2 outpatient claims > 30 days apart with a diagnosis code for PH (ICD-9 codes 416.0 or 416.8) and a prescription for an ERA (ambrisentan, bosentan, or macitentan) or a PDE5i (sildenafil or tadalafil). Erectile dysfunction doses were excluded. Patients had continuous health plan enrollment ≥3 months pre- and ≥6 months post-index. Proportion of days covered (PDC) were compared between ERA and PDE5i. Relationships between medication adherence measured by PDC, percent hospitalized, and mean hospitalizations were analyzed with descriptive statistics and modified Cox regression using a time-varying measure of PDC. Results: 755 ERA and 1,578 PDE5i patients were identified. Mean age of the PDE5i cohort was higher (53.0 vs. 51.9, p=0.011) and included fewer females (61.5% vs.

PULMONARY HYPERTENSION ASSOCIATION

74.5%, p<0.0001). Prevalence for some comorbidities was higher with the PDE5is, including: systemic hypertension (60.4% vs. 51.7%, p<0.0001), diabetes (29.2% vs. 21.6%, p<0.0001), renal failure (22.6% vs. 12.1%, p=0.0001), and obesity (20.9% vs. 14.7%, p<0.0012). As PDC increased from 40-59% to ≥ 80%, hospitalizations decreased from 45% to 23% for ERA, and 49% to 28% for PDE-5i. For patients with PDC ≥ 80%, ERA had a lower percent hospitalized (23% vs. 28%, p=0.02) and fewer hospital admissions (0.4 vs. 0.5, p=0.02) versus PDE-5i. An increase in PDC from 0.50 to 1.00 reduced hospitalization risk by 58% for ERA and 26% for PDE-5i patients. For ERA patients, an increase in adherence had a greater impact on reducing hospitalization risk than PDE-5i (HR=0.549 for PDC, p=0.018 and HR=0.321 for interaction of PDC with ERA therapy, p=0.013) based on a modified Cox hazards model controlling for demographics and baseline comorbidities. Conclusions: Patients treated with ERAs were younger, had fewer co-morbidities, were more adherent to therapy, and experienced fewer hospitalizations than PDE5i treated patients. This analysis suggests that adherence to PAH therapy was associated with greater risk reduction in hospitalizations for ERA vs. PDE5i. The reason for this difference is unknown. It may reflect differences in patient characteristics. ERA patients may have purer PAH phenotypes (WHO Group 1) for whom adherence has a greater impact on outcomes. These findings suggest that maximizing adherence is an important strategy to ensure the best possible outcomes for PAH patients.

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

RESEARCH ABSTRACTS & CASE STUDIES

1026

1027

National Trends of Hospitalization Characteristics in Patients With Pulmonary Hypertension Agarwal MA1, Shah M2, Patel B2, Garg L 2, Khouzam RN3 1 University of Tennessee Health Science Center, Memphis, TN, USA 2 Division of Cardiovascular Medicine, Lehigh Valley Health Network, Allentown, PA, USA 3 Division of Cardiovascular Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

Background: Limited contemporary data exists describing hospitalization characteristics for patients with pulmonary hypertension. Methods: Using ICD-9 CM codes in nationwide inpatient sample databases 2003 to 2014, all adult hospitalizations (age > 18 years) with a diagnosis of pulmonary hypertension were identified. Using univariate analyses, we studied hospitalization characteristics, reasons for admissions, co-existing comorbidities, procedures utilized and in-hospital mortality in these hospitalizations. Results: We identified 1,743,839 hospitalizations with a co-existing diagnosis of pulmonary hypertension with mean age-71.2 + 14.8 years, 60.2% females, 63.0% whites and 81.9% with public insurance. Top primary diagnoses in these hospitalizations were – heart failure (19.7%), COPD (6.3%), pneumonia (5.4%), acute respiratory failure (5.4%) and cardiac dysrhythmias (5.1%). Most common co-existing diagnosis were heart failure (60.7%), cardiac dysrhythmias (47.5%), coronary artery disease (41.4%), COPD (37.8%), valvular heart disease (37.3%), hypertension (37.2%), dyslipidemia (34.4%), chronic kidney disease (27.0%) and diabetes (26.2%). Most common procedures performed were: diagnostic heart catheterization (19.1%), mechanical ventilation (13.0%), blood transfusions

PULMONARY HYPERTENSION ASSOCIATION

(9.0%), heart-valve procedures (5.8%), hemodialysis (5.4%) and echocardiogram (5.0%). From 2003 to 2014, there was a significant decrease in hospitalizations with cardiovascular causes (51.2% to 43.8%) and pulmonary causes (24.8% to 18.9%) (all ptrend<0.001). There was a decrease in proportions of patients with primary diagnosis of congestive heart failure (22.2% to 19.4%), pneumonia (6.6% to 4.7%), COPD (8.8% to 4.6%), while increased for acute respiratory failure (4.7% to 5.5%), cardiac dysrhythmias (4.5% to 4.8%), septicemia (0.9% to 6.9%), acute kidney injury (1% to 2.6%) and chronic kidney disease (1.4% to 2.0%) (all ptrend<0.001). In-hospital mortality for patients with primary diagnosis of cardiovascular (4.1% to 3.8%) and pulmonary cause decreased (7.2% to 6.1%) while significantly increased for those with non-cardiopulmonary diagnosis (4.9% to 5.9%). Conclusions: Cardiovascular and pulmonary causes were the main reason for admissions and in-hospital mortality has significantly decreased for both of these categories. Interestingly, pulmonary hypertension patients are increasingly being admitted for non-cardiopulmonary causes and there is an urgent need for research and better inter-disciplinary clinical care to improve the mortality and morbidity of pulmonary hypertension patients.

Pulmonary Hypertension in Hereditary Hemorrhagic Telangiectasia

Harder E1, Fares W2 1 Yale University School of Medicine, New Haven, CT, USA 2 Johnson & Johnson, New Brunswick, NJ, USA

Purpose: The purpose of this analysis is to study the in-hospital characteristics and outcomes of hereditary hemorrhagic telangiectasia admissions with pulmonary hypertension in a large inpatient database. Background: Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disease resulting in abnormal blood vessel development throughout multiple organs. As such, it has a wide variety of manifestations including pulmonary hypertension (PH). PH associated with HHT may occur as either a pre-capillary pulmonary arterial hypertension (PAH) due to HHT-related genetic mutations or as a post-capillary form due to high cardiac output. Despite the potential severity of HHT-associated PH, there is little information available on outcomes in this group. The purpose of this analysis was therefore to evaluate the in-hospital characteristics and outcomes of the HHT-PH population. Methods: The 2000-2014 National Inpatient Sample (NIS) database was queried for all adult (18 years) discharges with HHT (International Classification of Disease, Ninth Revision, Clinical Modifications [ICD-9-CM] code 448.0 in any diagnosis column). The HHT population was then stratified by the presence of any pulmonary hypertension (identified by ICD-9-CM codes 416.0, 416.8, and 416.9). The primary outcome of interest was in-hospital mortality. Additional secondary outcomes included length of stay, total admission cost, and hospital and patient characteristics were also evaluated. Statistics were performed with survey procedures in SAS.

Results: From 2000 to 2014, there were 55,187 hospitalizations with HHT. Of these, 4,601 (8.3%) carried a concurrent diagnosis of PH (HHT-PH). The rate of HHT-PH admissions increased steadily from 5.1% in 2000 to 13.9% in 2014 (p<0.0001). HHT-PH hospitalizations more commonly occurred in females (vs. HHT admissions without PH [non-PH HHT], 71.6% vs. 59.2%, p<0.0001), the northeast (27.7% vs. 19.4%, p=0.0004), and urban teaching hospitals (61.0% vs. 48.7%, p=0.0001). Furthermore, HHT-PH admission was more frequently associated with private insurance (vs. non-PH HHT hospitalization, 76.7% vs. 68.1%, p=0.0003). HHT-PH admissions were associated with longer length of stay (vs. non-PH HHT, 5.4 vs. 4.4 days, p<0.0001) and higher total hospital cost ($39,874 vs. $28,735, p<0.0001). In HHT-PH, more common Elixhauser comorbidities included congestive heart failure (vs. non-PH HHT, 45.6% vs. 14.5%, p<0.0001), valvular heart disease (21.5% vs. 7.4%, p<0.0001), renal failure (15.1% vs. 7.2%, p<0.0001) and fluid-electrolyte disturbances (26.8% vs. 15.9%, p<0.0001). In-hospital mortality was higher in HHT-PH hospitalizations (vs. non-PH HHT, 3.5% vs. 1.8%, p=0.0005). On multivariate analysis (MVA) adjusted for patient demographics, hospital characteristics, and pre-existing comorbidities, HHT-PH status remained a significant predictor of in-hospital death (odds ratio [OR] 1.592, 95% confidence interval [CI] 1.024-2.475, p=0.039). Conclusions: PH is a relatively common complication of HHT, and admissions in HHT-PH have increased in frequency from 2000 to 2014. Hospitalization in HHT-PH is associated with a significantly higher incidence of inpatient mortality.

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1028

Real-World Dosing and Titration of Selexipag in Patients With Pulmonary Arterial Hypertension in the SPHERE Registry (SelexiPag: tHe UsErs dRug rEgistry): Interim Analysis Chakinala MM1, Kim NH2, Chin K3, Farber H4, Highland KB5, Hemnes A6, Carol Zhao C7, Keating M7, McLaughlin V8 Washington University School of Medicine, St. Louis, MO, USA 2 University of California San Diego, La Jolla, CA, USA 3 University of Texas, Southwestern Medical Center, Dallas, TX, USA 4 Boston University School of Medicine, Boston, MA, USA 5 Cleveland Clinic, Cleveland, OH, USA 6 Vanderbilt University Medical Center, Nashville, TN, USA 7 Actelion Pharmaceuticals US, Inc., South San Francisco, CA, USA 8 University of Michigan Medical Center, Ann Arbor, MI, USA

Background: Selexipag is a selective oral IP prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression and reduce the risk of hospitalization. The main objectives of the SPHERE registry are to describe: 1) dosing regimens and titration patterns; 2) disease characteristics; and 3) the clinical course of patients being treated with selexipag in real-world settings. The aim of the present report from SPHERE is to describe real-world dosing and titration patterns in patients newly initiated on selexipag. Methods: SPHERE is a currently enrolling US-based, multicenter, prospective, real-world, observational registry initiated in November 2016. Patients are eligible if newly initiated on selexipag or being treated with selexipag at the time of enrollment and have a documented titration regimen. Safety data are collected on exposure of selexipag during the study. Maintenance dose is defined as the first dose post-titration that was maintained for 14 days or more without dose interruption and/or dose change. Results: This analysis (data cut-off October 2, 2017) reports data from the first 250 patients enrolled. The

PULMONARY HYPERTENSION ASSOCIATION

median time since PAH diagnosis was 4.2 years (range: 0.0–63.3). The median total duration of selexipag treatment was 11.6 months (range: 0.1–21.5), and the median on-study duration was 3.1 months (range: 0.1–12.1). Most patients (92%) had initiated selexipag prior to study enrollment. Patient characteristics are shown in the Table. Of the 234 patients with PAH medication data available, 65 (27.8%) were taking monotherapy without a prostacyclin, 108 (46.2%) were taking dual therapy without a prostacyclin, and 56 (23.9%) were on a regimen containing a prostacyclin at the time of selexipag initiation (See Table). The median time from selexipag initiation until a maintenance dose was reached was 8.1 weeks (interquartile range 6.0 to 12.1 weeks). The median selexipag maintenance dose was 1200 µg BID (interquartile range 800 µg BID to 1600 µg BID). Twenty-four patients (9.6%) discontinued selexipag because of adverse events with diarrhea being the most commonly occurring one (4/250, 1.6%). Conclusions: In this first report of selexipag dosing in realworld settings, a median maintenance dose of 1200 µg BID was reached at a median of 8.1 weeks after initiation and no new safety signals were observed.

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RESEARCH ABSTRACTS & CASE STUDIES 1030

1029

Transitions From Inhaled, Intravenous, Subcutaneous, or Oral Prostacyclins to Selexipag: Interim Data From the SPHERE Registry (SelexiPag: tHe UsErs dRug rEgistry) Hemnes A1, Farber H2, Kim NH3, Chin K4, Chakinala MM5, Highland KB6, Carol Zhao C7, Keating M7, McLaughlin V8 1 Vanderbilt University Medical Center, Nashville, TN, USA 2 Boston University School of Medicine, Boston, MA, USA 3 University of California San Diego, La Jolla, CA, USA 4 University of Texas, Southwestern Medical Center, Dallas, TX, USA 5 Washington University School of Medicine, St. Louis, MO, USA 6 Cleveland Clinic, Cleveland, OH, USA 7 Actelion Pharmaceuticals US, Inc., South San Francisco, CA, USA 8 University of Michigan Medical Center, Ann Arbor, MI, USA

Background: The selective oral IP prostacyclin receptor agonist selexipag is approved to delay disease progression and reduce the risk of hospitalization in pulmonary arterial hypertension (PAH) patients. SPHERE is a US registry of PAH patients designed to provide data on real-world selexipag use. Here we report data on patients transitioning from inhaled, parenteral, or oral prostacyclins to selexipag. Methods: Enrollment began in November 2016 with a goal of enrolling 500 patients. Patients previously or newly initiated on selexipag are eligible, however previously initiated patients must have a documented titration regimen. Data are collected at routine clinic visits and patients are followed for up to 18 months. Transitioning patients were defined as those taking a prostacyclin for ≥30 days at the time of selexipag initiation or until ≤7 days before selexipag initiation. Results: This analysis (data cut-off October 2, 2017) reports data from 250 patients enrolled from 46 sites. The median time since PAH diagnosis was 4.2 years (range: 0.0–63.3). The median total duration of selexipag treatment was 11.6 months (range: 0.1–21.5). The median on-study duration was 3.1 months (range: 0.1–12.1). Sixty patients (24%) were transitioned to selexipag from prostacyclin and 190 (76%) were non-transitioned. At selexipag initiation,

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transitioning patients had a longer mean 6MWD (324.2 m [SD 175.4] vs. 312.0 m [SD 139.0]) than non-transitioned patients and a similar proportion were FC I/II (32% vs. 28%) and III/IV (58% vs 49%). At transition, 30 patients were on triple therapy consisting of an ERA, a PDE5i/sGC, and an inhaled (n=14), intravenous (n=10), oral (n=4), or subcutaneous (n=2) prostacyclin; and 19 were on dual therapy consisting of an ERA and a prostacyclin (n=11), or a PDE5i/sGC and a prostacyclin (n=8). Seven patients transitioned from inhaled (n=5) or oral (n=2) treprostinil monotherapy to selexipag monotherapy. Four patients were not taking a prostacyclin at the time of selexipag initiation but had discontinued their prostacyclin therapy for ≤7 days. Patients who transitioned from another prostacyclin to selexipag had a higher median maintenance dose of selexipag compared to non-transitioned patients (1400 µg BID [range: 200–1600] vs. 1200 µg BID [range: 100–1600]). The incidence and type of adverse events were similar between the two groups. Conclusions: In this real-world dataset, patients who transitioned to oral selexipag were most commonly on triple therapy and had a higher median selexipag maintenance dose compared to non-transitioned patients. Tolerability was similar between transitioned and non-transitioned patients.

Treatment With Prostacyclins Reduces Hospital Readmissions Among Patients With Pulmonary Arterial Hypertension Blanchette C1, Noone J1, Howden R1, Classi P2, Gordon K 2, Nelsen A 2 1 University of North Carolina, Charlotte, NC, USA 2 United Therapeutics, Durham, NC, USA

Purpose: The primary objective of this analysis was to evaluate hospital readmissions after initiating PCY treatment in PAH patients. Background: Pulmonary arterial hypertension (PAH) is characterized by high-blood pressure in the pulmonary vasculature and is a chronic, life-threatening disease. Commonly used PAH treatments include endothelin receptor antagonists, phosphodiesterase inhibitors, and prostacyclins (PCYs). PCYs while often considered gold-standard therapy, are commonly reserved for later stage disease. Methods: We employed a retrospective analysis using the U.S. Pharmetrics Database from 2011-2015 in patients with PAH, defined as >2 ICD-9-CM codes for pulmonary hypertension (416.0X or 416.8X) and evidence of right heart catheterization. Inclusion criteria required a hospitalization for PAH or a PAH-related condition with no history of PCY use. Outcomes between two cohorts were compared: 1) PAH patients discharged from hospital with PCY therapy (PCY group) vs. 2) PAH patients discharged from hospital with any combination of therapies except PCY therapy (alternative medical care [AMC] group). T-tests and ANOVAs were used to compare continuous variables and Chi-square tests were used to compare categorical variables. Cox proportional hazard model was used to generate hazard ratios for hospital readmission risk.

Results: The PCY group (n=110) was younger (mean age[SD] = 49.74[16.35] vs. 54.61[16.83]), had a higher proportion of females (64.55% vs. 46.56%) and a lower average Charlson Comorbidity Index (CCI) score (3.89[2.26] vs. 4.86[2.81]) compared to the AMC group (n=4270) (p<0.01). Treatment within the PCY group consisted of treprostinil (67.27%), epoprostenol (26.36%) or iloprost (6.36%). During the study period, 40.91% of the PCY group were readmitted to the hospital for PAH or a PAH-related condition compared to 52.18% for the AMC group (p=0.02). Mean time to hospital readmission was 397 days for the PCY group vs. 219 days for the AMC group (p<0.01). The rate of 30-day hospital readmissions for all-causes was 5.45% for the PCY group compared to 23.44% for the AMC group (p<0.01). After adjusting for age, gender and CCI, the hazard ratio for PAH and PAH-related hospital readmission risk was 0.64 for the PCY group (p<0.01, AMC group as reference cohort). Conclusions: PCY treatment is associated with a lower risk of hospital readmission, potentially warranting earlier use of these medicines. Additional studies need to be conducted to validate this finding.

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RESEARCH ABSTRACTS & CASE STUDIES 1031

Bone Morphogenetic Protein 9 is a Mechanistic Biomarker of Portopulmonary Hypertension

Circulating BMP9 is profoundly decreased in portopulmonary hypertension

Nikolic I , Yung LM , Yang P , Malhotra R , Paskin-Flerlage SD , Dinter T , Bocobo GA , McNeil M , Faugno AJ , Lai CSC , Upton PD4, Goumans MJ5, Zamanian RT6, Elliott G7, Morrell NW4, Chung RT8, Channick RW9, Roberts KE3, Yu PB1 1 Brigham and Women’s Hospital and Harvard Medical School, Division of Cardiovascular Medicine, Department of Medicine, Boston, MA, USA 2 Massachusetts General Hospital and Harvard Medical School, Division of Cardiology, Department of Medicine, Boston, MA, USA 3 Tufts Medical Center, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Boston, MA, USA 4 University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, Division of Respiratory Medicine, Department of Medicine, Cambridge, United Kingdom 5 Leiden University Medical Centre, Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden, Netherlands 6 Stanford University Medical Center, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford, CA, USA 7 Intermountain Medical Center and University of Utah, Department of Medicine, Salt Lake City, UT, USA 8 Massachusetts General Hospital and Harvard Medical School, Gastrointestinal Unit and Liver Center, Department of Medicine, Boston, MA, USA 9 Massachusetts General Hospital and Harvard Medical School, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston, MA, USA 1

Background: Bone morphogenetic protein 9 (BMP9) is a circulating endothelial quiescence factor with protective effects in pulmonary arterial hypertension (PAH). Loss-offunction mutations in BMP9 receptors and downstream effectors have been reported in heritable PAH. We sought to determine how an acquired deficiency of BMP9 signaling might contribute to PAH. Methods: Plasma levels of BMP9 and antagonist soluble endoglin (sEng) were measured in Group 1 PAH, Group 2 and 3 pulmonary hypertension (PH), and in patients with severe liver disease without PAH. Mice with CCl4-induced cirrhosis and portal hypertension were assessed for PH and levels of circulating BMP9. The impact of administering the BMP9 ligand trap ALK1-Fc was assessed in wild-type mice. Results: BMP9 levels were markedly lower in portopulmonary hypertension (PoPH) as compared to controls in a derivation cohort (46 pg/mL [IQR 21-71 pg/mL] vs. 210 pg/ mL [IQR 190-246 pg/mL], p<0.0001), and confirmed in a distinct validation cohort. Across both cohorts diminished BMP9 was present in PoPH but not other etiologies of Group 1 PAH (ROC-AUC=0.91±0.03, p<0.0001), but was an independent predictor of transplant-free survival (Cox HR 0.74 per 50 pg/mL increase, 95% CI 0.56-0.97. p=0.03) in Group 1 PAH regardless of PoPH status. Diminished BMP9 distinguished PoPH from patients with liver disease without

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PAH (223 pg/ml [IQR 153-282 pg/mL], p<0.0001 vs. PoPH), particularly among individuals with mild hepatic dysfunction (Model for End-Stage Liver Disease score ≤ 10), and was more sensitive for the presence of PoPH among patients with liver disease than echocardiographic RVSP, with equivalent specificity. BMP9 levels were decreased in mice with PH associated with CCl4-induced portal hypertension and cirrhosis, but were normal in other rodent models of PH including monocrotaline-treated rats, and SUGEN-hypoxia-treated rats and mice. Administration of potent BMP9 ligand trap ALK1-Fc severely exacerbated PH and pulmonary vascular remodeling in mice treated with hypoxia vs. hypoxia alone (50±8 mmHg vs. 34±1 mmHg, p=0.04).

Figure 1: Circulating BMP9 is profoundly decreased in PoPH.

Conclusions: BMP9 is a sensitive and specific biomarker of PoPH, predicting transplant-free survival and the presence of PAH in end-stage liver disease. In rodent models, acquired deficiency of BMP9 signaling can predispose to or exacerbate PH, thereby providing a new mechanistic link between PoPH and heritable PAH. These findings raise concerns about the effects of anti-angiogenic therapies targeting BMP9/ALK1 signaling, while describing a novel experimental model of severe PH and remodeling due to acquired loss of BMP signaling.

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Changes of Plasma Angiotensin-(1-7) in Patients With Pulmonary Arterial Hypertension Due to Congenital Heart Disease Before and After Intervention Closure Dai HL, Guang XF, Yin XL, Yang QF Department of Cardiology, Yan'an Affiliated Hospital of Kunming Medical University, Kunming, China

Background: The angiotensin (Ang) converting enzyme 2 (ACE2)-Ang-(1-7)-Mas receptor axis might be a promising therapeutic target for pulmonary arterial hypertension. We previously showed that serum Ang-(1-7) levels was decreased in the patients with pulmonary arterial hypertension (PAH) due to congenital heart disease (CHD). In this study, To observe the changes of plasma Angiotensin-(1-7) in patients with CHD-PAH before and after intervention closure. Methods: 59 patients with CHD and 20 normal control patients (group A) were involved in the research. The patients with CHD were divided into 21 cases of nonpulmonary hypertension (group B), 20 cases of mild pulmonary hypertension (group C) and 18 cases of moderate to severe pulmonary hypertension (group D). The serum levels of Ang-(1-7) were detected by enzyme-linked immunosorbent assay (ELISA) at 1 day before operation and 2 days after operation.

Results: Before operation, in group D, their serum Ang-(1-7) level was significantly lower than that in the group A, group B and group C (17.54±2.10 vs 19.31±1.34, 23.16±2.74, 20.07±2.11 pg/ml, P < 0.05). After operation, compared to 1 day before operation, echocardiographic assessment showed that pulmonary artery systolic pressure was decreased in group C and group D (all P < 0.05). In group C, their serum Ang-(1-7) level was increased (20.07±2.11 vs 20.45±2.20 pg/ml, P < 0.05); in group D, their serum Ang-(1-7) level was increased (17.54±2.10 vs 18.92±2.44 pg/ml, P < 0.001). Conclusions: Serum Ang-(1-7) levels declined in patients with CHD-PAH. The decline of pulmonary artery pressure was decreased accompanied by an increase in Ang-(1-7) after interventional closure. Detection of plasma Ang-(1-7) level may be beneficial to evaluate the postoperative prognosis in patients with CHD-PAH.

Digital Subtraction Pulmonary Angiography: An Old Technique With Novel Role in Children With Pulmonary Hypertension Das BB, Mills J, Jadotte MM, Chan KC Joe DiMaggio Children's Hospital Heart Institute, Hollywood, FL, USA Purpose: We report 3 pediatric cases of pulmonary hypertension (PH) whereby digital subtraction angiography (DSA) images provided additional information regarding pulmonary vascular and lung parenchymal pathology compared to traditional angiography. Background: It is essential to diagnose the etiology of PH in children for appropriate therapy. In a French series by Cottin et al, a 50% prevalence of PH is described with pulmonary fibrosis and emphysema syndrome in adults. In children, especially those with history of prematurity, bronchopulmonary dysplasia is commonly attributed to cause PH. Digital subtraction angiography can provide additional benefits in determining the cause of PH in children.

Methods: We reviewed retrospectively the hemodynamic data and DSA findings in 3 pediatric PH cases (Figure). Results: Table-1 describes the demographics and cardiac hemodynamic data. The DSA images in our patients with PH showed segmental hypoperfusion and abnormal capillary phase suggesting abnormal pulmonary vascularity and parenchymal changes in the setting of reactive PH. [Table] Conclusions: Digital subtraction angiography can provide additional information compared to traditional angiography in evaluation of PH in selected patients.

Figure 1: DSA findings in case 1-3

Table 1: Summary of PH patients and hemodynamic data

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RESEARCH ABSTRACTS & CASE STUDIES

RESEARCH ABSTRACTS & CASE STUDIES 1034

Methods: Adults born preterm (n=11; gestational age 28.2±0.8 weeks; current age 27±1 years) were recruited from the Newborn Lung Project at the University of Wisconsin-Madison, a prospective cohort of infants born 1988-1991 with birth weight <1500 g. Controls were recruited from the general population (n=10; age 26±1 years). All subjects were free from adult cardiopulmonary disease. Subjects underwent right heart catheterization with measurement of pulmonary vascular hemodynamics and cardiac magnetic resonance imaging (MRI) on a 3.0T scanner. Cardiac MR measures included assessment of RV function and RV circumferential strain. 4D flow imaging was acquired with a radially-undersampled PC VIPR sequence to assess RV kinetic energy, and RV energetic efficiency was defined as total kinetic energy across the cardiac cycle normalized to stroke volume. Mann-Whitney tests were performed to assess for statistical significance (p<0.05).

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Conclusions: Otherwise healthy young adults born premature demonstrate mild elevations in pulmonary pressures and vascular resistance, though most fall below current cut points for treatment of pulmonary vascular disease. In addition, they have a hypercontractile, energetically inefficient RV, which may provide mechanistic insight into the increased risk for heart failure in this population. Whether they will require earlier treatment of pulmonary vascular disease in order to maintain RV function warrants further study.

T erm

P r e te r m

R V E n e r g e t ic E f f ic ie n c y 2 .5

p = 0 .0 3

T erm

P r e te r m

Term

R V C o n tr a c t ile E f fic ie n c y 25

p = 0 .0 2

(m l/% )

T o t a l P u lm o n a r y R e s is t a n c e

S tr o k e V o lu m e /S tr a in

T P R ( m m H g /L /m in )

Results: Young adults born premature had mild elevations in mean pulmonary artery pressure and total pulmonary vascular resistance. Resting RV stroke volume, stroke volume index, and ejection fraction were similar between preterm and term subjects. However, cardiac output and cardiac index were significantly higher among preterm subjects secondary to a higher resting heart rate. RV strain analysis demonstrated increased peak RV circumferential strain among preterm subjects, suggesting a hypercontractile myocardium. When stroke volume was divided by peak RV circumferential strain as a measure of RV efficiency, preterm subjects exhibited reduced RV efficiency. 4D flow analysis also demonstrated a decreased RV energetic efficiency, requiring a higher kinetic energy for a given stroke volume.

p = 0 .0 0 6

m P A P (m m H g )

Background: Preterm birth, or less than 37 weeks completed gestation, affects one in 10 live births in the United States. While lung disease is the most frequently recognized complication of prematurity, adults born moderately to extremely preterm have a 3-fold increased risk for the development of pulmonary vascular disease and a 17-fold increased risk for heart failure. The right ventricle (RV) is disproportionately affected, with decreases in RV but not left ventricular (LV) ejection fraction in early adulthood identified in a prior single-center study. Here, we sought to characterize pulmonary vascular and RV function in young adults born premature.

M e a n P u lm o n a r y A r t e r y P r e s s u r e

E n e r g y (m l/m J )

Goss KN, Beshish A, Macdonald J, Barton GP, Mulchrone AM, Chesler NC, Francois C, Wieben O, Eldridge MW University of Wisconsin, Madison, WI, USA

S tr o k e V o lu m e /K in e tic

Early Pulmonary Vascular and Right Ventricular Dysfunction in Healthy Young Adults Born Prematurely

15 10 5 0

T erm

P r e te r m

Preterm

p = 0 .0 4 9

2 .0 1 .5 1 .0 0 .5 0 .0

T erm

P r e te r m

Hemodynamic and RV efficiency measures in young adults born premature. (A) Mean pulmonary artery pressure. (B) Total pulmonary resistance. (C) RV contractile efficiency, assessed by stroke volume divided by RV strain. (D) RV energetic efficiency, assessed by stroke volume divided by kinetic energy required. (E) RV 4D flow mapping in a term and preterm subject.

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Non-Invasive Ultrasonographic Cardiac Output Measurement in Pulmonary Arterial Hypertension Matusov Y1, Achamallah N1, Sager JS2 1 Santa Barbara Cottage Hospital, Santa Barbara, CA, USA 1 Cottage Pulmonary Hypertension Center, Santa Barbara Cottage Hospital, Santa Barbara, CA, USA Purpose: To determine whether cardiac index (CI) measured by the UltraSonic Cardiac Output Monitor (USCOM) system correlates with CI obtained using standard invasive hemodynamic measurement methods (thermodilution and the Fick method) during right heart catheterization. Background: Pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) are defined by hemodynamic parameters according to the World Health Organization (WHO). Hemodynamic parameters help guide treatment decisions and risk stratify patients. Low CI is associated with poor survival; the lung allocation score uses low CI as an exception to prioritize patients on the lung transplant list. Right heart catheterization is the current gold standard to determine hemodynamic parameters. Data from RHC are used to determine CI using the Fick and thermodilution methods. No validated non-invasive method exists to our knowledge in this group of patients. The USCOM is a portable, continuous-wave ultrasound device. The probe is placed at the sternal notch and directed at the aortic valve. A velocity time interval is measured by enveloping the pulsed systolic flow profile through the valve and multiplying this by a standardized cross-sectional aortic valve area to derive cardiac index, stroke volume index, and heart rate. USCOM is clinically validated in critically ill adults, children, cardiac surgical (including transplant) and post-surgical patients, and has shown good correlation with thermodilution, echocardiography and pre-set artificial heart parameters. Methods: Adult (> 18-year-old) patients admitted to our facility for a RHC who were suspected of having WHO Group 1 or 4 PAH were enrolled. USCOM measurements of CI were taken within 30 minutes of RHC. CI obtained

PULMONARY HYPERTENSION ASSOCIATION

by USCOM was compared to CI derived from Fick and thermodilution methods. All measurements were taken by two trained physician investigators. Patients were excluded if they did not meet criteria for Group 1 or 4 PAH based on RHC data. Correlation between methods determined using the Pearson correlation method, with statistical significance determined by t-test. Bland-Altman plots were used to analyze the agreement between the USCOM, Fick, and thermodilution methods. Results: In this preliminary data set, a total of 17 patients were enrolled and underwent RHC. Three did not meet criteria for WHO Group I or IV PAH. Average age of the remaining 14 patients was 52 years, and 13 (93%) were female. CI determined by USCOM and the Fick method had a Pearson correlation of 0.61 (p = 0.018), and CI by USCOM and thermodilution had an agreement of 0.74 (p = 0.0026); the Fick and thermodilution agreement was 0.76; p = 0.00162 (Fig 1). Bland-Altman plots demonstrated that all but one value were within the limits of agreement for USCOM with both Fick and thermodilution (Fig 2). Conclusions: Measurement of CI is vital in making decisions regarding treatment and prognosis in PAH. The USCOM system may provide a useful non-invasive tool for monitoring of cardiac function in this population. This preliminary data set demonstrates that, in WHO Group I and IV PAH patients, the non-invasive USCOM CI correlated with hemodynamics determined by invasive RHC. Notably, the USCOM and thermodilution CI had an agreement that was very similar to each other. Further studies are necessary to determine the utility of USCOM in PAH patients, and its potential role in the diagnosis and monitoring of treatment response in the outpatient setting.

Figure 1: Pearson correlates of USCOM vs Fick and thermodilution agreement

Figure 2: Bland-Altman plots of USCOM vs Fick and thermodilution (limits of agreement in hashed lines)

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RESEARCH ABSTRACTS & CASE STUDIES 1037

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Reliability of Systolic Pulmonary Artery Pressure by Doppler Echocardiography Compared to Right Heart Catheterization in Patients With Atrial Septal Defect: Analysis in a Large Patient Population Dai HL, Guang XF, Yin XL, Yang QF Department of Cardiology, Yan'an Affiliated Hospital of Kunming Medical University, Kunming, China Background: Pulmonary arterial hypertension (PAH) in patients with congenital heart disease (CHD) is associated with increased morbidity and mortality. While Doppler echocardiography(DE) has been a useful screening test in PAH, the presence of structural cardiac defects may affect the ability to reliably predict systolic pulmonary arterial pressure (sPAP). Therefore, the aim of this study was to analyze the reliability of noninvasive PAP assessment by Doppler echocardiography compared to invasive measurements in a large atrial septal defect (ASD) patient population. Methods: We retrospectively analyzed data from a large tertiary cardiology department over 2 years. Relationships between RHC- and DE-derived hemodynamics were assessed using the Pearson correlation. Bland-Altman analyses were performed to evaluate the agreement between DE and RHC measurements of sPAP.

Results: 763 ASD patients (mean age 32.8±19.4 years, 542 [71%] female gender) who underwent DE and right heart catheterization (RHC) examinations. A significant overestimation of the sPAP, sPAP was 43.8±13.4 mm Hg by DE and 37.8±11.8 mm Hg by RHC(P<0.001). There was moderate correlation between DE and RHC measurements of PASP (r = 0.501, P<0.001). Bland–Altman analysis showed a bias of 6.1 mm Hg for sPAP (95% limits of agreement -18.2 to +30.4 mm Hg). Conclusions: DE estimates of sPAP are overestimation in patients with ASD and should not be relied on to make the diagnosis of PAH.

Right Ventricular Transient Exertional Dilation (TED) in Pulmonary Hypertension – Is There Diagnostic Utility? El-Yafawi R, Wirth J, Rancourt D, Hacobian M, Atherton D, Cohen M Maine Medical Center, Portland, ME, USA Background: The role of exercise stress echocardiography (ESE) in PH diagnosis is not established. The aim of this study is to examine changes in right ventricular (RV) morphometry during rest and exercise in normal subjects compared with PH patients. Methods: Adult subjects (normal and those with well characterized PH) of both genders exercised on a recumbent bicycle ESE using a progressive workload protocol. Exercise was stopped at a rate-pressure product of 20,000 or for limiting symptoms. The echocardiographic recordings were subsequently analyzed by two independent sonographers. Five echocardiographic RV morphometric parameters [RV end systolic area (RVESA), RV end diastolic area (RVEDA), RV basal diameter (RVBD), RV mid diameter (RVMD) and RV longitudinal diameter (RVLD)] were measured at rest and maximal exercise. Each parameter was evaluated for inter-rater reliability. Acceptably reproducible RV measurements were analyzed by MannWhitney U test to determine statistical differences between the normal and PH subjects at rest and exercise.

Results: PH subjects (40) and normal subjects (38) between 18–66 years old were enrolled. Within the PH group 75% were female vs. 50% in the normal group (p=NS). RV measurements were adjusted for gender, height, BSA and workload. During exercise, RVESA, RVEDA and RMD significantly decreased in normal group (p<0.05) but significantly increased in PH group (p<0.01). Changes in RVESA, RVEDA, RVMD and RVLD during exercise were significantly different between PH and normal group (p < 0.001). An increase in RV size measurements during exercise had a ROC c-statistic of 0.93 for detecting pulmonary hypertension. Conclusions: During recumbent exercise, normal subjects demonstrate a statistically significant reduction in RV dimensions, while PH subjects demonstrate a statistically significant enlargement in RV dimensions which we term RV Transient Exertional Dilation (TED). Hence, right ventricular TED is a pathological feature in PH subjects not seen in normal subjects and is likely related to increased RV afterload. We postulate that recumbent ESE may have utility as a screening tool for patients with suspected pulmonary vascular disease or unexplained dyspnea.

Baseline characteristics

Figure 1: Bland—Altman plot of Doppler echocardiographic estimates of sPAP and RHC measurements

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Changes in RV parameters during exercise

RESEARCH ABSTRACTS & CASE STUDIES

ROC curve of increase in RV parameters to detect PH

Increase in RVMD, RVEDA, RVESA OR RVLD

Sensitivity and specificity of increase in RV parameters for diagnosis of PH

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1038

Risk Assessment and Prognosis Based on ESC/ERS Guidelines in Patients With Chronic Thromboembolic Pulmonary Hypertension Receiving Riociguat

Humbert M1, Farber H2, Ghofrani HA3, Busse D4, Meier C5, Hoeper MM6 1 Université Paris-Sud, Le Kremlin–Bicêtre, France 2 Boston University School of Medicine, Boston, MA, USA 3 University of Giessen and Marburg Lung Center, Giessen, Germany, member of the German Center for Lung Research (DZL), Imperial College London, London, UK 4 Chrestos Concept GmbH & Co. KG, Essen, Germany 5 Bayer AG, Berlin, Germany 6 Hannover Medical School, Hannover, Germany, member of the German Center for Lung Research (DZL) Background: At present, there are no established tools for risk prediction in patients with chronic thromboembolic pulmonary hypertension (CTEPH). For patients with pulmonary arterial hypertension (PAH), 2015 ESC/ERS treatment guidelines recommend regular risk assessment using a multidimensional approach incorporating clinical, exercise, imaging, and hemodynamic variables. Abbreviated versions of this risk assessment were found to discriminate between prognostic groups in PAH cohorts of the French, Swedish, and COMPERA registries. [1–3] We therefore conducted an exploratory assessment of the ESC/ERS risk models in patients with inoperable or persistent/recurrent CTEPH receiving riociguat in the CHEST studies. Methods: In CHEST-1, patients received placebo or riociguat adjusted up to 2.5 mg three times a day (tid) for 16 weeks. For patients entering the CHEST-2 open-label extension study, risk was assessed at baseline and Week 16 according to three methods: 1. French registry invasive analysis: quantified the number of ESC/ERS low-risk criteria present based on WHO functional class (FC), 6-minute walking distance (6MWD), right atrial pressure (RAP), and cardiac index. 2. French registry non-invasive analysis: quantified the number of low-risk criteria present for three non-invasive parameters: WHO FC, 6MWD, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP). 3. COMPERA analysis: assessed WHO FC, 6MWD, NT-proBNP, RAP, cardiac index, and mixed venous oxygen saturation; each criterion was graded 1–3 (1=low risk, 3=high risk) and the rounded mean defined the

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risk category. The association between meeting low-risk criteria at Week 16 of CHEST-1 with long-term outcomes in CHEST-2 was assessed by Kaplan–Meier analyses of observed data. Differences in the long-term outcome between risk groups were analyzed using the log-rank test. Results: After 16 weeks in CHEST-1, patients treated with riociguat (n=155) met a greater number of the low-risk criteria (French invasive and non-invasive) or improved their risk status (COMPERA) compared with baseline. The number of low-risk criteria at Week 16 discriminated between prognostic groups for both survival (French invasive p<0.0001; French non-invasive p=0.0231) and clinical worsening-free survival (p<0.0001 for both methods [Figure shows non-invasive analysis]). The COMPERA method discriminated between prognostic groups for both survival and clinical worsening-free survival (p<0.0001 for both).

Figure 1: Clinical worsening-free survival in CHEST-2 stratified by the number of low-risk non-invasive criteria at Week 16 in CHEST-1.

Conclusions: In this exploratory analysis, abbreviated versions of the ESC/ERS risk assessment were able to discriminate between prognostic groups when applied to patients with inoperable or recurrent/persistent CTEPH receiving riociguat in CHEST-2. Further evaluation of risk prediction in patients with CTEPH is therefore warranted. 1. Boucly A, et al. Eur Respir J 2017;50:1700889; 2. Hoeper MM, et al. Eur Respir J 2017;50:1700740; 3. Kylhammar D, et al. Eur Heart J 2017; doi: 10.1093/ eurheartj/ehx257.

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Serum Uric Acid as a Biomarker of Disease Severity in Scleroderma Patients With Pulmonary Arterial Hypertension Simpson C, Khair R, Kolb T, Hassoun PM, Damico R, Mathai SC Johns Hopkins University, Baltimore MD, USA

Background: Previous work by our group has shown that serum uric acid (UA) is significantly higher in patients with systemic sclerosis (SSc) complicated by pulmonary arterial hypertension (PAH) than in SSc patients without PAH, an observation that holds true when adjusted for age, sex, and renal function. Given that reliable and easily obtained predictors of outcomes in patients with SSc-PAH are lacking, we sought to determine the relationship between UA and disease severity and survival. Methods: Consecutive SSc patients referred to our center for evaluation of dyspnea and found to have PAH on right heart catheterization (RHC) were included. Subjects with significant obstructive or restrictive lung disease were excluded. Spearman correlation coefficients were used to assess relationships between UA and serum markers of disease severity, functional capacity, and resting hemodynamics. The association between baseline UA and survival was assessed using Cox proportional hazard modeling.

Results: 60 subjects diagnosed with PAH based on RHC were included. On average, subjects were 64±12 years of age; most were women (86%) with limited scleroderma and WHO functional class III symptoms. The median value of UA in the overall cohort was 7.3mg/dL. Serum UA correlated positively with proBNP (r=0.30, p=0.03), creatinine (r=0.50, p=0.001), mean pulmonary artery pressure (mPAP, r=0.45, p=0.004) and pulmonary vascular resistance (PVR, r=0.39, p=0.003), but was not significantly associated with sixminute walk distance, cardiac output, or cardiac index. Serum UA was associated with a trend toward increased risk of death (HR 1.44, 95% CI 0.98-2.11, p=0.16) after adjusting for age, sex, and eGFR. Conclusions: Our results show that in this cohort of incident SSc-PAH patients, serum UA is correlated with markers of disease severity. Further, baseline UA is associated with survival, though results did not reach statistical significance. Taken together, these results suggest that UA has the potential to serve as a novel biomarker for disease severity in patients with SSc-PAH.

Tissue Doppler Imaging on Transthoracic ECHO to Assess Prevalence of HIV-Associated Pulmonary Hypertension Singh N1, Shah S1, Ly V2, Ojeda-Martinez H1, Ajam MA 2 1 SUNY Downstate Medical Center, Brooklyn, NY, USA 2 Veterans Affairs, New York Harbor Healthcare System, Brooklyn, NY, USA

Background: Pulmonary Hypertension is classified based on etiology, with human immunodeficiency virus (HIV) associated disease falling into Group 1 Pulmonary Arterial Hypertension (PAH). The mortality of PAH is several folds higher in patients with HIV than without, reaching 40% for patients in World Health Organization Functional Class (WHO-FC) III-IV. Despite this poor prognosis, no evidence exists to support routine screening for HIV-associated PAH in high-risk populations. While transthoracic echocardiography (ECHO) has not shown ideal correlation with findings on right heart catheterization, use of ECHO is still a well-accepted noninvasive screening tool to assess for possible PAH. Several studies have used transthoracic echocardiogram (ECHO) to look at the prevalence of PAH in the HIV population with some studies estimating prevalence between 0.5 and 2%, however this has only been investigated in symptomatic patients. By using advanced but widely available echocardiographic techniques such as tissue doppler imaging (TDI), the accuracy of ECHO as a screening tool may improve. The purpose of this study was to further understand the clinical utility of screening asymptomatic HIV-positive patients for PAH. Given the reported poor survival in this population, identifying asymptomatic patients with PAH would allow for earlier surveillance and intervention. Methods: This was a retrospective review of HIV-infected patients at the Brooklyn VA. All HIV-positive patients seen in the HIV clinic between January 2015 to September 2016 were chart-reviewed and assessed for prevalence of pulmonary

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arterial systolic pressure (PASP) greater than 35mmHg as assessed by transthoracic ECHO to be suggestive of PAH. Those ECHOs with noted PAH were reassessed using Tissue Doppler Imaging (TDI) to estimate the pulmonary capillary wedge pressure (PCWP) via the mitral valve regurgitant velocity. Other variables such as age, gender, CD4 count, viral load, anti-retroviral therapy and cardiopulmonary comorbidities were also collected. Results: Of 100 HIV-positive patients who received a transthoracic ECHO from January 2015 to September 2016, 3 ECHOs were not done using TDI and 1 was done on a patient not in sinus rhythm. Of the remaining 96 patients, 15 had a PAH > 35mmHg with a PCWP less than 15mmHg. This suggests a prevalence of PAH of 15.6% (95% CI 9%24%) in this population. Out of these patients, only 13.3% were noted to have uncontrolled viral load, the remainder had suppressed viral loads and absolute CD4 >200. Conclusions: There is a higher prevalence of PAH found amongst the HIV-positive population at our institution than would be expected based on prior data. Given the elevated mortality of this disease, we propose that all HIV-positive patients should be screened with transthoracic ECHO for elevations in their PASP. TDI estimations of PCWP should be included in this screening to improve the sensitivity of this screening test. This information should be used to pursue guideline-directed diagnostic workup both at the time of screening and as symptoms develop.

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1041

Male Gender Predisposes PAH Patients to Reductive Stress and Disease Progression

Table 1: Patient Demographics

Rafikova O, Desai AA, Rafikov R University of Arizona, Tucson, AZ, USA

Patient Demographics (n=232)

Mean age Male gender Female gender

61.5 230 2

Table 2: Comorbidities in PAH v non-PAH Patients. Fisher exact test was used to test for associations between cohorts, however none of the associations were significant. Characteristics in PAH v non-PAH Patients

PAH (n=15)

non-PAH (n=81)

P-value)

CHF

5 (33.3%)

28 (34.6%)

1.0

COPD

2 (13.3%)

12 (14.8%)

1.0

Asthma

5 (6.2%)

1.0

ILD

1.0

OSA

1.0

CD4<250

3 (20%)

17 (21%)

1.0

Uncontrolled Viral Load

2 (13.3%)

5 (6.2%)

0.29

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Background: Pulmonary arterial hypertension (PAH) is a lethal disease characterized by increased pulmonary vascular resistance leading to right ventricular failure. Previous studies indicated that while females are more susceptible to PAH, male patients have a lower survival rate. Nevertheless, the particular mechanisms responsible for the worse prognosis in males are not clear. Male vascular cells were shown to be more prone to necrotic cell death compared to those derived from females. We now hypothesize that an ongoing pulmonary vascular necrosis in males mediates a redox shift of plasma environment toward more reduced, i.e., induces reductive stress, which contributes to PAH progression. Methods: In this study we analyzed the plasma samples collected from three different patient cohorts - 1) patients with a diagnosis of Group I PAH (PAH cohort); 2) patients that were diagnosed with non-PAH lung diseases (lung cohort); and 3) patients that were diagnosed with acute or chronic heart disease (heart cohort). All patients were prospectively recruited from the University of Arizona (UA). All subjects provided written consent to participate in this study with the approval of the UA institutional human subjects review board. Results: As a surrogate for vascular necrosis, we compared circulating high mobility group box 1 (HMGB1) levels, a damage-associated molecular patterns (DAMP) molecule released from necrotic cells, in male and female PAH patients, as well as in patients from lung and heart cohorts. Male, but not female, PAH patients had significantly elevated levels of plasma HMGB1 comparing to gender-

matched patients from lung and heart cohorts. Next, we used RedoxSys® Diagnostic System to evaluate the redox state of patient plasma. In strong accordance with previously published findings, there was a significant “oxidative shift” in male and female patients from lung cohort compared to other patient cohorts. Patients of either gender from the heart cohort had a reduced plasma state that could be explained, in part, by a previously reported history of myocardial damage or ischemic heart disease. However, in the PAH cohort, there was an evident gender disparity: female PAH patients exhibited significantly more oxidized plasma compared to heart cohorts, while males possessed a slightly more reduced plasma state. Importantly, there was also a distinct gender difference in the correlation between the redox parameters and markers of RV dysfunction. While in females, brain natriuretic peptide (BNP), an established marker of heart failure, was elevated in response to oxidative changes, males demonstrated a significant correlation of elevated BNP levels with increasing reductive stress levels. In particular, in male patients, every 1 µC of increase in total antioxidant activity resulted in 81% rise of BNP levels. Since RV dysfunction is the primary survival determinant in patients with PAH, our results suggest that the reductive stress is a potential marker for RV dysfunction and may contribute to the poor survival of males with PAH. Conclusions: This study reveals a predisposition of the male gender to reductive stress, which could contribute to the progression of PAH in males. This discovery inaugurates a novel concept of gender-specific redox pathobiology in PAH.

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Riociguat in Pediatric Pulmonary Arterial Hypertension: PATENT-CHILD Study Design and Rationale Beghetti M1, Wirsching G2, Bonnet D3, Ivy DD4, Moledina S5, Lippert S2, Ribeiro S2 1 University of Geneva, Geneva, Switzerland 2 Bayer AG, Berlin, Germany 3 Paris Descartes University, Paris, France 4 University of Colorado, Denver, USA 5 Great Ormond Street Hospital for Children, London, UK

Background: The development of treatments for children with pulmonary arterial hypertension (PAH) remains challenging due to strict regulatory requirements and ethical issues.[1] Use of PAH-targeted therapies is based on results in adults and expert opinion, as well as limited trials in pediatric PAH.[2] These trials have shown that endothelin receptor antagonists (ERAs), prostacyclin analogs (PCAs), and phosphodiesterase type 5 (PDE5) inhibitors can improve hemodynamics and functional capacity.[2] Clinical trials of riociguat include the placebo-controlled PATENT-1 study,[3] its long-term extension PATENT-2,[4] and the open-label RESPITE study.[5] These trials have shown that riociguat is effective[3,4] and well tolerated[3–5] in adults with PAH, but it has not been investigated in children. PATENT-CHILD (ClinicalTrials.gov identifier: NCT02562235) will evaluate the safety, tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) of riociguat, added to standard of care, in pediatric patients with PAH. Methods: PATENT-CHILD is an open-label, single-arm, individual dose-titration study in children and adolescents aged 6–17 years with PAH (diagnosed by right heart catheterization) in World Health Organization (WHO) functional class (FC) I–III. All patients must be on standard of care PAH-targeted therapies (ERA and/or PCA) for ≥12 weeks prior to the baseline visit, and will be classified as prevalent (receiving PAH medication at screening and in need of additional treatment) or incident (treatment naïve and stabilized on standard of care before addition of riociguat). Main exclusion criteria include concomitant PDE5 inhibitors, non-specific PDE inhibitors, nitrates, and nitric oxide (NO) donors, pre-treatment with NO donors within 2 weeks of Visit 1, active state of hemoptysis or pulmonary hemorrhage. The main study consists of a dose-adjustment phase up to 8 weeks and a maintenance phase up to 16 weeks (Figure). Eligible patients weighing <50 kg at screening

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will receive weight-adjusted doses of riociguat from 1 to 2.5 mg three times daily (TID) as granules for reconstitution into an oral pediatric suspension (0.15 mg/mL). Patients weighing ≥50 kg at screening will receive riociguat 1–2.5 mg TID as film-coated tablets. The primary outcome measures are change in safety and tolerability from baseline to Week 24 and PK/PD analyses. Safety and tolerability will be assessed by incidence of adverse events and serious adverse events, change in vital signs, left hand x-ray to monitor bone growth, and laboratory parameters. Exploratory efficacy endpoints comprise change from baseline to Week 24 in 6-minute walking distance, WHO FC, N-terminal pro-brain natriuretic peptide or brain natriuretic peptide, echocardiographic parameters, and time to clinical worsening. Questionnaires will be used to assess change in quality of life scores (SF10 and PedsQL) and the taste and texture of the pediatric formulation. Patients who complete the initial 24-week study are eligible for entry into a long-term extension phase until they reach the age of 18 years or until riociguat is licensed commercially for pediatric treatment (a 60-day safety followup will be provided for patients who choose not to proceed).

Figure 1: Dose-adjustment scheme for main study phase

Results: The planned enrollment of at least 20 patients on ERA therapy is ongoing. Conclusions: The PATENT-CHILD study will provide important new information about the potential use of riociguat in pediatric patients with PAH. 1. Beghetti M, Berger RM. Eur Respir Rev 2014;23:498–504; 2. Vorhies EE, Ivy DD. Paediatr Drugs 2014;16:43–65; 3. Ghofrani HA, et al. N Engl J Med 2013;369:330–340; 4. Ghofrani HA, et al. Lancet Respir Med 2016;4:361–371; 5. Hoeper MM, et al. Eur Respir J 2017;50:1602425.

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Background: In majority of pediatric cardiology practice worldwide, the derived calculated pulmonary vascular resistance (PVR) has been used as a parameter to evaluate children with pulmonary hypertension associated with congenital heart disease (PH/CHD). It has been debated whether the PVR is the ideal parameter to reflect the severity of PH/CHD due to its derived calculated value depends on oxygen consumption. While measuring oxygen consumption (VO2) is difficult and complicated to obtain the accurate value, therefore estimated VO2 from reliable reference has been utilized in many centers. To avoid using VO2, the ratio between the PVR and systemic vascular resistance or Rp/Rs has been used instead of PVR. The objective of this study is to define whether the basic pulmonary hemodynamic parameters could be used as parameters to correlate with PVR and Rp/Rs. Methods: Children with PH/CHD underwent cardiac catheterization. Derived calculated PVR was calculated from transpulmonary pressure gradient divided by the pulmonary blood flow. The PVR was tested and showed to be directly correlated with the Rp/Rs. The pulmonary hemodynamics especially the diastolic pulmonary pressure (dPAP), diastolic pressure gradient (DPG: difference between the dPAP and pulmonary capillary wedge pressure), pulmonary pulse pressure (PPP: difference between the systolic pulmonary

pressure and dPAP) and pulmonary artery proportional pulse pressure (PApPP) were compared and correlated with the PVR. The sensitivity and specificity of the pulmonary hemodynamic threshold value predict the PVR were determined. Results: The cardiac catheterization data of 65 children (mean age 6.37 years, range1-21 years, 34 male) was retrospectively reviewed. The dPAP, DPG and PPP were correlated with the PVR, r=0.81, 0.80 and 0.59 respectively. The dPAP > 19 mmHg had 85 % sensitivity and 71 % specificity to predict PVR > 3 WU.m² with area under the curve of 0.85. The ratio of the DPG > 11 mmHg had 82 % sensitivity and 78 % specificity to predict PVR > 3 WU.m² with area under the curve of 0.837. The PPP > 21 mmHg had 85 % sensitivity and 66% specificity to predict PVR > 3 WU.m² with area under the curve 0.891. While the PAPPP was not correlated to the PVR. Conclusions: The basic pulmonary hemodynamics particularly the dPAP DPG and PPP could be used to assess PH/CHD in children with reasonable correlation with the PVR. The direct measurement of dPAP has a better prediction of the PVR in comparison with the DPG and PPP.

Transition to Oral Treprostinil From Parenteral or Inhaled Treprostinil or as Add-On Therapy in Pediatric Subjects With Pulmonary Arterial Hypertension

Ivy D1, Feinstein J2, Yung D3, Mullen MP4, Kirkpatrick E5, Hirsch R6, Austin ED7, Fineman J8, Doran A9, Solum D9, Deng CQ9, Hopper RK10 1 Children’s Hospital of Colorado 2 Lucile Packard Children’s Hospital 3 Seattle Children’s Hospital 4 Boston Children’s Hospital 5 Children’s Hospital of Wisconsin 6 Cincinnati Children’s Hospital 7 Monroe Carell Jr. Children’s Hospital at Vanderbilt 8 University of California San Francisco 9

United Therapeutics

Children’s Hospital of Philadelphia

Background: Transition from parenteral to oral treprostinil has been successfully accomplished in adults with pulmonary artery hypertension (PAH) but data in pediatric patients are lacking. Methods: In Study TDE-PH-206, pediatric subjects treated with parenteral (Cohort 1) or inhaled (Cohort 2) treprostinil were transitioned to oral treprostinil. Prostacyclin-naive subjects on background oral PAH therapy were given oral treprostinil as add-on therapy (Cohort 3). Successful transition was defined as cessation of parenteral or inhaled prostacyclin at Week 4 (Cohorts 1 and 2) and oral treprostinil dose maintenance through Week 24 (Cohorts 1, 2, and 3). Subjects were monitored for adverse events (AEs), 6-Minute Walk Distance (6MWD), PAH symptoms, WHO Functional Class (FC), cardiac magnetic resonance imaging (cMRI), and cardiopulmonary exercise testing (CPET) through 24 weeks. Results: A total of 32 subjects (10 subjects each, Cohorts 1 and 2; 12 subjects Cohort 3) were enrolled. The mean age was 12.2 years (7 to 17 years) and 23 subjects (72%) were female. Most subjects had idiopathic PAH (75.0%) or PAH due to congenital heart disease (15.6%). All subjects were on background oral PAH therapy and 19%, 75%, and 6% were classified as WHO FC 1, 2, and 3, respectively.

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Cohort 1 subjects were receiving parenteral treprostinil at a median dose of 57.0 ng/kg/min (25.0 72.0 ng/kg/min) for 5.4 years (2.0-6.1 years). Cohort 2 subjects were receiving 4 inhaled treprostinil treatments per day (average 9 breaths per session) for 3.9 years (0.5-5.3 years). In total, 31 subjects (96.9%) successfully transitioned to oral treprostinil; 1 subject (Cohort 1) transitioned to oral treprostinil, then back to parenteral after experiencing syncope and WHO FC change from 2 to 3. Cohorts 1, 2, and 3 received a final mean oral treprostinil dose of 5.6, 3.3, and 4.5 mg TID, respectively, which is substantially higher by weight compared with doses achieved in adult studies. 1 subject (Cohort 3) was uptitrated from TID to QID dosing based upon clinical impression. All cohorts had variable changes in 6MWD, cMRI, and CPET. 1 subject (Cohort 3) required background therapy adjustment. Overall, 12 serious AEs were reported. Common drug-related AEs included headache (81%), diarrhea (69%), nausea (66%), vomiting (66%), and flushing (56%). Conclusions: Pediatric subjects successfully transitioned to oral treprostinil with preservation of exercise capacity and WHO FC. Prostanoid-related AEs were most common, and were similar to those reported in adults. Funded by United Therapeutics Corporation.

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RESEARCH ABSTRACTS & CASE STUDIES 1046

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Financial Burden of Medical Therapy in Patients With Pulmonary Arterial Hypertension (PAH) Ghandour M, Helmi H, Burger CD Mayo Clinic, Jacksonville, FL, USA

Background: Medical therapy for pulmonary arterial hypertension (PAH) is expensive and often has significant side effects. The purpose of this study is to assess the financial impact of PAH-specific therapy in the context of insurance drug coverage, out of pocket expenditures, utilization of supplemental assistance programs and compliance with therapy. Methods: A prospective survey study between November 2017 and February 2018 was conducted enrolling 50 PAH patients followed in the PH Center at Mayo Clinic Florida and a descriptive data analysis was performed focused on income stratification, correlation with insurance plans, outof-pocket-expenses, effects on treatment regimen choices and influence of aid from financial assistance programs. Results: 42 (84%) patients were women and 8 (16%) were men. The mean age at diagnosis and enrollment was 51 and 60 years, respectively. All patients were on PAH drug therapy: 13 (26%), 27(54%), 8 (16%) and 2(4%) on one, two, three and four-drug therapy, respectively. The majority, 38

(76%), had persistent PAH symptoms despite the medical therapy. In addition, 32 (64%) reported side effects from the PAH medications and 5 (10%) patients emphasized that medication lowered their mood. Financially, 30 (60%) of the patients had current monthly out-of-pocket expenses with an average of approximately $1000. Furthermore, 28 (54%) felt that the out-of-pocket expenses were financially burdensome. Notably, 17 (34%) required financial support from patient assistance programs, generally from nonprofit organizations. Importantly, 6 (12%) of the patients missed their drug dosages at least once per month, perhaps to extend the prescription duration. Conclusions: Most patients are symptomatic despite PAH-specific therapy. Furthermore, side effects are common. Most patients had health insurance that covered drug cost. Nonetheless, out-of-pocket expenses were significant. The survey results suggest that PAH has a substantial financial impact on patients that might affect their therapeutic compliance.

Frequency of Palliative Care Referrals in Newly Diagnosed Pulmonary Arterial Hypertension (PAH): The Pulmonary Hypertension Association Registry

Gray MP1, Wright R2, Khair RM2, Badesch D3, Bartolome S4, Boyle K5, Bull T3, Chakinala M6, De Marco T7, Elwing J8, Feldman J9, Ford HJ10, Frantz RP11, Grinnan DC12, Klinger JR13, Lammi MR14, McConnell JW15, Berman Rosenzweig E16, Runo JR17, Sager JS18, Shlobin OA19, Thenappan T20, Ventetuolo CE13, White RJ21, Williamson TL22, Zamanian RT23, Mathai SC2 1 Pulmonary Hypertension Association, Silver Spring, MD, USA 2 Johns Hopkins University, Baltimore, MD, USA 3 University of Colorado Denver, Denver, CO, USA 4 University of Texas Southwestern Medical Center, Dallas, TX, USA 5 University of Pennsylvania, Philadelphia, PA, USA 6 Washington University in St. Louis, St. Louis, MO, USA 7 UCSF Medical Center, San Francisco, CA, USA 8 University of Cincinnati, Cincinnati, OH, USA 9 Arizona Pulmonary Specialists, Phoenix, AZ, USA 10 University of North Carolina at Chapel Hill, Chapel Hill, MD, USA 11 Mayo Clinic, Rochester, MN, USA 12 Virginia Commonwealth University, Richmond, VA, USA 13 Rhode Island Hospital, Providence, RI, USA 14 University Medical Center, LCMC Health, New Orleans, LA, USA 15 Kentuckiana Pulmonary Associates, Louisville, KY, USA 16 Columbia University Medical Center College of Physicians and Surgeons, New York, NY, USA 17 University of Wisconsin, Madison, WI, USA 18 Santa Barbara Cottage Health System, Santa Barbara, CA, USA 19 Inova Health System, Falls Church, VA, USA 20 University of Minnesota, Minneapolis, MN, USA 21 University of Rochester Medical Center, Rochester, NY, USA 22 University of Kansas, Kansas City, KS, USA 23 Stanford University, Stanford, CA, USA

Background: In addition to a high mortality, PAH carries imposes significant morbidity with a high burden of disease. Despite improvements in functional capacity (FC) and delayed time-to-clinical-worsening in randomized clinical trials, changes in symptoms and health-related quality of life (HRQOL) are of limited magnitude and rarely achieve clinical significance. Palliative care (PC) improves HRQOL, decreases anxiety and depression, and improves survival in patients with various chronic and terminal diseases. However, there are no studies to date examining the role of PC in a PAH population. Therefore, we sought to determine the frequency of formal PC referrals in the PHA Registry (PHAR), and to characterize PAH patients referred to PC. Methods: We performed a cohort study of newly-evaluated patients ≥18 years of age with PAH. Baseline demographic, socioeconomic status (SES), clinical phenotype, and supportive care data were collected, as well as the SF-12 and emphasis-10. Time-to-PC-referral was determined by calculating the time from enrollment to reported PC referral, as captured by subsequent 6-month follow-up data entry per the PHAR protocol.

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Results: We included 145 newly diagnosed PAH patients in the analysis. Initial and subsequent assessment of PC referral status were made at each 6-month follow-up visit. Six (4.1%) were referred to PC at a median time of 14.7 months (IQR 8.6-20.4) after initial evaluation. PC referred patients were older, with lower BMI, shorter 6-minute walk distance, poor hemodynamics, usually on parenteral prostacyclin and supplemental oxygen therapy, and reported a worse HRQOL by EmPHasis-10 score at the time of enrollment (Table 1). Conclusions: Incident adult PAH patients enrolled in PHAR had a very low rate of referral to PC during immediate-term follow-up. PC referred patients were more likely to be receiving parenteral therapy and be on supplemental oxygen, and to report a worse HRQOL by EmPHasis-10 score at the time of enrollment. These findings demonstrate the need for further study into the role and timing of PC in PAH and to identify barriers to PC referral.

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Table 1: Characteristics of Patients Referred to PC

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Implantable System for Remodulin®: A Real-World Experience Study in Patients With Pulmonary Arterial Hypertension Bourge RC1, Shapiro SM2, Pozella P3, Harris DF4, Borg EH3, Nelsen AC3 1 The University of Alabama at Birmingham, Birmingham, AL, USA 2 Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA 3 United Therapeutics Corporation, Research Triangle Park, NC, USA 4 Insight & Measurement, LLC, Durham, NC, USA Background: The inherent risks and complex nature of intravenous (IV) and subcutaneous (SC) delivery of treprostinil with external pumps affect patient quality of life and limit use. The Implantable System for Remodulin was developed as an alternative route for treprostinil delivery and consists of an implantable pump, internal catheter tunneled from pump to central venous site, and handheld programmer. The pump is filled percutaneously with treprostinil as needed. The frequency of fills is determined by infusion rate and patient size and varies from every 1 to 3 months. Results of the open-label clinical trial evaluating the safety of the system have previously been described (DelIVery for Pulmonary Arterial Hypertension (PAH); NCT01321073). The purpose of this study was to gain a better understanding of the experience of patients participating in the clinical trial that continue to receive treprostinil with the system. Methods: Patients logged into a secure interactive website once a day for 6 days and completed a series of mixedmethods, quantitative and qualitative activities. Survey questions were pre-tested with PAH nurses and were designed to assess the effect of the implantable system on quality of life, satisfaction, and activities of daily living relative to patients’ previous experience with external IV/SC pumps. Tasks included selection of photos representing life before and after the implantable system and a hypothetical letter writing activity to describe their experience. Data were collected between January and November 2017. The study received approval from Western Institutional Review Board. Note that data were not collected on patient experience with external pumps prior to implantation of the system as a comparator.

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Results: 21 patients from DelIVery participated. Mean (SD) patient age was 52.14 (12.54) years. Mean (SD) patient reported time on the implantable system was 4.98 (0.70) years. 14 had been on IV treprostinil and 12 on SC treprostinil prior to implantation of the system (5 had used both). Over 70% of patients reported equal or more emergency room visits on their previous external pumps compared to the implantable system. Over 80% of patients reported that their previous external pumps took more time overall than the implantable system (travel and clinic time included). Over 80% of patients reported a better experience shopping for groceries and working. Over 90% of patients reported improved ability to do housework, sleep, and independence. All patients reported improved overall quality of life (Figure 1), improved confidence out in public, improved ability to travel long distances, a better bathing experience, and a better experience getting dressed. Finally, all patients reported that the benefits of the implantable system are worth the risks of the implanted system (long-term study results manuscript in preparation). Conclusions: Treprostinil patients report an improved overall experience with the implantable system compared to their prior IV/SC external pumps, specifically in areas of quality of life, satisfaction, and activities of daily living. Patient perspective data continues to be an increasingly important aspect of the healthcare landscape. Patient Reported Overall Quality of Life with the Implantable System.

Manifestations of Depression in Patients Receiving Goal-Directed Treatment for Pulmonary Arterial Hypertension Swisher J, Overton-Barnes R, Clay S, Collins C East Tennessee Pulmonary Hypertension Center, Knoxville, TN, USA

Purpose: The objective of this analysis was to evaluate the prevalence, severity and specific manifestations of depression in patients receiving goal-directed therapy for pulmonary arterial hypertension. Background: Pulmonary arterial hypertension (PAH) is a chronic debilitating disease resulting from well-described pathophysiologic changes in pulmonary arteries that increase pulmonary vascular resistance and lead to right ventricular failure. The disease is associated with impaired activity tolerance, social limitations, and financial burdens that decrease quality of life and provoke anxiety and depression. The prevalence of moderate to severe depression has been estimated as high as 26% in patients with PAH. The current analysis evaluates the prevalence and phenotypic manifestations of depression in treated patients meeting targeted PAH therapy goals compared to a group not achieving outcome goals. Methods: This is a retrospective analysis of clinical data collected from a cohort of PAH patients seen in a community pulmonary hypertension center between August 2016 and May 2017. Key data evaluated included patient demographics, 6 minute walk (MW) distance, WHO functional class (FC) and PHQ-9 depression survey responses. Only patients with a confirmed hemodynamic diagnosis of WHO Group I PAH were included. Further, patients were only included if they had completed all of the study parameters on a single visit during the study period, and they had been on a treatment regimen for PAH for at least 6 months. Targets for goal-directed therapy included a 6 MW distance of at least 400 meters and WHO FC I or 2 symptoms determined by a standardized questionnaire.

Results: 36 patients met all inclusion criteria for this analysis. Based on PHQ-9 scoring, 30.5% of the patients had no manifestations of depression, 30.5% had minimal depression, 30.5% had mild depression, and 8.5% had moderate depression. There was no relationship between 6 MW distance and severity of depression. There was a notable shift in functional class distribution with decreasing percentages of FC 1 and 2 patients and increasing percentages of FC 3 and 4 in patients with higher depression scores. Fourteen patients (39%) were meeting goal-directed therapy targets; they were compared with 22 patients (61%) not meeting at least one therapy target. There were no significant age or gender differences between these two groups. Median PHQ-9 depression scores were significantly lower in the group meeting PAH treatment goals (p=0.03). Significantly fewer patients in the group meeting treatment goals reported “having little interest or pleasure in doing things” and “feeling down, depressed, or hopeless” (p<0.05). Frequency and severity of all other manifestations of depression on the PHQ-9 questionnaire were lower in the group meeting treatment goals although did not meet statistical significance. Conclusions: Manifestations of depression are less frequent and severe when targeted PAH therapy regimens are effective in achieving treatment goals. Monitoring symptoms of depression in patients undergoing treatment for PAH will identify those that may benefit from adjunctive treatment for depression.

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Quality of Life and Needs for Support in Japanese Patients With Pulmonary Hypertension

Sato N1, Takemura N1, Murakami N2, Fukushima H1 1 Keio University School of Medicine, Tokyo, Japan 2 Pulmonary Hypertension Association Japan, Tokyo, Japan

Background: Treatment of pulmonary hypertension (PH) has developed and prognosis of patients with PH has improved. In addition, the quality of life (QOL) of patients with PH is estimated to be better. However, the QOL and the needs for support have not been evaluated sufficiently in Japanese patients with PH. Methods: To evaluate the QOL and needs for support of Japanese patients with PH, we planned a questionnaire survey targeted the members of Pulmonary Hypertension Association Japan over 16 years of age. The questionnaires consisted of the patients’ profiles, the 36-item Short Forum (SF-36v2) QOL questionnaire and our original questionnaire about the needs for support. Results: Eighty-nine patients (17 males and 72 females, response rate: 54.8%) filled out the questionnaires. Out of 89 patients, 51 patients were pulmonary arterial hypertension, 27 patients were chronic thromboembolic PH and 11 patients were PH with combined or unknown origins.

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Implementing a Transcultural Nursing Care Model to Improve Pulmonary Hypertension Medication Compliance Salinero M, Hyman T, Matos M, Pallares M, Bouza E, Valdes J, Bello A, Sandoval E, Reyes C South Miami Hospital Miami, FL, USA

The SF-36v2 questionnaire revealed physical component summary score (34.7+/-13.2, mean+/-SD) and role-social component summary score (34.7+/-13.2) of PH patients were significantly lower compared to Japanese standard values (50). On the other hand, mental component summary score (50.9+/-9.9) of the patients was equal to Japanese standard values (50). The questionnaire according to the needs for support clarified the level of satisfaction about familial support was high. In contrary, the level of satisfaction about social support, understanding of colleagues about patients’ life with PH and the information provision about PH were low. Conclusions: We demonstrated that role-social component of QOL is still compromised in Japanese patients with PH. It is hoped that the enhancement of social support including the awareness of PH is made to improve rolesocial component of QOL in addition to the physical and mental components.

Purpose: The goal of the performance improvement (PI) project was to decrease discontinuation rates of riociguat therapy by using a transcultural nursing model as opposed to a single nurse coordinator model. Background: Pulmonary hypertension (PH) medications have been proven to be effective in improving outcomes for patients suffering from PH. These medications have significant and expected side effects with complex titration regimens which can be confusing to patients which led to poor compliance and high rates of discontinuation. Patients’ race and ethnicity have been associated with poor medication compliance due to varying cultural expectations, language barriers, and socioeconomic status. Evidence also shows that minority groups are less likely to take medications for PH demonstrating the need to eliminate this disparity. Methods: A PI project was initiated to address high discontinuation rates in PH medications, specifically riociguat therapy. It was proposed that due to our highly culturally diverse patient population that we incorporate a transcultural nursing model to improve compliance and drug therapy continuation. The nursing model that was being used prior to the PI project was a single nurse

coordinator model. In this model, the PH coordinator was responsible for educating patients on the therapies as well as assessing patients during their initial and follow up visits. The coordinator was primarily an English-speaking nurse that would use interpretation services during PH appointments in the outpatient clinic. Beginning in November of 2016, the clinic implemented the transcultural nursing model where nursing assignments paired according to patients’ language and cultural background in order to facilitate transcultural communication. Results: After implementing the transcultural nursing model, the continuation rate for riociguat went from 55% to 79%. The model was very effective in improving patient compliance and drastically reducing the discontinuation rate of riociguat. The patients were able to converse with their nurse coordinating their care without the need for translation services which greatly improved the understanding of the plan of care. Conclusions: The implementation of a transcultural nursing model is an effective way of increasing the continuation rates of PH medications in a culturally diverse practice setting helping to reduce disparities.

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A Prospective Study to Describe Clinical and Tolerability Outcomes in Patients Transitioning From Bosentan or Ambrisentan to Macitentan McConnell JW, Robinson K, Royse M Kentuckiana Pulmonary Associates, Louisville KY, USA

Purpose: Describe clinical and tolerability outcomes associated with switching patients from bosentan or ambrisentan to macitentan, utilizing functional class, 6 minute walk distance (6 MWD) and quality of life. Background: Pulmonary Arterial Hypertension (PAH) is a rare, progressive disorder characterized by remodeling of the pulmonary vasculature and a rise in right ventricular (RV) afterload, which in turn leads to RV enlargement, RV dysfunction and clinical symptoms (Barst 2004). There is no cure at present for PAH with nine agents currently approved by the FDA in the US for treatment. Macitentan is the most recently approved endothelin receptor antagonist (ERA) indicated to delay disease progression. It was shown to reduce hospitalizations and reduce morbidity and mortality. It is a once daily oral medication and does not require regular monitoring for toxicity, unlike other ERAs. Switching from bosentan to macitentan has previously been evaluated in a retrospective study (Safdar 2017). Methods: In a prospective study, 21 patients were enrolled at a Pulmonary Hypertension Association accredited Center of Comprehensive Care and transitioned from background ERA of ambrisentan or bosentan to macitentan 10 mg and followed for one year. Safety labs, echocardiogram, 6MWD, functional class, Quality of Life utilizing SF-36 and Endothelin levels were measured during evaluation. Results: Mean +/-SD age at the start of the trial was 66.9 +/- 10.49. Eighty-six percent of participants were female and 14 % were male. Nineteen percent of patients were on ambrisentan and 81 % on bosentan for background ERA therapy. Patients were all WHO group I, 67% idiopathic,

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33% connective tissue disease. The mean time since diagnosis was 7 years +/- 3.78. Mean time on background ERA was 6.7 years +/- 3. At the beginning of the trial, 38% of patients were functional class II and 62% were functional class III. Eighteen (86%) patients completed the 12-month study. There were no drug related SAE’s. Thirty-three percent of patients did have a non-drug related SAE. Two patients had improved Functional Class from III to II and the rest of patients remained the same. Patients’ mean 6 MWD at baseline was 286.5 meters +/- 98.01. At one year, mean 6MWD was 275.5 meters +/- 110.60. The patients’ endothelin levels had no significant change over twelve months. Echocardiogram showed TAPSE had no significant change from baseline to week 24 and end of study. There was no statistically significant change in quality of life at end of study compared to baseline. Conclusions: A rapid switch from bosentan and ambrisentan to macitentan was well tolerated in patients while functional class, 6 MWD, endothelin level and TAPSE remained stable. The patients’ quality of life was consistent from baseline to end of study. In a group of patients with a long term diagnosis of PAH, there was no significant deterioration over a period of twelve months. References: Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004; 43 (12 Suppl S): 40S-7S. Safdar Z, Thakur A, Frost A. Tolerability of switch to macitentan from bosentan in pulmonary arterial hypertension. South Med J. 2017 Mar; 110 (3):223-228.

Evaluation of Pharmacist Discharge Counseling Process in Pulmonary Hypertension Patients Humphrey J, Miller A, Rechtien K, Hard M, Williamson T The University of Kansas Health System, Kansas City, KS, USA

Purpose: The purpose of this abstract is to evaluate the 30-day readmission rates after an institution-specific pharmacist discharge counseling process was implemented for patients with pulmonary arterial hypertension. Background: Patients with pulmonary arterial hypertension (PAH) frequently encounter episodes of disease exacerbation characterized by fluid overload and right heart failure resulting in hospitalization. Diuretics are a mainstay in treatment with the goal of decreasing total body volume in order to decrease stress on the heart to increase cardiac output and cardiac index. These patients present an opportunity to incorporate pharmacists into the discharge process by counseling on diuretics, fluid restriction, and diet compliance. Similar education has been associated with decreasing left-sided heart failure admissions therefore, it can be presumed to decrease admissions in the PAH population. Methods: The original study in 2015 found the most common reason for hospital admission was PAH exacerbations secondary to fluid overload in patients on prostacyclin therapy. Implementation of a standardized discharge process was a key phase of the previous study which included a patient specific diuretic handout and electronic communication with the outpatient PH nurses. Phase 3 of the original study assessed the effect of the discharge process by evaluating 30 day readmission rates

and the reason for readmission with the intended outcome of decreased admissions. Although no difference in 30-day readmissions was found at that time, positive outcomes with outpatient PH clinic nurses was noted via survey. Since that study, the pharmacists’ education and workflow has been continued for patients on any PAH therapy and diuretics. As a follow-up, this specific abstract is assessing compliance of the pharmacist education process and how it may affect 30-day readmission rates from May 1, 2015 to September 30, 2017, after the completion of the previous study. Results: There were 11 patients that met criteria for inclusion with volume overload, once again, being the most common reason for re-admission (45.5%). Of the patients readmitted within 30 days for fluid overload, 80% were counseled by a pharmacist and 60% of the counseling notes were forwarded to the outpatient PH nurse. Conclusions: Possible reasons why patients were not counseled by a pharmacist include patients being discharged from the intensive care unit, patients on a care team without a PH-specialized pharmacist, and PH pharmacist(s) unaware of admission if not on prostacyclin therapy. The low number of total 30-day readmissions over a 2.5 year period (n=11) may indicate, among other processes and standards of patient care, that pharmacist counseling benefits this patient population.

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Novel Analysis of Treprostinil Dose-Response Relationship Using Weight-Normalized Dosing Ramani G1, Shen E2, Broderick M2, Wasik A1, Rao Y2 1 University of Maryland, Baltimore Maryland, USA 2 United Therapeutics Corporation, Research Triangle Park, NC, USA

Background: Treprostinil is a prostacyclin analogue available in intravenous, subcutaneous (SC), inhaled, and oral administration routes for pulmonary arterial hypertension (PAH). Doses are titrated based on tolerability and clinical response. Because doses are individualized, conventional dose-response studies using randomized drug exposure are difficult to employ. In this novel analysis, we report outcomes with weight-normalized doses to SC and oral treprostinil. Methods: Data from patients receiving treatment in the pivotal SC treprostinil study were combined with the FREEDOM-M study of oral treprostinil. To facilitate pooling of dosing data, oral doses were converted to weight-based, continuous doses (ng/kg/min), accounting for patient weight and bioavailability. Patients were grouped into dose tertiles, based on doses achieved at week 12 in the clinical studies. Last observation carried forward (LOCF) was used to impute last observations of 6MWD, Borg dyspnea score (BDS), World Health Organization (WHO) functional class (FC), and dose. One-way analysis of variance (ANOVA) and Jonckheere-Terpstra tests were used to assess differences and linear trends in 6MWD, WHO FC, and Borg dyspnea score. Results: 466 patients were included in this analysis (SC, N=233; oral, N=233). The mean SC and oral treprostinil

dose at week 12 was 9.3 ng/kg/min and 13.8 ng/kg/min, respectively. There were differences in baseline characteristics (age, weight, PAH duration) between dose tertiles. Median doses in the low (N=151), medium (N=159), and high dose (N=156) tertiles were 3.7, 9.1, and 18.5 ng/ kg/min respectively and median 6MWD improvements were 13, 22, and 30 meters, respectively. There was a statistically significant difference in 6MWD improvement between low/high groups (p=0.013) and a statistically significant linear trend for 6MWD improvement with higher doses (p=0.0052). Significant differences in Borg dyspnea score was observed between the low/medium groups (p=0.007) and low/high groups (p<0.001) with median improvements of 0.0, 1.0, and 1.0 in the low, medium, and high groups, respectively. WHO FC improvement were not significantly different between dose groups. Conclusions: This combined analysis of SC and oral treprostinil provides evidence for the dose-response relationship of treprostinil. Increased treprostinil dose is associated with improvements in 6MWD and Borg dyspnea score. Although these improvements are relatively modest, treprostinil doses used in both studies are low compared to those routinely used in clinical practice. Results from this novel post-hoc analysis suggest that systemically administered treprostinil, in oral or SC formulations, produces statistically significant, dose-dependent therapeutic responses.

Pulsed Inhaled Nitric Oxide (iNO) Improves Exercise Tolerance in Severe Chronic Obstructive Pulmonary Disease (COPD) Patients With Pulmonary Hypertension (PH)

Haijan B1, Shivalkar B1, Ferreir F2, Van Holsbeke C2, Vos W2, De Backer J2, Sartoris K3, Warren DQ3, Hulkens A1, Parizel PM1, Cluckers J1, De Backer W1 1 Antwerp University Hospital, Antwerp, Belgium 2 FLUIDDA nv, Kontich, Belgium 3 Bellerophon Therapeutics, Warren, NJ, USA Purpose: A phase 2b iNO chronic treatment study was designed to investigate the clinical relevance of previously seen acute vasodilation with respect to changes in exercise tolerance and hemodynamics. Background: In the previous Functional Respiratory Imaging (FRI) trial (Int J Chron Obstruct Pulmon Dis. 2016;11:1533-1541), pulsed inhaled nitric oxide (iNO) was shown to cause an acute vasodilating effect in 6 severe WHO Group 3 PH associated with COPD patients on longterm oxygen treatment (LTOT). In a follow up telephone call patients also reported improvement in their symptoms up to 24 hours after a one-time 20-minute treatment with pulsed iNO. Methods: This study recruited 10 PH-COPD patients on long-term oxygen therapy (LTOT). Pulsed iNO was provided by the INOpulse® delivery system. For all patients, acute vasodilation under pulsed iNO, was assessed by FRI before starting a 4-week treatment with iNO (>12h/day). Exercise tolerance and hemodynamics were measured at baseline and after 4 weeks treatment with iNO (n=7).

Results: All 10 patients experienced acute increases in blood vessel volumes following iNO treatment (+4.2%, p=0.03). There was a significant association (p<0.01) between ventilation and vasodilation during iNO therapy, suggesting that regions with better ventilation experience more vasodilation. The patients who completed 4 weeks of iNO therapy experienced reductions in pulmonary arterial pressure (-19.9%, p=0.02) and had on average a 50.4±54.4 meter increase in 6MWD (p=0.04). The therapy was well tolerated with no safety concerns. Conclusions: FRI analyses demonstrated regional dilatation of blood vessels in the lungs following acute pulsed iNO treatment. Vasodilation occurs in well-ventilated areas as supported by the correlation with lobar ventilation. There were significant reductions in pulmonary artery pressures and improvements in 6MWD with four weeks of treatment with iNO. Chronic iNO therapy has the potential to significantly increase exercise tolerance in COPD patients with PH. There were no safety concerns.

Change in Exercise Capacity by Treprostinil Dose

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Figure 1: Regional vasodynamics in a patient (right) and the changes in 6MWD after 2 and 4 weeks of treatment in all patients (left)

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

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Submaximal Exercise Testing (SET) in Idiopathic Pulmonary Arterial Hypertension (IPAH) Menon DP, Ray JC, Burger CD Mayo Clinic, Jacksonville, FL, USA

Background: Despite multiple advancements in IPAH pharmacotherapy, mortality at the one year mark remains high at 15%. Assessment of disease progression and response to therapy remains an area of concern - 6-minute walk distances (6MWD) have limited sensitivity / specificity while cardiopulmonary exercise tests (CPETs) conversely, are too complex and expensive for routine follow up. Submaximal exercise testing (SET) potentially provides a compromise with simplistic, non-invasive testing but enhanced physiological data to assess the severity of the PAH. Particularly, SET provides end-tidal exhaled carbon dioxide (CO2) levels (PETCO2) that has been demonstrated to decrease with worsening disease. It also measures breathing efficiency [minute ventilation to exhaled CO2 (VE/ VCO2) ratio] that increases with disease progression. Both parameters have demonstrated correlations with right heart catheterization (RHC) metrics and prognostic risk scores in IPAH patients. We aim to address gaps in knowledge regarding SET parameter patterns with varying medication regimens in this cohort, particularly in the face of changing treatment paradigms favoring upfront combination therapy. Methods: We conducted a retrospective study utilizing longitudinal data from approximately 80 IPAH patients followed at PH clinic at Mayo Clinic, Florida from 20002017. Exclusion criteria included recurrent PH post-transplant and NYHA-IV patients in right heart failure. An online database including demographics, vitals and BMI, diagnoses, group of PH, New York Heart Association or WHO Functional Class (FC), 6MWD, Brain Natriuretic Peptide (BNP), current medication regimen, echocardiographic and RHC data (if obtained peri-SET date) and SET data (VE/VCO2, PETCO2) was utilized. Statistical analysis included use of Wilcoxon-Mann-Whitney / Kruskal-Wallis Tests for analysis of non-parametric data and correlation analyses. SET device Shape-HF™ (Shape Medical Systems, Inc.) was used for the study and the protocol involved continuous evaluation of vitals while obtaining data on breathing efficiency (VE/VCO2 slope) and PETCO2. Standard SET testing (6 minutes total – 2 minutes of rest followed by 3 minutes step exercise and a minute of rest) was performed. Goal respiratory exchange ratio (RER) of <0.9 was considered the primary indicator of submaximal testing.

Results: • In WHO functional class 1 and 2 patients (Figure 1), overall, there was no significant difference in ventilatory assessments between patients on monotherapy (Endothelin Receptor Antagonists - ERA, Phosphodiesterase -5 inhibitors - PDE5I, Prostacyclins - PCs) or dual therapy (combinations of ERA, PDE5I or PCs) independent of FC. Nonetheless, a comparison of monotherapy with ERAs against ERA + PDE5I combination in FC I-II revealed higher PETCO2s and lower breathing efficiency ratios in the combination cohort for FC II, with a trend for difference in PETCO2 for FC I patients. This suggests that combination therapy may result in reduced physiologic dead space fractions. • We additionally evaluated changes in SET metrics immediately after addition of a medication class to treatment regimen and its correlations with standard lab/echocardiographic parameters, Functional class and 6MWD. Correlations of these with SET changes at the final SHAPE testing data point while on that regimen before a further medication up-titration was made, was also evaluated. Different patterns of statistically significant correlations were noted in both cases as detailed in Table 1. • Of note, 6MWD showed no correlation with both PETCO2 and Ve/VCO2 early after an up-titration, but showed statistically significant correlations at later time points with consistent therapy on each regimen. This strongly suggests that 6MWD could lag as an indicator of clinical response to therapy when compared with SET. Conclusions: Overall, SET presents a non-invasive, low risk testing method for serial longitudinal follow up of IPAH patients. Multiple studies have demonstrated SETs utility in IPAH severity stratification and prognostication given its correlation with established disease severity scores. We present novel data evaluating its ability in assessing response to therapy via pulmonary vascular perfusion and dead space fractions in IPAH. Our preliminary results suggest that SET may have increased sensitivity in identifying subclinical disease progression compared to the more conventional assessments including 6MWD. In addition, within cohorts that have achieved a “favorable” functional class (WHO I-II), SET may have in role in identifying suboptimal responders, especially with patients on monotherapy, with potential applicability in tailoring individualized clinical decision making.

Figure 1: SET parameters in patients in Functional class I, II

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2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

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Early and late changes in SET metrics after addition of a medication class and its correlation with markers of disease severity

Hemodynamic Effects of the Oral Prostacyclin (IP) Receptor Agonist Ralinepag in Pulmonary Arterial Hypertension (PAH) Torres F1, Farber H2, Ristic AD3, McLaughlin V4, Adams J5, Turner S5, Klassen P5, Escribano-Subias P6, Sood N7, Keogh AM8, Rubin L9 1 Southwestern Medical Center, Dallas, TX, USA 2 Boston University School of Medicine, Boston, MA, USA 3 Belgrade University School of Medicine, Department of Cardiology of the Clinical Center of Serbia, Belgrade, Serbia 4 University of Michigan, Ann Arbor, MI, USA 5 Arena Pharmaceuticals, San Diego, CA, USA 6 Departamento de Cardiologia, Hospital 12 de Octubre, Madrid, Spain 7 University of Texas Health Science Center of Houston, Houston, TX, USA 8 Department of Cardiology, St Vincent’s Hospital, Sydney, Australia 9 University of California, San Diego School of Medicine, La Jolla, CA, USA

Purpose: To evaluate the efficacy, safety, and tolerability of ralinepag in a multinational double-blind Phase 2 study. Background: Ralinepag is a novel, next-generation, oral, highly selective IP receptor agonist with optimized receptor activation and a half-life of ~24 hours. Ralinepag has antiproliferative and vasodilatory activities on pulmonary smooth muscle cells and pulmonary arteries. Methods: Adults with stable functional class (FC) II–IV PAH and 6-minute walk distance (6MWD) of 100–500 m, on single or dual background PAH treatment, were randomized 2:1 to receive ralinepag (n=40) or placebo (n=21) for 9 weeks of titration, then 13-week maintenance. Treatment was initiated at 10 µg twice daily (bid) and titrated weekly up to 300 µg bid, as tolerated. Right heart catheterization was performed at baseline (BL) and at 22 weeks. The primary efficacy endpoint was change in pulmonary vascular resistance (PVR) from BL to Week 22. Additional analyses included changes in 6MWD, hemodynamics, safety and tolerability.

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Results: Patients were FC II/III/IV (56%/43%/2%) with mean 6MWD of 378±104 m (SD). BL median PVR was 705 (ralinepag) and 480 (placebo) dyn·s·cm–5. 35% of ralinepag patients and 52% of placebo patients were receiving background monotherapy; 65% and 48%, respectively, were receiving dual therapy. Ralinepag reduced median PVR by 163.9 dyn·s·cm–5 from BL, compared with a 0.7 dyn·s·cm-5 increase on placebo (P=0.02). Patients receiving ralinepag had a 29.8% reduction in PVR compared with placebo (P=0.03), and a 20.1% reduction from BL. 6MWD increased by 36.2 m in the ralinepag group, which was not significantly different from placebo. There were two deaths, both in the placebo group. Serious adverse events (AEs) occurred in 10% of patients on ralinepag and 29% of those on placebo. The most common treatment-emergent AEs were as expected for IP receptor agonists. Conclusions: Ralinepag significantly reduced PVR compared with placebo in patients with FC II–IV Group 1 PAH on single or dual background therapy.

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Phase 1 Study Results of LIQ861, an Inhaled Dry Powder Formulation of Treprostinil Roscigno R1, Vaughn T1, Wargin WW2, Williams RL 2, Forsythe C3, Hunt T3 1 Liquidia Technologies, Morrisville, NC, USA 2 Nuventra, Inc., Durham, NC, USA 3 PPD Development, Austin TX, USA Purpose: Treprostinil (Tre) is a synthetic analog of prostacyclin approved for inhalation administration to patients with pulmonary arterial hypertension (PAH) via nebulized Tyvaso® Inhalation Solution (Tre Solution) administered four times daily. The time required for nebulizer preparation, administration and cleaning is a burden to patients. Liquidia is developing LIQ861, a convenient, inhaled dry powder formulation of Tre that offers a simple, portable alternative treatment regimen. Background: LIQ861 is specifically designed to improve the therapeutic profile of Tre by enhancing deep lung delivery and achieving higher dose levels than current inhaled therapies. Using our proprietary PRINT® technology, LIQ861 particles are a precise, uniform size (1 µm) and trefoil pollen-like shape. Liquidia conducted a Phase 1 randomized, double-blind, placebo-controlled, single ascending dose study in 57 healthy adult subjects who received 25 mcg to 150 mcg in two inhalations per capsule using an approved “off-the-shelf” dry powder inhaler (DPI) device (RS00 Model 8, Plastiape SpA, Lecco, Italy). The study’s primary objectives were to characterize Tre PK, evaluate the safety and tolerability of inhaled LIQ861 and assess the performance of the DPI. Methods: Successive gender-balanced cohorts of 8 healthy volunteers were randomly assigned to active (n=6) or placebo (n=2). Dosing was initiated in the first cohort at

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a dose level of 25 mcg treprostinil. Additional cohorts of 8 subjects were enrolled to investigate escalating single doses of LIQ861 at 50, 75, 100, 125, and 150 mcg Tre. PK samples and safety assessments were performed pre- and post-dose administration. A Safety Review Committee was consulted after each cohort to review safety findings and interim PK results. Tre PK parameters and dose proportionality were characterized. Results: LIQ861 was generally well-tolerated at all dose levels in the study. No dose limiting toxicity was observed and no SAEs were reported. No notable or significant findings were reported with vital signs, physical examinations and laboratory evaluations. The median Tre Tmax was between 10 and 20 min post-dose and both Cmax and AUCinf tended to dose proportionality. Conclusions: LIQ861 was well-tolerated at Tre doses up to 150 mcg with no SAEs and only mild AEs. Tre exposure (Cmax& AUCinf) from LIQ861 was dose proportional from 25 to 150 mcg. At higher doses, 50% of subjects had measurable Tre at 4 hrs. No dose limiting toxicity was observed and the maximum tolerated dose (MTD) was not reached. Currently, a Phase 3 study titled “Investigation of the Safety and Pharmacology of Dry Powder Inhalation of Treprostinil (INSPIRE)” evaluating LIQ861 in patients with PAH is in progress (NCT03399604).

Rationale and Design of TRACE: A Double-Blind, Placebo-Controlled Phase 4 Study in Pulmonary Arterial Hypertension to Assess the Effect of Selexipag on Physical Activity, Patient-Reported Symptoms and Their Impact, in Daily Life Preston IR1, Frantz R2, Hemnes A3, Rosenkranz S4, Skaara H5, Pfister T6, Humbert M7, Howard L8 Tufts Medical Center, Boston, MA, USA 2 Mayo Clinic, Rochester, MN, USA 3 Vanderbilt University, Nashville, TN, USA 4 University of Cologne, Köln, Germany 5 Pulmonary Hypertension Association (PHA) Europe, Vienna, Austria 6 Actelion Pharmaceuticals Ltd, Allschwil, Switzerland 7 Université Paris-Sud, Le Kremlin-Bicêtre, France 8 Hammersmith Hospital, London, UK

Background: Impaired daily life physical activity (DLPA) is associated with poor quality of life and adverse cardiovascular outcomes. Recent studies have shown that DLPA is reduced in patients with pulmonary arterial hypertension (PAH) and associated with worse outcomes, indicating the importance of monitoring DLPA in PAH. In addition, patient-reported outcomes (PROs) are increasingly recognized tools of quality of life assessment. Selexipag is an oral IP prostacyclin receptor agonist, indicated for the treatment of PAH to delay disease progression and reduce the risk of hospitalization. The objective of TRACE is to evaluate the effect of selexipag on DLPA and on patientreported disease symptoms in PAH. This exploratory study will help to better understand the validity and usefulness of patient-centric elements as novel endpoints in future clinical trials in PAH. Methods: This ongoing multi-center, double-blind, randomized, exploratory Phase 4 study randomizes (1:1) 100 patients to receive selexipag or placebo for 24 weeks. Eligible PAH patients are 18–75 years, in World Health Organization functional class (WHO FC) II or III, with a 6-minute walk distance (6MWD) ≥100 m, and on stable treatment with an endothelin receptor antagonist alone or in combination with a phosphodiesterase-5 inhibitor or soluble guanylate cyclase stimulator. DLPA is measured by the wrist-worn accelerometer ActiGraph GT9X Link, day and night during a 14 day baseline period and throughout

the 24-week treatment period (Figure). Daily data upload on a provided smartphone allows wear-time monitoring. Patients remain blinded to their activity levels and sleep parameters until the end of study. PAH symptoms and their impact are assessed by completing the PAH-SYMPACT® questionnaire on the smartphone. The PAH-SYMPACT® questionnaire is the first PAH-specific PRO instrument developed and validated according to the FDA guidance. PAH-SYMPACT® is completed during three 7-day periods during the baseline period, and at weeks 15 and 23. Results: The primary endpoint is change from baseline to week 24 in actigraphy-assessed DLPA, as measured by: daily time spent in non-sedentary activity, total DLPA per day, total sleep time, wake time after sleep onset, number of awakenings and sleep efficiency. Secondary endpoints include change in score from baseline in cardiovascular symptoms, cardiopulmonary symptoms, physical impact and cognitive/emotional impact domains of PAH-SYMPACT®, change in WHO FC, 6MWD, Borg dyspnea index and NT-proBNP. Safety and tolerability of selexipag are monitored. Conclusions: TRACE is the first international, multi-center, randomized PAH study designed to utilize actigraphy combined with PRO to assess response to treatment.

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RESEARCH ABSTRACTS & CASE STUDIES 1059

Study design

Results of the Prospective, Multicenter, Single-Arm, Open-Label, Phase 4 MOTION Study of Riociguat in Pulmonary Arterial Hypertension Sood N1, Aranda A 2, Platt D3, Kleinjung F4, O’Brien G3 1 The Ohio State University, Columbus, OH, USA 2 Cardiovascular Center of Puerto Rico and the Caribbean, San Juan, PR, USA 3 Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ, USA 4 Bayer AG, Berlin, Germany

Background: Pulmonary arterial hypertension (PAH) is a progressive disease with debilitating impact on exercise capacity and health-related quality of life (HRQoL). Treatment studies typically aim to improve functional capacity—as measured by treatment-related change in 6-minute walk distance (6MWD)—and to prevent progression of disease. Few trials have evaluated treatment-related change in patient-reported outcomes (PROs) such as HRQoL. The MOTION study (NCT02191137) is designed to explore PROs in patients with PAH who are treated with riociguat. Methods: MOTION is a prospective, multicenter, singlearm, open-label, phase 4, 24-week trial designed to assess whether riociguat monotherapy will improve PROs among newly diagnosed PAH patients not on therapy. Patients received riociguat over a 10-week titration phase, from a starting dosage of 0.5 mg 3 times daily (TID) increased every 2 weeks in 0.5-mg increments, until individual optimal dosage (up to a maximum of 2.5 mg TID) was reached. Patients remained on therapy during a 14-week maintenance phase. The primary endpoint is the reported change from baseline (BL) in the Living with Pulmonary Hypertension (LPH) questionnaire after 24 weeks of treatment. LPH scores range from 0–105; higher scores indicate worse HRQoL. Secondary variables include change from BL to Week 16 in the LPH, as well as change

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from BL to Weeks 16 and 24 in the Work Limitation Questionnaire-8, the Short Form-12, World Health Organization Functional Class, Modified Borg Dyspnea Scale, and 6MWD.1 Results: All data are reported as mean ± standard deviation (SD). There were 97 patients screened; 75 patients were enrolled, and 10 patients did not complete the trial due to death (n=4), adverse event (n=2), patient withdrawal (n=3), and other reasons (n=1). Of the 65 patients who completed the trial, Week 24 LPH data were available for 58 patients. The study population was predominantly female (88%, n=66) and white non-Hispanic/ Latino (79%, n=59), with mean age of 62 (±11) years. PAH was categorized as idiopathic (65%, n=49), connective tissue disease–associated (28%, n=21), portal hypertension (3%, n=2), anorexigen/amphetamine-associated PAH (1%, n=1), and familial (1%, n=1). LPH score improved from baseline to last visit by −5.4 (±27.8) in the intent-to-treat analysis (n=75, P=0.048), and from baseline to Week 24 by −10.8 (±21.9) in the completers analysis (n=58, P=0.0002). Conclusions: These data suggest that riociguat monotherapy may significantly improve HRQoL, as measured by improvements in the LPH score among newly diagnosed patients with PAH.

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Transitioning Prostanoid Therapy in Pulmonary Arterial Hypertension: Aggregate Cohort Data From One Specialty Pharmacy D'Albini L, Porco L, Hahn J Accredo Health Group, Inc., Pittsburg, PA, USA

Background: Prostacyclin therapy has been considered first line for patients with WHO functional class IV pulmonary arterial hypertension (PAH) since the original intravenous epoprostenol formulation was approved by the FDA in 1995. Since then, another twelve novel medications indicated for the treatment of PAH have received regulatory approval, six of which fall into the prostanoid category. Secondary to narrow therapeutic indices and delicate pharmacokinetics, transitions involving prostanoid therapies must be attempted with caution. Particularly problematic are transitions in which both the index drug (from which the patient is weaning) and the target drug (to which the patient is moving) fall into the prostanoid category – epoprostenol (two brands), iloprost, selexipag, or treprostinil (three brands). Methods: A retrospective cohort analysis of patients transitioning from one prostanoid therapy to another between 01/01/2016 and 12/31/2017 was conducted using the specialty pharmacy electronic medical record. Records were included in the analysis if the primary diagnosis of record was PAH, the patient age fell between 18 and 89 years, and a complete transition detail assessment was performed by a pharmacist. Data collected for each transition included the following: time on the index drug prior to the transition, dose and patient reported side effects of the index drug at the time of transition, and patient reported symptoms of PAH with prescriber adjudicated functional class at the time of transition. Additionally, the presence or

absence of background therapy with endothelin receptor antagonists (ETRAs), phosphodiesterase type-5 inhibitors (PDE-5), or a soluble guanylate cyclase stimulator (sGC) either alone or in combination was collected. The time to transition, site of transition and primary reason for the transition were available for a subset of the sample. Results: 1397 prostanoid transitions occurred across 1253 unique patients (144 patients transitioned more than once during the study period). Globally, the majority of patients (985 of 1397; 71%) were on the index prostanoid greater than six months prior to transitioning to an alternate. Patients denied all side effects to the index prostanoid in 60% (839 of 1397) of the transitions. Over half (820 of 1397; 59%) of the patients reported symptoms of PAH at the start of their transition. Thirteen percent of patients transitioned from one prostanoid to another without the benefit of PAH specific background therapy (ETRA/PDE-5/sGC). Prostanoid transition by route of administration is detailed in Figure 1. Statistics around site of, time to, and primary reason for the prostanoid transition varied greatly by route of administration of both the index and target drugs. Conclusions: There is great variability among prostanoid transitions with respect to route of administration of both the index and target drugs. The majority of patients who transitioned reported symptoms of PAH but denied side effects of the index prostanoid at the time of transition. Figure 1: Transition Type

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RESEARCH ABSTRACTS & CASE STUDIES 1061 Figure 1 Use of an Obese Population in Phase I to Evaluate the Pharmacology of Oral CXA-10, a Nitro-Fatty Acid Cell Signaling Agent, as a Disease-Modifying Therapy in Pulmonary Arterial Hypertension

MCP-1 Changes from Baseline Day 7 and Day 14 by Treatment (A) in the 150 mg Treatment Group Compared to Placebo (B)

A MCP-1 Changes from Baseline by Treatment

B MCP-1 Changes from Baseline 150 mg Treatment Group Compared to Placebo

Tarka E1, Chieffo C1, Botbyl J2, Perry KT3, Blok TM3, Jorkasky DK1 1 Complexa Inc, Berwyn PA, USA 2 Provonix, Mullica Hill NJ, USA 3 Innovative Analytics, Kalamazoo MI, USA

Background: Excessive production of reactive oxygen species (ROS) that can lead to vascular damage may play a significant role in Pulmonary Arterial Hypertension (PAH). This damage induces excessive cellular inflammatory responses, with increased production of cytokines specifically monocyte chemoattractant protein (MCP-1) and interleukin-6 (IL-6), chemokines, adipokines and growth factors as well as an increase in WBC infiltration and activity, fibrosis and cell death. In the right ventricle (RV), there is a transition from an adaptive pressure overloaded RV to a maladaptive response. Causes may be due to insufficient RV contractility, myocardial fibrosis, capillary rarefaction and disturbed metabolism. Many of these pathways are the major targets for CXA-10 activity, and therefore, key to improving both the pulmonary vasculature and cardiac abnormalities of PAH. CXA-10 is an electrophilic nitro-fatty acid that modulates anti-oxidant, antiinflammatory and anti-fibrotic pathways through activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1), heat shock proteins (HSPs) and reduction in nuclear factor kappa B (NFκB), toll-like receptor 4 (TLR4) and xanthine oxidoreductase (XOR) activity.

doses of CXA-10. Cohorts of obese (Body Mass Index 27.0 to 39.5kg/m2) male subjects (n=10 to 12) received CXA-10 (25, 150 or 450mg) or placebo orally once daily for 14 days. Subjects were studied under confined controlled conditions, including diet, to minimize variability in biomarker evaluation and Body Mass Index (BMI).

Methods: We studied an obese population as a surrogate for diseases with impairment in metabolic and inflammatory pathways, like PAH, to evaluate the pharmacology of CXA10 and to identify a dose range prior to the initiation of Phase 2. The following key biomarkers, MCP-1, IL-6, leptin and lipids were measured prior to and following multiple

Conclusions: Utilizing an obese population enabled target validation of CXA-10 for key biomarkers such as MCP-1 and IL-6 that track with disease progression in PAH and establishment of a dose range for a Phase 2 study to investigate this potential disease-modifying therapy.

Results: Consistent decreases in serum MCP-1, IL6, leptin, cholesterol, and triglycerides were observed at 150 mg. These reductions were clinically meaningful (equivalent to a 30 lb. weight loss) for leptin and significantly different from placebo for MCP-1 and triglycerides. In the 150 mg dose group, LS mean difference from placebo in MCP-1 and triglyceride concentrations were -228.5 pg/mL (95% CI: -387.2, -69.77 pg/mL, Figure 1) and -59.60 mg/dL (95% CI: 102.3, 16.91 mg/dL, Figure 2) respectively at Day 14. The % reduction in leptin concentrations was 21.5% in the 150 mg dose group compared to an increase of 35% in the placebo dose group on Day 14. Oral CXA-10 was safe and generally tolerated. Dose-limiting tolerability of diarrhea and nausea was observed at the 450 mg dose which was reduced with food.

Figure 2

Figure 1: MCP-1 Changes from Baseline Day 7 and Day 14 by Treatment (A) in the 150 mg Treatment Group Compared to Placebo (B)

Mean Change from Baseline in Triglyceride Concentrations Over 28 Days (A) and on Day 15 (B) by Treatment

A. Mean Change from Baseline in Triglyceride Concentrations Over 28 Days by Treatment

B. Mean Change from Baseline in Triglyceride Concentrations on Day 15 by Treatment

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*Significantly different from Placebo (LS Mean Difference = -59.0 (95% CI: -102.3, -16.91)

Figure 2: Mean Change from Baseline in Triglyceride Concentrations Over 28 Days (A) and on Day 15 (B) by Treatment

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1063

A Case of HIV-Associated Pulmonary Arterial Hypertension in the Setting of Cardiomyopathy George MP1, Dillingham J2, Chanin J2, Shafton A 2 1 National Jewish Health, Denver CO, USA 2 Saint Joseph Hospital, Denver CO, USA

Purpose: To describe a case of concomitant HIVassociated pulmonary arterial hypertension (HIV-PAH) and HIV-associated cardiomyopathy in the setting of recent seroconversion. Background: There have been reports of HIV-associated cardiomyopathy in the literature that describe left heart failure in the setting of HIV seroconversion, and HIV-PAH has been well-described. However, to our knowledge this is the first report of concomitant HIV-PAH with left ventricular cardiomyopathy in the setting of recent seroconversion. Methods: Our patient is a 47-year-old previously healthy and active man who was doing well until he was diagnosed with “walking pneumonia” approximately 7 months prior to presentation. He recovered, but one month prior to presentation developed dry cough and progressive dyspnea on exertion, which progressed to the point of presyncope when clearing his car windshield, and later when walking to his car across the parking lot. He suffered increased fatigue and night sweats, and was taken to the emergency room by his friends. On presentation he was relatively well-appearing and not hypoxic. He had no edema, but did have significantly elevated jugular venous pulsations and an accentuated second pulmonic heart sound. On echocardiogram he had severe right ventricular dilation with a right ventricular systolic pressure (RVSP) at least 60 mmHg, moderate-to-severe right atrial dilation, and moderately reduced left ventricular (LV) function with global hypokinesis and an ejection fraction of 30%. His right heart catheterization revealed a mean right atrial

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pressure of 12 mmHg, mean pulmonary artery pressure of 48 mmHg, and pulmonary artery occlusion pressure of 8 mmHg with a PA saturation of 50%. His cardiac index was 1.1 L/min/m2 and pulmonary vascular resistance 16.5 Wood Units. To better understand the relative contributions of LV cardiomyopathy and HIV-PAH to his disease, a cardiac MRI was performed and demonstrated biventricular failure with global LV hypokinesis, an LV ejection fraction 28% and right ventricular ejection fraction of 10%. He was also newly diagnosed with HIV-1 (viral load 33,000, CD4 543), with his last HIV test negative 6 months prior to presentation. Given our findings, the diagnosis of concomitant HIV-PAH and HIV-cardiomyopathy in the setting of seroconversion was made. The patient was placed on lisinopril, spironolactone and tadalafil upfront, and was initiated on antiretroviral therapy. He was discharged home on a life vest. Results: After two weeks on therapy, he continued to have fatigue, but his dyspnea on exertion improved. His repeat echocardiogram at that time showed that his LV function normalized, and he now had only a borderline reduction RV function with persistent elevation of RVSP. With his improvement in cardiomyopathy, his life vest was discontinued, ambrisentan added, and the patient continues to improve under close monitoring on dual agent therapy. Conclusions: We describe successful treatment HIV-PAH with rapid sequential combination therapy in the setting of HIV-associated cardiomyopathy likely related to recent HIV-1 seroconversion.

A Review of High Risk OB Patients With PAH Savage L, Pinson J, Grinnan D, Lester C VCU Health, Richmond, VA, USA

Purpose: To describe a single center experience in the pregnant patient with pulmonary arterial hypertension. Background: Pulmonary hypertension (PH) remains a contraindication to pregnancy. However, with the increased number of proven treatment options, outcomes have improved. Despite these improvements in the pregnant patient, Kiely et al (2013) report maternal mortality between 12% and 33%. It is recognized that the right ventricle (RV) is the Achilles heel in PH. Due to progressive narrowing in the pulmonary arterial vasculature, RV afterload increases leading to right heart failure and even death. In pregnancy, the normal physiology changes significantly in relation to several factors. Oxygen consumption increases by 30% and blood volume can increase by 40-50% by 32-36 weeks' gestation (Weiss 2000 and Bonica 1995). These changes result in higher cardiac output. Accordingly, this strain on the RV can produce symptoms of failure, shortness of breath and edema. However, it has been shown that fluid shifts in the immediate post-partum period place the patient at the greatest risk of mortality and morbidity (Weiss 1998). In addition, it has been postulated that hormonal changes during pregnancy can be protective in their "vasodilatory" properties which is reduced immediately after delivery. Lastly, the "procoagulant effect may cause obstruction of the vasculature by thrombosis" (Keily 2013). This is thought to further compromise the narrowed vasculature in the pulmonary artery. Methods: Retrospective review of our center's pregnant patients between 2006-2017. The following variables were identified: WHO group, treatment, age, race, management during pregnancy and in the post-partum period, maternal outcomes, and number of pregnancies.

Results: This descriptive review from 2006-2017 reveals severity of disease, age at time of pregnancy, management strategies during and after pregnancy using a multi-disciplinary approach. The cohort consists of 8 women with 20 pregnancies among them. All of them were WHO Group 1:{2 - idiopathic, 3 - congenital heart disease, 2 - mixed connective disease, and 1 - CTEPH}. Demographics revealed: RACE - 2/8 Caucasians, 5/8 African American, 1/8 Asian. AGE range at the time of pregnancy: 19-33 years old. There was one maternal death postpartum (5%). All but one patient had multiple pregnancies. 50% of patients presented to an outside hospital during their pregnancy. 10/20 (50%) were managed at this center during their entire pregnancy. Conclusions: PH remains a contraindication to pregnancy. However, it has been documented in one center's experience, that with a multi-disciplinary approach, early treatment, vigilant monitoring during pregnancy and postpartum, successful outcomes can occur. PH patients who became pregnant tended to have multiple pregnancies. For those patients known to our practice prior to pregnancy, they were routinely monitored and repeatedly counseled regarding the risks of pregnancy. Patients with financial and social resources tended to weigh the risk of pregnancy making a more informed decision to become pregnant and follow-up with recommended monitoring. Further study is needed to determine if pregnancy is more likely among socially and financially disadvantaged PH patients.

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1064

Methamphetamine Associated Pulmonary Arterial Hypertension in Pregnancy Beutner M, Gill K, Balasubramanian V UCSF-Fresno Medical Education Program, Fresno, CA, USA

Purpose: Our case illustrates a patient who was diagnosed with severe Methamphetamine Associated PAH at the 27th week of gestation, who was successfully treated with parenteral prostacyclin therapy culminating in a successful outcome. Background: Despite advanced therapies, maternal mortality in women with WHO Group I Pulmonary Arterial Hypertension (PAH) remains high in pregnancy and is especially high during the post-partum period. Early termination of pregnancy is generally recommended. There is scant data pertaining to the phenotype of Methamphetamine Associated PAH (MAPAH) and its related pregnancy outcomes.

Results: 38-year-old woman G5P4 at 28 weeks and 5 days gestation with past medical history of chronic methamphetamine use presented to outside hospital complaining of worsening dyspnea on exertion. Dyspnea preceded the pregnancy by 1 year, but symptoms worsened significantly as her pregnancy progressed, with dramatic reduction in exercise tolerance. Patient was referred and admitted to our institution to allow for urgent evaluation for Pulmonary Hypertension. Echocardiogram showed severely dilated right ventricle, septal flattening, moderately dilated right atrium, and right ventricular systolic pressure 80 mmHg.

Right heart catheterization showed right atrial pressure 18 mmHg, pulmonary artery pressure 80/38 mmHg, mean pulmonary artery wedge pressure of 15 mmHg, cardiac output by Fick’s method of 6.3 L/min, cardiac index 3.15 L/ min/m2, and pulmonary vascular resistance of 5.87 woods units. Patient was admitted to the Intensive Care Unit and started on intravenous Treprostinil. After multidisciplinary family meeting with Pulmonology, High Risk OB/GYN, Neonatology, ECMO team, and Cardiac Anesthesiology it was decided that patient would be managed expectantly with plans for a scheduled caesarian section at 31 weeks gestation. The planned C-section was uncomplicated, and results in the delivery of a baby girl who required minimal neonatal intensive care monitoring. After delivery, patient was transitioned to subcutaneous Treprostinil. Mother and baby were discharged home 11 days after delivery. Patient’s functional status has been steadily improving since discharge from hospital. Now 7 months after her pregnancy, she is WHO functional Class II on Subcutaneous Treprostinil. Conclusions: Despite the detection of PAH late during her pregnancy, a methodical, systematic and multidisciplinary “teamwork” approach along with patient education resulted in a successful outcome in this young mother with MAPAH.

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Takayasu’s Arteritis in a Patient With Dasatinib-Induced PAH Samant M, McEvoy C Barnes Jewish Hospital/Washington University in St. Louis, MO, USA Background: Tyrosine kinase inhibitor therapy has revolutionized treatment for patients with chronic myeloid leukemia (CML), warranting the investigation of potential toxicities. Drug or toxin induced pulmonary hypertension (PH) manifests as pulmonary arterial hypertension (PAH), or WHO Group I disease. Dasatinib-induced PAH has been described previously, and is estimated to occur in < 1% of patients on chronic dasatinib treatment. After discontinuation of therapy, most patients show improvement in clinical and hemodynamic parameters, but some require therapy for PAH. Takayasu arteritis is an inflammatory disease involving the aorta and its branches, and has been associated with PH when there is disease involvement of pulmonary arteries. Here we report a case of a patient with history of CML and dasatinib-induced PAH who then developed Takayasu’s arteritis. Methods: Case: A 28-year-old female with history of CML presented to our institution for evaluation of possible PH. She was diagnosed with CML in 2011 and was initiated on dasatinib from 2011 to 2015. She had multiple bone marrow biopsies from 2012 onward showing remission. In January 2016, she developed dyspnea on exertion after minimal ambulation. She developed a dry cough, two-pillow orthopnea, and abdominal distension. She underwent right heart catheterization (RHC) significant for pulmonary arterial pressure (PAP) mean of 84 mmHg, pulmonary capillary wedge pressure of 16 mmHg, cardiac output of 2.5, and pulmonary vascular resistance (PVR) of 11.1 Woods units (WU). Her workup revealed negative V/Q scan, no evidence of lung disease, negative autoimmune workup, and negative left heart catheterization. Her dasatinib was held and she was transitioned to imatinib, after which she noticed an improvement in her dyspnea. She was initiated on dual upfront therapy with tadalafil and ambrisentan. She had repeat RHC 6 months after therapy that showed marked improvement: PAP of 32/13, mean of 22, PVR of 2.6 WU. She was continued on ambrisentan monotherapy. Four months later after going on a hiking trip in Utah, she noted new chest pain, fevers, and unintentional weight loss, which resolved and were followed by a dry cough. Blood pressure was 107/72 on left arm, 130/70 on right arm. Her

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echocardiogram on that visit showed normal ventricular size and function with a normal PAP. She had CT chest showing circumferential wall thickening around descending thoracic aorta and left subclavian artery and smooth luminal narrowing. There was no evidence of involvement of the pulmonary arteries. Infectious workup was negative, including HIV, RPR, coccidioides antibody, Histoplasma antigen. Autoimmune workup was also negative including IgG levels, ANA, ENA, ANCA, anti-Scl 70, CCP. Her ESR and CRP were elevated at 109 mm/hr and 49 mg/L, respectively. These findings were concerning for Takayasu’s vasculitis. She was initiated on prednisone 60 mg daily with rheumatology referral. She had rapid improvement in her symptoms on steroids. She had a follow up imaging showing marked improvement in soft tissue thickening around greater thoracic vessels, with a drop in her inflammatory markers. Conclusions: While there have been several reports of dasatinib-induced pulmonary hypertension, to our knowledge there have been no described cases of dasatinib- induced PAH followed by development of Takayasu’s arteritis. Takayasu’s can in itself cause pulmonary hypertension through vasculopathy, left heart disease, and chronic thromboembolic disease. While the rate of PA involvement of disease can reach up to 56%, the rate of development of true PH in Takayasu’s is only 12-13%. Our patient had no evidence of PA involvement at time of diagnosis and her PA pressures were normal by echocardiogram. There are no reports of Takayasu’s being caused by therapy for PH or for CML, indicating that our patient’s disease was idiopathic. Her vasculitis responded well to prednisone, and she maintains on ambrisentan and imatinib. Long-term follow-up of this patient will be essential, as any progression of her Takayasu’s could lead to worsening PH. She could then potentially require additional PH therapy as well as stenting of her pulmonary arteries. Additional research is required in determining whether there is a link between prior hematologic malignancy and developing inflammatory conditions such as Takayasu’s.

Treatment of Pulmonary Hypertension in the Setting of Interstitial Lung Disease With Intravenous Prostacyclin Therapy Duncan M, Krishnan S, Driscoll T, Blakley A Indiana University Health Pulmonary Hypertension Clinic, Indianapolis, IN, USA

Background: Pulmonary hypertension (PH) in the presence of interstitial lung disease (ILD) is associated with an increase in mortality.1-2 PH due to ILD is categorized as PH World Health Organization (WHO) Group 3. Currently, PH specific medications available on the market are approved by the Food and Drug Administration (FDA) only for PH WHO Group 1 and Group 4. Intravenous (IV) prostacyclin therapy has been successfully utilized before in the setting of ILD. Reported here is a case of a patient with PH WHO Group 3 due to ILD and profound treatment response to IV prostacyclin therapy. Results: 61 year old African American male with a history of pulmonary fibrosis was referred with worsening hypoxia for emergent lung transplant evaluation. Upon admission, the patient required Optiflow at 40 L per minute at 80% inspired oxygen to maintain oxygen saturations greater than 90% at rest. An echocardiogram (ECHO) showed severely reduced right ventricular ejection fraction, moderate pericardial effusion and estimated right ventricular systolic pressure (RVSP) of 100 mmHg. Consequently, a right heart catheterization (RHC) was performed which revealed a mean pulmonary artery (PA) pressure of 45 mmHg, cardiac index of 1.6, pulmonary capillary wedge pressure (PCWP) of 11 mmHg, and a pulmonary vascular resistance (PVR) of 11.9 Woods Units. Though the patient had chest

computed tomography (CT) findings consistent with moderate ILD, his PH appeared out of proportion to his lung disease. Therefore, treatment was initiated in an intensive care unit (ICU) setting with treprostinil IV, initiated at 2 ng/kg/min and slowly titrated to 14 ng/kg/min, and sildenafil 20 mg by mouth three times daily. Repeat ECHO, 4 weeks after initial, estimated right ventricle (RV) mean pressure to be 40 mmHg with resolution of the pericardial effusion. The patient was successfully discharged to home requiring no supplemental oxygen at rest or with activity. Conclusions: Pulmonary vasodilator therapy is only FDA approved for PH WHO Group 1 and Group 4. If therapy is used for PH WHO Group 3, IV therapy is usually avoided due to concern for worsening ventilation perfusion mismatch. In our case, we showed that there is a role for IV therapy in the treatment of PH WHO Group 3 in the setting of ILD. Both prostacyclin therapy with treprostinil IV, and phosphodiesterase-5 (PDE-5) enzyme inhibitor therapy with sildenafil, were utilized. This case demonstrates that intravenous pulmonary vasodilator therapy can safely and effectively be used in carefully selected patients with PH WHO Group 3 due to ILD. This case also emphasizes the importance of exploring all potential treatable etiologies of worsening hypoxia in a patient with advanced lung disease who presents for emergent lung transplant evaluation.

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RESEARCH ABSTRACTS & CASE STUDIES 1067

Echo

Advanced Pulmonary Vasodilator Therapy for an Infant With Atypical Presentation of Alveolar Capillary Dysplasia Parker C, Colglazier E, Fineman J UCSF, San Francisco, CA, USA

Purpose: To describe a case study with implications for advanced pulmonary vasodilator therapy in an atypical presentation of alveolar capillary dysplasia with misaligned veins. Background: Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is a rare developmental lung disorder (Janney et al., 1981). The pathological findings of ACDMPV are described as malposition of pulmonary veins adjacent to small pulmonary arteries, medial thickening of small pulmonary arteries, deficient lobular development, a paucity of alveolar wall capillaries, and occasional lymphangiectasis (Langston, 1991). Infants with ACDMPV are most often full term, and typically present within the first few hours to days life with hypoxemic respiratory failure and severe, refractory persistent pulmonary hypertension of the newborn (PPHN) that is unresponsive to pharmacologic agents and extracorporeal membrane oxygenation (ECMO) (Sen et al., 2004; Chelliah et al., 1995; Steinhorn et al., 1997). Other congenital anomalies involving the cardiac, gastrointestinal genitourinary and musculoskeletal systems are common (Sen et al., 2004; Bishop et al., 2011). Additionally, heterozygous mutations or genomic deletions of the FOXF1 gene have been reported in 80-90% of infants with ACDMPV (Reiter et al. 2016; Szafranski et al., 2016). In the last two decades late and atypical presentations of infants with ACDMPV have been described (Abdallah et al., 1993; Licht et al., 2004; Shankar et al., 2006; Ahmed et al., 2008; Kodama et al., 2012; Ito et al., 2015, Reiter et al., 2016). Results: This case study will describe a full term, onemonth old female infant with a history of omphalocele, repaired DOL 1, who presented with acute on chronic respiratory distress, hypoxia, and fever. An echo at that time demonstrated suprasystemic right ventricular pressures and a right-to-left atrial shunt. Persistent hypoxia led to intubation and treatment with inhaled nitric oxide (iNO), milrinone, and epinephrine. Initiation of iNO

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Date 1/5/2018 Vasodilator None Treatment

Echo Findings

increased systemic saturations from low 80’s to high 90’s. A lung biopsy demonstrating a confirmatory diagnosis of ACDMPV was well tolerated. Interestingly, the pathology was patchy, with areas of normal alveolar-capillary units. Her genetics were positive for a Phe85Leu mutation of the FOXF1 gene. Given her atypical presentation, patchy pathology, and sustained response to iNO, she was aggressively treated with advanced pulmonary vasodilator therapy (sildenafil and subcutaneous treprostinil). The goal of treatment was to enable discharge to home and undergo outpatient evaluation for lung transplant. Her response to advanced therapy has been dramatic. An echocardiogram obtained one month after initiation of therapy has estimated RV is ~50% systemic, saturations remain in the 90’s, and the infant is tolerating enteral feeds with good weight gain. Conclusions: Infants with ACDMPV presenting outside the neonatal period suggest there are phenotypical variations of the disease. More recent case reports have described infants with ACDMPV and FOXF1 gene mutations (Kodama et al. 2012; Ito et al. 2015; Reiter J et al. 2016) surviving outside the neonatal period. The longest living child with ACDMPV and FOXF1 gene mutation described in the literature was 38-months-old (Ito et al. 2015). Additionally, unlike in classic ACDMPV, histopathologic findings of this infant were not distributed uniformly and were not diffuse. More recently, infants with late and atypical presentations ACDMPV have undergone successful bilateral lung transplantations. Towe et al. (2018) presented a case series from St. Louis Children’s Hospital/Washington University in which 6 infants with atypical ACDMPV underwent bilateral lung transplantations between 4-20 months of age. Three transplanted children are alive at 5-16 years of age, similar to outcomes for infants transplanted for other indications. As demonstrated by this case study, advanced pulmonary vasodilator therapies may prolong time to transplant for infants with atypical presentation of ACDMPV.

2/5/2018 • Oxygen 1 LNC • Sildenafil 0.75 mg/kg every 6 hours • Subcutaneous Treprostanil 62 ng/kg/min

Suprasystemic right ventricular systolic pressures with TR jet of 108 mm Hg (cuff SBP 85 mm Hg) • Septal wall bowing to the left ventricle • PFO with bidirectional shunt • Dilated right ventricle with normal systolic function • No PDA. •

Greater than 50% systemic right ventricular pressure based on systolic septal position • Right ventricular hypertrophy • Moderate right ventricular hypertrophy • Mild right ventricular dilation • Small PFO with bidirectional shunting • Good biventricular function •

Chest CT with angio

CXR

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Palliative Care Involvement in Pulmonary Arterial Hypertension Patient Care: Single-Center Experience

Paulus S1, Fowler J2 1 Aurora HealthCare, Milwaukee, WI, USA 2 Aurora HealthCare, Burlington, WI, USA

Background: Medical advances and increased therapy options have helped to improve survival rates in patients with pulmonary arterial hypertension (PAH). Still, throughout the treatment course, individuals will experience various challenges related to expected medication effects, symptom burden, and stress from their progressive, chronic disease. Palliative care can provide an extra layer of support to help address these challenges and improve quality of life for PAH patients. Methods: Assembly of information regarding triggers for palliative care and the role of palliative care in PAH patients at our center. Results: Our providers and nurse coordinators attended a brief seminar on how to introduce palliative care to patients and learn triggers for when to refer patients in order to streamline the involvement of palliative care (Table 1). All PAH patients seen at our center have easy access to palliative care since we have a designated palliative care nurse practitioner in our clinic. When a patient meets a trigger for palliative care, they are referred for consultation. Uniquely, two patients (1 female, age 84 and 1 male, age

75) both with WHO group I PAH associated with congenital heart disease on IV Remodulin received palliative care in their home. Both patients initially met with palliative care in the outpatient clinic and were then set up with in-home services. One patient had visits from a nurse practitioner associated with our healthcare system and the other patient had services through a private agency. They were able to be seen in their home (versus traveling to the clinic) and were provided medical therapy for pain relief and ease of breathing. Eventually, they transitioned to a comfort care focus. They received their last shipment of Remodulin when they entered hospice and were weaned down and off of it. Both patients’ families called to report they died peacefully at home approximately one month after entering hospice. Conclusions: Many opportunities exist to integrate palliative care into care for PAH patients to help improve quality of life during active treatment and when patients decide to transition to a comfort care focus. Palliative care should have an active role in the care for PAH patients.

Two or more hospital admissions/ED visits in the last 6 months for same problem NYHA WHO Functional Class IV Limited additional medical therapies that can be offered Patients who are not candidates for transplant or who opt out

Ventavis to Selexipag Conversion

Litton K, Curry K Allegheny General Hospital, Cardiovascular Institute, Pittsburgh, PA, USA Purpose: 58 yr old female PAH patient. She has stable WHO functional class I- II symptoms secondary to her pulmonary hypertension and right ventricular dysfunction. She denies any secondary effects from Ventavis. Patient reports that being on Ventavis is inconvenient and negatively impacts her daily life. Background: 57 y.o. female who has a history of pulmonary hypertension with a BMP O2 mutation that was initially diagnosed in April of 2003. Patient first diagnosed with pulmonary hypertension in April of 2003 after having several months of increasing shortness of breath. Was diagnosed with severe pulmonary hypertension by right heart catheterization as well as a left main compression by her main pulmonary artery. She required urgent treatment with IV prostacyclin in June 2003. She requested to come off her IV prostacyclin and was transitioned to Ventavis in 2007. She was also started on Sildenafil in 2015, after worsening of her PAH noted by TTE/echocardiogram Patient currently has no shortness of breath at rest or with her daily activities of living. She has no shortness of breath walking a block or flight of stairs. She denies orthopnea PND, but does have mild lower extremity edema. She denies syncope, presyncope, exertional lightheadedness or palpitations. Over the past 11 years, she has been about 90% compliant with her Ventavis inhalations. Patient requested to be transitioned to oral prostacyclin, so plan was developed and currently in process of transitioning pt.

Methods: 1) Met with PHARMD to discuss the patients plan and medication transition. PharmD developed the transition plan from Ventavis to Selexipag 2) Prior Authorization and arranging the Medication 3) Meeting with Patient/Medical Provider/PharmD and RN Clinical Coordinator and providing one on one education 4) PLAN over eight (8) weeks.

Week 1 2 3 4 5 6 7 8

Ventavis 5 mcg 6 times daily 5 mcg 6 times daily 2.5 mcg 6 times daily 2.5 mcg 6 times daily Off Off Off Off

Selexipag 200 mcg bid 400 mcg bid 600 mcg bid 800 mcg bid 1000 mcg bid 1200 mcg bid 1400 mcg bid 1600 mcg bid

Results: 1) There is no published data on this specific transition. There is a case report on Tyvaso to Selexipag and there is a study, TRANSIT 1., looking at converting patients from Tyvaso to Selexipag. 2) Plan has been developed and currently in the process of transitioning the patient from the Ventavis to Selexipag 3) Patient progress and tolerance will be monitored closely 4) Will closely monitor patient and do vital sign monitoring/6MWT and 3 month post transition will perform a Right Heart Cath. Conclusions: 1) Currently in the process of collecting the data 2) Results and how the patient tolerated the transition have not been finalized. Results will be posted at the end of the transition period, as well as the clinical signs/ symptoms and 6MWT and RHC results.

Specific disease triggers: aspiration pneumonia, COPD, sepsis, Stage 3 or 4 cancer, end stage renal or hepatic disease, dementia Older than age 70 with multiple co-morbidities (to discuss goals) Goal setting – address code status and advance directives Pain, anxiety, insomnia, and other symptom management issues from underlying disease or medications Expected transition from curative to comfort care focus

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Table 1: Palliative Care Triggers

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Epoprostenol-Induced Colitis in a Patient With HIV Associated Pulmonary Arterial Hypertension: A Case Report Stevens G, Bains J, Giri P Loma Linda University Health, CA, USA

Background: HIV-associated Pulmonary Hypertension (HIV-PH) is a rare complication occurring in 1 out of every 200 HIV infected patients (1). Its pathophysiology is still unclear but there are similarities in the histopathology of HIV-PH and Primary Pulmonary Hypertension and hence, treatment is also similar. Patients should receive pulmonary arterial hypertension directed therapy to improve symptoms and cardiac function along with close monitoring of any side effects. We present a case of HIV-PH with New York Heart Association (NYHA) functional class 3 treated with intravenous Epoprostenol with subsequent development of severe colitis which resolved on a lower dose of Epoprostenol therapy. Methods: 31 year old African American female presented with a 5 month history of worsening orthopnea, chest pain and shortness of breath with minimal exertion. She had a syncopal episode while walking to her car with no post-ictal changes. On physical examination, she had a loud P2, notable S3 with elevated JVD and bilateral lower extremity swelling. At that time, she was noted to have NYHA functional class 3 and a transthoracic echocardiogram revealed severe RV dilation, mild RA dilation, LV EF of 4550%, D septum and RVSP of 70mmHg. Serum BNP done at that time was 637 pg/mL. Right heart catheterization showed mPAP of 52 mmHg, end-expiratory PAWP of 18 mmHg, CO at 2.30 l/ml, PVR at 13 WU with no response to vasodilator challenge. A thorough work up for pulmonary hypertension was performed which revealed that she was HIV positive with CD4 count of 356 mm3 and HIV RNA viral load of 11,300 copies/mL. She was diuresed with Furosemide and Metolazone and started on Macitentan 10mg qd, Riociguat 0.5mg tid and Epoprostenol therapy at 10ng/kg/ min and had improvement of symptoms to NYHA functional class 2. Six weeks after therapy, she developed lower quadrant abdominal pain. The pain was described as cramping, worse with oral intake and associated with nausea, vomiting and resulting inability to tolerate any oral intake. She had a 40 pound weight loss during that time without any episodes of diarrhea or fever. CT Abdomen showed pan colitis and she was admitted as inpatient for IV hydration. She had an endoscopy performed which showed mild gastropathy, as well as a sigmoidoscopy and a colonoscopy which showed normal bowel mucosa. Multiple biopsies were taken from the gastric antrum, duodenum, colon sigmoid and rectum which revealed benign mucosa with mild superficial chronic inflammation. Her Epoprostenol therapy was titrated down to 4ng/kg/min and her symptoms significantly improved. Repeat BNP was 41 pg/mL and repeat cardiac catheterization showed mPAP of 42 mmHg, PCWP of 4 mmHg, CO of 3.67 l/ml and PVR 119

PULMONARY HYPERTENSION ASSOCIATION

of 10.9 WU. She continued to remain hemodynamically stable with improvement of stable symptoms and functional class. Results: Epoprostenol is a prostacyclin with vasodilatory effects that has been successfully used to treat HIV-PH. After 1 year of intravenous Epoprostenol infusion, it has been shown that Epoprostenol can effectively lower the mean pulmonary artery pressures by 21.7%, pulmonary vascular resistance by 54.9% and improve cardiac output by 51.4% in patients with HIV-PH (2). The benefit of initiation of antiretroviral therapy (ART) is still unclear for HIV-PH, but most patient are treated with ART irrespective of this diagnosis (3). The main side effects of Epoprostenol include flushing (58%), headache (49%), nausea/vomiting (32%) and hypotension (16%). There have been no reported cases of colitis associated with the administration of Epoprostenol. Other pulmonary hypertension medications specifically Bosentan (an endothelin-1 receptor antagonist) and Sildenafil (a phosphodiesterase inhibitor) have been known to have drug interaction with ART, more specifically Ritonavir, which this patient was not on. The severity of pulmonary hypertension also does not correlate to the level immunodeficiency (4). Conclusions: HIV-PH is a rare condition which needs further research for better understanding of its pathophysiology and subsequent treatment options. A high clinical suspicion is needed for any drug-induced colitis especially when initiating pulmonary arterial hypertension therapy as a fine balance of symptom management and beneficence to the patient needs to be achieved.

Fast Pass: How to Start Higher Doses of Oral Treprostinil by Using IV Epoprostenol Salinero M, Hyman T, Matos M, Pallares M, Jimenez J South Miami Hospital, Miami, FL, USA

Purpose: To target higher oral treprostinil doses rapidly by using IV epoprostenol preloading. Background: IV epoprostenol is a high-risk medication with no current guidelines for rapid initiation, titration, and transition from IV to oral therapy. In the PAH patient population, successful treatment depends on individualized patient therapy. This patient presented with worsening shortness of breath, fatigue and severe pulmonary hypertension naïve to prostacyclin therapy, World Health Organization (WHO) group 1 functional class IV, who was a poor candidate for IV therapy. The preplanned IV to p.o. protocol was initiated in the ICU setting; the hemodynamics were monitored via swan-ganz catheter. IV epoprostenol was infused via a central line to a maximum tolerated dose which allowed for a higher oral dose to be tolerated; this would not have been possible with the traditional dosing schedule. Methods: IV epoprostenol is a high-risk medication with no current guidelines for rapid initiation, titration, and transition from IV to oral therapy. In the PAH patient population, successful treatment depends on individualized patient therapy. This patient presented with worsening shortness of breath, fatigue and severe pulmonary hypertension naïve to prostacyclin therapy, World Health Organization (WHO) group 1 functional class IV, who was a poor candidate for IV therapy. The preplanned IV to p.o. protocol was initiated in the ICU setting; the hemodynamics were monitored via swan-ganz catheter. IV epoprostenol was infused via a central line to a maximum tolerated dose which allowed for a higher oral dose to be tolerated; this would not have been possible with the traditional dosing schedule.

Results: Baseline hemodynamics showed markedly elevated pulmonary pressures, elevated pulmonary vascular resistance, right ventricular pressure 120/25, pulmonary pressure 120/40, with a mean of 65, pulmonary wedge pressure 18, cardiac output 3.35, pulmonary vascular resistance 1066, and systemic artery pressure 100/52. Hemodynamically the patient improved over the first night as evidenced by markedly decreased PA pressures and increased cardiac output. Swan-ganz was removed on day2, CVP pressure remained elevated at 21. Vitals at discharge were 120/70, heart rate 80, O2 98% on 3 liters. The patient was able to tolerate a rapid initiation, titration, and transition from IV epoprostenol to a higher dose oral treprostinil therapy within a shorter time span than the traditional titration schedule for oral prostacyclin therapy. A right heart catheterization 3 months following the IV to oral transition was completed and showed a decrease in pulmonary vascular resistance of approximately 50% when compared to previous reports, from 1066 to 535. The patient experienced mild nausea, vomiting, and flushing during the admission, but remained hemodynamically stable. Conclusions: For the patients whose condition would best be managed by oral treprostinil rather than IV epoprostenol therapy, pre-loading the patient using IV epoprostenol and then rapidly titrating with oral treprostinil can be done safely and effectively in the hospital setting to achieve higher dosing with better side effect management.

References 1. Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med 2008; 177:108. 2. Aguilar RV, Farber HW. Epoprostenol (prosta¬cyclin) therapy in HIV-associated pulmonary hypertension. Am J Respir Crit Care Med 2000; 162:1846. 3. Barbaro G, Lucchini A, Pellicelli AM, et al. Highly active antiretroviral therapy compared with HAART and bosentan in combination in patients with HIV-associated pulmonary hypertension. Heart 2006; 92:1164. 4. Speich R, Jenni R, Opravil M, Pfab M, Russi EW. Primary pulmonary hypertension in HIV infection. Chest. 1991 Nov;100(5):1268-71.

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Outpatient Transition of Parenteral to Oral Prostacyclin in Pulmonary Arterial Hypertension Morris KL, Kelkhoff A, Schmit A, Ravichandran A St. Vincent Hospital Indianapolis, IN, USA

Background: Pulmonary arterial hypertension (PAH) is a progressive, incurable disease with a rapidly progressing number of treatment options. Traditionally, prostacyclin therapies have been underutilized (1). Now with oral formulations available such as treprostinil, increased access to this important therapeutic pathway may improve patient outcomes, inclusive of quality of life and cost. (2,3) One strategy has been to transition patients from parenteral to oral prostacyclin therapy through a 5 day inpatient hospitalization regimen in 33 patients (4). We seek to describe our experience through a more rapid inpatient or outpatient based transition. Methods: We retrospectively reviewed charts for those transitioned from parenteral to oral treprostinil within St. Vincent Medical Group in Indianapolis, IN between in 2017-18. Charts were extensively analyzed for baseline data, including transthoracic echocardiogram and hemodynamics, along with outcome analysis before and after treprostinil transition. Results: Six patients were transitioned from parenteral to oral prostacyclin therapy within a rapid 2-5 day observation admission or outpatient setting. Table 1 illustrates our 3 patients that have Group 1 pulmonary arterial hypertension

Successful Transition From Subcutaneous Treprostinil to Oral Treprostinil in a Patient With Pulmonary Arterial Hypertension: A Case Study Fearon-Clarke J, Goldschmidt M, Hollasch K Morristown Medical Center Morristown, NJ, USA

on double or triple therapy with the prostacyclin. Transitions were safe and successful in all patients. Conclusions: Based on our limited experience, it is safe to rapidly transition patients from parenteral to oral treprostinil in an outpatient fashion while maintaining functional status, ease of administration, cost and quality of life for the patient and health system. References: 1. Badesch et al. Pulmonary Arterial Hypertension: Baseline Characteristics from the REVEAL registry. CHEST. 2010. 137: 376-387. 2. Jing et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation. 2013; 127 (5): 624- 33. 3. Tapson et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelan receptor antagonist and/or phosphodiesterase type 5 therapy; a randomized controlled trial. Chest. 2012; 142(6): 1383. 4. Chakinala, et al. Transition from parenteral to oral treprostinil in pulmonary arterial hypertension. J Heart Lung Transplant. 2017; 36; 193-201.

Purpose: Describe the experience of one patient transitioned from subcutaneous (SC) treprostinil to oral treprostinil at home. Background: Pulmonary arterial hypertension (PAH) is a rare disease that is characterized by elevated pressures in the pulmonary arteries that result in vascular remodeling and right heart failure. Treatment strategies are geared towards physiologic pathways that are up or down regulated. Oral agents such as phosphodiesterase type 5 inhibitors, endothelin receptor antagonists and soluble guanylate cyclase stimulator are often used in combination as first line agents. Parenteral prostacyclin is usually reserved for patients with advanced disease. Parenteral prostacyclin medications though they have clear benefit are often burdensome with risk related to route of administration such as infection with intravenous (IV) route or site pain with SC route of administration. Side effects from this class of drug can be intolerable and thus may slow up-titration or limit optimal dosing. Orenitram® (treprostinil), an oral prostacyclin was FDA approved in 2002 for the treatment of WHO Group 1 PAH to improve exercise capacity. There are no data from randomized clinical trials on transitioning patients from parenteral to oral prostacyclin therapy. Information is obtained through multicenter open label study, retrospective analyses, case series and case report. Review of these data revealed variable results with typical transition occurring over 4 - 5 days in a hospital setting. Methods: 56-year-old man with WHO group 1 PAH on SC treprostinil at 40 ng/kg/min requested to be transitioned as an outpatient to oral treprostinil due to SC site pain and ease of an oral drug administration. He was clinically stable with New York Heart Association Functional Class II symptoms with an average 6-minute walk distance (6MWD) of 385 meters. Right heart catheterization obtained prior to

the transition showed pulmonary artery mean pressure of 28 mmHg, normal cardiac index and pulmonary artery saturation. Based on his body weight of 98.5 kg the comparable dose of oral treprostinil was calculated to be 28 mg daily or approximately 9 mg three times daily. Oral treprostinil was initiated at 1 mg three times daily (TID) and at the same time SC treprostinil was decreased by 6 ng/kg/ min. Weekly dosing titration schedule included decreasing SC treprostinil by 6 ng/kg/min as oral treprostinil was increased by 1 mg TID to an initial goal of 7 mg TID over a seven-week period. Patient was monitored closely with coordinated visits between Pulmonary Hypertension Nurse Practitioner and Specialty Pharmacy RN visits. Results: Subcutaneous treprostinil was discontinued when patient was on oral treprostinil 7 mg TID. At this time, patient complained of exertional dyspnea in extreme cold weather and had evidence of fluid retention. His diuretic dose requirement was increased and oral treprostinil was further up-titrated over another 3 weeks to a goal dose of 10 mg TID. At this dose, patient was back to his baseline breathing and exercise tolerance and his 6MWD remained stable. Patient did not experience any increased prostacyclin side effects and was otherwise clinically stable during the entire transition process. Conclusions: The initial goal dose of oral treprostinil 7 mg TID was underestimated due to the patient near normal pulmonary pressures prior to the transition. This was a successful and seamless transition from SC treprostinil to oral treprostinil. The current data available occurs in the hospital setting. Based on this one patient encounter, it may be safe to do a slow transition at home on a case by case basis.

Table 1: Outpatient (Patients 1-3) and rapid inpatient (Patients 4-6) transition from parenteral to oral treprostinil. 121

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Successful Transition From Oral Selexipag to Subcutaneous Treprostinil George MP1, Coons J2, Kim D1, Buckner JK1, Mathier M2 1 National Jewish Health, Denver CO, USA 2 University of Pittsburgh, Pittsburgh PA, USA

Purpose: We describe a protocol for conversion from oral selexipag to subcutaneous (SQ) treprostinil. Background: Despite advances in oral medications exploiting the prostacyclin pathway, pulmonary hypertension remains a progressive disease, and in some patients it may be necessary to convert to parenteral therapy. To date, there are no published protocols describing this conversion. Methods: Our patient is a 33-year-old woman with idiopathic pulmonary arterial hypertension diagnosed in 2015, on triple drug therapy (tadalafil 40mg daily, ambrisentan 10mg daily, selexipag 1600 mcg BID) who suffered recurrent admissions for right ventricular failure and volume overload. She was admitted for conversion from selexipag to SQ treprostinil. She had been at maximum dose selexipag currently (1600mcg BID) without side effects. Our goal was to initiate and increase her medication to an initial goal of 20ng/kg/min SQ treprostinil, initiated during her inpatient admission with continued dose increases as an outpatient. Given the difference in half lives of selexipag (active metabolite, 6.2-13.5 h) and treprostinil (4 h), we developed a protocol in the interest of avoiding underdosing (leading to worsening right ventricular failure) and overdosing (leading to hypotension). Protocol: On the night of admission we

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reduced the patient’s evening dose of selexipag to 1000 mcg BID, and the following morning began SQ remodulin at 2.5 ng/kg/min. Over the subsequent days we decreased the evening dose of selexipag by 200 mcg every night and increased the daily dose of treprostinil as tolerated by 2.5 ng/kg/min. We monitored the patient’s vital signs and symptoms per routine, and also asked her to repeat her hall walk daily to be able to detect worsening exertional dyspnea, which would be an earlier symptom than any discomfort at rest. Results: Our patient successfully weaned her selexipag over the next 5 days, and was able to increase her SQ treprostinil to 12.5 ng/kg/min by the time of discharge. She had mild side effects of headache and flushing, but no dose-limiting side effects. She was able to walk farther each day without stopping and reported decreased exertional dyspnea. We continued her titration over the next several weeks to a goal dose of 24 ng/kg/min, at which she had improved hemodynamics, and ultimately were dose limited by reduction in systemic vascular resistance. Conclusions: This is the first report of successful transition from selexipag to SQ treprostinil.

Risk Assessment and Prognosis Based on ESC/ERS Guidelines in Patients With Pulmonary Arterial Hypertension Receiving Riociguat

Background: ESC/ERS 2015 treatment guidelines recommend regular risk assessment of patients with pulmonary arterial hypertension (PAH) using a multidimensional approach, including clinical, imaging, exercise, and hemodynamic variables. Patients can be stratified into three risk groups (low, intermediate, and high risk) for mortality at 1 year. Abbreviated versions of this risk assessment were found to discriminate between prognostic groups in incident PAH cohorts of the French, Swedish, and COMPERA registries. [1–3] We evaluated three of these tools in patients with PAH receiving riociguat in the PATENT studies. Methods: In PATENT-1, patients with PAH received placebo or riociguat adjusted up to 2.5 mg three times a day (tid) or 1.5 mg tid (exploratory dose, not included in this analysis) for 12 weeks. For patients entering the PATENT-2 open-label extension study, risk was assessed at baseline and Week 12 according to three methods: 1. French registry invasive analysis: quantified the number of ESC/ ERS low-risk criteria present based on WHO functional class (FC), 6-minute walking distance (6MWD), right atrial pressure (RAP), and cardiac index. 2. French registry noninvasive analysis: quantified the number of low-risk criteria present for WHO FC, 6MWD, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP). 3. COMPERA analysis: assessed WHO FC, 6MWD, NT-proBNP, RAP, cardiac index, and mixed venous oxygen saturation; each was graded 1–3 (1=low risk, 3=high risk) and the rounded mean defined risk category. The association between meeting low-risk criteria at Week 12 of PATENT-1 with long-term outcomes in PATENT-2 was assessed by

Kaplan–Meier analyses of observed data. Differences in the long-term outcome between risk groups were analyzed using the log-rank test. Results: At entry into PATENT-1, approximately 50% of patients were pretreated with a PAH therapy, and the mean time since diagnosis was 2.4 years (1.9 years in treatmentnaïve and 3.0 years in pretreated patients). Patients receiving riociguat 2.5 mg tid in PATENT-1 (n=231) met a greater number of the low-risk criteria or improved their risk status after 12 weeks compared with baseline. Using the French non-invasive method, the number of low-risk criteria at PATENT-1 Week 12 discriminated between prognostic groups for both clinical worsening-free survival (p=0.0001; Figure) and survival (p=0.0126), while the invasive method discriminated for clinical worsening-free survival (p=0.0078) but not overall survival. The COMPERA method discriminated between prognostic groups for both clinical worsening-free survival (p=0.0023) and survival (p=0.0099) based on risk group at Week 12. Conclusions: This study reproduced the results from an assessment of abbreviated ESC/ERS risk scores in retrospective analyses of registry databases, in a post hoc analysis from a prospective pivotal study database of both incident and prevalent patients receiving riociguat. 1. Boucly A, et al. Eur Respir J 2017;50:1700889; 2. Hoeper MM, et al. Eur Respir J 2017;50:1700740; 3. Kylhammar D, et al. Eur Heart J 2017; doi: 10.1093/ eurheartj/ehx257.

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RESOURCES FOR YOU AND FOR YOUR PATIENTS For You

For Your Patients In Person

PHA Medical Education On-Demand: An invitation to organize a no-cost CME meeting for your local medical community, with logistics and faculty provided by PHA PHA Preceptorship Program: A day-long, comprehensive program led by experienced PH specialists at nationally recognized PAH centers that instructs front-line clinicians in the highest quality of care for PH patients

PHA on the Road: PH Patients and Families Education Forum: A free, day-long educational forum that seeks to provide education and support to patients and their family members across the country living with PH through interactive presentations, educational sessions and networking opportunities

Local Support Group Meetings: 182 PHA support groups have held meetings thus far in 2018 to provide PH Professional Network Symposium: A biennial symposium that brings together physicians, researchers knowledge, support and empowerment to patients with PH and non-physician clinicians from across the globe to discuss the latest advances and research in PH Building Medical Education in PH (BME) Program: A program that creates partnerships between PHA and PH programs at members’ affiliate PH centers across the country to support continuing education in the medical community PH Care Centers (PHCC): An initiative to establish a program of accredited centers with expertise in PH that aspires to improve overall quality of care and 2018 PHA Scientific Sessions improve patient outcomes

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Figure 1: Clinical worsening-free survival stratified by the number of low-risk non-invasive criteria at Week 12 in PATIENT-1.

PHA Registry (PHAR): A registry of patient data that will help researchers evaluate trendsProfessionals and practice patterns to determine which treatments work best

In Print PH Clinical Quick Reference Guide: A brochure on the classifications of PH, recommended diagnostic testing protocols, treatments and follow-up of patients

Understanding Pulmonary Hypertension: A brochure for newly-diagnosed PH patients and their families for information on PH screening, diagnosis and treatments

PH Awareness Waiting Room Poster: For display in your clinic, a poster that teaches people about the symptoms of PH and when to contact their doctor

Roadmap to Hope: A brochure for newly-diagnosed PH patients and their families for information on complying with care, finding support and joining the PH community Pulmonary Hypertension: A Patient’s Survival Guide: An in-depth manual for PH patients at all stages, written by a patient and medically reviewed by experts, that explains the disease and coping tips for patients to live their best life Online

PHA Online University: Free online CME available 24/7 PHAOnlineUniv.org PH Clinicians and Researchers (PHCR): PHA’s medical membership network for PH-treating physicians and Ph.D.-level researchers interested in pulmonary hypertension PH Professional Network (PHPN): PHA’s medical membership network for non-physician clinicians, nurses and allied health professionals who care for PH patients

PHA Classroom: Free online education for patients and caregivers on a variety of medical and lifestyle topics at PHAClassroom.org Empowered Patient Toolkit: Templates, check-lists and tips to help patients manage their health care Patient-to-Patient Support Line: 800-748-7274: A toll-free line answered by friendly volunteer patients who are there for anyone who needs someone to talk to about PH

PHA’s Research Program: A program that provides grants to promising researchers in the field of pulmonary hypertension 125

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PHA RESEARCH GRANT AWARD RECIPIENTS 2016 TO 2018

PHA Robyn J. Barst, M.D. Pediatric PH Research and Mentoring Fund 2016

The Aldrighetti Research Award for Young Investigators Sponsorship support provided by Actelion Pharmaceuticals

Meghan Bernier, M.D. “LOX-1: A Therapeutic Target for Pulmonary Hypertension in Lung Endothelium” Christen White Cranford Pediatric PH Research and Mentoring Grant

2017

Christen White Cranford Pediatric PH Research and Mentoring Grant December 1, 2016 - November 30, 2016 T32 Research Fellow The Johns Hopkins Hospital

December 1, 2017 - November 30, 2019 Instructor of Medicine University of Pennsylvania

Rachel Hopper, M.D. “Comprehensive Analysis of Persistent Pulmonary Hypertension in Congenital Diaphragmatic Hernia”

Nadine Al-Naamani, M.D., M.S. “Effect of Obesity on Treatment Response in Pulmonary Arterial Hypertension”

2016

December 1, 2016 - November 30, 2016 Attending Physician The Children’s Hospital of Philadelphia

December 1, 2016 - November 30, 2018 Professor, Pneumology L’Université Laval

Sheila Krishnan, D.O. “Hypoxia-Dependent Epigenetic Modifications in the Pulmonary Vasculature”

Olivier Boucherat, Ph.D. “Forkhead-Box (FOX) Transcription Factors in Pulmonary Arterial Hypertension”

PHA/ATS Research Fellowship in Pulmonary Arterial Hypertension 2017

Andrew John Sweatt, M.D. “Deep Immunophenotyping of Pulmonary Arterial Hypertension by Unsupervised Machine Learning” December 1, 2017 - November 30, 2019 Instructor of Medicine Stanford University 2016

Farbod Rahaghi, M.D., Ph.D. “CT Imaging Markers of Pulmonary Arterial and Venous Remodeling in Pulmonary Hypertension” December 1, 2016 - November 30, 2018 Instructor, Pulmonary and Critical Care Brigham and Women’s Hospital

Cordelia’s Pediatric PH Research and Mentoring Grant December 1, 2016 - November 30, 2016 Pulmonary and Critical Care Fellow Indiana University

PHA Proof of Concept Award 2016

Kazuyo Kegan, Ph.D. “Illuminating AMPK Function in Crosstalk Between Insulin Resistance and Pulmonary Hypertension” December 1, 2016 - November 30, 2017 Assistant Professor Anesthesiology and Critical Care Medicine Johns Hopkins University

PHA/NHLBI Mentored Clinical Scientist (K08)/Mentored Patient-Oriented Research Career Development (K23) Award 2016

John Huetsch, M.D. “The Calpain/CaMKII/NHE Signaling Pathway in PAH” July 01, 2016 - June 30, 2021 Instructor of Medicine Johns Hopkins University 127

PULMONARY HYPERTENSION ASSOCIATION

2018 PHA SCIENTIFIC SESSIONS AND EDUCATION FOR MEDICAL PROFESSIONALS

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PHA LEADERSHIP Board of Trustees Officers: Roger Towle Chair Stephen L. White, Ph.D. Immediate Past Chair Karen Fagan, M.D. Chair-Elect Sally Maddox Secretary Tony Lahnston Treasurer

Members At Large: Erika S. Berman Rosenzweig, M.D. Colleen Brunetti, M.Ed., C.H.C. Frank Cann Colleen Connor Laura D’Anna, Dr.P.H., M.P.A. Ramona Doyle, M.D., M.Sc. Stacey Gausling, OT/L Amy Kimber, R.N., APNP Jessie Kohler, Esq. Mitchell Koppelman, Ph.D. Michael McGoon, M.D. Vallerie McLaughlin, M.D. Rita Orth, R.N. Ronald J. Oudiz, M.D. Diane Ramirez Fran Rogers, M.S.N., CRNP Traci Stewart, R.N., M.S.N., CHFN Doug Taylor Melisa Wilson, ARNP, ACNP-BC

Ex-Officio Brad A. Wong Members Emeriti Dorothy Olson Harry Olson Jerry Paton Pat Paton, R.N. Ed Simpson Judith Simpson, R.N., Ed.S. Honorary Carl Hicks

Karen Fagan, M.D. Immediate Past Chair Ronald J. Oudiz, M.D. Chair-Elect Steven H. Abman, M.D. William R. Auger, M.D. Todd Bull, M.D. Murali M. Chakinala, M.D., FCCP Kelly Chin, M.D. Lorinda Chung, M.D. Mardi Gomberg-Maitland, M.D., M.Sc. Anna Hemnes, M.D.

Steven M. Kawut, M.D., M.S. James R. Klinger, M.D. Tim Lahm, M.D. Roberto F. Machado, M.D. Stephen C. Mathai, M.D., M.H.S. Michael Mathier, M.D. John H. Newman, M.D. Ioana Preston, M.D. Jeffrey Sager, M.D., MSCE Robert J. Schilz, D.O., Ph.D. Oksana A. Shlobin, M.D., FCCP Sean Studer, M.D., M.Sc. Fernando Torres, M.D. Terence Trow, M.D. Timothy L. Williamson, M.D. Joel A. Wirth, M.D. Delphine Yung, M.D.

PH Professional Network Executive Committee Amy Kimber, R.N., APNP Chair Melisa Wilson, ARNP, ACNP-BC Immediate Past Chair Fran Rogers, M.S.N., CRNP Chair-Elect 129

PULMONARY HYPERTENSION ASSOCIATION

Cheri Abbott, R.N., CCRP Johnell Diwan, R.N., B.S.N. Martha Kingman, D.N.P., FNP-C Mary Knabe, R.N., M.S.N. Susie McDevitt, R.N., M.S.N., ACNP

would like to thank

for sponsoring the 2018 PHA Scientific Sessions Program Book.

Scientific Leadership Council Erika S. Berman Rosenzweig, M.D. Chair

The Pulmonary Hypertension Association

Liaisons Amy Kimber, R.N., APNP Fran Rogers, M.S.N., CRNP Rita Orth, R.N. Distinguished Advisors David B. Badesch, M.D. Bruce Brundage, M.D. Richard Channick, M.D. C. Gregory Elliott, M.D. Michael D. McGoon, M.D. Vallerie V. McLaughlin, M.D.

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