Vol 7, No 3 - PHA Online University

Advances in 

Pulmonary 

Hypertension 

Official Journal of the Pulmonary Hypertension Association 

Autumn 2008 

Vol 7, No 3 

Highlights From 

Scientific Sessions 

of PHA’s International 

Conference 

See description on page 318 

CME in This Issue

Table of Contents 

Guest Editor for this issue: 

Karen Fagan, MD 

University of South Alabama 

College of Medicine 

Mobile, Alabama 

320 Profiles in Pulmonary 

Hypertension: 

Vallerie V. McLaughlin, MD 

330 Advances in Pulmonary 

Hypertension CME Section 

332 The Metabolic Syndrome 

and Cardiac Function 

337 National Heart Lung and Blood 

Institute Hopkins Specialized 

Center in Clinical Oriented 

Research (SCCOR): Molecular 

Determinants of Pulmonary 

Arterial Hypertension 

341 Specialized Center in Clinical 

Oriented Research (SCCOR) 

Update: Mechanisms and Treatment 

of Lung Vascular Disease 

in Infants and Children 

343 Getting More From Right Heart 

Catheterization: A Focus on the 

Right Ventricle 

346 Animal Models of Human 

Severe PAH 

351 Self-Assessment Examination 

353 Pulmonary Hypertension 

Roundtable Discussion 

Publisher 

Pulmonary Hypertension Association 

Michael D. McGoon, MD, Chair of the Board 

Rino Aldrighetti, President 

Donica Merhazion, Associate Director of Medical Services 

PHA Office 


801 Roeder Rd. Suite 400 

Silver Spring, MD 20910-4496 

301-565-3004, 301-565-3994 (fax) 

www.phassociation.org 

© 2009 by Pulmonary Hypertension Association. All rights reserved. 

None of the contents may be reproduced in any 

form whatsoever without the written permission of PHA. 

ISSN: 1933-088X (print); 1933-0898 (online) 

Editorial Offices 

Advances in Pulmonary Hypertension, DataMedica, 

P.O. Box 1688, Westhampton Beach, NY 11978 

Tel (631) 288-7733 Fax (631) 288-7744 

E-mail: sbelsonchapman@aol.com 

Publishing Staff 

Stu Chapman, Executive Editor 

Natalie Timoshin, Associate Editor 

Gloria Catalano, Production Director 

Michael McClain, Design Director 

Advances in Pulmonary Hypertension is circulated to cardiologists, 

pulmonologists, rheumatologists, and other selected 

physicians by the Pulmonary Hypertension Association. The 

contents are independently determined by the Editor and the 

Editorial Advisory Board. All past issues of the journal are available 

at: www.PHAssociation.org/Medical/Advances_in_PH/ 

Cover Image 

Images suggest how severe pulmonary arterial hypertension 

can cause right ventricular dilatation and failure. (Images 

courtesy of Ivan McMurtry, PhD) 

Guest Editor’s Memo 

From PHA’s Scientific Sessions, a Time for 

Reflection on the Progress Toward a Cure 

As Guest Editor for this issue of Advances in Pulmonary Hypertension, 

I looked forward to reviewing the submission of manuscripts because 

I knew the content would reflect the exciting agenda we put together 

for the third Scientific Sessions held in conjunction with the 2008 

Pulmonary Hypertension Association (PHA) International Conference 

in Houston. As Chair of the Scientific Sessions Committee I had the 

privilege of overseeing the scope of the program and helping to coordinate 

content development. For readers who were fortunate enough to 

attend, the Scientific Sessions and conference once again offered an 

outstanding opportunity to meet with specialists in PH and explore why this program offers 

clinicians so much to think about and apply in their practices as they explore translational 

research in this disease. 

As researchers, we are always impressed and encouraged by the pace of work on this 

disease throughout the world and our content in this issue demonstrates some of the 

progress we are making in gaining a better understanding of the pathophysiology of PH, 

its mechanisms and treatment. Despite the progress in this regard, the attendance at the 

Conference by hundreds of patients and their families who signed up for the patient 

portion of he program reminded us of how much further we need to go before we can say 

we have a cure for PH. In achieving that goal, there will be numerous incremental steps 

such as the reports in this publication that serve as benchmarks for how far we have come 

on this huge journey. 

In this issue of the journal we express our gratitude to the following authors for their 

contributions to the growing body of knowledge on the disease: Heiko Bugger, MD, PhD 

and E. Dale Abel, MD, PhD, Paul M. Hassoun, MD, Kurt Stenmark MD, Hunter C. Champion, 

MD, PhD, and Ivan F. McMurtry, PhD. I woud also like to thank the participants in 

the Pulmonary Hypertension Roundtable Discusssion, including Todd Bull, MD, Omar 

Minai, MD, and Dr McMurtry. 

Karen A. Fagan, MD 

Guest Editor 

Editor’s Memo 

A few years after I began to work in the field of PH with my mentor, 

Dr. Bruce Brundage, I missed what would have been my 1 st International 

PHA conference in 1998: my son was born 2 days before the meeting 

started. At the time I did not know what I would be missing. At the 

following PHA conference, I found out what all the fuss was about. 

In 2000, over 700 patients, caregivers, practitioners and researchers 

converged on a sold-out hotel in suburban Chicago, and everyone poured 

their hearts (and minds) out to better the PH community. Children wearing 

backpacks with IV pumps inside, patients parading on stage showing 

off the latest pump-concealing fashions, and PH experts volunteering their time and 

expense to inform, teach and learn about PH were among the many highlights of that and 

each subsequent meeting I attended. To say that the biennial International Conferences 

and Scientific Sessions of the Pulmonary Hypertension Association are one of the most 

emotionally draining yet inspirational and uplifting events in the lives of anyone involved 

in PH would be a major understatement. This issue’s coverage of the most recent PHA 

meeting, the 8 th International Conference and Scientific Sessions of the Pulmonary Hypertension 

Association thus holds a special place in my heart. Dr. Karen Fagan, Guest Editor 

of this issue and Chair of the PHA Scientific Sessions held in Houston last June, did a 

fantastic job putting together an entire issue devoted to the Conference, in which over 

1100 people from 17 different countries attended. From original scientific contributions 

to an expert Roundtable, all focused on the Scientific Sessions, plus an international 

commentary on PH and connective tissue disease issues covered in the last Summer issue 

of Advances, I am sure you too will learn and hopefully be inspired to attend the next 

International Conference. 

Ronald J. Oudiz, MD 

Editor-in-Chief

Editorial Advisory Board 

Editor-in-Chief 


Associate Professor of Medicine 

UCLA School of Medicine 

Director, Liu Center for Pulmonary 

Hypertension 

Division of Cardiology 

Los Angeles Biomedical Research 

Institute at Harbor-UCLA 

Medical Center 

Torrance, California 

Immediate Past Editor 



Director, Pulmonary Hypertension 

Program 

University of Michigan Health System 

Ann Arbor, Michigan 

Editor-in-Chief Elect 

Richard Channick, MD 

Professor of Clinical Medicine 

Pulmonary and Critical Care Division 

University of California, San Diego Medical 

Center 

San Diego, California 

Associate Editors 

Erika Berman Rosenzweig, MD 

Assistant Professor of Pediatrics 

Department of Pediatrics 

Columbia College of Physicians 

and Surgeons 

New York, New York 

Todd Bull, MD 


Medical Director, ICU Anshutz 

Inpatient Pavilion 

Division of Pulmonary Sciences and 

Critical Care Medicine 

University of Colorado Health Sciences 

Center 

Denver, Colorado 

Robert Schilz, DO, PhD 

Medical Director of Lung Transplantation 

and Pulmonary Vascular Disease 

University Hospital of Cleveland 

Case Western Reserve University 

Cleveland, Ohio 

Editorial Board 

Teresa De Marco, MD 

Director, Heart Failure and 

Pulmonary Hypertension Program 

University of California, San Francisco 

San Francisco, California 

Eli Gabbay, MD 

Associate Professor 

University of Western Australia 

School of Medicine and Pharmacology 

Medical Director, Advanced Lung Disease 

and Pulmonary Vascular Unit 

Royal Perth Hospital 

Perth, Australia 

Kristin Highland, MD 

Assistant Professor 

Division of Pulmonary and Critical 

Care Medicine 

Director, Pulmonary Hypertension Clinic 

Medical University of South Carolina 

Charleston, South Carolina 

Omar Minai, MD 

Staff Physician 

Cleveland Clinic 

Cleveland, Ohio 

Myung H. Park, MD 

Director, Pulmonary Vascular 

Diseases Program 

University of Maryland School of 

Medicine 

Baltimore, Maryland 

Ioana Preston, MD 

Assistant Professor of Medicine 

Tufts-New England Medical Center 

Boston, Massachusetts 

Zeenat Safdar, MD 


Department of Medicine, 

Pulmonary & Critical Care Section 

Pulmonary Hypertension Center 

Baylor College of Medicine 

Houston, Texas 

Rajan Saggar, MD 


Division of Pulmonary and Critical Care 

Medicine and Hospitalists 

David Geffen School of 

Medicine at UCLA 

Los Angeles, California 

Francisco Soto, MD 

Assistant Professor 


Program 

Medical College of Wisconsin 

Milwaukee, Wisconsin 

Fernando Torres, MD 


Program 

UT Southwestern Medical Center 

Dallas, Texas 

Program Description 

The mission of Advances in Pulmonary Hypertension 

is to serve as the premiere 

forum for state of the art information regarding 

diagnosis, pathophysiology, and treatment of 

pulmonary hypertension. The 2003 Venice revision 

of the World Health Organization Classification 

serves as a guide to categories of 

pulmonary hypertension addressed by the Journal. 

While focusing on WHO Group I PAH, the 

other categories (Group II, Left heart 

disease; Group III, Associated with lung disease 

and/or hypoxemia; Group IV, Thrombotic 

and/or Embolic Disease; Group V, Miscellaneous) 

are also addressed. This mission is 

achieved by a combination of invited review articles, 

Roundtable discussions with panels 

consisting of international experts in PH, and 

original contributions. In addition, a special 

section entitled “Profiles in Pulmonary Hypertension”recognizes 

major contributors to the 

field and serves as an inspiring reminder of the 

rich and collegial history of dedication to advancing 

the field. 

Objectives 

• Provide up-to-date information regarding diagnosis, 

pathophysiology, and treatment 

of pulmonary hypertension. 

• Serve as a forum for presentation and discussion 

of important issues in the field, including 

new paradigms of disease 

understanding and investigational trial design. 

• Recognize and preserve the rich history of 

individuals who have made major contributions 

to the field via dedication to patient 

care, innovative research, and furthering the 

mission of the PH community to cure pulmonary 

hypertension. 

The Scientific Leadership 

Council of the Pulmonary 

Hypertension Association 

The scientific program of the Pulmonary 

Hypertension Association is guided by 

the association’s Scientific Leadership 

Council. The Council includes the 

following health care professionals: 


SLC Chair 

University of Michigan Health System 


David B. Badesch, MD 

SLC Immediate Past Chair 

University of Colorado Health 

Sciences Center 


John H. Newman, MD 

SLC Chair Elect 

Vanderbilt Medical School 

Nashville, Tennessee 

Robyn J. Barst, MD 


Raymond L. Benza, MD 

University of Alabama Health System 

Birmingham, Alabama 

Todd Bull, MD 




Richard N. Channick, MD 

UCSD Medical Center 

San Diego, California 

C. Gregory Elliott, MD 

LDS Hospital 

University of Utah School of Medicine 

Salt Lake City, Utah 

Karen A. Fagan, MD 


College of Medicine 


Adaani Frost, MD 

Baylor College of Medicine 

Houston, Texas 

John Granton, MD 

Toronto General Hospital 

Toronto, Canada 

Nazzareno Galiè, MD 

Institute of Cardiology 

University of Bologna 

Bologna, Italy 

Nicholas S. Hill, MD 

Division of Pulmonary, Critical Care 

and Sleep Medicine 

Tufts-New England Medical Center 


Marius Hoeper, MD 

Hannover Medical school 

Hannover, Germany 

Dunbar Ivy, MD 




Zhi-Cheng Jing, MD 

Fu wai Heart Hospital 

Beijing, China 

Anne M. Keogh, MD 

St. Vincent’s Public Hospital 

Sydney, Australia 

Michael J. Krowka, MD 

Mayo Clinic 

Rochester, Minnesota 

James E. Loyd, MD 

Vanderbilt University Medical Center 


Michael D. McGoon, MD 

Chair, PHA Board of Trustees 

Pulmonary Hypertension Clinic 

Mayo Clinic 


Srinivas Murali, MD 

Allegheny General Hospital 

Pittsburgh, Pennsylvania 


Liu Center for Pulmonary Hypertension 

Los Angeles Biomedical Research 

Institute 

Harbor-UCLA Medical Center 

Torrance, California 

Marlene Rabinovitch, MD 

Stanford University School of Medicine 

Stanford, California 

Erica Berman-Rosenzweig, MD 

Columbia-Presbyterian Medical Center 


Ivan M. Robbins, MD 

SLC Scientific Sessions Committee 

Vanderbilt University 


Julio Sandoval, MD 

Cardiopulmonary Department 

National Institute of Cardiology 

of Mexico 

Tlalpan, Mexico 

Richard Silver, MD 

Medical University of South Carolina 

Charleston, South Carolina 

Victor F. Tapson, MD 

Division of Pulmonary and Critical 

Care Medicine 

Duke University Medical Center 

Durham, North Carolina 

Liaisons 

Arlene Schiro, RN, MA, ACNP-BC 

Chair, PH Resource Network 

Massachusetts General Hospital 


Joanne Sperando Schmidt 

Patient Liaison 

Emeritus Members 

Bruce H. Brundage, MD 

St. Charles Medical Center-Bend 

Bend, Oregon 

Alfred P. Fishman, MD 

University of Pennsylvania Health 

System 

Philadelphia, Pennsylvania 

The Mission of the Scientific Leadership 

Council is to provide medical and scientific 

guidance and support to the PHA by: 

• Developing and disseminating knowledge 

for diagnosing and treating pulmonary 

hypertension 

• Advocating for patients with pulmonary hypertension 

• Increasing involvement of basic and clinical 

researchers and practitioners 

More information on PHA’s Scientific 

Leadership Council and associated 

committees can be found at: 

www.PHAssociation.org/SLC/ 

Advances in Pulmonary Hypertension 319

In a Remarkably Short Time, 

Vallerie McLaughlin, MD, Joins 

a Select Group of Investigators 

Blazing a Trail in PH Research 

Vallerie V. 

McLaughlin, MD 

The career path of Vallerie V. McLaughlin, 

MD, appeared clearly headed toward 

her choice of echocardiography until opportunity 

knocked on her office door in 

the form of Stuart Rich, MD, one of the 

country’s foremost experts on pulmonary 

hypertension (PH). Dr Rich offered her 

the chance to work with him on the PH 

service at the University of Illinois Hospital 

and Clinics in Chicago. Fresh from 

a cardiology fellowship at Northwestern 

University and from advanced training and research in 

echocardiography, Dr McLaughlin recognized the compelling 

opportunity to work with PH patients at a critical 

juncture in their care, soon after the emergence of prostacyclin 

treatment. 

Accepting the offer, Dr McLaughlin embarked on a remarkable 

journey, first under the tutelage of Dr Rich and 

in the last 10 years during which she has been an integral 

part of every pivotal trial in PH as the spectrum of therapy 

grew significantly. Those first PH patients, however, provided 

the initial momentum for her commitment to the 

field. “They came to us so short of breath and we were 

able to help them with epoprostenol. It was a rewarding 

opportunity to make them better.” As an Associate Professor 

of Medicine at Rush Medical College, Chicago, 

Dr McLaughlin then became Associate Director, Rush 

Heart Institute Center of Pulmonary Heart Disease. 

“Everyone comes to a time when they need to take 

off on their own and it was time for me to venture out,” 

she recalled, citing her next opportunity to become director 

of the pulmonary hypertension program at the University 

of Michigan. The program at Michigan has become 

one of the leading PH centers in the country. The author 

or co-author of more than 60 peer-reviewed articles, 

Dr McLaughlin is now the Principal Investigator of the 

Data Coordinating Center and Chairperson of the Steering 

Committee for the Pulmonary Hypertension Breakthrough 

Initiative, supported by The Cardiovascular Medical Research 

and Education Fund (CMREF). The CMREF mission 

is the support of research to uncover the etiology and 

pathogenesis of idiopathic pulmonary arterial hypertension 

(IPAH, or PPH), in pursuit of the ultimate goal of its treatment 

and cure. 

The Initiative procures the lungs of patients with PH 

who are undergoing a lung transplant, processes them, 

and distributes them for scientific study, according to 

Dr McLaughlin. “We hope that by getting diseased lungs 

into researchers’ hands we can make a real breakthrough 

in this disease. The main research interest of this project 

is basic science—including the pathology, proteomics, 

and genomics of PH. We have a center that is culturing 

endothelial, smooth muscle, and adventitial cells so we 

can do in vitro work with actual cells from PH patients.” 

Continuing her commitment to the programs of the 

Pulmonary Hypertension Association, Dr McLaughlin last 

year became the chair of PHA’s Scientific Leadership 

Council. Helping to coordinate PHA’s educational initiatives 

and multi-industry support, she oversees a broad 

range of initiatives such as the 30-city tour of educational 

programs, a preceptorship program, an online component 

offering different educational tracks for specialists and 

generalists and various regional events for patients and 

physicians. 

Despite her leadership position as Principal Investigator 

on numerous trials and her role in spearheading other 

research and educational activities, Dr McLaughlin is 

quick to offer her appreciation to colleagues who she says 

have served her so well as mentors and role models. Comments 

from some of these colleagues are among the 

following tributes offered to Dr McLaughlin. 

“Val is a highly dedicated PH physician and investigator. 

She is clearly loved by her patients, and she’s highly respected 

by her colleagues in the field. I don’t know quite 

how she does it all – she travels extensively, and yet is 

somehow able to serve as the director of a highly successful 

PH program at the University of Michigan, lead an 

effort to develop a comprehensive consensus statement for 

the American College of Cardiology, help to coordinate the 

PAH Breakthrough Initiative, serve as Chair of the Scientific 

Leadership Council for the PHA, and be a mom. There 

simply are not enough hours in the day to do this, and I 

happen to know that Val works through much of the night 

and on weekends as well – having received emails sent at 

some very early morning hours, and throughout the weekend. 

We are all very fortunate to have such a highly 

talented, hardworking, and dedicated colleague.” 

—David Badesch, MD 

“Val McLaughlin’s dedication to advancing research in 

pulmonary hypertension, educating others in the field, and 

her incredible energy and drive have been an inspiration 

to many, including me. The numerous, widely quoted 

papers bearing her name as first author testify to her importance 

in the field of clinical research in pulmonary 

hypertension. Although she is chronologically my junior, 

she has, in fact been a valued mentor!” 

—Richard Channick, MD 

“I first got to know Vallerie during the 2nd WHO PPH Sym- 

320 Advances in Pulmonary Hypertension

Advances in Pulmonary Hypertension 

Author Guidelines 2008 

Scope of Manuscripts 

Advances in Pulmonary Hypertension considers 

the following types of manuscripts for publication: 

• Reviews that summarize and synthesize peerreviewed 

literature to date on relevant topics in a 

scholarly fashion and format. 

• Letters to the Editor 

• Clinical Case Studies 

Manuscript Submission 

Authors are required to submit their manuscripts 

in an electronic format, preferably by email to 

the Editor-in-Chief, Richard Channick, MD, 

rchannick@ucsd.edu. Please provide manuscripts 

in a word processing program. Images should be 

submitted electronically as well. 

All material reproduced from previously published, 

copyrighted material should contain a full credit line 

acknowledging the original source. Authors are responsible 

for obtaining permission to reproduce 

such material. 

Contact Information: List all authors, including mailing 

address, titles and affiliations, phone, fax, and email. 

Please note corresponding author. 

Peer Review and Editing: Manuscripts will be peer reviewed. 

Accepted manuscripts will be edited for clarity, 

spelling, punctuation, grammar, and consistency with 

American Medical Association (AMA) style. 

Manuscript Preparation 

Length: Full-length manuscripts should not exceed 

4,000 words, including references. Please limit the 

reference list to 50 citations. Manuscripts should be 

accompanied by figures and/or tables. Generally, 4 to 5 

figures and 2 to 3 tables are preferred for each manuscript. 

Please include a brief description to accompany 

these items, as well as a key for all abbreviated 

words. 

Spacing: One space after commas and periods. Manuscripts 

should be double spaced. Manuscripts should 

not contain an abstract but an introduction is recommended. 

References: All submissions should include numbered 

references that are referred to in the text by superscripts 

and that conform to AMA style. Example: 

Lewczuk J, Piszko P, Jagas J, et al. Prognostic factors 

in medically treated patients with chronic pulmonary 

embolism. Chest. 2001;119:818-823. 

Copyright: Manuscripts and accompanying material 

are accepted for exclusive publication in Advances in 

Pulmonary Hypertension. None of the contents may 

be reproduced without permission of the Pulmonary 

Hypertension Association. To request permission, 

please contact Donica Merhazion, PHA Associate 

Director of Medical Services, 240 485 0744 or 

Donica@phassociation.org 

posium in Evian in 1998. It took no time whatsoever to 

know she had what it takes to become a top leader in the 

PH field. In addition to being bright, she was, and still is, 

incredibly compassionate, a critical thinker who does not 

take the written word as carte blanche but at the same 

time is truly modest regarding her significant contributions 

to the field. She knows how to ask questions, and question 

what may be considered “accepted” with grace. I have had 

the great pleasure to watch her grow and flourish. And although 

she has an enormous amount on her plate at one 

time, she never neglects any commitment she makes; and 

yet, she maintains the equipoise to know how important 

her children and family are to her, and she to them. I am 

not saying that what Vallerie has been able to accomplish 

is easy but I am certain that she has done it not for the accolades 

from others but because she is truly passionate 

about her career as she is about her family; and with her 

passion, she is able to make it work!!”—Robyn Barst, MD 

“Dr McLaughlin is a true leader in the field of pulmonary 

hypertension. She is involved in many of the important 

projects ongoing in this area and her commitment to the 

PHA is unwavering. I have had the opportunity to work 

with Val during my tenure on the SLC of the PHA and have 

always been impressed by her ability to quickly identify the 

key elements of any perceived problem or plan and at her 

skill at providing potential solutions and improvements. 

Her prominence in the field is evidenced by her authorship 

on many of the important papers and position statements 

that have been recently published and her skill as a physician 

is highlighted by the respect of her peers and the testimony 

of her patients. Personally, she has been an 

important mentor in my career and I am very happy to see 

her receive this well deserved recognition. The interesting 

thing is she is just now hitting her stride so we will continue 

to see great contributions from Val for years to 

come.”—Todd Bull, MD ■ 


Building Medical 

Education in PH: 

A Partnership Initiative to 

Advance Medical Understanding of 

Pulmonary Hypertension 

Building Medical Education in PH events are designed 

to foster partnerships between PHA and PH Centers to 

promote continuing education in the field of Pulmonary 

Hypertension through CME educational events. 

Upcoming Events for 

Medical Professionals Include: 

February 13, 2009 

Warrensville Heights, OH 

PAH in the Real World: Managing 

the Aspects of a Frequently 

Missed Diagnosis Symposium 

University Hospitals Case 

Medical Center 

Pulmonary Arterial Hypertension is a frequently misunderstood 

diagnosis. This one-day symposium will offer lectures, case studies 

and open discussions with key opinion leaders in the area of 

pulmonary hypertension. After attending this symposium, one 

should better understand this unusual disease process. Visit 

http://cme.case.edu or call 216-983-1239. 

March 13 – 14, 2009 

San Francisco, CA 

2nd International Conference 

on Neonatal and Childhood 

Pulmonary Vascular Disease 

University of California, 

San Francisco 

It is increasingly clear that pulmonary vascular pathology is integral 

to a number of childhood disorders. In this symposium, we will 

bring together international experts to explore our current understanding 

of the basic pathobiology as well as new and future 

therapies for neonatal, pediatric and adult pulmonary vascular 

disease. Visit https://www.cme.ucsf.edu/cme/ or call 415-476-4251. 

June 4, 2009 

Hartford, CT 

3rd Annual Pulmonary 

Hypertension Symposium 

Yale University School of Medicine 

This one-day symposium will provide current educational information 

to properly diagnosis and treat pulmonary hypertension. 

More information will be available in 2009. To view the agenda 

from Yale’s 2nd Annual PH Symposium visit 

http://cme.yale.edu/conferences/. 

To partner with PHA in Building Medical Education in PH for 

your upcoming CME event, please contact Jennie Carman, 

Meetings Planning Associate, at 301-565-3004 x763 or 

BME@PHAssociation.org.

SECOND 

WIND 

IN PAH

FLOLAN: 

Over a Decade of 

Experience in PAH 

INDICATION: FLOLAN is indicated for the long-term intravenous treatment of primary pulmonary hypertension and pulmonary hypertension associated 

with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy. 

IMPORTANT SAFETY INFORMATION: Chronic use of FLOLAN is contraindicated in patients with congestive heart failure due to severe left ventricular 

systolic dysfunction. 

FLOLAN should not be used chronically in patients who develop pulmonary edema during dose initiation. 

FLOLAN must be reconstituted only as directed using STERILE DILUENT for FLOLAN. FLOLAN must not be reconstituted or mixed with any other 

parenteral medications or solutions prior to or during administration. 

Abrupt withdrawal or reductions in delivery of FLOLAN, as well as overdoses, may result in hemodynamic instability, including rebound pulmonary 

hypertension or fatal hypotension. 

FLOLAN should be used only by clinicians experienced in the diagnosis and treatment of pulmonary hypertension. 

FLOLAN is a potent inhibitor of platelet aggregation. Therefore, an increased risk for hemorrhagic complications should be considered, particularly for 

patients with other risk factors for bleeding. 

During chronic use, FLOLAN is delivered continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless 

contraindicated, anticoagulant therapy should be administered to PPH and PH/SSD patients receiving FLOLAN to reduce the risk of pulmonary 

thromboembolism or systemic embolism through a patent foramen ovale. In order to reduce the risk of infection, aseptic technique must be used in the 

reconstitution and administration of FLOLAN as well as in routine catheter care. Dosage of FLOLAN during chronic use should be adjusted at the first 

sign of recurrence or worsening of symptoms. 

Chronic adverse events reported during clinical trials include headache, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, 

and anxiety/nervousness. 

Serious adverse events have been reported during post-approval use of FLOLAN. These include sepsis, anemia, hypersplenism, thrombocytopenia, 

pancytopenia, splenomegaly, and hyperthyroidism. 

Excessive doses of FLOLAN may acutely result in systemic hypotension, tachycardia, headache, flushing, nausea and vomiting, or diarrhea; excessive 

doses administered chronically can lead to the development of a hyperdynamic state and high-output cardiac failure.* 

* Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hypertension: 

ACCP evidence-based clinical practice guidelines. Chest. 2004;126(1, suppl):35S-62S. 

Please see adjacent page for brief summary of full prescribing information. 

© 2008 Gilead Sciences, Inc. All rights reserved. FLO07203PAD May 2008 

Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc. 

FLOLAN is a registered trademark of GlaxoSmithKline Group of Companies.

FLOLAN ® (epoprostenol sodium) for Injection 

Brief Summary of full prescribing information. See full prescribing information. Rx only. 

INDICATIONS AND USAGE: 

FLOLAN is indicated for the long-term intravenous treatment of primary pulmonary hypertension and pulmonary 

hyperten sion associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do 

not respond ade quately to conventional therapy. 

CONTRAINDICATIONS: 

The chron ic use of FLOLAN in patients with congestive heart failure due to severe left ventricular systolic dysfunction 

is therefore con traindicated. Some patients with pulmonary hypertension have developed pulmonary edema during 

dose initiation, which may be asso ciated with pulmonary veno-occlusive disease. FLOLAN should not be used 

chronically in patients who develop pulmonary edema during dose initiation. FLOLAN is also contraindicated in patients 

with known hypersensitivity to the drug or to structurally related compounds. 

WARNINGS: 

FLOLAN must be reconstituted only as directed using Sterile Diluent for FLOLAN. FLOLAN must not be reconstituted 

or mixed with any other parenteral medications or solutions prior to or during administration. Abrupt 

Withdrawal: Abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of FLOLAN 

may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia. In 

clinical trials, one Class III PPH patient’s death was judged attributable to the interruption of FLOLAN. Abrupt withdrawal 

should be avoided. Sepsis: See ADVERSE REACTIONS: Adverse Events Attributable to the Drug Delivery System. 

PRECAUTIONS: 

General: FLOLAN should be used only by clinicians experienced in the diagnosis and treatment of pulmonary hypertension. 

FLOLAN is a potent pulmonary and systemic vasodilator. Dose initiation with FLOLAN must be performed in a 

setting with adequate personnel and equipment for physiologic monitoring and emergency care. Dose initiation in 

controlled PPH clini cal trials was performed during right heart catheterization. In uncontrolled PPH and controlled 

PH/SSD clinical trials, dose initiation was performed without cardiac catheterization. The risk of cardiac catheterization 

in patients with pulmonary hyper tension should be carefully weighed against the potential benefi ts. During dose initiation, 

asymptomatic increases in pul monary artery pressure coincident with increases in cardiac output occurred rarely. 

In such cases, dose reduction should be considered, but such an increase does not imply that chronic treatment is 

contraindicated. FLOLAN is a potent inhibitor of platelet aggregation. Therefore, an increased risk for hemorrhagic 

complications should be considered, particularly for patients with other risk factors for bleeding (see PRECAUTIONS: 

Drug Interactions). During chronic use, FLOLAN is delivered continuously on an ambulatory basis through a permanent 

indwelling central venous catheter. Unless contraindicated, anticoagulant therapy should be administered to PPH and 

PH/SSD patients receiv ing FLOLAN to reduce the risk of pulmonary thromboembolism or systemic embolism through a 

patent foramen ovale. In order to reduce the risk of infection, aseptic technique must be used in the reconstitution and 

administration of FLOLAN as well as in routine catheter care. Because FLOLAN is metabolized rapidly, even brief interruptions 

in the delivery of FLOLAN may result in symptoms associated with rebound pulmonary hypertension including 

dyspnea, dizziness, and asthenia. The decision to initiate therapy with FLOLAN should be based upon the understanding 

that there is a high likelihood that intra venous therapy with FLOLAN will be needed for prolonged periods, possibly 

years, and the patient’s ability to accept and care for a permanent intravenous catheter and infusion pump should be 

carefully considered. Dosage of FLOLAN during chronic use should be adjusted at the fi rst sign of recurrence or worsening 

of symptoms attributable to pulmonary hypertension or the occurrence of adverse events associated with FLOLAN 

(see DOSAGE AND ADMINISTRATION). Following dosage adjustments, standing and supine blood pressure and heart 

rate should be monitored closely for several hours. Information for Patients: Patients receiving FLOLAN should receive 

the following information. FLOLAN must be recon stituted only with Sterile Diluent for FLOLAN. FLOLAN is infused 

continuously through a permanent indwelling central venous catheter via a small, portable infusion pump. Thus, therapy 

with FLOLAN requires commitment by the patient to drug reconstitution, drug administration, and care of the permanent 

central venous catheter. Sterile technique must be adhered to in preparing the drug and in the care of the 

catheter, and even brief interruptions in the delivery of FLOLAN may result in rapid symptomatic deterioration. A patient’s 

decision to receive FLOLAN should be based upon the understanding that there is a high likelihood that therapy 

with FLOLAN will be needed for prolonged periods, possibly years. The patient’s ability to accept and care for a permanent 

intravenous catheter and infusion pump should also be carefully considered. Drug Interactions: Additional reductions 

in blood pressure may occur when FLOLAN is administered with diuretics, antihypertensive agents, or other vasodilators. 

When other antiplatelet agents or anticoagulants are used concomitantly, there is the potential for FLOLAN to 

increase the risk of bleeding. However, patients receiving infusions of FLOLAN in clinical trials were maintained on 

anticoagulants without evidence of increased bleeding. In clinical trials, FLOLAN was used with digoxin, diuretics, anticoagulants, 

oral vasodilators, and supplemental oxygen. In a pharmacokinetic substudy in patients with congestive 

heart failure receiving furosemide or digoxin in whom therapy with FLOLAN was initiated, apparent oral clearance values 

for furosemide (n = 23) and digoxin (n = 30) were decreased by 13% and 15%, respectively, on the second day of 

therapy and had returned to baseline values by day 87. The change in furosemide clearance value is not likely to be 

clinically signifi cant. However, patients on digoxin may show elevations of digoxin concentrations after initiation of 

therapy with FLOLAN, which may be clinically signifi cant in patients prone to digoxin toxicity. Carcinogenesis, Mutagenesis, 

Impairment of Fertility: Long-term studies in animals have not been performed to evaluate carcinogenic 

potential. A micronucleus test in rats revealed no evidence of mutagenicity. The Ames test and DNA elution tests were 

also negative, although the instability of epoprostenol makes the signifi cance of these tests uncertain. Fertility was not 

impaired in rats given FLOLAN by subcutaneous injection at doses up to 100 mcg/kg/day (600 mcg/m 2 /day, 2.5 times 

the recommended human dose [4.6 ng/kg/min or 245.1 mcg/m 2 /day, IV] based on body surface area). Pregnancy: 

Pregnancy Category B. Reproductive studies have been performed in pregnant rats and rabbits at doses up to 

100 mcg/kg/day (600 mcg/m 2 /day in rats, 2.5 times the recommended human dose, and 1,180 mcg/m 2 /day in rabbits, 

4.8 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility 

or harm to the fetus due to FLOLAN. There are, however, no adequate and well-controlled studies in pregnant women. 

Because animal reproduction studies are not always predictive of human response, this drug should be used during 

pregnancy only if clearly needed. Labor and Delivery: The use of FLOLAN during labor, vaginal delivery, or cesarean 

section has not been adequately studied in humans. Nursing Mothers: It is not known whether this drug is excreted in 

human milk. Because many drugs are excreted in human milk, caution should be exercised when FLOLAN is administered 

to a nursing woman. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. 

Geriatric Use: Clinical studies of FLOLAN in pulmonary hypertension did not include suffi cient numbers of subjects 

aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience 

has not identifi ed differences in responses between the elderly and younger patients. In general, dose selection 

for an elderly patient should be cautious, usually starting at the low end of the dosing range, refl ecting the greater 

frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. 

ADVERSE REACTIONS: 

During clinical trials, adverse events were classifi ed as follows: (1) adverse events during dose initiation and escalation, 

(2) adverse events during chronic dosing, and (3) adverse events associated with the drug delivery system. 

Adverse Events During Dose Initiation and Escalation: During early clinical trials, FLOLAN was increased in 2-ng/ 

kg/min increments until the patients developed symptomatic intolerance. The most common adverse events and the 

adverse events that limited further increases in dose were generally related to vasodilation, the major pharmacologic 

effect of FLOLAN. The most common dose-limiting adverse events (occurring in ≥1% of patients) were nausea, vomiting, 

headache, hypoten sion, and fl ushing, but also include chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal 

pain, musculoskeletal pain, and tachycardia. Adverse events reported in ≥1% of patients receiving FLOLAN 

(n = 391) during dose initiation and escalation are: fl ushing 58%; headache 49%; nausea/vomiting 32%; hypotension 

16%; anxiety, nervousness, agitation 11%; chest pain 11%; dizziness 8%; bradycardia 5%; abdominal pain 5%; musculoskeletal 

pain 3%; dyspnea 2%; back pain 2%; sweating 1%; dyspepsia 1%; hypesthesia/paresthesia 1%; and 

t ach y c ar dia 1%. Adverse Events During Chronic Administration: Interpretation of adverse events is complicated by 

the clinical features of PPH and PH/SSD, which are similar to some of the pharmacologic effects of FLOLAN (e.g., dizziness, 

syncope). Adverse events probably related to the underlying disease include dyspnea, fatigue, chest pain, edema, 

hypoxia, right ventricular fail ure, and pallor. Several adverse events, on the other hand, can clearly be attributed to 

FLOLAN. These include headache, jaw pain, fl ushing, diarrhea, nausea and vomiting, fl u-like symptoms, and anxiety/ 

nervousness. Adverse Events During Chronic Administration for PPH: In an effort to separate the adverse effects of 

the drug from the adverse effects of the underlying disease, the following is a listing of adverse events that occurred at 

a rate at least 10% dif ferent in the 2 groups [FLOLAN (n = 52), conventional therapy (n = 54)] in controlled trials for 

PPH (events are listed by incidence for FLOLAN followed by conventional therapy): Occurrence More Common with 

FLOLAN: General: chills/fever/sepsis/fl u-like symptoms (25%, 11%); Cardiovascular: tachycardia (35%, 24%), fl ushing 

(42%, 2%); Gastrointestinal: diarrhea (37%, 6%), nausea/vomiting (67%, 48%); Musculoskeletal: jaw pain 

(54%, 0%), myalgia (44%, 31%), nonspecifi c musculoskeletal pain (35%, 15%); Neurological: anxiety/nervousness/ 

tremor (21%, 9%), dizziness (83%, 70%), headache (83%, 33%), hypesthesia, hyper esthesia, paresthesia (12%, 2%). 

Occurrence More Common With Standard Therapy: Cardiovascular: heart failure (31%, 52%), syncope (13%, 

24%), shock (0%, 13%); Respiratory: hypoxia (25%, 37%). Thrombocytopenia has been reported during uncontrolled 

clinical trials in patients receiving FLOLAN. 

Additional adverse events that occurred at a rate with less than 10% difference reported in PPH patients receiving 

FLOLAN ® (epoprostenol sodium) for injection plus conventional therapy (n = 52) compared to conventional therapy alone 

(n = 54) during controlled clinical trials (events are listed by incidence for FLOLAN followed by conventional therapy): 

General: asthenia (87%, 81%); Cardiovascular: angina pectoris (19%, 20%), arrhythmia (27%, 20%), bradycardia 

(15%, 9%), supraventricu lar tachycardia (8%, 0%), pallor (21%, 30%), cyanosis (31%, 39%), palpitation (63%, 61%), 

cerebrovascular accident (4%, 0%), hemorrhage (19%, 11%), hypotension (27%, 31%), myocardial ischemia (2%, 

6%); Gastrointestinal: abdominal pain (27%, 31%), anorexia (25%, 30%), ascites (12%, 17%), constipation (6%, 

2%); Metabolic: edema (60%, 63%), hypokalemia (6%, 4%), weight reduction (27%, 24%), weight gain (6%, 4%); 

Musculoskeletal: arthralgia (6%, 0%), bone pain (0%, 4%), chest pain (67%, 65%); Neurological: confusion (6%, 

11%), convulsion (4%, 0%), depression (37%, 44%), insomnia (4%, 4%); Respiratory: cough increase (38%, 46%), 

dyspnea (90%, 85%), epistaxis (4%, 2%), pleural effusion (4%, 2%); Skin and Appendages: pruritus (4%, 0%), rash 

(10%, 13%), sweating (15%, 20%); Special Senses: amblyopia (8%, 4%), vision abnormality (4%, 0%). Adverse 

Events During Chronic Administration for PH/SSD: In an effort to separate the adverse effects of the drug from the 

adverse effects of the underlying disease, the following is a listing of adverse events that occurred at a rate at least 

10% different in the 2 groups [FLOLAN (n = 56) and conventional therapy (n = 55)] in the controlled trial for patients 

with PH/SSD (events are listed by incidence for FLOLAN followed by conventional therapy): Occurrence More Common 

With FLOLAN: Cardiovascular: fl ushing (23%, 0%), hypotension (13%, 0%); Gastrointestinal: anorexia (66%, 47%), 

nausea/vomiting (41%, 16%), diarrhea (50%, 5%); Musculoskeletal: jaw pain (75%, 0%), pain/neck pain/arthralgia 

(84%, 65%); Neurological: headache (46%, 5%); Skin and Appendages: skin ulcer (39%, 24%), eczema/rash/urticaria 

(25%, 4%). Occurrence More Common With Conventional Therapy: Cardiovascular: cyanosis (54%, 80%), 

pallor (32%, 53%), syncope (7%, 20%); Gastrointestinal: ascites (23%, 33%), esophageal refl ux/gastritis (61%, 

73%); Metabolic: weight decrease (45%, 56%); Neurological: dizziness (59%, 76%); Respiratory: hypoxia (55%, 

65%). Additional adverse events that occurred at a rate with less than 10% difference reported in PH/SSD patients 

receiving FLOLAN plus conventional therapy (n = 56) or conventional therapy alone (n = 55) during controlled clinical 

trials (adverse events occurred in at least 2 patients in either treatment group and are listed by inci dence for FLOLAN 

followed by conventional therapy): General: asthenia (100%, 98%), hemorrhage/hemorrhage injection site/hemorrhage 

rectal (11%, 2%), infection/rhinitis (21%, 20%), chills/fever/sepsis/fl u-like symptoms (13%, 11%); Blood and 

Lymphatic: thrombocytopenia (4%, 0%); Cardiovascular: heart failure/heart failure right (11%, 13%), myocardial 

infarction (4%, 0%), palpitation (63%, 71%), shock (5%, 5%), tachycardia (43%, 42%), vascular disorder peripheral 

(96%, 100%), vascular disorder (95%, 89%); Gastrointestinal: abdominal enlargement (4%, 0%), abdominal pain 

(14%, 7%), con stipation (4%, 2%), fl atulence (5%, 4%); Metabolic: edema/edema peripheral/edema genital (79%, 

87%), hypercalcemia (48%, 51%), hyperkalemia (4%, 0%), thirst (0%, 4%); Musculoskeletal: arthritis (52%, 45%), 

back pain (13%, 5%), chest pain (52%, 45%), cramps leg (5%, 7%); Respiratory: cough increase (82%, 82%), dyspnea 

(100%, 100%), epistaxis (9%, 7%), pharyngitis (5%, 2%), pleural effusion (7%, 0%), pneumonia (5%, 0%), 

pneumothorax (4%, 0%), pulmonary edema (4%, 2%), respiratory disorder (7%, 4%), sinusitis (4%, 4%); Neurological: 

anxiety/hyperkinesia/nervousness/tremor (7%, 5%), depression/depression psychotic (13%, 4%), hyperesthesia/ 

hypesthesia/paresthesia (5%, 0%), insomnia (9%, 0%), somnolence (4%, 2%); Skin and Appendages: collagen disease 

(82%, 84%), pruritus (4%, 2%), sweat (41%, 36%); Urogenital: hematuria (5%, 0%), urinary tract infection (7%, 

0%). Although the relationship to FLOLAN administration has not been established, pulmonary embolism has been reported 

in several patients taking FLOLAN and there have been reports of hepatic failure. Adverse Events Attributable 

to the Drug Delivery System: Chronic infusions of FLOLAN are delivered using a small, portable infusion pump through 

an indwelling central venous catheter. During controlled PPH trials of up to 12 weeks’ dura tion, up to 21% of patients 

reported a local infection and up to 13% of patients reported pain at the injection site. During a controlled PH/SSD 

trial of 12 weeks’ duration, 14% of patients reported a local infection and 9% of patients reported pain at the injection 

site. During long-term follow-up in the clinical trial of PPH, sepsis was reported at least once in 14% of patients and 

occurred at a rate of 0.32 infections/patient per year in patients treated with FLOLAN. This rate was higher than reported 

in patients using chronic indwelling central venous catheters to administer parenteral nutrition, but lower than reported 

in oncology patients using these catheters. Malfunctions in the delivery system resulting in an inadvertent bolus 

of or a reduc tion in FLOLAN were associated with symptoms related to excess or insuffi cient FLOLAN, respectively (see 

ADVERSE REACTIONS: Adverse Events During Chronic Administration). Observed During Clinical Practice: In addition 

to adverse reactions reported from clinical trials, the following events have been identifi ed during post-approval use of 

FLOLAN. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be 

made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, 

or potential causal connection to FLOLAN. Blood and Lymphatic: Anemia, hypersplenism, pancytopenia, splenomegaly. 

Endocrine and Metabolic: Hyperthyroidism. 

OVERDOSAGE: 

Signs and symptoms of excessive doses of FLOLAN during clinical trials are the expected dose-limiting pharmacologic effects 

of FLOLAN, including flushing, headache, hypotension, tachycardia, nausea, vomiting, and diarrhea. Treatment will 

ordinarily require dose reduction of FLOLAN. One patient with secondary pulmonary hypertension accidentally received 50 mL 

of an unspecifi ed concentration of FLOLAN. The patient vomited and became unconscious with an initially unrecordable 

blood pressure. FLOLAN was dis continued and the patient regained consciousness within seconds. In clinical practice, 

fatal occurrences of hypoxemia, hypotension, and respiratory arrest have been reported following overdosage of FLOLAN. 

DOSAGE AND ADMINISTRATION: 

Important Note: FLOLAN must be reconstituted only with STERILE DILUENT for FLOLAN. Reconstituted solutions of 

FLOLAN must not be diluted or administered with other parenteral solutions or medications (see WARNINGS). Dosage: 

Continuous chronic infusion of FLOLAN should be administered through a central venous catheter. Temporary peripheral 

intravenous infusion may be used until central access is established. Chronic infusion of FLOLAN should be ini tiated at 

2 ng/kg/min and increased in increments of 2 ng/kg/min every 15 minutes or longer until dose-limiting pharmaco logic 

effects are elicited or until a tolerance limit to the drug is established and further increases in the infusion rate are not 

clinically warranted (see Dosage Adjustments). If dose-limiting pharmacologic effects occur, then the infusion rate should 

be decreased to an appropriate chronic infusion rate whereby the pharmacologic effects of FLOLAN are tolerated. In clinical 

tri als, the most common dose-limiting adverse events were nausea, vomiting, hypotension, sepsis, headache, abdominal 

pain, or respiratory disorder (most treatment-limiting adverse events were not serious). If the initial infusion rate of 2 ng/ 

kg/min is not tolerated, a lower dose that is tolerated by the patient should be identifi ed. In the controlled 12-week trial in 

PH/SSD, for example, the dose increased from a mean starting dose of 2.2 ng/kg/min. During the first 7 days of treatment, 

the dose was increased daily to a mean dose of 4.1 ng/kg/min on day 7 of treatment. At the end of week 12, the mean dose 

was 11.2 ng/kg/min. The mean incremental increase was 2 to 3 ng/kg/min every 3 weeks. Dosage Adjustments: Changes 

in the chronic infusion rate should be based on persistence, recurrence, or worsening of the patient’s symptoms of pulmonary 

hypertension and the occurrence of adverse events due to excessive doses of FLOLAN. In general, increases in dose 

from the initial chronic dose should be expected. Increments in dose should be considered if symptoms of pulmonary hypertension 

persist or recur after improving. The infu sion should be increased by 1- to 2-ng/kg/min increments at intervals 

suffi cient to allow assessment of clinical response; these intervals should be at least 15 minutes. Following establishment 

of a new chronic infusion rate, the patient should be observed, and standing and supine blood pressure and heart rate 

monitored for several hours to ensure that the new dose is tolerated. During chronic infusion, the occurrence of dose-limiting 

pharmacological events may necessitate a decrease in infusion rate, but the adverse event may occasionally resolve 

without dosage adjustment. Dosage decreases should be made gradually in 2-ng/kg/min decrements every 15 minutes or 

longer until the dose-limiting effects resolve. Abrupt withdrawal of FLOLAN or sudden large reductions in infusion rates 

should be avoided. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), infusion rates of FLOLAN 

should be adjusted only under the direction of a physician. Administration: FLOLAN is administered by continuous intravenous 

infusion via a central venous catheter using an ambu latory infusion pump. During initiation of treatment, FLOLAN 

may be administered peripherally. 

To avoid potential interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous 

infusion sets. A multi-lumen catheter should be considered if other intravenous therapies are routinely administered. To 

facilitate extended use at ambient temperatures exceeding 25°C (77°F), a cold pouch with frozen gel packs was used in 

clinical trials. Any cold pouch used must be capable of maintaining the temperature of reconstituted FLOLAN between 2° 

and 8°C for 12 hours. Reconstitution: FLOLAN is stable only when reconstituted with STERILE DILUENT for FLOLAN. 

FLOLAN must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during 

administration. Storage and Stability: Unopened vials of FLOLAN are stable until the date indicated on the package 

when stored at 15° to 25°C (59° to 77°F) and protected from light in the carton. Unopened vials of STERILE DILUENT for 

FLOLAN are stable until the date indicated on the package when stored at 15° to 25°C (59° to 77°F). Prior to use, reconstituted 

solutions of FLOLAN must be protected from light and must be refrigerated at 2° to 8°C (36° to 46°F) if not used 

immediately. Do not freeze reconstituted solutions of FLOLAN. Discard any reconstituted solution that has been 

frozen. Discard any reconstituted solution if it has been refrigerated for more than 48 hours. 

©2008, GlaxoSmithKline. All rights reserved. January 2008 FLL:1PI

FOR PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION (PAH) WITH NYHA CLASS II-IV SYMPTOMS 

Joanne 

REMODULIN patient 

Infused with POSSIBILITIES 

When initial PAH therapy loses its momentum, think REMODULIN 

The first and only prostacyclin available for both SC and IV infusion 

Improves symptoms associated with exercise 1,2 

Improves hemodynamics 1 

May be titrated to effect 

Multiple pump options 

No ice packs 

Up to 72 hours (SC) or 48 hours (IV) between reservoir changes 

Indications: REMODULIN ® (treprostinil sodium) Injection is indicated for the treatment of pulmonary arterial hypertension in patients with NYHA 

Class II-IV symptoms to diminish symptoms associated with exercise. It may be administered as a continuous subcutaneous infusion or continuous 

intravenous infusion; however, because of the risks associated with chronic indwelling central venous catheters, including serious blood stream 

infections, continuous intravenous infusion should be reserved for patients who are intolerant of the subcutaneous route, or in whom these risks 

are considered warranted. 

REMODULIN is indicated to diminish the rate of clinical deterioration in patients requiring transition from Flolan ® (epoprostenol sodium) for 

Injection; the risks and benefits of each drug should be carefully considered prior to transition. 

Important Safety Information: Chronic intravenous infusions of REMODULIN are delivered using an indwelling central venous catheter. 

This route is associated with the risk of blood stream infections (BSI) and sepsis, which may be fatal. 

REMODULIN is contraindicated in patients with hypersensitivity to REMODULIN, its ingredients, or similar drugs. REMODULIN is a potent vasodilator. 

It lowers blood pressure, which may be further lowered by other drugs that also reduce blood pressure. REMODULIN inhibits platelet aggregation 

and therefore, may increase the risk of bleeding, particularly in patients on anticoagulants. Abrupt withdrawal or sudden large reductions in dosage 

of REMODULIN may result in worsening of PAH symptoms and should be avoided. Caution should be used in patients with hepatic or renal problems. 

The most common side effects of REMODULIN included those related to the method of infusion. For subcutaneous infusion, infusion site pain and 

infusion site reaction (redness and swelling) occurred in the majority of patients. These symptoms were often severe and could lead to treatment with 

narcotics or discontinuation of REMODULIN. For intravenous infusion, line infections, sepsis, arm swelling, paresthesias, hematoma and pain were most 

common. General side effects (>5% more than placebo) were diarrhea, jaw pain, vasodilation, and edema. 

References: 1. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, 

a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, 

placebo-controlled trial. Am J Respir Crit Care Med. 2002;165(6):800-804. 2. REMODULIN [package insert]. 

United Therapeutics Corporation; 2008. 

For important safety and other information, please see brief summary of 

full prescribing information on the back of this page. 

REMODULIN is a registered trademark of United Therapeutics Corporation. 

Flolan is a registered trademark of GlaxoSmithKline. 

REM_JAd_JUN08v.4 

Empowering Prostacyclin

REMODULIN ® (treprostinil sodium) Injection 

BRIEF SUMMARY 

The following is a brief summary of the full prescribing information on Remodulin 

(treprostinil sodium) Injection. Please review the full prescribing information prior 

to prescribing Remodulin. 

INDICATIONS AND USAGE 

Remodulin is indicated for the treatment of pulmonary arterial hypertension in 

patients with NYHA Class II-IV symptoms to diminish symptoms associated with 

exercise. It may be administered as a continuous subcutaneous (SC) infusion or 

continuous intravenous (IV) infusion; however, because of the risks associated 

with chronic indwelling central venous catheters, including serious blood stream 

infections, continuous IV infusion should be reserved for patients who are 

intolerant of the subcutaneous route, or in whom these risks are considered 

warranted. 

Remodulin is indicated to diminish the rate of clinical deterioration in patients 

requiring transition from Flolan ® ; the risks and benefits of each drug should be 

carefully considered prior to transition. 

DESCRIPTION 

Remodulin ® (treprostinil sodium) Injection is a sterile sodium salt supplied in 20 mL 

vials in four strengths, containing 1 mg/mL, 2.5 mg/mL, 5 mg/mL or 10 mg/mL of 

treprostinil. Each mL also contains 5.3 mg sodium chloride (except for the 10 

mg/mL strength which contains 4.0 mg sodium chloride), 3.0 mg metacresol, 6.3 

mg sodium citrate, and water for injection. 

CONTRAINDICATIONS 

Remodulin is contraindicated in patients with known hypersensitivity to the drug or 

to structurally related compounds. 

WARNINGS 

Adverse Events Attributable to the Intravenous Drug Delivery System 

Chronic IV infusions of Remodulin are delivered using an indwelling central 

venous catheter. This route is associated with the risk of blood stream infections 

(BSIs) and sepsis, which may be fatal. 

In an open-label study of IV treprostinil (n=47), there were seven catheter-related 

line infections during approximately 35 patient years, or about 1 BSI event per 5 

years of use. A CDC survey of seven sites that used IV treprostinil for the 

treatment of PAH found approximately 1 BSI (defined as any positive blood 

culture) event per 3 years of use. 

PRECAUTIONS 

General 

Remodulin should be used only by clinicians experienced in the diagnosis and 

treatment of PAH. Remodulin is a potent pulmonary and systemic vasodilator. 

Initiation of Remodulin must be performed in a setting with adequate personnel 

and equipment for physiological monitoring and emergency care. Therapy with 

Remodulin may be used for prolonged periods, and the patient’s ability to 

administer Remodulin and care for an infusion system should be carefully 

considered. Dose should be increased for lack of improvement in, or worsening of, 

symptoms and it should be decreased for excessive pharmacologic effects or for 

unacceptable infusion site symptoms. Abrupt withdrawal or sudden large 

reductions in dosage of Remodulin may result in worsening of PAH symptoms and 

should be avoided. 

Information for Patients 

Patients receiving Remodulin should be given the following information: 

Remodulin is infused continuously through a SC or surgically placed indwelling 

central venous catheter, via an infusion pump. Therapy with Remodulin will be 

needed for prolonged periods, possibly years, and the patient's ability to accept 

and care for a catheter and to use an infusion pump should be carefully 

considered. In order to reduce the risk of infection, aseptic technique must be 

used in the preparation and administration of Remodulin. Additionally, patients 

should be aware that subsequent disease management may require the initiation 

of an alternative IV prostacyclin therapy, Flolan ® (epoprostenol sodium). 

Drug Interactions 

Reduction in blood pressure caused by Remodulin may be exacerbated by drugs 

that by themselves alter blood pressure, such as diuretics, antihypertensive 

agents, or vasodilators. Since Remodulin inhibits platelet aggregation, there is 

also a potential for increased risk of bleeding, particularly among patients 

maintained on anticoagulants. During clinical trials, Remodulin was used 

concurrently with anticoagulants, diuretics, cardiac glycosides, calcium channel 

blockers, analgesics, antipyretics, nonsteroidal anti-inflammatories, opioids, 

corticosteroids, and other medications. Remodulin has not been studied in 

conjunction with Flolan or Tracleer ® (bosentan). 

Effect of Other Drugs on Remodulin 

In vivo studies: Acetaminophen - Analgesic doses of acetaminophen, 1000 mg 

every 6 hours for seven doses, did not affect the pharmacokinetics of Remodulin, 

at a SC infusion rate of 15 ng/kg/min. 

Effect of Remodulin on Other Drugs 

In vitro studies: Remodulin did not significantly affect the plasma protein binding of 

normally observed concentrations of digoxin or warfarin. 

In vivo studies: Warfarin - Remodulin does not affect the pharmacokinetics or 

pharmacodynamics of warfarin. The pharmacokinetics of R- and S- warfarin and 

the INR in healthy subjects given a single 25 mg dose of warfarin were unaffected 

by continuous SC Remodulin at an infusion rate of 10 ng/kg/min. 

Hepatic and Renal Impairment 

Caution should be used in patients with hepatic or renal impairment. 

Carcinogenesis, Mutagenesis, Impairment of Fertility 

Long-term studies have not been performed to evaluate the carcinogenic potential 

of treprostinil. In vitro and in vivo genetic toxicology studies did not demonstrate 

any mutagenic or clastogenic effects of treprostinil. Treprostinil sodium did not 

affect fertility or mating performance of male or female rats given continuous SC 

infusions at rates of up to 450 ng treprostinil/kg/min [about 59 times the 

recommended starting human rate of infusion (1.25 ng/kg/min) and about 8 times 

the average rate (9.3 ng/kg/min) achieved in clinical trials, on a ng/m2 basis]. In 

this study, males were dosed from 10 weeks prior to mating and through the 2- 

week mating period. Females were dosed from 2 weeks prior to mating until 

gestational day 6. 

Pregnancy 

Pregnancy Category B - In pregnant rats, continuous SC infusions of treprostinil 

sodium during organogenesis and late gestational development, at rates as high 

as 900 ng treprostinil/kg/min (about 117 times the starting human rate of infusion, 

on a ng/m 2 basis and about 16 times the average rate achieved in clinical trials), 

resulted in no evidence of harm to the fetus. In pregnant rabbits, effects of 

continuous SC infusions of treprostinil during organogenesis were limited to an 

increased incidence of fetal skeletal variations (bilateral full rib or right rudimentary 

rib on lumbar 1) associated with maternal toxicity (reduction in body weight and 

food consumption) at an infusion rate of 150 ng treprostinil/kg/min (about 41 times 

the starting human rate of infusion, on a ng/m 2 basis, and 5 times the average rate 

used in clinical trials). In rats, continuous SC infusion of treprostinil from 

implantation to the end of lactation, at rates of up to 450 ng treprostinil/kg/min, did 

not affect the growth and development of offspring. Because animal reproduction 

studies are not always predictive of human response, Remodulin should be used 

during pregnancy only if clearly needed. 

Labor and delivery 

No treprostinil sodium treatment-related effects on labor and delivery were seen in 

animal studies. The effect of treprostinil sodium on labor and delivery in humans is 

unknown. 

Nursing mothers 

It is not known whether treprostinil is excreted in human milk or absorbed 

systemically after ingestion. Because many drugs are excreted in human milk, 

caution should be exercised when Remodulin is administered to nursing women. 

Pediatric use 

Safety and effectiveness in pediatric patients have not been established. Clinical 

studies of Remodulin did not include sufficient numbers of patients aged 40 ng/kg/min. Abrupt cessation of infusion should be 

avoided (see PRECAUTIONS). Restarting a Remodulin infusion within a few 

hours after an interruption can be done using the same dose rate. Interruptions for 

longer periods may require the dose of Remodulin to be re-titrated. 

Administration 

SC Infusion 

Remodulin is administered subcutaneously by continuous infusion, via a selfinserted 

SC catheter, using an infusion pump designed for SC drug delivery. To 

avoid potential interruptions in drug delivery, the patient must have immediate 

access to a backup infusion pump and SC infusion sets. The ambulatory infusion 

pump used to administer Remodulin should: (1) be small and lightweight, (2) be 

adjustable to approximately 0.002 mL/hr, (3) have occlusion/no delivery, low 

battery, programming error and motor malfunction alarms, (4) have delivery 

accuracy of ±6% or better and (5) be positive pressure driven. The reservoir 

should be made of polyvinyl chloride, polypropylene or glass. 

For SC infusion, Remodulin is delivered without further dilution at a calculated 

SC Infusion Rate (mL/hr) based on a patient’s Dose (ng/kg/min), Weight (kg), and 

the Vial Strength (mg/mL) of Remodulin being used. During use, a single 

reservoir (syringe) of undiluted Remodulin can be administered up to 72 hours at 

37C. The SC Infusion rate is calculated using the following formula: 

SC Infusion Rate 

(mL/hr) 

*Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng 

IV Infusion 

Remodulin must be diluted with either Sterile Water for Injection or 0.9% 

Sodium Chloride Injection and is administered intravenously by continuous 

infusion, via a surgically placed indwelling central venous catheter, using an 

infusion pump designed for intravenous drug delivery. If clinically necessary, a 

temporary peripheral intravenous cannula, preferably placed in a large vein, may 

be used for short term administration of Remodulin. Use of a peripheral 

intravenous infusion for more than a few hours may be associated with an 

increased risk of thrombophlebitis. To avoid potential interruptions in drug 

delivery, the patient must have immediate access to a backup infusion pump and 

infusion sets. The ambulatory infusion pump used to administer Remodulin 

should: (1) be small and lightweight, (2) have occlusion/no delivery, low battery, 

programming error and motor malfunction alarms, (3) have delivery accuracy of 

±6% or better of the hourly dose, and (4) be positive pressure driven. The 

reservoir should be made of polyvinyl chloride, polypropylene or glass. Diluted 

Remodulin has been shown to be stable at ambient temperature for up to 48 hours 

at concentrations as low as 0.004 mg/mL (4,000 ng/mL). When using an 

appropriate infusion pump and reservoir, a predetermined intravenous infusion 

rate should first be selected to allow for a desired infusion period length of up to 48 

hours between system changeovers. Typical intravenous infusion system 

reservoirs have volumes of 50 or 100 mL. With this selected Intravenous Infusion 

Rate (mL/hr) and the patient’s Dose (ng/kg/min) and Weight (kg), the Diluted 

Intravenous Remodulin Concentration (mg/mL) can be calculated using the 

following formula: 

Step 1 

Diluted IV 

Remodulin 

Conc. (mg/mL) 

The Amount of Remodulin Injection needed to make the required Diluted 

Intravenous Remodulin Concentration for the given reservoir size can then be 

calculated using the following formula: 

Step 2 

Amount of 

Remodulin 

Injection 

(mL) 

= 

Diluted IV 

Remodulin Conc. 

(mg/mL) 

Remodulin Vial 

Strength (mg/mL) 

x 

Total Volume of 

Diluted Remodulin 

Solution in 

Reservoir 

(mL) 

The calculated amount of Remodulin Injection is then added to the reservoir along 

with the sufficient volume of diluent (Sterile Water for Injection or 0.9% Sodium 

Chloride Injection) to achieve the desired total volume in the reservoir. 

In patients requiring transition from Flolan: 

Transition from Flolan to Remodulin is accomplished by initiating the infusion of 

Remodulin and increasing it, while simultaneously reducing the dose of 

intravenous Flolan. The transition to Remodulin should take place in a hospital 

with constant observation of response (e.g., walk distance and signs and 

symptoms of disease progression). During the transition, Remodulin is initiated at 

a recommended dose of 10% of the current Flolan dose, and then escalated as 

the Flolan dose is decreased (see table below for recommended dose titrations). 

Patients are individually titrated to a dose that allows transition from Flolan therapy 

to Remodulin while balancing prostacyclin-limiting adverse events. Increases in 

the patient’s symptoms of PAH should be first treated with increases in the dose of 

Remodulin. Side effects normally associated with prostacyclin and prostacyclin 

analogs are to be first treated by decreasing the dose of Flolan. 

Recommended Transition Dose Changes 

Step Flolan Dose Remodulin Dose 

1 Unchanged 10% Starting Flolan Dose 

2 80% Starting Flolan Dose 30% Starting Flolan Dose 





7 0 

Dose 

(ng/kg/min) 

110% Starting Flolan Dose + 

additional 5-10% increments as 

needed 

HOW SUPPLIED 

Remodulin ® is supplied in 20 mL multi-use vials at concentrations of 1 mg/mL, 2.5 

mg/mL, 5 mg/mL, and 10 mg/mL treprostinil, as sterile solutions in water for 

injection, individually packaged in a carton. Unopened vials of Remodulin are 

stable until the date indicated when stored at 15 to 25 o C (59 to 77 o F). Store at 

25 o C (77 o F), with excursions permitted to 15-30 o C (59-86 o F) [see USP Controlled 

Room Temperature]. 

During use, a single reservoir (syringe) of undiluted Remodulin can be 

administered up to 72 hours at 37 o C. Diluted Remodulin Solution can be 

administered up to 48 hours at 37 o C when diluted to concentrations as low as 

0.004 mg/mL in Sterile Water for Injection or 0.9% Sodium Chloride Injection. A 

single vial of Remodulin should be used for no more than 30 days after the initial 

introduction into the vial. 

Parenteral drug products should be inspected visually for particulate matter and 

discoloration prior to administration whenever solution and container permit. If 

either particulate matter or discoloration is noted, Remodulin should not be 

administered. 

United Therapeutics Corp., Research Triangle Park, NC 27709 

©Copyright 2008 United Therapeutics Corp. All rights reserved. 

Rx only 

February 2008 

Refer to Full Package Insert 

for Complete Information 

REM_PIBrief_FEB08v.2 

= 

= 

Dose 

(ng/kg/min) 

x 

x 

Weight 

(kg) 

Remodulin Vial Strength 

(mg/mL) 

Weight 

(kg) 

IV Infusion Rate (mL/hr) 

x 0.00006* 

x 0.00006

Announcing the Programs of the 

new PHA Medical Education Fund 

Thirty-City Medical Education Tour 

PHA’s Thirty-City Medical Education Tour will visit cities 

remote from larger PH centers across the United States, 

aiming to present information on the diagnosis and management 

of PAH to physicians and other health professionals 

that do not have regular access to comprehensive sessions 

on pulmonary hypertension. This will encourage collaborative 

peer team building and provide more resources for referrals 

to specialized centers. Programs will begin in the spring of 

2009. Physician CME and nursing CEU credits will be available. 

For information on the specifics of this program and 

the cities where events will take place, please email 

30CityTour@PHAssociation.org. 

Committee Chair 

Darren Taichman, MD 

Penn-Presbyterian Medical Center 

Philadelphia, Pennsylvania 

Committee Advisor 

Michael McGoon, MD 

Mayo Clinic 


Preceptorship Program 

The new Preceptorship Program will facilitate direct 

education and training of medical professionals, focusing on 

cardiologists, pulmonologists, rheumatologists and primary 

care physicians that have PAH patients. This program is 

aimed at improving connections between referring physicians 

and specialists. Led by experienced pulmonary hypertension 

specialists in clinical settings, this program will offer physician 

CME and nursing CEU credits for participants. For more 

information about the Preceptorship Program, please 

email Preceptorship@PHAssociation.org. 


Todd Bull, MD 

University of Colorado 

Health Sciences Center 



Vallerie McLaughlin, MD 

University of Michigan 


PHA Online University 

The PHA Online University will be a focused information 

resource for medical education in pulmonary hypertension 

and will address all levels of expertise and medical interest. 

The website will be launched in the spring of 2009, and 

aims to be the most comprehensive online resource on 

pulmonary hypertension for primary care physicians, 

specialists and allied health professionals. Physician CME 

and Nursing CEU components will be built into the website. 

For information on PHA Online University, please email 

PHAOnlineUniv@PHAssociation.org. 


Robert Frantz, MD 

Mayo Clinic 


PHA on the Road: PH Patients and 

Families Education Forum 

The new Medical Education Program for Patients, PHA 

on the Road, will be visiting Southern California, Southeast 

Michigan, Central Florida and New England in the spring 

of 2009. The goal of these one-day education seminars is 

to present information on the mechanisms, diagnosis and 

treatment of PAH to patients and their family members in 

a face-to-face setting. For information about PHA on the 

Road, please email ontheroad@PHAssociation.org. 


Charles Burger, MD 

Mayo Clinic Florida 

Jacksonville, Florida 


David Badesch, MD 

University of Colorado 


Aurora, Colorado 

The programs of the PHA Medical Education 

Fund are made possible through unrestricted 

educational grants from our sponsors: 

PLATINUM: 

GOLD: 

SILVER:

Advances in Pulmonary Hypertension CME Section 

Program Overview 

Pulmonary arterial hypertension (PAH), an incurable 

disease, is characterized by medial hypertrophy, intimal 

fibrosis, and in situ thrombi in small muscular pulmonary 

arteries. PAH was considered a rapidly fatal illness with 

a median survival of 2.8 years in the 1980s when no 

evidence-based therapies were available. Since then 

the treatment of this disease has made tremendous 

advances, and the last 10 years have seen the discovery 

of new medications that have positively influenced the 

prognosis and survival of patients with PAH. 

This self-study activity is based on 5 articles that review 

the latest information on new treatments, combinations 

of therapies, and data from phase 1 and 2 clinical trials. 

This activity is jointly sponsored by the University of 

Michigan Medical School and the Pulmonary Hypertension 

Association and supported by an unrestricted 

education grant from Actelion Pharmaceuticals US, Inc, 

Encysive Pharmaceuticals, Inc, Gilead Sciences, Inc, 

Pfizer, Inc, and United Therapeutics Corporation. 

Target Audience 

This self-study activity is appropriate for cardiologists, 

pulmonologists, rheumatologists, and other physicians 

who treat patients with pulmonary hypertension. 

Learning Objectives 

Upon completion of this activity participants will be 

able to: 

1. Review the various animal models used in PH 

research to date 

2. Compare and contrast the different pathological 

findings in animal models of PH 

3. Define the metabolic syndrome 

4. Define “diabetic cardiomyopathy” 

5. Review the effects of metabolic syndrome on 

energy production in cardiac myocytes 

6. Identify novel hemodynamic measurements that 

can be made during right heart catheterization 

Self-Assessment Examination 

See pages 351 and 352 for self-assessment questions, 

answer key, and evaluation form. 

Faculty 


Chief, Division of Pulmonary and 

Critical Care Medicine 



Contributing Authors 

Heiko Bugger, MD, PhD 

Division of Endocrinology, Metabolism and 

Diabetes 

Program in Human Molecular Biology and 

Genetics 


E. Dale Abel, MD, PhD 

Division of Endocrinology, Metabolism and 

Diabetes 

Program in Human Molecular Biology and 

Genetics 


Paul M. Hassoun, MD 

Professor of Medicine and Director of the 


Division of Pulmonary and Critical Care Medicine 

Johns Hopkins University, School of Medicine 

Kurt Stenmark, MD 


Developmental Lung Biology Laboratory 

University of Colorado at Denver and 


Hunter C. Champion, MD, PhD 

Pulmonary Hypertension Program and 

Division of Cardiology 

Department of Medicine 

Johns Hopkins Medical Institutions 

Ivan F. McMurtry, PhD 

Departments of Pharmacology and 

Medicine and Center for Lung Biology 


Agenda 

The Metabolic Syndrome and Cardiac Function 

Heiko Bugger, MD, PhD and 

E. Dale Abel, MD, PhD 

National Heart Lung and Blood Institute Hopkins 

Specialized Center in Clinical Oriented Research 

(SCCOR): Molecular Determinants of Pulmonary 

Arterial Hypertension 



(SCCOR) Update: Mechanisms and Treatment of 

Long Vascular Disease in Infants and Children 


Getting More From Right Heart Catheterization: 

A Focus on the Right Ventricle 


Animal Models of Human Severe PAH 



Accreditation Statement 

This activity has been planned and implemented in 

accordance with the Essential Areas and Policies of the 

Accreditation Council for Continuing Medical Education 

(ACCME) through the joint sponsorship of the University 

of Michigan Medical School and the Pulmonary Hypertension 

Association. The University of Michigan is accredited 

by the ACCME to provide continuing medical education 

to physicians. 

Credit Designation 

The University of Michigan Medical School designates 

this activity for a maximum of 2.0 AMA PRA Category 1 

Credits. Physicians should claim credit commensurate 

with the extent of their participation in the activity. 

Instructions for Earning Credit 

This activity is a self-study program; a self-assessment 

examination is included on page 351 to help physicians 

review important points. A form is also included on page 

352 for physicians to evaluate the CME activity. Completion 

of this activity involves reading the journal and 

completing the self-assessment examination and evaluation 

form, which may take up to 2 hours. Credits for this 

self-study program are available from February 1 2009 

through February 1 2010. There is no fee for this 

program. 

Please note that this self-study program may also be 

viewed online at: http://www.cme.med.umich.edu 

University of Michigan Privacy Statement 

http://www.cme.med.umich.edu/privacy.asp 

Sponsorship 

This CME self-study program is jointly sponsored by 

the University of Michigan Medical School and the 

Pulmonary Hypertension Association. 

Support 

This CME self-study program is supported by an educational 

grant from Actelion Pharmaceuticals US, Inc., 

Encysive Pharmaceuticals, Inc., Gilead Sciences, Inc., 

Pfizer, Inc., and United Therapeutics Corporation. 

Oversite and Accreditation 

Arlene Bradford, BA 

Assistant Director 

Office of CME 

University of Michigan Medical School 

Disclosures 

The Accreditation Council for Continuing Medical Education 

and the Association of American Colleges has standards 

and guidelines to ensure that individuals participating 

in CME activities are aware of relationships between 

authors and commercial companies that could potentially 

affect the information presented. To be disclosed 

to participants are all personal financial relationships with 

a commercial interest whose products are relevant to the 

content of this CME activity. The University of Michigan 

Medical School follows these national policies to ensure 

balance, independence, objectivity, and scientific rigor in 

all its CME activities. Each author was asked to complete 

a disclosure information form for this activity. Disclosures 

are reported below. 

Karen Fagan, MD, in the past 12 months has had no 

relevant personal financial relationship with regard to the 

content of this CME activity. Dr. Fagan is on the Speaker 

Panel, Advisory Board and Research Review Committee 

of Gilead. 

Heiko Bugger, MD, PhD, in the past 12 months has had 

no relevant personal financial relationship with regard to 

the content of this CME activity. 

E. Dale Abel, MD, PhD, in the past 12 months has had no 


content of this CME activity. 

Paul M. Hassoun, in the past 12 months has had no 



Kurt Stenmark, MD, in the past 12 months has had no 



Hunter C. Champion, MD,PhD, in the past 12 months has 

had no relevant personal financial relationship with regard 

to the content of this CME activity. He has served as a 

Consultant for Actelion, Gilead, Pfizer, and United 

Therapeutics. 

Ivan F. McMurtry, PhD, in the past 12 months has had no 



Arlene Bradford, BA, has no relevant personal financial 

relationships to disclose. 

CME Reviewer 

Kevin M. Chan, MD 



University of Michigan Health Systems 


Dr Chan has no relevant personal financial relationships 

to disclose. 


Continuing Medical Education Section 

The Metabolic Syndrome and Cardiac Function 

Heiko Bugger, MD, PhD and E. Dale Abel, MD, PhD 

Division of Endocrinology, Metabolism and Diabetes 

Program in Human Molecular Biology and Genetics 


Salt Lake City, Utah 

Heiko Bugger, MD 

E. Dale Abel, MD 

The metabolic syndrome includes obesity, insulin resistance, dyslipidemia, 

and type 2 diabetes mellitus. It increases the risk of developing 

cardiovascular diseases, including heart failure. Evidence 

is emerging that changes in energy metabolism might contribute 

to the development of cardiac myocyte contractile dysfunction. 

The focus of our laboratory is in understanding the potential molecular 

mechanisms for these abnormalities. 

Over 40% of US citizens older than 60 years have metabolic 

syndrome and the prevalence of the metabolic syndrome parallels 

the global epidemic of obesity and diabetes. 1 What is unknown 

is the prevalence of the metabolic syndrome and/or type 2 

diabetes in patients with pulmonary hypertension. More importantly, 

the impact that these comorbidities may have on right ventricular 

performance and patient outcomes is not known. The 

objective of this article is to review the cardiac effects of the metabolic 

syndrome and highlight possible areas for investigation in determinants 

of right ventricular dysfunction. 

Metabolic Alterations 

Obesity, insulin resistance and diabetes increase the risk of developing 

cardiovascular disease. 2-4 Many believe that the major 

determinant of cardiovascular complications in the metabolic syndrome 

is coronary artery disease. Our work suggests that the metabolic 

alterations that occur in obesity and type 2 diabetes can 

also affect cardiac structure and function independently of hypertension 

or coronary artery disease. In addition, after adjusting 

for age, blood pressure, weight, cholesterol, and coronary artery 

disease, obesity is associated with an increased risk of heart failure. 

3,5,6 This “diabetic cardiomyopathy” is defined as ventricular 

Address for reprints and other correspondence: E. Dale Abel, MD, Chief, Division 

of Endocrinology and Professor of Medicine and Biochemistry, Division 

of Endocrinology, Metabolism and Diabetes, Program in Human Molecular 

Biology and Genetics, University of Utah School of Medicine, 15 N. 2030 

East, Rm 3110, Salt Lake City, UT 84112; email: stacis@hmbg.utah.edu. 

Acknowledgments—Studies in the Abel laboratory are supported by research 

grants from the National Institutes of Health: UO1HL70525, UO1 HL087947 

(Animal Models of Diabetes Complications Consortium [AMDCC)]); RO1 

HL70070 and RO1 HL73167, the American Heart Association, and the Juvenile 

Diabetes Research Foundation. Dr Bugger is supported by a postdoctoral 

fellowship from the German Research Foundation. 

systolic or diastolic dysfunction occurring in diabetic patients in 

the absence of coronary artery disease and hypertension. 7-9 Several 

studies have identified the presence of lipid material in the 

hearts of patients who are obese or have type 2 diabetes who have 

had nonischemic heart failure. 10,11 The transcriptional profile of 

these lipid-laden hearts is similar to that of the Zucker diabetic rat 

(ZDF), an animal model of lipotoxicity and contractile dysfunction, 

which suggests that dysregulation of fatty acid metabolism 

in failing human hearts may contribute to contractile dysfunction. 

Most mechanistic insights into obesity-related cardiomyopathy 

and diabetic cardiomyopathy have come from rodent studies. The 

most widely investigated models are db/db mice (leptin receptor 

mutation), ob/ob mice (leptin deficiency), and ZDF rats (leptin receptor 

mutation). All of these models have obesity, insulin resistance, 

and hyperglycemia in common, although to varying degrees 

in each model. 12,13 These animals do not develop atherosclerosis, 

which allows an evaluation of the effects of obesity, insulin resistance, 

and type 2 diabetes in the heart that are independent of 

coronary artery disease. 13,14 Each of these animal models is associated 

with evidence of contractile dysfunction, both systolic and 

diastolic, which further supports the existence of an obesity-related 

and/or diabetic cardiomyopathy. 15-24 

Pathophysiology 

Patients with type 2 diabetes have decreased whole-body aerobic 

capacity that may be related to decreased expression of mitochondrial 

proteins in skeletal muscle. 25-28 Mitochondrial function 

and morphology are also abnormal in prediabetic and diabetic 

states and include a reduction in overall mitochondrial size and 

content and a 30% reduction in ATP synthesis. 29-32 What is not 

clear is whether these skeletal muscle mitochondrial abnormalities 

represent a genetic predisposition to the metabolic syndrome 

or acquired defects. 33,34 

Cardiac muscle mitochondria have been less well studied. A 

few indirect studies suggest that myocardial mitochondrial function 

is altered in obesity and diabetes as evidenced by increased 

oxygen consumption and reduced cardiac efficiency. 35 Which are, 

in turn, associated with increased myocardial fatty acid use and 

impaired glucose tolerance. More direct evidence for cardiac mi- 


Figure. Model for Synergistic Effects of Insulin Resistance and FA Excess in Precipitating Mitochondrial 

Dysfunction in Hearts. FA, fatty acids; ROS, reactive oxygen species; UCP, uncoupling protein; ANT, adenine 

nucleotide translocase; ATP, adenosine triphosphate; ADP, adenosine diphosphate. 

tochondrial dysfunction in patients with type 2 diabetes has come 

from studies using 31 P nuclear magnetic resonance (NMR) spectroscopy. 

Findings from these studies suggest that patients with 

type 2 diabetes have reduced cardiac phosphocreatine/adenosine 

triphosphate (ATP) ratios, and impaired high-energy phosphate 

metabolism and a cardiac energy deficit. 36,37 Phosphocreatine/ATP 

ratios are also decreased in failing hearts of other etiologies, which 

are associated with mitochondrial dysfunction. 38-40 In addition, 

plasma-free fatty acid concentrations were found to correlate negatively 

with phosphocreatine/ATP ratios in patients with diabetes. 37 

This may be due to increased expression of uncoupling proteins 

(UCPs) that reduce the efficiency of ATP production and lead to 

reduced phosphocreatine/ATP ratios. Increased lipid deposition 

has been found in diabetic cardiomyopathy and may exceed mitochondrial 

fatty acid oxidative capacity. This results in increased 

lipid storage instead of oxidation and lipotoxic effect. 11 

In contrast with human studies, mitochondrial function has 

been directly investigated in several animal models of metabolic 

syndrome. Mitochondrial dysfunction is present in the type 2 diabetic 

rodent heart as demonstrated by reduced mitochondrial 

respiration and ATP synthesis. 41-43 Mitochondrial structural defects 

and abnormal mitochondrial proliferation also occur in ob/ob 

mice. 44-46 

The heart depends on continuous oxidative metabolism for 

ATP generation to maintain contractile function. Mitochondria account 

for approximately 40% of cardiomyocyte volume. The normal 

heart generates ATP mainly from the mitochondrial oxidation 

of fatty acids (60% to 70% of ATP generated) and to a lesser extent 

from glucose, lactate, and other substrates (30% to 40%). 19,20,23 

The increased myocardial fatty acid oxidative capacity in obesity 

and diabetes are mediated, in part, by increased activity of peroxisome 

proliferator-activated receptors (PPARs) (in particular 

PPARα). PPARα has been shown to be a central regulator of fatty 

acid oxidation in the heart by increasing the expression of genes 

involved in virtually every step of cardiac fatty acid utilization. 47 

Conversely PPARα reduces the expression of genes that regulate 

glucose use and thereby contribute to reduced glucose oxidation. 

Mice with cardiac overexpression of 

PPARα mimicked the metabolic phenotype 

of the diabetic heart, which implicates 

PPARα in the regulation of cardiac 

metabolism in the diabetic heart. 

Theoretical calculations of the yield 

of ATP per oxygen atom consumed show 

that fatty acids are a less efficient fuel 

when compared with glucose. 48 It is calculated 

that shifting from 100% palmitate 

to 100% glucose would increase the 

ATP yield per molecule of oxygen consumed 

by 12% to 14%. Thus, increased 

fatty acid use in the diabetic heart may 

be energetically detrimental because of 

the higher oxygen cost to produce ATP. 

The higher oxygen cost and the decrease 

in cardiac efficiency may contribute to 

the development of contractile dysfunction 

in the metabolic syndrome. Cardiac 

energy depletion may become even more 

pronounced by the coexistence of hypertension 

(a common comorbidity in 

the metabolic syndrome), which increases 

the energy demand for the heart. In addition, these mechanisms 

may also contribute to the increased susceptibility to 

ischemic damage and poorer outcomes after myocardial infarction. 

The mechanisms for increased myocardial oxygen consumption 

and decreased cardiac efficiency are incompletely understood. 

Our findings suggest increased mitochondrial uncoupling 

as one underlying mechanism. 43,49 Mitochondrial uncoupling increases 

oxygen consumption without proportionately increasing 

mitochondrial ATP production. The energy deficit that results may 

explain the lack of increase in cardiac contractile function and 

reduced cardiac efficiency. 

One of the mechanisms leading to cardiac mitochondrial uncoupling 

in type 2 diabetes may be the increased expression of 

UCPs (Figure). These proteins allow the H+ generated from the 

transfer of electrons from oxygen to re-enter the mitochondrial intermembrane 

space without generation of ATP from adenosine 

diphosphate (ADP) thus uncoupling oxygen consumption from ATP 

generation. Several UCPs have been identified. 50-59 Both UCP2 

and UCP3 are expressed in the heart, but their roles are still unclear. 

60,61 Circulating free fatty acid levels correlate with the expression 

of UCP2 and UCP3 in the human heart, which suggests 

that plasma free fatty acid concentrations may regulate cardiac 

UCP expression, possibly through activation of PPARα-response elements 

in the UCP promoter regions. 61-65 

Proton leak via the adenine nucleotide translocator (ANT) may 

also lead to uncoupling (Figure). This protein was shown to mediate 

uncoupling by fatty acids and to lower mitochondrial membrane 

potential in heart and skeletal muscle. 66,67 Studies that used 

inhibitors of ANT suggest that the large part of mitochondrial uncoupling 

was mediated by UCPs, but that a small part of proton 

leak was also mediated by ANT activity. 49 

Another mechanism that may lead to decreased cardiac contractility 

is through generation of reactive oxygen species (ROS). 

Mitochondria are the principal source of ROS in cells. Normally, 

electrons are funneled through the redox carriers of the respiratory 

chain to molecular oxygen reducing O 2 

to water. Even during nor- 


mal metabolism, some electrons leak from the respiratory chain, 

which results in the generation of reactive incompletely reduced 

forms of oxygen, such as superoxide and hydroxyl anions. Increased 

electron delivery from increased glucose oxidation or increased 

fatty acid oxidation have been shown to increase 

mitochondrial ROS generation. 68,69 

ROS can severely harm the cell through oxidation of proteins, 

DNA (including mitochondrial DNA), and nitrosylation of proteins 

(through generation of reactive nitrogen species) and lead to improper 

protein function (Figure). Oxidative stress is widely accepted 

as a key player in the development and progression of 

diabetes and its complications, including cardiac pathologies. 70-74 

In diabetes, ROS may be predominantly derived from mitochondria 

as opposed to cytosolic origins. 68,75,76 Mitochondria are not 

only the origin, but also the target of oxidative stress. In addition 

to the direct effects on proteins and DNA, ROS can also induce 

mitochondrial uncoupling. 49 

Most studies that investigate the effect of ROS on mitochondrial 

function in diabetic hearts have been performed in type 1 diabetic 

models. In these animal models, cardiac mitochondrial 

respiratory dysfunction has been demonstrated and, in some studies, 

improved antioxidant defense was able to at least partially, if 

not completely, restore mitochondrial respiratory function. 77-80 The 

possibility that the mechanisms by which ROS causes mitochondrial 

damage are similar in type 2 diabetes and is supported by 

several similar observations in type 2 diabetic models. 49,78,81-83 

A recent study suggests that mitochondrial ROS overproduction 

may play a greater role in impairing mitochondrial energetics 

in models of insulin resistance and obesity versus models of insulin 

deficiency and type 1 diabetes. 84 It appears likely that ROS 

plays a central role in impaired mitochondrial energy metabolism 

by participating in mitochondrial uncoupling (in type 2 diabetes 

and cardiac efficiency) thus directly damaging mitochondrial proteins. 

Both mechanisms probably contribute to a deficit in energy 

reserve and contribute to the development of contractile dysfunction. 

Cardiac performance also depends on the influx of Ca2+. It exposes 

active sites on actin, which interact with myosin crossbridges 

in an energy-requiring reaction. At the end of the contraction, 

Ca2+ is rapidly removed from the cytosol. Ca2+ exchange 

between these subcellular compartments is believed to provide a 

mechanism for matching energy production to energy demand 

under physiological conditions or increased workload and is 

termed the “parallel activation model.” 85 

Although some Ca2+ is exported via the sarcolemmal membrane, 

the bulk of Ca2+ is resequestered in the sarcoplasmic reticulum 

by the activity of sarcoplasmic/endoplasmic reticulum 

Ca2+-ATPase 2a (SERCA2a). 86-88 Contractile dysfunction in the 

diabetic heart has been proposed to be the consequence of abnormalities 

in sarcoplasmic reticulum Ca2+ handling and has 

been specifically attributed to the decreased expression of 

SERCA2a. 89-93 

It has recently been demonstrated that mitochondrial biogenesis 

occurs in hearts of obese and insulin resistant animals. 44,45 

However, this was not associated with increased mitochondrial 

respiration or ATP generation. We have also observed increased 

mitochondrial density and DNA content in ob/ob and db/db mice 

despite impaired ADP stimulated respiration and ATP synthesis. 

43,44,49 These observations raise the question whether mitochondrial 

biogenesis is adaptive or maladaptive in the metabolic 

syndrome. 

Given that animal models of the metabolic syndrome exhibit 

insulin resistance the question arises whether cardiac insulin 

resistance may contribute to the development of contractile 

dysfunction. Since the animal models are characterized by systemic 

metabolic alterations, evaluation of the contribution of insulin 

resistance to cardiomyocyte contractile dysfunction is 

challenging. To approach this problem, we generated mice with a 

deletion of the insulin receptor (CIRKO mice) restricted to the 

cardiomyocyte. 94 

CIRKO mice have reduced insulin-stimulated glucose uptake 

and also have a modest decrease in contractile function, thereby 

insulin resistance may be a contributing factor in contractile dysfunction 

in the metabolic syndrome. This may be caused by decreased 

mitochondrial gene expression, which limits oxidative 

capacity and impairs mitochondrial energetics and contractile 

function in CIRKO mice. If this is correct, then CIRKO hearts may 

be more susceptible to injury when subjected to increased energy 

demands 

CIRKO mice subjected to pressure overload through transverse 

aortic banding or following chronic β-adrenergic stimulation 

resulted in worse left ventricular dysfunction, left ventricular 

dilation, and interstitial fibrosis compared to controls. 95,96 These 

findings support the notion that insulin resistance may play a 

role in the development of contractile dysfunction in the metabolic 

syndrome, and impaired myocardial mitochondrial oxidative 

capacity due to reduced insulin action could be an underlying 

mechanism. 

Conclusion 

It is probable that no one single mechanism, but rather the combination 

of several mechanisms, leads to cardiac dysfunction in 

the metabolic syndrome. We propose that mitochondrial dysfunction 

compromises cardiac ATP generation and leads to contractile 

dysfunction. Novel treatments that target these abnormalities 

might lead to new therapeutic avenues for the prevention 

of cardiac dysfunction. What is not known is if the mechanisms 

of cardiac dysfunction outlined above can be extrapolated 

to the right ventricle. 

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Specialized Centers of Clinically 

Oriented Research Programs in 

Pulmonary Hypertension Reported 

Progress at the PHA Scientific Sessions 

Karen A. Fagan, MD, Guest Editor 

University of South Alabama College of Medicine 


Recently, the National Heart, Lung, and Blood Institute 

awarded 2 Specialized Centers of Clinically Oriented Research 

(SCCOR) program grants in pulmonary hypertension. 

The SCCOR program requires clinical and basic scientists 

with a broad range of skills to work together on a unified 

theme, with special emphasis on clinically relevant research. 

The goal of the SCCOR program is to encourage multidisciplinary 

research on clinically relevant problems to allow 

basic science findings to be more rapidly applied to clinical 

situations. It is expected that over 50% of the funded research 

is clinical and interactions between clinical and basic 

scientists are expected to strengthen the research, enhance 

the translation of fundamental research findings to the clinical 

setting, and identify new research directions. In addition, 

each SCCOR project must have a defined organizational and 

administrative structure to enhance and enable interactions 

between investigators to increase the rate of translation of 

basic research findings to clinical applications. 

At the recent Scientific Sessions at the Pulmonary Hypertension 

Association 8 th International Conference, the principal 

investigators for the 2 SCCOR programs in pulmonary 

hypertension—Dr Paul Hassoun from Johns Hopkins University 

and Dr Kurt Stenmark from the University of Colorado 

Denver School of Medicine, reported on progress made in 

each of their research programs. These are summarized in 

the following reports. 

National Heart Lung and Blood Institute 

Hopkins Specialized Center in Clinical Oriented 

Research (SCCOR): Molecular Determinants of 

Pulmonary Arterial Hypertension 


Professor of Medicine and 

Director of the Pulmonary Hypertension Program 


Johns Hopkins University, School of Medicine 

Baltimore, MD 


SCCOR Investigators: Paul M. Hassoun: overall Principal Investigator, 

Project 1 leader and administrative core leader; Hunter C. 

Champion: Project 2 leader; Fredrick Wigley: Project 3 leader; 

Roger A. Johns: Project 4 leader; Michael Crow: Project 5 leader; 

Noah Lechtzin: data management and statistics; Allen Myers: 

pathology core; Kathleen C. Barnes: genetics/genomics core; Jennifer 

van Eyk: proteomics core; and Jens Vogel-Claussen: imaging 

core. 

Pulmonary arterial hypertension (PAH) is the leading cause of mortality 

in patients with the spectrum of scleroderma-related diseases. 

In addition, recent large clinical trials of PAH suggest that 

patients with scleroderma-related PAH have increased mortality 

and a significantly poorer response to therapy compared with patients 

who have idiopathic PAH. Although the reason for this discrepancy 

remains unclear, we hypothesized for this SCCOR that 

the overall worse outcome in scleroderma-related PAH is related 

to more severe structural changes involving the pulmonary vasculature 

(PV) and the right ventricle (RV), resulting in marked RV- 

PV dysfunction. Therefore, this SCCOR project is focused on 

understanding the complex PV and RV remodeling, resulting RV- 

PV uncoupling, and their crucial impact on morbidity and mortality 

in PAH. 

In this SCCOR, we use scleroderma-related PAH as a clinical 

paradigm, contrasting it to idiopathic PAH, because of its particular 

severity, lack of response to available PAH therapy, and potential 

underlying genetic factors that dictate outcome. Because 

of the extensive expertise of our team in molecular and diagnostic 

pulmonary medicine and cardiology, we have the unique opportunity 

to not only characterize RV-PV responses in scleroderma-related 

PAH with increased sensitivity and clarity, but to 

also identify new molecular targets for potential therapy using 

state of the art imaging and genomic and proteomic technology. 

Relying on novel imaging systems and molecular tools, we proposed 

to conduct rigorous phenotypic characterization of patients 

who have scleroderma-related PAH. Our focus on animal models 

provides us with additional candidate genes and proteins for characterization 

and targeting in human studies. 

We have the opportunity to validate the clinical importance of 

these genes in a large cohort of well-phenotyped patients with 

PAH, using functional genomics and proteomic approaches with 

characterization of potentially important polymorphisms. We hope 


Survival probablility (%) 

13 

12 

11 

10 

9 

27 

26 25 

8 

7 

6 5 

4 

5 

3 

24 

5/27 patients 

25 

23 

2 

22 

0 

0 

11/13 patients 

Delayed Enhancement 

Mass (g/m 2 ) 

Figure 2. Gadolinium delayed enhancement is seen essentially at RV insertion 

site. Right graph shows no difference in scar mass between idiopathic 

PAH and PAH-SS patients. 

Note: 11 of 13 patients with hyponatremia who died had sclerodermarelated 

PAH. 

4.0 

3.0 

2.0 

1.0 

0 

IPAH 

PAH-SSc 

Time (months) 

PAH-SSc 

Figure 1. Kaplan and Meier estimates of survival (all-cause mortality) 

in patients stratified by serum sodium. 

that our data will provide new insights into the molecular basis for 

rational strategies for patients who have scleroderma-related PAH, 

and elucidate the relationship of RV-PV dysfunction to the activation 

of pathological gene expression in genetically susceptible 

patients. 

In summary, the Hopkins SCCOR application represents a consortium 

of investigators with multidisciplinary expertise. The common 

goal to use state-of-the-art physiological, molecular, and 

genomic and proteomic approaches as well as novel phenotyping 

instrumentation that will provide the deepest understanding of 

the critical pathobiological processes of RV-PV dysfunction and 

uncoupling to date, and define key genetic determinants relevant 

to scleroderma-related PAH. The 5 human and animal projects 

are supported by 6 highly interactive cores (administration, data 

management/bioinformatics, molecular pathology, genomic and 

genotyping, proteomics, and imaging). We anticipate our work will 

provide a foundation for meaningful translational research that 

will facilitate development of new strategies, uncover therapeutic 

targets, and define new biomarkers and prognostic indicators that 

will limit the current dismal outcome of scleroderma-associated 

PAH. 

Progress 

The major goals of this SCCOR project are to develop reliable 

measures of RV-PV function, to characterize patterns of gene expression 

and identify candidate gene polymorphisms associated 

with susceptibility to PAH, and to use these tools to guide therapy 

aimed at RV-PV dysfunction in scleroderma-related PAH. As part 

of our SCCOR activities, we have recently demonstrated that hyponatremia 

is a significant indicator of survival (Figure 1) in patients 

with PAH, in particular in patients with scleroderma-related 

PAH. 1 Hyponatremia is 9 times more likely to be present in scleroderma-related 

PAH when controlling for hemodynamics and renal 

function, which suggests that up-regulation of the renine-aldosterone-angiotensin 

system (RAAS) in response to hemodynamic 

stress from PAH differs between idiopathic PAH and sclerodermarelated 

PAH. Based on this and other clinical findings that indicate 

the involvement of RAAS activation in scleroderma-related PAH, 

some members of our team are focusing their effort on genes pertinent 

to neurohormonal activation such as adreno-medullin. 

Characterizing RV-PV Function 

To characterize optimal measures of RV-PV function in scleroderma-related 

PAH we use a combination of hemodynamic data 

obtained from right heart catheterization data, echocardiographic 

parameters, and cardiac MRI with gadolinium imaging and stress 

test (adenosine infusion). We compare these data to patients with 

idiopathic PAH. RV function is an important determinant of prognosis 

in pulmonary hypertension as it is the single most significant 

prognostic marker of survival. In a prospectively studied cohort of 

63 consecutive patients with PH who were referred for a clinically 

indicated right heart catheterization we demonstrated that the degree 

of tricuspid annular displacement (tricuspid annular plane 

systolic excursion or TAPSE) powerfully reflects RV function and 

prognosis in PAH. 2 Specifically, we demonstrated that a low 

TAPSE value of less than 1.8 cm was associated with greater RV 

systolic dysfunction, more RV remodeling, and right ventricle-left 

ventricle disproportion. More importantly, this study demonstrated 

that TAPSE could predict survival when these patients were followed 

over time on therapy. This is now a widely quoted study 

among the PH community. 

In addition, we have focused on several cardiac MRI parameters 

obtained prospectively and within 2 to 4 hours of right heart 

catheterization. Pulmonary distensibility is of interest because of 

the potential of increased fibrosis that can cause stiffening of the 

proximal pulmonary arteries in scleroderma-related PAH and contribute 

to RV-PV uncoupling. This analysis has generated some 

intriguing results comparing scleroderma patients with and without 

PAH and controls. We have also focused on myocardial scarring 

in PAH patients and postulated that patients who have 

scleroderma-related PAH might have increased scar mass compared 

to patients with idiopathic PAH. Although we found no difference 

in scar mass between the 2 groups (Figure 2), scar mass 

as assessed by cardiac MRI correlated strongly with RV end diastolic 

volume in patients with scleroderma-related PAH but not in 

those with idiopathic PAH (Table). 

Candidate Genes for Scleroderma-Related PAH 

We have published our first observation for the use of genomic 

profiling in patients with scleroderma-related PAH (compared with 

patients who have idiopathic PAH). Briefly, we hypothesized that 

PAH-associated genes identified by expression profiling of peripheral 

blood mononuclear cells from patients with idiopathic 

PAH can also be identified in peripheral blood mononuclear cells 


Table. Correlation of Hemodynamic and MRI 

Morphology Variables With Scar Mass in 

Scleroderma-Related PAH 

r 

P 

Right ventricular –0.391 NS 

ejection fraction 

Right ventricular end 0.729 NS 

diastolic mass index 

Right ventricular end 0.970 .0014 

diastolic volume index 

Mean pulmonary 0.600 NS 

artery pressure 

Pulmonary vascular 0.682 NS 

resistance 

Cardiac index –0.294 NS 

Figure 3. Color display of genes discriminating between idiopathic PAH and 

PAH-SS versus controls and assorted according to disease severity. Red, increased 

expression versus control; green, lower expression. 

from scleroderma-related PAH. Gene expression profiles of peripheral 

blood mononuclear cells collected from patients with idiopathic 

PAH, those with scleroderma-related PAH, and healthy 

controls were generated using HG_U133A_2.0 GeneChips. Disease 

severity in consecutive patients was assessed by functional 

status and hemodynamic measurements. As shown in Figure 3, 

there were many genes that were up- or down-regulated concordantly 

or not in the 2 groups. Our data demonstrate that peripheral 

blood mononuclear cells from patients with sclerodermarelated 

PAH carry distinct transcriptional expression. 3 Deciphering 

the role of genes involved in vascular remodeling and PAH de-

velopment may reveal novel targets for treatment for this devastating 

disorder, which is one of the most important goals of this 

SCCOR project. 

Biological Validation 

To establish biological validation of high-risk alleles in selected 

PAH candidate genes via mid- and high-throughput genotyping in 

a large cohort of scleroderma-related PAH patients we have collected 

over 1400 DNA samples (mostly patients with scleroderma 

of whom 10% have scleroderma-related PAH). We used these 

samples for further DNA analysis and to identify single nucleotide 

polymorphisms of candidate genes identified in our SCCOR projects 

dedicated to human and animal studies. We have also established 

collaborations with other investigators from the PH 

community to share additional DNA samples. We will begin high 

throughput genotyping as early as December 1, 2008. The goal is 

to perform wide-scale single nucleotide polymorphisms analysis 

on several candidate genes (from a current total list of 

39 genes). 

Conclusion 

We continue to gain significant momentum and synergy with other 

SCCOR investigators and have moved all aspects of our project 

forward. We anticipate that the coming year will be, like this past 

year, extremely productive now that we have most of our techniques 

and analytical tools in place. More importantly, we hope 

that our efforts will help clarify the pathobiology underlying scleroderma-related 

PAH and its current poor outcome and identify 

new molecular targets for the design of targeted therapies. 

References 

1. Forfia P, Mathai SC, Fisher MR, et al. Hyponatremia predicts right heart failure 

and poor survival in pulmonary arterial hypertension. Am J Respir Crit 

Care Med. 2008;177:1364-1369. 

2. Forfia PR, Fisher MR, Mathai SC, et al. Tricuspid annular displacement 

predicts survival in pulmonary hypertension. Am J Respir Crit Care Med. 

2006;174:1034-41. 

3. Grigoryev DN, Fisher MR, Mathai SC, et al. Identification of candidate genes 

in scleroderma-related pulmonary arterial hypertension. Transl Res. 2008;151: 

197-207. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 




(SCCOR) Update: Mechanisms and Treatment of Lung 

Vascular Disease in Infants and Children 



Developmental Lung Biology Laboratory 

University of Colorado at Denver and Health Sciences Center 

Aurora, Colorado 


SCCOR Investigators: John Kinsella: Principal Investigator (PI) 

Project 1; Robin Shandas, PI, Dunbar Ivy, Co-PI: Project 2; Kurt 

Stenmark. PI: Project 3; Carl White, PI: Project 4. 

In contrast to lung branching morphogenesis, studies of the 

mechanisms that regulate lung vascular development and that 

link capillary growth with alveolarization are relatively recent and 

limited in scope. Lack of information regarding lung vascular 

growth and its connection with alveolar growth is unfortunate, 

because developmental abnormalities of the pulmonary circulation 

contribute to the pathogenesis of several important neonatal 

cardiopulmonary disorders including pulmonary hypertension 

(PH) in the newborn. 

There is growing recognition that the importance of understanding 

basic mechanisms of lung vascular growth in the context 

of human disease may be best highlighted in the setting of 

bronchopulmonary dysplasia (BPD). BPD is a significant health 

care problem associated with acute and long-term pulmonary 

consequences. 

Recent data from animal and clinical studies suggest that impaired 

vascular growth may contribute to abnormalities of lung architecture, 

especially decreased alveolarization, and thus play a 

critical role in the pathogenesis of BPD. However, little is known 

about the mechanisms of pulmonary vascular injury in the immature 

lung, the impact of this injury on growth and development 

of the lung, or its contribution to the pathogenesis of BPD 

and PH. 

The overall goal of this SCCOR project is to generate clinical 

and basic information that will provide insight into the mechanisms 

contributing to pulmonary vascular abnormalities that 

characterize BPD, to evaluate currently available therapies aimed 

at reducing lung injury and restoring vascular and lung growth, 

and to examine in animal models new approaches to ameliorate 

perinatal lung injury and restore vascular and lung growth. Two 

clinical and 2 basic projects address these objectives. The clinical 

projects evaluate the impact of inhaled nitric oxide (iNO) on 

BPD and the development of improved techniques to assess the 

presence of PH and the responses to therapy in infants with PH. 

The 2 basic projects dissect the mechanisms that contribute to 

lung vascular remodeling in murine, rodent, ovine, and bovine 

models and evaluate the effects of novel pharmacological agents 

on lung vascular disease in these models. The long-term goal is 

to use information derived from these models to develop new and 

improved therapies for the infant with BPD and/or PH. 

Noninvasive Inhaled NO in Premature Newborns 

Project 1 is a randomized, placebo-controlled and masked pilot 

trial of low-dose, noninvasive iNO in premature newborns (500- 

1250 grams birth weight) that do not require intubation for respiratory 

failure in the first 36 hours of life. The rationale and 

background for this study have been recently summarized. 1,2 The 

aims of the study are to determine if iNO reduces BPD/mortality 

in premature newborns who do not require intubation in the first 

24 hours of life and to determine if noninvasive iNO treatment 

decreases early and late pulmonary vascular abnormalities in this 

population. 

Advanced Imaging and Diagnostics for Pediatric PH 

The overall goal of Project 2 is to develop and evaluate more 

comprehensive measures of pulmonary arterial hypertension 

using a combination of advanced cardiovascular imaging and sophisticated 

computational modeling. The overall hypothesis for 

these studies is that pulmonary vascular input impedance provides 

a more comprehensive measure of pulmonary vascular 

function than pulmonary vascular resistance (PVR) alone since 

impedance includes both dynamic (stiffness or compliance) and 

steady state (resistance) components of the vascular circuit. 

Measurement of PVR is the current standard for evaluating 

PH and pulmonary vascular reactivity in children with pulmonary 

arterial hypertension (PAH). However, PVR measures only the 

mean component of right ventricular afterload and neglects pulsatile 

or dynamic effects. Increased stiffness in the pulmonary 

vasculature is increasingly appreciated to affect right ventricular 

afterload and to perpetuate distal pulmonary vascular disease. 

The investigators in this project, therefore, recently developed 

and validated a method to measure pulmonary vascular input impedance 

(a parameter which evaluates dynamic [stiffness] and resistive 

components of the vasculature) and demonstrated excel- 


lent correlation between impedance measurements and PVR as 

well as a correlation between impedance measurements and pulmonary 

vascular stiffness. 3,4 

The investigators have demonstrated that impedance can be 

measured routinely and easily in the cardiac catheterization laboratory. 

Most importantly, the investigators have demonstrated 

that impedance is a better predictor of disease outcome in pediatric 

patients with PAH than is simple measurement of PVR. 4 

Similar observations have been made in adult studies of PH by 

the SCCOR program at Johns Hopkins. They have demonstrated 

that impedance is a better and more effective way of evaluating 

PH than measuring PVR alone. Work in this project may establish 

improved methods to evaluate and follow the impact of pharmacological 

interventions in patients with PAH. 

Circulating Fibrocytes in Hyperoxic Lung 

Vascular Remodeling 

The long-term goal of Project 3 is to determine the role of circulating 

fibrocytes (precursors of mesenchymal cells) in neonatal 

lung vascular remodeling. There is good evidence that mesenchymal 

progenitor cells are recruited to the injured lung in 

young animals (mice, rats, calves) and play important roles in 

the pulmonary hypertensive process. 5 There are few data that 

demonstrate recruitment of progenitor cells to the vasculature of 

humans with PAH. Therefore, in collaboration with one of the 

major groups investigating adult PH (Vanderbilt University), tissues 

from patients with severe PAH were evaluated to determine 

the presence of cells expressing progenitor cell markers (CD133). 

A significant increase in the accumulation of CD133+ cells 

both in intimal lesions and in the perivascular regions of pulmonary 

arteries from patients with severe PH was observed. Because 

questions have arisen as to how these cells might affect 

vascular structure or function, we evaluated the possibility that 

they exerted their effects through a process of cell fusion and/or 

heterokaryon formation. This is one mechanism through which 

stem cells are often thought to exert their effects. Extensive 

analysis, however, did not demonstrate any evidence for fusion of 

these recruited cells to local vascular cells. 6 The recruited inflammatory/progenitor 

cells appear to exert effects on structure 

and function of blood vessels through processes other than cell 

fusion. 

These are important findings because they demonstrate that 

human PAH is associated with progenitor cell recruitment just 

as has been shown in animal models. We are currently collecting 

tissues from human infants with PH to carry out similar studies. 

In addition, we continue our efforts to determine the mechanisms 

through which inflammatory cells and progenitor cells are 

recruited to the lung. We are following up on our observations 

demonstrating that superoxide radical (O 2- 

) plays a critical role in 

initiating and perpetuating the remodeling process in the injured 

lung. 7,8 Having shown that transgenic overexpression of EC-SOD 

attenuated superoxide-induced signaling and dramatically attenuated 

PH and remodeling, we have embarked on studies (in 

collaboration with the University of Colorado Denver) to evaluate 

the effects of EC-SOD mimetics in rodent models of PH. 7 

Hypoxia-Inducible Factors in Neonatal PH 

The long-term goal of Project 4 is to develop agents that can 

specifically increase lung vascularization and thereby restore 

alveolarization to more normal levels. In important background 

studies the investigators established that hypoxia inducible factors 

(HIFs), important regulators of vascular endothelial growth 

factor (VEGF), are decreased in experimental acute lung injury. 9 

The investigators are testing the hypothesis that prolylhydroxylase 

inhibitors (PHDI), agents that stabilize the transcription factor 

HIF, can decrease PH in the newborn by restoring the fetal VEGF/ 

eNOS axis. 10 

Unfortunately, in preliminary experiments, PHDIs were found 

to cause increased lethality in premature baboons, apparently due 

to immunomodulation with an exuberant inflammatory response 

(unpublished observation). These effects were thought to be due 

to overexpression of HIF1α. Therefore, the investigators have 

worked to develop methods to selectively activate HIF2α in the 

hopes that activation of this pathway will selectively result in protective 

angiogenic effects. The investigators have developed targeted 

stabilization of HIF2α, and they have demonstrated that 

overexpression of HIF2α increases adenosine A 2A 

receptor expression. 

Importantly, the investigators show that overexpression 

of adenosine A 2A 

receptor in endothelial cells can increase endothelial 

cell proliferation and endothelial branching. Thus, significant 

progress is being made in determining the mechanisms 

through which transcription factors can be selectively manipulated 

to achieve the desired beneficial effects in the neonatal lung. 

References 

1. Kinsella, JP. Inhaled nitric oxide in the term newborn. Early Hum Dev. 

2008;84:709-716. 

2. Kinsella JP, Abman SH. Inhaled nitric oxide in the premature newborn. J 

Pediatr. 2007;151:10-15. 

3. Hunter KS, Gross JK, Lanning CJ, et al. Noninvasive methods for determining 

pulmonary vascular function in children with pulmonary arterial hypertension: 

application of a mechanical oscillator model. Cong Heart Dis. 

2008;3:106-116. 

4. Hunter KS, Lee PF, Lanning CJ, et al. Pulmonary vascular input impedance 

is a combined measure of pulmonary vascular resistance and stiffness and 

predicts clinical outcomes better than PVR alone in pediatric patients with 

pulmonary hypertension. Am Heart J. 2008;155:166-174. 

5. Frid MG, Brunetti JA, Burke DL, et al. Hypoxia-induced pulmonary vascular 

remodeling requires recruitment of circulating mesenchymal precursors of a 

monocyte/macrophage lineage. Am. J. Pathol. 2006;168:659-669. 

6. Majka SM, Skokan M, Wheeler L, et al. Evidence for cell fusion is absent 

in vascular lesions associated with pulmonary arterial hypertension. Am J 

Physiol Lung Cell Mol Physiol. 2008;295:L1028-L1039. Epub 2008 Oct 17. 

7. Nozik-Grayck E, Suliman HB, Majkaa SM, et al. Lung EC-SOD overexpression 

attenuates hypoxic induction of Egr-1 and chronic hypoxic pulmonary 

vascular remodeling. Am J Physiol Lung Cell Mol Physiol. 2008;295: 

L422-L430. 

8. Nozik-Grayck E, Stenmark KR. Role of reactive oxygen species in chronic 

hypoxia-induced pulmonary hypertension and vascular remodeling. Adv Exp 

Med Biol. 2007;618:101-112. 

9. Grover TR, Asikainen TM, Kinsella JP, Abman SH, White CW. Hypoxia-inducible 

factors HIF-1alpha and HIF-2alpha are decreased in an experimental 

model of severe respiratory distress syndrome in preterm lambs. Am J 

Physiol Lung Cell Mol Physiol. 2007;292:L1345-51. Epub 2007 Feb 16. 

10. Asikainen TM, White CW. HIF stabilizing agents: shotgun or scalpel? Am 

J Physiol Lung Cel. Mol Physiol. 2007;293:L555-L556. 



Getting More From Right Heart Catheterization: 

A Focus on the Right Ventricle 



and Division of Cardiology 

Department of Medicine 

Johns Hopkins Medical Institutions 

Baltimore, MD 

Hunter C. 

Champion, MD, PhD 

The primary challenge in the care of the patient with advanced 

pulmonary hypertension (PH) is right ventricular dysfunction with 

concomitant right heart failure, which is the most important cause 

of mortality in the disease. It is increasingly evident that the interaction 

of the heart and pulmonary circulation is a very important 

aspect that is largely understudied and our previous 

assessment of right ventricular function has been relatively crude. 

Here, we highlight the future of integrative assessment of ventricular-pulmonary 

vascular coupling via hemodynamic measures. 

Current Use of Right Heart Catheterization 

Cardiac catheterization remains the gold standard for diagnosing 

pulmonary hypertension, assessing disease severity, and determining 

prognosis and response to therapy. By directly measuring 

pressures and indirectly measuring flow, right heart catheterization 

allows for determination of prognostic markers such as right 

atrial pressure, cardiac output, and mean pulmonary artery pressure. 

1 This procedure has been shown to be safe, with no deaths 

reported in the NIH registry study. 1 In addition, a recent study reported 

a procedure-related mortality of 0.055%. 2 

Right heart catheterization determines the presence or absence 

of pulmonary hypertension, may define the underlying etiology, 

and allows for prognostication. The most critical aspect of 

right heart catheterization is that it is performed appropriately, 

and the data are interpreted accurately. Since end-expiratory intrathoracic 

pressure most closely correlates with atmospheric pressure, 

it is important that all right ventricular, pulmonary artery, 

pulmonary wedge, and left ventricular pressures be measured at 

end-expiration. 3-5 This is especially true in patients in whom there 

can be significant variation between inspiratory and end-expiratory 

vascular pressures (obese patients and patients with intrinsic lung 

disease). 

After determination of the presence of PH, pulmonary venous 

pressures should be evaluated by the pulmonary capillary wedge 

Address for reprints and other correspondence: Hunter C. Champion, MD, 

PhD, FAHA, FPVRI, Assistant Professor of Medicine, Division of Cardiology, 

Department of Medicine, Johns Hopkins Medical Institutions, 720 Rutland 

Avenue, Ross 835, Baltimore, MD 21205-2109; email: hcc@jhmi.edu. 

pressure (PCWP). Pulmonary arterial hypertension (PAH) is defined 

by a PCWP of 15 mmHg or less. 5,6 This value is based on the 

normal PCWP or left ventricular end diastolic pressure (LVEDP) of 

less than 8 mmHg and the observation that ~14 mmHg is 2 standard 

deviations from a normal PCWP. 3 

With the exception of patients with severe tricuspid regurgitation, 

both thermodilution and Fick methods are reliable in patients 

with PAH for the measurement of cardiac output. 7 

Vasodilator challenges with inhaled nitric oxide or intravenous 

epoprostenol or adenosine are encouraged in all patients at the 

time of diagnosis and in follow-up studies. 3 

Other Testing During Right Heart Catheterization 

Exercise and fluid challenge 

Some patients with pulmonary vascular disease are not symptomatic 

at rest, but have symptoms with exertion. This observation 

provides a potential for exercise or volume challenge during right 

heart catheterization to better diagnose early pulmonary vascular 

disease. In patients with risk factors for nonsystolic left ventricle 

(LV) dysfunction (sleep disordered breathing, systemic hypertension, 

obesity, diabetes/glucose intolerance) one should consider 

confrontational testing (to uncover potential increases in PCWP) 

by administering a fluid bolus challenge or exercise during right 

heart catheterization particularly if the patient has a resting PCWP 

between 8 and 15 mmHg. 

With regard to the threshold of a mean pulmonary arterial pressure 

(PAP) of 30 mmHg with exercise, the data to support this as 

a disease state that is similar to resting PAH are much less robust. 

The number of pulmonary hemodynamic studies that include 

exercise are made up of a smaller number of patients. 8 

Exercise pulmonary hemodynamics have been reported in 218 

healthy subjects (125 in one study of subjects aged 14 to 69 

years). 8-10 

The purpose of exercise is not only to examine pulmonary arterial 

pressure in response to exertion. Rather, the benefit of confrontational 

testing is the observation of the change/increase in 

PCWP in an effort to diagnose pulmonary venous hypertension or 

nonsystolic heart failure. Although protocols for exercise and work- 


a 

Figure. (a) Schematic showing the measurement of augmentation index using the pulmonary arterial waveform. 

This augmentation index (∆P/PAPP) relates the change in pressure (∆P) to the pulmonary arterial pulse pressure 

(PAPP) and gives an estimation of pulmonary vascular stiffness. (b) Schematic showing a sample RV pressure 

volume loop relationship including effective arterial elastance (Ea), end-systolic pressure volume relation (ESPVR), 

and end diastolic pressure volume loop relationship (EDPVR). 

load vary from study to study, and maximal workload exercise has 

been tested in few subjects, the main goal of exercise is to increase 

heart rate to 85% maximal age-predicted heart rate as is 

used in cardiology stress testing. Given increased thoracic pressure 

changes with exercise, particularly in overweight and/or deconditioned 

patients, it is critical that measurements be made at 

end-expiration to ensure uniformity in interpretation. 

An increase in PCWP to greater than 15 mmHg in response to 

exercise or fluid challenge suggests the presence of pulmonary 

venous hypertension, a condition with dramatically different management 

than PAH. Because cardiac output can increase up to 5- 

fold above baseline, pulmonary vascular resistance (PVR) normally 

decreases with exercise. 8,9 Poor prognostic signs in exercise right 

heart catheterization are: (1) the inability of the right ventricle 

(RV) to augment in response to exercise, ie, lack of a significant 

increase in cardiac output; (2) angina; and (3) presyncopal symptoms 

or frank syncope. 

Novel Hemodynamic Techniques 

Assessment of the pulmonary arterial pressure waveform. Chronic 

pulmonary hypertension results from an increase in pulmonary 

vascular resistance, which is a simple measure of the opposition 

to the mean component of flow. However, given the low resistance/high 

compliance nature of the pulmonary circulation, the 

pulsatile component of hydraulic load is also critical to consider. 

The fact that the mean and the pulsatile components of flow are 

dependent on different portions of the pulmonary circulation suggests 

that they can be controlled separately, without much overlap. 

The pulmonary circulation is pulsatile with multiple bifurcations; 

and wave reflection is an inevitable consequence. When the 

forward pressure wave from the heart collides with the backward 

pressure wave that was reflected from the bifurcations, pressure 

increases and flow decreases. Because the often used PVR only 

takes into account mean flow, it does not allow for changes in 

pulsatility of the pulmonary circuit. 11-14 One must consider the 

elastic properties of the pulmonary circulation and impedance on 

RV performance rather than the pure resistive properties since the 

heart could not function if it were not for the elastic properties of 

b 

pulmonary vasculature. During 

systole, the pulmonic valve is 

open at a time when the mitral 

valve is closed. Thus, if it were 

not for the elastic properties of 

the pulmonary vasculature, the 

heart could not develop forward 

flow. 12-14 

Pulse pressure indicates the 

amplitude of pulsatile stress. 

Pulse pressure is mainly determined 

by both the characteristics 

of ventricular ejection and arterial 

compliance, so that the lower 

the compliance, the higher the 

pulse pressure. Moreover, pressure 

waveform analysis performed 

in the time-domain makes 

it possible to calculate the timing 

and extent of wave reflection 

in systemic and pulmonary circulation 

using measures such as 

augmentation index (as shown in the Figure) which roughly represents 

reflected wave summation (∆P) in the pulmonary circuit 

and normalizes for pulmonary arterial pulse pressure. 15-23 

These values can be easily obtained at the time of right heart 

catheterization and the future studies will compare both analyses 

as potential prognostic indicators in patients with pulmonary hypertension. 

24 

Right ventricular pressure volume loop relations. The use of 

pressure-volume (PV) loop analysis as a means of measuring loadindependent 

contractility has largely been restricted to the study 

of LV hemodynamics and the interaction between the LV and the 

systemic vasculature. 21,25-36 This has primarily been due to geometric 

differences between the 2 ventricles and the optimal conductance 

properties required for proper volume measurements 

and the belief that it is difficult to obtain consistent data using 

conductance measurements in the crescent-shaped RV. 

Under conditions of normal PAP and RV function, an analysis 

of the RV PV loop is somewhat complicated given the crescent 

shape of the normal RV (Figure) and the ellipsoid shape of the PV 

loop obtained under these conditions. However, under conditions 

of even only modestly increased load, the RV changes shape to 

one resembling the more spherical LV and allows for measurement 

of end-systolic elastance (Ees) and effective arterial elastance 

(Ea) as well as the more accurate measurements of indices 

of RV systolic and diastolic function as well as RV/PA coupling 

(Figure). 

The performance of such studies is relatively easy and can be 

made in the same acquisition time as making measurements 

using FDA-approved equipment. Essentially, all of the currently 

used PAH therapies, particularly the phosphodiesterase inhibitors 

and endothelin receptor antagonists as well as many of the emerging 

experimental therapies (eg, imatinib) have primary—positive 

or negative—effects on the myocardium. 37-44 Thus, a study of the 

intrinsic contractility of the RV is perhaps the only reliable way to 

separate the effects of these therapies on pulmonary arterial systolic 

pressure versus the RV myocardium. In that sense, studies 

of the RV contractility are not only relevant to the clinical management 

of PAH patients but critical for the interpretation of data 

from clinical trials as well. 


Summary 

While traditional resting right heart catheterization techniques 

still remain the gold standard for diagnosing pulmonary hypertension 

and managing patients on therapy, there are novel techniques 

that do not add significant time or risk to the procedure 

that may add greatly to our understanding of the RV and the interaction 

of the RV with the pulmonary circulation. 

References 

1. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary 

pulmonary hypertension. Results from a national prospective registry. Ann Intern 

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2. Hoeper MM, Lee SH, Voswinckel R, et al. Complications of right heart 

catheterization procedures in patients with pulmonary hypertension in experienced 

centers. J Am Coll Cardiol. 2006;48:2546-2552. 

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Mann DL, Zipes DP, eds. Braunwald’s Heart Disease: A textbook of cardiovascular 

medicine. 8th ed. Philadelphia: Saunders Elsevier; 2007:449. 

4. Grossman W B. Pulmonary Hypertension. 3rd ed. Philadelphia: Saunders; 

1988. 

5. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment 

of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(Suppl 

12):40S-47S. 

6. Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet. 1998;352 

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7. Hemnes AR, Champion HC. Right heart function and haemodynamic in 

pulmonary hypertension. Int J Clin Pract Suppl. 2008 Jul;(160):11-19. 

8. Reeves JT, Dempsey JA, Grover RF. Pulmonary circulation during exercise. 

In: Weir EK, Reeves JT, eds. Pulmonary Vascular Physiology and Pathophysiology. 

1st ed. New York: Marcel Dekker, Inc; 1989:107-135. 

9. Brower R, Permutt S. Exercise and the Pulmonary Circulation. In: Whipp 

BJ, Wasserman K, eds. Exercise: Pulmonary Physiology and Pathophysiology 

in Lung Biology in Health and Disease. Vol 52. New York: Marcel Dekker, Inc; 

1991:201-221. 

10. Ehrsam RE, Perruchoud A, Oberholzer M, Burkart F, Herzog H. Influence 

of age on pulmonary haemodynamics at rest and during supine exercise. Clin 

Sci (Lond). 1983;65:653-660. 

11. Huez S, Brimioulle S, Naeije R, Vachiery JL. Feasibility of routine pulmonary 

arterial impedance measurements in pulmonary hypertension. Chest. 

2004;125:2121-2128. 

12. Kussmaul WG, Noordergraaf A, Laskey WK. Right ventricular-pulmonary 

arterial interactions. Ann Biomed Eng. 1992;20:63-80. 

13. Parmley WW, Tyberg JV, Glantz SA. Cardiac dynamics. Annu Rev Physiol. 

1977;39:277-299. 

14. Piene H. Pulmonary arterial impedance and right ventricular function. 

Physiol Rev. 1986;66:606-652. 

15. Castelain V, Herve P, Lecarpentier Y, Duroux P, Simonneau G, Chemla D. 

Pulmonary artery pulse pressure and wave reflection in chronic pulmonary 

thromboembolism and primary pulmonary hypertension. J Am Coll Cardiol. 

2001;37:1085-1092. 

16. Ewalenko P, Stefanidis C, Holoye A, Brimioulle S, Naeije R. Pulmonary 

vascular impedance vs. resistance in hypoxic and hyperoxic dogs: effects of 

propofol and isoflurane. J Appl Physiol. 1993;74:2188-2193. 

17. Fourie PR, Coetzee AR. Effect of compliance on a time-domain estimate 

of the characteristic impedance of the pulmonary artery during acute pulmonary 

hypertension. Med Biol Eng Comput. 1993;31:468-474. 

18. Ha B, Lucas CL, Henry GW, Frantz EG, Ferreiro JI, Wilcox BR. Effects of 

chronically elevated pulmonary arterial pressure and flow on right ventricular 

afterload. Am J Physiol. 1994;267(1 Pt 2):H155-165. 

19. Lambermont B, D’Orio V, Gerard P, Kolh P, Detry O, Marcelle R. Time domain 

method to identify simultaneously parameters of the windkessel model 

applied to the pulmonary circulation. Arch Physiol Biochem. 1998;106:245- 

252. 

20. Lieber BB, Li Z, Grant BJ. Beat-by-beat changes of viscoelastic and inertial 

properties of the pulmonary arteries. J Appl Physiol. 1994;76:2348-2355. 

21. O’Rourke MF, Yaginuma T, Avolio AP. Physiological and pathophysiological 

implications of ventricular/vascular coupling. Ann Biomed Eng. 1984;12: 

119-134. 

22. Pagnamenta A, Bouckaert Y, Wauthy P, Brimioulle S, Naeije R. Continuous 

versus pulsatile pulmonary hemodynamics in canine oleic acid lung injury. 

Am J Respir Crit Care Med. 2000;162(3 Pt 1):936-940. 

23. Zuckerman BD, Orton EC, Latham LP, Barbiere CC, Stenmark KR, Reeves 

JT. Pulmonary vascular impedance and wave reflections in the hypoxic calf. J 

Appl Physiol. 1992;72:2118-2127. 

24. Mahapatra S, Nishimura RA, Sorajja P, Cha S, McGoon MD. Relationship 

of pulmonary arterial capacitance and mortality in idiopathic pulmonary arterial 

hypertension. J Am Coll Cardiol. 2006;47:799-803. 

25. Chen CH, Nakayama M, Nevo E, Fetics BJ, Maughan WL, Kass DA. Coupled 

systolic-ventricular and vascular stiffening with age: implications for pressure 

regulation and cardiac reserve in the elderly. J Am Coll Cardiol. 1998; 

32:1221-1227. 

26. Cho PW, Levin HR, Curtis WE, et al. Pressure-volume analysis of changes in 

cardiac function in chronic cardiomyoplasty. Ann Thorac Surg. 1993;56:38-45. 

27. Kass DA. Age-related changes in venticular-arterial coupling: pathophysiologic 

implications. Heart Fail Rev. 2002;7:51-62. 

28. Kass DA. Clinical evaluation of left heart function by conductance catheter 

technique. Eur Heart J. 1992;13 (Suppl E):57-64. 

29. Kass DA, Midei M, Graves W, Brinker JA, Maughan WL. Use of a conductance 

(volume) catheter and transient inferior vena caval occlusion for 

rapid determination of pressure-volume relationships in man. Cathet Cardiovasc 

Diagn. 1988;15:192-202. 

30. Kelly RP, Ting CT, Yang TM, et al. Effective arterial elastance as index of 

arterial vascular load in humans. Circulation. 1992;86:513-521. 

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32. Liu CP, Ting CT, Yang TM, et al. Reduced left ventricular compliance in 

human mitral stenosis. Role of reversible internal constraint. Circulation. 

1992;85:1447-1456. 

33. Nussbacher A, Gerstenblith G, O’Connor FC, et al. Hemodynamic effects 

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34. Pak PH, Kass DA. Assessment of ventricular function in dilated cardiomyopathies. 

Curr Opin Cardiol. 1995;10:339-344. 

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Physiol Rev. 1982;62:570-623. 

36. O’Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular 

disease in brain and kidney: cause and logic of therapy. Hypertension. 

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37. Hemnes AR, Zaiman A, Champion HC. PDE5A inhibition attenuates 

bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition 

of ROS generation and RhoA/Rho kinase activation. Am J Physiol 

Lung Cell Mol Physiol. 2008;294:L24-33. 

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beta-adrenergic inotropy modulation by phosphodiesterase type 5. Circulation. 

2007;115:2159-2167. 

39. Takimoto E, Champion HC, Belardi D, et al. cGMP catabolism by phosphodiesterase 

5A regulates cardiac adrenergic stimulation by NOS3-dependent 

mechanism. Circ Res. 2005;96:100-109. 

40. Takimoto E, Champion HC, Li M, et al. Chronic inhibition of cyclic GMP 

phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med. 

2005;11:214-222. 

41. Nagendran J AS, Gurtu V, Webster L, Ross DB, Rebeyka IM, Michelakis 

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Animal Models of Human Severe PAH 


Departments of Pharmacology and 

Medicine and Center for Lung Biology 


Mobile, Alabama, USA 


Based on differences in clinical presentation, diagnostic findings, 

and response to treatment, human pulmonary hypertension (PH) 

has been subdivided into 5 categories. These include 1 : 

• Pulmonary arterial hypertension (PAH) 

• PH with left-sided heart disease 

• PH associated with respiratory disorders and/or hypoxemia 

• PH caused by chronic thrombotic and/or embolic disease 

• PH caused by miscellaneous other disorders affecting the 

pulmonary vasculature. 

The PAH category encompasses the idiopathic and familial 

forms of PH as well as those that occurr secondarily to several 

other diseases or conditions, including connective tissue disease, 

congenital systemic-to-pulmonary shunts, HIV infection, portal 

hypertension, hemoglobinopathies, and ingestion of drugs and 

toxins. This group also includes pulmonary veno-occlusive disease, 

pulmonary capillary hemangiomatosis, and persistent pulmonary 

hypertension of the newborn. 

Address for reprints and other correspondence: Ivan F. McMurtry, PhD, Professor, 

Departments of Pharmacology and Medicine and Center for Lung Biology, 

University of South Alabama, 307 N. University Blvd., Mobile, AL 

36688; email: ifmcmurtry@usouthal.edu. 

Characteristics of PAH 

While any form of PH can contribute to patient debilitation and 

mortality, PAH is a particularly severe and progressive form that 

frequently leads to right heart failure and premature death. 2-4 The 

pathogenesis of the increased precapillary pulmonary vascular resistance 

(PVR) is generally ascribed to combined effects of vasoconstriction, 

arterial wall remodeling, and in situ thrombosis. 5-8 

What appears to distinguish PAH from other forms of PH is the 

severity of the arteriopathy. Whereas the early phase of PAH has 

been described as histologically nonspecific, showing medial hypertrophy 

and mild intimal thickening of muscular pulmonary arteries, 

the later more progressive stage involves formation of 

complex cellular and fibrotic neointimal and plexiform lesions that 

obstruct and obliterate medium and small pulmonary arteries and 

arterioles. 9-13 This cellular and fibrotic luminal obliteration presumably 

accounts for the poor responsiveness of most adult PAH 

patients to acute administration of conventional pulmonary vasodilators, 

and the irreversibility of the hypertension following 

corrective surgery in some PAH patients with congenital heart 

diseases. 12-16 

Current Treatment of PAH 

The goals for the treatment of PAH are to reduce PVR and pulmonary 

arterial pressure, and thereby to reverse the pressure overload 

of the right ventricle to prevent failure and death. 2,3,17 In 

addition to adjunctive therapy with anticoagulants, diuretics, inotropes, 

and supplemental oxygen, patients with PAH who are not 

candidates for calcium channel blockers are currently treated with 

prostacyclin analogs, endothelin-1 receptor blockers, and/or phosphodiesterase 

type 5 inhibitors. This treatment improves symptoms 

and quality of life, but a recent meta-analysis of several 

clinical trials of these agents in patients with severe PAH showed 

only moderate reductions in PVR and pulmonary arterial pressure. 

18,19 There was no statistically significant decrease in mortality. 

These disappointing results do not duplicate those found in 

animal studies, which show that these classes of drugs, and numerous 

others, largely prevent and in some cases reverse chronic 

hypoxia- and monocrotaline-induced PH in rats. 20-23 

Classical Animal Models of PH 

The limitations of using chronically hypoxic and monocrotaline-injected 

rats as models of human severe PAH have been previously 

discussed. 22,24-28 The PH in these models is due largely to sustained 

vasoconstriction. 29-31 Notably, there is no formation of obstructive 

intimal lesions in the peripheral pulmonary arteries. 

Whether there is loss, rarefaction, of pulmonary microvessels, or 

simply impaired filling of these vessels with indicator due to 

spasm of upstream hypertensive arteries, is controversial. 31-33 In 

any case, it is apparent that preventing or reversing the sustained 

constriction and increased muscularization and adventitial thickening 

of pulmonary arteries in these 2 rodent models is not equivalent 

to “dissolving” the obliterative neointimal and other complex 

vascular lesions, and/or reversing unconventional mechanisms of 

vasoconstriction, that seemingly account for the high pulmonary 

vascular resistance (PVR) in human severe PAH. The same limitations 

apply to chronically hypoxic and monocrotaline pyrrole-injected 

mice, which typically show even less pulmonary artery 


Table. Animal Models That Develop Obstructive, Neointimal 

Lesion-Associated Pulmonary Hypertension 

Animal Model Cells of Obstructive Lesions 

Rat Left pneumonectomy + MCT 53 SMCs 

Left pneumonectomy + MCT + 

MCT in younger animals 63 

ET B 

receptor deficient +MCT 45 

Sugen 5416 + chronic hypoxia 57 

Athymic and Sugen 5416 58 

ECs in perivascular lesions 

ECs and SMCs 

ECs 

ECs and B-lymphocytes with 

perivascular inflammatory cells 

Mouse S100A4/Mts1 over expression 43 SMCs with perivascular inflammatory 

cells 

S100A4/Mts1 over expression 

exacerbated by infection with 

M1γherpesvirus 68 54 

Lung-specific IL-6 over 

expression exacerbated by 

chronic hypoxia 55 

Repeated inhalation of ? 

Stachybotrys chartarum spores 51 

SMCs with perivascular 

inflammatory cells 

ECs and T-lymphocytes with 

perivascular inflammatory cells 

Beagle Dehydromonocrotaline 64 ? 

Macaque SHIV-nef infection 65 ECs and SMCs with lymphatic infiltration 

Calf Aorta-pulmonary artery ? 

anastamosis 66 

Piglet Aorta-pulmonary artery ? 

anastamosis 67 

remodeling than rats. 34-35 Although chronically hypoxic bovine 

calves and fawn-hooded rats develop severe PH with marked medial 

and adventitial thickening of pulmonary arteries, there are no 

reports of obliterative neointimal lesions in the resistance arteries 

of these models. 36-40 

Animal Models of PAH 

Studies of the classic chronically hypoxic and monocrotaline-injected 

models of PH have produced an abundance of important information 

on cellular and molecular mechanisms of pulmonary 

vasoconstriction and medial and adventitial remodeling. However, 

investigators who evaluate new therapeutic strategies for severe 

PAH should consider using more recent animal models of obstructive, 

neointimal lesion-associated PH. At least 10 different 

rodent models of peripheral pulmonary artery neointimal lesion 

formation have now been described and studied (Table). 41-67 

These models develop PH accompanied by formation of obstructive 

cellular lesions in the lumen of small pulmonary arteries 

and arterioles, in addition to increased medial muscularization 

of proximal and distal pulmonary arteries. The proliferative neointimal 

lesions are variously reported to comprise phenotypically abnormal 

smooth muscle cells, endothelial cells, cells that express 

both endothelial and smooth muscle cell markers, and inflammatory 

cells. This is similar to the cellular heterogeneity reported in 

the lesions of human forms of PAH. 9-11,13 

The lesions in some of these models are 

considered to resemble the plexiform lesions 

of human PAH. 43,54,55,57,63 

In addition to the rodent models, 

PAH arteriopathy has also been observed 

in young beagles who have been exposed 

to dehydromonocrotaline (an endothelial 

cell-toxic metabolite of monocrotaline), 

macaques infected with SHIV-nef (a 

chimeric viral construct containing the 

HIV nef gene in a simian immunodeficiency 

virus backbone), and calves and 

piglets with anastamosis of the left lower 

lobe pulmonary artery to the aorta. 64-67 

Not all studies of aortopulmonary shunts 

in young pigs, however, have found 

formation of peripheral neointimal lesions. 

68 

Treatment of Animal Models 

With regard to using the rodent models of 

neointimal PAH to identify more effective 

therapeutic drugs, the 3-hydroxy-3- 

methyl-glutaryl-CoA (HMG-CoA) reductase 

inhibitor simvastatin has been found 

to attenuate the development of PAH 

and, in a more clinically relevant experiment, 

to reverse the established disease 

and promote survival in left pneumonectomized 

plus monocrotaline-injected 

rats. 48,50 Similar results, albeit not with 

complete reversal of hypertension and 

neointimal lesions, were seen with triptolide 

treatment, an agent that has antitumor, 

antiangiogenic, and antiproliferative 

effects; rapamycin, an immunosuppressant 

and antiproliferative agent; and the naturally occurring 

steroid hormone dehydroepiandrosterone (DHEA). 42,44,49,61 

Although DHEA treatment did not completely reverse the PAH, it 

was associated with 100% survival as compared to 30% in DHEAuntreated 

rats. 

In the Sugen 5416 (vascular endothelial growth factor [VEGF] 

receptor blocker) -injected plus chronic hypoxia-exposed rat 

model, treatment with the bradykinin antagonist B9430, the caspase 

inhibitor Z-Asp-2,6-dichlorobenzoyloxymethylketone, or the 

anti-cancer drug sorafenib prevented development of the 

PAH. 47,56,57 With respect to reversal studies, treatment with the 

bradykinin receptor agonist B9972 or simvastatin arrested progression 

of the established PAH but did not reverse the hypertension 

or neointimal lesions. 59,60 Several other drugs with a 

variety of actions, including the anticancer drugs cyclophosphamide 

and paclitaxel, the angiotensin-converting enzyme inhibitor 

lisinopril, the angiotensin II type 1 receptor blocker 

irbesartan, the bradykinin antagonist B9430, the antiangiogenic 

agent thalidomide, the peroxisome proliferator-actived receptor-γ 

agonist PGJ2, and the calcium channel blocker nifedipine, failed 

to arrest progression of the PAH. No reversal experiment with sorafenib 

has been reported. Even so, clinical trials with both simvastatin 

and sorafenib in PAH are currently under way. 


Conclusion 

Although it is not clear how closely any of the neointimal animal 

models mimic the multifactorial pathobiology of human PAH, it is 

probable that they will provide insights into pathological cellular 

and molecular signaling pathways and potentially effective therapies 

that would not be revealed or rigorously tested in the classic 

chronically hypoxic and monocrotaline-injected models. 

Another point is that while prevention studies may provide useful 

information, the more clinically relevant experiment is to determine 

if the treatment reverses the neointimal arteriopathy and hypertension 

once they are well established. Finally, it needs to be 

noted that even if a novel drug or therapeutic strategy is found to 

effectively reverse PAH, and/or prevent right ventricular failure 

and death, in one or more of the animal models, that doesn’t necessarily 

mean it will work in the human forms of PAH. The cellular 

and molecular pathogenesis of obstructive vascular lesions, 

and the mechanisms of right ventricular dysfunction, that develop 

over a few weeks in the animal models may not duplicate that 

which occurs over months or years in human PAH. Careful and 

rigorous clinical trials will be required to establish the safety and 

efficacy of any new therapy in patients. 69 

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causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. 

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60. Taraseviciene-Stewart L, Scerbavicius R, Stewart JM, et al. Treatment of 

severe pulmonary hypertension: a bradykinin receptor 2 agonist b9972 causes 

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62. West J, Harral J, Lane K, et al. Mice expressing bmpr2r899x transgene 

in smooth muscle develop pulmonary vascular lesions. Am J Physiol Lung Cell 

Mol Physiol. 2008;295:L744-755. 

63. White RJ, Meoli DF, Swarthout RF, et al. Plexiform-like lesions and increased 

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64. Gust R, Schuster DP. Vascular remodeling in experimentally induced subacute 

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65. Marecki JC, Cool CD, Parr JE, et al. Hiv-1 nef is associated with complex 

pulmonary vascular lesions in shiv-nef-infected macaques. Am J Respir Crit 

Care Med. 2006;174:437-445. 

66. Fasules JW, Tryka F, Chipman CW, et al. Pulmonary hypertension and arterial 

changes in calves with a systemic-to-left pulmonary artery connection. 

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67. Bousamra M, 2nd, Rossi R, Jacobs E, et al. Systemic lobar shunting induces 

advanced pulmonary vasculopathy. J Thorac Cardiovasc Surg. 2000; 

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68. Wauthy P, Abdel Kafi S, Mooi WJ, et al. Inhaled nitric oxide versus prostacyclin 

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Surg. 2003;126:1434-1441. 

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of pulmonary arterial hypertension. Circulation. 2008;118:1195-1201. 

The Pulmonary Hypertension Association 

presents the 2009 PH Resource Network Symposium 

Leading Progress, r 

Creating Partnerships: 

rships: 

Empowering the Interdisciplinary ry PH Team 

September 24 – 26, 2009 

Hyatt Regency Crystal City in Arlington, VA 

Sessions on September 25 th and 26 th will feature topics such as... 

Diagnostic interpretation 

PH and related conditions 

REVEAL outcomes and new areas of research 

Recent advances in treatment, diagnosis and care 

Clinical practice issues 

...and more 

Advocacy Day on September 24 th will include a brief training 

followed by small group meetings at the Capitol with your 

representatives in Congress. 

CNE, CEU & CPE credits will be available 

Registration for this unique event will open March 2009. 

Visit www.PHAssociation.org/PHRN/Symposium 

for the latest updates on registration, speakers and topics. 

To MDs: 

Please pass on to nurses and 

other allied health professionals sionals to make sure that the latest advances 

in the care and 

treatment of PH patients 

are incorporated into your practice!

Connective Tissue Disease-Associated 


Christopher P. Denton PhD, FRCP 

Professor of Experimental Rheumatology 

Royal Free Campus, University College London 

Head of Scleroderma Service, Royal Free Hospital 

London, UK 

I was very excited to see a whole issue of Advances in Pulmonary 

Hypertension (Vol. 7, No. 2, Summer 2008) devoted to 

connective tissue disease associated pulmonary hypertension 

(PH). As a practicing rheumatologist in a center that manages 

a large cohort of more than 1000 scleroderma cases, and a 

center that benefits from having a pulmonary hypertension centre 

embedded within it, all of the topics covered in this issue 

were very relevant. 

Scleroderma has the highest frequency of pulmonary hypertension 

of any of the rheumatic disease and is especially challenging 

to manage as cases often have co-morbidity that affects 

assessment and may lead to poor outcome. There are also particular 

challenges for diagnosis and assessment. All of these 

points were highlighted and I was especially pleased to see the 

emphasis that was put on autoantibodies as useful tests is 

assessing risk of developing pulmonary arterial hypertension 

(PAH) in scleroderma. Less invasive tests focused on at-risk 

Address for reprints and other correspondence: Christopher P. Denton, PhD 

FRCP, Professor of Experimental Rheumatology, Centre for Rheumatology, 

Royal Free Hospital, London,NW3 2QG. email: denton@rfhsm.ac.uk 

groups will be essential for timely detection and treatment of 

PAH in connective tissue disease. 

Scleroderma and the antiphospholipid syndromes were 

very clearly reviewed and the articles offered clear insight into 

the likely differences in frequency of PAH in these diseases 

and also the potential contribution of thrombosis to contribute. 

Being mindful of pathogenic mechanisms is likely to underpin 

better therapy in connective tissue disease associated 

pulmonary hypertension. One of the challenges faced daily in 

managing connective tissue disease associated PAH is the 

co-existence of interstitial lung fibrosis. The degree to which 

many patients should have PAH or PH secondary to lung fibrosis 

remains a topic of considerable debate and I was interested 

to see how this challenge was tackled in some of the major 

centres in the USA. 

Without doubt, the most engaging and relevant part of this 

excellent issue was the round table discussion. Almost all of 

the important points raised are as relevant to practice in the 

UK and other European centres as they are in USA. It is clear 

from the answers to many key questions that this whole topic 

requires more research and better information. However, with 

exciting projects such as PHAROS for scleroderma and complementary 

exercises ongoing in Europe, I was left with optimism 

about clinical practice for patients with connective tissue disease-associated 

pulmonary hypertension, even if the outcomes 

for many patients do not seem to be as good as in idiopathic 

PAH. 

In conclusion, there are more similarities than differences 

in the approach to PAH in Europe and the USA based upon 

these articles. This is a testament to the strong international 

collaboration in clinical trials and educational programs that 

exist in the fields of connective tissue disease and pulmonary 

hypertension.

Self-Assessment Examination 

See answer key on next page 

1. Chronically hypoxia is a frequently used model for PH. 

All of the following are features of chronically hypoxic 

animal models except 

a. Right ventricular hypertrophy 

b. Occlusive intimal vascular lesions 

c. Medial hypertrophy 

d. Thrombosis 

2. True or false: The tat protein is implicated in the 

pulmonary vascular abnormalities seen in the Simian 

HIV infected macaques. 

a. True 

b. False 

3. Which statement is FALSE: 

a. Most studies using animal models of PH are 

prevention models. 

b. Right heart failure is a common feature of animal 

models of PH. 

c. PH models using mice have relatively less vascular 

remodeling compared to other species. 

4. Metabolic syndrome is defined by all of the following 

abnormalities except: 

a. Diabetes 

b. Hypertension 

c. Hyperlididemia 

d. Obesity 

7. Poor prognostic signs in exercise right heart catheterization 

include all of the following EXCEPT: 

a. Increased cardiac output 

b. Decrease in pulmonary vascular resistance 

c. Angina 

d. Presyncopal symptoms or frank syncope 

8. Conventional hemodynamic assessment during right 

heart catheterization does not allow for consideration of 

which of the following: 

a. Left-sided filling pressures 

b. Pulmonary vascular resistance 

c. Pulsatile stress 

ERRATUM 

In the last issue of Advances in Pulmonary Hypertension 

there was an error on the posttest. 

1. The answer should have been E (B and C), but 

this is a typo as it says “C and D.” The correct 

answer is either B or C. A is wrong, therefore D is 

wrong. 

5. “Diabetic cardiomyopathy” is defined as impaired 

ventricular function in diabetics with: 

a. Hypertension 

b. Ischemic heart disease 

c. Both of the above 

d. Neither of the above 

6. Ventricular dysfunction in patients with metabolic 

syndrome is associated with abnormalities in which of 

the following subcellular organelles: 

a. Nucleus 

b. Golgi apparatus 

c. Mitochondria 

d. Caveoli 


ACCP Update and New Treatments for 

PAH Project # 406602 

Individuals wishing CME credit for this self-study activity 

should read the text, answer the self-assessment examination 

questions, complete the form below,* and send 

by US mail or fax to the following address by February 1, 

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CME credit. Your test will be scored and your participation 

will be entered into the CME records at the 

University of Michigan Medical School. 

Office of Continuing Medical Education 

Attn: Pamela Little 

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Your certificate will be mailed within 3 weeks of receipt 

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Circle one correct answer 

Additional comments about this self-study activity: 

1. a b c d 6. a b c d 

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Pulmonary Hypertension Roundtable 

PHA Scientific Sessions Provide a Great 

Window Into Treatment Breakthroughs 

While Inspiring Physicians and Patients Alike 


Todd Bull, MD 


Omar A. Minai, MD 

This roundtable discussion, reviewing the proceedings 

from the Pulmonary Hypertension Association’s Eighth 

International PH Conference and Scientific Sessions 

in Houston in 2008, was moderated by Karen Fagan, 

MD, Chief, Division of Pulmonary and Critical Care 

Medicine, University of South Alabama, Mobile, Alabama. 

It included Todd Bull, MD, Associate Professor 

of Medicine, Division of Pulmonary Sciences and Critical 

Care Medicine, University of Colorado Health Sciences 

Center, Aurora, Colorado; Ivan F. McMurtry, PhD, 

Professor, Department of Pharmacology, University of 

South Alabama School of Medicine, Mobile, Alabama; 

and Omar A. Minai, MD, Staff Physician in the Department 

of Pulmonary, Allergy, and Critical Care Medicine 

and the Lung Transplant Center at the Cleveland 

Clinic, Cleveland, Ohio. 

Dr Fagan: The first thing I wanted 

to do is to thank you for attending 

the Scientific Sessions. As you 

know, 2008 was the third Scientific 

Sessions that were held in 

conjunction with the PHA (Pulmonary 

Hypertension Association) 

International Conference meeting. 

The ultimate goal of the Sessions 

was to provide the medical professionals 

who volunteer their time 

during the medically led sessions 

and the patient and family oriented 

sessions an opportunity to 

hear state-of-the-art scientific 

speakers, and interact with their 

peers before they’re put to work in the International 

Conference. I am a little biased because I chaired the 

2008 Scientific Sessions committee; I think it went 

well. 

I think we were successful in bringing together a 

diverse crowd and I’d like to hear what your impression 

was of what you heard and enjoyed about the 

meeting. 

Dr Minai: The PHA International Conference provides 

a great opportunity for physicians to hear lectures on 

cutting edge research, to network with other physicians 

who may be doing similar work, and to discuss ideas 

that later blossom into novel studies. To me this is a 

unique meeting in that it is the only one in our field 

“The PHA International 

Conference provides 

a great opportunity for 

physicians to hear lectures 

on cutting edge 

research, to network 

with other physicians who may be 

doing similar work, and to discuss 

ideas that later blossom into novel 

studies. To me this is a unique meeting 

in that it is the only one in our 

field that brings patients and physicians 

together.”–Dr Minai 

that brings patients and physicians together. This experience 

serves to “humanize” the disease for professionals 

who focus on basic science research and don’t 

have the opportunity to meet patients. In addition, this 

meeting provides a unique opportunity to the greater 

pulmonary hypertension (PH) community to recognize 

the achievements and breakthroughs in this field and 

to recognize and honor people who give of their precious 

time and other resources to the cause of PH. The meeting 

allows us to truly see the breadth of the true of impact 

of PH on patients, their caregivers, and families. 

Dr Bull: The Scientific Sessions have become a part 

of the Conference that I enjoy thoroughly. The first 

meeting I attended was one of the earlier forays into 

this and I think it has progressed beautifully to date. 

The most recent Scientific Session was fantastic and 

built beautifully on the previous 

sessions. A key strength is bringing 

speakers outside the PH 

community to the meeting to talk 

about new ideas and directions 

to consider in PH. For those of 

us in the PH community, we 

have a general understanding of 

what everyone’s working on and 

of course are excited to hear 

about new directions they’re taking 

with their own work. But, this 

meeting allows the opportunity to 

stimulate new thoughts and new 

directions. 

This year I particularly enjoyed 

the pharmacogenomics discussion. Where the 

field of pharmacogenomics has arisen from was fascinating 

not just from a historical perspective but also 

where we may take it in the years to come. It really 

tied in well to some of the work that Ray Benza has 

been working on, and where we’d like to take this from 

a PH standpoint. Quite frankly it transcends more than 

just PH and the Dick Weinshilboum approach 

was great. I also really enjoyed Hunter Champion’s talk 

on the molecular basis of right ventricular (RV) dysfunction. 

Dr Minai: Hunter Champion’s talk about the molecular 

basis of RV dysfunction really stood out to me. Even 

though PH is a disease of the pulmonary vasculature, 


the real cause of most morbidity and mortality in our patients is 

RV (dys)function. I thought Hunter did a great job of delivering the 

message while making it understandable and interesting to the 

general audience which included not only basic scientists but clinicians 

and patients as well. 

Dr Fagan: I also thought that the pharmacogenomics talk by 

Dr Weinshilboum was great. He was able to show how pharmacogenomics 

doesn’t just have the promise of impacting therapy in 

a wide range of diseases, he actually showed concrete examples 

of the role of this technology in patient care today. I don’t know 

how far into the future we are until we have this type of personalized 

medicine in PH, but it certainly raised the hope that maybe 

through pharmacogenomics we’ll understand a little bit more 

about which patients should be on which initial therapies and 

which patients may not respond even to combination treatments. 

I think that the hopefulness and the potential promise of this line 

of investigation is totally exciting. 

Dr Bull: I agree, and I think all of us tell the 

patient after we complete their evaluation, we 

will pick a therapy. A patient will ask, “Is this 

going to work?” And our answer is, “We’re 

going to have to wait and see.” And we can 

look at the odds and tell you what we think is 

going to happen. Of course at this juncture 

really honestly we don’t know. We’ve all had 

patients who have significant improvements 

with a phosphodiesterase inhibitor, for example, 

and others it does not seem to touch. 

There’s got to be something to that. We’re just 

not smart enough yet to know who will benefit 

from what drug up front. In the future, 

pharmacogemonics may give us some insight. 

It is my experience that when I consider therapy, 

especially oral therapy, that my recommendations 

are more based on toxicity then 

efficiacy, ie, this treatment potentially could cause this problem 

as opposed to this, may really help. Pharmacogenomics may help 

in both areas to identify persons with expected benefit as well as 

persons with higher likelihood of toxicity. 

Dr Minai: Karen and Todd, I completely agree. When we look at 

clinical trials of oral medications in PH, we find that several medications 

have very similar overall efficacy in a cluster of patients 

and we tend to focus on the mean or average response rate. However, 

within each study population there are patients who respond 

extremely well, ie, much better than average and those that don’t 

respond at all to the same medication. Currently, we lack a reliable 

method of identifying these subgroups with any degree of accuracy. 

The patient who responds poorly to one medication may 

respond very well to another medication. Pharmacogenomics holds 

the promise of helping us match the patient with the right drug up 

front. That would be a great benefit to physicians in choosing therapy 

and to patients in this rapidly progressing disease. 

Dr Fagan: To be able to sit in the clinic with a patient and to have 

on a piece of paper an assessment about what they’re most likely 

to respond to is a powerful thought. It might limit the “wait and 

see” period after starting a treatment to see if it has any effect. It 

also might limit the possibility of losing ground. 

“My current work is 

looking at gene expression 

profiling and 

peripheral bloodcells 

and people with PH. 

My hypothesis is that 

we can gain information about PH by 

looking at immune-related cells from 

the blood. Part of the difficulty has 

always been that the lung tissue, 

where PH is manifest, is not readily 

accessible in our patients. So we 

need to find surrogate tissue to 

examine. We’re looking at the blood 

cells as a surrogate marker of the 

disease and have had some success 

using this approach.” –Dr Bull 

Dr McMurtry: Not only was Dr Weinshilboum’s talk on pharmacogenomics 

up to date and educational; it was also very entertaining. 

He is a personable and skillful lecturer, and anyone who 

gets the chance to hear him speak should definitely do so. 

Dr Fagan: I also thought Dale Able’s lecture on metabolic determinants 

of a cardiac myocyte performance was really intriguing. 

His work has illuminated the mechanisms of cardiac dysfunction 

associated with the metabolic syndrome. I was really impressed 

with his ability to make the incredible complex metabolic signaling 

pathways approachable to clinicians and to people who are 

nonmetabolic researchers. It really reminded me that our patients 

have comorbidities that they’re bringing to the table as well. So it’s 

not just what their genes are, it’s not just whether they have scleroderma 

or whether they’ve got congenital heart disease, but they 

bring all sorts of other things to the table that can directly impact 

their overall heath and PH treatment. Obviously one of those are 

people who have metabolic syndrome related 

to obesity. There are several articles that are 

beginning to look more carefully at the effects 

of metabolism on cardiac performance. 

It certainly spurred me to think about RV 

performance in a different way. 

Dr Minai: Several studies have established 

a clear link between the metabolic syndrome 

and cardiovascular disease. Despite recent 

studies, this link remains tantalizingly close 

but as yet unproven in PH. Studies looking 

at the association between PH and obesity 

and sleep apnea have reported mixed results. 

This is an area that requires further 

study. 

Dr Bull: We tend to hone in on the pulmonary 

vascular bed and the RV response to 

pressure overload but our patients live in the 

real world and have all the diseases of the real world and how 

these things interact in a more sophisticated manner is important 

to consider. So I thought that was a great lecture as well. 

Dr Fagan: The meeting gave us a chance to also look at clinical 

and translational research opportunities. I know that you, Todd, 

participated in some research at these scientific sessions and I 

was hoping you could tell us how you did it, some of the difficulties 

in doing research away from your own primary site and what 

you thought about how the meeting contributes to your research. 

Dr Bull: This is actually my second time doing research at the 

PHA conference. In Minneapolis I was working on the same project. 

It is only possible through the generosity of PHA and most importantly, 

the patients who attend the PHA meeting. My current 

work is looking at gene expression profiling and peripheral blood 

cells and people with PH. My hypothesis is that we can gain information 

about PH by looking at immune-related cells from the 

blood. Part of the difficulty has always been that the lung tissue, 

where PH is manifest, is not readily accessible in our patients. 

So we need to find surrogate tissue to examine. We’re looking at 

the blood cells as a surrogate marker of the disease and have had 

some success using this approach. This success has been in large 

part due to the PHA conference research. Greg Elliot really started 


performing research at the PHA conference at the very first meeting 

at Stone Mountain in Georgia. He realized then that in this rare 

disease a meeting where patients from all over the world come 

together would be a great opportunity to learn more about the disease 

and hopefully help improve how we diagnose and treat PH. 

In a one-day period at the PHA meeting, I can get a year’s worth 

of samples; it would take us that long to collect the same amount 

in our clinic and we have a pretty busy clinic. For my work, we obtain 

a blood sample, isolate the peripheral blood mononuclear cell 

component, and then look at gene expression. One factor is that 

after we draw the blood, we need to arrange to have a laboratory 

nearby available to us. 

Dr Fagan: How do you do that? 

Dr Bull: Through networking. At the University of Minnesota I got 

in touch with the chief of pulmonary who 

then put me in contact with a principal investigator 

in a lab that had the materials and 

equipment that I needed. We had to get IRB 

approval for these studies at the University 

of Minnesota. We did the same thing in Houston. 

As soon as we were done drawing blood 

at the conference we rushed it over to the university 

where we pro-cessed samples, finishing 

at about 2 o’clock in the morning. It was 

an onerous process, but we got great samples 

that we hope will translate into great data. 

The next phase is to collect the clinical information 

from the study subjects. 

The most important part of this is really 

the patients’ participation. The patients have really been fantastic; 

they’ve lined up at lunchtime, in between their sessions, and 

are willing to donate blood. It is an amazing thing to see and we 

are very appreciative of their help. 

I think that at this most recent meeting there were at least 6 

to 7 groups doing research. There almost wasn’t enough room for 

us all in the research room. I think when we do this again we’ll 

have to get more space. It’s been working remarkably well and 

there’s potential to make it even better. Greg Elliot has been the 

driving force behind this so we owe him a lot. 

Dr Fagan: The focus of the PHA in terms of its advocacy for patients 

includes research. One great thing that I have noticed is 

that more and more non-clinician researchers are coming to the 

meeting, especially the Scientific Sessions. Ivan, you gave an excellent 

review of the current animal models of PH that are used 

in research. You are also a great example of non-clinicians who attend 

this meeting, many of whom are seeing patients with PH for 

the first time. Ivan, perhaps you could share your thoughts about 

the conference as a PhD scientist who’s done PH research for 40 

years with limited patient contact. 

Dr McMurtry: Attending and participating in the PHA meeting was 

an incredible experience for me. I’ve presented results of my research 

on animal models of PH at numerous scientific meetings 

over the past 40 years. This was the first time I had PH patients, 

and their family members, personally thank me for my contributions 

to their treatment. I actually got a sense of what it must be 

“Attending and participating 

in the PHA 

meeting was an incredible 

experience 

for me. I’ve presented 

results of my research 

on animal models of PH at numerous 

scientific meetings over the past 40 

years. This was the first time I had 

PH patients, and their family members, 

personally thank me for my contributions 

to their treatment.”–Dr McMurtry 

like to be a rock star, since I had patients giving me hugs and requesting 

to have their pictures taken with me! It was a heartwarming 

and motivating experience, and I would recommend to 

any PhD scientist working in the field of PH to attend the meeting 

and experience first hand the appreciation and hope of PH 

patients. 

Dr Fagan: I was very fortunate to see some of the interactions that 

you had with the patients, Ivan. They really did acknowledge and 

appreciate your work. It was as meaningful to them as it was for 

you. It highlights that we really need to encourage non-clinician 

scientists to come to this conference even more. As a clinician I 

get a lot of appreciation from my patients all the time. I think people 

who are not in the clinic but are in the research lab don’t get 

to see the end result from the work they’re doing and how much 

their efforts have impacted on the lives of patients. 

Dr Minai: That is part of PHA’s strength that 

it brings together clinicians and researchers, 

physicians and patients, physicians from various 

medical fields including pulmonology, 

cardiology, and rheumatology for the sole 

purpose of improving care and outcomes in 

patients with PH. Since this is the largest 

PH conference in the world and draws physicians 

and patients from around the globe, 

this forum provides a unique opportunity for 

research that would not be possible at any 

single center. The PHA is committed to patient 

advocacy and research and therapeutic 

advancement in the field of PH and this 

conference is a true reflection of that commitment on several levels. 

Dr Bull: I think that’s a great point. I always leave the PHA meeting 

inspired. When you come to the PHA and you see the determination 

and energy, you’re reminded about why it is you do what 

you do, why you’ve selected this as your career. More people 

should have this experience 

Dr Fagan: I think many of us come to the PHA because we already 

have not just a professional but a personal commitment to the patients 

of the organization. We really need to get to our colleagues 

and say, yes this is a different meeting than you’ll ever go to, but 

it is very worthwhile. Here’s the opportunity to see some very high 

quality state-of-the-art science but these other days you have the 

chance to interact and see what your work has done for these patients. 

I think it’s important to encourage people to come and see 

that. 

Dr Fagan: I would like to thank you all for your participation in this 

discussion. It is remarkable to look back and see how far the PH 

community has come and the Scientific Sessions and International 

Conference are just a small part of that. I know that the 

Scientific Sessions will remain an important part of the meeting 

and am delighted that Dr. Ivan Robbins from Vanderbilt University 

will be taking the lead role in the Scientific Sessions for 2010. 

Hopefully we can encourage new participants in the conference in 

the future. ■ 


In the treatment of pulmonary arterial hypertension (PAH) 

(WHO Group 1, Class II or III symptoms) 

Living with PAH 

can be complicated... 

Choosing a therapy 

should not be. 

Please see below for important safety information, including 

boxed WARNINGS on the possible risk of liver injury and the 

risk of serious birth defects. 

INDICATION: LETAIRIS is an endothelin receptor antagonist indicated for 

the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) 

in patients with WHO Class II or III symptoms to improve exercise capacity 

and delay clinical worsening. 

Clinical worsening is defined as the first occurrence of death, lung 

transplantation, hospitalization for PAH, atrial septostomy, study 

withdrawal due to the addition of other PAH therapeutic agents, or study 

withdrawal due to early escape. 1 

Early escape criteria were two or more of the following after a 

minimum treatment period of 4 weeks: ≥20% decrease in 6-minute walk 

distance; worsening WHO functional class; worsening right ventricular 

failure; rapidly progressing cardiac, hepatic, or renal failure; and refractory 

systolic hypotension 5× ULN or if elevations are accompanied by bilirubin >2× ULN 

or by signs or symptoms of liver dysfunction 

• May cause fetal harm if taken during pregnancy 

• Must exclude pregnancy before the start of treatment 

• Prevent pregnancy thereafter by the use of two reliable methods 

of contraception 

Important safety information regarding hepatotoxicity 

LETAIRIS is not recommended in patients with elevated aminotransferases 

(>3× ULN) at baseline because monitoring liver injury may be more difficult. 

If aminotransferase elevations are accompanied by clinical symptoms of 

liver injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right 

upper quadrant abdominal discomfort, itching, or jaundice) or increases in 

bilirubin >2× ULN, LETAIRIS treatment should be stopped. There is no 

experience with the reintroduction of LETAIRIS in these circumstances. 

Contraindication 

• Do not administer LETAIRIS to a pregnant woman because it can cause 

fetal harm 

Warnings and precautions 

• Decreases in hemoglobin have been observed within the first few weeks 

of treatment with LETAIRIS; measure hemoglobin prior to initiation, at 

1 month, and periodically thereafter 

• Mild to moderate peripheral edema. Peripheral edema occurred more 

frequently in elderly patients (age ≥65 years) receiving LETAIRIS (29%; 

16/56) compared to placebo (4%; 1/28) 

• Peripheral edema is a known class effect of endothelin receptor 

antagonists. In addition, there have been postmarketing reports of fluid 

retention occurring within weeks after starting LETAIRIS which required 

intervention with a diuretic, fluid management, or, in some cases, 

hospitalization for decompensating heart failure 

Drug interactions 

• Use caution when LETAIRIS is coadministered with cyclosporine A 

• Use caution when LETAIRIS is coadministered with strong CYP3A 

inhibitors (e.g., ketoconazole) or CYP2C19 inhibitors (e.g., omeprazole) 

• Use caution when LETAIRIS is coadministered with inducers of P-gp, 

CYPs, and UGTs

Letairis® (ambrisentan) is indicated for the treatment of PAH (WHO Group 1, Class II or III symptoms) 

LETAIRIS offers 

Simple dosing 

One pill, once a day 1 

Two therapeutically effective doses 1 

• Available in 5 mg and 10 mg tablets 

• Initiate treatment at 5 mg once daily, and consider increasing the dose to 10 mg if 5 mg is tolerated 

Designed for everyday. 

Reliable improvements 

Up to +59 m placebo-adjusted mean change from baseline in 6MWD * at 12 weeks with LETAIRIS †1 

• LETAIRIS was studied in two 12-week, randomized, double-blind, placebo-controlled, multicenter studies (ARIES-1, N=201, and ARIES-2, N=192); 

6MWD was the primary endpoint 1 

—ARIES-1: +51 m (10 mg, p3% incidence in the combined LETAIRIS treatment 

group and more frequent than in the placebo group, with a difference of ≥1% between the 

LETAIRIS and placebo groups. 

* 6MWD=6-minute walk distance; baseline mean 6MWD was 341 ± 76 m in ARIES-1 and 

348 ± 84 m in ARIES-2. 2 

† 

Improvements in exercise capacity were greater for younger patients than for elderly patients 

(≥65 years), and greater for patients with idiopathic PAH (IPAH) than for those with associated 

PAH (APAH). Results of such subgroup analyses must be interpreted with caution. 

References: 1. LETAIRIS [Prescribing Information]. Foster City, Calif: Gilead Sciences, Inc; 

October 2008. 2. Data on file. Gilead Sciences, Inc. 

© 2008 Gilead Sciences, Inc. All rights reserved. 

ABS0130 December 2008 

LETAIRIS is a registered trademark and Gilead and the 

Gilead logo are trademarks of Gilead Sciences, Inc.

LETAIRIS® (ambrisentan) 5 mg and 10 mg Tablets 

Brief summary of full prescribing information. See full prescribing information. Rx only. 

WARNING: POTENTIAL LIVER INJURY 

LETAIRIS (ambrisentan) can cause elevation of liver aminotransferases (ALT and AST) 

to at least 3 times the upper limit of normal (ULN). LETAIRIS treatment was associated 

with aminotransferase elevations >3× ULN in 0.8% of patients in 12-week trials and 

2.8% of patients including long-term open-label trials out to one year. One case of 

aminotransferase elevations >3× ULN has been accompanied by bilirubin elevations 

>2× ULN. Because these changes are a marker for potentially serious liver injury, 

serum aminotransferase levels (and bilirubin if aminotransferase levels are elevated) 

must be measured prior to initiation of treatment and then monthly. In the postmarketing 

period with another endothelin receptor antagonist (ERA), bosentan, rare 

cases of unexplained hepatic cirrhosis were reported after prolonged (>12 months) 

therapy. In at least one case with bosentan, a late presentation (after >20 months of 

treatment) included pronounced elevations in aminotransferases and bilirubin levels 

accompanied by non-specific symptoms, all of which resolved slowly over time after 

discontinuation of the suspect drug. This case reinforces the importance of strict 

adherence to the monthly monitoring schedule for the duration of treatment. 

Elevations in aminotransferases require close attention. LETAIRIS should generally 

be avoided in patients with elevated aminotransferases (>3× ULN) at baseline 

because monitoring liver injury may be more difficult. If liver aminotransferase 

elevations are accompanied by clinical symptoms of liver injury (such as nausea, 

vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases 

in bilirubin >2× ULN, treatment should be stopped. There is no experience with the 

re-introduction of LETAIRIS in these circumstances. 

CONTRAINDICATION: PREGNANCY 

LETAIRIS is very likely to produce serious birth defects if used by pregnant women, as 

this effect has been seen consistently when it is administered to animals [see 

Contraindications (4.1)]. Pregnancy must therefore be excluded before the initiation 

of treatment with LETAIRIS and prevented thereafter by the use of at least two 

reliable methods of contraception unless the patient has had a tubal sterilization or 

Copper T 380A IUD or LNg 20 IUD inserted, in which case no other contraception is 

needed. Obtain monthly pregnancy tests. Because of the risks of liver injury and birth 

defects, LETAIRIS is available only through a special restricted distribution program 

called the LETAIRIS Education and Access Program (LEAP), by calling 1-866-664-LEAP 

(5327). Only prescribers and pharmacies registered with LEAP may prescribe and 

distribute LETAIRIS. In addition, LETAIRIS may be dispensed only to patients who are 

enrolled in and meet all conditions of LEAP [see WARNINGS, Prescribing and Distribution 

Program for LETAIRIS]. 

INDICATIONS AND USAGE: LETAIRIS is indicated for the treatment of pulmonar y ar terial hyper tension 

(WHO Group 1) in patients with WHO class II or III symptoms to improve exercise capacity and delay 

clinical worsening. 

DOSAGE AND ADMINISTRATION: Adult Dosage: Initiate treatment at 5 mg once daily with or 

without food, and consider increasing the dose to 10 mg once daily if 5 mg is tolerated.Tablets may be 

administered with or without food. Tablets should not be split, crushed, or chewed. Doses higher 

than 10 mg once daily have not been studied in patients with pulmonary arterial hypertension (PAH). 

Liver function tests should be measured prior to initiation and during treatment with LETAIRIS [see 

Warnings and Precautions (5.1)]. Women of Childbearing Potential: Pregnancy tests should be 

obtained monthly in women of childbearing potential taking LETAIRIS [see Contraindications (4.1)]. 

Pre-existing Hepatic Impairment: LETAIRIS is not recommended in patients with moderate or 

severe hepatic impairment [see Special Populations (8.7)]. 

CONTRAINDICATIONS: Pregnancy Category X: Teratogenicity is a class effect of endothelin 

receptor antagonists. There are no data on the use of LETAIRIS in pregnant women. LETAIRIS is 

contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or 

if the patient becomes pregnant while taking this drug, the patient should be apprised of the 

potential hazard to a fetus. 

WARNINGS AND PRECAUTIONS: Potential Liver Injury (see BOXED WARNING): Treatment with 

endothelin receptor antagonists has been associated with dose-dependent liver injury manifested 

primarily by elevation of serum aminotransferases (ALT or AST), but sometimes accompanied by 

abnormal liver function (elevated bilirubin). The combination of aminotransferases greater than 

3-times the upper limit of normal (>3× ULN) and total bilirubin >2× ULN is a marker for potentially 

serious hepatic injury. Liver function tests were closely monitored in all clinical studies with LETAIRIS. 

For all LETAIRIS-treated patients (N=483), the 12-week incidence of aminotransferases >3× ULN 

was 0.8% and >8× ULN was 0.2%. Liver chemistries must be measured prior to initiation of LETAIRIS 

and at least every month thereafter. If there are aminotransferase elevations >3× ULN and ≤5× 

ULN, they should be re-measured. If the confirmed level is >3× ULN and ≤5× ULN, reduce the daily 

dose or interrupt treatment and continue to monitor every two weeks until the levels are 5× ULN and ≤8× ULN, LETAIRIS should be discontinued 

and monitoring should continue until the levels are 8× ULN, treatment should be stopped and re-initiation should not be considered. If aminotransferase 

elevations are accompanied by clinical symptoms of liver injury (such as anorexia, nausea, vomiting, 

fever, malaise, fatigue, right upper quadrant abdominal discomfort, itching, or jaundice) or increases 

in bilirubin >2× ULN, LETAIRIS treatment should be stopped. Hematological Changes: Decreases 

in hemoglobin concentration and hematocrit have followed administration of other endothelin 

receptor antagonists and were observed in clinical studies with LETAIRIS. These decreases were 

observed within the first few weeks of treatment with LETAIRIS, and stabilized thereafter. The mean 

decrease in hemoglobin from baseline to end of treatment for those patients receiving LETAIRIS in 

the 12-week placebo-controlled studies was 0.8 g/dL. Marked decreases in hemoglobin (>15% 

decrease from baseline resulting in a value below the lower limit of normal) were observed in 7% of 

all patients receiving LETAIRIS (and 10% of patients receiving 10 mg) compared to 4% of patients 

receiving placebo. The cause of the decrease in hemoglobin is unknown, but it does not appear to 

result from hemorrhage or hemolysis. Hemoglobin must be measured prior to initiation of LETAIRIS 

and should be measured at one month and periodically thereafter. If a clinically significant decrease 

in hemoglobin is observed and other causes have been excluded, discontinuation of treatment 

should be considered. Peripheral Edema: Peripheral edema is a known class effect of endothelin 

receptor antagonists. In addition, there have been post-marketing reports of fluid retention occurring 

within weeks after starting LETAIRIS which required intervention with a diuretic, fluid management, 

or, in some cases, hospitalization for decompensating heart failure. Co-administration of LETAIRIS 

and Cyclosporine A: Cyclosporine is a strong inhibitor of P-glycoprotein (P-gp), Organic Anion 

Transport Protein (OATP), and CYP3A4. In vitro data indicate ambrisentan is a substrate of P-gp, OATP 

and CYP3A. Therefore, use caution when LETAIRIS is co-administered with cyclosporine A because 

cyclosporine A may cause increased exposure to LETAIRIS [see Drug Interactions (7)]. Coadministration 

of LETAIRIS and Strong CYP3A and 2C19 Inhibitors: Use caution when LETAIRIS 

is co-administered with strong CYP3A-inhibitors (e.g., ketoconazole) and CYP2C19-inhibitors (e.g., 

omeprazole) [see Drug Interactions (7)]. Prescribing and Distribution Program for LETAIRIS: 

Because of the risks of liver injury and birth defects, LETAIRIS is available only through a special 

restricted distribution program called the LETAIRIS Education and Access Program (LEAP). Only 

prescribers and pharmacies registered with LEAP may prescribe and distribute LETAIRIS. In addition, 

LETAIRIS® (ambrisentan) may be dispensed only to patients who are enrolled in and meet all 

conditions of LEAP. To enroll or receive more information visit www.letairis.com or call 1-866-664-LEAP 

(5327). 

ADVERSE REACTIONS: Clinical Trials Experience: Safety data for LETAIRIS were obtained from 

two 12-week, placebo-controlled studies in patients with PAH (ARIES-1 and ARIES-2) and four 

nonplacebo-controlled studies in 483 patients with PAH who were treated with doses of 1, 2.5, 5, or 

10 mg once daily. The exposure to LETAIRIS in these studies ranged from 1 day to 4 years (N=418 for 

at least 6 months and N=343 for at least 1 year). In ARIES-1 and ARIES-2, a total of 261 patients 

received LETAIRIS at doses of 2.5, 5, or 10 mg once daily and 132 patients received placebo. The 

adverse events that occurred in >3% of the patients receiving LETAIRIS and were more frequent on 

LETAIRIS than placebo are shown in Table 1. 

Table 1 Adverse Events in >3% of PAH Patients Receiving 

LETAIRIS and More Frequent than Placebo 

Placebo (N=132) 

LETAIRIS (N=261) 

Adverse event n (%) n (%) Placebo-adjusted (%) 

Peripheral edema 14 (11) 45 (17) 6 

Nasal congestion 2 (2) 15 (6) 4 

Sinusitis 0 (0) 8 (3) 3 

Flushing 1 (1) 10 (4) 3 

Palpitations 3 (2) 12 (5) 3 

Nasopharyngitis 1 (1) 9 (3) 2 

Abdominal pain 1 (1) 8 (3) 2 

Constipation 2 (2) 10 (4) 2 

Dyspnea 4 (3) 11 (4) 1 

Headache 18 (14) 38 (15) 1 

Note: This table includes all adverse events >3% incidence in the combined LETAIRIS treatment group and more 

frequent than in the placebo group, with a difference of ≥1% between the LETAIRIS and placebo groups. 

Most adverse drug reactions were mild to moderate and only nasal congestion was dose-dependent. 

Fewer patients receiving LETAIRIS had adverse events related to liver function tests compared to 

placebo. Peripheral edema was similar in younger patients (

START WITH CONFIDENCE 

REVATIO: for patients with PAH as early as class II 

• REVATIO is indicated for the treatment of 

pulmonary arterial hypertension (WHO 

Group I) to improve exercise ability 

– WHO Group I 

• A first-line treatment for class II and 

class III 1 

– Updated American College of Chest Physicians 

evidence-based clinical practice guidelines 

• The lowest-priced oral PAH therapy* 

– REVATIO 20 mg tid 

*Based on wholesale acquisition cost: First DataBank Inc., 2008. Actual 

pharmacy or out-of-pocket costs may vary. Price comparisons do 

not imply comparable efficacy and safety. The pivotal trial for REVATIO 

included patients who were predominantly functional classes II and III, 

and the pivotal trial for Tracleer ® included patients who were 

predominantly functional class III. 

REVATIO is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise ability. The efficacy of REVATIO has not been 

evaluated in patients currently on bosentan therapy. 

The use of REVATIO and organic nitrates in any form, at any time, is contraindicated. 

Co-administration of REVATIO with potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, and ritonavir) is not recommended as serum 

concentrations of sildenafil substantially increase. Co-administration of REVATIO with CYP3A4 inducers, including bosentan; and more potent inducers 

such as barbiturates, carbamazepine, phenytoin, efavirenz, nevirapine, rifampin, and rifabutin, may alter plasma levels of either or both 

medications. Dosage adjustment may be necessary. 

Before starting REVATIO, physicians should carefully consider whether their patients with underlying conditions could be adversely affected by the mild 

and transient vasodilatory effects of REVATIO on blood pressure. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients 

with pulmonary veno-occlusive disease (PVOD) and administration of REVATIO to these patients is not recommended. Should signs of 

pulmonary edema occur when sildenafil is administered, the possibility of associated PVOD should be considered. 

The most common side effects of REVATIO (placebo-subtracted) were epistaxis (8%), headache (7%), dyspepsia (6%), flushing (6%), and insomnia (6%). 

Adverse events were generally transient and mild to moderate. 

Caution is advised when PDE5 inhibitors, such as REVATIO, are administered with -blockers as both are vasodilators with blood pressure lowering effects. 

REVATIO should be used with caution in patients with anatomical deformation of the penis or patients who have conditions which may predispose them to priapism. 

In PAH patients, the concomitant use of vitamin K antagonists and REVATIO resulted in a greater incidence of reports of bleeding (primarily epistaxis) 

versus placebo. The incidence of epistaxis was higher in patients with PAH secondary to CTD (sildenafil 13%, placebo 0%) than in PPH patients 

(sildenafil 3%, placebo 2%). 

Non-arteritic anterior ischemic optic neuropathy (NAION) has been reported rarely post-marketing 

in temporal association with the use of PDE5 inhibitors for the treatment of erectile dysfunction, 

including sildenafil. It is not possible to determine if these events are related to PDE5 

inhibitors or to other factors. Physicians should advise patients to seek immediate medical 

attention in the event of sudden loss of vision while taking PDE5 inhibitors, including REVATIO. 

Sudden decrease or loss of hearing has been reported in temporal association with the intake 

of PDE5 inhibitors, including REVATIO. It is not possible to determine whether these events are 

related directly to the use of PDE5 inhibitors or to other factors. Physicians should advise 

patients to seek prompt medical attention in the event of sudden decrease or loss of 

hearing while taking PDE5 inhibitors, including REVATIO. 

Tracleer (bosentan) is a registered trademark of Actelion Pharmaceuticals. 

Please see brief summary of prescribing information on adjacent page. 

REVATIO contains sildenafil citrate, the 

same active ingredient found in Viagra ® 

www.pfizerpro.com

Reference: 1. Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest. 2007;131:1917-1928. 

Brief summary of prescribing information 

INDICATIONS AND USAGE 

REVATIO is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise ability. 

The efficacy of REVATIO has not been evaluated in patients currently on bosentan therapy. 

CONTRAINDICATIONS 

Consistent with its known effects on the nitric oxide/cGMP pathway (see CLINICAL PHARMACOLOGY), sildenafil was shown 

to potentiate the hypotensive effects of nitrates, and its administration to patients who are using organic nitrates, either 

regularly and/or intermittently, in any form is therefore contraindicated. 

REVATIO is contraindicated in patients with a known hypersensitivity to any component of the tablet. 

WARNINGS 

The concomitant administration of the protease inhibitor ritonavir (a highly potent CYP3A4 inhibitor) substantially increases 

serum concentrations of sildenafil, therefore co-administration with REVATIO is not recommended (see Drug Interactions and 

DOSAGE AND ADMINISTRATION). 

REVATIO has vasodilator properties, resulting in mild and transient decreases in blood pressure (see 

PRECAUTIONS). Prior to prescribing REVATIO, physicians should carefully consider whether their patients with 

certain underlying conditions could be adversely affected by such vasodilatory effects, for example patients with resting 

hypotension (BP 170/110); 

• Patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases); 

• Patients currently on bosentan therapy. 

PRECAUTIONS 

General 

Before prescribing REVATIO, it is important to note the following: 

• Caution is advised when phosphodiesterase type 5 (PDE5) inhibitors are co-administered with alpha-blockers. PDE5 

inhibitors, including sildenafil, and alpha-adrenergic blocking agents are both vasodilators with blood pressure lowering 

effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some 

patients, concomitant use of these two drug classes can lower blood pressure significantly, leading to symptomatic 

hypotension. In the sildenafil interaction studies with alpha-blockers (see Drug Interactions), cases of symptomatic 

hypotension consisting of dizziness and lightheadedness were reported. No cases of syncope or fainting were reported 

during these interaction studies. Consideration should be given to the fact that safety of combined use of PDE5 inhibitors 

and alpha-blockers may be affected by other variables, including intravascular volume depletion and concomitant use of 

anti-hypertensive drugs. 

• REVATIO should be used with caution in patients with anatomical deformation of the penis (such as angulation, 

cavernosal fibrosis or Peyronie’s disease) or in patients who have conditions, which may predispose them to priapism (such 

as sickle cell anemia, multiple myeloma or leukemia). In the event of an erection that persists longer than 4 hours, the 

patient should seek immediate medical assistance. If priapism (painful erections greater than 6 hours in duration) is not 

treated immediately, penile tissue damage and permanent loss of potency could result. 

• In humans, sildenafil has no effect on bleeding time when taken alone or with aspirin. In vitro studies with human platelets 

indicate that sildenafil potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide donor). The 

combination of heparin and sildenafil had an additive effect on bleeding time in the anesthetized rabbit, but this 

interaction has not been studied in humans. 

• The incidence of epistaxis was higher in patients with PAH secondary to CTD (sildenafil 13%, placebo 0%) than in PPH 

patients (sildenafil 3%, placebo 2%). The incidence of epistaxis was also higher in sildenafil-treated patients with 

concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist). 

• The safety of REVATIO is unknown in patients with bleeding disorders and patients with active peptic ulceration. 

Information for Patients 

Physicians should discuss with patients the contraindication of REVATIO with regular and/or intermittent use of 

organic nitrates. 

Sildenafil is also marketed as VIAGRA ® for male erectile dysfunction. 

Physicians should advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both 

eyes while taking all PDE5 inhibitors, including REVATIO. Such an event may be a sign of non-arteritic anterior ischemic optic 

neuropathy (NAION), a cause of decreased vision including permanent loss of vision, that has been reported rarely postmarketing 

in temporal association with the use of all PDE5 inhibitors when used in the treatment of male erectile 

dysfunction. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other 

factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced 

NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE5 

inhibitors (see ADVERSE REACTIONS). 

Physicians should advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while 

taking all PDE5 inhibitors, including REVATIO. These events, which may be accompanied by tinnitus and dizziness, have been 

reported in temporal association to the intake of PDE5 inhibitors, including REVATIO. It is not possible to determine whether 

these events are related directly to the use of PDE5 inhibitors or to other factors (see ADVERSE REACTIONS, Clinical Trials 

and Post-Marketing Experience). 

Drug Interactions 

In PAH patients, the concomitant use of vitamin K antagonists and sildenafil resulted in a greater incidence of reports of 

bleeding (primarily epistaxis) versus placebo. 

Effects of Other Drugs on REVATIO 

In vitro studies: Sildenafil metabolism is principally mediated by the CYP3A4 (major route) and CYP2C9 (minor route) 

cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these 

isoenzymes may increase sildenafil clearance. 

In vivo studies: Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil 

clearance and/or an increase of oral bioavailability when co-administered with CYP3A4 substrates and the 

combination of CYP3A4 substrates and beta-blockers. These were the only factors with a statistically significant impact on 

sildenafil pharmacokinetics. 

Population data from patients in clinical trials indicated a reduction in sildenafil clearance when it was 

co-administered with CYP3A4 inhibitors. Sildenafil exposure without concomitant medication is shown to be 

5-fold higher at a dose of 80 mg t.i.d. compared to its exposure at a dose of 20 mg t.i.d. This concentration range covers the 

same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A4 inhibitors (except 

for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). Cimetidine (800 mg), a nonspecific CYP inhibitor, 

caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy 

volunteers. When a single 100 mg dose of sildenafil was co-administered with erythromycin, a CYP3A4 inhibitor, at steady 

state (500 mg twice daily [b.i.d.] for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). In a study 

performed in healthy volunteers, co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state 

(1200 mg t.i.d.) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil C max and a 210% increase in 

sildenafil AUC. Stronger CYP3A4 inhibitors will have still greater effects on plasma levels of sildenafil 

(see DOSAGE AND ADMINISTRATION). 

In another study in healthy volunteers, co-administration with the HIV protease inhibitor ritonavir, a potent CYP3A4 inhibitor, 

at steady state (500 mg b.i.d.) with sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil C max and 

a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours, the plasma levels of sildenafil were still approximately 

200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked 

effects on a broad range of P450 substrates (see WARNINGS and DOSAGE AND ADMINISTRATION). Although the interaction 

between other protease inhibitors and REVATIO has not been studied, their concomitant use is expected to increase 

sildenafil levels. 

In a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg t.i.d.), with the endothelin 

receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of cytochrome P450 2C19) at steady state 

(125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil C max. The combination of both 

drugs did not lead to clinically significant changes in blood pressure (supine or standing). Concomitant administration of 

potent CYP3A4 inducers is expected to cause greater decreases in plasma levels of sildenafil. 

In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker doxazosin (4 mg or 8 mg) were 

administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these 

study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 

8/4 mmHg, respectively, were observed. Mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, 

and 4/5 mmHg, respectively, were also observed. There were infrequent reports of patients who experienced symptomatic 

postural hypotension. These reports included dizziness and light-headedness, but not syncope (see PRECAUTIONS: General). 

Concomitant administration of oral contraceptives (ethinyl estradiol 30 µg and levonorgestrel 150 µg) did not affect the 

pharmacokinetics of sildenafil. 

Concomitant administration of a single 100 mg dose of sildenafil with 10 mg of atorvastatin did not alter the 

pharmacokinetics of either sildenafil or atorvastatin. 

Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil. 

Effects of REVATIO on Other Drugs 

In vitro studies: Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 

(IC50 >150 µM). 

In vivo studies: When sildenafil 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to 

hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 

7 mmHg diastolic. 

No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized 

by CYP2C9. 

Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg). 

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood 

alcohol levels of 0.08%. 

In healthy subjects, co-administration of 125 mg b.i.d. bosentan and 80 mg t.i.d. sildenafil resulted in a 63% decrease in 

AUC of sildenafil and a 50% increase in AUC of bosentan. 

In a study of healthy volunteers, sildenafil (100 mg) did not affect the steady-state pharmacokinetics of the HIV protease 

inhibitors saquinavir and ritonavir, both of which are CYP3A4 substrates. 

Sildenafil had no impact on the plasma levels of oral contraceptives (ethinyl estradiol 30 µg and levonorgestrel 150 µg). 

Carcinogenesis, Mutagenesis, Impairment of Fertility 

Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose 

resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33 and 37 times, for male and 

female rats, respectively, the human exposure at the Recommended Human Dose (RHD) of 20 mg t.i.d. Sildenafil was not 

carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a 

maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. 

Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human 

lymphocyte and in vitro mouse micronucleus assays to detect clastogenicity. 

There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose 

producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite 19 and 38 times, for males and 

females, respectively, the human exposure at the RHD of 20 mg t.i.d. 

Pregnancy 

Pregnancy Category B. No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in pregnant rats or 

rabbits, dosed with 200 mg sildenafil/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 

32- and 68-times, respectively, the RHD of 20 mg t.i.d. In a rat pre- and postnatal development study, the 

no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis). There are no 

adequate and well-controlled studies of sildenafil in pregnant women. 

Nursing Mothers 

It is not known if sildenafil citrate and/or metabolites are excreted in human breast milk. Since many drugs are excreted in 

human milk, caution should be used when REVATIO is administered to nursing women. 

Pediatric Use 

Safety and Effectiveness of sildenafil in pediatric pulmonary hypertension patients has not been established. 

Geriatric Use 

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, but studies did not include sufficient 

numbers of subjects to determine whether they respond differently from younger subjects. Other reported clinical 

experience has not identified differences in response between the elderly and younger pulmonary arterial hypertension 

patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased 

hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 

ADVERSE REACTIONS 

Clinical Trials 

Safety data were obtained from the pivotal study and an open-label extension study in 277 treated patients with pulmonary 

arterial hypertension. Doses up to 80 mg t.i.d. were studied. 

The overall frequency of discontinuation in REVATIO-treated patients at the recommended dose of 20 mg t.i.d. was low (3%) 

and the same as placebo (3%). 

In the pivotal placebo-controlled trial in pulmonary arterial hypertension, the adverse drug reactions that were reported by 

at least 3% of REVATIO patients treated at the recommended dosage (20 mg t.i.d.) and were more frequent in REVATIO 

patients than placebo patients, are shown in Table 1. Adverse events were generally transient and mild to moderate in 

nature. 

Table 1. Sildenafil Adverse Events in 3% of Patients and More Frequent Than Placebo 

ADVERSE EVENT % 

Epistaxis 

Headache 

Dyspepsia 

Flushing 

Insomnia 

Erythema 

Dyspnea exacerbated 

Rhinitis nos 

Diarrhea nos 

Myalgia 

Pyrexia 

Gastritis nos 

Sinusitis 

Paresthesia 

Placebo (n=70) Sildenafil 20 mg t.i.d. (n=69) Placebo Subtracted 

1 

9 

8 

39 46 

7 

741130643000 13 

6 

10 6 

7674976333 6 

5 

4 

4 

3 

3 

3 

3 

3 

3 

At doses higher than the recommended 20 mg t.i.d. there was a greater incidence of some adverse events including 

flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were 

predominately color-tinge to vision, but also increased sensitivity to light or blurred vision. 

In the pivotal study, the incidence of retinal hemorrhage at the recommended sildenafil 20 mg t.i.d. dose was 1.4% versus 

0% placebo and for all sildenafil doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both the 

recommended dose and at all doses studied was 1.4% for sildenafil versus 1.4% for placebo. The patients experiencing 

these events had risk factors for hemorrhage including concurrent anticoagulant therapy. 

Post-Marketing Experience 

In post-marketing experience with sildenafil citrate at doses indicated for male erectile dysfunction, serious 

cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, 

ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary 

hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of 

the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were 

reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil 

without sexual activity. Others were reported to have occurred hours to days after use concurent with sexual activity. It is 

not possible to determine whether these events are related directly to sildenafil citrate, to sexual activity, to the patient’s 

underlying cardiovascular disease, or to a combination of these or other factors. 

When used to treat male-erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of 

decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with 

the use of phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil citrate. Most, but not all, of these patients had 

underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc 

ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not 

possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient’s underlying 

vascular risk factors or anatomical defects, to a combination of these factors, or to other factors (see PRECAUTIONS/ 

Information for Patients). 

Cases of sudden decrease or loss of hearing have been reported post-marketing in temporal association with the use of 

PDE5 inhibitors, including REVATIO. In some of the cases, medical conditions and other factors were reported that may have 

also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible 

to determine whether these reported events are related directly to the use of REVATIO, to the patient’s underlying risk 

factors for hearing loss, a combination of these factors, or to other factors (see PRECAUTIONS, Information for Patients). 

OVERDOSAGE 

In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses 

but rates were increased. 

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to 

accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine. 

October 2007 

RVU00055 ©2008 Pfizer Inc. All rights reserved. Printed in USA/August 2008 

U.S. Pharmaceutical

In pulmonary arterial hypertension (PAH) 

WHO Class III or IV 

1 

Tracleer goes beyond 

symptomatic relief 

* 

* 

† 

*BREATHE-1 Multicenter, randomized, double-blind, 

placebo-controlled study to assess the efficacy and safety 

of Tracleer (125 mg BID, 250 mg BID) in patients with WHO 

functional class III or IV PAH (N=213). All patients (n=144, 

Tracleer group; n=69, control group) participated in the first 

16 weeks. A subset of this population (n=35, Tracleer group; 

n=13, control group) continued for up to 28 weeks. 

Clinical worsening was defined as the combined endpoint 

of death, hospitalization for treatment related to PAH, 

discontinuation of therapy due to worsening PAH, or 

initiation of epoprostenol therapy. 2 

WHO functional class status 1,2 Placebo—Baseline: 94.2% 

Class III, 5.8% Class IV. Week 16: 0% Class I, 27.5% Class II, 

63.8% Class III, 8.7% Class IV. Tracleer—Baseline: 90.3% 

Class III, 9.7% Class IV. Week 16: 2.1% Class I, 36.1% Class 

II, 56.3% Class III, 5.6% Class IV. 

†Study 351 Randomized, double-blind, placebo-controlled 

study of Tracleer 125 mg BID in patients with WHO 

functional class III or IV PAH (N=32). 3 

RAP, right atrial pressure; CI, cardiac index; PVR, pulmonary 

vascular resistance; PAP, pulmonary arterial pressure 

Please visit www.TRACLEER.com to learn more 

about Tracleer and PAH. 

A Cornerstone of 

Oral Therapy 

Please see brief summary of prescribing information, 

including boxed warnings, on following page. 

Important safety information 

Liver 

and pregnancy warnings: Potential 

for 

serious liver injury (including, 

after 

prolonged treatment, rare cases of 

liver 

failure and unexplained hepatic cirrhosis in a setting of 

close monitoring)—Liver monitoring 

of all patients is essential prior to initiation n of treatment and monthly thereafter. e 

High potential for major birth defects— 

Pregnancy 

must 

be excluded and prevented 

by 

two forms 

of 

birth control; 

monthly 

pregnancy 

tests 

should be 

obtained. 

Because 

of 

these risks, Tracleer 

may 

only 

be prescribed through the Tracleer 

Access 

Program. 

Contraindicated icated for 

use with cyclosporine A and glyburide.

Use of TRACLEER ® requires attention to two significant concerns: 1) potential for serious liver injury, and 2) potential 

damage to a fetus. 

WARNING: Potential liver injury 

TRACLEER ® causes at least 3-fold (upper limit of normal; ULN) elevation of liver aminotransferases (ALT and AST) in 

about 11% of patients, accompanied by elevated bilirubin in a small number of cases. Because these changes are a 

marker for potential serious liver injury, serum aminotransferase levels must be measured prior to initiation of treatment 

and then monthly (see WARNINGS: Potential Liver Injury). In the post-marketing period, in the setting of 

close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (>12 months) therapy 

with TRACLEER ® in patients with multiple co-morbidities and drug therapies. There have also been rare reports of liver 

failure. The contribution of TRACLEER ® in these cases could not be excluded. 

In at least one case the initial presentation (after > 20 months of treatment) included pronounced elevations in 

aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly over time 

after discontinuation of TRACLEER ® . This case reinforces the importance of strict adherence to the monthly monitoring 

schedule for the duration of treatment and the treatment algorithm, which includes stopping TRACLEER ® with a rise of 

aminotransferases accompanied by signs or symptoms of liver dysfunction. 

Elevations in aminotransferases require close attention. TRACLEER ® should generally be avoided in patients with 

elevated aminotransferases (> 3 x ULN) at baseline because monitoring liver injury may be more difficult. If liver 

aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, 

fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 x ULN, treatment should 

be stopped. There is no experience with the re-introduction of TRACLEER ® in these circumstances. 

CONTRAINDICATION: Pregnancy. TRACLEER ® (bosentan) is very likely to produce major birth defects if used by pregnant 

women, as this effect has been seen consistently when it is administered to animals (see CONTRAINDICATIONS). 

Therefore, pregnancy must be excluded before the start of treatment with TRACLEER ® and prevented thereafter by 

the use of a reliable method of contraception. Hormonal contraceptives, including oral, injectable, transdermal, and 

implantable contraceptives should not be used as the sole means of contraception because these may not be effective 

in patients receiving TRACLEER ® (see PRECAUTIONS: Drug Interactions). Therefore, effective contraception through 

additional forms of contraception must be practiced. Monthly pregnancy tests should be obtained. 

Because of potential liver injury and in an effort to make the chance of fetal exposure to TRACLEER ® (bosentan) as 

small as possible, TRACLEER ® may be prescribed only through the TRACLEER ® Access Program by calling 1 866 228 

3546. Adverse events can also be reported directly via this number. 

INDICATIONS AND USAGE: TRACLEER ® is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in patients 

with WHO Class III or IV symptoms, to improve exercise ability and decrease the rate of clinical worsening. 

CONTRAINDICATIONS: See BOX WARNING for CONTRAINDICATION to use in pregnancy. 

Pregnancy Category X. TRACLEER ® is expected to cause fetal harm if administered to pregnant women. Bosentan was teratogenic 

in rats given oral doses ≥ 60 mg/kg/day (twice the maximum recommended human oral dose of 125 mg, b.i.d., on a mg/m 2 basis). In 

an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, 

mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses of 60 and 300 mg/kg/day (2 and 10 

times, respectively, the maximum recommended human dose on a mg/m 2 basis). Although birth defects were not observed in rabbits 

given oral doses of up to 1500 mg/kg/day, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The 

similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other 

endothelin receptor antagonists indicates that teratogenicity is a class effect of these drugs. There are no data on the use of TRACLEER ® 

in pregnant women. Pregnancy must be excluded before the start of treatment with TRACLEER ® and prevented thereafter by use of 

reliable contraception. It has been demonstrated that hormonal contraceptives, including oral, injectable, transdermal, and 

implantable contraceptives may not be reliable in the presence of TRACLEER ® and should not be used as the sole contraceptive 

method in patients receiving TRACLEER ® (see Drug Interactions: Hormonal Contraceptives, Including Oral, Injectable, 

Transdermal and Implantable Contraceptives). Input from a gynecologist or similar expert on adequate contraception should 

be sought as needed. TRACLEER ® should be started only in patients known not to be pregnant. For female patients of childbearing 

potential, a prescription for TRACLEER ® should not be issued by the prescriber unless the patient assures the prescriber that she is 

not sexually active or provides negative results from a urine or serum pregnancy test performed during the first 5 days of a normal 

menstrual period and at least 11 days after the last unprotected act of sexual intercourse. Follow-up urine or serum pregnancy tests 

should be obtained monthly in women of childbearing potential taking TRACLEER ® . The patient must be advised that if there is any 

delay in onset of menses or any other reason to suspect pregnancy, she must notify the physician immediately for pregnancy testing. 

If the pregnancy test is positive, the physician and patient must discuss the risk to the pregnancy and to the fetus. 

Cyclosporine A: Co-administration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of 

bosentan. Therefore, concomitant use of TRACLEER ® and cyclosporine A is contraindicated. 

Glyburide: An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. 

Therefore co-administration of glyburide and TRACLEER ® is contraindicated. 

Hypersensitivity: TRACLEER ® is also contraindicated in patients who are hypersensitive to bosentan or any component of 

the medication. 

WARNINGS: Potential Liver Injury (see BOX WARNING): Elevations in ALT or AST by more than 3 x ULN were observed in 11% 

of bosentan-treated patients (N = 658) compared to 2% of placebo-treated patients (N = 280). Three-fold increases were seen 

in 12% of 95 PAH patients on 125 mg b.i.d. and 14% of 70 PAH patients on 250 mg b.i.d. Eight-fold increases were seen in 2% 

of PAH patients on 125 mg b.i.d. and 7% of PAH patients on 250 mg b.i.d. Bilirubin increases to ≥3 x ULN were associated with 

aminotransferase increases in 2 of 658 (0.3%) of patients treated with bosentan. The combination of hepatocellular injury (increases 

in aminotransferases of > 3 x ULN) and increases in total bilirubin (≥ 3 x ULN) is a marker for potential serious liver injury. Elevations 

of AST and/or ALT associated with bosentan are dose-dependent, occur both early and late in treatment, usually progress slowly, 

are typically asymptomatic, and usually have been reversible after treatment interruption or cessation. Aminotransferase elevations 

also may reverse spontaneously while continuing treatment with TRACLEER ® . Liver aminotransferase levels must be measured prior 

to initiation of treatment and then monthly. If elevated aminotransferase levels are seen, changes in monitoring and treatment must 

be initiated. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, 

fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 x ULN, treatment should be stopped. 

There is no experience with the re-introduction of TRACLEER ® in these circumstances. Pre-existing Liver Impairment: Liver aminotransferase 

levels must be measured prior to initiation of treatment and then monthly. TRACLEER ® should generally be avoided in 

patients with moderate or severe liver impairment. In addition, TRACLEER ® should generally be avoided in patients with elevated 

aminotransferases (> 3 x ULN) because monitoring liver injury in these patients may be more difficult (see BOX WARNING). 

PRECAUTIONS: Hematologic Changes: Treatment with TRACLEER ® caused a dose-related decrease in hemoglobin and hematocrit. 

Hemoglobin levels should be monitored after 1 and 3 months of treatment and then every 3 months. The overall mean decrease 

in hemoglobin concentration for bosentan-treated patients was 0.9 g/dL (change to end of treatment). Most of this decrease of 

hemoglobin concentration was detected during the first few weeks of bosentan treatment and hemoglobin levels stabilized by 

4–12 weeks of bosentan treatment. In placebo-controlled studies of all uses of bosentan, marked decreases in hemoglobin (> 15% 

decrease from baseline resulting in values < 11 g/dL) were observed in 6% of bosentan-treated patients and 3% of placebotreated 

patients. In patients with pulmonary arterial hypertension treated with doses of 125 and 250 mg b.i.d., marked decreases 

in hemoglobin occurred in 3% compared to 1% in placebo-treated patients. A decrease in hemoglobin concentration by at least 

1 g/dL was observed in 57% of bosentan-treated patients as compared to 29% of placebo-treated patients. In 80% of those patients 

whose hemoglobin decreased by at least 1 g/dL, the decrease occurred during the first 6 weeks of bosentan treatment. During the 

course of treatment the hemoglobin concentration remained within normal limits in 68% of bosentan-treated patients compared 

to 76% of placebo patients. The explanation for the change in hemoglobin is not known, but it does not appear to be hemorrhage 

or hemolysis. It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. 

If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and 

need for specific treatment. Fluid retention: In a placebo-controlled trial of patients with severe chronic heart failure, there was 

an increased incidence of hospitalization for CHF associated with weight gain and increased leg edema during the first 4-8 weeks 

of treatment with TRACLEER ® . In addition, there have been numerous post-marketing reports of fluid retention in patients with 

pulmonary hypertension, occurring within weeks after starting TRACLEER ® . Patients required intervention with a diuretic, fluid 

management, or hospitalization for decompensating heart failure. Pulmonary Veno-Occlusive Disease (PVOD): Should signs 

of pulmonary edema occur when TRACLEER ® is administered the possibility of associated PVOD should be considered and 

TRACLEER ® should be discontinued. Pulmonary Arterial Hypertension Associated with HIV Infection: There is limited clinical 

trial experience with the use of TRACLEER ® in patients with PAH associated with HIV infection who are treated concomitantly 

with antiretroviral medications. An interaction study between bosentan and lopinavir+ritonavir in healthy subjects showed 

increased plasma concentrations of bosentan and decreased concentrations of lopinavir+ritonavir (see PRECAUTIONS: Drug 

Interactions). Due to the potential for interactions related to the inducing effect of bosentan on CYP450, which could affect 

the efficacy of some antiretroviral therapies, patients should be monitored carefully regarding their HIV infection. Conversely, 

due to the inhibition of organic anion-transporting polypeptides (OATP) by ritonavir, there may be an increase in exposure to 

bosentan. The potential for an increased risk of hepatic toxicity and hematological adverse events cannot be excluded. 

Information for Patients: Patients are advised to consult the TRACLEER ® Medication Guide on the safe use of TRACLEER ® . The 

physician should discuss with the patient the importance of monthly monitoring of serum aminotransferases and urine or serum 

pregnancy testing and of avoidance of pregnancy. The physician should discuss options for effective contraception and measures 

to prevent pregnancy with their female patients. Input from a gynecologist or similar expert on adequate contraception should be 

sought as needed. 

Drug Interactions: Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these enzymes may increase the plasma concentration 

of bosentan (see ketoconazole). Concomitant administration of both a CYP2C9 inhibitor (such as fluconazole or amiodarone) 

and a CYP3A4 inhibitor (such as ketoconazole, itraconazole, or ritonavir) with bosentan will likely lead to large increases in plasma 

concentrations of bosentan. Co-administration of such combinations of a potent CYP2C9 inhibitor plus a CYP3A4 inhibitor with 

TRACLEER ® is not recommended. Bosentan is an inducer of CYP3A4 and CYP2C9. Consequently plasma concentrations of drugs 

metabolized by these two isozymes will be decreased when TRACLEER ® is co-administered. Bosentan had no relevant inhibitory 

effect on any CYP isozyme in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4). Consequently, TRACLEER ® is not expected to 

increase the plasma concentrations of drugs metabolized by these enzymes. 

Hormonal Contraceptives, Including Oral, Injectable, Transdermal, and Implantable Contraceptives: An interaction 

study demonstrated that co-administration of bosentan and the oral hormonal contraceptive Ortho-Novum ® produced 

average decreases of norethindrone and ethinyl estradiol levels of 14% and 31%, respectively. However, decreases in 

exposure were as much as 56% and 66%, respectively, in individual subjects. Therefore, hormonal contraceptives, including 

oral, injectable, transdermal, and implantable forms, may not be reliable when TRACLEER ® is co-administered. Women 

should practice additional methods of contraception and not rely on hormonal contraception alone when taking TRACLEER ® . 

Specific interaction studies have demonstrated the following: 

Cyclosporine A: During the first day of concomitant administration, trough concentrations of bosentan were increased by about 

30-fold. Steady-state bosentan plasma concentrations were 3- to 4-fold higher than in the absence of cyclosporine A. The 

concomitant administration of bosentan and cyclosporine A is contraindicated (see CONTRAINDICATIONS). Co-administration of 

bosentan decreased the plasma concentrations of cyclosporine A (a CYP3A4 substrate) by approximately 50%. 

Tacrolimus: Co-administration of tacrolimus and bosentan has not been studied in man. Co-administration of tacrolimus and 

bosentan resulted in markedly increased plasma concentrations of bosentan in animals. Caution should be exercised if tacrolimus 

and bosentan are used together. 

Glyburide: An increased risk of elevated liver aminotransferases was observed in patients receiving concomitant therapy with 

glyburide. Therefore, the concomitant administration of TRACLEER ® and glyburide is contraindicated, and alternative hypoglycemic 

agents should be considered (see CONTRAINDICATIONS). Co-administration of bosentan decreased the plasma concentrations 

of glyburide by approximately 40%. The plasma concentrations of bosentan were also decreased by approximately 30%. Bosentan 

is also expected to reduce plasma concentrations of other oral hypoglycemic agents that are predominantly metabolized by CYP2C9 

or CYP3A4. The possibility of worsened glucose control in patients using these agents should be considered. 

Ketoconazole: Co-administration of bosentan 125 mg b.i.d. and ketoconazole, a potent CYP3A4 inhibitor, increased the plasma 

concentrations of bosentan by approximately 2-fold. No dose adjustment of bosentan is necessary, but increased effects of bosentan 

should be considered. 

Simvastatin and Other Statins: Co-administration of bosentan decreased the plasma concentrations of simvastatin (a CYP3A4 

substrate), and its active -hydroxy acid metabolite, by approximately 50%. The plasma concentrations of bosentan were not affected. 

Bosentan is also expected to reduce plasma concentrations of other statins that have significant metabolism by CYP3A4, such 

as lovastatin and atorvastatin. The possibility of reduced statin efficacy should be considered. Patients using CYP3A4 metabolized 

statins should have cholesterol levels monitored after TRACLEER ® is initiated to see whether the statin dose needs adjustment. 

Warfarin: Co-administration of bosentan 500 mg b.i.d. for 6 days decreased the plasma concentrations of both S-warfarin (a 

CYP2C9 substrate) and R-warfarin (a CYP3A4 substrate) by 29 and 38%, respectively. Clinical experience with concomitant 

administration of bosentan and warfarin in patients with pulmonary arterial hypertension did not show clinically relevant 

changes in INR or warfarin dose (baseline vs. end of the clinical studies), and the need to change the warfarin dose during the 

trials due to changes in INR or due to adverse events was similar among bosentan- and placebo-treated patients. 

Digoxin, Nimodipine and Losartan: Bosentan has no significant pharmacokinetic interactions with digoxin and nimodipine, and 

losartan has no significant effect on plasma levels of bosentan. 

Sildenafil: In healthy subjects, co-administration of multiple doses of 125 mg b.i.d bosentan and 80 mg t.i.d. sildenafil 

resulted in a reduction of sildenafil plasma concentrations by 63% and increased bosentan plasma concentrations by 50%. 

A dose adjustment of neither drug is necessary. This recommendation holds true when sildenafil is used for the treatment of 

pulmonary arterial hypertension or erectile dysfunction. 

Iloprost: In a small, randomized, double-blind, placebo-controlled study (the STEP trial), 34 patients treated with bosentan 125 

mg bid for at least 16 weeks tolerated the addition of inhaled iloprost (up to 5 mcg 6 to 9 times per day during waking hours). 

The mean daily inhaled dose was 27 mcg and the mean number of inhalations per day was 5.6. 

Rifampicin: Coadministration of bosentan and rifampicin in normal volunteers resulted in a mean 6-fold increase in bosentan 

trough levels after the first concomitant dose, but about a 60% decrease in bosentan levels at steady-state. The effect of bosentan 

on rifampicin levels has not been assessed. When consideration of the potential benefits and known and unknown risks leads to 

concomitant use, measure LFTs weekly for the first 4 weeks before reverting to normal monitoring. 

Lopinavir and ritonavir: Co-administration of TRACLEER ® 125 mg twice daily and lopinavir+ritonavir 400 mg + 100 mg twice 

daily during 9.5 days in healthy subjects resulted in initial trough plasma concentrations of bosentan that were approximately 

48-fold higher than those measured after TRACLEER ® administered alone. At steady state, plasma concentrations of bosentan 

were approximately 5-fold higher than with TRACLEER ® administered alone. Inhibition by ritonavir of OATP-mediated 

uptake into hepatocytes, reducing the clearance of bosentan, most likely explains this interaction. After co-administration of 

TRACLEER ® , the plasma exposures to lopinavir and ritonavir at steady state decreased by approximately 14% and 17%, 

respectively. When TRACLEER ® is administered concomitantly with lopinavir+ritonavir or other ritonavir-boosted protease 

inhibitors, there should be appropriate monitoring of TRACLEER ® tolerability and ongoing HIV status (see PRECAUTIONS). 

Carcinogenesis, Mutagenesis, Impairment of Fertility: Two years of dietary administration of bosentan to mice produced 

an increased incidence of hepatocellular adenomas and carcinomas in males at doses as low as 450 mg/kg/day (about 8 times 

the maximum recommended human dose [MRHD] of 125 mg b.i.d., on a mg/m 2 basis). In the same study, doses greater than 

2000 mg/kg/day (about 32 times the MRHD) were associated with an increased incidence of colon adenomas in both males 

and females. In rats, dietary administration of bosentan for two years was associated with an increased incidence of brain 

astrocytomas in males at doses as low as 500 mg/kg/day (about 16 times the MRHD). In a comprehensive battery of in vitro 

tests (the microbial mutagenesis assay, the unscheduled DNA synthesis assay, the V-79 mammalian cell mutagenesis assay, 

and human lymphocyte assay) and an in vivo mouse micronucleus assay, there was no evidence for any mutagenic or clastogenic 

activity of bosentan. Impairment of Fertility/Testicular Function: Many endothelin receptor antagonists have profound 

effects on the histology and function of the testes in animals. These drugs have been shown to induce atrophy of the seminiferous 

tubules of the testes and to reduce sperm counts and male fertility in rats when administered for longer than 10 weeks. 

Where studied, testicular tubular atrophy and decreases in male fertility observed with endothelin receptor antagonists appear 

irreversible. In fertility studies in which male and female rats were treated with bosentan at oral doses of up to 1500 

mg/kg/day (50 times the MRHD on a mg/m 2 basis) or intravenous doses up to 40 mg/kg/day, no effects on sperm count, sperm 

motility, mating performance or fertility were observed. An increased incidence of testicular tubular atrophy was observed in 

rats given bosentan orally at doses as low as 125 mg/kg/ day (about 4 times the MRHD and the lowest doses tested) for two 

years but not at doses as high as 1500 mg/kg/day (about 50 times the MRHD) for 6 months. Effects on sperm count and motility 

were evaluated only in the much shorter duration fertility studies in which males had been exposed to the drug for 4-6 weeks. 

An increased incidence of tubular atrophy was not observed in mice treated for 2 years at doses up to 4500 mg/kg/day (about 

75 times the MRHD) or in dogs treated up to 12 months at doses up to 500 mg/kg/day (about 50 times the MRHD). There are 

no data on the effects of bosentan or other endothelin receptor antagonists on testicular function in man. 

Pregnancy, Teratogenic Effects: Category X (See CONTRAINDICATIONS). 

Special Populations: Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are 

excreted in human milk, breastfeeding while taking TRACLEER ® is not recommended. Pediatric Use: Safety and efficacy in pediatric 

patients have not been established. Use in Elderly Patients: Clinical experience with TRACLEER ® in subjects aged 65 or older has not 

included a sufficient number of such subjects to identify a difference in response between elderly and younger patients. 

ADVERSE REACTIONS: Adverse Events: See BOX WARNING for discussion of liver injury and PRECAUTIONS for discussion 

of hemoglobin and hematocrit abnormalities. Safety data on bosentan were obtained from 12 clinical studies (8 placebo-controlled 

and 4 open-label) in 777 patients with pulmonary arterial hypertension, and other diseases. Doses up to 8 times the currently 

recommended clinical dose (125 mg b.i.d.) were administered for a variety of durations. The exposure to bosentan in these trials 

ranged from 1 day to 4.1 years (N = 89 for 1 year; N = 61 for 1.5 years and N = 39 for more than 2 years). Exposure of 

pulmonary arterial hypertension patients (N = 235) to bosentan ranged from 1 day to 1.7 years (N = 126 more than 6 months and 

N = 28 more than 12 months). Treatment discontinuations due to adverse events other than those related to pulmonary hypertension 

during the clinical trials in patients with pulmonary arterial hypertension were more frequent on bosentan (5%; 8/165 patients) than 

on placebo (3%; 2/80 patients). In this database the only cause of discontinuations >1%, and occurring more often on bosentan was 

abnormal liver function. The adverse drug reactions that occurred in ≥ 3% of the bosentan-treated patients and were more common 

on bosentan in placebo-controlled trials in pulmonary arterial hypertension at doses of 125 or 250 mg b.i.d. are shown in Table 1: 

Table 1. Adverse events* occurring in ≥ 3% of patients treated with bosentan 125-250 mg b.i.d. and more common on bosentan in 

placebo-controlled studies in pulmonary arterial hypertension 

Adverse Event 

Bosentan (N = 165) Placebo (N = 80) 

No. % No. % 

Headache 36 22% 16 20% 

Nasopharyngitis 18 11% 6 8% 

Flushing 15 9% 4 5% 

Hepatic function abnormal 14 8% 2 3% 

Edema, lower limb 13 8% 4 5% 

Hypotension 11 7% 3 4% 

Palpitations 8 5% 1 1% 

Dyspepsia 7 4% 0 0% 

Edema 7 4% 2 3% 

Fatigue 6 4% 1 1% 

Pruritus 6 4% 0 0% 

*Note: only AEs with onset from start of treatment to 1 calendar day after end of treatment are included. All 

reported events (at least 3%) are included except those too general to be informative, and those not reasonably 

associated with the use of the drug because they were associated with the condition being treated or are very 

common in the treated population. 

In placebo-controlled studies of bosentan in pulmonary arterial hypertension and for other diseases (primarily chronic heart 

failure), a total of 677 patients were treated with bosentan at daily doses ranging from 100 mg to 2000 mg and 288 patients 

were treated with placebo. The duration of treatment ranged from 4 weeks to 6 months. For the adverse drug reactions that 

occurred in ≥ 3% of bosentan-treated patients, the only ones that occurred more frequently on bosentan than on placebo 

(≥ 2% difference) were headache (16% vs. 13%), flushing (7% vs. 2%), abnormal hepatic function (6% vs. 2%), leg edema 

(5% vs. 1%), and anemia (3% vs. 1%). 

Post-Marketing Experience: Hypersensitivity, Rash, Thrombocytopenia, Jaundice, Anemia requiring transfusion: There have 

been several post-marketing reports of angioneurotic edema associated with the use of bosentan. The onset of the reported cases 

occurred within a range of 8 hours to 21 days after starting therapy. Some patients were treated with an antihistamine and their 

signs of angioedema resolved without discontinuing TRACLEER ® . In the post-marketing period, in the setting of close monitoring, 

rare cases of unexplained hepatic cirrhosis were reported after prolonged (> 12 months) therapy with TRACLEER ® in patients with 

multiple co-morbidities and drug therapies. There have also been rare reports of liver failure. The contribution of TRACLEER ® in these 

cases could not be excluded (see BOX WARNING). 

Manufactured by: 

Marketed by: 

Patheon, Inc. 

Actelion Pharmaceuticals US, Inc. 

Mississauga, Ontario, L5N 7K9, CANADA 

South San Francisco, CA 94080, USA 

References for previous pages: 1. Data on file, Actelion Pharmaceuticals. 2. Rubin LJ, Badesch DB, Barst RJ, et al. 

Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903. 3. Channick RN, Simonneau G, 

Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: 

a randomised placebo-controlled study. Lancet. 2001;358:1119-1123. 

© 2009 Actelion Pharmaceuticals US, Inc. All rights reserved. 07 354 01 03 0209 

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ay 

m ® r 

P 

Access 

so be reported directly via this number. 

ACLEER 

R ® n 

hyperte 

is indicated for the treatment of pulmonary arterial 

wors 

clinical 

to improve exercise ability and decrease the rate of 

ms, 

ARNING 

OX WA 

B 

r 

o 

f 

N 

IO 

TI 

RAINDICAT 

ONTR 

C . 

to use in pregnancy 

EER 

L ® m 

wo 

administered to pregnant 

harm if 

is expected to cause fetal 

125 m 

dose of 

/kg/day (twice the maximum recommended human oral 

includin 

effects, 

teratogenic 

bosentan showed dose-dependent 

n rats, 

doses of 6 

Bosentan increased stillbirths and pup mortality at oral 

sels. 

recommended human dose on a mg/m 

m 2 t 

Although birth defec 

basis). 

plasma concentrations of bosentan in rabbits were lower tha 

g/kg/day, 

mice an 

ced by bosentan and those observed in endothelin-1 knockout 

ndicatesthatteratogenicityisaclasseffectofthesedrugs.Thereareno 

with TRACLEER 

treatment 

of 

be excluded before the start 

ust 

m ® d 

an 

been demonstrated that hormonal contraceptives, including oral, 

TRACLEER 

of 

presence 

the 

in 

reliable 

be 

not 

y ® u 

be 

not 

should 

and 

ACLEER 

R ® ( i 

C 

l 

H 

i 

D I 

by 

thereafter 

prevented 

nd 

and 

transdermal, 

njectable, 

be effective 

e these may not 

through 

contraception 

ctive 

tained. 

RACLEER 

T ® s 

a 

(bosentan) 

228 

866 

calling 1 

rogram by 

in patients 

nsion (WHO Group I) 

ening. 

Bosentan was teratogenic 

men. 

on a mg/m 

b.i.d., 

g, 

m 2 n 

I 

basis). 

the head, 

of 

ng malformations 

0 and 300 mg/kg/day (2 and 10 

observed in rabbits 

ts were not 

The 

an those reached in the rat. 

d in animals treated with other 

dataontheuseofTRACLEER 

o ® 

by use of 

prevented thereafter 

injectable, transdermal, and 

contraceptive 

sole 

the 

as 

used 

bl 

j 

I 

l 

O 

di 

l 

I 

Nimodipine and Los 

Digoxin, 

effec 

losartan has no significant 

Sildenafil: 

subjects, 

healthy 

In 

resulted in a reduction of sildenafil 

A dose adjustment of neither drug 


Iloprost: 

randomized, 

In a small, 

mg bid for at least 16 weeks tolerated 


ifampicin: 

R 

n 

Coadministratio 

conc 

the first 

trough levels after 

bee 

not 

has 

levels 

rifampicin 

on 

s 

measure LFTs 

use, 

concomitant 

and ritonavir: 

Lopinavir 


daily during 9.5 days in healthy 

48-fold higher than those measured 

tan were approximately 5-fold 

uptake into hepatocytes, reducing 

TRACLEER ® 

exposures 

plasma 

the 

, 

TRACLEER 

When 

respectively. 

inhibitors, there should be appropriate monitoring of TRACLEER 

Carcinogenesis, Mutagenesis, 

an increased incidence of hepatocellular 

artan: 

s 

t 

pharmacokinetic interactions wi 

Bosentan has no significant 

bosentan. 

on plasma levels of 

ct 

bosentan 

b.i.d 

mg 

125 

of 

doses 

multiple 

of 

co-administration 

subjects, 

sildenafil plasma concentrations by 63% and increased bosentan plasma 

drug is necessary. This recommendation holds true when sildenafil 


randomized, double-blind, placebo-controlled study (the STEP trial), 34 patients 

tolerated the addition of inhaled iloprost (up to 5 mcg 6 to 9 times per 


mea 

a 

in 

resulted 

volunteers 

normal 

in 

rifampicin 

and 

bosentan 

of 

steady 

a 60% decrease in bosentan levels at 

about 

but 

dose, 

comitant 

know 

and 

benefits 

potential 

the 

of 

consideration 

When 

assessed. 

en 

monitoring. 

4 weeks before reverting to normal 

the first 

weekly for 

of TRACLEER 

Co-administration ® lopinavir+ritonavir 

125 mg twice daily and 

healthy subjects resulted in initial trough plasma concentrations of bosentan 

after TRACLEER 

measured ® plasma 

administered alone. At steady state, 

higher than with TRACLEER 

5-fold ® by 

administered alone. Inhibition 

reducing the clearance of bosentan, most likely explains this interaction. 

approximately 

by 

decreased 

state 

steady 

at 

ritonavir 

and 

lopinavir 

to 

exposures 

TRACLEER ® 

other 

or 

lopinavir+ritonavir 

with 

concomitantly 

administered 

is 

inhibitors, there should be appropriate monitoring of TRACLEER ® tolerability and ongoing HIV status (see 

Impairment of Fertility: 

Mutagenesis, 

administration 

wo years of dietary 

Two 

hepatocellular adenomas and carcinomas in males at doses as low as 450 

and 

th digoxin and nimodipine, 

sildenafil 

t.i.d. 

mg 

80 

and 

bosentan 

plasma concentrations by 50%. 

sildenafil is used for the treatment of 

patients treated with bosentan 125 

per day during waking hours). 

bosentan 

in 

increase 

6-fold 

n 

bosentan 

of 

The effect 

y-state. 

to 

leads 

risks 

unknown 

and 

wn 

lopinavir+ritonavir 400 mg + 100 mg twice 

bosentan that were approximately 

concentrations of bosen 

plasma - 

by ritonavir of OATP-mediated 

interaction. After co-administration of 

17%, 

and 

14% 

approximately 

protease 

ritonavir-boosted 

other 

tolerability and ongoing HIV status (see PRECAUTIONS). 

of bosentan to mice produced 

450 mg/kg/day (about 8 times 

TR 

receiving 

patients 

in 

method 

and Implantable 

ransdermal 

Tr 

TRACLEER 

needed. 

as 

be sought 

TRA 

a prescription for 

potential, 

n 

provides 

active or 

sexually 

not 

11 

least 

period and at 

menstrual 

should be obtained monthly in w 

any o 

menses or 

of 

delay in onset 

is positive, 

the pregnancy test 

If 

A 

yclosporine 

C 

r 

Co-administ 

: 

concomitan 

Therefore, 

bosentan. 

lyburide 

G 

f 

An increased risk o 

: 

g 

Therefore co-administration of 

Hypersensitivity TRACLEER 

: ® 

the medication. 

ARNINGS: 

WA 

j 

Inj 

er 

Live 

al 

Potentia 

(N 

patients 

bosentan-treated 

of 

1 

on 

PAH patients 

95 

12% of 

in 

b.i.d 

mg 

125 

on 

AH patients 

PA 

of 

aminotransferase increases in 2 

> 3 x UL 

in aminotransferases of 

T associated w 

ALT 

AST and/or 

of 

and 

re typically asymptomatic 

a 

ACLEER 

R ® e 

se 

( , 

Contraceptives 

Hormonal 

Interactions: 

Drug 

Contraceptives 

e 

a 

on 

expert 

similar 

or 

gynecologist 

from a 

Input 

). 

R ® 

e 

f 

For 

to be pregnant. 

known not 

in patients 

should be started only 

LEER 

C ® s 

as 

unless the patient 

be issued by the prescriber 

should not 

performed duri 

test 

serum pregnancy 

from a urine or 

negative results 

Follow-up u 

intercourse. 

sexual 

of 

unprotected act 

the last 

days after 

taking TRACLEER 

childbearing potential 

omen of 

w ® t 

mus 

The patient 

. 

notify the physician imm 

she must 

pregnancy, 

reason to suspect 

other 

discuss the risk to the pregnancy and 

must 

the physician and patient 

increas 

markedly 

in 

resulted 

bosentan 

and 

A 

cyclosporine 

of 

ation 

TRACLEER 

use of 

t 

n ® . 

and cyclosporine A is contraindicated 

enzyme elevations was observed in patients receiving glyburide 

liver 

lyburide and TRACLEER 

g ® . 

is contraindicated 

® bosentan 

is also contraindicated in patients who are hypersensitive to 

y 

ury 

j 

e 

se 

( G 

ARNIN 

OX WA 

B 3 

more than 

AST by 

T or 

in ALT 

Elevations 

): 

Th 

280). 

(N = 

patients 

placebo-treated 

2% of 

to 

compared 

658) 

N = 

Eight-fo 

b.i.d. 

mg 

250 

on 

PAH patients 

70 

14% of 

and 

b.i.d. 

mg 

25 

≥3 

to 

increases 

Bilirubin 

b.i.d. 

mg 

250 

on 

AH patients 

PA 

7% of 

and 

d. 

h 

The combination of 

patients treated with bosentan. 

of 

658 (0.3%) 

of 

potential 

for 

is a marker 

bilirubin (≥ 3 x ULN) 

and increases in total 

N) 

and late in treatm 

both early 

occur 

with bosentan are dose-dependent, 

cessation 

interruption or 

treatment 

sually have been reversible after 

u 

Injectable, 

Oral, 

Including 

should 

contraception 

dequate 

childbearing 

of 

emale patients 

she is 

that 

sures the prescriber 

a normal 

of 

5 days 

ng the first 

serum pregnancy tests 

urine or 

there is any 

if 

be advised that 

pregnancy testing. 

ediately for 

to the fetus. 

of 


plasma 

sed 

concomitantly with bosentan. 

bosentan or any component of 

ULN were observed in 11% 

x 

seen 

were 

increases 

ree-fold 

2% 

in 

seen 

were 

increases 

ld 

with 

associated 

ULN were 

x 

3 

injury (increases 

hepatocellular 

injury. 

erious liver 

s 

s 

Elevation 

slowly, 

progress 

usually 

ment, 

Aminotransferase elevations 

n 

an increased incidence of hepatocellular 

the maximum recommended human 


and females. In rats, dietary administration 

astrocytomas in males at doses 

tests (the microbial mutagenesis 

and human lymphocyte assay) 

activity of bosentan. 

genic 

Impairment 

effects on the histology and function 

erous tubules of the testes and 

Where studied, testicular tubular 

pear irreversible. In fertility studies 

mg/kg/day (50 times the MRHD 

motility, mating performance or 

rats given bosentan orally at doses 

years but not at doses as high as 

were evaluated only in the much 

An increased incidence of tubular 

75 times the MRHD) or in dogs 


eratogenic Effe 

Te 

, 

Pregnancy, 

Populations: 

pecial 

S 

g 

n 

sin 

Nurs 

breastfe 

excreted in human milk, 

been establish 

atients have not 

p 

hepatocellular adenomas and carcinomas in males at doses as low as 450 

dose [MRHD] of 125 mg b.i.d., on a mg/m 

human 2 same 

basis). In the 

times the MRHD) were associated with an increased incidence of colon 

administration of bosentan for two years was associated with an 

doses as low as 500 mg/kg/day (about 16 times the MRHD). In a comprehensive 

mutagenesis assay, the unscheduled DNA synthesis assay, the V-79 mammalian 

and an in vivo mouse micronucleus assay, there was no evidence 

Fertility/Testicular Function: 

of Fertility/Testicular 

Impairment 

receptor 

Many endothelin 

function of the testes in animals. These drugs have been shown to induce 

and to reduce sperm counts and male fertility in rats when administered 

tubular atrophy and decreases in male fertility observed with endothelin 

studies in which male and female rats were treated with bosentan 

on a mg/m 

MRHD 2 effects 

basis) or intravenous doses up to 40 mg/kg/day, no 

or fertility were observed. An increased incidence of testicular tubular 

doses as low as 125 mg/kg/ day (about 4 times the MRHD and the 

as 1500 mg/kg/day (about 50 times the MRHD) for 6 months. Effects 

much shorter duration fertility studies in which males had been exposed 

tubular atrophy was not observed in mice treated for 2 years at doses 

dogs treated up to 12 months at doses up to 500 mg/kg/day (about 50 


Category X ( 

ts: 

c 

e 

e 

S . 

TIONS) 

RAINDICAT 

CONTR 

s: 

hers 

Moth 

g 

m 

human 

in 

excreted 

is 

drug 

this 

whether 

known 

not 

is 

It 

eding while taking TRACLEER 

e ® . 

recommended 

s not 

i : 

c Use 

ric 

atr 

ia 

edi 

P 

S 

ed 

h : 

ents 

atie 

y Pa 

erly 

de 

n Eld 

se in 

Us 

R 

experience with TRACLEE 

linical 

C ® u 

n s 

i 


same study, doses greater than 

colon adenomas in both males 

increased incidence of brain 

comprehensive battery of in vitro 

mammalian cell mutagenesis assay, 

for any mutagenic or clasto 

evidence - 

receptor antagonists have profound 

atrophy of the seminif 

induce - 

administered for longer than 10 weeks. 

receptor antagonists ap 

endothelin - 

bosentan at oral doses of up to 1500 

effects on sperm count, sperm 

tubular atrophy was observed in 

lowest doses tested) for two 

Effects on sperm count and motility 

exposed to the drug for 4-6 weeks. 

up to 4500 mg/kg/day (about 

50 times the MRHD). There are 


are 

drugs 

many 

Because 

milk. 

Safety and efficacy in pediatric 

has not 

older 

jects aged 65 or 

bj 

and 

are typically asymptomatic, 

also may reverse spontaneously 

and the 

treatment 

to initiation of 

aminotransf 

liver 

If 

initiated. 

be 

jaundice, 

pain, 

abdominal 

fever, 

no experience with the 

There is 

be meas 

must 

transferase levels 

sever 

moderate or 

with 

patients 

b 

aminotransferases (> 3 x ULN) 

RECAUTIONS: 

P 

C 

c 

ogic 

ematolo 

He 

Hemoglobin levels should be 

crit. 

for 

concentration 

hemoglobin 

in 

was 

concentration 

hemoglobin 

bosentan treatm 

4–12 weeks of 

resultin 

from baseline 

decrease 

wit 

patients 

In 

patients. 

treated 

3% c 

in 

occurred 

hemoglobin 

in 

b 

1 g/dL was observed in 57% of 

whose hemoglobin decreased by 

hemogl 

the 

treatment 

of 

course 

The 

placebo patients. 

to 76% of 

recommended 

is 

It 

hemolysis. 

or 

hemog 

in 

decrease 

marked 

a 

If 

treatment 

specific 

for 

eed 

n 

u 

lu 

Fl 

cessation 

interruption or 

treatment 

usually have been reversible after 

with TRACLEER 

hile continuing treatment 

w ® e 

aminotransferas 

Liver 

. 

changes in m 

elevated aminotransferase levels are seen, 

If 

en monthly. 

inju 

liver 

of 

symptoms 

clinical 

by 

accompanied 

are 

elevations 

erase 

ULN, 

x 

2 

≥ 

bilirubin 

in 

increases 

or 

fatigue) 

or 

lethargy 

unusual 

or 

, 

TRACLEER 

e-introduction of 

r ® . 

n these circumstances 

i 

L 

ng 

stin 

xis 

e-ex 

re 

Pr 

TRACLEER 

and then monthly. 

treatment 

to initiation of 

ured prior 

s 

® s 

TRACLEER 

In addition, 

impairment. 

e liver 

r ® o 

be av 


injury in these patients may be more difficult 

ecause monitoring liver 

es: 

hange 

Ch 

R 

TRACLEE 

with 

reatment 

T ® s 

decrea 

dose-related 

a 

caused 

and then every 3 mont 

treatment 

1 and 3 months of 

e monitored after 

treatme 

of 

end 

to 

(change 

g/dL 

0.9 

was 

patients 


r 

he 

and 

treatment 

bosentan 

of 

few weeks 

first 

the 

during 

detected 

marked de 

bosentan, 

uses of 

all 

In placebo-controlled studies of 

ent. 


6% of 

in 

observed 

were 

g/dL) 

11 

< 

values 

in 

ng 

25 

and 

125 

of 

doses 

with 

treated 

hypertension 

arterial 

pulmonary 

h 

hemoglo 

in 

A decrease 

patients. 

placebo-treated 

1% in 

to 

compared 

placebo-treated pat 

bosentan-treated patients as compared to 29% of 

b 

of 

6 weeks 

the decrease occurred during the first 

1 g/dL, 

least 

at 

y 

bosent 

68% of 

in 

limits 

normal 

within 

remained 

concentration 

obin 

does 

it 

but 

known, 

not 

the change in hemoglobin is 

e explanation for 

a 

1 and 3 months, 

be checked after 

hemoglobin concentrations 

d that 

undertaken 

be 

should 

evaluation 

further 

occurs, 

concentration 

lobin 

on: 

etentio 

re 

d 

id 

h 

c 

severe 

with 

patients 

of 

trial 

placebo-controlled 

a 

n 

I 

Aminotransferase elevations 

n. 

be measured prior 

levels must 

must 

monitoring and treatment 

vomiting, 

nausea, 

as 

(such 

ury 

stopped. 

be 

should 

treatment 

ment: 

rm 

mpair 

Im 

er 

ive 

L 

o 

amin 

iver 

L - 

be avoided in 


with elevated 

in patients 

ided 

see 

( G 

ARNIN 

OX WA 

B . 

) 

hemato 

and 

hemoglobin 

in 

e 

s - 

mean decrease 

The overall 

hs. 

of 

decrease 

this 

of 

Most 

ent). 

by 

stabilized 

levels 

emoglobin 

creases in hemoglobin (> 15% 

placebo- 

3% of 

and 

patients 

decreases 

marked 

b.i.d., 

mg 

0 

least 

at 

by 

concentration 

obin 

those patients 

In 80% of 

ients. 

During the 

osentan treatment. 

compared 

patients 

an-treated 

to be hemorrhage 

appear 

not 

thereafter. 

3 months 

and every 

and 

cause 

the 

determine 

to 

n 

was 

there 

failure 

heart 

hronic 

been establish 

patients have not 

of 

number 

included a sufficient 

IONS: 

DVERSE REACTI 

A 

e 

ve 

Adv 

a 

hemoglobin and hematocrit 

of 

patien 

777 

in 

open-label) 

4 

and 

(125 

dose 

clinical 

recommended 

yea 

4.1 

to 

day 

1 

from 

ranged 

hypertension 

arterial 

pulmonary 

Tr 

N = 28 more than 12 months). 

trials in patien 

during the clinical 

2/80 patients). 

on placebo (3%; 

The adv 

function. 

liver 

abnormal 

on bosentan in placebo-controll 

able 1. 

Ta 

r 

Adverse events* occu 

placebo-controlled studies in pu 

Adverse Event 

Headache 

Nasopharyngitis 

Flushing 

Hepatic function abnormal 

limb 

lower 

dema, 

E 

ed. 

h : 

ents 

atie 

y Pa 

erly 

de 

n Eld 

se in 

Us 

R 

experience with TRACLEE 

linical 

C 

u 

in s 

jects to identify a difference in response between elderly an 

such subj 

s: 

ents 

Eve 

se 

rs 

e 

e 

S 

G 

ARNIN 

OX WA 

B 

d 

an 

injury 

liver 

of 

discussion 

or 

f 

P 

Safety data on bosentan were obtained from 12 clinica 

abnormalities. 

Dose 

diseases. 

other 

and 

hypertension, 

arterial 

pulmonary 

with 

nts 

exposu 

The 

durations. 

of 

variety 

a 

for 

administered 

were 

b.i.d.) 

mg 

5 

mor 

for 

39 

= 

N 

and 

years 

1.5 

for 

61 

= 

N 

year; 

1 

for 

89 

= 

(N 

rs 

(N = 

years 

1.7 

to 

day 

from 1 

ranged 

bosentan 

to 

235) 

(N = 

patients 

n 

than those rela 

discontinuations due to adverse events other 

eatment 

on bose 

hypertension were more frequent 

nts with pulmonary arterial 

and occurrin 

discontinuations >1%, 

In this database the only cause of 

the bosentan-treated pa 

occurred in ≥ 3% of 

verse drug reactions that 

250 mg 

125 or 

doses of 

hypertension at 

ed trials in pulmonary arterial 

and 

patients treated with bosentan 125-250 mg b.i.d. 

ring in ≥ 3% of 

hypertension 

ulmonary arterial 

osentan (N = 165) 

B 

l 

P 

o. 

N % . 

No 

6 

3 % 

2 

2 6 

1 

8 

1 % 

1 

1 6 

5 

1 % 

9 4 

4 

1 % 

8 2 

3 

1 % 

8 4 

has not 

older 

jects aged 65 or 

bj 

patients. 

d younger 

RECAUTIONS 

P 

n 

discussio 

for 

studies (8 placebo-controlled 

al 

currently 

the 

times 

8 

to 

up 

es 

trials 

these 

in 

bosentan 

to 

ure 

of 

Exposure 

years). 

2 

than 

re 

and 

months 

6 

than 

more 

126 

= 

ated to pulmonary hypertension 

than 

8/165 patients) 

ntan (5%; 

g more often on bosentan was 

tients and were more common 

are shown in Table 1: 

g b.i.d. 

more common on bosentan in 

lacebo (N = 80) 

% 

20% 

8% 

5% 

3% 

5% 

treatment. 

specific 

for 

eed 

n 

u 

lu 

Fl 

hospit 

an increased incidence of 

TRACLEER 

with 

treatment 

f 

o ® . 

occurr 

hypertension, 

pulmonary 

management, or hospitalization 

of pulmonary edema occur when 

TRACLEER ® 

discontinued. 

should be 

trial experience with the use of 

with antiretroviral medications. 

increased plasma concentrations 

Interactions 

potential 

). Due to the 

the efficacy of some antiretroviral 

due to the inhibition of organic 


s: 

Patients 

nformation for 

I 

i 

Pat 

th 

with 

discuss 

should 

physician 

avoida 

of 

and 

testing 

pregnancy 

their 

with 

pregnancy 

prevent 

to 

as needed. 

sought 

rug Interactions: 

D 

s 

Bosentan i 

bosentan (see ketocon 

tration of 

(such as 

and a CYP3A4 inhibitor 

Co 

bosentan. 

of 


RACLEER 

T ® d 

t 

i 

on: 

etentio 

re 

d 

id 

h 

c 

severe 

with 

patients 

of 

trial 

controlled 

placebo 

a 

In 

gain and increased leg ede 

associated with weight 

CHF 

talization for 

fl 

of 

reports 

post-marketing 

numerous 

been 

have 

there 

addition, 

In 

TRACLEER 

starting 

after 

weeks 

within 

ng 

i ® intervention 

required 

Patients 

. 

for decompensating heart failure. 

hospitalization 

Disease 

eno-Occlusive 

Pulmonary Veno-Occlusive 

TRACLEER 

when ® PVOD 

is administered the possibility of associated 

discontinued. 

Infection: 

Pulmonary Arterial Hypertension Associated with HIV 

TRACLEER 

of ® who 

AH associated with HIV infection 

in patients with PAH 

medications. An interaction study between bosentan and lopinavir+ritonavir 

concentrations of bosentan and decreased concentrations of lopinavir+ritonavir 

potential for interactions related to the inducing effect of bosentan on 

antiretroviral therapies, patients should be monitored carefully regarding their 

(OATP) by ritonavir, there may be 

organic anion-transporting polypeptides (OATP) 


the TRACLEER 

are advised to consult 

nts 

e ® e 

Medication Guide on th 

serum aminotra 

of 

monitoring 

monthly 

of 

importance 

the 

patient 

he 

effective 

for 

options 

discuss 

should 

physician 

The 

pregnancy. 

of 

ance 

adeq 

on 

expert 

similar 

or 

gynecologist 

from a 

Input 

patients. 

female 

these enzymes ma 

Inhibition of 

s metabolized by CYP2C9 and CYP3A4. 

(such 

both a CYP2C9 inhibitor 


Concomitant 

nazole). 

lea 

likely 

with bosentan will 

ritonavir) 

or 

itraconazole, 

ketoconazole, 

inhibitor 

CYP2C9 

potent 

a 

of 

combinations 

such 

of 

-administration 

l 

tl 

C 

CYP2C9 

d 

CYP3A4 

f 

d 

i 

i 

t 

d B 

was 

there 

failure, 

heart 

hronic 

4-8 weeks 

ema during the first 

with 

patients 

in 

retention 

uid 

intervention with a diuretic, fluid 

(PVOD): 

Disease 

signs 

Should 

PVOD should be considered and 

Infection: 

clinical 

There is limited 

who are treated concomitantly 

lopinavir+ritonavir in healthy subjects showed 

(see 

lopinavir+ritonavir 

Drug 

PRECAUTIONS: 

on CYP450, which could affect 

their HIV infection. Conversely, 

be an increase in exposure to 


TRACLEER 

safe use of 

e ® e 

Th 

. 

serum 

or 

urine 

and 

ansferases 

measures 

and 

contraception 

e 

be 

should 

contraception 

quate 

increase the plasma concen 

y - 

amiodarone) 

fluconazole or 

as 

in plasma 

d to large increases 

with 

inhibitor 

CYP3A4 

a 

plus 

d 

f 

ti 

t 

, 

Hypotension 

Palpitations 

Dyspepsia 

Edema 

Fatigue 

Pruritus 

ons 

with 

AEs 

only 

*Note: 

3 

least 

s (at 

reported events 

associated with the use o 

common in the treated pop 

In placebo-controlled studies of 

failure), a total of 677 patients 

were treated with placebo. The 

occurred in ≥ 3% of bosentan-treated 

(≥ 2% difference) were headache 


Experience 

Post-Marketing 

post-marketing rep 

been several 

ho 

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were associated with the condition 

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pulation. 

of bosentan in pulmonary arterial hypertension and for other diseases 

patients were treated with bosentan at daily doses ranging from 100 mg 

The duration of treatment ranged from 4 weeks to 6 months. For the 

bosentan-treated patients, the only ones that occurred more frequently on 

headache (16% vs. 13%), flushing (7% vs. 2%), abnormal hepatic function 


: u 

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included. 

are 

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reasonably 

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being treated or 

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to 2000 mg and 288 patients 

the adverse drug reactions that 

on bosentan than on placebo 

function (6% vs. 2%), leg edema 

have 

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transfusion: 

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the reported cases 

of 

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and 

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with 

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recommend 

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any 

on 

effect 


Hormonal Contraceptives, Including 

tion study demonstrated that 

norethindrone 

of 

decreases 

average 

56 

as 

much 

as 

were 

exposure 

transdermal, 

injectable, 

oral, 

should practice additional methods 


yclosporine A: 

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bosentan 

Steady-state 

30-fold. 

b 


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pl 

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tro 


ransdermal, and Implantable Contraceptives: 

Including Oral, Injectable, Transdermal, 

co-administration of bosentan and the oral hormonal contraceptive 

respectively 

31%, 

and 

14% 

of 

levels 

estradiol 

ethinyl 

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hormo 

Therefore, 

jects. 

subj 

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66%, 

% and 

TRACLEER 

when 

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forms, 

implantable 

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methods of contraception and not rely on hormonal contraception alone 


bose 

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contraceptive 

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in 

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including 

contraceptives, 

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co-administered. 

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when taking TRACLEER 

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about 

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p 

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multiple co-morbidities and drug 

be excluded (se 

cases could not 

Manufactured by: 

Inc. 

Patheon, 

L5N 7K9, 

Ontario, 

Mississauga, 

previous pa 

References for 

pulmona 

Bosentan therapy for 

the d 

Effects of 

al. 

et 

Sitbon O, 

a randomised placebo-control 

© 2009 Actelion Pharmaceutica 

py 

) 

( 

g 

p 

p 

The contr 

failure. 

liver 

There have also been rare reports of 

g therapies. 

e 

G 

ARNIN 

BOX WA 

Marketed by: 

). 

Inc. 

Actelion Pharmaceuticals US, 

USA 

CA 94080, 

South San Francisco, 

CANADA 

ges: 

a . 

1 . 

Actelion Pharmaceuticals 

ata on file, 

D . 

2 s 

Bade 

Rubin LJ, 

hypertension. 

y arterial 

r d. 

J Me 

ngl 

En 

N . 

2002;346:896-903 

d . 

3 a 

Ch 

bosentan in patients with pul 

antagonist 

endothelin-receptor 

dual 

ed study. 

l t. 

ance 

L . 

2001;358:1119-1123 

t 

07 354 01 03 0209 

rights reserved. 

All 

Inc. 

ls US, 

a 

p 

TRACLEER 

ibution of 

r ® e 

in thes 

al. 

et 

RJ, 

Barst 

sch DB, 

Simonneau G, 

annick RN, 

monary hypertension: 

1200 Folsom Street San Francisco, CA 94103 tel 415.421.2900 fax 415.421.5842 www.andresendigital.com

We can’t thank you enough. 

Take a closer look and see how much you helped raise 

at the Gilead Sciences event during CHEST 2008, for the 

benefit of the Pulmonary Hypertension Association. 

Physicians from around the world joined in this effort 

Argentina, Austria, Brazil, Canada, Colombia, Egypt, Greece, India, Ireland, Italy, Japan, 

Kuwait, Malaysia, Mexico, Nigeria, Portugal, Romania, Saudi Arabia, Serbia, South Korea, 

Switzerland, Turkey, United States of America 

Proudly sponsored by 

For the benefit of 

© 2008 Gilead Sciences, Inc. All rights reserved. ABS3187 December 2008 

Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc.

Program Announcement: 

New Application Deadline: February 12, 2009 Resubmission Deadline: March 12, 2009 

New Application Deadline: June 12, 2009 Resubmission Deadline: July 12, 2009 


Association (PHA) 

National Heart, Lung, and 

Blood Institute (NHLBI) 

Jointly Sponsored 

Mentored Clinical Scientist Development Award (K08) & 

Mentored Patient-Oriented Research Career Development Award (K23) 

PURPOSE: K08 

• To support the development of outstanding clinician research 

scientists in the area of pulmonary hypertension. 

• To provide specialized study for clinically trained professionals 

who are committed to a career in research in pulmonary 

hypertension and have the potential to develop into independent 

investigators. 

• To support a 3 to 5 year period of supervised research experience 

that integrates didactic studies with laboratory or clinically 

based research. 

• To support research that has both intrinsic research importance 

and merit as a vehicle for learning the methodology, theories, 

and conceptualizations necessary for a well-trained independent 

researcher. 

MECHANISM: 

Awards in response to the program announcement will use the 

National Institutes of Health (NIH) K08 or the K23 mechanism. 

PURPOSE: K23 

• To support career development of investigators who have 

made a commitment to focus their research endeavors on 

patient-oriented research. 

• To support a 3 to 5 year period of supervised study and 

research for clinically trained professionals who have the 

potential to develop into productive, clinical investigators 

focusing on patient-oriented research in pulmonary hypertension. 

• To support patient-oriented research, which is defined as 

research conducted with human subjects (or on material of 

human origin, such as tissues, specimens, and cognitive 

phenomena) for which an investigator directly interacts with 

human subjects. 

• To support areas of research that include: 1) mechanisms of 

human disease; 2) therapeutic interventions; 3) clinical trials; 

and 4) development of new technologies. 

FUNDING:* 

The award will be funded by PHA and NHLBI and the KO8 

and/or the K23 will be awarded in 2009. 

FOR MORE INFORMATION: 

Visit: www.PHAssociation.org/support/ResearchFunding.asp 

* Restrictions apply. Please see complete announcement 

at the website listed above. 

Advances in 



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