JACC 2009 PAH Expert Consensus Document

doi:10.1016/j.jacc.2009.01.004

2009;53;1573-1619; originally published online Mar 30, 2009;J. Am. Coll. Cardiol.Varga

Myung H. Park, Robert S. Rosenson, Lewis J. Rubin, Victor F. Tapson, and John McGoon,Harrison W. Farber, Jonathan R. Lindner, Michael A. Mathier, Michael D.

Vallerie V. McLaughlin, Stephen L. Archer, David B. Badesch, Robyn J. Barst, Thoracic Society, Inc.; and the Pulmonary Hypertension Association

in Collaboration With the American College of Chest Physicians; American DevelopedExpert Consensus Documents and the American Heart Association

Report of the American College of Cardiology Foundation Task Force on ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension: A

This information is current as of April 30, 2012

http://content.onlinejacc.org/cgi/content/full/53/17/1573located on the World Wide Web at:

The online version of this article, along with updated information and services, is

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Journal of the American College of Cardiology Vol. 53, No. 17, 2009© 2009 by the American College of Cardiology Foundation and the American Heart Association, Inc. ISSN 0735-1097/09/$36.00P

EXPERT CONSENSUS DOCUMENT

ACCF/AHA 2009 Expert Consensus Document onPulmonary HypertensionA Report of the American College of Cardiology Foundation Task Force onExpert Consensus Documents and the American Heart Association

Developed in Collaboration With the American College of Chest Physicians; American Thoracic Society, Inc.;and the Pulmonary Hypertension Association

ublished by Elsevier Inc. doi:10.1016/j.jacc.2009.01.004

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WritingCommitteeMembers

ypertension: a report of the An Expert Consensus Docum

allerie V. McLaughlin, MD, FACC, FAHA,FCCP, Chair*

tephen L. Archer, MD, FACC, FAHA†avid B. Badesch, MD, FCCP‡obyn J. Barst, MD, FACC, FAHA, FCCP†arrison W. Farber, MD, FAHA, FCCP†

onathan R. Lindner, MD, FACCichael A. Mathier, MD, FACC*

merican College of Cardiology Foundation Task Forceents. J Am Coll Cardiol 2009;53:1573–619.

of CardiologyElsevier’s perm

by ocontent.onlinejacc.orgDownloaded from

yung H. Park, MD, FACC*obert S. Rosenson, MD, FACC, FAHA*ewis J. Rubin, MD, FAHA, FCCP�ictor F. Tapson, MD*

ohn Varga, MD, FACR¶

American College of Cardiology Foundation Representative, †Amer-can Heart Association Representative, ‡American Thoracic Societyepresentative, §Pulmonary Hypertension Association Representative,

American College of Chest Physicians Representative, ¶American

Michael D. McGoon, MD, FACC, FCCP§ College of Rheumatology Representative

ACCFTask ForceMembers

Robert A. Harrington, MD, FACC, FAHA,Chair

Jeffrey L. Anderson, MD, FACC, FAHA#Eric R. Bates, MD, FACCCharles R. Bridges, MD, MPH, FACC,

FAHAMark J. Eisenberg, MD, MPH, FACC,

FAHAVictor A. Ferrari, MD, FACC, FAHACindy L. Grines, MD, FACC#Mark A. Hlatky, MD, FACC, FAHAAlice K. Jacobs, MD, FACC, FAHASanjay Kaul, MD, MBBS, FACC, FAHA

Robert C. Lichtenberg, MD, FACC#Jonathan R. Lindner, MD, FACC#David J. Moliterno, MD, FACCDebabrata Mukherjee, MD, FACCGerald M. Pohost, MD, FACC, FAHA#Robert S. Rosenson, MD, FACC, FAHARichard S. Schofield, MD, FACC, FAHA#Samuel J. Shubrooks, JR, MD, FACC, FAHA#James H. Stein, MD, FACC, FAHACynthia M. Tracy, MD, FACC, FAHA#Howard H. Weitz, MD, FACCDeborah J. Wesley, RN, BSN, CCA

#Former Task Force member during the writing effort

his document was approved by the American College of Cardiology Foundationoard of Trustees in November 2008 and by the American Heart Association Sciencedvisory and Coordinating Committee January 2009.The American College of Cardiology Foundation requests that this document be

ited as follows: McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW,indner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ,apson VF, Varga J. ACCF/AHA 2009 expert consensus document on pulmonary

This article has been copublished in the April 28, 2009, issue of Circulation.Copies: This document is available on the World Wide Web sites of the American

College of Cardiology (www.acc.org) and the American Heart Association (www.americanheart.org). For copies of this document, please contact Elsevier Inc. ReprintDepartment, fax (212) 633-3820, e-mail [email protected].

Permissions: Modification, alteration, enhancement, and/or distribution of thisdocument are not permitted without the express permission of the American College

Foundation or the American Heart Association. Please contactission department at [email protected].

n April 30, 2012

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http://www.americanheart.org

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1574 McLaughlin et al. JACC Vol. 53, No. 17, 2009Expert Consensus Document on Pulmonary Hypertension April 28, 2009:1573–619

TABLE OF CONTENTS

reamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1575

. Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1576

1.1. Pathology and Pathogenesis . . . . . . . . . . . . . . . . . .1576

1.2. Classification and Epidemiology . . . . . . . . . . . . . .1576

1.3. Natural History and Survival. . . . . . . . . . . . . . . . . . .1576

1.4. Screening and Diagnostic Assessment . . . . . . .1576

1.5. Evidenced-Based Treatment Algorithm . . . . . . .1577

1.6. Reassessing Patients Over Time: How toFollow Patients on Treatment . . . . . . . . . . . . . . . . .1577

1.7. Non-Pulmonary Arterial HypertensionPulmonary Hypertension Populations . . . . . . . .1577

1.8. Pulmonary Arterial Hypertension inCongenital Heart Disease . . . . . . . . . . . . . . . . . . . . . .1577

1.9. Pediatric Pulmonary Arterial Hypertension. . . . .1578

. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1578

. Pathology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . .1578

3.1. Histology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1578

3.2. The Right Ventricle . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1578

3.3. Molecular Abnormalities in PulmonaryArterial Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . .1579

3.4. Genetics of PulmonaryArterial Hypertension . . . . . . . . . . . . . . . . . . . . . . . . .1579

3.5. Abnormalities in the Blood and Endotheliumin Pulmonary Arterial Hypertension . . . . . . . . . . . .1579

3.6. Prostacyclin and Thromboxane A2 . . . . . . . . . . . .1579

3.7. Endothelin-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1579

3.8. Nitric Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1579

3.9. Additional Vasoactive Substances. . . . . . . . . . . .1579

3.10. Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1579

3.11. Pulmonary Artery Smooth Muscle Cellsin Pulmonary Arterial Hypertension . . . . . . . . . .1580

. Classification and Epidemiology of PulmonaryArterial Hypertension (WHO Group I) . . . . . . . . . . . . . .1580

4.1. Idiopathic Pulmonary Arterial Hypertension . . . . .1580

4.2. Familial Pulmonary Arterial Hypertension . . . . .1580

4.3. Pulmonary Arterial HypertensionAssociated With Congenital Heart Disease . . . . . .1580

4.4. Pulmonary Arterial HypertensionAssociated With Connective Tissue Diseases . . .1580

4.5. Pulmonary Arterial HypertensionAssociated With Human ImmunodeficiencyVirus Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1580

4.6. Pulmonary Arterial HypertensionAssociated With Portal Hypertension . . . . . . . . . .1581

4.7. Pulmonary Arterial HypertensionAssociated With Drugs and Toxins . . . . . . . . . . . . .1582

4.8. Pulmonary Arterial Hypertension
Associated With Hemoglobinopathies. . . . . . . . . .1582
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4.9. Pulmonary Arterial HypertensionAssociated With Other Etiologies . . . . . . . . . . . . . .1582

4.10. Pulmonary Arterial HypertensionAssociated With Pulmonary Venousor Capillary Abnormalities . . . . . . . . . . . . . . . . . . . . .1582

. Natural History and Survival . . . . . . . . . . . . . . . . . . . . . . . .1582

5.1. Medical Therapy for Pulmonary ArterialHypertension: Impact Upon Survival . . . . . . . . . .1583

5.2. Factors Impacting Survival andFacilitating Assessment of Prognosis. . . . . . . . . .1583

5.3. Functional Class . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1583

5.4. Exercise Tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1583

5.5. Hemodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1584

5.6. Echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1584

5.7. Magnetic Resonance Imaging . . . . . . . . . . . . . . . . .1584

5.8. Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1584

5.9. Summary of Recommendations . . . . . . . . . . . . . . .1585

. Screening and Diagnostic andHemodynamic Assessment . . . . . . . . . . . . . . . . . . . . . . . . . .1585

6.1. Definition of Pulmonary Hypertension. . . . . . . .1585

6.2. Diagnostic Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . .1585

6.3. Echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1585

6.4. Exercise Echocardiography . . . . . . . . . . . . . . . . . . . .1586

6.5. Newer Imaging Techniques in the DiagnosticAssessment of Pulmonary Hypertension. . . . . . .1586

6.6. Invasive Hemodynamic Assessment . . . . . . . . . .1588

6.7. Right Heart Catheterization . . . . . . . . . . . . . . . . . . .1589

6.8. Components of an OptimalInvasive Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1590

6.9. Safety of Heart Catheterization. . . . . . . . . . . . . . .1591

6.10. Spontaneous Variability in PulmonaryArtery Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1591

6.11. Ambulatory Measurement ofPulmonary Hemodynamics . . . . . . . . . . . . . . . . . . . . .1591

6.12. Acute Vasodilator Testing . . . . . . . . . . . . . . . . . . . . .1591

6.13. Agents for Acute Vasodilator Testing . . . . . . . .1591

6.14. Definition of Responders to AcuteVasodilator Testing in PulmonaryArterial Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . .1591

6.15. Vasodilator Testing in PulmonaryArterial Hypertension Subsets . . . . . . . . . . . . . . . .1592

6.16. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1592

. Evidence-Based Treatment Algorithm . . . . . . . . . . . . .1592

7.1. General Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1593

7.2. Background Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . .1593

7.3. Calcium Channel Blockers . . . . . . . . . . . . . . . . . . . . .1593

7.4. Prostanoids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1594

7.5. Epoprostenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1594

7.6. Treprostinil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1594

7.7. Iloprost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1595

7.8. Endothelin Receptor Antagonists . . . . . . . . . . . . .1595

7.9. Bosentan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1595

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1575JACC Vol. 53, No. 17, 2009 McLaughlin et al.April 28, 2009:1573–619 Expert Consensus Document on Pulmonary Hypertension

7.10. Sitaxsentan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1596

7.11. Ambrisentan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1596

7.12. Phosphodiesterase Inhibitors . . . . . . . . . . . . . . . . .1597

7.13. Sildenafil. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1597

7.14. Tadalafil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1597

7.15. Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . .1597

7.16. Limitations of Clinical Trials inPulmonary Arterial Hypertension . . . . . . . . . . . . .1598

7.17. Cost Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . .1598

7.18. Invasive Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1598

7.19. Atrial Septostomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1598

7.20. Lung and Combined Heart andLung Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . .1599

7.21. Pulmonary Thromboendarterectomy . . . . . . . . . .1599

7.22. Right Ventricular Assist Device . . . . . . . . . . . . . . .1599

7.23. Treatment Algorithm. . . . . . . . . . . . . . . . . . . . . . . . . . . .1599

. Reassessing Patients Over Time:How To Follow Patients on Treatment . . . . . . . . . . . . .1600

8.1. Role of Nurses in Managing PulmonaryArterial Hypertension Patients atSpecialty Centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1601

. Non-Pulmonary Arterial HypertensionPulmonary Hypertension Populations . . . . . . . . . . . . .1601

9.1. WHO Group 2: PulmonaryVenous Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . .16029.1.1. Systolic Heart Failure and

Pulmonary Hypertension. . . . . . . . . . . . . . . . . .16029.1.2. Diastolic Heart Failure and

Pulmonary Hypertension. . . . . . . . . . . . . . . . . .16039.1.3. Valvular Dysfunction and

Pulmonary Hypertension. . . . . . . . . . . . . . . . . .1603

9.2. WHO Group 3: Hypoxia-AssociatedPulmonary Hypertension . . . . . . . . . . . . . . . . . . . . . . .16039.2.1. Chronic Obstructive Pulmonary Disease

and Pulmonary Hypertension . . . . . . . . . . . . .16039.2.2. Interstitial Lung Disease and

Pulmonary Hypertension. . . . . . . . . . . . . . . . . .16049.2.3. Sleep Disordered Breathing . . . . . . . . . . . . . . .1604

9.3. WHO Group 4: ThromboembolicPulmonary Hypertension . . . . . . . . . . . . . . . . . . . . . . .16049.3.1. Surgical and Invasive Therapy . . . . . . . . . . . .16059.3.2. Medical Therapy . . . . . . . . . . . . . . . . . . . . . . . . . .16059.3.3. Pulmonary Hypertension in the

Cardiac Surgical Patient . . . . . . . . . . . . . . . . . . .16059.3.4. Preoperative Pulmonary Hypertension . . . . . . .16059.3.5. Postoperative Pulmonary Hypertension . . . . . .1606

9.4. Summary of Recommendations . . . . . . . . . . . . . . .1606

0. Congenital Heart Disease-Related PulmonaryArterial Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1607

1. Pediatric Pulmonary Arterial Hypertension. . . . . . .1608

11.1. Persistent Pulmonary Hypertensionof the Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1608

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2. Pulmonary Hypertension Centersof Excellence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1609

eferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1609

ppendix 1. Author Relationships With Industrynd Other Entities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1615

ppendix 2. Peer Reviewer Relationships Withndustry and Other Entities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1617

reamble

his document has been developed by the American Col-ege of Cardiology Foundation (ACCF) Task Force onxpert Consensus Documents (ECDs), and was cospon-

ored by the American Heart Association (AHA). Expertonsensus Documents are intended to inform practitioners

nd other interested parties of the opinion of the ACCF andosponsors concerning evolving areas of clinical practicend/or technologies that are widely available or new to theractice community. Topics chosen for coverage by expertonsensus documents are so designed because the evidencease, the experience with technology, and/or the clinicalractice are not considered sufficiently well developed to bevaluated by the formal ACCF/AHA practice guidelinesrocess. Often the topic is the subject of ongoing investi-ation. Thus, the reader should view the ECD as the bestttempt of the ACCF and the cosponsors to inform anduide clinical practice in areas where rigorous evidence mayot be available or the evidence to date is not widelyccepted. When feasible, ECDs include indications orontraindications. Some topics covered by ECDs will beddressed subsequently by the ACCF/AHA Practiceuidelines Committee.Because the development of expert consensus documents

epends on the knowledge and experience of experts andnvestigators in the field, many of whom have relationshipsith industry (RWI), the policy addressing writing com-ittee members’ RWI must be realistic, workable, and

mplemented in a way that protects the integrity of therocess while allowing an open and honest exchange of theost up-to-date information. Every possible effort is made

o formulate a writing committee with a reasonable balancef RWI. Specifically, all members of the writing panel aresked to provide disclosure statements of all relationshipshat might be perceived as real or potential conflicts ofnterest. Participation in the writing committee is depen-ent on a review of all relevant RWI by the task force tonsure balance so that fair and unbiased consensus can beeached. In addition, statements of RWI are reported orallynd in writing to all members of the writing panel at everyeeting and conference call and are updated as changes

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In the case of pulmonary hypertension, because of theelatively small number of experts engaged in clinical carend research in this area, identifying experts without RWIn this disease area was a challenge. To mitigate this concernnd reduce the risk of bias, extensive peer review wasompleted in addition to review and approval by the AHA’scientific Advisory Coordinating Committee (SACC) andhe ACCF’s Board of Trustees. SACC members only partic-pate in the review and approval process if they have no relevantWI themselves. To provide complete transparency, the RWI

nformation for writing committee members and peer review-rs are published in the appendixes of the document.

Robert A. Harrington, MD, FACCChair, ACCF Task Force onExpert Consensus Documents

. Executive Summary

ulmonary hypertension (PH) is a complex, multidisci-linary disorder. Recent advances have led to increasedecognition and new therapies. While some data exist toorm treatment guidelines, other areas have been inade-uately explored.

.1. Pathology and Pathogenesis

ulmonary arterial hypertension (PAH) is a syndromeesulting from restricted flow through the pulmonary arte-ial circulation resulting in increased pulmonary vascularesistance and ultimately in right heart failure. Multipleathogenic pathways have been implicated in the develop-ent of PAH, including those at the molecular and genetic

evels and in the smooth muscle and endothelial cells anddventitia. The imbalance in the vasoconstrictor/vasodilatorilieu has served as the basis for current medical therapies,

lthough increasingly it is recognized that PAH also in-olves an imbalance of proliferation and apoptosis (favoringhe former).

.2. Classification and Epidemiology

hile previously considered a rare disease, the most recentvidence from a French registry suggests that the prevalencef PAH is about 15 per million (1). Idiopathic pulmonaryrterial hypertension (IPAH) is more prevalent in womennd was the most common type of PAH in the Frenchegistry. Familial PAH often results from a mutation in theone morphogenic protein receptor-2 (BMPR2) and isnherited as an autosomal dominant disease with incompleteenetrance and genetic anticipation. PAH is also associatedith congenital heart disease (CHD), connective tissueiseases, drugs and toxins, human immunodeficiency virusHIV), portal hypertension, hemoglobinopathies, and my-loproliferative disorders. Primary PH formerly encom-assed idiopathic, familial, and anorexigen induced PAH.hese groups together comprise World Health Organiza-

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nclude Group II, PH with left heart disease, Group III, PHssociated with lung diseases and/or hypoxemia, Group IV,H due to chronic thrombotic and/or embolic disease, androup V, miscellaneous causes of PH (Table 1).

.3. Natural History and Survival

he prognosis of PAH is poor, with an approximately 15%ortality within 1 year on modern therapy (2). Predictors ofpoor prognosis include: advanced functional class, poor

xercise capacity as measured by 6-minute walk (6MW) testr cardiopulmonary exercise test, high right atrial (RA)ressure, significant right ventricular (RV) dysfunction,vidence of RV failure, low cardiac index, elevated brainatriuretic peptide (BNP), and underlying diagnosis ofcleroderma spectrum of diseases.

.4. Screening and Diagnostic Assessment

atients at sufficient risk for the development of PAH toarrant periodic screening include those with a knownMPR2 mutation, scleroderma spectrum of diseases, andortal hypertension who are undergoing evaluation for liverransplantation. The most appropriate study to obtain inatients suspected of having PH based on history, physical

able 1. Revised WHO Classification of PH

. Pulmonary arterial hypertension (PAH)1.1. Idiopathic (IPAH)1.2. Familial (FPAH)1.3. Associated with (APAH):

1.3.1. Connective tissue disorder1.3.2. Congenital systemic-to-pulmonary shunts1.3.3. Portal hypertension1.3.4. HIV infection1.3.5. Drugs and toxins1.3.6. Other (thyroid disorders, glycogen storage disease,

Gaucher’s disease, hereditary hemorrhagic telangiectasia,hemoglobinopathies, chronic myeloproliferative disorders,splenectomy)

1.4. Associated with significant venous or capillary involvement1.4.1. Pulmonary veno-occlusive disease (PVOD)1.4.2. Pulmonary capillary hemangiomatosis (PCH)

1.5. Persistent pulmonary hypertension of the newborn. Pulmonary hypertension with left heart disease

2.1. Left-sided atrial or ventricular heart disease2.2. Left-sided valvular heart disease

. Pulmonary hypertension associated with lung diseases and/or hypoxemia3.1. Chronic obstructive pulmonary disease3.2. Interstitial lung disease3.3. Sleep disordered breathing3.4. Alveolar hypoventilation disorders3.5. Chronic exposure to high altitude3.6. Developmental abnormalities

. Pulmonary hypertension due to chronic thrombotic and/or embolicdisease (CTEPH)

4.1. Thromboembolic obstruction of proximal pulmonary arteries4.2. Thromboembolic obstruction of distal pulmonary arteries4.3. Nonthrombotic pulmonary embolism (tumor, parasites,

foreign material). Miscellaneous

Sarcoidosis, histiocytosis X, lymphangiomatosis, compression ofpulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)

eprinted from Simonneau et al. (32).

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ECG) is an echocardiogram. Evaluation for other potentialtiologies, such as thromboembolic disease, is appropriate inll patients suspected of having PAH. The diagnosis ofAH requires confirmation with a complete right heartatheterization (RHC). The current hemodynamic defini-ion of PAH is a mean pulmonary artery pressure (mPAP)reater than 25 mm Hg; a pulmonary capillary wedgeressure (PCWP), left atrial pressure, or left ventricularnd-diastolic pressure (LVEDP) less than or equal to 15m Hg; and a pulmonary vascular resistance (PVR) greater

han 3 Wood units (3). Acute vasodilator testing, whichnvolves the administration of pharmacologic agents to testhe presence of pulmonary vasoreactivity, has prognositicalue and should be performed in all IPAH patients whoight be considered potential candidates for long-term

alcium-channel blocker therapy. Those with overt righteart failure or hemodynamic instability should not undergocute vasodilator testing. The definition of an acute re-ponder is a reduction in mPAP of at least 10 mm Hg to anbsolute mPAP of less than 40 mm Hg without a decreasen cardiac output. Vasodilator testing should be performedy centers with experience in the administration of thesegents and the interpretation of the results.

.5. Evidenced-Based Treatment Algorithm

oals of treatment include improvement in the patient’symptoms, quality of life, and survival. Objective assess-ents to measure treatment response include improvement

n exercise capacity (6MW test, cardiopulmonary exerciseest, treadmill test), hemodynamics, and survival. Generaleasures that should be addressed include diet, exercise,

ppropriate vaccinations, and avoidance of pregnancy. War-arin anticoagulation is recommended in all patients withPAH based on 1 prospective and 2 retrospective observa-ional, uncontrolled trials. Diuretics are used for symptom-tic management of RV volume overload. Oxygen is rec-mmended to maintain oxygen saturation greater than 90%.alcium channel blockers are indicated only for patientsho have a positive acute vasodilator response as described

n the preceding text. Patients treated with calcium channellockers should be followed closely for both the safety andhe efficacy of this therapy. Continuous intravenous epopro-tenol improves exercise capacity, hemodynamics, and sur-ival in IPAH and is the preferred treatment option for theost critically ill patients. Although expensive and cumber-

ome to administer, epoprostenol is the only therapy forAH that has been shown to prolong survival. Treprostinil,prostanoid, may be delivered via either continuous intra-

enous or subcutaneous infusion. Iloprost is a prostanoidelivered by an adaptive aerosolized device 6 times daily.he delivery system and side effects of the prostanoids

hould be carefully considered when assessing patients forrostanoid therapy. The endothelin receptor antagonists areral therapies that improve exercise capacity in PAH. Liverunction tests must be monitored indefinitely on a monthly
asis. Phosphodiesterase (PDE)-5 inhibitors also improve u

xercise capacity and hemodynamics in PAH. In general,atients with poor prognostic indexes should be initiated onarenteral therapy, while patients with class II or early IIIymptoms commonly commence therapy with either endo-helin receptor antagonists or PDE-5 inhibitors. Given theultiple mechanisms of action, there is scientific rationale

or the use of combination therapy for PAH, which is anrea of active investigation. Initial results are encouragingnd more combination therapy trials are underway. Lungransplantation is an option for selected patients whorogress despite optimal medical management.

.6. Reassessing Patients Over Time:ow to Follow Patients on Treatment

ue to the complex nature of the disease and its treatments,AH patients must be closely followed. In general, officeisits should be more frequent for patients with advancedymptoms, right heart failure, and advanced hemodynamicsnd those on parenteral or combination therapy. Suchatients generally should be seen every 3 months (or morerequently). Less ill patients on oral therapy generally shoulde seen every 3 to 6 months. Most experts obtain anssessment of functional class and exercise capacity, such as

6MW or graded treadmill test, with each office visit.urse clinicians experienced in the care of PAH patients

hould be an integral part of chronic outpatient management.

.7. Non-Pulmonary Arterial Hypertensionulmonary Hypertension Populations

ost cardiologists and pulmonologists will see PH associ-ted with elevated left heart filling pressures much morerequently than PAH. Any disorder that elevates left heartlling pressures, including systolic dysfunction, diastolicysfunction, and valvular heart disease, can result in elevatedulmonary artery pressures. Treatment should be directed athe underlying left heart disease. In rare instances, PAH-pecific therapy may be considered if the underlying causeas been optimally treated, the PCWP is normal or mini-ally elevated, the transpulmonary gradient and pulmonary

ascular resistance are significantly elevated, and the pa-ient’s symptoms suggest that PAH-specific therapy mayield clinical benefit. This subset of patients may be de-cribed as those with “disproportionate” PH (greater thanxpected on the basis of their elevated left heart pressure orung disease). Experts caution against widespread treatmentor non-PAH PH until clinical trial data indicate whetheruch patients benefit from them. The potential adverseffects of PAH-specific therapies in such patients includeorsening fluid retention, pulmonary edema, and ventila-

ion perfusion mismatch.

.8. Pulmonary Arterial Hypertension inongenital Heart Disease

he incidence of CHD is approximately 8 per 1,000 liveirths (4), and approximately 30% of children who do not
ndergo surgical repair will develop pulmonary vascular


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.9. Pediatric Pulmonary Arterial Hypertension

ersistent PH of the newborn is a syndrome characterizedy increased pulmonary vascular resistance, right to lefthunting, and severe hypoxemia. Treatment options includenhaled nitric oxide (iNO) and extracorporeal membranexygenation. Pediatric IPAH is treated similar to that indults. A higher percentage of children are acute respondersnd candidates for calcium channel blockers.

. Introduction

he field of PH has evolved substantially over the pastecade. While there are some data from which evidenceased guidelines for PAH have been generated, otherspects of the assessment and management of PH have beenargely unexplored.

The writing committee consisted of acknowledged ex-erts in the field of PH. In addition to members designatedy the ACCF and AHA, the Writing Committee includedepresentation from the American College of Chest Physi-ians (ACCP); the American College of Rheumatology; themerican Thoracic Society, Inc. (ATS); and the Pulmonaryypertension Association (PHA). This diverse representa-

ion reflects the multidisciplinary nature of PH. Represen-ation by an outside organization does not necessarily implyndorsement. This document was reviewed by 4 officialepresentatives from the ACCF and AHA; organizationaleview by the ACCP, ATS, and PHA; as well as by 13ontent reviewers. This document was approved for publi-ation by the governing bodies of the ACCF in November008 and AHA in February 2009. In addition, the govern-ng boards of the ACCP, ATS, and PHA formally endorsedhis document. This document will be considered currentntil the Task Force on ECDs revises it or withdraws itrom publication.

This statement is the first ACCF/AHA Clinical Expertonsensus Document on PH. At its first meeting, eachember of this ACCF/AHA Writing Committee indicated

ny relationships with industry, and these relationships wereeiterated at each subsequent meeting and on each confer-nce call. Relevant conflicts of the writing committee andeer reviewers are reported in Appendixes 1 and 2, respec-ively. At the first meeting the writing committee discussedhe topics to be covered in the document and assigned leaduthors for each section. The entire writing group reviewedach section and discussed important issues for furtherrafts. The committee met again to come to a consensus onutstanding issues, and further meetings and teleconfer-nces occurred between the chairman and writing group
embers who were not present at the meetings to ensure (

onsensus on important points. In instances where there wasot consensus amongst the writing group, a majority opin-

on and a minority opinion is presented. Each writing groupember has read and approved the entire document. Out-

ide peer review was also undertaken before the documentas finalized.

. Pathology and Pathogenesis

AH is a syndrome resulting from restricted flow throughhe pulmonary arterial circulation, which leads to patholog-cal increases in PVR and ultimately to right heart failure5). The predominant cause of increased PVR is loss ofascular luminal cross section due to vascular remodelingroduced by excessive cell proliferation and reduced rates ofpoptosis, although excessive vasoconstriction plays a sig-ificant role in approximately 20% of patients (6,7).Improved understanding of the disease pathways in

AH, even if a single primary cause remains elusive, has ledo therapeutic strategies, including the administration ofrostanoids, the antagonism of endothelin receptors, andnhibition of PDE-5. Future therapeutic options identifiedy basic studies include inhibiting pyruvate dehydrogenaseinase (PDK), the serotonin transporter (5-HTT), thentiapoptotic protein survivin, several transcription factorsnotably hypoxia inducible factor-1 alpha [HIF-1 alpha]uclear factor activating T lymphocytes [NFAT]), andugmenting voltage-gated potassium channel channels (e.g.,v1.5). Additional therapies in early clinical development

nclude vasoactive intestinal peptide and tyrosine kinasenhibitors. Administration of angiogenic factors and stemells and agents targeting mitochondrial dysfunction maylso have therapeutic promise.

.1. Histology

AH is a panvasculopathy predominantly affecting smallulmonary arteries (also called “resistance arteries” becausehey regulate regional blood flow in the lung) (8). PAH isharacterized by a variety of arterial abnormalities, includingntimal hyperplasia, medial hypertrophy, adventitial prolif-ration, thrombosis in situ, varying degrees of inflammation,nd plexiform arteriopathy. An individual patient mayanifest all of these lesions, and the distribution of lesionsay be diffuse or focal. Our understanding of the natural

istory of the evolution of vascular lesions in PAH, exceptor patients with CHD, is limited because biopsies are rarelybtained in adult patients. However, it is believed thatedial hypertrophy is an earlier and more reversible lesion

han intimal fibrosis or plexogenic arteriopathy.

.2. The Right Ventricle

V function is a major determinant of functional capacitynd prognosis in PAH (5). While RV hypertrophy andilatation are initiated by increased afterload (i.e., elevatedVR), the adequacy of the RV’s compensatory response

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ndividuals. It remains unclear why some RVs compensatehile others decompensate, manifest as thinning and dila-

ation of the wall, and reduce the RV ejection fraction. Theeonatal RV is much more tolerant of increased PVR,artially explaining the better survival in children with PAHssociated with CHD. RV function could potentially bemproved by effective therapies to regress pulmonary vascu-ar obstruction or by directly improving RV contractileunction.

.3. Molecular Abnormalities in Pulmonaryrterial Hypertension

he pathobiological mechanisms of PAH have recentlyeen reviewed (9). The PAH “phenotype” is characterizedy endothelial dysfunction, a decreased ratio of apoptosis/roliferation in pulmonary artery smooth muscle cellsPASMCs), and a thickened, disordered adventitia in whichhere is excessive activation of adventitial metalloproteases.ike cancer and atherosclerosis, PAH does not have a singleause: a “multi-hit model” is more likely.

.4. Genetics of Pulmonary Arterial Hypertension

AH is inherited in less than 10% of cases (1,10). Muta-ions in 2 genes in the transforming growth factor betaeceptor pathway, BMPR2, and activin-like kinase 1 haveeen implicated in the pathogenesis of familial PAH.MPR2 modulates vascular cell growth by activating the

ntracellular pathways of SMAD and LIM kinase (11–13)any different BMPR2 mutations occur in familial PAH.

hese mutations, which lead to loss of function in theMAD signaling pathway, are prevalent in familial PAHprevalence �75%) (11,12). Activin-like kinase 1 muta-ions, detected in a group of patients with hereditaryemorrhagic telangiectasia and PAH (13), are also thoughto result in growth-promoting alterations of SMAD-ependent signaling. Overexpression of a dominant nega-ive form of BMPR2 in PASMC leads to PAH and Kv1.5ownregulation in transgenic mice (14,15).

.5. Abnormalities in the Blood and Endothelium inulmonary Arterial Hypertension

n the vascular lumen, PAH is characterized by plateletshat are depleted of serotonin and elevation of plasmaerotonin (16). Endothelial dysfunction is common inAH. The PAH endothelium is characterized by increasedroduction of vasoconstrictor/mitogenic compounds, suchs endothelin and thromboxane, and deficient production ofasodilators, such as prostacyclin (17–19). Elevated levels ofbrinopeptide A and plasminogen activator inhibitor-1 andeduced levels of tissue plasminogen activator contribute tohe procoagulant state. Endothelial injury may also exposehe underlying smooth muscle cells to circulating mitogensnd growth factors that stimulate cell proliferation.

.6. Prostacyclin and Thromboxane A2

he prostanoids prostacyclin and thromboxane A2 are
ajor arachidonic acid metabolites. Prostacyclin is a potent o

asodilator, inhibits platelet activation, and has antiprolif-rative properties, whereas thromboxane A2 is a potentasoconstrictor and promotes proliferation platelet activa-ion. In PAH, the balance between these 2 molecules ishifted toward thromboxane A2 (17), favoring thrombosis,roliferation, and vasoconstriction. Additionally, prostacy-lin synthase is decreased in the small- and medium-sizedulmonary arteries in PAH (20).

.7. Endothelin-1

ndothelin-1 (ET-1) is a potent vasoconstrictor and stim-lates PASMC proliferation. Plasma levels of ET-1 arencreased in PAH and correlate with severity of PAH andrognosis (21). Moreover, clearance of ET-1 in the pulmo-ary vasculature is reduced in PAH (19).

.8. Nitric Oxide

itric oxide (NO) is a vasodilator and inhibitor of plateletctivation and vascular smooth-muscle cell proliferation.O is produced by 3 isoforms of nitric oxide synthases

NOS). Decreased endothelial NOS (NOS3) has beenbserved in PAH patients (18). Once formed, the effects ofO are largely mediated by cyclic guanosine monophos-

hate (cGMP) which is rapidly inactivated by PDE, espe-ially the PDE-5 isoenzymes. eNOS knockout mice displayH and even more profound systemic hypertension (22).DE-5 is present in large amounts in the lung, giving

ationale for the use of PDE-5 inhibitors in PAH.

.9. Additional Vasoactive Substances

erotonin (5-hydroxytryptamine) is a vasoconstrictor andromotes PASMC hypertrophy and hyperplasia. Allelicariation in serotonin transporter (5-HTT) and the-hydroxytryptamine 2B receptor (5-HT2B), have beenescribed in platelets and lung tissue from patients withAH (23). Transgenic mice overexpressing the serotonin

ransporter have PAH and decreased Kv1.5 expression (14).espite these observations, the level of serotonin alone is

ot likely a determinant of PAH, since serotonin-reuptakenhibitors are in widespread clinical use but are not associ-ted with an increased incidence of PAH and may, in fact,e a potential PAH therapy (24). Vasoactive intestinaleptide (VIP) is a member of the glucagon-growthormone-releasing superfamily and has a pharmacologicrofile similar to prostacyclins. Serum and lung tissue VIP

evels are decreased in PAH patients, and exogenous VIP mayecrease pulmonary artery pressure (PAP) and PVR, inhibitlatelet activation, and reduce PASMC proliferation (25).

.10. Inflammation

utoantibodies, proinflammatory cytokines, and inflamma-ory infiltrates have been observed in some cases of PAH,uggesting that inflammation may contribute to the devel-
pment of some forms of PAH (26).


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.11. Pulmonary Artery Smooth Muscle Cells inulmonary Arterial Hypertension

n PAH, PASMCs have a collection of abnormalities thatavor a decreased apoptosis/proliferation ratio. These abnor-alities include inappropriate activation of transcription

actors (HIF-1 alpha and NFAT), decreased expression ofertain K� channels (e.g., Kv1.5 and Kv2.1), and de novoxpression of the antiapoptotic protein survivin. Severalbnormalities are observed in human PAH and in rodentodels of PAH (notably loss of Kv1.5, activation of

urvivin, and nuclear translocation of HIF-1 alpha) (27,28).he PASMCs in PAH also display excessive proliferation

n response to transforming growth factor beta, and thisropensity to accumulate unwanted cells is exacerbated bympaired smooth muscle cell apoptosis. The impaired apo-tosis appears to be multifactorial, related to abnormalitochondrial hyperpolarization, activation of transcription

actors (such as HIF-1 alpha and NFAT), and de novoxpression of the antiapoptotic protein survivin (27). Thisccurs in both the PASMCs and endothelial cells (29).nother factor that promotes calcium overload andASMC proliferation is increased expression of transient

eceptor potential channels, which promotes calcium over-oad (30).

In PAH the adventitia is fragmented, permitting celligration and creating mitogenic peptides, such as tenascin

31). It is conceivable that inhibition of metalloproteasesay have therapeutic potential in PAH.While great strides have been made in understanding the

asic mechanisms of the pathobiology and the pathogenesisf PAH over the past 2 decades, our understanding is farrom complete. Ongoing investigation into many novelathways will potentially lead to more therapeutic options inhe decades to come. Figure 1 (31a) summarizes many ofhe relevant cellular pathways in the pathogenesis of PAH.

. Classification and Epidemiology ofulmonary Arterial HypertensionWHO Group I)

he current classification of PH is depicted in Table 1 (32).

.1. Idiopathic Pulmonary Arterial Hypertension

PAH is a rare disease, with a female/male ratio of 1.7:1 andmean age at diagnosis of 37 years (10). Most recent

pidemiologic data suggest that the prevalence of PAH maye up to 15 per million, with a prevalence of IPAH of aboutper million (1). Interestingly, recent studies suggest the

ge range of affected individuals may be increasing, as casesf IPAH have been reported in many patients greater than0 years old (33).

.2. Familial Pulmonary Arterial Hypertension

ereditary transmission of PAH has been reported in
pproximately 6% to 10% of patients with PAH; in 50% to t

0% of these individuals, mutations in BMPR2 have beendentified (34,35). Mutations in BMPR2 have been foundn up to 25% of patients with IPAH (36), in 15% of PAHelated to fenfluramine use, and rarely in patients with otherorms of associated PAH (37,38). The mutations inMPR2 in familial pulmonary arterial hypertension

FPAH) are characterized by genetic anticipation and in-omplete penetrance. The phenotype is not expressed in allenerations, but when expressed, occurs at an earlier age ands associated with more severe and rapidly progressiveisease (39,40).

.3. Pulmonary Arterial Hypertension Associatedith Congenital Heart Disease

AH is a well-recognized complication of uncorrectedncreased pulmonary blood flow associated with CHD andystemic-to-pulmonary shunts. The development of PAHnd subsequent reversal of shunt flow (Eisenmenger syn-rome) occurs more frequently when blood flow is ex-remely high and the shunt exposes the pulmonary vascu-ature to systemic level pressures, such as occurs with aentricular septal defect, patent ductus arteriosus, or truncusrteriosus. However, PAH may also occur with lowressure-high flow abnormalities, such as with atrial septalefects.

.4. Pulmonary Arterial Hypertension Associatedith Connective Tissue Diseases

primary pulmonary arteriopathy occurs most commonlyn patients with the limited cutaneous form of systemicclerosis, formerly referred to as the CREST (calcinosis,aynaud’s, esophageal dysfunction, sclerodactaly, telangec-

asias) variant. Although at autopsy, 65% to 80% of indi-iduals have histopathological changes consistent withAH, less than 10% develop clinically apparent disease (41).urveillance echocardiography suggests that there is a sub-tantial prevalence of mild to moderate PH in connectiveissue disease patients (41,42). However, the managementnd natural history of such patients has not been welltudied. Histology consistent with PAH has also beenbserved in systemic lupus erythematosus, mixed connectiveissue disease, and rheumatoid arthritis.

.5. Pulmonary Arterial Hypertension Associatedith Human Immunodeficiency Virus Infection

opulation studies of individuals infected with HIV suggesthat the incidence of PAH is approximately 0.5%, or 6 to 12imes that of the general population, and has not declinedignificantly with aggressive antiretroviral therapy (43–45).he occurrence of PAH is independent of the CD4 countr previous opportunistic infections, but appears related to
he duration of HIV infection (46). Although PAH occurs


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ith greater frequency in individuals who have used intra-enous drugs, no clear etiological link has been establishedith foreign body emboli or the portal hypertension fre-uently observed in these same individuals because ofoncomitant infection with hepatitis B or C. Because HIVoes not directly infect vascular endothelial cells or smoothuscle cells, the mechanism of PAH in HIV infection

emains unclear. Routine screening for PAH in HIV is notecommended due to the relatively low disease prevalence in

igure 1. Relevant Pathways in the Pathogenesis of Pulmonary Ar

chematic depicting the potential “hits” involved in the development of PAH. A risezation, which opens VDCCs; upregulated TRPC channels that participate in forminge.g., serotonin, endothelin, or leukotriene receptors] ➂ and their downstream signanhibits the BMP-signaling pathway that leads to antiproliferative and proapoptotic efMP-RI downregulation ➃ and inhibition of Kv channel function and expression ➀ attnd release ➄ from PASMCs enhance 5-HT production and downregulate BMP-RIA inxide and prostacyclin synthesis ➅ in PAECs would attenuate the endothelium-deriveASMC proliferation. Increased activity and expression of the 5-HTT ➆ would serve aariety of splicing factors, transcription factors, protein kinases, extracellular metallootypical transition of normal cells to contractive or hypertrophied cells and to maint-HT indicates 5-hydroxytryptamine; 5-HTT, 5-HT transporter; 5-HTR, 5-hydroxytryptoprotein; BMP-RI, BMP type I receptor; BMP-RII, BMP type II receptor; BMPR-IA, BMP rrol; Em, membrane potential; ET-1, endothelin-1; ET-R, endothelin receptor; GPCR, Gated potassium channel; MAPK, mitogen-activated protein kinase; NO/PGI2, nitric oypertension; PASMC, pulmonary artery smooth muscle; PDGF, platelet-derived growLC�, PLC gamma; PKC, protein kinase C; ROC, receptor-operated calcium channel;tore-operated channel; SR, sarcoplasmic reticulum; TIE2, tyrosine-protein kinase rehannel. Reprinted from Yuan and Rubin (31a).

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.6. Pulmonary Arterial Hypertension Associatedith Portal Hypertension

n a large autopsy series, histological changes consistentith PAH occurred in 0.73% of individuals with cirrhosis,times the prevalence in all autopsies (47). Hemodynamic

tudies have estimated the prevalence of PAH in thesendividuals at 2% to 6%; however, the prevalence may beigher in patients referred for liver transplantation (48). Theisk of developing PAH increases with the duration of

Hypertension

�]cyt in PASMCs (due to increased Kv channel activity ➀ and membrane depolar-r- and store-operated Ca2� channels ➁; and upregulated membrane receptors

scades) causes pulmonary vasoconstriction, stimulates PASMC proliferation, andn PASMCs. Dysfunction of BMP signaling due to BMP-RII mutation and BMP-RII/PASMC apoptosis and promote PASMC proliferation. Increased Ang-1 synthesis

s and further enhance PASMC contraction and proliferation, whereas inhibited nitricxing effect on pulmonary arteries and promote sustained vasoconstriction anddditional pathway to stimulate PASMC growth via the MAPK pathway. In addition, anases, and circulating growth factors would serve as the “hits” to mediate the phe-

progression of PAH.ng-1, angiopoietin; AVD, apoptotic volume decrease; BMP, bone morphogeneticr IA; Ca2�, calcium ion; Co-Smad, common smad; cyt, cytosine; DAG, diacylglyc-in-coupled receptor; IP3, inositol 1,4,5-trisphosphate; K, potassium; Kv, voltage-rostacyclin; PAEC, pulmonary arterial endothelial cell; PAH, pulmonary arterialor; PIP2, phosphatidylinositol biphosphate; PLC, phospholipase C; PLC�, PLC-beta;d, receptor-activated smad signaling pathway; RTK, receptor tyrosine kinase; SOC,

; TRPC, transient receptor potential channel; and VDCC, voltage-dependent calcium

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nclear, but cirrhosis without the presence of portal hyper-ension appears insufficient for the development of PAH.ortal hypertension patients may also develop PH related toigh flow states and left ventricular (LV) diastolic dysfunc-ion, which are important to distinguish from PAH.

.7. Pulmonary Arterial Hypertension Associatedith Drugs and Toxins

ssociation between anorexigens (appetite suppressantrugs that increase serotonin release and block serotonineuptake) and PAH was initially observed in the 1960shen an epidemic of IPAH (then termed PPH) was noted

n Europe following the introduction of aminorex fumarate49). Upon withdrawal of this medication, the incidence ofAH decreased to background; however, structurally relatedompounds, such as fenfluramine and dexfenfluramine,ere subsequently developed in the 1980s. Exposure to

hese agents for as little as 3 months also has been associatedith an increased incidence of IPAH (50). Epidemiologic

tudies have also linked the development of PAH toapeseed oil (51), L-tryptophan (52), and illicit drugs suchs methamphetamine and cocaine (53,54).

.8. Pulmonary Arterial Hypertension Associatedith Hemoglobinopathies

H is increasingly recognized in patients with sickle cellisease, with a prevalence reported as high as 30% inchocardiography-based studies (55,56). A more recenteport suggests that the proportion of patients with sickleell disease who have PAH is much lower, less than 10%57). It also highlights other factors that may contribute toH in sickle cell disease patients including thromboembolicisease, restrictive lung disease, and left heart disease.

hether the PH is the cause of the increased mortality ors a surrogate marker remains unclear; however, the 2-year

ortality rate in these patients is approximately 50%55,56). The pathobiology of PH in sickle cell disease isikely multifactorial: sickle cell related pulmonary vasculopa-hy, asplenia, pulmonary parenchymal and vascular injuryrom acute chest syndrome, and systemic loss of bioavailableO by hemoglobin released during hemolysis and increased

xidant burden (58). Plasma levels of endothelin-1 arelevated in patients with sickle cell disease (59). Despite theelatively mild nature of the PH in many of these patients,he histopathology is often quite similar to PAH, includinglexiform lesions. Hemodynamic parameters in PH associ-ted with sickle cell disease are often different from those inther forms of PAH. PAP and PVR are often lower thanhat observed in IPAH, yet patients with sickle cell diseasend PH are often very symptomatic. In contrast to patientsith other forms of PAH, who by definition have normalV systolic and diastolic function, sickle cell disease-PHatients often have elevated left heart filling pressuresuggesting impaired LV diastolic function. They also haveecreased hemoglobin and a high cardiac output but have

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omozygous beta-thalassemia and hereditary spherocytosisave also been associated with the development of PH60,61).

.9. Pulmonary Arterial Hypertension Associatedith Other Etiologies

H clinically and histologically indistinguishable fromPAH has been observed in approximately 15% of individ-als with hereditary hemorrhagic telangiectasia, an autoso-al dominant vascular dysplasia (13,62). There is also an

ssociation between thrombocytosis, chronic myelodysplas-ic syndrome, and the development of PAH (63). Lastly, aigh incidence of asplenia and thyroid disease have beeneported in patients with PAH (64,65).

.10. Pulmonary Arterial Hypertension Associatedith Pulmonary Venous or Capillary Abnormalities

n rare instances, the typical histological findings of PAHre associated with an occlusive venopathy (pulmonaryeno-occlusive disease) or a microvasculopathy (pulmonaryapillary hemangiomatosis). In addition to the histology ofAH, these entities also exhibit the findings of pulmonaryenous hypertension, including pulmonary hemosiderosis,nterstitial edema, and lymphatic dilation (66). Althoughhe clinical presentation is usually indistinguishable fromAH, rapid development of pulmonary edema after admin-

stration of vasodilators such as epoprostenol has beeneported in both entities (67,68) and is often a clue to theppropriate diagnosis.

. Natural History and Survival

he prognosis of PAH and variables influencing the prog-osis have recently been reviewed (69). The natural historyf IPAH has been well characterized. The National Insti-utes of Health (NIH) Registry followed 194 patients withPAH enrolled at 32 clinical centers from 1981 to 198570). The estimated median survival was 2.8 years, with 1-,-, and 5-year survival rates of 68%, 48%, and 34%,espectively. Studies from Japan, India, and Mexico haveuggested similar results, with a median survival in the rangef 2 to 3 years.Prognosis is also influenced by underlying etiology (Fig-

re 2). The prognosis in patients with PAH associated withhe scleroderma spectrum of diseases appears to be worsehan for IPAH, and the untreated 2-year survival rate maye as low as 40% (71). Even with epoprostenol therapy,atients with PAH related to the scleroderma spectrum ofiseases have a less favorable outcome (72), although recentata suggest that in the era of expanding PAH therapy,rognosis may be improving (73). Data from 2 studiesprospective and retrospective) suggest that patients with

IV-associated PAH appear to have similar survival ashose with IPAH (43,74), and deaths in this setting areost commonly related to PAH. It is clear that patients
ith CHD have a better prognosis than those with IPAH,


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lthough it is uncertain whether this reflects the relativeouth of these patients, their better adapted right ventricles,r the potential advantages of a residual shunt. In a studyvaluating 100 adults with severe PAH, 37 of whom hadisenmenger syndrome and 6 of whom had previously

epaired congenital heart defects, actuarial survival of non-ransplanted patients was 97%, 89%, and 77% at 1, 2, and 3ears, respectively, compared with 77%, 69%, and 35% at 1,, and 3 years, respectively, for patients with IPAH (75). Incohort of epoprostenol-treated PAH patients, survival wasreater for those with CHD than for IPAH (72).

.1. Medical Therapy for Pulmonary Arterialypertension: Impact Upon Survival

he positive impact of epoprostenol on survival in IPAHas been well described in 1 randomized controlled trial andsingle center, observational, uncontrolled trials (76–78).ong-term epoprostenol therapy appears to improve hemo-ynamics and quality of life in patients with PAH andHD who fail conventional therapy (79), and improvementas been demonstrated in the scleroderma spectrum ofiseases population (80), but trials large enough to ade-uately assess survival benefit are not available.Long-term observational studies with first line bosentan

nd treprostinil have also suggested an improved survival inAH, although controlled clinical trial data are not available

81,82). Calcium channel blockers may favorably influenceurvival in the small proportion of patients with IPAH whoemonstrate a significant vasodilator response at RHC83,84). Anticoagulation therapy has been associated withmproved survival in IPAH (83) as well as in diet drug-nduced PAH (85) in open label, uncontrolled series.

owever, a large, prospective randomized trial with thepecific purpose of looking at this end point has not been

igure 2. Mean Survival of Patients With PAH Based on Etiology

HD indicates congenital heart disease; CTD, connective tissue disease; HIV, humaPAH, idiopathic pulmonary arterial hypertension; and Portopulm, portopulmonary hyp

onducted. Recent registry data indicate an 85% survival pcontent.onlinejaDownloaded from

ate at 1 year for patients with PAH observed at a singleenter from 1982 to 2006 (2).

.2. Factors Impacting Survival andacilitating Assessment of Prognosis

mportant prognostic factors have recently been reviewed69) and will be briefly summarized.

.3. Functional Class

he NIH cohort study showed that among 194 patientsho received a diagnosis of IPAH between 1981 and 1985,

he risk of death was higher among patients in New Yorkeart Association (NYHA) functional class III or IV than

mong those in NYHA functional class I or II. In the NIHegistry, the median survival among patients presenting withYHA functional class I and II symptoms was nearly 6

ears versus 2.5 years for patients with functional class IIIymptoms and just 6 months for patients who presentedith functional class IV symptoms (70). Other series have

onfirmed the importance of functional class as a prognosticariable, even during treatment (77,78). Mortality is highern both treated and untreated functional class III butarticularly in functional class IV IPAH patients. Patientsho improved to functional class I or II status with

poprostenol had a better prognosis than patients whoemained in functional class III or IV (77,78).

.4. Exercise Tolerance

n the pivotal epoprostenol IPAH trial, performance in thenencouraged 6MW test was found to be an independentredictor of survival, leading to use of this test as therimary end point for many prospective trials (76). Othertudies have suggested the prognostic value of this test; in

unodeficiency virus related;ion. Adapted from McLaughlin et al. (69).

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aseline and after 3 months of therapy was associated withurvival by univariate analysis (78,86).

Maximal oxygen consumption (peak VO2) determined byrogressive, exercise testing with cycle ergometry has beenound to be an independent predictor of survival in 1 studyn patients with IPAH (87); Kaplan-Meier analysis in thistudy revealed that patients with a peak VO2 greater than0.4 mL/kg/min had significantly better 1-year survivalhan patients with lower peak VO2 values. Patients with aeak systemic blood pressure greater than 120 mm Hg alsoad a better 1-year survival than those patients who did notchieve this systemic blood pressure. In IPAH patientsreated with epoprostenol, treadmill exercise time has alsoeen shown to be predictive of survival (77). Cardiopulmo-ary exercise testing is used less frequently in PAH clinicalrials due to lack of methodologic consistency amongifferent centers. The Naughton-Balke treadmill test re-orted in exercise metabolic equivalents is a useful means ofssessing functional capacity in PAH patients (88).

.5. Hemodynamics

ll large published evaluations implicate hemodynamics asn important predictor of survival (70,77,78). In the NIHegistry, 3 hemodynamic variables were associated with anncreased risk of death by univariate analysis: increased

PAP (odds ratio [OR]: 1.16; 95% confidence interval:.05 to 1.28), increased mean right atrial pressure (mRAP)OR: 1.99; 95% confidence interval: 1.47 to 2.69), andecreased cardiac index (CI) (OR: 0.62; 95% confidence

nterval: 0.46 to 0.82). These 3 variables were also predictiven a multivariate analysis. Data from the NIH registry weresed to formulate a regression equation in which these 3ariables were used to estimate survival. Data from Mexicon the pre-epoprostenol era support the validity of the NIHquation, and suggest the importance of other predictorsuch as decreased mixed venous oxygen (MVO2) andncreased heart rate (89). Interestingly, mPAP was not aredictor based upon these data, and this is likely due to theventual decrease in mPAP as the right ventricle fails.aseline hemodynamic variables appear to have less prog-ostic value in patients with IPAH who are treated withpoprostenol (78). Based upon available data, it is agreedhat mRAP, CI, and mPAP are predictive of survival, withhe understanding that as RV function worsens, mPAP mayctually decrease. Experienced clinicians use mRAP and CIogether with other clinical parameters to prognosticate.

True vasodilator responders have an excellent prognosis,ith up to a 95% survival at 5 years (83,84). Although theain purpose of acute vasodilator testing is to identify

atients that might respond to oral calcium channel block-rs, the results of vasodilator testing also have prognosticmplications. The issue of whether degree of vasodilatoresponsiveness has prognostic implications in patients whore treated with medical therapies other than calciumhannel blockers is controversial. However, calcium channel
lockers should not be considered as PAH-specific therapy a

f there is not an acute response to a short acting vasodilator.n a large series of patients with IPAH receiving long-termntravenous epoprostenol, the change in PVR acutely withdenosine was predictive of survival by a univariate analysis77).

.6. Echocardiography

hile echocardiography has been a pivotal screening test inAH, studies evaluating the prognostic value of echocar-iographic parameters have been limited to relatively smalleries. RA and RV enlargement, reduced RV function,isplacement of the intraventricular septum, tricuspid re-urgitation (TR), the Tei index, and pericardial effusionave been evaluated. The presence of any degree of pericar-ial effusion has proven a consistent predictor of mortality90). The Doppler echocardiographic index (“Tei index” oryocardial performance index), an index of combined RV

ystolic and diastolic function obtained by dividing the sumf both isovolumetric contraction and relaxation intervals byhe ejection time, appears to be predictive of an adverseutcome on univariate analysis and by multivariate regres-ion analysis (91,92). Clinicians often rely on the subjectiveppearance of the RA and RV to make clinical decisions,ven without formal size measurements.

.7. Magnetic Resonance Imaging

ardiac magnetic resonance (MR) imaging accurately as-esses size and function of the RV with a high degree ofeproducibility. RV function is an important prognositicndicator in PAH and cardiac MR imaging of poor RVunction, including stroke volume less than or equal to 25L/m2, RV end-diastolic volume greater than or equal to

4 mL/m2, and LV end-diastolic volume less than or equalo 40 mL/m2, were found to be independent predictors ofortality and treatment failure in a study of 64 patients

93). Additionally, pulmonary artery stiffness, as measuredy relative cross-sectional area change was predictive ofurvival in a cohort of 86 PAH patients studied with MRmaging (94). Those with a relative cross-sectional area changef less than 16% had a greater mortality than those with valuereater than 16%.

.8. Biomarkers

oth atrial natriuretic peptide and BNP have been shown toorrelate with survival in IPAH and to correlate with otherredictors of survival. BNP and NT-proBNP appear to beetter independent predictors (95,96). Increased uric acidevels, which may reflect impaired oxidative metabolism,ave been shown to be increased with severity of functionallass and hemodynamics in IPAH, and among the nonin-asive tests studied, independently correlated with mortality97). Detectable cardiac troponin T also confers a poorrognosis, potentially due to the effect of RV ischemia (98).f the above biomarkers, proBNP levels are increasingly

eing used and appear to correlate with RV enlargement
nd dysfunction.


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.9. Summary of Recommendations

uccessful prognostication of survival is crucial in planningppropriate therapeutic measures including aggressive med-cal therapy and transplantation, and should encompass

ultiple variables. The most conclusive data are available forPAH, and limited data are available for associated forms ofAH. Important prognostic variables are summarized inable 2 (PAH: Determinants of Prognosis) (99). While this

able is meant to provide guidance, in many instances, theame patient may have a high-risk finding, a low-risknding, and/or a finding between the 2. This scheme allowsor latitude in the composite assessment of an individualatient by the experienced physician.

. Screening and Diagnostic andemodynamic Assessment

.1. Definition of Pulmonary Hypertension

he term PH refers to the presence of abnormally highulmonary vascular pressure. PAH is a category of PHVenice Group 1) (Table 1) (32); the 2 terms are notynonymous. The conventional definition of PAH used inlinical studies includes an mPAP of greater than 25 mm Hgt rest in the setting of a normal pulmonary arterial wedgeressure of 15 mm Hg or less with a PVR greater than 3

ood units. Patients enrolled in the NIH registry ofrimary PH (now IPAH) in the 1980s had the followingemodynamic characteristics: an mPAP of 60 plus or minus8 mm Hg, cardiac index of 2.3 plus or minus 0.9/min/m2, and pulmonary arterial wedge pressure of 8 plusr minus 4 mm Hg (10). This hemodynamic definition hasubsequently been applied in enrollment requirements inirtually every randomized clinical treatment trial along withdditional criteria including functional classification andMW test to ensure that a relatively advanced stage of

able 2. PAH*: Determinants of Prognosis

Determinants of Risk Lower Risk (Good Prognosi

linical evidence of RV failure No

rogression of symptoms Gradual

HO class† II, III

MW distance‡ Longer (greater than 400 m)

PET Peak VO2 greater than 10.4 mL/kg/min

chocardiography Minimal RV dysfunction

emodynamics RAP less than 10 mm Hg, CI greater than

NP§ Minimally elevated

eprinted from McLaughlin and McGoon (99). *Most data available pertains to IPAH. Little data is avas the functional classification for PAH and is a modification of the New York Heart Association functioegarding the influence of BNP on prognosis, and many factors including renal function, weight, age

6MW indicates 6-minute walk; BNP, brain natriuretic peptide. CI, cardiac index; CPET, cardioressure; RV, right ventricle; and WHO, World Health Organization.

isease was studied. lcontent.onlinejaDownloaded from

.2. Diagnostic Strategy

he diagnostic strategy for PH depends on the context inhich it is employed: 1) detection of a substrate in which

he likelihood of a pulmonary vasculopathy may be height-ned; 2) discovery of the presence of PH; 3) classification ofhe type of PH; 4) confirmation of the presence of suspectedH; and 5) determination of an appropriate treatmentategory. The approach to diagnosis has been previouslyutlined (3). The general strategy for assessment is shown inigure 3.

UBSTRATE RECOGNITION

ertain medical conditions and genetic susceptibilities areecognized as predisposing a person to the development ofAH, and were reviewed in Section 4 of this document.isk factors for PAH and consensus screening guidelines

re displayed in Table 3.

ISCOVERY OF PULMONARY HYPERTENSION

discovery strategy is required for patients who are at riskf having PH, including those with genetic substrates, riskactors, or suggestive symptoms or physical examinationndings. The most common presenting symptoms of PH

nclude dyspnea on exertion, fatigue, chest pain, syncope,alpitations, and lower extremity edema. Common physicalxamination findings are displayed in Table 4 (100). TheXR and ECG may display markers suggestive of PH thatear further evaluation (Figure 4).

.3. Echocardiography

f PH is suspected based on the history, risk factor assess-ent, and physical examination, an echocardiogram is the

ext appropriate study. The Doppler echocardiogram canimultaneously provide an estimate of RV systolic pressure,unctional and morphologic cardiac sequelae of PH, anddentification of possible cardiac causes of PH. Commonchocardiographic findings of PAH are featured in Figure 5.n the absence of other potential etiologies of PH, such as

Higher Risk (Poor Prognosis)

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Significantly elevated

or other forms of PAH. One should not rely on any single factor to make risk predictions. †WHO classss. ‡6MW distance is also influenced by age, gender, and height. §As there is currently limited datander may influence BNP, absolute numbers are not given for this variable.ary exercise testing; peak VO2, average peak oxygen uptake during exercise; RAP, right atrial

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ystolic pressure of greater than 40 mm Hg generallyarrants further evaluation in the patient with unexplainedyspnea. Additionally, other echocardiographic findings,

ncluding RA or RV enlargement or intraventricular septalattening, may also trigger further evaluation. Echocardi-graphy can also identify coexistent abnormalities that doot themselves cause PAH but support a specific diagnosisTable 5), although many of these findings lack specificity.

The spectral Doppler profile of TR is too weak ornsufficient to measure the RV to RA pressure gradient inpproximately 10% to 25% of patients with PH referred forvaluation (101,102). When this problem is encountered,he spectral TR signal can be enhanced by intravenous bolusdministration of a small amount of agitated saline contrast,r with commercially available encapsulated microbubbleontrast agents that are indicated for use to enhance the LVndocardial borders. Very small amounts of these agents areequired for Doppler enhancement, and encapsulated agentshould be used with caution in patients with severe pulmo-

Pivotal Tests

Echocardiogram

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igure 3. Diagnostic Approach to PAH

eneral guidelines for the evaluation of pulmonary hypertension. Since the suspicionis of PAH requires that certain data support a specific diagnosis. In addition, the dible possibilities. Pivotal tests are those that are essential to establishing a diagnoxclusion of diagnoses other than IPAH. All pivotal tests are required for a definitivebstructive pulmonary disease on PFTs), does not preclude that another abnormalityr predominant. Contingent tests are recommended to elucidate or confirm results oombination of pivotal and appropriate contingent tests contribute to assessment ofive diagnosis may require additional specific evaluations not necessarily included inNA, antinuclear antibody serology; CHD, congenital heart disease; CPET, cardiopulmXR, chest X-ray; ECG, electrocardiogram; HIV, human immunodeficiency virus scree

unction test; PH, pulmonary hypertension; RA, rheumatoid arthritis; RAE, right atrialVSP, right ventricular systolic pressure; SLE, systemic lupus erythematosus; TEE, terfusion scintigram.

ary vascular disease (102a). In these instances, the presence Ccontent.onlinejaDownloaded from

f right heart chamber enlargement or septal flatteninguggests elevated right heart pressures.

.4. Exercise Echocardiography

hile hemodynamics are most often measured at rest,atients usually experience dyspnea with exercise, leading ton interest in the utility of exercise echocardiography toetect “exercise-induced PH.” Exercise echocardiography ishallenging both to perform and interpret and is generallysed in a research setting. It may not be possible to discern bychocardiography alone to what extent elevated left heart fillingressure might contribute to “exercise-induced PH” in anndividual patient. The consensus is that no treatment deci-ions can be made on the basis of exercise-induced PH alone.

.5. Newer Imaging Techniques in the Diagnosticssessment of Pulmonary Hypertension

here is considerable interest in the utilization of newermaging techniques in the assessment of patients with PH.

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may arise in various ways, the sequence of tests may vary. However, the diagno-is of idiopathic pulmonary arterial hypertension is one of excluding all other reason-any type of PAH either by identification of criteria of associated disease orsis and baseline characterization. An abnormality of one assessment (such asic thromboembolic disease on VQ scan and pulmonary angiogram) is contributingivotal tests, and need only be performed in the appropriate clinical context. The

ifferential diagnoses in the right-hand column. It should be recognized that defini-eneral guideline. 6MWT indicates 6-minute walk test; ABGs, arterial blood gases;exercise test; CT, computerized tomography; CTD, connective tissue disease;tn, hypertension; LFT, liver function test; PE, pulmonary embolism; PFT, pulmonaryement; RH Cath, right heart catheterization; RVE, right ventricular enlargement;ophageal echocardiography; VHD, valvular heart disease; and VQ Scan, ventilation-

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re being explored to assess RV mass, volumes, and func-ion, and in the area of chronic thromboembolic pulmonaryypertension (CTEPH). Promising MR markers ofAH include change in the ratio of septal curvature, RVjection fraction, RV volume, noninvasively measured car-iac index, and delayed hyperenhancement (measured usingadolinium-enhanced MR imaging) (93).

LASSIFICATION

n most cases, PH is discovered during evaluation forymptoms (dyspnea, fatigue, chest pain, syncope, or edema).nce suspected, based on echocardiographic criteria, a

earch for a potential underlying association or cause muste undertaken in order to treat the PH appropriately anddvise regarding prognosis and adjunctive therapy. At theutset, all causes of PAH (Group 1) and non-PAH (Groupsto 5) PH must be considered. The algorithm in Figure 3

eflects the fact that both appropriate assessment for under-ying cause (Table 1) as well as the hemodynamic patternsee the following text) are required.

It is important to exclude other disorders that cause PHuring the diagnostic evaluation, as etiology of PH dictatesreatment. While much of the evaluation is self evident inigure 3, special emphasis on excluding CTEPH is appro-riate. Approximately 3% to 4% of those who experience an

able 3. Approach Following Substrate Recognition

Substrate F

MPR2 mutation Echocardiogram yearlevidence of PAH (hiright heart chambe

st degree relative of patient with BMPR2 mutationor within pedigree of 2 or more patients with adiagnosis of PAH

Genetic counseling angenotyping; proceed

ystemic sclerosis Echocardiogram yearlevidence of PAH (hiright heart chambe

IV infection Echocardiogram if symRHC if echo demonventricular systolicenlargement)

ortal hypertension Echocardiogram if OLdemonstrates evidesystolic pressure or

rior appetite suppressant use (fenfluramine) Echocardiogram only

ongenital heart disease with shunt Echocardiogram and Rrepair of defect if si

ecent acute pulmonary embolism Ventilation-perfusion (if symptomatic; pul

ickle cell disease Echocardiogram yearlevidence of PAH (hiright heart chambe

MPR2 indicates bone morphogenic protein receptor 2; HIV, human immunodeficiency virus; L-R,eart catheterization.

cute pulmonary embolus (PE) do not fully resolve the o


hrombus burden, despite anticoagulation, and go on toevelop CTEPH (103). On the other hand, one half ofhose patients who are ultimately diagnosed with CTEPHo not give a history of an acute PE. CTEPH has recentlyeen reviewed (104). The screening test of choice to excludeTEPH in the patient with otherwise unexplained dyspnea

nd PH is the radionuclide perfusion scan. A normal or veryow probability essentially excludes CTEPH, and a highrobability scan warrants further evaluation with a pulmo-ary angiogram. Clinical judgment is required for thoseith a nondiagnostic scan, and based on the clinical

uspicion and presence of underlying parenchymal lungisease, further evaluation may be warranted. At theurrent time, spiral or PE protocol CT, while excellentor excluding an acute PE in the appropriate clinicaletting, is less sensitive than the perfusion scan to excludeTEPH. It is important to rule out CTEPH even in

hose with an underlying risk factor for PAH, such as thecleroderma spectrum of diseases population, as theherapeutic implications of the diagnosis are substantial.n some patients, such as those with parenchymal lungisease and a low likelihood of CTEPH, the perfusioncan may be difficult to interpret and a PE protocol CTay be useful. CT is also useful to determine the extent

Assessment Rationale

if echocardiogram demonstratesht ventricular systolic pressure orgement)

Early detection of PAH; 20% chance ofdeveloping PAH

mmendation for BMPR2ove if positive

Autosomal dominant transmission


About 8% (by RHC) �27% (byechocardiogram screening)prevalence of PAH in systemicsclerosis (27,78)

s or signs suggestive of PAH;s evidence of PAH (high rightre or right heart chamber

0.5% prevalence of PAH

idered; RHC if echocardiogramf PAH (high right ventricularheart chamber enlargement)

4% prevalence of PAH in candidatesfor OLT; PAH is predictive of poorOLT outcome

ptomatic Incidence of PAH is approximately0.005% if agent used greater than3 months

t time of diagnosis; considernt L-R shunt present

High probability of PAH developing inunrepaired shunt (Eisenmengersyndrome)

cintigraphy 3 months after eventy angiogram if positive

3% risk of chronic thromboembolicPH; negative VQ scan excludeschronic thromboembolism


Increased mortality if PH present,early detection of PH, 30% developPH, about 10% develop PAH

right; OLT, orthotopic liver transplantation; PAH, pulmonary arterial hypertension; and RHC, right

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ONFIRMATION

lthough Doppler echocardiography and associated find-ngs may suggest the presence of PH, RHC (with anccurate assessment of PVR) is required to confirm theiagnosis and to define the hemodynamic profile in greateretail and accuracy.

.6. Invasive Hemodynamic Assessment

areful invasive assessment of pulmonary hemodynamics isivotal in the evaluation of any patient with suspected PAH.he utility of RHC is dependent on the accuracy and

ompleteness of the data obtained. Essential components ofhe RHC are summarized in Table 6.

Many of the causes of elevated PA pressure (PH) are not

able 4. Features of the Physical Examination Pertinent to the

Sign

Physical Signs Tha

ccentuated pulmonary component of S2 (audible at apex in over 90%)

arly systolic click

idsystolic ejection murmur

eft parasternal lift

ight ventricular S4 (in 38%)

ncreased jugular “a” wave

Physical Signs That Sug

oderate to severe PH

Holosystolic murmur that increases with inspiration

Increased jugular v waves

Pulsatile liver

Diastolic murmur

Hepatojugular reflux

dvanced PH with right ventricular failure

Right ventricular S3 (in 23%)

Distention of jugular veins

Hepatomegaly

Peripheral edema (in 32%)

Ascites

Low blood pressure, diminished pulse pressure, cool extremities

Physical Signs That Suggest Possibl

entral cyanosis

lubbing

ardiac auscultatory findings, including systolic murmurs, diastolic murmurs,opening snap, and gallop

ales, dullness, or decreased breath sounds

ine rales, accessory muscle use, wheezing, protracted expiration, productive co

besity, kyphoscoliosis, enlarged tonsils

clerodactyly, arthritis, telangiectasia, Raynaud phenomenon, rash

eripheral venous insufficiency or obstruction

enous stasis ulcers

ulmonary vascular bruits

plenomegaly, spider angiomata, palmary erythema, icterus, caput medusa,ascites

H indicates pulmonary hypertension.

aused by pulmonary vascular pathology. For example, PH ccontent.onlinejaDownloaded from

ommonly occurs with high transpulmonary flow in theetting of exercise, anemia, pregnancy, sepsis, portopulmo-ary syndrome, or thyrotoxicosis. In these conditions, theulmonary vascular bed is anatomically normal and the PHesolves when the cardiac output returns to normal levels.he transpulmonary gradient (PAP mean-wedge) is signif-

cantly elevated in PAH patients, but not in patients whoseH is due to increased cardiac output, left heart myocardial,r valvular disease. There is a small subset of the patientsith diseases causing passive PH who have a disproportion-

te elevation of PVR (identified somewhat arbitrarily byVR greater than 3 Wood units and a transpulmonaryradient greater than 20 mm Hg) (see Section 9, Non-ulmonary Arterial Hypertension Pulmonary Hypertensionopulations).It was the committee’s majority opinion that diagnostic

luation of PH

Implication

ect Severity of PH

High pulmonary pressure increases force of pulmonic valve closure

Sudden interruption of opening of pulmonary valve into high-pressure artery

Turbulent transvalvular pulmonary outflow

High right ventricular pressure and hypertrophy present

High right ventricular pressure and hypertrophy present

Poor right ventricular compliance

Moderate to Severe PH

Tricuspid regurgitation

Pulmonary regurgitation

High central venous pressure

Right ventricular dysfunction

Right ventricular dysfunction or tricuspid regurgitation or both

Right ventricular dysfunction or tricuspid regurgitation or both

Reduced cardiac output, peripheral vasoconstriction

erlying Cause or Associations of PH

Abnormal V/Q, intra-pulmonary shunt, hypoxemia, pulmonary-to-systemicshunt

Congenital heart disease, pulmonary venopathy

Congenital or acquired heart or valvular disease

Pulmonary congestion or effusion or both

Pulmonary parenchymal disease

Possible substrate for disordered ventilation

Connective tissue disorder

Possible venous thrombosis

Possible sickle cell disease

Chronic thromboembolic PH

Portal hypertension

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e clarified as requiring elevated PVR as opposed to simplyn elevated mPAP in the setting of a normal left heart fillingressure (105,106). PVR is a more robust diagnostic crite-ion for PAH because it reflects the influence of transpul-onary gradient and cardiac output and is only elevated if

he vascular obstruction occurs within the precapillary pul-onary circulation. PVR is a useful measure to apply to

atients with increased mPAP. PVR distinguishes passiveH (elevated mPAP, normal PVR) from PH caused byulmonary vascular disease (elevated mPAP, elevated PVR).y definition, PVR and mPAP are both elevated in PAH.owever, PVR can also be elevated in patients with valve

isease or LV disease (some of whom have an element ofulmonary artery disease, in addition to passive PH). PAHemains a diagnosis of exclusion. After excluding lungisease, thromboembolic disease, LV disease, or valve dis-ase, the diagnostic criteria for PAH requires both a mPAPreater than 25 mm Hg and a PVR greater than 3 Woodnits. In such a setting, PAH is the most likely cause of theH. Invasive hemodynamic studies are essential to establishcorrect diagnosis: therefore, the committee cautions

gainst over-reliance on noninvasive, echocardiographicallyerived estimates of PAP. If one considers a generalardiology population, PAP will be elevated much moreften due to left heart diseases (systolic or diastolic dysfunc-ion) or valvular disease than by true pulmonary vascular

Prominent CentralPulmonary Artery

PeripheralHypovascularity

Right Descending Pulmonary Artery

A

B

igure 4. Chest X-Ray and ECG in PAH

ostero-anterior and lateral chest X-ray (top) shows decreased peripheral lung vascuatient with idiopathic PAH. ECG (bottom) of the same patient reveals right atrial enomplex. ECG indicates electrocardiogram; and PAH, pulmonary arterial hypertension

isease. It was the minority opinion that the requirement for wcontent.onlinejaDownloaded from

n elevation in PVR greater than 3 Wood units not bencluded as a component of the hemodynamic definition ofAH. These committee members cited primarily high flowonditions as potential exceptions to this definition, includ-ng uncorrected CHD, sickle cell disease, and portopulmo-ary hypertension. At certain stages of these disorders, someatients might have elevated mPAP, but a normal PVR dueo a high cardiac output, yet have pulmonary vascularisease histologically. Ultimately, it may be proposed thatlevated PAP alone is sufficient to diagnosis PH, whereasVR must be included to diagnose PAH.

.7. Right Heart Catheterization

ome patients initially suspected of having PAH will notequire catheterization, having had an alternative diagnosisstablished by noninvasive testing. However, all patientshat are still suspected of having PAH after noninvasivevaluation should undergo RHC prior to initiation ofherapy. The utility of RHC is dependent on the accuracynd completeness of the data obtained. The sequence in thisiagnostic algorithm, with the RHC reserved for those whofter noninvasive screening are considered “probable PAHatients,” allows the procedure to be focused on measuringAP, calculating PVR, and performing vasodilator testing.hile RHC remains the gold standard assessment of

emodynamics in PH, most often, measurements are made

RV Enlargement

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f hemodynamic compromise. Exercise RHC is technicallyifficult, both to perform and interpret, and while not usedoutinely in most clinical settings, is an area of activenvestigation.

.8. Components of an Optimal Invasive Evaluation

he rigorous diagnosis of PAH in the catheterizationaboratory should include wedging a balloon flotation cath-ter in several segments of the pulmonary vasculature.

easurement of the wedge pressure, a surrogate for lefttrial pressure in the absence of pulmonary vein obstruction,s useful to exclude PH due to left heart diseases; the wedgeressure may be normal in some segments in pulmonaryeno-oclusive disease. The wedge pressure should be mea-ured at end-expiration of a spontaneous respiratory cycle. Ifn optimal wedge pressure tracing cannot be obtained, or ifhere is any question about the accuracy of the wedgeressure tracing, a measurement of LV end-diastolic pres-

igure 5. Echocardiographic Features of PAH

A) Parasternal short axis view. (B) Apical 4 chamber view. Common echocardio-raphic findings in PAH include: right atrial enlargement; right ventricular enlarge-ent; abnormal contour, flattening, or reverse curvature of the interventricular

eptum; and underfilled left heart chambers. LA indicates left atrial; LV, left ventric-lar; RA, right atrial; and RV, right ventricular. Reprinted with permission from theniversity of Michigan.

ure should be obtained. As PCWP measurements areIs


ometimes inaccurate, a direct measurement of LVEDP isecommended in patients in whom left heart disease is theikely etiology, such as those with symptoms of orthopnea orssociated risk factors. Thermodilution cardiac output, ifesults are consistent when measured in triplicate, can bedequate in PAH patients, provided there is not severericuspid regurgitation or an intracardiac shunt. Indeed,here are data suggesting that even in the presence of lowardiac output and significant tricuspid regurgitation thehermodilution technique correlates well with the Fickechnique in patients with PH (107). However, becauseevere tricuspid regurgitation is not uncommon in PAH, aick determination of cardiac output may be required.otential errors related to the Fick measurement includessumptions and inaccurate measurements of oxygen con-umption. Without a reliable measure of cardiac output, thebility to calculate PVR and to interpret acute vasodilatoresting is compromised.

able 5. Causes for PH Identified by Echocardiography

onditions That Predispose to Pulmonary Hypertension

Congenital or acquired valvular disease (MR, MS, AS, prosthetic valvedysfunction)Left ventricular systolic dysfunctionImpaired left ventricular diastolic function (hypertensive heart disease, HCM,Fabry’s disease, infiltrative cardiomyopathies)Other obstructive lesions (coarctation, supravalvular AS, subaortic membrane,cor triatriatum)Congenital disease with shunt (ASD, VSD, coronary fistula, patent ductusarteriosus, anomalous pulmonary venous return)Pulmonary embolus (thrombus in IVC, right-sided cardiac chamber, or PA;tricuspid or pulmonic valve vegetation)Pulmonary vein thrombosis/stenosis

indings That Suggest Specific Disease Entity

Left-sided valve changes (SLE, anorexigen use)Intra-pulmonary shunts (hereditary hemorrhagic telangiectasia)Pericardial effusion (IPAH, SLE, systemic sclerosis)

S indicates aortic stenosis; ASD, atrial septal defect; HCM, hypertrophic cardiomyopathy; IPAH,diopathic pulmonary arterial hypertension; IVC, inferior vena cava; MR, mitral regurgitation; MS,itral stenosis; PA, pulmonary artery; SLE, systemic lupus erythematosus; and VSD, ventricular

eptal defect.

able 6. Essential Components of Invasive Hemodynamicssessment

xygen saturations (SVC, IVC, RV, PA, SA)

ight atrial pressure

ight ventricular pressure

ulmonary artery pressure, systolic, diastolic, mean

ulmonary arterial wedge pressure, left atrial pressure, or left ventricularend-diastolic pressure

ardiac output/index

ulmonary vascular resistance

ystemic blood pressure

eart rate

esponse to acute vasodilator

VC indicates inferior vena cava; PA, pulmonary artery; RA, right atrium; RV, right ventricle; SA,ystemic artery; and SVC, superior vena cava.



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.9. Safety of Heart Catheterization

lthough RHC and pulmonary angiography are invasive,hey can be performed safely by experienced operators evenn patients with severe PH and right heart failure. A recenttudy retrospectively reviewed over 5,000 RHC proceduresnd prospectively collected an additional 1,500 procedures,or a total of 7,218 RHC procedures performed at 20 majorulmonary vascular centers over a 5-year period (108). Theesults from the retrospective and the prospective analysesere almost identical. Overall, 76 (1.1%) serious events were

eported. The most frequent complications were related toenous access (e.g., hematoma, pneumothorax), followed byrrhythmias and hypotensive episodes related to vagal reac-ions or pulmonary vasoreactivity testing. The vast majorityf these complications were mild to moderate in intensitynd resolved either spontaneously or after appropriate in-ervention. Four fatal events were recorded in associationith any of the catheter procedures, only 1 of which wasirectly related to the performance of the procedure, result-

ng in an overall procedure-related mortality of 0.05%.

.10. Spontaneous Variability inulmonary Artery Pressure

ascular pressure measurements obtained during RHC maye influenced by ventilation in 2 ways that must be consid-red in the interpretation of hemodynamic variables: 1)ormal fluctuations in PAP and flow that occur as aunction of phasic, dynamic changes during breathing; and) larger, partly artifactual swings in pressure that may occururing exercise, hyperventilation, valsalva, or in the settingf chronic lung disease. The normal decrease in intratho-acic pressure that is caused by inspiration slightly reducesAP relative to atmospheric pressure and increases venous

eturn to the right heart, resulting in an increase in pulmo-ary blood flow. With passive exhalation, intrathoracicressure approaches atmospheric pressure. These effects inormal individuals are small, but become accentuated dur-

ng assisted ventilation or in patients with lung disease. Ouronsensus was that physicians can reduce variability byonsistently measuring pressures over 2 to 3 respiratoryycles at end-exhalation when intrathoracic pressure islosest to atmospheric.

.11. Ambulatory Measurement ofulmonary Hemodynamics

espite the “definitive” role of RHC, the procedure is

able 7. Agents for Acute Vasodilator Testing

Epoprostenol

oute of Administration Intravenous infusion Intraveno

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ulmonary hemodynamic conditions during the patients’aily lives. Thus, using a single value for a hemodynamicarameter as a baseline assessment of disease that is knowno progress or against which to judge the effects of therapyisks mistaking spontaneous variability for a meaningfulifference (or lack of difference). Ongoing investigation ofn implantable monitor that provides continuous RV andA hemodynamics (109,110) may provide a more reliableeans of assessing the course of selected patients (111).

.12. Acute Vasodilator Testing

he rationale for vasodilator testing in the diagnosticvaluation of PAH patients is based on 2 factors: 1) acuteasodilator responsiveness identifies patients with a betterrognosis; and 2) responders are more likely to have austained beneficial response to oral calcium channel block-rs than nonresponders and could be treated with these lessxpensive drugs (84,112).

.13. Agents for Acute Vasodilator Testing

cute vasodilator testing is usually performed during theame procedure as the diagnostic catheterization. Thedeal vasodilator agent for PAH is selective for theulmonary circulation and has rapid onset and offset offfect. Acute vasodilator testing is most commonly per-ormed using iNO (113), intravenous epoprostenol (114),r intravenous adenosine (115) (Table 7). Although theres no evidence-based guideline for selection of vasodila-ors, it is our consensus that iNO is the preferredasodilator, while intravenous epoprostenol and intrave-ous adenosine are acceptable alternatives. The optimalose of iNO has not been established by a clinical trial.owever, in clinical practice, it is common to use doses

f 20 to 40 ppm for 5 minutes. Repeat hemodynamicshould be obtained while on iNO and it may then beiscontinued, without weaning, after the hemodynamicata are obtained. The choice of vasodilator remains onef operator preference; however, one should not usealcium channel blockers, sodium nitroprusside, or ni-rates for acute vasodilator testing as the safety andfficacy of these agents for acute vasodilator testing hasot been established in PAH patients.

.14. Definition of Responders to Acute Vasodilatoresting in Pulmonary Arterial Hypertension

he definition of a “positive” response is controversial.sing the definition of a positive response as a 20% fall in

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NO, Sitbon et al. (84) found only 70 responders out of 557atients with IPAH (12.6%), a rate lower than that reportedy Rich et al. (83) in 64 IPAH patients (26.6%) or by Weirt al. (116) in the NIH registry (55%) (83,84,116). Moremportantly, Sitbon et al. (81) observed that only 38 of the0 acute responders (6.8% of the total IPAH study popu-ation) displayed long-term improvement with calciumhannel blocker therapy. Logistic regression analysis iden-ified the following variables achieved during acute vasodi-ator administration that were associated with long-termalcium channel blocker therapy success: a reduction inPAP to less than 37 mm Hg, a fall in mPAP greater than

1%, a reduction in PVR to less than 6.7 Wood units, andfall in PVR greater than 45%. These authors noted,

owever, that 6 long-term responders to calcium channellockers failed to meet these a posteriori criteria of acuteesponse.

Based largely on the data from the Sitbon series, theuropean Society of Cardiology and the ACCP guidelinesroposed that an acute response to acute vasodilator testinge defined as a decrease in mPAP by at least 10 mm Hg ton absolute level of less than 40 mm Hg without a decreasen cardiac output (105,117). While the sensitivity of theseriteria are insufficient to capture all patients who may beesponsive to long-term calcium channel blocker therapy,hey are sufficiently specific to identify patients who arenlikely to benefit from this form of therapy and for whomther treatments are appropriate. There are little data onhich to make recommendations in the patient with anPAP less than 40 mm Hg at baseline. In the event that

uch a patient had a substantial (less than 20%) reduction inPAP in the setting of a normal cardiac output, it would be

easonable to administer a trial of calcium channel blockersnd assess the clinical response.

.15. Vasodilator Testing in Pulmonary Arterialypertension Subsets

he best data supporting the use of acute vasodilator testingo determine prognosis comes from IPAH patients. Limitedata exist, but suggest that responders to vasodilators areare among other groups, including those with the BMPR2enotype (118) anorexigen induced PAH (119), and thoseith scleroderma spectrum of diseases (120). Caution is

equired in testing patients with concomitant LV disease, asulmonary edema in response to iNO or epoprostenol haseen reported in patients with stable heart failure due to lefteart disease (121) or with pulmonary venoocclusive disease,ossibly relating to vasodilatation and flooding of theapillary bed in response to a highly selective arterialasodilator.

ETERMINING TREATMENT

n general, distinguishing optimal treatment strategiesroadly depends on the diagnostic categories, hemodynam-cs, severity of the disease, and associated findings. (See
ection 6.15.) t

.16. Summary

e recommend the following, with respect to diagnosticssessment for PH:

1. Certain individuals with predisposing risk factors war-rant periodic screening for PAH (Table 3).

2. Patients in whom there is an index of suspicion of PHbased on history, risk factor assessment, physical exam-ination, CXR, and ECG warrant further evaluation.

3. The most appropriate initial study to evaluate patientsin whom PH is suspected is a Doppler echocardiogram.

4. Evaluation for other etiologies of PH, for example,CTEPH, is appropriate in all instances (Figure 3).

5. The diagnosis of PAH requires confirmation by acomplete RHC. The hemodynamic definition of PAHis an mPAP greater than 25 mm Hg, a PCWP/LAP/LVEDP less than or equal to 15 mm Hg, and a PVRgreater than 3 Wood units.

6. Acute vasodilator testing should be performed in allIPAH patients who might be considered potentialcandidates for long-term therapy with oral calciumchannel blockers. IPAH patients in whom chroniccalcium channel blocker therapy would not be consid-ered, such as those with overt right heart failure orhemodynamic instability, need not undergo acute vaso-dilator testing.

7. Acute vasodilator testing should be performed at cen-ters experienced in the administration of these agentsand in the interpretation of the results.

8. The definition of an acute response that may warrantinitiation of long-term therapy with oral calcium chan-nel blockers is a decrease in mPAP of at least 10 mmHg to an absolute mPAP of less than 40 mm Hgwithout a decrease in cardiac output. Although thisstringent definition may misclassify a few patients whocould be treated effectively with long-term oral calciumchannel blockers, it will reliably identify those who areleast likely to benefit from oral calcium channel blockertherapy and, therefore, provides the greatest degree ofsafety.

9. Patients with PAH due to conditions other than IPAHhave a very low rate of long-term responsiveness to oralcalcium channel blocker therapy. Accordingly, the de-cision to proceed with acute testing in such patientsshould be individualized.

0. Acute vasodilator testing is not indicated, and may beharmful, in patients with significantly elevated left heartfilling pressures.

. Evidence-Based Treatment Algorithm

reatment of PAH has evolved considerably over the pastecade due in part to advances in knowledge of the basicathobiology of the disease and the availability of agents
hat target known derangements in the pathobiologic pro-


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ess. Treatment algorithms have been formulated by theCCP, the European Society of Cardiology, and a panel of

xperts who convened at the Third World Symposium onulmonary Hypertension held in Venice, Italy, in 2003

105,117,122). Notably, the clinical data on which theselgorithms are based were conducted primarily in patientsith IPAH and PAH related to connective tissue disease

nd anorexigens. A smaller number of trials have alsoncluded PAH related to CHD and HIV. These clinicalrial data cannot necessarily be extrapolated to those withther types of PH, including those related to left heartisease and hypoxemic lung disease, or other types of WHOroup I PAH.Treatment goals in PAH patients are numerous. Improv-

ng the patients symptoms, which commonly include dys-nea, is paramount. Enhancing functional capacity, mea-ured objectively by an assessment of exercise enduranceuch as the 6MW or a cardiopulmonary exercise test, is alsotreatment objective. Given the severe hemodynamic de-

angements in PAH, lowering PAP and normalizing car-iac output are important treatment goals. Another impor-ant goal is to reverse or at least prevent progression of theisease, that is, prevent the need for more therapies,ospitalization, and lung transplantation. Last, we strive to

mprove survival, which, while important, is rarely an endoint in clinical trials of PAH treatment due to the smallumber of patients and limited duration of the trials.

.1. General Measures

hile limited data exist on which to base recommendationsegarding exercise, we encourage low level graded aerobicxercise, such as walking, as tolerated. Intensive exerciseraining was studied in a randomized fashion in 30 patientsho were stable on disease-targeted medical therapy. After5 weeks, those who received exercise training demon-trated improvements in 6MW test, quality of life, func-ional class, and peak oxygen consumption (123). Patientsre advised to avoid heavy physical exertion or isometricxercise (straining against a fixed resistance) as this mayvoke exertional syncope. Exposure to high altitudes mayontribute to hypoxic pulmonary vasoconstriction and mayot be well tolerated. Similarly, some patients may requirexygen on commercial aircraft. While there are no datarom controlled trials, we recommend that patients with areflight pulse oximetry saturation of less than 92% shouldeceive supplemental oxygen (124). A sodium restricted dietless than 2,400 mg per day) is advised and is particularlymportant to manage volume status in patients with RVailure. Routine immunizations, such as those against influ-nza and pneumococcal pneumonia, are advised.

The hemodynamic fluctuations of pregnancy, labor, de-ivery, and the postpartum period are potentially devastatingn PAH patients. Some series have demonstrated a 30% to0% maternal mortality rate (125). Current guidelinesecommend that pregnancy be avoided or terminated early
n women with PAH (117). It is important to discuss d

ffective methods of birth control with women with PAH ofhild-bearing potential, although the preferred method isot clear. While estrogen-containing contraceptives may

ncrease risk of venous thromboembolism, currently avail-ble lower-dose preparations with concurrent warfarin an-icoagulation are a reasonable option. Surgical sterilizationnd barrier methods are also alternatives.

.2. Background Therapy

everal agents are commonly used in the treatment of PAHespite relatively little controlled trial data. Anticoagulantsave been studied in 3 noncontrolled observational series inatients with primarily IPAH, 1 prospective and 2 retro-pective (83,85,126). An improvement in survival witharfarin anticoagulation has been observed. Per our com-ittee’s consensus, we recommend warfarin anticoagulation

n IPAH patients titrated to an international normalizedatio of 1.5 to 2.5. Few data exist to guide recommendationsor patients with associated forms of PAH. We recommendnticoagulation in such patients with more advanced dis-ase, such as those on continuous intravenous therapy, inhe absence of contraindications. Diuretics are indicated toanage RV volume overload, which is commonly manifest

s elevated jugular venous pressure, lower extremity edema,nd abdominal distention. In some cases, intravenous di-retics are required. Serum electrolytes and renal functionhould be closely monitored. As hypoxemia is a potentulmonary vasoconstrictor, most experts recommend oxy-en supplementation to maintain oxygen saturation above0%. There are few data pertaining to the use of digoxin inAH. One acute study demonstrated that the administra-

ion of intravenous digoxin in IPAH patients produced aodest increase in cardiac output and a reduction in

irculating norepinephrine levels, although longer-term datare not available (127). Digoxin is sometimes used in thoseatients with right heart failure and a low cardiac output andn patients with atrial arrhythmias.

.3. Calcium Channel Blockers

he enthusiasm for the use of calcium channel blockers inPAH dates back to 1992 with the publication of a studyhat demonstrated 95% 5-year survival in a very select groupf patients with IPAH who exhibited an acute vasodilatoresponse to calcium channel blockers (83). More recent dataegarding vasodilator testing were discussed previously (Sec-ion 6). The current consensus definition of a response isow defined as a fall in mPAP of greater than or equal to 10m Hg, to an mPAP less than or equal to 40 mm Hg, with

n unchanged or increased cardiac output. While manyxperts also perform vasodilator testing on patients withssociated forms of PAH, true responders are very uncom-on. Patients who meet these criteria may be treated with

alcium channel blockers and should be followed closely foroth safety and efficacy of calcium channel blocker therapy.f a patient who meets the definition of an acute response
oes not improve to functional class I or II on calcium


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hannel blocker therapy, the patient should not be consid-red a chronic responder, and alternative or additional PAHherapy should be instituted. Long acting nifedipine, dilti-zem, or amlodipine are the most commonly used calciumhannel blockers. Due to its potential negative inotropicffects, verapamil should be avoided.

.4. Prostanoids

s previously discussed, prostacyclin synthase is reduced inAH patients, resulting in inadequate production of pros-

acyclin I2, a vasodilator with antiproliferative effects. Ad-inistering prostanoids has been a mainstay of PAH

herapy for more than a decade. There are currently 3ommercially available prostanoids: epoprostenol, treprosti-il, and iloprost.

.5. Epoprostenol

ntravenous epoprostenol improves functional class, exerciseolerance, hemodynamics, and survival in IPAH. An openabel, randomized trial of 81 functional class III and IVPAH patients demonstrated significant improvements inhe primary end point of 6MW test (32 m increase withpoprostenol versus 15 m decrease with conventional ther-py alone, placebo-corrected change of 47 m) and inecondary end points including hemodynamics and qualityf life (76). Eight patients, all of whom were randomized toonventional therapy alone, died over the course of the2-week trial, suggesting a survival benefit of the drug (p�.003). Longer-term observational studies have confirmedhe chronic benefits of intravenous epoprostenol in IPAHatients. In a series of 178 functional class III and IV IPAHatients, Sitbon et al. (78) reported improved survival withntravenous epoprostenol compared to historical controlsith 1-, 2-, 3-, and 5-year survival rates of 85%, 70%, 63%,

nd 55%, respectively. Similarly, in a series of 162 functionallass III and IV patients, intravenous epoprostenol resultedn improved survival as compared with the predicted survivalased on the NIH equation with 1-, 2-, 3-, and 5-yearurvival rates of 88%, 76%, 63%, and 56%, respectively (77).mprovements in functional class, exercise endurance, andemodynamics were noted in both of these observationaltudies.

Intravenous epoprostenol has also been evaluated in PAHssociated with the scleroderma spectrum of diseases. Aulticenter, open label, randomized trial demonstratedarked improvements in exercise endurance (median

hange �46 m with epoprostenol, �48 m with conven-ional therapy alone) and hemodynamics, but no effect onortality after 12 weeks of therapy (80). Observational

eries have also reported favorable effects of intravenouspoprostenol in patients with numerous forms of associatedAH (72,79,128–131).Epoprostenol must be delivered by continuous intrave-

ous infusion. Each patient must learn the techniques ofterile preparation of the medication, operation of the
mbulatory infusion pump, and care of the central venous s

atheter. Intravenous epoprostenol is commonly started inhe hospital at a dose of 2 ng/kg/min and the dose is furtherdjusted up based on symptoms of PAH and side effects ofhe drug. While the dosing must be highly individualized,ost experts believe that the optimal dose range for chronic

herapy is between 25 and 40 ng/kg/min for most adultatients, when used as monotherapy. Chronic overdoseometimes results in high cardiac output failure, and theong-term consequences of this are unknown and may beetrimental (132). Common side effects include headache,

aw pain, flushing, nausea, diarrhea, skin rash, and muscu-oskeletal pain. Infections and infusion interruptions can beife-threatening. Given its considerable complexity, epopro-tenol use should be limited to centers experienced with itsdministration and with systematic follow-up of patients.

.6. Treprostinil

reprostinil is a stable prostanoid with an elimination halfife of about 4.5 hours that was first studied using subcuta-eous administration during a 12-week, placebo controlled,ulticenter, randomized trial of 470 patients with func-

ional class II, III, or IV PAH (IPAH, connective tissueisease of CHD related) (133,134). Subcutaneous trepros-inil resulted in a modest but statistically significant betweenreatment group median increase of 16 m of the 6MW test,hich was dose related. The change in 6MW test was a

esult of improvement in the group receiving treprostinil,nd there was no change in 6MW test in the placebo group.dverse effects included pain or erythema at the site of the

ubcutaneous infusion in 85% of patients. Other commonide effects include headache, diarrhea, rash, and nausea.he Food and Drug Administration (FDA) approved

ubcutaneous treprostinil in 2002 for use in functional classI, III, and IV PAH.

More recently, intravenous treprostinil has been studiedn an open label, uncontrolled fashion. Tapson et al. (135)eported an 82 m improvement (from 319 plus or minus2 m to 400 plus or minus 26 m, p�0.001) of 6MW test in6 functional class III or IV PAH patients treated withntravenous treprostinil as monotherapy. In a similar openabel trial, Gomberg-Maitland et al. (136) transitioned 31unctional class II and III PAH patients from intravenouspoprostenol to intravenous treprostinil. Twenty-seven pa-ients completed the transition, and 4 were transitionedack to epoprostenol. Exercise endurance as measured byhe 6MW test was maintained among the patients complet-ng the transition (438 plus or minus 16 m at baseline, 439lus or minus 16 m at week 12), although there was aodest increase in PAP and decrease in CI. Notably, the

ose of intravenous treprostinil at the end of 12 weeks wasore than twice the dose of intravenous epoprostenol at the

tart of the study (83 ng/kg/min versus 40 ng/kg/min). In004, the FDA approved the use of intravenous treprostiniln functional class II, III, and IV PAH patients in whomubcutaneous infusion is not tolerated. Intravenous trepro-
tinil has a side effect profile similar to intravenous epopro-


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tenol. A Centers for Disease Control and Prevention reportecently raised the concern for an increased risk of blood-tream infections, particularly with gram-negative organ-sms, in patients receiving intravenous treprostinil (137).atheter infections can be life threatening. The overall

nfection rate with treprostinil was significantly greater thanhat of epoprostenol (incidence ratio 2.57, 95% confidencenterval: 1.81 to 3.64), with a higher rate of gram-negativeacteremia. There was considerable variability from one siteo another. Inclusion of the index site that made the initialbservation, the retrospective nature of the study, and site toite variation, with some just including treprostinil patientss opposed to both epoprostenol and treprostinil, are amonghe limitations of this observation. This finding has led toevised recommendations regarding catheter care (138).linically, it also highlights the importance in the choice of

mpiric antibiotics in those suspected of having a blood-tream infection. Investigational trials with both inhalednd oral formulations of treprostinil are ongoing. Given theomplexity of administration of both intravenous and sub-utaneous treprostinil, administration should be limited toenters with experience with this agent.

.7. Iloprost

loprost is a prostanoid that can be delivered by an adaptiveerosol device that has been studied in a 12-week, multi-enter, placebo-controlled, randomized trial of 207 func-ional class III and IV patients with either IPAH, PAHssociated with scleroderma spectrum of diseases or appetiteuppressants, or PH related to inoperable chronic throm-oembolic disease (139). This study utilized a novel com-osite end point of improvement in functional class by at

east 1 level and improvement in 6MW test by at least 10%n the absence of clinical deterioration. The combinedlinical end point was met by 16.8% of those receivingnhaled iloprost compared to 4.9% of those receiving pla-ebo (p�0.007). The treatment effect on the 6MW test wasmean increase of 36 m in favor of iloprost (p�0.004). Thisas attributable to both an improvement in the iloprostroup and a deterioration in the placebo group. Longer-erm outcomes with iloprost monotherapy are conflicting.n a study of 24 iloprost-treated IPAH patients, Hoeper etl. (140) reported sustained benefits in exercise capacity andemodynamics at 1 year. More recently, Opitz et al. (141)eported event-free survival rates of 53%, 29%, and 20% at, 2, and 3 years, respectively, in IPAH patients treated withloprost monotherapy. Common side effects of inhaledloprost include cough, headache, flushing, and jaw pain.loprost was approved by the FDA in 2004 for functionallass III and IV PAH.

.8. Endothelin Receptor Antagonists

ndothelin-1 is a vasoconstrictor and a smooth muscleitogen that may contribute to the development of PAH.ttempting to treat PAH by endothelin receptor blockade

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athogenic role of endothelin-1 in PAH, as discussed inection 3.

.9. Bosentan

n an initial effort to evaluate bosentan in PAH, a relativelymall, randomized, double-blind, placebo-controlled, mul-icenter study of 32 functional classes III or IV IPAH orcleroderma spectrum of diseases associated patients PAHere randomized to receive bosentan versus placebo (2:1

atio) (142). After 12 weeks, the 6MW test improved by0 m (from 360 plus or minus 19 m at baseline to 430 plusr minus 14 m at week 12; p�0.05) in the bosentan arm,hereas no improvement was seen with placebo (355 plus orinus 25 m at baseline and 349 plus or minus 44 m at week

2). The median change from baseline was 51 m withosentan versus �6 m with placebo. The mean differenceetween treatment arms in the 6MW test was 76 plus orinus 31 m (mean plus or minus SEM) in favor of bosentan

95% confidence interval: 12 to 139; p�0.021). Bosentanmproved cardiac index and reduced mPAP and PVR.unctional class improved in patients treated with bosentan.A second double-blind, placebo-controlled study evalu-

ted bosentan in 213 patients with WHO functional classesII to IV PAH (either idiopathic or associated with con-ective tissue disease) who were randomized to placebo orosentan 125 or 250 mg twice daily for a minimum of 16eeks (62.5 mg twice daily for 4 weeks, then target dose)

143). The primary end point was change in exerciseapacity (assessed by 6MW test), and secondary end pointsncluded changes in Borg dyspnea index, WHO functionallass, and time from randomization to clinical worsening.fter 16 weeks, bosentan improved the 6MW test by 36 m,hereas deterioration (�8 m) was seen with placebo, and

he difference between treatment groups in the mean changen 6MW test was 44 m in favor of bosentan (95% confi-ence interval: 21 to 67 m, p�0.0002). No dose responseor efficacy could be ascertained, although the placebo-orrected improvement in 6MW test for the currentlyDA-approved dose of 125 mg twice daily was 35 m. Thistudy was the first to assess time to clinical worsening, aomposite morbidity and mortality end point. Time tolinical worsening was defined in this study as time to death,ung transplantation, hospitalization for PH, lack of clinicalmprovement or worsening leading to discontinuation, needor epoprostenol therapy, or atrial septostomy. The risk oflinical worsening was reduced by bosentan compared withlacebo (p�0.0015). Abnormal hepatic function (as indi-ated by elevated levels of alanine aminotransferase and/orspartate aminotransferase), syncope, and flushing occurredore frequently in the bosentan group. Abnormal hepatic

unction was dose-dependent, being more frequently re-orted as an adverse event in the high dosage bosentanroup (250 mg twice daily) than in the low dosage group125 mg twice daily) (14% versus 5%, respectively).

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ore recently published. McLaughlin et al. (82) reported


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hat open label, first-line therapy with bosentan, with theddition or transition to other therapy as needed, resulted inaplan-Meier survival estimates of 96% at 12 months and9% at 24 months. At the end of 12 and 24 months, 85%nd 70% of patients, respectively, remained alive and onosentan monotherapy. Similar survival rates of 90% and7% at 1 and 2 years were reported in a single centeretrospective analysis (144). However, based on predefinedlinical criteria, 44% of patients required prostanoid therapyuring follow up. Sitbon et al. (145) compared open labelurvival in functional class III IPAH treated with bosentanith historical data from similar patients treated with

poprostenol. Baseline characteristics for the 139 patientsreated with bosentan and the 346 patients treated withpoprostenol suggested that the epoprostenol cohort hadore severe disease. Kaplan-Meier survival estimates after 1

nd 2 years were 97% and 91%, respectively, in theosentan-treated cohort and 91% and 84% in the epopro-tenol cohort.

Bosentan therapy has also been evaluated by Galie et al.146) in a multicenter, double-blind, randomized, andlacebo-controlled study in patients with functional class IIIisenmenger syndrome (the BREATHE-5 [Tracleer

Bosentan) in Patients With Pulmonary Arterial Hyperten-ion Related to Eisenmenger Physiology] study). Fifty-fouratients were randomized 2:1 to bosentan versus placebo for6 weeks. Bosentan did not worsen oxygen saturation, andompared with placebo, bosentan reduced pulmonary vas-ular resistance index, decreased mPAP, and increasedxercise capacity. Four patients discontinued due to adversevents, 2 (5%) in the bosentan arm and 2 (12%) in thelacebo arm. Open label data with bosentan suggest clinicalmprovements in HIV patients with PAH, while prelimi-ary data suggest benefits in those with inoperable CTEPHnd early stage disease (147,148). Bosentan has also recentlyeen evaluated in a mildly symptomatic or functional class IIopulation (149). In this study, 168 PAH patients (IPAH,PAH, PAH associated with connective tissue disease,norexigen use, HIV, CHD) with a mean baseline 6MWest of 435 m were randomized to receive bosentan orlacebo for 26 weeks. There was a significant improvementn one coprimary end point, change in PVR, but not thether, change in 6MW test. There was an improvement inhe secondary end point of time to clinical worsening. Thedverse event profile with bosentan was similar to previoustudies.

Bosentan is currently widely used in patients with PAH.lose follow-up over time, of both efficacy and safety, is

ncouraged. The FDA requires that liver function tests behecked monthly, and that the hematocrit should behecked every 3 months. In addition to potential hepato-oxicity, other side effects include anemia and the develop-ent of edema. Hormonal methods of birth control may be

ess effective with concurrent administration of bosentan,nd barrier techniques of contraception are recommended.
his is particularly important because bosentan is poten- s

ially teratogenic. There is concern that the endothelinntagonists as a class may be capable of causing testiculartrophy and male infertility. Younger males who mayonsider conceiving should be counseled regarding thisossibility prior to taking these drugs.

.10. Sitaxsentan

itaxsentan is more selective for the ETA receptor. In aandomized, double-blind, placebo-controlled trial (theTRIDE-1 [Sitaxsentan to Relieve Impaired Exercise]rial) 178 NYHA functional class II, III, and IV patientsith either IPAH, PAH related to connective tissue disease,r PAH related to congenital systemic to pulmonary shunts,ere equally randomized to receive placebo, sitaxsentan 100g, or sitaxsentan 300 mg orally once daily. Sitaxsentan

mproved exercise capacity, as assessed by 6MW test, andunctional class after 12 weeks of treatment. The incidencef liver function abnormalities was more favorable for the00 mg dose, that is, the incidence of elevated aminotrans-erase values (greater than 3� normal), which reversed in allases, was 3% for the placebo group, 0% for the 100-mgroup, and 10% for the 300-mg group. In an earlier pilottudy, sitaxsentan was associated with fatal hepatitis whensed at higher doses (150). The most frequently reportedaboratory adverse event was increased international nor-

alized ratio or prothrombin time, related to sitaxsentan’snhibitory effect on the CYP2C9 P450 enzyme, the princi-al hepatic enzyme involved in the metabolism of warfarin.The STRIDE-2 study randomized 247 PAH patients

245 were treated) with IPAH or PAH associated withonnective tissue disease or CHD to blinded placebon�62), blinded sitaxsentan 50 mg (n�62) or 100 mgn�61), or open-label bosentan (n�60) (151). At week 18,atients treated with sitaxsentan 100 mg had an increasedMW test compared with the placebo group (31.4 m,�0.03), and improved functional class (p�0.04). Thelacebo-subtracted treatment effect for sitaxsentan 50 mgas 24.2 m (p�0.07) and for open-label bosentan, 29.5 m

p�0.05). The incidence of elevated hepatic transaminasesgreater than 3 times the upper limit of normal) was 6% forlacebo, 5% for sitaxsentan 50 mg, 3% for sitaxsentan 100g, and 11% for bosentan. Sitaxsentan is currently approved

n the European Union, Canada, and Australia, but not inhe United States.

.11. Ambrisentan

mbrisentan is a relatively selective antagonist of the ETAeceptor. A phase 2 dose-ranging study evaluated thefficacy and safety of 4 doses of ambrisentan in patients withAH (152). In this double-blind study, 64 patients withPAH or PAH associated with connective tissue disease,norexigen use, or HIV infection were randomized toeceive various doses of ambrisentan (1, 2.5, 5, or 10 mg)nce daily for 12 weeks. The 6MW test (plus 36.1 m, p0.0001) improved from baseline with ambrisentan, with

imilar increases for each dose group (range plus 33.9 to plus by on April 30, 2012 cc.org


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8.1 m). Adverse events were generally unrelated to dose,ncluding the incidence of elevated serum aminotransferaseoncentrations greater than 3 times the upper limit oformal (incidence of 3.1%). Two pivotal phase III clinicalrials of ambrisentan in PAH have been completed andandomized 202 and 192 patients with PAH respectively tolacebo or ambrisentan. Doses of 5 and 10 mg of ambrisen-an were compared with placebo in ARIES (Ambrisentan inulmonary Arterial Hypertension, Randomized, Double-lind, Placebo-Controlled, Multicenter, Efficacy Study)-1,nd doses of 2.5 and 5 mg of ambrisentan were comparedith placebo in ARIES-2 (153). After 12 weeks, there were

mprovements in the primary end point of 6MW test inoth studies. The change in mean 6MW test in ARIES-1as plus 22.8 m and plus 43.6 m for the 5- and 10-mgoses, respectively, and minus 7.8 m in the placebo group.n ARIES-2 it was plus 22.2 m and plus 49.4 m for the 2.5-nd 5-mg doses, respectively, and minus 10.1 m in thelacebo group. The secondary end point of time to clinicalorsening was improved with active therapy in ARIES-2.mbrisentan was FDA approved in June 2007 for PAHatients with functional class II and III symptoms. As alass, endothelin receptor antagonists have the potential foriver injury and teratogenicity. The incidence of transami-ases elevations at 1 year was 2.8% in the clinical trials.onthly monitoring of liver function tests, a monthly

regnancy test in women of child-bearing potential, anderiodic hemoglobin measurements are required. Otherotential side effects include lower extremity edema, whichs more frequent (29%) and severe in patients over 65 yearsf age, and nasal congestion (154). Precautions regardingontraception and testicular atrophy are similar to bosentan.

.12. Phosphodiesterase Inhibitors

s discussed in Section 3, the vasodilatory effects of NOepend upon its ability to augment and sustain cGMP content

n vascular smooth muscle. NO activates guanylate cyclase,hich increases cGMP production. Cyclic GMP causes va-

orelaxation, but its effects are short-lived due to the rapidegradation of cGMP by PDEs. PDE-5 hydrolyzes cAMPnd cGMP, limiting their intracellular signaling. PDE-5nhibitors, such as sildenafil and tadalafil, might therefore bexpected to enhance or prolong the effects of these vasodilatingand perhaps antiproliferative) cyclic nucleotides.

.13. Sildenafil

ildenafil is a specific PDE5 inhibitor that has been utilizedreviously for treatment of erectile dysfunction. TheUPER-1 (Sildenafil Use in Pulmonary Arterial Hyperten-ion) study was a randomized, double-blind, placebo-ontrolled trial that assigned 278 patients with PAH (eitherPAH or PAH associated with connective tissue disease orith repaired congenital systemic-to-pulmonary shunts) tolacebo or sildenafil (20, 40, or 80 mg) orally 3 times dailyor 12 weeks (155). The 6MW test increased from baseline
n all sildenafil groups, with mean placebo-corrected treat- e

ent effects of 45, 46, and 50 m for 20-, 40-, and 80-mgoses of sildenafil, respectively (p�0.001 for all compari-ons). This appeared to be entirely related to improvementsith active therapy, as there was little change in 6MW test

n the placebo group. All sildenafil doses reduced the mPAPnd improved functional class. The incidence of clinicalorsening did not differ significantly between the patients

reated with sildenafil versus placebo. Long-term dataavailable only at a dose of 80 mg 3 times daily) in 222atients completing 1 year of treatment with sildenafilonotherapy showed sustained improvement from baseline

t 1 year in the 6MW test (51 m). The FDA-approved dosef sildenafil in patients with PAH is 20 mg administeredrally 3 times daily. Side effects include headache, flushing,yspepsia, and epistaxis. There has been considerable dis-ussion as to whether or not higher doses might conferdditional hemodynamic benefit, but such doses continue toe “off-label” (156).

.14. Tadalafil

nother longer-acting PDE inhibitor, tadalafil, is currentlyndergoing clinical study. Like sildenafil, tadalafil has beenpproved previously by the FDA for treatment of erectileysfunction. However, it remains investigational in patientsith PAH.

.15. Combination Therapy

iven the availability of medications that target differentathologic processes, combination therapy is an attractiveheoretical option in PAH, just as in LV systolic dysfunc-ion. The goal of combination therapy should be to maxi-ize efficacy, while minimizing toxicity. The safety and

fficacy of combination therapy in PAH is a subject of activenvestigation. To date, there are 3 small, placebo-controlled,ombination therapy trials. One studied functional class IIIr IV patients with either IPAH or PAH related toonnective tissue disease starting on intravenous epoproste-ol and randomized them to receive bosentan or placebo157). This small, underpowered study failed to demon-trate the benefits of combination therapy. More recently,nhaled iloprost has been studied in patients who remainedymptomatic (NYHA functional class III or IV) while ontable bosentan therapy for at least 3 months (158). In thisulticenter, placebo-controlled, randomized trial, 67 pa-

ients with PAH (94% NYHA functional class III, meanaseline 6MW test 355 m) were randomized to receivenhaled iloprost, (5 mcg, 6 to 9 times per day) or placebo.fter 12 weeks, the primary efficacy measure, post inhala-

ion 6MW test, improved by 30 m in the iloprost group andm in the placebo group, for a placebo-adjusted difference

f plus 26 m (p�0.051). There were also improvements inYHA functional class (p�0.002), time to clinical worsen-

ng (p�0.022) and postinhalation mPAP (p�0.001) andVR (p�0.001). However, a study with a similar design was

erminated early due to a futility analysis (159). The primary
nd point, change in 6MW test, improved by 1 m in the


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lacebo group but declined by 9 m in the iloprost group.one of the secondary end points, including functional

lass, peak oxygen uptake, and time to clinical worsening,iffered between the groups. Most recently, the addition ofildenafil (target dose 80 mg 3 times daily) or placebo wasvaluated in 267 PAH patients who remained symptomaticith a 6MW test of 100 to 450 m while on a stable dose of

ntravenous epoprostenol for at least 3 months (160).atients treated with sildenafil experienced a placebo-djusted improvement in 6MW test of 28.8 m (p�0.0002)t 16 weeks, as well as improvements in mPAP, cardiacutput, and time to clinical worsening. Several smaller, openabel observational studies have suggested benefit of com-ination therapy. Multiple randomized controlled trials ofombination therapy are currently ongoing, and to ade-uately study the safety and efficacy of combination therapy,e encourage enrollment into randomized controlled trials.

.16. Limitations of Clinical Trials inulmonary Arterial Hypertension

hile the medications studied in the clinical trials reviewed inhe preceding text represent, in our view, advancements in theare of PAH patients, many patients still remain symptomatic,ith a suboptimal quality of life and impaired hemodynamicsespite treatment. With the exception of calcium channellockers in a robust responder, most therapies reduce PAP by0% to 20%. A recent meta-analysis of 16 randomized trials inAH found the following: 1) a nonsignificant reduction inll-cause mortality (relative risk 0.70, 95% confidence interval:.41 to 1.22); 2) a significant improvement in exercise capacitys assessed by the 6MW test of 42.6 m (95% confidencenterval: 27.8 to 57.8 m); and 3) an improved dyspnea status byt least 1 functional class (relative risk 1.83, 95% confidencenterval: 1.26 to 2.66) (161). Notably, with one exception,hese trials were all 8 to 16 weeks in duration. None wereowered to detect a survival benefit. More recently, a meta-nalysis performed on 21 randomized controlled trials (3140atients) in PAH patients published through October 2008eported improvements in the 6MW distance and a 43%ecrease in mortality in patients treated with PAH-specificherapies versus patients randomized to placebo (161a). Addi-ionally, the role of PAH-specific therapy in certain subgroupsas not been adequately studied. For example, a meta-analysisf the scleroderma spectrum of diseases related PAH patientsncluded in 10 randomized controlled trials of oral therapy failedo demonstrate an improvement in exercise capacity in thisubgroup (162). Interestingly, this is contrary to the study ofpoprostenol performed specifically in the scleroderma spectrumf diseases population, which demonstrated the greatest improve-ent in 6MW test ever reported in a clinical trial in PAH (117).

.17. Cost Considerations

linical trials in PAH have not included analysis regardingost/benefit ratio, quality-adjusted life years saved, or num-er needed to treat. The PAH-specific therapies are expen-
ive. The approximate annual cost for sildenafil is $12 761, d

or bosentan is $55 890, for ambrisentan is $56 736, and forloprost is $92 146. Because dosing is individualized and aatient’s weight factors into the amount of drug used, theres considerable variation in the cost of epoprostenol andreprostinil from patient to patient. Based on a 70-kgatient at the lower end of the dosing spectrum, the annualost for epoprostenol is $33 153 and for treprostinil is97 615. These costs may be much higher for larger patientsnd at higher doses (163).

.18. Invasive Therapies

espite advances in the medical treatment for PAH, manyatients experience progressive functional decline, largelyelated to worsening right heart failure. It is in these patientshat interventional and surgical therapeutic options shoulde considered, including atrial septostomy and lung orombined heart and lung transplantation. In patients withH caused by chronic pulmonary thromboembolism, sur-ical thromboendarterectomy may be beneficial. A body oflinical data has emerged to help guide the utilization ofhese strategies, and reviews of their role in the therapy ofatients with PAH have recently been published (164–166).ther surgical approaches, such as RV mechanical assis-

ance, are under investigation.

.19. Atrial Septostomy

s right heart function worsens in response to ongoingevere PAH, patients experience progressive dyspnea, as-ites, edema, and may have presyncope or syncope. Atrialeptostomy creates a right to left inter-atrial shunt, decreas-ng right heart filling pressures and improving right heartunction and left heart filling. While the created shuntecreases systemic arterial oxygen saturation, it is antici-ated that the improved cardiac output will result in overallugmentation of systemic oxygen delivery.

Several case series have reported hemodynamic and clin-cal improvement following the procedure (167–169). Im-roved cardiac output appears to be the principal hemody-amic benefit; the magnitude of the improvement hasanged from 15% to nearly 60%. Improvements in NYHAunctional class and 6MW test have also been reported169). Reported success rates for bridging patients to trans-lantation with septostomy range from 30% to 40%167,168). Procedural mortality is high, however, with anstimate of 15% based on published series (though this hasanged from 5% to 50% in the different centers). This mortalitys undoubtedly driven by the severity of PAH and right heartailure of the patients undergoing the procedure. At the sameime, however, this mortality clearly contributes to the practicef reserving the procedure for critically ill patients. Within thisroup, those with advanced age, renal dysfunction, and theost severe derangements in hemodynamics and systemic

xygenation face the greatest procedural risk.Atrial septostomy may be performed by either blade or

raded balloon dilation techniques, both of which have been
escribed previously. Recently, the utility of a customized


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eptostomy device (170) and the use of intracardiac echo-ardiographic imaging to guide the location and extent ofeptostomy creation (171) have been reported. Ongoingdvances may yield improved outcomes in the future.

Currently, atrial septostomy is recommended for patientsith severe PAH and intractable right heart failure despiteaximal medical therapy, including optimized PAH-specific

gents and inotropes. Indeed, this represents a very narrowindow and identification of appropriate patients requires

xperience and judgment. The goals of the procedure arealliation and restoration and maintenance of clinical stabilityntil a transplant can be performed. Atrial septostomy shoulde performed only by experienced operators in centers with theesources to care for such critically ill patients. The procedurehould be considered before hemodynamic compromise andnd-organ dysfunction is too far advanced.

.20. Lung and Combined Heart andung Transplantation

ung transplantation has been an option for the therapy forelect patients with end-stage pulmonary disease for the past5 years. Currently, approximately 4% of the approximately,700 single lung (SLTx), double lung (DLTx), and com-ined heart and lung (HLTx) transplants annually per-ormed worldwide in adults are for the primary indication ofAH (172). While patients with PAH undergoing trans-lantation face an increase in operative mortality, their longerm outcomes are comparable with patients with otherrimary indications (172). The International Society foreart and Lung Transplant registry reports 1-, 3-, 5-, and

0-year survivals of 66%, 57%, 47%, and 27%, respectively,n PAH patients undergoing transplant. By way of compar-son, survival rates for all patients transplanted were 78%,1%, 49%, and 25% at these respective time points (172,173).

There is no agreement on the optimal type of transplan-ation for patients with PAH. While acceptable outcomesave been demonstrated with SLTx, many centers preferLTx to limit the reperfusion injury that has been reported

n the donor lung of PAH patients undergoing SLTx (174).he decision to perform HLTx in PAH patients is based on

he severity of cardiac decompensation. The combinedrocedure is generally reserved for patients with intractableight heart failure, especially when a patient has becomeependent on inotropic support. Combined heart and lungransplant is also often required in patients with PAH in theetting of complex CHD, although in some instancesombining SLTx or DLTx with simultaneous repair of theongenital cardiac abnormality may be feasible (175). Also,atients with PH and concomitant advanced left heartisease may be considered for HLTx. Finally, when PAH isot the primary indication for lung transplantation, the pres-nce of secondary PH and its sequelae may similarly impact thehoice of transplant type. Choice of procedure is thereforeependent on the patient characteristics, as well as the desire toptimally use scarce donor organs, the ease (or difficulty) of
ach surgical procedure, and a given center’s preference. i

Transplantation as a potential therapeutic option should beiscussed with PAH patients at the time of diagnosis. Timingf referral is challenging, and local practices and organ avail-bility must be considered. Patients who are otherwise goodransplant candidates should be referred when they have annacceptable response to PAH therapies. In the current patientrioritization scheme used by the United Network for Organharing, patients with PAH may be assigned a lung allocationcore below that of patients with other common diagnoses,uch as pulmonary fibrosis. In addition, a determination that aatient is functional class IV paradoxically lowers the patient’score (a recognition of the worsened peri- and posttransplantutcomes observed in these patients). The thoracic committeef the United Network for Organ Sharing is constantlyeviewing and revising this process. Application for an excep-ion based on certain hemodynamic criteria is now possible forAH patients. Revisions to the scoring system to includehanges in bilirubin and creatinine are being discussed. Once aatient has been evaluated and considered a candidate forransplantation, aggressive follow up and therapy are requiredo maintain cardiac function and improve the likelihood that aombined heart and lung transplant will not be required.

.21. Pulmonary Thromboendarterectomy

atients with suspected PAH should undergo evaluation forTEPH. As discussed in the preceding text, the screening

ool of choice for CTEPH is perfusion scanning. If indic-tive of CTEPH, a pulmonary angiogram should be per-ormed. Patients are considered to be candidates for pulmo-ary thromboendarterectomy (PTE) if they have surgicallyccessible disease and present acceptable surgical risk. Theoal of PTE is to remove sufficient material from theulmonary arteries to substantially lower PVR and improveardiac output. The diagnostic evaluation of patients withTEPH, surgical technique, and outcomes have been

eviewed recently (104). This complex and life-saving therapys best performed at high-volume centers as the learning curvend required support systems are prohibitive for most hospitals.

.22. Right Ventricular Assist Device

he development of refractory right heart failure portends arave prognosis in patients with PAH. Left- and biventricu-ar assist devices have proven effective in supporting patientsith severe left- and biventricular failure. Preclinical studiesave suggested the usefulness of right ventricular assistevice (RVAD) support in a model of PH (176). While arowing body of literature has emerged demonstrating thetility of RVAD support in patients with acute postopera-ive RV failure, often in the presence of PH, its utility inatients with PAH has not as yet been tested.

.23. Treatment Algorithm

he optimal therapy for a patient is a highly individualizedecision, taking into account many factors including: sever-
ty of illness, route of administration, side effects, comorbid


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. Reassessing Patients Over Time:ow to Follow Patients on Treatment

hile guidelines for the diagnosis and initial treatment haveeen developed recently, a guideline focusing on how toeassess patients over time has been lacking. Almost all of theandomized clinical trials studying PAH therapies to date haveeen short-term studies, usually 12 to 16 weeks in duration.urthermore, the long-term experiences published thus farsually detail single center experiences, without placebo orontrol groups, making it difficult to infer generalized practiceatterns. Most importantly, treatment of PAH is a rapidlyvolving field with emergence of new information and devel-pment of novel therapies, which have further hampered

igure 6. Treatment Algorithm for PAH

ackground therapies include warfarin anticoagulation, which is recommended in alleart failure. Oxygen is recommended to maintain oxygen saturation greater than 90otential candidates for long-term therapy with calcium channel blockers (CCBs). Patesponsiveness to oral CCBs, and the value of acute vasodilator testing in such patired, such as those with right heart failure or hemodynamic instability, should not uive acute vasodilator response, and such patients need to be followed closely bothesting and are considered lower risk based on clinical assessment (Table 2), oral then is not appropriate, the other treatments would need to be considered based onred high risk based on clinical assessment (Table 2), continuous treatment with intecommended. If a patient is not a candidate for continuous IV treatment, the otherisk of each treatment. Epoprostenol improves exercise capacity, hemodynamics, anlthough expensive and difficult to administer, epoprostenol is the only therapy for Pinuous IV or subcutaneous (SC) infusion. Iloprost is a prostacyclin analogue deliverere oral therapies that improve exercise capacity in PAH. Liver function tests must bxercise capacity. Combination therapy should be considered when patients are notnd/or atrial septostomy is challenging and is reserved for patients who progress de

reation of a coherent guideline outlining ongoing evaluation. pcontent.onlinejaDownloaded from

The complexity of the disease and the rapid advancesccurring in PAH mandate a guideline outlining long-termanagement recommendations. Although the therapies

hat have been approved thus far have been effective inmproving quality of life and outcome to varying degree,linical experience has demonstrated that some patientsrogress despite treatment while others decline after initialmprovement. Furthermore, long-term experiences withpoprostenol have demonstrated the importance of vigilantarly follow-up, since patients who remain in functionallass III or IV despite therapy have poor outcomes andhould be considered for lung transplant (77,78).

Important prognostic indicators, both at baseline and onreatment, were reviewed in Section 5 of this document.hese include WHO functional class, exercise endurance

6MW test or CPET), and echocardiographic and hemo-ynamic parameters. There are emerging data regarding the

ts with IPAH without contraindication. Diuretics are used for management of rightcute vasodilator testing should be performed in all IPAH patients who may bewith PAH due to conditions other than IPAH have a very low rate of long-termeeds to be individualized. IPAH patients in whom CCB therapy would not be consid-acute vasodilator testing. †CCBs are indicated only for patients who have a posi-

fety and efficacy. ‡For patients who did not have a positive acute vasodilatorwith ERA or PDE-5I would be the first line of therapy recommended. If an oral regi-

nt’s profile and side effects and risk of each therapy. §For patients who are consid-us (IV) prostacyclin (epoprostenol or treprostinil) would be the first line of therapyies would have to be considered based on patient’s profile and side effects andival in IPAH and is the preferred treatment option for the most critically ill patients.t has been shown to prolong survival. Treprostinil may be delivered via either con-n adaptive aerosolized device 6 times daily. The endothelin receptor antagonistsitored indefinitely on a monthly basis. Phosphodiesterase inhibitors also improveding adequately to initial monotherapy (Table 8). �Timing for lung transplantation

optimal medical treatment.

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ions on the frequency and extent of longitudinal follow upf the PAH patient are displayed in Table 8.Combining agents of different classes for the treatment of

AH patients who remain symptomatic and do not achievereatment goals is an area of active research. Limited datarom randomized controlled trials suggest that outcomes areetter when multiple agents are used in such patients, andarger randomized controlled trials to address this issue arenderway. Addition of an endothelin receptor antagonist,DE-5 inhibitor, or a prostanoid could also be consideredutside of a trial setting. If a patient improves with thedditional agent, it is unclear whether the initial agenthould be continued or discontinued.

.1. Role of Nurses in Managing Pulmonary Arterialypertension Patients at Specialty Centers

t is our opinion that nurses provide a crucial link betweenhe physician(s) and patient in all PAH specialty centers.irst, competent nursing education of the patient, triage,nd medical assessment are necessary to manage PAHatients who not only have complex disease but also needomplex therapies, such as intravenous or subcutaneousrostanoids. Frequent telephone calls are necessary duringnitiation, after an episode of decompensation, and foreriodic evaluation with these treatments. It is also crucialor patients to be proactive in the management of theirisease and to be instructed to communicate with the nurses

n the event of clinical problems. This is best accomplishedhen patients are given specific instructions, access to theursing staff, and a shared sense of responsibility foranaging their disease and treatment plan.Nurses also provide emotional support to patients and

heir families, especially during the initial period of

able 8. Longitudinal Evaluation of the PAH Patient*

linical Course Stable; no increase in symptoms and/or de

hysical Examination No evidence of right heart failure

unctional Class I/II

MWD Greater than 400 m

chocardiogram RV size/function normal

emodynamics RAP normal

CI normal

NP Near normal/remaining stable or decreasin

reatment Oral therapy

requency of Evaluation Q 3 to 6 months‡

C Assessment Every clinic visit

MWT Every clinic visit

chocardiogram§ Q 12 months or center dependent

NP� Center dependent

HC Clinical deterioration and center dependen

For patients in the high-risk category, consider referral to a PH specialty center for consideravaluation for patients in FC III and/or 6MWD between 300 to 400 m would depend on compositetable on established therapy, follow-up assessments can be performed by referring physician(s)dvised not to rely on its evaluation as the sole parameter to make therapeutic decisions. �TheBNP indicates brain natriuretic peptide; CI, cardiac index; FC, functional class; MWD, molecula

trial pressure; RHC, right heart catheterization; and RV, right ventricle.

ccepting the diagnosis or with acute illness. They spend I


ime educating patients on the disease process andnswering questions regarding different therapies or is-ues on how PAH impacts activities of daily living. Also,urses are often the ones patients and their families turno for assistance for help in navigating through insuranceompanies and dealing with realities associated withnancial aspects of PAH therapies. Indeed, one of theistinguishing features that marks a group as a PAHpecialty center is the availability of competent and caringursing staff dedicated to meeting the unique challengesf patients with PAH (Table 9). Additionally, specialtyharmacies that dispense many of the PAH therapiesmploy nurses and pharmacists who play a key role inducating patients about the therapies.

. Non-Pulmonary Arterial Hypertensionulmonary Hypertension Populations

hile recent evidence points to an increase in the numberf patients with WHO Group 1 PAH (1), the number of

ensation Unstable; increase in symptoms and/or decompensation

Signs of right heart failure

IV†

Less than 300 m

RV enlargement/dysfunction

RAP high

CI low

Elevated/increasing

Intravenous prostacyclin and/or combination treatment

Q 1 to 3 months

Every clinic visit

Every clinic visit

Q 6 to 12 months or center dependent

Center dependent

Q 6 to 12 months or clinical deterioration

r advanced therapies, clinical trials, and/or lung transplantation. †The frequency of follow-upiled assessments on other clinical and objective characteristics listed. ‡For patients who remainpecialty centers. §Echocardiographic measurement of PASP is estimation only and it is stronglyof serial BNP levels to guide management in individual patients has not been established.t distribution; MWT, minute walk test; PAH, pulmonary arterial hypertension; Q, every; RAP, right

able 9. The Role of Nurses in Managing PAH Patients atpecialty Centers

Clinical Indication Frequency of Phone Triage/Management

fter initiation of IVprostacyclin

1 to 2�/week to weekly until dose titration/symptoms stable

hronic IV prostacyclin Q 1 to 2 months and prn

fter initiation of combinationtherapy

Q 2 to 4 weeks and/or prn

fter initiation of oral regimen Q 1 to 2 months and/or prn

fter discharge from hospitalfor PAH decompensation

Q days to 1 week for 1 to 2 weeks

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atients with PH related to chronic left heart diseaseWHO Group 2) or chronic hypoxic states (WHO Group) is far greater. It is universally agreed that such patientsequire optimization of therapies targeting their underlyingisease state (tailored heart failure interventions for patientsith congestive heart failure, for example). However, it isot uncommon that even with such optimization, clinicallyeaningful PH remains. A subset of patients may be

escribed as having PH “out of proportion” to their under-ying disease state. Examples would include patients with a

odest degree of obstructive lung disease or left heartisease that nonetheless manifest severe PH. Some havepeculated that these patients have a form of PAH that mayerit therapy with PAH-specific agents. Unfortunately,

here are relatively few data available to guide decisionaking regarding the use of PAH-specific therapies for

hese patients. Other populations in which the use of theseherapies is controversial include those with CTEPH andhose with PH following a variety of cardiac surgicalrocedures. This section explores the diagnostic and thera-eutic approach to these patient populations.

.1. WHO Group 2: Pulmonary Venous Hypertension

.1.1. Systolic Heart Failure and Pulmonary Hypertension

espite significant advances in the treatment of patientsith systolic heart failure with neurohormonal modulators

ncluding angiotensin-converting enzyme inhibitors, beta-lockers, and spironolactone, the morbidity and mortalitymong patients with advanced heart failure remains high177). Development of PH, which usually progresses toffect RV function, signals progression of disease and poorutcome (5). PH in association with left heart failure usuallyccurs initially as pulmonary venous hypertension. Over aeriod of time, partly as an adaptive mechanism againstulmonary edema, an increase in pulmonary artery resis-ance may ensue.

Although optimizing neurohormonal antagonists re-ains the mainstay in treating patients with systolic heart

ailure, efforts to target PAH by applying similar principlessed in treating idiopathic PAH have been pursued. TheIRST (Flolan International Randomized Survival Trial)tudy enrolled 471 patients with advanced heart failure toeceive continuous epoprostenol infusion plus standard carer standard care alone (178). Although a hemodynamicmprovement was seen among patients receiving epoproste-ol with an increase in CI and a decrease in PCWP andVR, the study was terminated early due to a strong trend

oward increased mortality rates in patients receivingpoprostenol. Several explanations given included the long-erm detrimental effects observed with systemic vasodilata-ion in systolic heart failure and possible hazardous effects ofpoprostenol among patients with ischemia. Based on thendings of this study, chronic use of epoprostenol inatients with systolic heart failure is contraindicated. The
nly other prostanoid-based agent tested in patients with s

hronic heart failure is inhaled iloprost (179). Investigatorsave reported hemodynamic benefits of short-term use of

loprost in heart transplant candidates with increased PAP.ignificant decreases in mPAP and PVR was demonstrated.Similar to increase in activation of several other neuro-

ormonal systems, the level of endothelin (ET)-1 is alsoncreased in chronic heart failure (180). Studies investigat-ng the short-term hemodynamic effect of endothelin re-eptor antagonists (ERAs) in patients with chronic heartailure were initially encouraging. A 2-week therapy withonselective ERA bosentan in 36 patients with symptom-tic heart failure despite treatment with standard regimenesulted in a reduction of both systemic and pulmonaryressures and increase in cardiac output (181). These initialncouraging results prompted long-term randomized trials.n the REACH-1 (Research on Endothelin Antagonists inhronic Heart Failure) study, 370 patients with advancedeart failure (NYHA functional class IIIB/IV) receivedosentan or placebo. However, this trial was stopped pre-aturely due to safety issues, namely elevated liver

ransaminases, and the question of possible long-termenefit using lower doses was raised based on observing arend towards reduction in heart failure-related morbiditynd mortality among patients who received therapy (182).he ENABLE (Endothelin Antagonist Bosentan for Low-

ring Cardiac Events in Heart Failure) trial enrolled over600 patients and studied lowered doses of bosentan versuslacebo (183). However, no improvement in outcome wasemonstrated between patients treated with bosentan andonventional treatment versus conventional treatment alone.here was an increased risk of early heart failure exacerba-

ions due to fluid retention in patients treated with bosentan.Several hypotheses have been raised regarding the lack of

mprovement seen with the addition of ERAs in heartailure patients. One reason may lie in patient selection.ndothelin receptor blockers reduce PAP and increase

ardiac output in patients with IPAH (142). It is possiblehat adding ERAs may prove to be beneficial only foratients with chronic heart failure and PH. Indeed, a recenteport described 5 patients who were deemed ineligible foreart transplantation due to severe irreversible PH (184). A-week trial of bosentan resulted in decreased PVR, makinghe patients eligible for heart transplantation, which they allnderwent successfully. Another case report illustrates aatient who was considered for heart and lung transplanta-ion secondary to biventricular dysfunction and severe PH185). After 3 months of therapy on bosentan, improvementn LV function and PAP made him eligible for double lungransplantation. Larger studies are needed to determine theafety and benefit of adding ERAs to currently usedeurohormonal antagonists among patients with chroniceart failure and PH.Two small reports have demonstrated safety and hemo-

ynamic effects of short-term use of sildenafil in patientsith congestive heart failure and PH (186,187). An acute

tudy has shown that sildenafil administration improved by on April 30, 2012 cc.org


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eak VO2, reduced VE/VCO2 slope, and produced pulmo-ary vasodilatation during rest and exercise in patients witheart failure and PH (188). In addition, sildenafil treatmentor 12 weeks improved exercise capacity and quality of life inatients with systolic heart failure and PH, compared withlacebo-treated patients (189). Longer-term use of PDE-5nhibitors in heart failure patients has not been investigatedo date.

.1.2. Diastolic Heart Failure and Pulmonary Hypertension

iastolic heart failure refers to clinical syndromes in whichatients present with heart failure symptoms with preservedV systolic function. The predominant underlying struc-

ural abnormalities in diastolic heart failure are concentricypertrophy and/or remodeling. This is often caused byhronic pressure overload, usually due to hypertension. Thether characteristics associated include normal or reducedV volume, abnormal diastolic function, and left atrialnlargement (190). These abnormalities impair the fillingrocess of the left ventricle, especially under conditions that

ncrease the heart rate (i.e., exercise or arrhythmia), resulting innadequate cardiac performance and clinical symptoms.

Treatment strategies for diastolic heart failure includereating hypertension and preventing or aiming for regres-ion of hypertrophy, accomplished mainly by usingngiotensin-converting enzyme inhibitors and angiotensineceptor blockers. Strict volume control is necessary, ob-ained through diuretics and sodium restriction. Preventionf tachyarrhythmia and controlling the heart rate to opti-ize diastolic filling time are most often achieved using

eta-blockers and calcium channel blockers. Furthermore,mproving lusitropy and preventing ischemia are also im-erative when considering treatment strategy.There are no established guidelines for treatment of

iastolic heart failure. Many patients with this syndromehare similar risk profiles such as hypertension, diabetesellitus, LV hypertrophy, atrial fibrillation, sleep disordered

reathing (SDB), and atherosclerotic disease. Therefore,ome of the general principles used in treating systolic heartailure patients have been applied. A few small studies havehown that angiotensin receptor blockers improve exerciseolerance. The CHARM (Candesartan in Heart failure:ssessment of Reduction in Mortality and morbidity)-reserved trial suggested that treatment with candesartan

educes hospitalization related to diastolic heart failure,hough mortality benefit was not seen (191).

When patients present with both diastolic heart failurend elevated PAP, measures to optimally treat systemicypertension and normalize volume status must be in place.erforming RHC with careful attention paid to obtainingccurate PCWP, and in most cases LVEDP, is important inlacing the correct diagnosis. Paradoxically, it is possiblehat the PCWP or LVEDP might be normal in such aatient with severe RV failure and low cardiac output. IfAP remains elevated despite normalizing systemic blood
ressure and attaining euvolemic status, it is unclear if h

onsideration should be given to targeted therapy for PAH.urthermore, in the presence of hypertrophy and/or echo-ardiographic evidence of abnormal relaxation, it is un-nown what PAP should be considered “out of proportion”o the presence of left heart changes. No studies are availableo guide this therapeutic decision.

.1.3. Valvular Dysfunction and Pulmonary Hypertension

evelopment of PH in association with valvular dysfunctionas been shown to be a marker of advanced disease.osenhek et al. (192) reported their findings from prospec-

ively following 132 consecutive patients with severe degen-rative mitral regurgitation for 62 plus or minus 26 months.his group used criteria consisting of development of

ymptoms, LV enlargement or dysfunction, recurrent atrialbrillation, or PH. Evaluation of event-free survival dem-nstrated the presence of symptoms to be correlated withorst outcome; however, among this cohort, only 5 patientseveloped new onset of atrial fibrillation or PH. This studys in accordance with the U.S. and European practiceuidelines recommendation for surgery in asymptomaticatients with MR with regards to presence of PH. Theuideline recommends systolic PAP exceeding 50 mm Hgo be a IIa indication for surgery (193).

Elevated estimated RV systolic pressure on echocardiog-aphy has multiple potential etiologies. When an etiologyuch as left heart disease or pulmonary disease is found, thenderlying disorder should be treated aggressively. In manynstances the PAP will decline with appropriate manage-

ent of the underlying disorder. If the estimated PAPemains elevated, and the patient remains symptomatic,urther evaluation, including an RHC, may be appropriate.

.2. WHO Group 3: Hypoxia-Associatedulmonary Hypertension

he respiratory diseases most frequently associated with PHre chronic obstructive pulmonary disease, interstitial lungisease, and SDB. Less common pulmonary abnormalities,uch as chronic hypoventilation syndromes and high alti-ude exposure, can also produce PH, but will not beiscussed here. These are categorized as WHO Group IIIH. The topic of pulmonary diseases and the heart has

ecently been reviewed (194).

.2.1. Chronic Obstructive Pulmonary Disease andulmonary Hypertension

hronic obstructive pulmonary disease (COPD) is a highlyrevalent lung disorder of the lung parenchyma, includingirways, resulting in a ventilatory limitation to exertion,ecurring respiratory infections, and often chronic hypoxiand hypercapnea. COPD, predominantly caused by smok-ng, is associated with pulmonary vascular changes includingntimal thickening, which decreases luminal cross-sectionalrea (195,196). While PH is thought to be common inatients with COPD, its exact prevalence is uncertain and is
eavily influenced by disease severity: two thirds of patients


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ith advanced COPD have been reported to have PHetected echocardiographically (197). More recently, theardiopulmonary hemodynamics of a retrospective series of98 patients with COPD has been published (198).wenty-seven patients (3%) had severe PH, defined as anPAP greater than 40 mm Hg. Interestingly, 16 of these 27

ad another possible cause of PH, such as anorexigenxposure, connective tissue disease, thromboembolic dis-ase, or LV disease. In only 11 patients, or 1.1%, wasOPD the only potential etiology of the PH. The medianAP in these 11 patients was 48 mm Hg. These patientsad an unusual pattern of cardiopulmonary abnormalitiesith mild to moderate airway obstruction, severe hypox-

mia, hypocapnea, and a very low diffusing capacity forarbon monoxide.

In a similar series, among 215 patients with severeOPD who underwent RHC to evaluate candidacy for

ither lung transplantation or lung volume reduction sur-ery, PH, defined as an mPAP greater than 25 mm Hg, wasresent in 50.2% of patients (199). The PH was character-zed as moderate (mPAP 35 to 45 mm Hg) in 9.8% andevere (mPAP greater than 45 mm Hg) in 3.7%. A clusternalysis identified a subgroup of atypical patients character-zed by moderate impairment of the pulmonary mechanicsith moderate to severe PH and severe hypoxemia. Obser-ations suggest that a different biological mechanism resultsn changes in the pulmonary vascular bed in susceptibleatients and that severe PH occurs in the presence of lungisease rather than as a result of the lung disease. Forxample, a genetic predisposition to PH in COPD patients,s a result of a 5-HTT polymorphism, has been described,hich may predispose to more severe PH in hypoxemicatients with COPD (200).In the vast majority of COPD patients, PH is mild and

reatment should be directed at the underlying COPD. Thishould include bronchodilator and anti-inflammatory ther-py, and most importantly, oxygen. Patients who presentith severe PH should be evaluated for another diseaserocess that is responsible for the high PAP before it isttributed to the COPD. Specific treatment of PH in theetting of COPD has not been adequately studied. Openabel, uncontrolled observations with both bosentan andildenafil have suggested benefit, although adequately de-igned trials are lacking (201–203). Worsening V/Q mis-atch, resulting in further hypoxemia due to nonselective

asodilatation is a potential risk.

.2.2. Interstitial Lung Disease and Pulmonary Hypertension

nterstitial lung disease (ILD) is a heterogeneous group ofisorders generally featuring inflammatory and/or fibroticestruction of the pulmonary parenchyma, and commonlyssociated with PH (204). Idiopathic pulmonary fibrosisIPF) is a relatively common form of ILD. The prevalencef PH as determined by echocardiogram in patients withPF is uncertain, but has been reported to be as high as 40%
n a general IPF population (205) and 60% in patients with o

PF referred for lung transplant evaluation (206). As withOPD, the magnitude of PH in patients with IPF is oftenodest, though a sizeable minority may have more marked

ressure (207). Recent data have shown a lack of correlationetween lung function variables and PAP in patients withPF, suggesting mechanisms other than the degree ofbrosis underlying the PH seen in this disease (205). Thereatment of PH associated with ILD should begin withptimal treatment of the ILD, potentially including immu-omodulatory therapies and supplemental oxygen. The rolef PAH-specific therapies in the treatment of PH associatedith ILD has not been adequately investigated.Sarcoidosis is a disease of unknown etiology, often

rouped among the ILDs and commonly associated withH. According to the 2003 classification, PH associatedith sarcoidosis falls into Group V or “miscellaneous” PH.s in COPD, the frequency with which PH complicates

arcoidosis appears to increase with disease severity (208). Amall, uncontrolled study reported clinical improvement inatients with severe PH associated with sarcoidosis treatedhronically with intravenous epoprostenol (209). A con-rolled trial of bosentan in this population is scheduled toegin in the near future.

.2.3. Sleep Disordered Breathing

DB, especially when accompanied by frequent and severeypoxemia, can produce PH. Generally, the magnitude ofhe pressure elevation is modest even in severe cases of sleeppnea. Accordingly, if a patient with SDB is found to haveevere PH, a complete diagnostic evaluation should bendertaken to assess for other possible etiologies of the PH.t the same time, all patients with PH should be evaluated

nd treated (if indicated) for SDB to limit the adverseulmonary vascular effects of the SDB (210).Therapy of PH associated with SDB centers on preven-

ion of episodic hypoxia by the provision of continuousositive airway pressure (with or without supplementalxygen) or, less commonly, with surgery or the use of an oralrosthesis. PAH-specific agents have not been studied inatients with PH associated with SDB, although they may besed when PH persists despite adequate therapy of the SDB.

.3. WHO Group 4: Thromboemboliculmonary Hypertension

TEPH is defined as PH associated with an elevatedPAP (greater than 25 mm Hg) caused by thromboemboli

n the pulmonary arterial system. A recent prospective,ongitudinal study following patients presenting with acuteE but with no other history of venous thromboembolismstimated the cumulative incidence of CTEPH to be 1.0%months after acute PE, 3.1% after 1 year, and 3.8% afteryears (103), suggesting that the disease may be much more

ommon than previously believed. Hoeper et al. (104) haveecently reviewed CTEPH in detail. The current model ofTEPH pathogenesis is based upon gradual formation of
rganized thromboemboli after deep venous thrombosis and


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E. No abnormality of the coagulation or fibrinolyticathway or of the pulmonary endothelium has been consis-ently identified except for anticardiolipin antibody (approx-mately 10% of patients) and elevated levels of factor VIII.plenectomy, ventriculo-atrial shunt, infected intravenous

ines, and chronic inflammatory states appear to be inde-endent risk factors for CTEPH (212).Pulmonary microvascular changes manifesting as pulmo-

ary hypertensive arteriopathy likely contribute to diseaserogression (211). Mechanisms for significant distal diseaseay involve: 1) obstructions of “small” subsegmental elastic

ulmonary arteries; 2) classic pulmonary arteriopathy ofmall muscular arteries and arterioles distal to nonob-tructed vessels; and 3) pulmonary arteriopathy of smalluscular arteries and arterioles distal to totally or partially

bstructed vessels. Distal pulmonary vasculopathy of bothccluded and nonoccluded pulmonary vasculature is char-cterized by lesions considered typical for IPAH, includinglexiform lesions.CT findings of CTEPH may be minimal and a

entilation-perfusion scan should always be considered inhe setting of possible CTEPH. A normal perfusion studyr the presence of multiple, small, subsegmental defectsake IPAH or another form of small-vessel PH more

ikely, and one or more mismatched segmental or largerefects generally indicates CTEPH. Occasionally, multipleismatched defects are seen in pulmonary veno-occlusive

isease, pulmonary capillary hemangiomatosis, fibrosingediastinitis, pulmonary vasculitis, or pulmonary artery

arcoma. CT or angiographic evidence of CTEPH includesouching, webs, or bands with or without poststenoticilatation, intimal irregularities, abrupt narrowing, or totalcclusion. Pulmonary angiography has been the cornerstonef managing patients with CTEPH for many years andonfirms the diagnosis and gives an indication of operability.

.3.1. Surgical and Invasive Therapy

TE is potentially curative, although it cannot be performedn a substantial proportion of patients (104,165,213,214)nd surgical success is dependent on careful patient selectionnd operator experience. Invasive therapeutic approachesther than PTE are currently limited. Possible alternativesnclude lung transplantation and balloon pulmonary dilationangioplasty) (164,215). The latter technique may be ben-ficial, but it is not, at present, routinely applied (215).

hile there are little clinical data to support the practice,nferior vena cava filter placement prior to PTE is standardt most large centers.

.3.2. Medical Therapy

s in PAH, diuretics and oxygen are used as indicated.ifelong anticoagulation therapy is prescribed. Pharmaco-

ogic therapies approved for use in treating IPAH are beingtudied in CTEPH in view of the potential for nonocclusivemall vessel vasculopathy. Most clinical evidence is currently
imited to small, uncontrolled trials. There has been 1 i

lacebo-controlled trial for CTEPH, which evaluatedosentan in patients with either inoperable disease orersistent PH following PTE (147). Patients treated withosentan demonstrated a reduction in PVR, but no changen 6MW test, compared with placebo.

Pharmacotherapy may be beneficial in 4 settings (216).irst, when PTE is not possible due to significant distalisease, medical therapy may be the only possibility, withransplant considered for the most severely ill individuals.econd, in high-risk patients with extremely poor hemody-amics, intravenous epoprostenol may be considered as aherapeutic bridge to PTE (217). Such individuals includehose with functional class IV symptoms, mPAP greaterhan 50 mm Hg, CI less than 2.0 L/min/m2, and PVRreater than 1,000 dyn·s·cm�5 (216). While this approachay improve surgical success, medical therapy should not

ignificantly delay PTE. Third, patients with persistent PHfter PTE (about 10% to 15%), and who often haveignificant residual distal pathology, should be consideredor medical therapy. Finally, when surgery is contraindicatedue to significant comorbidity, medical therapy can beonsidered. Data from open label observations of medicalherapy in CTEPH have been recently reviewed and areromising but do not permit derivation of a strong evidencease (104).

.3.3. Pulmonary Hypertension in theardiac Surgical Patient

s the spectrum of cardiac surgical procedures—coronaryevascularization, valve repair and replacement, mechanicalssist device implantation, and cardiac transplantation—haseen offered to an increasingly complex population ofatients, the importance of peri- and postoperative PH andight heart failure has become apparent. Often, PH is notedreoperatively and appropriate therapy may be initiatedrior to surgery. Less commonly, it develops peri-peratively without antecedent evidence of pulmonary vas-ular disease or right heart failure. Outcomes are signifi-antly worse in patients with perioperative PH and RVailure (218–220), prompting interest in the utility of newerherapies for this situation, including PAH-specific thera-ies. Little information has emerged thus far regarding thetility of these therapies in this setting, and concern existsegarding potential adverse effects should left-sided cardiaclling pressures not be normalized following surgery.

.3.4. Preoperative Pulmonary Hypertension

ignificant PH has been reported in several patient popu-ations in which cardiac surgery may be required, and it isarticularly common in patients with chronic mitral orortic valvular disease and in those with chronic severe lefteart failure (218–220). In the latter group, the presence ofignificant PH with a high PVR may disqualify a patientrom receiving an orthotopic cardiac transplantation. Re-ersibility of the high PVR is often assessed by the admin-
stration of short acting pulmonary and systemic arterial


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asodilators (221). Several reports describe the use ofhronic vasodilator agents or mechanical LV assistance toower PVR in patients with chronic left heart failure andnitially fixed PH. Specific PAH therapies are rarely used inatients with PH resulting from chronic valvular disease or

eft heart failure; the persistently elevated left-sided cardiaclling pressures generally seen in these patients puts them atisk for pulmonary edema when challenged with a selectiveulmonary vasodilator. Furthermore, studies have indicatedhat despite the adverse impact of PH on survival, surgicalortic or mitral valve replacement and percutaneous mitralalvuloplasty all have acceptable outcomes and frequentlyesult in regression of PH (218,222,223).

.3.5. Postoperative Pulmonary Hypertension

H may persist following cardiac surgery despite successfuleduction of left-sided cardiac filling pressures to normal orear-normal levels. In this circumstance, initiation of PAH-pecific therapy may be considered. It is advisable toerform full RHC to ensure normalization of left-sidedardiac filling pressures prior to beginning such treatment.e novo PH following cardiac surgery is quite unusual.Studies suggest that some patients with mitral stenosis

ave a significant rate of residual PH following successfulercutaneous balloon valvuloplasty (223) or surgical com-issurotomy or valve replacement (222). The incidence

ppears highest in patients with the greatest elevation ofVR preoperatively, and may be as high as 25% (223). PHay complicate aortic stenosis as well, and may also persist

ollowing surgical valve replacement (218). The incidence ofH following LV assist device implantation for chronicevere heart failure is uncertain. One study suggested thatearly 50% of such patients will have evidence of at leastild PH acutely upon weaning from cardiopulmonary

ypass (224). PH is fairly common following cardiac trans-lantation; the estimated incidence of at least mild PH haseen in excess of 60% (225). Severe PH following cardiacransplantation is rare, likely owing to aggressive preopera-ive screening for fixed PH in transplant candidates.

A number of therapeutic strategies have been employedor patients with PH with or without RV failure during andollowing cardiac surgery. In a population undergoing aariety of surgical interventions including coronary revascu-arization, valve repair and replacement, mechanical assistevice implantation, and cardiac transplantation, inhaledO, given at a dose of 20 ppm for a mean of 36 hours,

mproved pulmonary and systemic arterial pressures andardiac index (226). Other studies have shown similarenefits of NO in more homogenous populations with PHollowing valve surgery (227), ventricular assist device im-lantation (224), and cardiac transplantation (228). Onalance, inhaled NO is an effective short-term strategy forhe management of PH following cardiac surgery. Inhaledrostacyclin has also been used in patients with PH follow-ng valve surgery (229). A head-to-head comparison of
nhaled prostacyclin and NO in this population found both m

o be effective and to have better tolerability than intrave-ous nitroprusside (230). Inhaled iloprost has been useduccessfully in patients with PH and acute RV failure duringnd following cardiac transplantation (231). Sildenafil haseen reported to have beneficial hemodynamic effects whendministered by nasogastric tube in patients undergoingardiac surgery who develop intraoperative PH (232).

For more persistent PH following cardiac surgery, oralAH therapy may be considered. A small case seriesuggested that oral sildenafil may be helpful in weaningatients from intravenous or inhaled PAH therapy for PHollowing cardiac surgery (233). No clinical reports exist ofosentan used for this indication; however, a preclinicaltudy demonstrated its ability to prevent PH associated withardiopulmonary bypass (234).

.4. Summary of Recommendations

. Patients with PH require a thorough diagnostic eval-uation to elucidate the roles of pulmonary venoushypertension, chronic lung disease with hypoxemia,and/or pulmonary thromboembolism to the patho-genesis of their disease.

Accordingly, RHC, lung function and imaging studies,etermination of arterial oxygen saturation (at rest, withctivity, and overnight), and ventilation-perfusion scanningre all mandatory elements of the assessment of theseatients.. Patients with PH related to pulmonary venous hyper-

tension may be considered for PAH-specific therapyprovided:a. the cause of the pulmonary venous hypertension is

first optimally treated; andb. the PCWP is normal or only minimally elevated; andc. the transpulmonary gradient (TPG) and PVR are

significantly elevated; andd. the patient’s symptoms suggest that PAH-specific

therapy may yield clinical benefit.Treatment of such patients with PAH-specific therapy

hould be undertaken with great care, as these treatmentsay result in an increase in fluid retention, left-sided cardiac

lling pressures, and pulmonary edema, and result in clinicaleterioration. Decisions about whether and how to treatuch patients should be made on a case by case basis byxperienced PH caregivers.. Patients with PH related to chronic lung disease and

hypoxemia may be considered for PAH-specific ther-apy provided:a. the chronic lung disease and hypoxemia are first

optimally treated; andb. the TPG and PVR are significantly elevated; andc. the patient’s symptoms suggest that PAH-specific

therapy may yield clinical benefit.Treatment of such patients with PAH-specific therapy

hould be undertaken with great care, as these treatments
ay result in worsened hypoxemia and clinical deteriora-


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ion. Decisions about whether and how to treat suchatients should be made on a case by case basis byxperienced PH caregivers.. Patients with chronic thromboembolic PH may be

considered for PAH-specific therapy provided:a. appropriate secondary preventative measures, in-

cluding anticoagulation, has been instituted; andb. PTE has been performed or is not indicated; andc. the TPG and PVR are significantly elevated; andd. the patient’s symptoms suggest that PAH-specific

therapy may yield clinical benefit.Decisions about whether and how to treat such patients

hould be made on a case by case basis by experienced PHaregivers.. Patients with PH following cardiac surgery may be

considered for PAH-specific therapy provided:a. the surgery and concomitant medical therapy pro-

vide optimal treatment of the underlying cardiacdisease; and

b. the surgery and concomitant medical therapy resultin a normal or only minimally elevated PCWP; and

c. the TPG and PVR remain significantly elevated; andd. the patient’s clinical condition suggests that PAH-

specific therapy may yield clinical benefit.Decisions about whether and how to treat such patients

hould be made on a case by case basis by experienced PHaregivers.

0. Congenital Heart Disease-Relatedulmonary Arterial Hypertension

verall, the incidence of CHD is approximately 8 per 1,000ive births (235).

Many different forms of CHD are associated with anncreased risk for the development of pulmonary vascularisease (PVD). In patients with systemic-to-pulmonaryhunts, the type and size of the defect, as well as theagnitude of the shunt, are risk factors for the development

f PAH. Shear stress due to increased pulmonary blood flownd/or increased pulmonary artery pressure appears to playmajor role in the development of PVD related to CHD.ased on natural history studies, approximately 30% of allhildren born with CHD who do not undergo surgicalepair will develop PVD (235).

However, to date we have limited ability to determinehich patients develop early irreversible PVD. There ap-ears to be a difference between the pre- and post-tricuspidhunt lesions. The laminar shear stress induced by thencrease in pulmonary blood flow alone may not be the sames the laminar and circumferential pressure shear stressnduced by post-tricuspid shunt lesions, for example, aentricular septal defect. Patients with small- to moderate-ized ventricular septal defects develop PVD in only approx-mately 3% of cases; in contrast, almost all patients with an
nrepaired truncus arteriosus develop PVD, while approx- r

mately 50% with a large ventricular septal defect and 10%ith an atrial septal defect develop PVD. In addition, there

s significant biologic variability in the clinical presentationnd prognosis. While some children with the same under-ying CHD develop irreversible PVD in the first year of life,thers with the same CHD may maintain acceptable levelsf pulmonary vascular resistance for many years. A recenttudy demonstrated BMPR2 mutations in patients withAH in CHD. Mutations in BMPR2 occur in patientsith FPAH and IPAH. These data raise the possibility that

he presence of a genetic predisposition in some patientsith CHD may contribute to the observed biologic vari-

bility (236). Further investigation into the role of geneticutations may offer insight into which children with CHD

hould undergo surgical repair during early infancy. How-ver, whether early therapeutic interventions halt or reversehe progression of the PVD remains unclear.

Over the past several decades, advances in pediatricardiology/cardiac surgery have increased the number ofatients with CHD surviving into adulthood. However,espite surgical correction of large systemic-to-pulmonaryhunts in infancy, surgical repair does not guarantee thatatients will not develop PVD postoperatively, and thuslthough early diagnosis and improved cardiac surgery haveignificantly decreased the number of patients overall withisenmenger syndrome, some of these patients, for reasons

hat remain unclear, develop progressive PVD followingurgical repair. In addition to the symptoms and complica-ions associated with PAH without Eisenmenger syndrome,atients with Eisenmenger syndrome have additional co-orbid conditions due to right-to-left shunting and hypox-

mia resulting in hematologic, hemostatic, cerebrovascular,enal, rheumatologic, and cardiac complications.

With respect to therapeutic interventions, whether med-cal or surgical, risk:benefit considerations need to be care-ully evaluated based on the natural history of the conditions well as on an individual basis. The survival and long termutcome for patients with classic Eisenmenger syndrome isuite different than for patients with other forms of PAH,uch as IPAH/FPAH or PAH related to connective tissueisease (72). Untreated, survival rates are 80% at 5 years andpproximately 40% at 25 years. Despite the differences intiology and prognosis, PAH associated with CHD sharesimilarities with IPAH, for example, pulmonary vascularistopathology. Based on these similarities, therapeuticodalities demonstrated to be efficacious in patients with

PAH are beginning to be evaluated in patients with PAHssociated with CHD based on presumed similar pathobi-logy. As opposed to patients with IPAH, in whom theikelihood of acute pulmonary vasoreactivity with effectiveong-term calcium channel blockade therapy is less than0%, this is virtually nonexistent in patients with PAHelated to CHD. To date, the only disease-specific targetedAH therapy that has been demonstrated to be efficacious

n patients with PAH related to CHD is the ETA/ETB
eceptor antagonist bosentan. Although this trial was only


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6 weeks in duration, a relatively short period of time foratients with Eisenmenger syndrome in whom the naturalistory is significantly more protracted than for IPAH,osentan improved exercise capacity and decreased pulmo-ary vascular resistance without worsening systemic arterialxygen saturation; the safety and tolerability profile wasomparable to that observed with previous PAH bosentanrials (146). In addition, although not randomized con-rolled trials, several open label uncontrolled studies haveeported improved exercise capacity and hemodynamicsincluding improvement in systemic arterial oxygen satura-ion) with chronic intravenous epoprostenol (79,130). Theisk of complications with chronic intravenous epoproste-ol, such as paradoxical emboli, needs to be carefullyeighed in patients with unrepaired or residual congenitaleart defects. Whether nonparenterally administered pro-tanoids such as inhaled or oral prostanoids will prove to befficacious remains to be determined. In addition, whetherDE-5 inhibitors such as sildenafil will be efficacious inatients with PAH/CHD will require further study.

1. Pediatric Pulmonary Arterial Hypertension

1.1. Persistent Pulmonary Hypertensionf the Newborn

ersistent pulmonary hypertension of the newborn (PPHN)s a syndrome characterized by increased pulmonary vascularesistance, right-to-left shunting, and severe hypoxemia.PHN is frequently associated with pulmonary parenchy-al abnormalities, including meconium aspiration, pneu-onia, sepsis, lung hypoplasia, and alveolar capillary dys-

lasia. In some instances there is no evidence of pulmonaryarenchymal disease, and the etiology is unknown. Thus,lthough PPHN is multifactorial in origin, the nature of thenderlying defect(s) causing failure to adapt to extrauterineife is uncertain. This is not surprising, since the mecha-isms responsible for achieving a normal fall in PVR at birthre poorly understood. In the mature pulmonary circulation,he interaction between healthy endothelial and smoothuscle cells produces a balance between relaxation and con-

raction favoring relaxation due to release of endothelium-erived NO. Whether failure to achieve the normal reductionn PAP at birth is due to failure of endothelium-dependentnd/or independent relaxation, a primary structural abnor-ality of the pulmonary vascular smooth muscle cells, or an

xcess of vasoconstrictor agents such as endothelin or throm-oxane remains unclear. Increased circulating endothelin-1evels have been reported after birth in these neonates.

owever, the primary abnormality most likely varies witharious risk factors similar to what is postulated for variousther forms of PAH. The rationale for treating with inhaledO and possibly a PDE-5 inhibitor such as sildenafil is due

o an absolute or relative lack of endogenous NO. Lungecruitment strategies facilitated by high frequency ventila-
ion may be particularly useful in enhancing the efficacy of d

nhaled NO. Extracorporeal membrane oxygenation hasmproved survival for neonates with refractory hypoxemia,lthough it may be associated with significant morbidityi.e., hemorrhagic, neurologic, and other complications). Thefficacy of inhaled NO has also been demonstrated in multi-enter randomized clinical trials, (i.e., improved oxygenationnd reduction in the need for extracorporeal membrane oxy-enation). However, despite the significant advances in treat-ent strategies for PPHN, this condition continues to have an

nacceptably high morbidity and mortality rate of approxi-ately 10% to 20%.

1.2. Pediatric Pulmonary Arterial Hypertension

ithout treatment, the natural history for children withPAH is worse than in adults; however, with treatment, theutcome appears better in children than in adults. Unfor-unately, due to limited data in children with PAH, man-gement decisions are often extrapolated from adult studies.he selection of optimal therapy is complex, as there are no

onsistently successful treatments, and some agents maynvolve complicated delivery systems, specific dosing regi-

ens, side effects, and potential complications. Further-ore, if the disease progresses, the treatment may have to be

evised based on risk:benefit considerations.In the absence of studies specifically reporting the clinical

esponse of children to PAH therapy, similar clinical strat-gies have been suggested for the management of PAH inhildren; however, without evidence-based data, theseuidelines must be used with caution. It should also beighlighted that children not infrequently have a very highAP but remain in functional class II due to the absence ofV failure during childhood. Those with syncope or near

yncope, despite their functional class based on their level ofyspnea, should be treated aggressively, as one would treat aunctional class IV patient. Based on expert consensus, thenitial approach following the diagnosis of PAH in a childs, in the absence of a contraindication, to treat the childith digitalis and diuretics, anticoagulation with warfarin,

nd supplemental oxygen if clinically indicated. Patientsho are responders to acute vasoreactivity testing are also

reated with high-dose calcium channel blockade; nonre-ponders and responders who remain functional class III areonsidered for treatment with either an endothelin receptorntagonist, for example, bosentan, a PDE-5 inhibitor, forxample, sildenafil, or a prostanoid, for example, inhaledloprost. Functional class IV children and class III patientsho do not improve with an endothelin receptor antagonist,DE-5 inhibitor, or inhaled prostanoid should be consid-red for treatment with an intravenous prostanoid, forxample, epoprostenol/treprostinil. Due to differences inetabolic activity in children versus adults, acute and

hronic pharmacokinetic studies are helpful to determineptimal dosing in children. With the advent of new drugsith targeted mechanisms of action, combination therapy mayecome an attractive option for children who fail to improve or
eteriorate with a single agent; however, clinical data are


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urrently limited. Finally, atrial septostomy and lung or heart-ung transplantation can be considered for refractory PAH.

Based on similar pathobiology and pathophysiology inhildren and adults with various forms of PAH, the con-ensus amongst the PH community is that the diseases arehe same in children and in adults. The increased under-tanding of FPAH further supports this, with geneticnticipation highlighting the biologic variability that existsn many forms of PAH. However, in IPAH, a significantlyreater percentage of children (up to 40%) are acute re-ponders compared with adults, and the younger the child ist the time of diagnosis, the greater the likelihood of acuteulmonary vasoreactivity with acute vasodilator testing.ncontrolled trials have reported that long-term adminis-

ration of high-dose calcium channel blockade prolongsurvival in children, similar to that reported in adults (237).owever, despite continued calcium channel blockade ther-

py, the benefit observed in IPAH children who areesponders (97% 5-year survival) is not always preservedong term (10-year survival 81%) and treatment success at0 years in children who are acute responders is less than0% (238). Consequently, children who are acutely respon-ive at diagnosis still have a significant risk for treatmentailure long term on calcium channel blockade and needlose follow-up. Serial reevaluation, including repeat acuteasodilator testing, is necessary in these children to maintainn optimal therapeutic regimen.

Open label, uncontrolled studies with intravenouspoprostenol in IPAH children have demonstrated sus-ained clinical and hemodynamic benefits for over 10 years.ong-term intravenous epoprostenol has also been used

uccessfully in children with PAH associated with CHD,mproving hemodynamics and quality of life parameters.

ata on bosentan therapy for PAH in children remainimited. A retrospective analysis of 86 children with IPAHr PAH-CHD demonstrated beneficial long-term effects ofosentan (alone or in combination with intravenous epopro-tenol) on functional capacity, hemodynamics, and survivaln children with PAH (239). Subsequent analysis of theubgroup with PAH and CHD also demonstrated clinicalnd hemodynamic improvement similar to the experienceith adult Eisenmenger patients.Assessing safety and efficacy, particularly in young pedi-

tric patients, is problematic, that is, accurate assessment ofxercise capacity even in children old enough to exercise israught with difficulty. In addition, due to the biologicariability of PAH with the progressive nature more oftenore severe in the pediatric patients compared with adults,

thical issues become more problematic when consideringong observational periods to assess overall morbidity and

ortality. Long-term safety issues are equally problematichen initiating therapy with unknown long-term safety

ffects in children. Thus, although clinical investigation withhildren with PAH is more difficult and often approachedithout enthusiasm, the potential rewards for having a signif-

cant impact on overall quality of life as well as long-termcontent.onlinejaDownloaded from

urvival should far outweigh the difficulties and impediments ineveloping improved therapeutic modalities for children.

2. Pulmonary Hypertensionenters of Excellence

AH is a rare disease with a high mortality. Given theomplex nature of this disease, if at all possible, mostatients should be managed at or in conjunction with aAH Center of Excellence. Centers that specialize in PAHffer physicians with expertise and experience in this com-licated disease, nursing staff specially trained to assist in theanagement of PAH patients and the complex therapies for

his disease, and often clinical trials of investigational agents.ultidisciplinary programs enlist the expertise of both cardi-

logists and pulmonologists, and commonly rheumatologists,epatologists, infectious disease specialists, hematologists,ransplant physicians, psychologists, and social workers.

taff

merican College of Cardiology Foundationohn C. Lewin, MD, Chief Executive Officerharlene May, Senior Director, Science and Clinical Policyanja Kharlamova, Associate Director, Science andClinical Policy

areen Pourhamidi, MS, MPH, Senior Specialist,Evidence-Based Medicinearıa Velasquez, Specialist, Science and Clinical Policy

rin A. Barrett, Senior Specialist, Science and Clinical Policy

merican Heart Associationancy Brown, Chief Executive Officerose Marie Robertson, MD, FAHA, FESC, ChiefScience Officerayle R. Whitman, PhD, RN, FAHA, FAAN, Senior VicePresident, Office of Science Operations

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ey Words: ACCF/AHA Expert Consensus Document y pulmonaryypertension y pulmonary arterial hypertension y hemodynamics yrostacyclin y endothelin receptor antagonists y phosphodiesterase
nhibitors.
PPENDIX 1. AUTHOR RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES—ACCF/AHA 2009XPERT CONSENSUS DOCUMENT ON PULMONARY HYPERTENSION

Committee MemberConsulting Fees/

Honoraria Speaker’s Bureau

Ownership/Partnership/

Principal Research GrantBoard ofDirectors

Expert Witnessor Consultant

r. Vallerie V.McLaughlin (Chair)

● Actelion*● CoTherix*● Gilead/Myogen*● Pfizer

● Actelion*● CoTherix● Gilead/Myogen● Pfizer

None ● Actelion*● CoTherix*● Encysive*● Lung Rx*● Pfizer*● United

Therapeutics*

None No

r. Stephen L.Archer

None None None None None No

r. David Badesch ● Actelion*● Amgen● CoTherix*● Encysive*● Gilead/Myogen*● GlaxoSmithKline● InterMune● Mondo Biotech● Pfizer*● PR

Pharmaceuticals● Scios● United

Therapeutics/Lung Rx

None None ● Actelion*● CoTherix*● Encysive*● Gilead/Myogen*● Lilly/ICOS*● Pfizer*● United

Therapeutics/Lung Rx

● PulmonaryHypertensionAssociation

Yes. Diet druglitigation.

r. Robyn J. Barst ● Actelion*● CoTherix*● Encysive*● Generamedix● Gilead/Myogen● GlaxoSmithKline● INO Therapeutics*● Lung Rx● Medtronic● MondoBIOTECH● Pfizer*● Novartis● United

Therapeutics*

● Actelion*● CoTherix*● Encysive*● Gilead● INO Therapeutics● Pfizer*

None ● Actelion*● CoTherix*● Encysive*● Gilead/Myogen● INO Therapeutics*● Lung Rx● Medtronic● MondoBIOTECH● Novartis● Pfizer*● United

Therapeutics*

None Yes. Diet druglitigation.

r. Harrison W.Farber

● Actelion● Gilead/Myogen● United Therapeutics

● Actelion● Encysive● Gilead/Myogen● Pfizer

None ● Actelion● Epix● Gilead● Scios*

None No

r. Jonathan R.Lindner




D

D

D

D

D

D

D

T

a

d

m

i


Committee MemberConsulting Fees/

Honoraria Speaker’s Bureau


Principal Research GrantBoard ofDirectors

Expert Witnessor Consultant

r. Michael A.Mathier

● Actelion*● Gilead/Myogen

● Actelion*● CoTherix● Encysive● GlaxoSmithKline● Scios

None ● Actelion* None No

r. Michael D.McGoon

● Actelion● CoTherix*● Medtronic● United

Therapeurtics

None None ● Actelion*● CoTherix*● Encysive● Gilead/Myogen*● Medtronic*● Pfizer*● United Therapeutics

None No

r. Myung H. Park ● Actelion*● CoTherix● Encysive● Pfizer● United Therapeutics

● Actelion*● CoTherix● Encysive● Pfizer● United Therapeutics

None ● Actelion*● CoTherix

None No

r. Robert S.Rosenson

● Abbott● Anthera● AstraZeneca*● Daiichi Sankyo● LipoScience● Roche

None ● LipoScience* None ● Grain Board No

r. Lewis J. Rubin ● Actelion*● Aires● CoTherix*● Encysive*● Gilead/Myogen*● Mondo Biotech● Pfizer● United

Therapeutics*

None ● Aires● United

Therapeutics*

● Actelion*● CoTherix*● Gilead/Myogen*● Pfizer*● United

Therapeutics*

None Yes. Diet druglitigation(plaintiff).

r. Victor F. Tapson ● Actelion*● CoTherix*● Encysive● Gilead/Myogen*● Lungs Rx*● Pfizer● United Therapeutics

● Actelion*● Gilead/Myogen*

None ● Actelion*● CoTherix*● Encysive*● Gilead/Myogen*● Lungs Rx*● Pfizer*● United

Therapeutics*

None Yes. Diet druglitigation.

r. John Varga ● Actelion* None None None None No

his table represents the relevant relationships of committee members with industry and other entities that were reported orally at the initial writing committee meeting and updated in conjunction with

ll meetings and conference calls of the writing committee during the document development process. It does not necessarily reflect relationships with industry at the time of publication. A person is

eemed to have a significant interest in a business if the interest represents ownership of 5% or more of the voting stock or share of the business entity, or ownership of $10 000 or more of the fair

arket value of the business entity; or if funds received by the person from the business entity exceed 5% of the person’s gross income for the previous year. A relationship is considered to be modest

f it is less than significant under the preceding definition. Relationships noted in this table are modest unless otherwise noted. *Significant (greater than $10 000) relationship.



AE

D

D

D

D

D

D

D

D

D

D


PPENDIX 2. PEER REVIEWER RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES—ACCF/AHA 2009XPERT CONSENSUS DOCUMENT ON PULMONARY HYPERTENSION

PeerReviewer Representation Consultant Speaker


Principal Research

Institutional,Organizational, orOther Financial

Benefit Expert Witness

r. Robert S.Rosenson

Official Reviewer—ACCF Task Forceon ClinicalExpertConsensusDocuments

● Abbott● Anthera● AstraZeneca*● Daiichi Sankyo● LipoScience● Roche

None ● LipoScience* None ● Grain Board No

r. Vincent F.Carr

Official Reviewer—ACCF Board ofGovernors


r. Patrick T.O’Gara

Official Reviewer—ACCF Board ofTrustees


r. Karen A.Fagan

Official Reviewer—AHA

● Gilead/Myogen ● Gilead/Myogen None None None No

r. StuartRich

Official Reviewer—AHA


r. Kamal K.Mubarak

OrganizationalReviewer—AmericanCollege of ChestPhysicians

● Actelion● Encysive● Gilead/Myogen● United

Therapeutics

● Actelion● Encysive● Gilead/Myogen

None ● Actelion● Encysive● Gilead/Myogen● Lilly/ICOS

None No

r. FranciscoSoto

OrganizationalReviewer—AmericanCollege of ChestPhysicians

● Actelion*● Gilead/Myogen

● Actelion* None None ● Actelion*● Encysive*● Pfizer*

No

r. NicholasS. Hill

OrganizationalReviewer—AmericanThoracic Society

● Actelion● Gilead/Myogen● United

Therapeutics

● Actelion● Gilead/Myogen

None ● Actelion*● Epix● Gilead/Myogen*● Lilly*● Lung RX*● Pfizer*● United

Therapeutics*

None No

r. Ronald J.Oudiz

OrganizationalReviewer—PulmonaryHypertensionAssociation

● Actelion● Gilead/Myogen● GlaxoSmithKline● Lilly/ICOS● Lung RX● Pfizer● United

Therapeutics

● Actelion● Gilead/Myogen● Pfizer● United

Therapeutics

None ● Actelion● Gilead/Myogen● GlaxoSmithKline● Lilly/ICOS● Lung RX● Pfizer● United

Therapeutics

None No

r. IvanRobbins

OrganizationalReviewer—PulmonaryHypertensionAssociation

● Actelion● Gilead/Myogen

None ● Actelion● Gilead/Myogen

● Actelion● BioMarin● Gilead/Myogen● Pfizer● United

Therapeutics

None 2006, 2007;Representedplaintiffs incasesinvolving thepotential roleof appetitesuppressantsin thedevelopmentof pulmonaryhypertension.



D

D

D

D

D

D

D

D

D

D




Principal Research



r. JavedButler

Content Reviewer—ACCF HeartFailure &TransplantCommittee

None ● Boehringer● Ingelheim*● GlaxoSmithKline*● Novartis*

None None None No

r. David E.Lanfear


● Thoratec None None None None No

r. Donna F.Petruccelli



r. LouisBezold

Content Reviewer—ACCF AdultCongenital &PediatricCardiologyCouncil


r. MerylCohen



r. Jeffrey A.Feinstein


● Eli Lilly● United

Therapeutics

None None ● iNOTherapeutics

● Pfizer

None No

r. Charles R.Bridges

Content Reviewer—ACCF TaskForce onClinical ExpertConsensusDocuments


r. AliceJacobs



r. David J.Moliterno


● BostonScientific

● Schering-Plough

None None None ● Boston Scientific No

r. DebabrataMukherjee





D

D

M

Tpocc




Principal Research



r. Richard S.Schofield


● Medtronic ● AtCor Medical● Novartis● Scios

None None None No

r. James H.Stein


● Amgen● LipoScience● Merck● Pfizer

● KOS● Pfizer*● Takeda*

● WisconsinAlumniResearchFoundation

● AstraZeneca*● Bristol-Myers

Squibb*● LipoScience● PreMD● Sanofi-Aventis● Sonosite

● KOS No

s. DeborahWesley-Farrington



his table represents the relevant relationships with industry and other entities that were disclosed at the time of peer review. It does not necessarily reflect relationships with industry at the time ofublication. A person is deemed to have a significant interest in a business if the interest represents ownership of 5% or more of the voting stock or share of the business entity, or ownership of $10 000r more of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person’s gross income for the previous year. A relationship isonsidered to be modest if it is less than significant under the preceding definition. Relationships in this table are modest unless otherwise noted. Names are listed in alphabetical order within eachategory of review. *Significant (greater than $10 000) relationship.



doi:10.1016/j.jacc.2009.01.004

2009;53;1573-1619; originally published online Mar 30, 2009;J. Am. Coll. Cardiol.Varga

Myung H. Park, Robert S. Rosenson, Lewis J. Rubin, Victor F. Tapson, and John McGoon,Harrison W. Farber, Jonathan R. Lindner, Michael A. Mathier, Michael D.

Vallerie V. McLaughlin, Stephen L. Archer, David B. Badesch, Robyn J. Barst, Thoracic Society, Inc.; and the Pulmonary Hypertension Association

in Collaboration With the American College of Chest Physicians; American DevelopedExpert Consensus Documents and the American Heart Association

Report of the American College of Cardiology Foundation Task Force on ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension: A

This information is current as of April 30, 2012

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