Vol 14, No 2; 2015

ISSN 1933-088X

Pulmonary HypertensionOff icial Journal of the Pulmonary Hypertension Association

Advances in

Research Reviews Oksana A. Shlobin, MD; Jonathan D. Rich, MD

Overview of WHO Group 2 Pulmonary Hypertension Due to Left Heart Disease Christopher F. Barnett, MD, MPH; Van N. Selby, MD

The Right Ventricle: A Not-So-Innocent Bystander in Pulmonary Hypertension Due to Left Heart Disease Brian A. Houston, MD; Steven Hsu, MD; Emmanouil Tampakakis, MD; Ryan J. Tedford, MD

Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction: Clinical Relevance, Management, and Future Directions Rebecca Cogswell, MD; Thenappan Thenappan, MD

Pulmonary Hypertension Due to Valvular Heart Disease: Aortic and Mitral Ryan Karl Kaple, MD; Evelyn M. Horn, MD

Ask the Expert: Is Cardiac Magnetic Resonance Imaging Underutilized in the Diagnosis of Pulmonary Hypertension? Jordan Ray, MD; Charles Burger, MD; Joseph Blackshear, MD; Robert Safford, MD, PhD; Patricia Mergo, MD; Brian Shapiro, MD

Roundtable: Pulmonary Hypertension Due to Left Heart Disease Teresa De Marco, MD; Brian Shapiro, MD; James Fang, MD; Barry Borlaug, MD; Srinivas Murali, MD

Pulmonary Hypertension and Left Heart Disease

Editorial Advisory Board

Editor-in-ChiefCharles Burger, MDProfessor of MedicineMayo Clinic College of MedicineMedical Director, PH ClinicMayo Clinic FloridaJacksonville, Florida

Immediate Past Editor-in-ChiefMyung Park, MDAssociate Professor of MedicineDirector, Pulmonary Vascular Diseases

ProgramDivision of CardiologyUniversity of Maryland School of

MedicineBaltimore, Maryland

Editor-in-Chief ElectHarrison Farber, MDProfessor of MedicineDirector, Pulmonary Hypertension CenterBoston University/Boston Medical CenterBoston, Massachusetts

Associate EditorsKelly Chin, MDAssistant Professor of MedicineUniversity of Texas Southwestern

Medical CenterDallas, Texas

Dunbar Ivy, MDProfessor of PediatricsUniversity of ColoradoDenver Health Sciences CenterDenver, Colorado

Deborah Jo Levine, MDAssociate ProfessorPulmonary and Critical Care MedicineLung Transplant PulmonologistDirector of Pulmonary Hypertension CenterDivision of Cardiothoracic SurgeryUniversity of Texas Health Science

Center at San AntonioSan Antonio, TexasSection Editor

Ioana Preston, MDCo-Director, Pulmonary Hypertension

CenterTufts Medical CenterBoston, MassachusettsSection Editor

Sean M. Studer, MD, MScChief of MedicineWoodhull Medical CenterNew York UniversityNew York, New YorkSection Editor

Fernando Torres, MDDirector, Pulmonary Hypertension ClinicUniversity of Texas Southwestern Medical

CenterDallas, TexasInternational Editor

Editorial BoardLynette M. Brown, MDAssistant Professor of MedicineUniversity of Utah School of MedicineMurray, Utah

Jeffrey D. Edelman, MDAssociate Professor of MedicinePulmonary and Critical Care DivisionUniversity of WashingtonVA Puget Sound Health Care SystemSeattle, Washington

Paul Forfia, MDAssociate Professor of MedicineMedical Director, Pulmonary

Hypertension Program and RightHeart Failure

Temple Heart and Vascular CenterTemple University School of MedicinePhiladelphia, Pennsylvania

Sean Gaine, MD, PhDDirector, National Pulmonary

Hypertension UnitMater Misericordiae University HospitalUniversity College DublinDublin, Ireland

Anna Hemnes, MDAssistant Professor of MedicineAssistant Director, Pulmonary Vascular

CenterVanderbilt UniversityNashville, Tennessee

Richard Krasuski, MDDirector of Adult Congenital Heart

Disease ServicesCleveland ClinicCleveland, Ohio

Usha Krishnan, MDAssociate Professor of PediatricsColumbia University Medical CenterAssociate Director, Pulmonary

Hypertension CenterNew York, New York

Jonathan Rich, MDAssistant Professor in Medicine-CardiologyNorthwestern University Feinberg School

of MedicineAdvanced Heart Failure and Transplant

CardiologistNorthwestern Memorial HospitalChicago, Illinois

Oksana Shlobin, MDCo-Director, Pulmonary Hypertension

ProgramAssistant Director, Advanced Lung

Disease and Transplant ProgramInova Health SystemFalls Church, Virginia

Crystal Weber, RNNurse ClinicianDuke University Medical CenterDurham, North CarolinaPHPN Section Editor

Program DescriptionThe mission of Advances in Pulmonary Hy-pertension is to serve as the premiere forumfor state of the art information regardingdiagnosis, pathophysiology, and treatmentof pulmonary hypertension. The 2008 DanaPoint revision of the World Health Orga-nization Classification serves as a guide tocategories of pulmonary hypertension ad-dressed in Advances in Pulmonary Hyperten-sion. While focusing on WHO Group 1PAH, the other categories (Group 2, pul-monary venous hypertension; Group 3, as-sociated with chronic lung disease and/orhypoxemia; Group 4, pulmonary embolichypertension; Group 5, miscellaneous) arealso addressed. This mission is achieved bya combination of invited review articles,roundtable discussions with panels consist-ing of international experts in PH, and orig-inal contributions.

Objectives● Provide up-to-date information regard-

ing diagnosis, pathophysiology, and treat-ment of pulmonary hypertension.

● Serve as a forum for presentation anddiscussion of important issues in the field,including new paradigms of disease un-derstanding and investigational trialdesign.

The Scientific Leadership Council of the Pulmonary Hypertension AssociationThe scientific program of the Pulmonary Hypertension Association is guided by the association’s Scientific Leadership Council. The Council includes the following health care professionals.

Karen A. Fagan, MDChairChief of Pulmonology, Critical CareProfessor of Internal Medicine and PharmacologyUniversity of South AlabamaMobile, AL

Richard N. Channick, MDImmediate Past ChairAssociate Professor of MedicineHarvard Medical SchoolDirector, Pulmonary Hypertension ProgramMassachusetts General HospitalBoston, MA

Erika S. Berman Rosenzweig, MDChair-ElectAssociate Professor of Clinical Pediatrics in MedicineColumbia Presbyterian Medical CenterNew York, NY

Serpil C. Erzurum, MDChair, Department of PathobiologyLerner Research InstituteThe Cleveland Clinic FoundationCleveland, OH

Michael A, Mathier, MDChair, PHA Online University CommitteeAssistant Professor of MedicineDirector of Pulmonary Hypertension ProgramUniversity of Pittsburg Medical CenterPittsburgh, PA

Ronald J. Oudiz, MDChair, Insurance Advocacy CommitteeProfessor of MedicineDirector, Liu Center for Pulmonary HypertensionLA Biomedical Research Institute at Harbor-UCLA

Medical CenterTorrance, CA

Myung H. Park, MDDirector, Pulmonary Vascular Diseases ProgramDivision of CardiologyUniversity of Maryland Medical CenterBaltimore, MD

Robert J. Schilz, DO, PhDMedical Director, Lung Transplantation and

Pulmonary Vascular DiseaseAssociate Professor of MedicineCase Western Reserve University School of MedicineCleveland, OH

Ian Adatia, MBChBProfessor of PediatricsUniversity of AlbertaDirector, Pulmonary Hypertension ClinicStollery Children’s HospitalAlberta, Canada

Todd M. Bull, MDChair, Research CommitteeAssociate Professor of MedicineUniversity of ColoradoDenver, CO

Murali M. Chakinala, MDAssociate ProfessorWashington University School of MedicineDivision of Pulmonary and Critical CareSt. Louis, MO

Lorinda Chung, MDAssistant Professor of MedicineStanford UniversityPalo Alto, CA

Charles D. Burger, MDEditor-In-Chief, Advances in Pulmonary HypertensionProfessor of MedicineMayo Clinic College of MedicineJacksonville, FL

Hyong (Nick) Kim, MDAssociate Clinical Professor of Medicine

Director, Pulmonary Vascular MedicineUniversity of California San DiegoLa Jolla, CA

James R. Klinger, MDDirector, Pulmonary Hypertension CenterAssociate Professor of MedicineBrown UniversityProvidence, RI

Irene M. Lang, MDProfessor of Vascular BiologyDeputy Chair, Division of CardiologyMedical University of ViennaVienna, Austria

Roberto F. Machado, MDAssociate Professor of MedicineUniversity of Illinois at ChicagoChicago, IL

Stephen C. Mathai, MD, MHSAssistant Professor of MedicineJohns Hopkins UniversityBaltimore, MD

John H. Newman, MDVanderbilt University School of MedicineNashville, TN

Ioana R. Preston, MDChair, Education CommitteeCo-Director, Pulmonary Hypertension CenterAssociate Professor of MedicineTufts University School of MedicineBoston, MA

Virginia Steen, MDProfessor, Division of RheumatologyGeorgetown University Medical CenterWashington, DC

Duncan J. Stewart, MDVice President, ResearchThe Ottawa HospitalOttawa, ON, Canada

Sean Studer, MD, MScChief of MedicineNYU-Woodhull Medical CenterBrooklyn, NY

Fernando Torres, MDHead of Lung Transplant and Pulmonary HTN

ProgramAssociate Professor of Internal MedicineUniversity of Texas Southwestern Medical CenterDallas, TX

Terence Trow, MDAssociate Professor of MedicineDirector, Pulmonary Vascular Disease ProgramSection of Pulmonary and Critical Care MedicineYale School of MedicineNew Haven, CT

Joel A. Wirth, MDDivision of Pulmonary & Critical Care Medicine,

Maine Medical CenterPortland, MATufts University School of MedicineBoston, MA

Roham T. Zamanian, MDAssociate Professor of MedicineStanford School of MedicineStanford, CA

LiaisonsMelisa Wilson, ARNP, ACNP-BC (voting)Chair, PH Professional NetworkOrlando Health Heart InstituteOrlando, FL

Crystal Weber, RN (non-voting)Chair-Elect, PH Professional NetworkChair, PH Professional Network Publications CommitteeDuke UniversityDurham, NC

Rita Orth, RNPHA Board MemberLos Angeles, CA

SLC Distinguished Advisory CommitteeDavid B. Badesch, MDProfessor of MedicineClinical Director, Pulmonary Hypertension CenterUniversity of Colorado Health Sciences CenterAurora, CO

Bruce Brundage, MDProfessor of Medicine EmeritusDavid Geffen School of Medicine at UCLABend, OR

C. Gregory Elliott, MDProfessor of MedicineUniversity of Utah School of MedicineMurray, UT

Michael D. McGoon, MDProfessor of MedicineMayo ClinicRochester, MN

Vallerie V. McLaughlin, MDDirector, Pulmonary Hypertension ProgramProfessor of MedicineUniversity of Michigan CVC Cardiovascular MedicineAnn Arbor, MI

The mission of the Scientific Leadership Council is toprovide medical and scientific guidance and support tothe PHA for:� Developing and disseminating knowledge fordiagnosing and treating pulmonary hypertension.

� Advocating for patients with pulmonary hypertension.� Increasing involvement of basic and clinicalresearchers and practitioners.

More information on PHA’s Scientific LeadershipCouncil and associated committees can be found at www.PHAssociation.org/SLC/

62 Editor’s MemoCharles Burger, MD

62 Guest Editors’ MemoTeresa De Marco, MD

68 Research ReviewsOksana A. Shlobin, MD; Jonathan D. Rich, MD

70 Overview of WHO Group 2 Pulmonary Hypertension Due to LeftHeart DiseaseChristopher F. Barnett, MD, MPH; Van N. Selby, MD

79 The Right Ventricle: A Not-So-Innocent Bystander in PulmonaryHypertension Due to Left Heart DiseaseBrian A. Houston, MD; Steven Hsu, MD; Emmanouil Tampakakis, MD;Ryan J. Tedford, MD

88 Pulmonary Hypertension Due to Heart Failure With Preserved EjectionFraction: Clinical Relevance, Management, and Future DirectionsRebecca Cogswell, MD; Thenappan Thenappan, MD

95 Pulmonary Hypertension Due to Valvular Heart Disease: Aortic and MitralRyan Karl Kaple, MD; Evelyn M. Horn, MD

102 Ask the Expert: Is Cardiac Magnetic Resonance Imaging Underutilized in theDiagnosis of Pulmonary Hypertension?Jordan Ray, MD; Charles Burger, MD; Joseph Blackshear, MD;Robert Safford, MD, PhD; Patricia Mergo, MD; Brian Shapiro, MD

105 Roundtable: Pulmonary Hypertension Due to Left Heart DiseaseTeresa De Marco, MD; Brian Shapiro, MD; James Fang, MD;Barry Borlaug, MD; Srinivas Murali, MD

Advances inPulmonary HypertensionOfficial Journal of the Pulmonary Hypertension Association

CONTENTSPUBLISHERPulmonary Hypertension AssociationKaren A. Fagan, MDRino Aldrighetti, President and CEO

PHA OFFICEPulmonary Hypertension Association801 Roeder Road, Ste 1000Silver Spring, MD 20910301-565-3004; 301-565-3994 (fax)

PUBLISHING OPERATIONSDeborah L. McBride,Managing EditorMcBride Strategic Servicesdeb@msspubs.com

Copyright ©2015 by Pulmonary HypertensionAssociation. All rights reserved. None of thecontents may be reproduced in any formwhatsoever without the written permission ofPHA.

Advances in Pulmonary Hypertension is availableonline at www.PHAOnlineUniv.org/journal

Advances in Pulmonary Hypertension iscirculated to cardiologists, pulmonologists,rheumatologists, and other selected healthcareprofessionals by the Pulmonary HypertensionAssociation. The contents of the articles areindependently determined by the Editor-in-Chief and the Editorial Advisory Board.

Advances in Pulmonary Hypertension: Author Guidelines

General InformationAdvances in Pulmonary Hypertension: Official Journal of thePulmonary Hypertension Association is a quarterly publi-cation directed by an editorial board of renowned expertswith the oversight of the Association’s Scientific Lead-ership Council. Its mission is to help physicians in theirclinical decision making by informing them of importanttrends affecting their practice and providing an analysis ofthe impact of new findings and current information in thepeer-reviewed literature. Each article is reviewed andapproved by members of the Editorial Advisory Board.

While most articles are invited by the editorial board, thefollowing submissions will be considered for publication:

• Reviews that summarize and synthesize peer-reviewedliterature to date on relevant topics

• Letters to the Editor• Clinical case studies

Submitted manuscripts are reviewed by the editorial boardand other experts in the field. Acceptance of manuscriptsis determined by factors such as quality, relevance, andperceived value to clinical decision making.

Manuscript Preparation and Submission ProcessSubmissions should be sent via e-mail as an attachedWord document to the managing editor, Deborah

McBride, at deb@msspubs.com Manuscripts should bedouble-spaced and follow AMA style. Full-length manu-scripts should not exceed 4,000 words including references.References should be limited to 50 entries. No more than5 figures should accompany the manuscript. Acceptablefile formats are .gif, .tif, and .jpg. Each figure should be aseparate file and figure legends should appear at the end ofthe manuscript. Each figure should be cited by number inthe manuscript. Tables should be self-explanatory anddetails of the table should not be repeated in the manu-script. Tables should be prepared as part of the Worddocument. No more than 3 tables should be included withthe manuscript. References should conform to AMA styleand be numbered consecutively in the text. Referencenumbers should be placed in parentheses at the end of therelevant sentence.

Accepted manuscripts will be edited for clarity, spelling,punctuation, grammar, and consistency with AMA style.

CopyrightAuthors must confirm they have rights to all material sub-mitted by including a copyright release form with themanuscript. The form can be downloaded from the PHAWeb site, www.PHAssociation.org. Authors acknowledgethe material has not been previously published nor is beingconsidered for publication elsewhere simultaneously withconsideration by Advances in Pulmonary Hypertension.

Any previously published figures, tables, etc. must containa full credit-line from the copyright owner. Authors areresponsible for obtaining permission to reproduce suchmaterial and must provide that material in reproducibleform.

Manuscripts are accepted for exclusive publication inAdvances in Pulmonary Hypertension and will be copy-righted by the Pulmonary Hypertension Association.

Conflict of Interest DisclosuresA statement of any and all grant, contract, and industrialsupport or proprietary interests of the author(s) related tothe subject matter must be submitted with the manuscript.

ChecklistAuthors should be certain to include the following withthe manuscript:

1. Title page listing all authors with their academicdegree(s) and affiliations.

2. Corresponding author contact information includinge-mail and phone number.

3. Copyright release form signed by all authors4. Conflict of Interest forms for all authors5. List of approximately 5 key words for indexing

purposes6. Summary of the paper not exceeding 250 words in the

format of Background; Objectives; Summary/Conclusions

61Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

EDITOR’S MEMO

The Challenges of PulmonaryHypertension in Left HeartDisease

Pulmonary hypertension (PH) is a rela-tively common complication of leftheart disease and represents a chal-lenging clinical situation for providersand patients alike. The aging demo-graphic in the United States andwidespread use of echocardiography inthese patients often results in patients’being referred for a consult to evaluatethe PH. The percentage of patientsevaluated in PH centers is sizeable andseemingly increasing. Unfortunately,

PH-specific treatment options arelimited. The 5th World Symposium onPulmonary Hypertension concludedthat “there is no validated treatment”for PH due to left heart disease.1

Indeed, there is an argument againstuse of pulmonary arterial hypertensionmedications outside clinical trials due tolack of proven efficacy and potential forharm.2 Regardless, there is a criticalneed for PH experts to have a thoroughunderstanding of the pathophysiology,clinical presentations, and most appro-priate management recommendations.The current issue, guest edited by Dr.Teresa De Marco, offers a wonderful

opportunity to review all of those issuesin detail.

Charles Burger, MDProfessor of MedicineMayo Clinic College of MedicineMedical Director, PH ClinicJacksonville, Florida

References1. Vachiery JL, Adir Y, Barbera JA, et al. Pul-monary hypertension due to left heart disease. J AmColl Cardiol. 2013;62(25 Suppl):D100-D108.2. Wiener RS, Ouellete DR, Diamond E, et al.An official American Thoracic Society/AmericanCollege of Chest Physicians policy statement: theChoosing Wisely top 5 list in adult pulmonarymedicine. Chest. 2014;145:1383-1391.

GUEST EDITOR’S MEMO

Pulmonary hypertension (PH) is acommon complication of left heartdisease (LHD), often related to severityof the underlying condition. Pulmonaryhypertension due to LHD (PH-LHD) ismost common in patients with heartfailure, with preserved (HFpEF) orreduced ejection fraction (HFrEF), andnegatively impacts symptoms, exercisecapacity, and outcome. PH-LHD hasbeen recognized as a growing problem interms of definition, classification, anddifferential diagnosis; but also for itsinfluence on outcome and therapy.Indeed, distinguishing between pul-monary arterial hypertension (PAH) andHFpEF can be challenging. Comparedwith PAH, patients with PH due toHFpEF are more often older, female,and have a history of systemic hyper-tension, atrial fibrillation, and many ofthe features of the metabolic syndrome.

The current hemodynamic definition ofPH-LHD combines a mean pulmonaryartery pressure �25 mm Hg, a pul-monary artery wedge pressure �15 mmHg, with variable transpulmonary gra-dient, diastolic pulmonary gradient, andpulmonary vascular resistance dependingon the presence of isolated post-capillaryPH versus combined post- and pre-capillary PH. However, the hemo-dynamic definition and the associatedterminology have clinical deficiencies andare explored in this issue. Efforts torefine the definition are required and areongoing. Other than treating the under-lying condition, management of PH inLHD remains an unmet medical needlacking an evidence-based approach andany specific approved therapy. Theabove-mentioned challenges afford anopportunity for a focused review of PHLHD. This issue of Advances in Pul-

monary Hypertension begins with acomprehensive overview by Drs. Barnettand Selby; followed by a sophisticateddiscussion of the right ventricle in PHLHD by Drs. Tedford, Houston, Hsuand Tampakakis; a clinically applicablesummary of HFpEF with PH by Drs.Cogswell and Thenappan; and endingwith a detailed review of valvular heartdisease–associated PH by Drs. Hornand Kaple. I congratulate the authorson an outstanding issue of Advancesin PH.

Teresa De Marco, MDProfessor of Medicine and SurgeryDirector of Advanced Heart Failure andPulmonary HypertensionMedical Director of Heart TransplantationUCSF Medical CenterSan Francisco, California

62 Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

NO RIGHT HEART CATH, NO V/Q SCAN, NO DIAGNOSIS

diagnosis is through a right heart catheterization, but are you taking the next step? Every patient with

For more information, please visit:

www.PHAOnlineUniv.org/DiagnosisTreatment/AboutPH

In the treatment of pulmonary arterial hypertension (PAH, WHO Group I )

IMPORTANT SAFETY INFORMATION

BOXED WARNING: EMBRYO-FETAL TOXICITY Do not administer OPSUMIT to a pregnant female

because it may cause fetal harm. Females of reproductive potential: Exclude

pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception.

For all female patients, OPSUMIT is available only through a restricted program called the OPSUMIT Risk Evaluation and Mitigation Strategy (REMS).

CONTRAINDICATIONSPregnancy: OPSUMIT may cause fetal harm when administered to a pregnant woman. OPSUMIT is contraindicated in females who are pregnant. If OPSUMIT is used during pregnancy, apprise the patient of the potential hazard to a fetus.

WARNINGS AND PRECAUTIONS Embryo-fetal Toxicity and OPSUMIT REMS ProgramDue to the risk of embryo-fetal toxicity, OPSUMIT is available for females only through a restricted program called the OPSUMIT REMS Program. For females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods, and obtain monthly pregnancy tests.

Notable requirements of the OPSUMIT REMS Program include: Prescribers must be certified with the program by

enrolling and completing training. All females, regardless of reproductive potential, must

enroll in the OPSUMIT REMS Program prior to initiating OPSUMIT. Male patients are not enrolled in the REMS.

Females of reproductive potential must comply with the pregnancy testing and contraception requirements.

Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive OPSUMIT.

Hepatotoxicity Other ERAs have caused elevations of aminotransferases,

hepatotoxicity, and liver failure. The incidence of elevated aminotransferases in the SERAPHIN study >3 × ULN were 3.4% for OPSUMIT vs 4.5% for placebo, and >8 × ULN were 2.1% vs 0.4%, respectively. Discontinuations for hepatic adverse events were 3.3% for OPSUMIT vs 1.6% for placebo.

Obtain liver enzyme tests prior to initiation of OPSUMIT and repeat during treatment as clinically indicated.

Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching).

If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 × ULN, or by clinical symptoms of hepatotoxicity, discontinue OPSUMIT. Consider re-initiation of OPSUMIT

HELP HER WRITE FUTURE CHAPTERSOnce-daily OPSUMIT® (macitentan) is the first and only oral PAH therapy indicated to

both delay disease progression and reduce hospitalization for PAH

OPSUMIT is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression.

Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment).

OPSUMIT also reduced hospitalization for PAH. Effectiveness was established in a long-term study in PAH patients with

predominantly WHO Functional Class II-III symptoms treated for an average of 2 years.

– Patients were treated with OPSUMIT monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled prostanoids.

– Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%).

OPSUMIT is a registered trademark of Actelion Pharmaceuticals, Ltd.© 2014 Actelion Pharmaceuticals US, Inc. All rights reserved. MAC-00408 0514 www.OpsumitHCP.com

when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.

Hemoglobin Decrease Decreases in hemoglobin concentration and hematocrit

have occurred following administration of other ERAs and in clinical studies with OPSUMIT. These decreases occurred early and stabilized thereafter.

In the SERAPHIN study, OPSUMIT caused a mean decrease in hemoglobin (from baseline to 18 months) of about 1.0 g/dL vs no change in the placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the OPSUMIT group vs 3.4% for placebo. Decreases in hemoglobin seldom require transfusion.

Initiation of OPSUMIT is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated.

Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue OPSUMIT.

Decreased Sperm CountsOther ERAs have caused adverse effects on spermatogenesis. Counsel men about potential effects on fertility.

ADVERSE REACTIONSMost common adverse reactions (more frequent than placebo by ≥3%) were anemia (13% vs 3%), nasopharyngitis/pharyngitis (20% vs 13%), bronchitis (12% vs 6%), headache (14% vs 9%), influenza (6% vs 2%), and urinary tract infection (9% vs 6%).

DRUG INTERACTIONS Strong inducers of CYP3A4 such as rifampin significantly

reduce macitentan exposure. Concomitant use of OPSUMIT with strong CYP3A4 inducers should be avoided.

Strong inhibitors of CYP3A4 like ketoconazole approximately double macitentan exposure. Many HIV drugs like ritonavir are strong inhibitors of CYP3A4. Avoid concomitant use of OPSUMIT with strong CYP3A4 inhibitors. Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment.

Please see Brief Summary of Prescribing Information, including BOXED WARNING for embryo-fetal toxicity, on adjacent pages.

Patient dramatization

Rx only

BRIEF SUMMARY

The following is a brief summary of the full Prescribing Information for OPSUMIT®

(macitentan). Please review the full Prescribing Information prior to prescribing OPSUMIT.

WARNING: EMBRYO-FETAL TOXICITY

• Do not administer OPSUMIT to a pregnant female because it may cause fetal harm [see Contraindications (Pregnancy), Warnings and Precautions (Embryo-fetal Toxicity), Use in Specific Populations (Pregnancy)].

• Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception [see Use in Special Populations (Females and Males of Reproductive Potential)].

• For all female patients, OPSUMIT is available only through a restricted program called the OPSUMIT Risk Evaluation and Mitigation Strategy (REMS) [see Warnings and Precautions (OPSUMIT REMS Program)].

INDICATIONS AND USAGE

Pulmonary Arterial Hypertension

OPSUMIT® is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment). OPSUMIT also reduced hospitalization for PAH.

Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients were treated with OPSUMIT monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled prostanoids. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%).

CONTRAINDICATIONS

Pregnancy

OPSUMIT may cause fetal harm when administered to a pregnant woman. OPSUMIT is contraindicated in females who are pregnant. OPSUMIT was consistently shown to have teratogenic effects when administered to animals. If OPSUMIT is used during pregnancy, apprise the patient of the potential hazard to a fetus [see Warnings and Precautions (Embryo-fetal Toxicity) and Use in Specific Populations (Pregnancy)].

WARNINGS AND PRECAUTIONS

Embryo-fetal Toxicity

OPSUMIT may cause fetal harm when administered during pregnancy and is contraindicated for use in females who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods and obtain monthly pregnancy tests [see Dosage and Administration section 2.2 in full Prescribing Information and Use in Specific Populations (Pregnancy, Females and Males of Reproductive Potential) ].

OPSUMIT is available for females through the OPSUMIT REMS Program, a restricted distribution program [see Warnings and Precautions (OPSUMIT REMS Program) ].

OPSUMIT REMS Program

For all females, OPSUMIT is available only through a restricted program called the OPSUMIT REMS Program, because of the risk of embryo-fetal toxicity [see Contraindications (Pregnancy), Warnings and Precautions (Embryo-fetal Toxicity), and Use in Specific Populations (Pregnancy, Females and Males of Reproductive Potential) ].

Notable requirements of the OPSUMIT REMS Program include the following:

• Prescribers must be certified with the program by enrolling and completing training.

• All females, regardless of reproductive potential, must enroll in the OPSUMIT REMS Program prior to initiating OPSUMIT. Male patients are not enrolled in the REMS.

• Females of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (Females and Males of Reproductive Potential) ].

• Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive OPSUMIT.

Further information is available at www.OPSUMITREMS.com or 1-866-228-3546. Information on OPSUMIT certified pharmacies or wholesale distributors is available through Actelion Pathways at 1-866-228-3546.

Hepatotoxicity

Other ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. The incidence of elevated aminotransferases in the study of OPSUMIT in PAH is shown in Table 1.

Table 1: Incidence of Elevated Aminotransferases in the SERAPHIN Study

OPSUMIT 10 mg (N=242)

Placebo (N=249)

>3 × ULN 3.4% 4.5%

>8 × ULN 2.1% 0.4%

In the placebo-controlled study of OPSUMIT, discontinuations for hepatic adverse events were 3.3% in the OPSUMIT 10 mg group vs. 1.6% for placebo. Obtain liver enzyme tests prior to initiation of OPSUMIT and repeat during treatment as clinically indicated.

Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching). If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 × ULN, or by clinical symptoms of hepatotoxicity, discontinue OPSUMIT. Consider re-initiation of OPSUMIT when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.

Hemoglobin Decrease

Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and were observed in clinical studies with OPSUMIT. These decreases occurred early and stabilized thereafter. In the placebo-controlled study of OPSUMIT in PAH, OPSUMIT 10 mg caused a mean decrease in hemoglobin from baseline to up to 18 months of about 1.0 g/dL compared to no change in the placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the OPSUMIT 10 mg group and in 3.4% of the placebo group. Decreases in hemoglobin seldom require transfusion. Initiation of OPSUMIT is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated [see Adverse Reactions (Clinical Trial Experience) ].

Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)

Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue OPSUMIT.

Decreased Sperm Counts

Other ERAs have caused adverse effects on spermatogenesis. Counsel men about potential effects on fertility [see Use in Specific Populations (Females and Males of Reproductive Potential) and Nonclinical Toxicology (Carcinogenesis, Mutagenesis, Impairment of Fertility) ].

ADVERSE REACTIONS

Clinically significant adverse reactions that appear in other sections of the labeling include:

• Embryo-fetal Toxicity [see Warnings and Precautions (Embryo-fetal Toxicity) ]

• Hepatotoxicity [see Warnings and Precautions (Hepatotoxicity)]

• Decrease in Hemoglobin [see Warnings and Precautions (Hemoglobin Decrease) ]

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Safety data for OPSUMIT were obtained primarily from one placebo-controlled clinical study in 742 patients with PAH (SERAPHIN study). The exposure to OPSUMIT in this trial was up to 3.6 years with a median exposure of about 2 years (N=542 for 1 year; N=429 for 2 years; and N=98 for more than 3 years). The overall incidence of treatment discontinuations because of adverse events was similar across OPSUMIT 10 mg and placebo treatment groups (approximately 11%).

Table 2 presents adverse reactions more frequent on OPSUMIT than on placebo by ≥3%.

Table 2: Adverse Reactions

Adverse Reaction OPSUMIT 10 mg (N=242)

Placebo (N=249)

Anemia 13% 3%

Nasopharyngitis/pharyngitis 20% 13%

Bronchitis 12% 6%

Headache 14% 9%

Influenza 6% 2%

Urinary tract infection 9% 6%

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of OPSUMIT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: hypersensitivity reactions (angioedema, pruritus and rash)Respiratory, thoracic and mediastinal disorders: nasal congestion

OPSUMIT® (macitentan)

DRUG INTERACTIONS

Strong CYP3A4 Inducers

Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure. Concomitant use of OPSUMIT with strong CYP3A4 inducers should be avoided [seeClinical Pharmacology (Pharmacokinetics) ].

Strong CYP3A4 Inhibitors

Concomitant use of strong CYP3A4 inhibitors like ketoconazole approximately double macitentan exposure. Many HIV drugs like ritonavir are strong inhibitors of CYP3A4. Avoid concomitant use of OPSUMIT with strong CYP3A4 inhibitors [see Clinical Pharmacology (Pharmacokinetics)]. Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment [see Clinical Pharmacology (Pharmacokinetics)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category X.

Risk Summary

OPSUMIT may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Macitentan was teratogenic in rabbits and rats at all doses tested. A no-effect dose was not established in either species. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus [see Contraindications (Pregnancy) ].

Animal Data

In both rabbits and rats, there were cardiovascular and mandibular arch fusion abnormalities. Administration of macitentan to female rats from late pregnancy through lactation caused reduced pup survival and impairment of the male fertility of the offspring at all dose levels tested.

Nursing Mothers

It is not known whether OPSUMIT is present in human milk. Macitentan and its metabolites were present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions from macitentan in nursing infants, nursing mothers should discontinue nursing or discontinue OPSUMIT.

Pediatric use

The safety and efficacy of OPSUMIT in children have not been established.

Geriatric use

Of the total number of subjects in the clinical study of OPSUMIT for PAH, 14% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Females and Males of Reproductive Potential

Females

Pregnancy Testing: Female patients of reproductive potential must have a negative pregnancy test prior to starting treatment with OPSUMIT and monthly pregnancy tests during treatment with OPSUMIT. Advise patients to contact their health care provider if they become pregnant or suspect they may be pregnant. Perform a pregnancy test if pregnancy is suspected for any reason. For positive pregnancy tests, counsel patients on the potential risk to the fetus [see Boxed Warning and Dosage and Administration section 2.2 in full Prescribing Information].

Contraception: Female patients of reproductive potential must use acceptable methods of contraception during treatment with OPSUMIT and for 1 month after treatment with OPSUMIT. Patients may choose one highly effective form of contraception (intrauterine devices (IUD), contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see Boxed Warning].

Males

Testicular effects: Like other endothelin receptor antagonists, OPSUMIT may have an adverse effect on spermatogenesis [see Warnings and Precautions (Decreased Sperm Counts) and Nonclinical Toxicology (Carcinogenesis, Mutagenesis, Impairment of Fertility].

OVERDOSAGE

OPSUMIT has been administered as a single dose of up to and including 600 mg to healthy subjects (60 times the approved dosage). Adverse reactions of headache, nausea and vomiting were observed. In the event of an overdose, standard supportive measures should be taken, as required. Dialysis is unlikely to be effective because macitentan is highly protein-bound.

CLINICAL PHARMACOLOGY

PharmacokineticsSpecial Populations

There are no clinically relevant effects of age, sex, or race on the pharmacokinetics of macitentan and its active metabolite.

Renal impairment : Exposure to macitentan and its active metabolite in patients with severe renal impairment (CrCl 15-29 mL/min) compared to healthy subjects was increased by 30% and 60%, respectively. This increase is not considered clinically relevant.

Hepatic impairment: Exposure to macitentan was decreased by 21%, 34%, and 6% and exposure to the active metabolite was decreased by 20%, 25%, and 25% in subjects with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, and C), respectively. This decrease is not considered clinically relevant.

Drug Interactions

In vitro studies

At plasma levels obtained with dosing at 10 mg once daily, macitentan has no relevant inhibitory or inducing effects on CYP enzymes, and is neither a substrate nor an inhibitor of the multi-drug resistance protein (P-gp, MDR-1). Macitentan and its active metabolite are neither substrates nor inhibitors of the organic anion transporting polypeptides (OATP1B1 and OATP1B3) and do not significantly interact with proteins involved in hepatic bile salt transport, i.e., the bile salt export pump (BSEP) and the sodium-dependent taurocholate co-transporting polypeptide (NTCP).

In vivo studies

Effect of other drugs on macitentan: The effect of other drugs on macitentan and its active metabolite are studied in healthy subjects and are shown in Figure 1 below.

Figure 1

Effects of other strong CYP3A4 inhibitors such as ritonavir on macitentan were not studied, but are likely to result in an increase in macitentan exposure at steady state similar to that seen with ketoconazole [see Drug Interactions (Strong CYP3A4 Inhibitors)].

Effect of macitentan on other drugs

Warfarin: Macitentan once daily dosing did not alter the exposure to R- and S-warfarin or their effect on international normalized ratio (INR).

Sildenafil: At steady-state, the exposure to sildenafil 20 mg t.i.d. increased by 15% during concomitant administration of macitentan 10 mg once daily. This change is not considered clinically relevant.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Carcinogenicity studies of 2 years’ duration did not reveal any carcinogenic potential at exposures 75-fold and 140-fold the human exposure (based on AUC) in male and female mice, respectively, and 8.3- and 42-fold in male and female rats, respectively.

Mutagenesis: Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays that included a bacterial reverse mutation assay, an assay for gene mutations in mouse lymphoma cells, a chromosome aberration test in human lymphocytes, and an in vivo micronucleus test in rats.

Impairment of Fertility : Treatment of juvenile rats from postnatal Day 4 to Day 114 led to reduced body weight gain and testicular tubular atrophy at exposures 7-fold the human exposure. Fertility was not affected.

Reversible testicular tubular dilatation was observed in chronic toxicity studies at exposures greater than 7-fold and 23-fold the human exposure in rats and dogs, respectively. After 2 years of treatment, tubular atrophy was seen in rats at 4-fold the human exposure. Macitentan did not affect male or female fertility at exposures ranging from 19- to 44-fold the human exposure, respectively, and had no effect on sperm count, motility, and morphology in male rats. No testicular findings were noted in mice after treatment up to 2 years.

Animal Toxicology

In dogs, macitentan decreased blood pressure at exposures similar to the therapeutic human exposure. Intimal thickening of coronary arteries was observed at 17-fold the human exposure after 4 to 39 weeks of treatment. Due to the species-specific sensitivity and the safety margin, this finding is considered not relevant for humans.

There were no adverse liver findings in long-term studies conducted in mice, rats, and dogs at exposures of 12- to 116-fold the human exposure.

Manufactured for: Actelion Pharmaceuticals US, Inc. 5000 Shoreline Court, Ste. 200 South San Francisco, CA 94080, USA

ACT20150219

Reference: 1. OPSUMIT full Prescribing Information. Actelion Pharmaceuticals US, Inc. February 2015. ® OPSUMIT is a registered trademark of Actelion Pharmaceuticals, Ltd.

© 2015 Actelion Pharmaceuticals US, Inc. All rights reserved. MAC-00646 0215

SildenafilCmax

AUCtau

Cmax

0.0 0.5 1.0 1.5 2.0 2.5 0.0 0.5 1.0 1.5

AUCinf

Ctrough

AUCtau

Ctrough

AUCtau

Cyclosporine-A

Ketoconazole

Avoid

Avoid

Change relative to macitentan alone Change relative to macitentan alone

No dose adjustment

No dose adjustment

Rifampin

MacitentanPoint estimate and 90% CI

Active metabolitePoint estimate and 90% CIInteracting drug Recommendation

OPSUMIT® (macitentan) OPSUMIT® (macitentan)

RESEARCH REVIEWS

Section Editors:Oksana A. Shlobin, MDInova Health SystemFalls Church, Virginia

Jonathan D. Rich, MDNorthwestern University

Feinberg School of MedicineChicago, Illinois

In this issue of Advances, section editors Oksana Shlobin, MD, and Jonathan Rich,MD, review findings from 2 recently published studies focused on outcomes andimplications of the REVEAL registry.Farber HW, Miller DP, Poms AD, et al. Five-year Outcomes of Patients Enrolledin the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension(PAH) Disease Management (REVEAL). Chest. 2015 Jun 11. [Epub ahead of print]Benza RL, Miller DP, Foreman AJ, et al. Prognostic implications of serial risk scoreassessments in patients with pulmonary arterial hypertension: a Registry to EvaluateEarly and Long-Term Pulmonary Arterial Hypertension Disease (REVEAL)analysis. J Heart Lung Transplant. 2015;34(3):356-361.

With advances in pulmonary hyper-tension (PH)-specific therapy, theprognosis of pulmonary arterial hyper-tension (PAH) patients has improvedsignificantly. The National Institutes ofHealth (NIH) database provided themajority of the data on natural diseaseprogression. The REVEAL database wasthe second prospective longitudinalobservational registry of 55 US sites thatcompiled data on both incidental andprevalent PAH patients, and providedimportant information on disease pro-gression, prognostic factors, and survivalin the new era of PAH therapy. In2015, 2 articles analyzing the REVEALdatabase were published: one on 5-yearoutcomes of patients enrolled in thedatabase and another on prognosticimplications of serial risk scoreassessment.

The REVEAL registry enrolledhemodynamically diagnosed PAHGroup 1 patients consecutively fromMarch 2006 to December 2009. Demo-graphics, disease characteristics,hemodynamic data, and managementpractices data were collected. PriorREVEAL analysis demonstrated that achange in functional class (FC) corre-lated with survival. For example,worsening from FC III to FC IVpredicts worsened survival, andimprovement from FC III to FC I/IIcorrelated with improved outcomes. Themost recent paper analyzed 5-year sur-vival of both incident and prevalentpatients with idiopathic, familial, con-genital heart disease, and connectivetissue disease–associated PAH, stratifiedby baseline FC status. Primary survival

analysis was conducted for the entirepatient cohort (2039 prevalent and 710incident patients) and the secondaryanalysis for subgroups (incident vs prev-alent patients, age, gender, race, etiology,comorbidities, and baseline clinicalcharacteristics).

The study described the survival ratesfor the overall patient cohort (with 1-,3-, and 5-year survival of 90.4%, 76.2%,and 65.4% for prevalent patients vs86.3%, 69.3%, and 61.2% for 1, 3, and5 years for incident patients). Thepoorest outcomes were observed in FCIII and IV patients, with incidentpatients doing better (5-year survivalrates of 60.0% and 43.8% vs 57.0% and27.2% for prevalent patients, respec-tively). To compare, the NIH database5-year survival rate was 34% in largelyuntreated patients, indicating thatdespite therapy, prevalent patients pre-senting with FC IV symptoms continueto have a very poor prognosis andprobably have a phenotype of the diseaseless responsive to therapy. In contrast,newly diagnosed FC IV patients rep-resent a mostly treatment-naıvepopulation with greater opportunity forimprovement with PAH-specifictherapy. Interestingly, FC I and II sur-vival rates were numerically lower in theincident patient cohort (72.0% vs 77.7%in the pooled FC I and II group). Thisfinding is probably due to a better riskprofile of prevalent patients in lower FCgroups and survivor bias inherent toanalysis of pooled incident and prevalentpopulations. A significant number (30%)of incident FC III patients improved toFC I/II, likely due to administration of

PAH-specific therapy within 3 monthsof diagnosis. This suggests thattreatment should be initiated as early aspossible in the treatment-naıve patients,as they appear to be at greatest risk ofdisease progression and probably havethe greatest opportunity to experiencefunctional improvement.

When analyzed by etiology, FC atpresentation was also strongly associatedwith 5-year survival in specific etiologicalsubgroups in both incident and prevalentpopulations, with former subgroupsdoing better across the subgroups. Thestudy also examined the effect of changesin FC in a subgroup of 1866 prevalentand 614 incident patients within12 months of enrollment, confirming theresults of the previously published datathat improvement in FC has a positiveimpact on outcomes. Another subgroupanalysis examined the patients withmissing follow-up FC data to determinethe effect of other factors on survival andfound that white patients has a relativelyworse survival, and pulmonary vascularresistance �5 Wood units and bodymass index �30 provided protectivebenefit. The authors concluded thatsingle point-in-time FC measurement atenrollment remains an important pre-dictor of outcomes in PAH patients.

To better predict patients’ 1-year sur-vival, the data from REVEAL was usedto develop prognostic equation and asimplified risk score calculator and thenvalidated in several studies. The riskscore calculator uses 19 clinical variables,widely available in clinical practices, thusmaking it a useful and simple clinicaltool. The authors used the data from the

68 Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

REVEAL database to assess the prog-nostic implications of changes in the riskscore (increased by at least 1 [or prog-nosis worsened], unchanged, ordecreased by at least 1 [or prognosisimproved]), including the contributionsof the modifiable variables (such ashemodynamic and vital signs parameters,renal function, 6-minute walk distance[6MWD], brain natriuretic peptide[BNP] level, pericardial effusion status,diffusion lung capacity for carbon mon-oxide, age, and New York HeartAssociation [NYHA] FC) during a12-month period in 2529 patients.

Sixty-seven percent of incidentpatients started a new PAH therapy,with 35% of patients receiving combi-nation treatment and 25% a prostanoidduring the first year. In prevalentpatients, new medication was started in36% of patients, with 54% receivingcombination therapy and 34% prosta-noids. Numerically, more incident

patients had therapy escalation in com-parison to their baseline therapy.

At 12 months’ assessment when therisk score was recalculated, 38% had nochange, 32% had a decrease, and 30% anincrease in the score. The incident ornewly diagnosed patients were morelikely to improve (or have decreasedscores [44%]), in comparison to prev-alent patients (28%). Six individualvariables improved and/or worsened suf-ficiently to results in score change:NYHA FC, systolic blood pressure,heart rate, 6MWD, BNP, and presenceof pericardial effusion. When patientswere stratified by change in risk score,the 1-year survival was 93.7% in patientswhose score improved, 90.3% in patientswhose score was unchanged, and 84.6%in patients whose score worsened. Thefindings were similar in both prevalentand incident groups.

The authors examined the effect ofrisk score at baseline, its change, and the

risk score at 12 months’ reassessment aspredictors of subsequent 1-year survivalin 2 different multivariable Cox models.One analysis demonstrated that thechange in risk score significantly pre-dicted subsequent survival (hazard ratio[HR] of 1.67 [95% confidence interval(CI) 1.41–1.99] for worsened score andHR of 0.57 [95% CI 0.47–0.69] forimproved score), and another showedthat both the enrollment and follow-uprisk scores predicted survival with thelatter being a stronger predictor of sur-vival (HR 1.40 [95% CI 1.33–1.47] vsHR 1.10 [95% CI 1.04–1.15]), thusunderscoring the importance of ongoingrisk assessment and aggressive therapy tochange modifiable factors. The authorsconcluded that in addition to clinicalassessment, the REVEAL risk score cal-culator can be used as a prognostic toolserially and help individualize therapy inpatients to meet their specific treatmentneeds.

69Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

Overview of WHO Group 2 Pulmonary Hypertension Due toLeft Heart Disease

Christopher F. Barnett, MD, MPHNational Institutes of HealthCritical Care Medicine DepartmentBethesda, MD

Van N. Selby, MDUniversity of California, San FranciscoDivision of CardiologySan Francisco, CA

Background: Left heart disease (LHD) is the most common cause of pulmonaryhypertension (PH) and is associated with poor patient outcomes, especially amongpatients undergoing heart transplant evaluation.Implications for clinicians: Left heart disease should be considered in all patientsundergoing an evaluation for PH. Correct management of PH from LHD is tooptimize treatment of LHD. Pulmonary vasodilators used to treat pulmonary arterialhypertension should not be used in patients with PH from LHD.Conclusions: Additional research is needed to better understand how PH develops inpatients with LHD and to investigate the role for treatment targeting PH in thesepatients.

Left heart disease (LHD) is the mostcommon cause of pulmonary hyper-tension (PH), and occurs in patientswith heart failure with reduced ejectionfraction (HFrEF), heart failure with pre-served ejection fraction (HFpEF), andvalvular heart disease (Figure 1).1,2 Thepresence of PH in patients with LHD isassociated with reduced exercise tol-erance and reduced survival, especiallyfollowing heart transplant.3-10 Identi-fying LHD as the cause of PH iscritically important because it determinesthe correct approach to management,which is optimal treatment of the under-lying LHD with evidence-based and/orstandard-of-care pharmacologic or sur-gical therapies. In patients presentingwith PH-LHD, there is currently norole for treatment with pulmonaryarterial hypertension (PAH)–specifictherapies and, with few exceptions, theyshould not be administered because theyare costly, lack efficacy, and in somecases, are known to increase morbidityand mortality.

NOMENCLATURE,CLASSIFICATION, ANDDEFINITIONS OF PH-LHDThe nomenclature that has emerged tocategorize patients with PH-LHDattempts to describe the clinical context,pathophysiology, and hemodynamic fea-

tures seen in these patients. This hasresulted in a wide variety of terms usedin an effort to accurately describepatients with PH-LHD. Multiple dif-ferent terms, sometimes used incombination, may be appropriate todescribe the unique characteristics of anindividual patient with PH-LHD.Adding to this complexity is changes interminology that have occurred over timeas our understanding of PH-LHD hasevolved. Recent guidelines attempted tosimplify this language and to classifypatients with PH-LHD according tohemodynamic characteristics (Table 1).

The hemodynamic definition of PH isa sustained elevation in mean pulmonaryartery pressure (mPAP) �25 mm Hg.The usual hemodynamic findings in apatient with PH-LHD are mPAP�25 mm Hg in combination with ele-vated left heart filling pressures, definedas a pulmonary artery wedge pressure(PAWP) �15 mm Hg or left ventricularend diastolic pressure (LVEDP)�15 mm Hg. The clinical characteristics(ie, presence of reduced ejection fraction[EF], clinical features of HFpEF,presence of valvular heart disease) areconsidered together with the hemody-namic features to arrive at a finaldiagnosis of PH-LHD.

In patients with PH-LHD, it isimportant to characterize elevated mPAP

as resulting only from passive trans-mission of elevated left heart fillingpressures proximally into the pulmonarycirculation vs increased pulmonary arte-riolar resistance resulting from changesin the function and structure of pul-monary arterioles. The terms used todescribe patients in whom PH resultsfrom transmission of elevated left heartfilling pressures include pulmonaryvenous hypertension and passive PH.The most recent guidelines recommendusing the term isolated postcapillary PH(Ipc-PH) for this group of patients. Inthese patients, reduction of left heartfilling pressures to normal also reducesmPAP to normal.1,11

In other patients, the elevated mPAPis not fully accounted for by passive,proximal transmission of elevated leftheart filling pressures. In these patients,it is believed that long-standing eleva-tions in mPAP result in part fromvasoconstriction and remodeling of thepulmonary arterioles so that mPAP iselevated out of proportion to the PAWP.Terms that have been used to describethis hemodynamic profile include mixedand out-of-proportion PH. The mostrecent guidelines recommend using thesimple descriptive term “combined post-capillary and precapillary PH” (Cpc-PH).

Differentiating Ipc-PH from Cpc-PHis important because it has prognosticimplications, especially in patients under-going evaluation for heart transplant(Figure 2). Typically, PH-LHD hasbeen characterized by measures of resis-tance and pressure difference across the

Key Words—diastolic pressure gradient, hemodynamics, isolated postcapillary PH, left heart disease,valvular heart diseaseCorrespondence: christopher.barnett@nih.govDisclosure: The authors have nothing to disclose.

70 Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

pulmonary vasculature (Table 2).Patients have been considered to haveIpc-PH if the pulmonary vascular resis-tance (PVR) and transpulmonarygradient (TPG) are normal and Cpc-PHif the PVR and TPG are elevated.Recent guidelines support the use of thediastolic pressure gradient (DPG) to dif-ferentiate the hemodynamic subtypes ofPH-LHD.11 The rationale for this rec-ommendation is that the DPG is lessdependent on stroke volume and leftatrial pressure, and it was shown to bepredictive of survival and correlated withpathologic changes.12,13 However, theDPG is subject to error14,15 and the asso-ciation with survival is inconsistent, areminder that a single measurement israrely useful to characterize patients withPH.16-18

Vasodilator TestingFurther hemodynamic characterization ofCpc-PH is guideline-recommended in

patients with LHD-PH being con-sidered for heart transplantation becauseit identifies patients at risk for post-transplant right ventricular (RV) failureand death.19,20 Vasodilator studies areconducted with a right heart catheter inplace. A rapidly acting vasodilator isinfused, typically nitroprusside, and mea-surements of the PVR and TPG aremade.1 Among patients in whom thePVR and TPG are reduced to normallevels while maintaining a systemic sys-tolic blood pressure of �85 mm Hg, PHis considered to be reversible or reactive.In these patients post-transplant mor-tality is similar to patients without PH.21

Among patients in whom PVR andTPG cannot be reduced to normal, PHis considered not acutely reversible. Inmany of these patients, the PVR may belowered or become reversible after pro-longed reduction of PAWP withaggressive treatment with diuretics, vaso-dilators, inodilators, and mechanical

support so that patients can become eli-gible for heart transplantation.

EPIDEMIOLOGYAccurate prevalence estimates forPH-LHD are limited by factors such asreliance on echocardiographic assess-ments of pulmonary artery pressure(PAP) to identify affected patients,22,23

and inconsistent definitions and cutoffsto diagnose PH-LHD. Studies thatmake use of gold-standard invasivehemodynamics may be affected byreferral bias since sicker patients arelikely referred for right heart catheter-ization (RHC). Even well done invasivestudies only provide data at a single timepoint while the patient is at rest, fasting,and possibly sedated—all of which mayaffect hemodynamic measurements.24

Estimated rates of PH in LHD varywidely. The prevalence of Cpc-PH hasranged from 25% to 47% in hospi-talized patients, and was 40% in arecent large ambulatory HFrEF popu-lation.10,25,26 Among patients withHFpEF, PH is present in 36% to 83%.A large community study examinedechocardiograms from 244 patients withHFpEF and 719 hypertensive controls.Pulmonary hypertension, defined aspulmonary artery systolic pressure(PASP) �35 mm Hg was found in83% of HFpEF patients compared toonly 8% of controls. Using a higherPASP cutoff of 45 mm Hg would haveresulted in prevalence of about 50%,7,27

a rate similar to that found in anotherstudy of 299 patients with HFpEF.28 Asingle-center registry of patients under-going RHC found PH, defined as PVR�2.5 or TPG �12, in 69% of HFpEFpatients evaluated.29

Left-sided valvular heart disease is alsocommonly associated with PH and isimportant to recognize because it is anindication for valve replacement orrepair. Mitral stenosis is the valvularlesion most often associated with PH, ata rate of up to 73%.30 Pulmonary hyper-tension occurs at lower rates in patientswith mitral regurgitation (23%–44%)and aortic stenosis (29%–47%).31-37

PROGNOSISCompared to patients with LHD andno PH, patients with PH-LHD have

PH-LHD

Valvular heart disease

- Mitra l s tenosis

- Mitra l regurgita�on

- Aor�c s tenosis

- Aor�c regurgita�on

Heart failure with reduced ejec�on frac�on ( HFrEF)

- Nonischemic cardiomyopathy

- Ischemic cardiomyopathy

Heart failure with preserved ejec�on frac�on ( HFpEF)

Figure 1: Causes of pulmonary hypertension due to left heart disease (PH-LHD).

Table 1. Nomenclature for Pulmonary Hypertension-Left Heart Disease.

Currently recommended terminology Other commonly used terminology

Isolated postcapillary PH (Ipc-PH) Pulmonary venous hypertension (PVH)

Passive PH

Combined postcapillary and precapillaryPH (Cpc-PH)

Mixed PH

Out-of-proportion PH

PH � pulmonary hypertension.

71Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

worse outcomes, including worsesurvival.4,27,38-41 This is true in bothHFpEF and HFrEF and in studiesusing both echocardiography andinvasive hemodynamics to diagnosePH.41 Additionally, survival worsens asPAP increases. A study of patientsundergoing endomyocardial biopsyshowed a 25% increase in the risk ofdeath for every increase of 5 mm Hg inmPAP.4 Patients with Cpc-PH generallyhave more severe hemodynamicimpairment and worse prognosis com-pared to Ipc-PH.4,10,26

PATHOBIOLOGY ANDPATHOPHYSIOLOGYOur understanding of the pathophysi-ology of PH-LHD has improved inrecent years; however, significant gapsremain. It is believed that the first eventin the development of PH-LHD isincreasing left heart filling pressures andpulmonary venous hypertension. Evenwhen left ventricular (LV) systolicfunction is normal, diastolic filling abnor-malities may result in increased PAP.42

Additionally, elevated left heart fillingpressures also reduce compliance of the

pulmonary vasculature and increase RVafterload by enhancing pulmonary arterywave reflections.43 Next, pulmonary arte-riolar vasoconstriction occurs secondary toendothelial dysfunction characterized bydecreased production of and/or decreasedresponsiveness to nitric oxide (NO), aswell as overproduction of endothelin-1(ET-1), activation of the renin-angiotensin-aldosterone system (RAAS),and neurogenic activation. Elevated PAPslead to injury, followed by pathologicremodeling of the pulmonary arteriolesincluding muscularization, medial hyper-trophy, and neointimal proliferation.44-49

Ultimately the increased afterloadimposed on the RV leads to RV systolicdysfunction and failure.3,50

ASSESSMENT AND DIAGNOSTICAPPROACHMaking a diagnosis of PH-LHD ischallenging because symptoms are non-specific, diagnostic tests can be difficult

Vasodilator challenge

Measure PVR, TPG, DPG

Measure PAWP or LVEDP

Iden�fica�on of PH by RHC

mPAP ≥25 mm Hg

PAWP >15 mm HgLVEDP >15-18 mm Hg

PH-LHD (WHO Group 2)

TPG >12-15 mm Hg

PVR >2.5-3.0 Wood units

DPG ≥7 mm Hg

Cpc-PH

TPG ≤12-15 mm HgPVR ≤2.5-3.0 Wood units

Reversible, reac�ve, or vasoreac�ve PH

TPG >12-15 mm HgPVR >2.5-3.0 Wood units

Irreversible, fixed, refractory, or persistent PH

TPG >12-15 mm HgPVR >2.5-3.0 Wood unitsDPG <7 mm Hg

Ipc-PH

PAWP <15 mm HgLVEDP <15-18 mm Hg

Other PH (WHO Group 1, 3, 4, 5)

Figure 2: Classification and hemodynamic workup of PH-LHD. DPG � diastolic pulmonary gradient; LVEDP � left ventricular end-diastolic pres-sure; PADP � pulmonary artery diastolic pressure; PH � pulmonary hypertension; PAWP � pulmonary artery wedge pressure; RHC � rightheart catheterization.

Table 2. Hemodynamic Parameters Used in the Classification of Pulmonary Hypertension-LeftHeart Disease.

Parameter Calculation Criteria for Cpc-PH

Transpulmonary gradient mPAP - PAWP �12

Pulmonary vascular resistance (PVR) PVR/CO �2.5–3.0 WU

Diastolic pulmonary gradient PADP - PAWP �7 mm Hg

CO � cardiac output; PADP � pulmonary artery diastolic pressure; mPAP � mean pul-monary arterial pressure; PAWP � pulmonary artery wedge pressure; WU � Wood units.

72 Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

to interpret, and PH may be multifac-torial. Consequently, PH-LHD is oftenincorrectly diagnosed and treated asPAH, especially in elderly patients.51,52

A thoughtful and comprehensiveapproach to the evaluation of PH isneeded so that appropriate treatment canbe chosen.

History and Physical ExaminationInformation gathered during a compre-hensive history and physical examinationis important because it is used to prior-itize next steps in the diagnosticevaluation and to provide context for theinterpretation of diagnostic testing(Table 3). Details about congenital heart

disease, murmurs, valvular disease,HFrEF and HFpEF, and coronaryartery disease (CAD), as well as anassessment of risk factors for LHDshould be ascertained. Special attentionshould be paid to factors associated withHFpEF29 such as female gender,advanced age, diabetes, hypertension,

Table 3. Assessment of Left Heart Disease in Pulmonary Hypertension.

Initial Tests Contingent TestsFavors Primary Contribution of

LHD to PH Favors Alternative Etiology of PH

History Targeted imaging and serologicevaluation

● Known left ventricular structuraldisease (eg, MI,cardiomyopathy)

Conditions associated with WHO 1,3–5 PAH (eg, family history ofPAH, �BMPR2 mutation, HIV,collagen vascular disease,hemoglobinopathy, portalhypertension, COPD, interstitiallung disease, appetitesuppressant or other toxins,previous pulmonary embolism,congenital shunts)

● Presence of comorbiditiesassociated with LHD (eg, olderage, diabetes, obesity,hypertension)

● Orthopnea and paroxysmalnocturnal dyspnea

Physical Exam ● Left-sided S3 or S4 gallop ● Cyanosis, clubbing

● Left-sided murmurs (particularlymitral)

● Fine rales, protracted expiration,accessory muscle use,productive cough

● Displaced sustained apicalimpulse

● Raynaud phenomenon,sclerodactyly, telangiectasia

● Coarse rales● Pulmonary vascular bruits

● Splenomegaly, spider angiomata,palmar erythema

Electrocardiogram Exercise ECG Q waves, left ventricularhypertrophy, left atrialenlargement, left bundlebranch block, atrial fibrillation,inducible myocardial ischemiaduring exercise

Isolated right atrial enlargementand right ventricular hypertrophy, S1Q3T3 pattern

Echocardiogram(see Table 4)

Exercise echo ● LV systolic dysfunction ● Isolated right atrial or rightventricular enlargement

Transesophageal echo ● LV diastolic dysfunction ● Intraventricular septum flatteningor reverse curvature

● LV hypertrophy ● Pericardial effusion in theabsence of pericardial disease

● Mitral valve disease ● Congenital disease with shunt

● Cor triatriatum

Right heartcatheterization

Exercise ● PCWP or LVEDP � 15mm Hg ● PAP � 25 mm Hg with PCWP �15 mm Hg

Vasodilator test ● Abrupt increase in PCWP (to�20–25 mm Hg) with exerciseor volume loading

● Exercise PCWP and LVEDP �20–25 mm Hg

Volume loading ● Increase PCWP noted duringpulmonary-specific vasodilatortesting

Left heart catheterization

BMPR � bone morphogenic protein receptor; COPD � chronic obstructive pulmonary disease; ECG � electrocardiogram; HIV � humanimmunodeficiency virus; LV � left ventricular; LHD � left heart disease; LVEDP � left ventricular end-diastolic pressure; MI � myocardialinfarction; PAP � pulmonary artery pressure; PCWP � pulmonary capillary wedge pressure; PH � pulmonary hypertension; S1Q3T3 � Swave in lead I, Q wave and T wave inversion in lead III; WHO � World Health Organization.Reprinted with permission from Elsevier from Fang JC, DeMarco T, Givertz MM, et al. World Health Organization Pulmonary Hypertensiongroup 2: pulmonary hypertension due to left heart disease in the adult—a summary statement from the Pulmonary Hypertension Councilof the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2012;31(9):913-933.

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CAD, arrhythmias, and sleep-disorderedbreathing. Orthopnea and paroxysmalnocturnal dyspnea in a patient with PHstrongly suggest the presence of LHD.Physical examination findings that pointtoward LHD include pulmonarycrackles, left-sided S3 or S4, left-sidedmurmurs, or irregular heart sounds con-sistent with arrhythmia.

Diagnostic StudiesAn electrocardiogram and chest x-rayshould be performed in all patientsundergoing evaluation for PH. Thoughinsensitive and nonspecific, these studiesmay point to LHD as a cause of PHwith evidence of left heart disease suchas evidence for myocardial infarction,abnormal heart rhythms, cardiacchamber enlargement or wall thickness,pulmonary edema or congestion, and theabsence of parenchymal lung disease.

EchocardiographyEchocardiography is the most usefulnoninvasive modality for the evaluationof PH. It is easy to obtain and mayimmediately point to LHD as a cause ofPH (Table 4, Figure 3). Echocardio-graphic findings of diastolic dysfunctionare well described,53 but are potentiallyinsensitive for the diagnosis of

HFpEF.27,54,55 Therefore, HFpEFshould be suspected when findings suchas LV hypertrophy and left atrialenlargement are present.29 In acommunity-based study of 244 HFpEFpatients and 719 hypertensive controls,elevated PAP on echocardiography wasboth sensitive and specific for the diag-nosis of HFpEF,27 suggesting that thepresence of PH on echocardiography isoften itself evidence of HFpEF.

Echocardiographic estimation ofPASP is the most commonly usedmethod to assess for PH. To estimatethe PASP, the tricuspid regurgitant(TR) jet is imaged and interrogated withspectral Doppler in multiple echowindows, and the peak TR jet velocity isdetermined. The PASP is calculatedusing the modified Bernoulli equation:PASP�4(V2)�right atrial (RA)pressure. This technique is limitedbecause it cannot be utilized in patientswithout an adequate TR jet and spectralDoppler signal.9 Errors in estimation ofPASP may lead to important misclassifi-cation of PH.23

The shape of the ventricular outflowtract Doppler signal is useful to differen-tiate patents with PH-LHD. Transientflow deceleration in the right ventricularoutflow tract during systole is caused by

early return of reflected pulmonaryarterial waves, resulting in notchedpattern of the Doppler signal. Earlywave reflection occurs in the setting ofelevated PVR, and notching occursearlier in systole as PVR increases. Thus,the presence of PH without notchingstrongly favors a diagnosis of PH-LHD,specifically Ipc-PH.56

Echocardiography is also useful toassess for RV dysfunction, which is animportant marker of increased mor-tality.3,57 Abnormalities of RV size,thickness, and function also provideevidence of clinically significant PHwhen the PASP cannot be estimated, orindicate that the severity of PH is worsethan the estimated PASP suggests.Measurements including RV fractionalarea change, tricuspid annular systolicplane excursion (TAPSE), tissueDoppler imaging of the tricuspid valveannulus, and strain analysis may all beuseful to assess RV systolic functionand have prognostic value.57-59 Thesemeasurements have important limita-tions so that the overall impression ofan experienced echocardiographer isimportant.

Magnetic Resonance ImagingIn patients with suspected PH-LHD,cardiac magnetic resonance imaging(CMR) is useful to detect structuralabnormalities of the LV and left atrium,LV systolic function, presence of con-genital heart disease, and presence ofmyocardial fibrosis or infiltrative disease.Similarly, RV enlargement, hypertrophy,and systolic function are best determinedby CMR.

Right and Left Heart CatheterizationData from an optimally performedRHC must be incorporated togetherwith the patient’s clinical characteristicsand echocardiographic data to arrive ata final diagnosis of PH-LHD. Inpatients with PH-LHD, data from theRHC are also useful to optimizemedical management and are necessaryto assess risk in patients being con-sidered for transplantation andmechanical circulatory support. It iscrucial that the procedure be performedcorrectly and that data are properly col-lected and interpreted.60,61

Table 4. Distinguishing Pulmonary Hypertension-Left Heart Disease From Pulmonary ArteryHypertension Using Echocardiography.

Echo Parameter Echo Finding

Likelihood of

PH-LHD PAH

Ejection fraction �50% 1 2

Left atrial size LAD � 40 mm 1 2

LAVI � 28 mm/m2

LV wall thickness �11 mm 1 2

Transmitral Doppler Grade II/III diastolic dysfunction 1 2

Mitral regurgitation Severity � 1� 1 2

RV size RV-to-LV area � 1.0 2 1

Interventricular septum Systolic flattening 2 1

Lateral-septal TDI disparity

Interatrial septum Bowing into LA 2 1

RV systolic function TAPSE �1.5 cm 2 1

RVOT Doppler Notching 2 1

LAD � left atrial dimension; LAVI � left atrial volume index; LHD � left heart disease;LV � left ventricular; PH � pulmonary hypertension; RV � right ventricular; RVOT � rightventricular outflow; TDI � tissue Doppler imaging.Reprinted with permission from Elsevier from Fang JC, DeMarco T, Givertz MM, et al.World Health Organization Pulmonary Hypertension group 2: pulmonary hypertension dueto left heart disease in the adult—a summary statement from the Pulmonary HypertensionCouncil of the International Society for Heart and Lung Transplantation. J Heart LungTransplant. 2012;31(9):913-933.

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A complete hemodynamic assessmentincludes measurement of RA, RV, pul-monary artery and pulmonary arterywedge pressures, and cardiac output. Allpressures should be determined at endexpiration during spontaneous breathingto minimize the effects of intrathoracicpressure variation on the measurement.Thermodilution cardiac output whenmeasured in triplicate and injectedduring end expiration62 remains valideven in the setting of low cardiacoutput and severe TR.63

Incorrect determination of thePAWP may be secondary to manyerrors, including improper transducerposition and zeroing to atmospheric

pressure, waveform dampening, incom-pletely wedged catheter, placement inthe RV, measurement that is not at endexpiration, and use of the electronicmean obtained from the computermonitor. Mitral regurgitation causeslarge “v” waves that can be mistakenlyinterpreted as an elevated PAWP, con-founding the calculation of the TPGand DPG. This can be accounted forby reading the PAWP at the time ofthe “a” wave. Several recent studies haveexamined the relationship between thePAWP and LVEDP and found that asubstantial percentage of patients withPAWP �15 had LVEDP �15, whichcould lead to misclassification of

patients with PH-LHD as PAH. Mea-surement of the LVEDP should beconsidered when a reliable PAWPtracing could not be obtained or thevalue of the PAWP is inconsistent withthe expected value based on the clinicalpicture. Measurement performed man-ually on pressure tracings at endexpiration is most tightly correlatedwith LVEDP.64

Provocative TestingProcedures in the catheterization labo-ratory are performed while patients areat rest in a fasting state and often aftersedating medications have been admin-istered. Hemodynamic findings of LHD

PH iden�fied by echocardiography

Risk factors for LHD? - Age >60 years

- Valvular heart disease

- Reduced LV ejec�on frac�on

- Evidence of elevated LV pressures (LVH, diastolic dysfunc�on, LAE)

- Comorbidi�es suppor�ng LV disease (DM, Htn, CAD, obesity)

- Markedly elevated BNP

No risk factors

PAH

Proceed to right heart catheteriza�on

1-2 risk factors

PH-LHD likely

Consider right heart catheteriza�on

≥3 risk factors

PH-LHD

Consider right heart catheteriza�on

Figure 3: Evaluation of PH identified by echocardiography. BNP � brain-type natriuretic peptide; CAD � coronary artery disease; DM � dia-betes mellitus; Htn � hypertension; LAE � left atrial enlargement; LHD � left heart disease; LVH � left ventricular hypertrophy; PH � pulmonaryhypertension; PAH � pulmonary arterial hypertension.

75Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

may not be apparent under these condi-tions so that a diagnosis of LHD couldbe missed and patients are inappropri-ately diagnosed with PAH.65 Touncover hemodynamic abnormalitiesconsistent with LHD, measurement ofthe PAWP after provocative testingwith exercise or volume loading can beconsidered,61 especially in the setting ofa clinical history or echocardiographicfindings associated with HFpEF.61 Inone recent report, after fluid challenge,46 patients (22.2%) originally classifiedas having PAH were reclassified ashaving pulmonary venous hypertension,most secondary to LHD.66

MANAGEMENT OF PH-LHDWith few exceptions, the appropriatetherapy for PH-LHD is optimizingtreatment of the underlying LHD. In thecase of HFrEF and HFpEF, therapyshould include guideline-recommendedtreatments with diuretics, vasodilators,and neurohormonal antagonists, as well aswith device and surgical therapies whenappropriate.67 The benefits of these ther-apies were emphasized in a recent studyshowing that adjustment of diuretics andvasodilator agents in response to datafrom continuous PAP monitoring devicesreduced heart failure hospitalizations.68

Comorbidities that may contribute to PHsuch as sleep apnea, pulmonary embolism,and chronic obstructive pulmonary diseaseshould also be identified and aggressivelytreated.

Increased morbidity and mortalityassociated with PH in patients withLHD makes PH an attractive thera-peutic target. However, despite beneficialacute hemodynamic effects and smallstudies with phosphodiesterase type 5(PDE5) inhibitors that have shownimprovement in exercise capacity, nostudy has shown PAH therapies to bebeneficial in PH-LHD, and some PAHtherapies have been associated with sig-nificant adverse effects includingincreased mortality.1,8,69 Most studies ofPAH therapies in LHD have not specif-ically enrolled PH-LHD, so it ispossible that undetected benefits will befound in future trials.

Data demonstrating acute hemody-namic improvements including reducedPAWP, PVR, and increased cardiac

output provided the rationale for theFlolan International Randomized Sur-vival Trial (FIRST) of epoprostenol inHFrEF. However, the FIRST trial wasstopped early when a trend towardincreased mortality in the epoprostenolgroup was identified.70 Multiple trialsof endothelin receptor antagonists forthe treatment of HFrEF have been per-formed and shown either noimprovement or worsening edema andhospitalization. Several of these negativestudies have never been published.71-75

Phosphodiesterase type 5 inhibitorsalso have been shown to have beneficialacute hemodynamic benefits includingimprovements in gas exchange, skeletalmuscle function, diastolic function, andRV function69; reduced PVR and TPG;increasing cardiac output; improvementsin peak oxygen consumption and6-minute walk; and decreased heartfailure hospitalizations.76,77 Similarimprovements have been shown inpatients treated with the soluble guanylatecyclase stimulator riociguat.78 In clinicalpractice, sildenafil also decreases PVR andimproves RV function after heart trans-plantation and LVAD implantation.79,80

Despite these encouraging findings,long-term benefits of treatment withthese agents have not yet been demon-strated in a randomized controlled trial sothat they should not be routinely pre-scribed in patients with PH-LHD.Additional trials are now underway.

Prolonged treatment with intravenousvasodilators and mechanical support mayrestore vasodilator response in patientswith HFrEF found to have initially irre-versible Cpc-PH during heart transplantevaluation.81 In several reports, LV assistdevice support has been shown to beeffective in reversing PH permittingheart transplant without increased ratesof RV failure or death.79,82,83

CONCLUSIONMuch remains unknown aboutPH-LHD. An improved understandingof triggers and development of vascularchanges in PH-LHD as well as the rela-tionship between the LV and thepulmonary vasculature is needed. Failureof studies to demonstrate beneficiallong-term outcomes in PH-LHDpatients treated with pulmonary vasodi-

lators suggests that PH in this settingmay be a marker of severe or inade-quately treated left heart failure. Studiesthat are specifically designed to focus onpulmonary vasodilators in PH-LHDpatients with optimally managed LHDare needed.

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ventricular longitudinal strain correlates well withright ventricular stroke work index in patients withadvanced heart failure referred for heart transplan-tation. J Card Fail. 2012;18(3):208-215.59. Cameli M, Righini FM, Lisi M, et al. Com-parison of right versus left ventricular strainanalysis as a predictor of outcome in patients withsystolic heart failure referred for heart transplan-tation. Am J Cardiol. 2013;112(11):1778-1784.60. Champion HC, Michelakis ED, HassounPM. Comprehensive invasive and noninvasiveapproach to the right ventricle–pulmonary circu-lation unit: state of the art and clinical and researchimplications. Circulation. 2009;120(11):992-1007.61. Hoeper MM, Bogaard HJ, Condliffe R, et al.Definitions and diagnosis of pulmonary hyper-tension. J Am Coll Cardiol. 2013;62(25 Suppl):D42-D50.62. Stevens JH, Raffin TA, Mihm FG,Rosenthal MH, Stetz CW. Thermodilution cardiacoutput measurement. Effects of the respiratorycycle on its reproducibility. JAMA. 1985;253(15):2240-2242.63. Hoeper MM, Maier R, Tongers J, et al.Determination of cardiac output by the Fickmethod, thermodilution, and acetylene rebreathingin pulmonary hypertension. Am J Respir Crit CareMed. 1999;160(2):535-541.64. Ryan JJ, Rich JD, Thiruvoipati T, Swamy R,Kim GH, Rich S. Current practice for determiningpulmonary capillary wedge pressure predisposes toserious errors in the classification of patients withpulmonary hypertension. Am Heart J. 2012;163(4):589-594.65. Halpern SD, Taichman DB. Misclassificationof pulmonary hypertension due to reliance on pul-monary capillary wedge pressure rather than leftventricular end-diastolic pressure. Chest. 2009;136(1):37-43.66. Prasad A, Hastings JL, Shibata S, et al.Characterization of static and dynamic left ven-tricular diastolic function in patients with heartfailure with a preserved ejection fraction. Circ HeartFail. 2010;3(5):617-626.67. Writing Committee Members, Yancy CW,Jessup M, et al; American College of Cardiology

Foundation/American Heart Association TaskForce on Practice Guidelines. 2013 ACCF/AHAguideline for the management of heart failure: areport of the American College of CardiologyFoundation/American Heart Association TaskForce on practice guidelines. Circulation. 2013;128(16):e240-e327.68. Adamson PB, Abraham WT, Bourge RC,et al. Wireless pulmonary artery pressure moni-toring guides management to reducedecompensation in heart failure with preservedejection fraction. Circ Heart Fail. 2014;7(6):935-944.69. Cooper TJ, Guazzi M, Al-Mohammad A,et al. Sildenafil in Heart failure (SilHF). Aninvestigator-initiated multinational randomizedcontrolled clinical trial: rationale and design. EurJ Heart Fail. 2013;15(1):119-122.70. Califf RM, Adams KF, McKenna WJ, et al.A randomized controlled trial of epoprostenoltherapy for severe congestive heart failure: TheFlolan International Randomized Survival Trial(FIRST). Am Heart J. Jul 1997;134(1):44-54.71. Kalra PR, Moon JC, Coats AJ. Do results ofthe ENABLE (Endothelin Antagonist Bosentanfor Lowering Cardiac Events in Heart Failure)study spell the end for non-selective endothelinantagonism in heart failure? Int J Cardiol. Oct2002;85(2-3):195-197.72. McMurray JJ, Teerlink JR, Cotter G, et al;VERITAS Investigators. Effects of tezosentan onsymptoms and clinical outcomes in patients withacute heart failure: the VERITAS randomizedcontrolled trials. JAMA. 2007;298(17):2009-2019.73. Packer M, McMurray J, Massie BM, et al.Clinical effects of endothelin receptor antagonismwith bosentan in patients with severe chronic heartfailure: results of a pilot study. J Card Fail. Feb2005;11(1):12-20.74. Anand I, McMurray J, Cohn JN, et al;EARTH Investigators. Long-term effects of dar-usentan on left-ventricular remodelling and clinicaloutcomes in the EndothelinA Receptor AntagonistTrial in Heart Failure (EARTH): randomised,double-blind, placebo-controlled trial. Lancet. 2004;364(9431):347-354.

75. Kelland NF, Webb DJ. Clinical trials ofendothelin antagonists in heart failure: publicationis good for the public health. Heart. 2007;93(1):2-4.76. Lewis GD, Lachmann J, Camuso J, et al.Sildenafil improves exercise hemodynamics andoxygen uptake in patients with systolic heartfailure. Circulation. 2007;115(1):59-66.77 Lewis GD, Shah R, Shahzad K, et al. Silde-nafil improves exercise capacity and quality of lifein patients with systolic heart failure and secondarypulmonary hypertension. Circulation. 2007;116(14):1555-1562.78. Bonderman D, Ghio S, Felix SB, et al; LeftVentricular Systolic Dysfunction Associated WithPulmonary Hypertension Riociguat Trial(LEPHT) Study Group. Riociguat for patientswith pulmonary hypertension caused by systolic leftventricular dysfunction: a phase IIb double-blind,randomized, placebo-controlled, dose-ranginghemodynamic study. Circulation. 2013;128(5):502-511.79. Tedford RJ, Hemnes AR, Russell SD, et al.PDE5A inhibitor treatment of persistent pul-monary hypertension after mechanical circulatorysupport. Circ Heart Fail. 2008;1(4):213-219.80. Kulkarni A, Singh TP, Sarnaik A, WaltersHL, Delius R. Sildenafil for pulmonary hyper-tension after heart transplantation. J Heart LungTransplant. 2004;23(12):1441-1444.81. Alba AC, Rao V, Ross HJ, et al. Impact offixed pulmonary hypertension on post-heart trans-plant outcomes in bridge-to-transplant patients.J Heart Lung Transplant. 2010;29(11):1253-1258.82. Zimpfer D, Zrunek P, Sandner S, et al.Post-transplant survival after lowering fixed pul-monary hypertension using left ventricular assistdevices. Eur J Cardiothorac Surg. 2007;31(4):698-702.83. Martin J, Siegenthaler MP, Friesewinkel O,et al. Implantable left ventricular assist device fortreatment of pulmonary hypertension in candidatesfor orthotopic heart transplantation-a preliminarystudy. Eur J Cardiothorac Surg. 2004;25(6):971-977.

78 Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

The Right Ventricle: A Not-So-Innocent Bystander inPulmonary Hypertension Due to Left Heart Disease

Brian A. Houston, MDDivision of CardiologyDepartment of MedicineThe Johns Hopkins School of MedicineBaltimore, MD

Steven Hsu, MDDivision of CardiologyDepartment of MedicineThe Johns Hopkins School of MedicineBaltimore, MD

Emmanouil Tampakakis, MDDivision of CardiologyDepartment of MedicineThe Johns Hopkins School of MedicineBaltimore, MD

Ryan J. Tedford, MDDivision of CardiologyDepartment of MedicineThe Johns Hopkins School of MedicineBaltimore, MD

“After all, there are no innocent bystanders. . . what are they doing there in the firstplace?”—William S. Burroughs, “Exterminator!”

The most common disease associated with high pulmonary vascular pressures andright ventricular (RV) afterload is left heart disease (LHD). In this review, we willdiscuss the role right heart disease (RHD) plays in LHD progression, prognosis, andtreatment. We will first discuss the current definitions employed in RHD and itsepidemiology in various left heart diseases. We will next explore the pathophysiologyof RV dysfunction in LHD, including a discussion of the effects and components ofRV afterload and RV/left ventricular contractile interactions. Finally, we will describethe recently observed clinical implications of RV dysfunction in LHD and pertinenttherapeutic considerations.

Contemporary cardiologists have loudlydecried the disregard with which theright ventricle (RV) was historically held.In the early 17th century, Sir WilliamHarvey proclaimed, “the right ventriclemay be said to be made for the sake oftransmitting blood through the lungs,not for nourishing them.”1 However,between then and the late 20th century,the RV was largely ignored. Indeed, themost striking scientific findings con-cerning the RV were by investigatorswho sclerosed the RV in dogs2 and

completely bypassed the RV in humans3

only to find that circulation continuedrelatively unimpeded. Thus, the RV wasrelegated to the status of an innocentbystander in cardiac disease. We nowknow, of course, that cardiologists of theearly 20th century would have been well-served to ask just what the RV was“doing there in the first place.” Ascardiac surgery became more prevalent,surgeons began anecdotally noting theimportance of right-sided function inpredicting patient outcomes during and

after surgery. In the 1980s, investigatorsrealized that while a damaged orbypassed RV can support circulation inthe face of low afterload, RV functionplays an increasingly crucial role in thepresence of any disease state associatedwith elevated afterload.4 It became clearthat with any elevation in afterload,the RV becomes a not-so-innocentbystander.

DEFINITIONSThe International Right Heart Foun-dation Working Group recentlyproposed a comprehensive definition ofright heart failure as: “a clinical syn-drome due to an alteration of structureand/or function of the right heart circu-

Key Words—right ventricle, right ventricular failure, pulmonary hypertension due to left heart disease,heart failureCorrespondence: Ryan.Tedford@jhmi.eduDisclosures: The authors have no conflicts of interest to disclose.

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latory system that leads to suboptimaldelivery of blood flow (high or low) tothe pulmonary circulation and/or ele-vated venous pressures—at rest or withexercise.”5 Although the RV is a keycomponent of the right heart system(and our focus), it is important toremember that unfavorable alterations ofany component of the circulation fromthe systemic veins up to the pulmonarycapillaries can result in right heart failuresymptoms.

Similar to the left ventricle (LV), the3 determinants of RV function arepreload, contractility, and afterload.Defining afterload is particularlyimportant as the presence of elevated RVafterload in left heart disease (LHD)identifies an “RV at risk.” For thisreason, much attention has been placedon defining pulmonary hypertension(PH) in the context of LHD. Currently,PH is defined by a resting mean pul-monary artery pressure (mPAP) that isgreater than or equal to 25 mm Hg.4

Mean PAP is a function of the productof cardiac output (CO) and pulmonaryvascular resistance (PVR) as well as thedownstream left heart pressure (pul-monary artery wedge pressure[PAWP]/left atrial pressure [LAP] orleft ventricular end-diastolic pressure[LVEDP]):

mPAP � PVR � CO � PAWP

Thus, one can see that mPAP may beelevated due to increase in resistance, anincrease in flow (CO), or a downstreamincrease in left heart filling pressure. Incases of LHD, the latter variable pre-dominates, though we will discuss laterhow it can also contribute to acuteand chronic alterations in PVR andcapacitance.

The relative contributions of thesevarious components to an elevatedmPAP in a given patient carries prog-nostic and diagnostic information, soconsiderable attention has been paid tothe nomenclature employed to categorizediffering hemodynamic profiles.Recently, the Fifth World Symposiumon Pulmonary Hypertension proposedthe following: 1) isolated postcapillaryPH (IpcPH)—previously termed

“passive” PH; and 2) combined postcap-illary and precapillary PH (CpcPH)—previously called “reactive,” “out-of-proportion,” or “mixed PH.”6 IpcPH andCpcPH are differentiated hemodynami-cally by parameters that suggest acomponent of pulmonary vascular disease(ie, a precapillary component). Com-monly used parameters to differentiatebetween IpcPH and CpcPH include thetranspulmonary gradient (TPG), whichis the mPAP minus PAWP, PVR(TPG divided by CO), and the diastolicpulmonary gradient (DPG) [diastolicpulmonary artery pressure (dPAP)minus PAWP] (Table 1). Althoughinitially proposed as the sole discrimi-nator of CpcPH and IpcPH, morerecent studies have suggested the DPGmay not carry the prognostic signifi-cance originally thought,7-11 castingdoubt on its inclusion in diagnostic def-initions.

EPIDEMIOLOGYBefore delving into the details of rightheart disease (RHD) pathophysiology, itis important to identify the extent towhich LHD patients are affected byRHD. However, quantification of theprevalence of elevated pulmonarypressure (PH) in LHD carries importantcaveats. First, most large studies haveemployed echocardiography in estimatingsystolic pulmonary artery pressure(sPAP) even though mPAP is the truehemodynamic determinant of thepresence of PH. While mPAP can bederived from sPAP with a relative degreeof reliability,12,13 echocardiographic mea-surement of sPAP remains an inexacttechnique14,15 and requires an adequatetricuspid regurgitation jet. While moreprecise, retrospective studies employinghemodynamic data are susceptible toreferral bias and inadequate fluid optimi-zation status and could overestimate theprevalence of PH in LHD.

Even accounting for these limitations,it is clear that PH in LHD is a prevalentcondition. In patients with heart failurewith reduced ejection fraction (HFrEF),studies indicate that 26% to 86% ofpatients have PH.16-19 The prevalence ofCpcPH in HFrEF patients ranges from25% to 47%: a recent evaluation of alarge ambulatory HFrEF populationfound 40% with CpcPH.19 In patientswith heart failure with preserved ejectionfraction (HFpEF), the prevalence of PHhas ranged from 36% to 83%.20-22 Dataare more limited on the prevalence ofCpcPH in HFpEF. Using a precapillarycomponent definition of PVR �2.5Wood units or TPG�12 mm Hg,Thenappan found a prevalence of 68%among those patients in their PH reg-istry who had undergone right heartcatheterization.23 Given the heteroge-neity of HFpEF, vast differences inpopulation demographics present invarious publications may also affect thereported prevalence of PH.12,24,25

Finally, PH is prevalent in patients withleft-sided valvular disease, includingmitral stenosis (up to 73%),26,27 mitralregurgitation (23%–44%),28,29 and aorticstenosis (29%–47%).30-32

PATHOPHYSIOLOGY OFRHD IN LHDMechanisms of PH in LHD (IncreasingRV Afterload)In LHD, the inciting abnormalityleading to PH is an elevation in LAP,whether due to HFrEF, HFpEF, orvalvular disease. This leads to a passiveproportional increase in dPAP (andthus mPAP), which results in PH evenin the absence of alterations in the pul-monary vasculature.33 However, thepathophysiology is often more complexthan simple passive elevation inpressure. Even in the absence of struc-tural pulmonary vascular changes,passive elevations in pulmonary vascularpressure may contribute to a perceivedprecapillary component to PH. Unlikein the systemic circulation, compliance(or the blood storage capacity of thevessels) in the pulmonary vasculature ismore evenly distributed across the pul-monary bed, and the peripheral or distalvessels are responsible for most of thepulmonary vascular compliance.34,35

Table 1.

Hemodynamic profiles

IpcPH CpcPH

PAWP �15 mm Hg �15 mm Hg

DPG �7 mm Hg �7 mm Hg

TPG �12 mm Hg �12 mm Hg

PVR �3 mm Hg �3 mm Hg

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Thus, the principal determinant of pul-monary vascular compliance is usuallyPVR, with compliance declining in apredictable hyperbolic fashion as PVRrises.36-38 Elevations in left-sidedpressure significantly alter this paradig-matic relationship (Figure 1). As passivepressure increases, compliance declinesat a given PVR, leading to enhancedpulmonary wave reflections. Thesereflective waves return during ven-tricular systole to further increase sPAP.Because dPAP is unaffected by wavereflections, the TPG and PVRincrease.39,40

With further elevation in pulmonarypressures, alterations in pulmonaryvasoreactivity and structural damage

ensue. Smooth muscle vascular relax-ation is impaired, likely arising fromendothelial dysfunction due to alterationsin the nitric oxide,41 endothelin,42-44 andrenin-angiotensin-aldosterone signalingpathways.45 Further, elevated pulmonaryvascular pressure results in damage to thepulmonary capillaries. While plexiformlesions (the pathologic correlates ofWorld Health Organization [WHO]Group 1 PH) are notably absent,46,47

with sustained injury, deposition of typeIV collagen increases, and alterationsoccur in endothelial cell plasma mem-branes, cytoskeletal components, calciumhandling, and expression of variousgrowth factors.48-52 This contributes tophysical alveolar-capillary remodeling

and impairments in alveolar gasexchange.53 Further, chronic pressureelevations are associated with increasedmuscularization of the pulmonary arte-rioles and medial hypertrophy andneointima formation in the pulmonaryarteries and veins.46,47 All of thesechanges result in elevations in PVR anda pathologic transition from IpcPH toCpcPH. While improvement in PVRhas been described after proceduresreducing left-sided pressures (eg, mitralvalve surgery, left ventricular assistdevice), many patients have persistentelevations in PVR, which supports thepersistence of these pathologic changesto the PVR.54-57 The degree, timing,and prediction of the regression of these

Figure 1: Plot of pulmonary vascular resistance vs pulmonary vascular compliance, showing an inverse hyperbolic relationship between the 2determinants of afterload. The relationship in those normal left heart filling pressures (black dots and solid black line) is identical to a cohort ofpatients with known or suspected pulmonary arterial hypertension (grey line). With elevations in left heart filling pressures (those with pulmonaryartery wedge pressure �20; red dots), the curve shifts downward indicating lower pulmonary vascular compliance at a given resistance, andincreases in RV pulsatile load. Used with permission from Tedford et al. Circulation. 2012;125(2):289-297.

81Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

pathologic changes remains poorlyunderstood.

Response of the RV to Elevated AfterloadRV afterload is defined by ventricularwall stress occurring throughout ejection.LaPlace’s law defines wall stress (�)mathematically as a proportionalitybetween ventricular pressure duringejection (PEJ) multiplied by the ven-tricular radius of curvature (rEJ) dividedby the wall thickness (h).58

��PEJ � rEJ

h

When considering wall stress, 2important differences between the LVand RV must be considered. First, theRV is a thin-walled structure, so “h” inLaPlace’s equation is a small numbereven during systole. Second, while theradius of curvature (rEJ) declinesthroughout systole in the LV, mitigatingto some extent the increase in pressure,the rEJ declines less (or may actuallyincrease) in the RV during systole.59

Therefore, RV wall stress is highlydependent on and can be estimated bythe pressure (PEJ). By integrating theRV systolic pressure over the timebetween pulmonary valve opening andclosing (ejection), one can accurately cal-culate PEJ. Finally, by dividing the end-systolic pressure (ESP) by the strokevolume (SV), one can calculate a vali-dated “lumped” parameter of afterloadknown as the effective arterial elastance(Ea). In normal subjects, the RVpressure-volume loop is triangular aspressure decays throughout ejection intoa compliant vascular circuit. This makesdetermination of end-systolic pressure onroutinely employed invasive (right heartcatheterization) or noninvasive (echocar-diography) assessment difficult.However, in diseases leading to elevatedpulmonary pressures (eg, LHD), thereduction in compliance leads to anincrease in pulsatile loading (due to aug-mented early return of arterial wavereflections) and a rise in pressurethroughout ejection.39,60 Thus, ESP maybe closely approximated by peak sPAP(a value easily measured on right heart

catheterization), and Ea calculated bysPAP divided by SV (Figure 2).

The RV LaPlace relationshipdescribed above would predict that RVfunction would be sensitive to acuteincreases in pulmonary pressures. Indeed,in a dog model, Abel et al found that anacute increase in mPAP of a mere10–15 mm Hg resulted in a 30%reduction in right ventricular SV, while a40 mm Hg increase in mean systemarterial pressure only resulted in a 10%reduction in left ventricular SV.61 Thiswas paralleled in findings by Ghio et alwhere RV ejection fraction (RVEF) wasinversely proportional to mPAP in 377chronic heart failure patients.62

RV Contractile Adaptation and LV/RVContractile InteractionsWhile the RV is quite sensitive to acutechanges in pulmonary pressures, changesmay occur over time to improve contrac-tility, matching increases in afterload.While the beat-to-beat adaptation ofventricular contractile function based onpreload (heterometric adaptation,described by Starling’s law) is well-appreciated, the RV may also experienceaugmentation of contractile functionwith increased afterload conditions (eg,elevated Ea) over time, termed homeo-metric adaptation and described byAnrep’s law of the heart.63 In a normalRV, elevations in afterload are matchedby homeometric elevations in contractilefunction and perhaps even adaptivehypertrophy, and the RV and itsafterload remain well “coupled.”However, many diseases that affect theleft heart respect no septal boundary andmay lead to intrinsic RV contractiledysfunction as well. Furthermore, con-traction against a chronically elevatedafterload leads to adverse RV remodeling(maladaptive hypertrophy, dilation, andultimately contractile failure). In thesecases, RV contractile function cannotaugment to match an elevated afterload(it is “uncoupled” from its afterload),60

and either stroke volume must decline orpreload must increase to take advantageof heterometric adaptation to maintainCO.

Finally, it must be understood thatthe left and right ventricles do not existin isolation, and are instead highly inter-

dependent. In an elegant set ofexperiments in the early 1990s involvingelectrically isolated canine ventricles,Damiano et al demonstrated thatapproximately 30% to 50% of RV con-tractile energy is generated by LVcontraction.4 More recently, experimentshave suggested that septal function isessential for RV longitudinal contraction,which contributes up to 80% of RV sys-tolic function.64 Therefore, one canappreciate that even in the absence ofany intrinsic RV disease, compromise ofthe LV and/or the interventricularseptum (as commonly occurs in LHD)will result in a reduction in the con-tractile function of the RV.

CLINICAL AND THERAPEUTICIMPLICATIONS OF RHD INVARIOUS LHD STATESHeart FailureIn a study of 463 patients with HFrEFundergoing hemodynamic catheter-ization, Miller et al found that thepresence of any PH was correlated withan elevated risk of death (adjusted HR2.24, P�0.001).65 Furthermore, patientswith a PVR �3 Woods units (termed“mixed PH” in this study) had a signifi-cantly elevated risk of death comparedwith those patients with a PVR �3(“passive PH”), thus establishing theprognostic import of RV afterload inLHD, and specifically the poor prog-nosis portended by HF patients with PHand significant precapillary component.Several studies had previously establishedthat HFrEF patients with reduced RVfunction (defined primarily by echocar-diographically derived parameters)carried a worse prognosis. In 2001, Ghioand colleagues studied the additive prog-nostic value of combining measures ofRV afterload (mPAP) and RV systolicfunction (thermodilution-derived RVEF)in 377 patients with heart failure under-going hemodynamic catheterization. Inthis study, patients with elevated mPAPand preserved RVEF comprised a smallportion of the population, but had asimilar prognosis to patients with anormal mPAP. Patients with an elevatedmPAP and reduced RVEF were over7 times more likely to die or undergourgent transplantation when comparedwith patients with normal RVEF and

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normal mPAP.62 This finding highlightsthat neither RV function nor pulmonarypressures should be considered in iso-lation; it is the inability of the RV toremain coupled to its afterload that likelydrives disease progression.

For patients with HFpEF, elevatedpulmonary pressures carry a worse prog-nosis as well. In a heart failure cohortwith both HFpEF and HFrEF patients,Bursi found increasing tertiles of echocar-

diographically derived sPAP to beassociated with worse survival, inde-pendent of LV ejection fraction(LVEF).66 In 2014, Melenovsky and col-leagues identified RV dysfunction as thestrongest predictor of death in an HFpEFpopulation.67 Later the same year,Mohammed and colleagues demonstratedthat the addition of RV dysfunction(defined by semiquantitative echocardio-graphic assessment) to elevated afterload

carries an increased risk of mortality andhospitalization, similar to HFrEF.68

When considering therapy of RHD inthe setting of heart failure, one mustremember the contribution of elevatedleft atrial pressure to RV afterload. AsPAWP rises, not only does dPAP pas-sively increase, but pulsatile RV load alsoincreases, leading to out-of-proportionelevations in sPAP, TPG, and PVR asdescribed above. Dupont and colleagues

Figure 2: Right Ventricular Pressure Volume (PV) Loop from a patient with mild pulmonary hypertension due to heart failure with preservedejection fraction. The width of the PV loop is the stroke volume (SV; red-dotted line). Due to the shape of the PV loop with pulmonary hyper-tension, end-systolic pressure (ESP) is closely approximated by peak pulmonary artery systolic pressure. Effective arterial elastance (blue line),a “lumped” parameter of afterload, can then be estimated as systolic pulmonary artery pressure divided by SV.

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found that pulmonary artery compliance(estimated as SV/pulmonary pulsepressure) was a better predictor of bothRV dysfunction as well as transplant-freesurvival than PVR.69 The authors sug-gested that compliance (like Ea) lumpsboth resistive (PVR) and pulsatile com-ponents into a single measure of RVload. Compliance was also recentlyshown to predict survival in those heartfailure patients with normal PVR.40

These studies may suggest that measuresof total RV afterload, rather than specifi-cally the precapillary component, are thebest hemodynamic predictors of survivalin heart failure, and further support thenotion that RV function and loadinfluence outcome in left heart failure.Therefore, the importance of adequatelytreating elevated left heart filling pres-sures to improve RV afterload andcontractile efficiency cannot be over-stated. Similarly, therapeutic decisionsdependent on measures of RV afterload(eg, heart transplantation for patientswith elevated PVR) should only be basedon hemodynamics obtained when theleft heart filling pressures are optimallytreated. To assess and treat RHD in leftheart failure, one must first maximallytreat the failing left heart.

For patients with continued elevationsin RV afterload despite optimization ofleft heart filling pressures, evidence-basedtherapeutic options are limited. Giventhe afterload sensitivity of the RV andthe poor prognosis portended by elevatedPVR in heart failure, it seems logicalthat a pharmacologic reduction in theprecapillary component of RV afterloadwould benefit patients with heart failure.Phosphodiesterase-5 (PDE-5) inhibitorssuch as sildenafil inhibit degradation ofcyclic guanosine monophosphate,enhancing signaling through the nitricoxide pathway, and seem tailor-made fortherapy of heart failure complicated byRHD. Indeed, early studies showedgreat promise for sildenafil in bothHFrEF and heart failure.70-74 However,the RELAX study, a multicenter,double-blind, placebo-controlled,parallel-group, randomized clinical trialof 216 stable outpatients with HFpEF,found that sildenafil did not improveexercise capacity or clinical status com-pared with placebo.75 In a substudy of

RELAX, Borlaug and colleagues shedlight on a potential mechanism of thisfinding by demonstrating that whilesildenafil improved endothelial functionand reduced systemic load, it wasassociated with a reduction in LV con-tractility and ultimately had no effect onpulmonary artery systolic pressure inthese patients.76

Other PH-specific pharmacologicagents studied in LHD have met witheven more disappointing results. TheFIRST study, a multicenter, interna-tional, randomized study in 471 HFrEFpatients, demonstrated that epoprostenolfailed to improve exercise capacity orquality of life and was terminated earlydue to a strong trend toward decreasedsurvival.77 Echoing the PDE-5 expe-rience, endothelin-1 antagonists such asbosentan showed early promise in animaland small hemodynamic studies ofpatients with PH-LHD.78,79 However,in the large-scale REACH clinical trial,bosentan therapy failed to improve out-comes and was instead associated with ahigher early risk of heart failure events.80

Importantly, no multicenter randomizedstudy has exclusively enrolled heartfailure patients with a significant precap-illary component, and it remainsunknown if PH-specific therapy couldbenefit this population.

Recently, Borlaug and colleagues dem-onstrated the administration ofdobutamine (a �-1 agonist) to HFpEFpatients resulted in improvements inRVEF. Surprisingly, however, theywere able to demonstrate that thisimprovement was solely due to reductionin RV afterload unrelated to reduction inleft heart pressures, suggesting that theseHFpEF patients had an underlyingreversible pulmonary vasoconstrictionthat is responsive to �-adrenergictherapy.81 This suggests a potentiallynovel direction for pharmacologictherapy for RHD in HFpEF patients,though prior experience with�-adrenergic stimulatory therapy inheart failure advises caution.82

Left-sided Valvular DiseaseMitral stenosis represents the paradig-matic left-sided valvular diseaseassociated with the development of PH.Fortunately, correction of the underlying

valvular disease usually results in reso-lution of PH, though improvement maytake up to a year to be evident.83,84

Young patients with a shorter durationof disease tend to demonstrate moremarked improvement, perhaps due tothe absence of truly irreversible pul-monary vascular changes. Preoperativeseverity of PH does not affect outcomesin patients undergoing balloon mitralvalvuloplasty, and even patients withvery high pulmonary pressures (mPAP�50 mm Hg) may undergo mitral valvereplacement surgery with resultant post-operative improvements in pulmonaryvascular hemodynamics.85 Aortic ste-nosis is also associated with thedevelopment of PH, and correction ofthe underlying valvular disorder is simi-larly associated with an improvementin pulmonary hemodynamics. Even inpatients with severe PH (sPAP �60mm Hg), recent studies show benefitfor aortic valve replacement.86

LV Assist Device TherapyWith the growing heart failure popu-lation and continued scarcity of suitabletransplant organs, left ventricular assistdevice (LVAD) therapy is becomingincreasingly common as both a bridge totransplant and long-term treatmentoption for end-stage heart failure. WhileLVAD therapy reduces RV afterload bylowering the left heart filling pressures,up to 40% of patients experience clinicalright heart failure after LVAD implan-tation,87 and right heart failure isassociated with increased mortality post-LVAD.88 The explanations for theobserved RV failure are myriad andinclude damage to the RV and septumduring surgery, disadvantageous changesin ventricular interdependence mitigatedby reduced LV contractility, changes inseptal architecture, and alterations in RVshape all in the setting of a suddenlyelevated CO.89-92 Therefore, in patientsbeing considered for LVAD implan-tation, careful preoperative considerationof RV function is crucial to avoid poten-tially catastrophic post-LVAD RVfailure.

In surgeries involving cardiopulmonarybypass and pericardiotomy (such as tra-ditional LVAD implantation), Rainademonstrated that the RV alters its con-

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tractile pattern from longitudinal totransverse, though overall RV functionremained normal in the face of normalafterload.93 It has been postulated thatthe transverse RV contractile pattern ismore sensitive to alterations in afterload,and indeed a retrospective hemodynamicanalysis from our group showed that theRV has an increased sensitivity toafterload in LVAD patients.94 Fur-thermore, it appears that while RVfunction worsens immediately afterLVAD implantation, it improves overthe ensuing 12 to 36 months in amanner almost wholly dependent on aconcomitant improvement in RVafterload. Thus, in the patient strugglingwith post-LVAD RV failure, aggressiveafterload reduction and “tincture of time”may lead to improvements in RVfunction.

CONCLUSIONRight heart disease is common in leftheart disease and carries important prog-nostic implications. When assessingpatients with RHD in the context ofLHD, one must consider the contribu-tions of both postcapillary andprecapillary components of RV afterload,remembering that postcapillary compo-nents (elevated PAWP)—in addition topassive elevations in pressure—can causeaugmented pulsatile loading of the RVout of proportion to the PVR. Therapyof RHD in LHD should focus first onmaximally treating the respective leftheart condition and then consideringtherapeutic options to reduce RVafterload or potentially augment contrac-tility. In every variety of LHD, one mustremember that the RV is not aninnocent bystander, but is an activeplayer in the game.

References1. Harvey W. Exercitatio Anatomica de MotuCordis et Sanguinis in Animalibus. 1628.2. Starr I, Jeffers WA, Meade RH. The absenceof conspicuous increments of venous pressure aftersevere damage to the right ventricle of the dog,with discussion of the relation between clinicalcongestive failure and heart disease. Am Heart J.1943;26(3):291.3. Fontan F, Baudet E. Surgical repair of tri-cuspid atresia. Thorax. 1971;26(3):240-248.4. Damiano RJ Jr, La Follette P Jr, Cox JL,Lowe JE, Santamore WP. Significant left ven-tricular contribution to right ventricular systolic

function. Am J Physiol. 1991;261(5 Pt 2):H1514-H1524.5. Mehra MR, Park MH, Landzberg MJ, LalaA, Waxman AB. Right heart failure: toward acommon language. Pulm Circ. 2013;3(4):963-967.6. Vachiery J, Adir Y, Barbera JA, et al. Pul-monary hypertension due to left heart diseases.J Am Coll Cardiol. 2013;62(25 Suppl):D100-D108.7. Tampakakis E, Leary PJ, Selby VN, et al. Thediastolic pulmonary gradient does not predict sur-vival in patients with pulmonary hypertension dueto left heart disease. JACC Heart Fail. 2015;3(1):9-16.8. Tedford RJ, Beaty CA, Mathai SC, et al.Prognostic value of the pre-transplant diastolic pul-monary artery pressure-to-pulmonary capillarywedge pressure gradient in cardiac transplant recip-ients with pulmonary hypertension. J Heart LungTransplant. 2014;33(3):289-297.9. Al-Naamani N, Prestion IR, Paulus JK, HillNS, Roberts KE. Pulmonary Arterial CapacitanceIs an Important Predictor of Mortality in HeartFailure With a Preserved Ejection Fraction. JACCHeart Fail. 2015;3(6):467-474.10. Selby VN, Vachiery J, Fang JC, et al. TheDiastolic Pulmonary Gradient as a Predictor ofAdverse Outcomes in Patients With AcuteDecompensated Heart Failure. J Heart LungTransplant. 2014;33(4 Suppl):S40.11. Tampakakis E, Tedford RJ. Reply: character-ization of pulmonary hypertension in heart failureusing the diastolic pressure gradient: theconundrum of high and low diastolic pulmonarygradient. JACC Heart Fail. 2015;3(5):426-427.12. Chemla D, Castelain V, Provencher S,Humbert M, Simonneau G, Herve P. Evaluationof various empirical formulas for estimating meanpulmonary artery pressure by using systolic pul-monary artery pressure in adults. Chest. 2009;135(3):760-768.13. Kind T, Faes TJ, Vonk-Noordegraaf A,Westerhof N. Proportional relations between sys-tolic, diastolic and mean pulmonary artery pressureare explained by vascular properties. Cardiovasc EngTechnol. 2011;2(1):15-23.14. Arcasoy SM, Christie JD, Ferrari VA, et al.Echocardiographic assessment of pulmonary hyper-tension in patients with advanced lung disease.Am J Respir Crit Care Med. 2003;167(5):735-740.15. Fisher MR, Forfia PR, Chamera E, et al.Accuracy of Doppler echocardiography in thehemodynamic assessment of pulmonary hyper-tension. Am J Respir Crit Care Med. 2009;179(7):615-621.16. Cappola TP, Felker GM, Kao WH, HareJM, Baughman KL, Kasper EK. Pulmonary hyper-tension and risk of death in cardiomyopathy:patients with myocarditis are at higher risk. Circu-lation. 2002;105(14):1663-1668.17. Khush KK, Tasissa G, Butler J, McGlothlinD, De Marco T; ESCAPE Investigators. Effect ofpulmonary hypertension on clinical outcomes inadvanced heart failure: analysis of the EvaluationStudy of Congestive Heart Failure and PulmonaryArtery Catheterization Effectiveness (ESCAPE)database. Am Heart J. 2009;157(6):1026-1034.18. Aronson D, Eitan A, Dragu R, Burger AJ.Relationship between reactive pulmonary hyper-

tension and mortality in patients with acutedecompensated heart failure. Circ Heart Fail.2011;4(5):644-650.19. Miller WL, Grill DE, Borlaug BA. Clinicalfeatures, hemodynamics, and outcomes of pul-monary hypertension due to chronic heart failurewith reduced ejection fraction: pulmonary hyper-tension and heart failure. JACC Heart Fail. 2013;1(4):290-299.20. Lam CS, Roger VL, Rodeheffer RJ, BorlaugBA, Enders FT, Redfield MM. Pulmonary hyper-tension in heart failure with preserved ejectionfraction: a community-based study. J Am CollCardiol. 2009;53(13):1119-1126.21. Guazzi M, Borlaug BA. Pulmonary hyper-tension due to left heart disease. Circulation. 2012;126(8):975-990.22. Burke MA, Katz DH, Beussink L, et al.Prognostic importance of pathophysiologic markersin patients with heart failure and preserved ejectionfraction. Circ Heart Fail. 2013;7(2):288-299.23. Thenappan T, Shah SJ, Gomberg-MaitlandM, et al. Clinical characteristics of pulmonaryhypertension in patients with heart failure and pre-served ejection fraction. Circ Heart Fail. 2011;4(3):257-265.24. Shah SJ. Matchmaking for the optimizationof clinical trials of heart failure with preservedejection fraction: no laughing matter. J Am CollCardiol. 2013;62(15):1339-1342.25. Klapholz M, Maurer M, Lowe AM, et al;New York Heart Failure Consortium. Hospital-ization for heart failure in the presence of a normalleft ventricular ejection fraction: results of the NewYork Heart Failure Registry. J Am Coll Cardiol.2004;43(8):1432-1438.26. American College of Cardiology/AmericanHeart Association Task Force on Practice Guide-lines; Society of Cardiovascular Anesthesiologists;Society for Cardiovascular Angiography and Inter-ventions; Society of Thoracic Surgeons; BonowRO, Carabello BA, Kanu C, et al. ACC/AHA2006 guidelines for the management of patientswith valvular heart disease: a report of theAmerican College of Cardiology/American HeartAssociation Task Force on Practice Guidelines(writing committee to revise the 1998 Guidelinesfor the Management of Patients with ValvularHeart Disease): developed in collaboration with theSociety of Cardiovascular Anesthesiologists:endorsed by the Society for CardiovascularAngiography and Interventions and the Society ofThoracic Surgeons. Circulation. 2006;114(5):e84-e231.27. Hart SA, Krasuski RA, Wang A, Kisslo K,Harrison JK, Bashore TM. Pulmonary hyper-tension and elevated transpulmonary gradient inpatients with mitral stenosis. J Heart Valve Dis.2010;19(6):708-715.28. Saraiva RM, Yamano T, Matsumura Y, et al.Left atrial function assessed by real-time3-dimensional echocardiography is related to rightventricular systolic pressure in chronic mitral regur-gitation. Am Heart J. 2009;158(2):309-316.29. Barbieri A, Bursi F, Grigioni F, et al; MitralRegurgitation International DAtabase (MIDA)Investigators. Prognostic and therapeutic implica-tions of pulmonary hypertension complicating

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degenerative mitral regurgitation due to flail leaflet:a multicenter long-term international study. EurHeart J. 2011;32(6):751-759.30. Silver K, Aurigemma G, Krendel S, Barry N,Ockene I, Alpert J. Pulmonary artery hypertensionin severe aortic stenosis: incidence and mechanism.Am Heart J. 1993;125(1):146-150.31. Melby SJ, Moon MR, Lindman BR, BaileyMS, Hill LL, Damiano RJ Jr. Impact of pul-monary hypertension on outcomes after aortic valvereplacement for aortic valve stenosis. J ThoracCardiovasc Surg. 2011;141(6):1424-1430.32. Johnson LW, Hapanowicz MB, BuonannoC, Bowser MA, Marvasti MA, Parker FB Jr. Pul-monary hypertension in isolated aortic stenosis.Hemodynamic correlations and follow-up. J ThoracCardiovasc Surg. 1988;95(4):603-607.33. Harvey RM, Enson Y, Ferrer MI. A recon-sideration of the origins of pulmonary hyper-tension. Chest. 1971;59(1):82-94.34. Sipkema P, Latham RD, Westerhof N,Rubal BJ, Slife DM. Isolated aorta setup forhemodynamic studies. Ann Biomed Eng. 1990;18(5):491-503.35. Saouti N, Westerhof N, Helderman F, et al.RC time constant of single lung equals that ofboth lungs together: a study in chronic thrombo-embolic pulmonary hypertension. Am J PhysiolHeart Circ Physiol. 2009;297(6):H2154-H2160.36. Lankhaar JW, Westerhof N, Faes TJ, et al.Quantification of right ventricular afterload inpatients with and without pulmonary hypertension.Am J Physiol Heart Circ Physiol. 2006;291(4):H1731-H1737.37. Lankhaar JW, Westerhof N, Faes TJ, et al.Pulmonary vascular resistance and compliance stayinversely related during treatment of pulmonaryhypertension. Eur Heart J. 2008;29(13):1688-1695.38. Bonderman D, Martischnig AM, Vonbank K,et al. Right ventricular load at exercise is a cause ofpersistent exercise limitation in patients with normalresting pulmonary vascular resistance after pul-monary endarterectomy. Chest. 2011;139(1):122-127.39. Tedford RJ, Hassoun PM, Mathai SC, et al.Pulmonary capillary wedge pressure augments rightventricular pulsatile loading. Circulation. 2012;125(2):289-297.40. Pellegrini P, Rossi A, Pasotti M, et al. Prog-nostic relevance of pulmonary arterial compliancein patients with chronic heart failure. Chest. 2014;145(5):1064-1070.41. Cooper CJ, Jevnikar FW, Walsh T, Dick-inson J, Mouhaffel A, Selwyn AP. The influenceof basal nitric oxide activity on pulmonary vascularresistance in patients with congestive heart failure.Am J Cardiol. 1998;82(5):609-614.42. Cody RJ, Haas GJ, Binkley PF, Capers Q,Kelley R. Plasma endothelin correlates with theextent of pulmonary hypertension in patients withchronic congestive heart failure. Circulation. 1992;85(2):504-509.43. Tsutamoto T, Wada A, Maeda Y, Adachi T,Kinoshita M. Relation between endothelin-1spillover in the lungs and pulmonary vascular resis-tance in patients with chronic heart failure. J AmColl Cardiol. 1994;23(6):1427-1433.44. Giaid A, Yanagisawa M, Langleben D, et al.Expression of endothelin-1 in the lungs of patients

with pulmonary hypertension. N Engl J Med. 1993;328(24):1732-1739.45. Cargill RI, Lipworth BJ. Lisinopril attenuatesacute hypoxic pulmonary vasoconstriction inhumans. Chest. 1996;109(2):424-429.46. Delgado JF, Conde E, Sanchez V, et al. Pul-monary vascular remodeling in pulmonaryhypertension due to chronic heart failure. EurJ Heart Fail. 2005;7(6):1011-1016.47. Rich S, Rabinovitch M. Diagnosis andtreatment of secondary (non-category 1) pulmonaryhypertension. Circulation. 2008;118(21):2190-2199.48. Townsley MI, Fu Z, Mathieu-Costello O,West JB. Pulmonary microvascular permeability.Responses to high vascular pressure after inductionof pacing-induced heart failure in dogs. Circ Res.1995;77(2):317-325.49. Lee YS. Electron microscopic studies on thealveolar-capillary barrier in the patients of chronicpulmonary edema. Jpn Circ J. 1979;43(10):945-954.50. Negrini D, Passi A, de Luca G, MiserocchiG. Pulmonary interstitial pressure and pro-teoglycans during development of pulmonaryedema. Am J Physiol. 1996;270(6 Pt 2):H2000–H2007.51. Palestini P, Calvi C, Conforti E, Botto L,Fenoglio C, Miserocchi G. Composition, bio-physical properties, and morphometry of plasmamembranes in pulmonary interstitial edema. Am JPhysiol Lung Cell Mol Physiol. 2002;282(6):L1382-L1390.52. Kerem A, Yin J, Kaestle SM, et al. Lungendothelial dysfunction in congestive heart failure:role of impaired Ca2� signaling and cytoskeletalreorganization. Circ Res. 2010;106(6):1103-1116.53. Guazzi M. Alveolar gas diffusion abnormal-ities in heart failure. J Card Fail. 2008;14(8):695-702.54. Camara ML, Aris A, Padro JM, Caralps JM.Long-term results of mitral valve surgery inpatients with severe pulmonary hypertension. AnnThorac Surg. 1988;45(2):133-136.55. Klotz S, Wenzelburger F, Stypmann J, et al.Reversible pulmonary hypertension in heart trans-plant candidates: to transplant or not to transplant.Ann Thorac Surg. 2006;82(5):1770-1773.56. Morgan JA, Paone G, Nemeh HW, et al.Impact of continuous-flow left ventricular assistdevice support on right ventricular function.J Heart Lung Transplant. 2013;32(4):398-403.57. Mikus E, Stepanenko A, Krabatsch T, et al.Reversibility of fixed pulmonary hypertension inleft ventricular assist device support recipients. EurJ Cardiothorac Surg. 2011;40(4):971-977.58. Stillwell GK. The Law of Laplace. Someclinical applications. Mayo Clin Proc. 1973;48(12):863-869.59. Greyson CR. The right ventricle and pul-monary circulation: basic concepts. Rev EspCardiol. 2010;63(1):81-95.60. Tedford RJ, Mudd JO, Girgis RE, et al.Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension. CircHeart Fail. 2013;6(5):953-963.61. Abel FL, Waldhausen JA. Effects of altera-tions in pulmonary vascular resistance on rightventricular function. J Thorac Cardiovasc Surg.1967;54(6):886-894.

62. Ghio S, Gavazzi A, Campana C, et al. Inde-pendent and additive prognostic value of rightventricular systolic function and pulmonary arterypressure in patients with chronic heart failure. J AmColl Cardiol. 2001;37(1):183-188.63. Cingolani HE, Perez NG, Cingolani OH,Ennis IL. The Anrep effect: 100 years later. Am JPhysiol Heart Circ Physiol. 2013;304(2):H175-H182.64. Brown SB, Raina A, Katz D, Szerlip M,Wiegers SE, Forfia PR. Longitudinal shorteningaccounts for the majority of right ventricular con-traction and improves after pulmonary vasodilatortherapy in normal subjects and patients with pul-monary arterial hypertension. Chest. 2011;140(1):27-33.65. Miller WL, Grill DE, Borlaug BA. Clinicalfeatures, hemodynamics, and outcomes of pul-monary hypertension due to chronic heart failurewith reduced ejection fraction: pulmonary hyper-tension and heart failure. JACC Heart Fail. 2013;1(4):290-299.66. Bursi F, McNallan SM, Redfield MM, et al.Pulmonary pressures and death in heart failure: acommunity study. J Am Coll Cardiol. 2012;59(3):222-231.67. Melenovsky V, Hwang S, Lin G, RedfieldMM, Borlaug BA. Right heart dysfunction inheart failure with preserved ejection fraction. EurHeart J. 2014;35(48):3452-3462.68. Mohammed SF, Hussain I, AbouEzzeddineOF, et al. Right ventricular function in heartfailure with preserved ejection fraction: a com-munity based study. Circulation. 2014;130(25):2310-2320.69. Dupont M, Mullens W, Skouri HN, et al.Prognostic role of pulmonary arterial capacitance inadvanced heart failure. Circ Heart Fail. 2012;5(6):778-785.70. Alaeddini J, Uber PA, Park MH, Scott RL,Ventura HO, Mehra MR. Efficacy and safety ofsildenafil in the evaluation of pulmonary hyper-tension in severe heart failure. Am J Cardiol. 2004;94(11):1475-1477.71. Guazzi M, Tumminello G, Di Marco F,Fiorentini C, Guazzi MD. The effects ofphosphodiesterase-5 inhibition with sildenafil onpulmonary hemodynamics and diffusion capacity,exercise ventilatory efficiency, and oxygen uptakekinetics in chronic heart failure. J Am Coll Cardiol.2004;44(12):2339-2348.72. Lewis GD, Shah R, Shahzad K, et al. Silde-nafil improves exercise capacity and quality of lifein patients with systolic heart failure and secondarypulmonary hypertension. Circulation. 2007;116(14):1555-1562.73. Behling A, Rohde LE, Colombo FC, Gold-raich LA, Stein R, Clausell N. Effects of5�-phosphodiesterase four-week long inhibitionwith sildenafil in patients with chronic heart fail-ure: a double-blind, placebo-controlled clinical trial.J Card Fail. 2008;14(3):189-197.74. Guazzi M, Vicenzi M, Arena R, GuazziMD. Pulmonary hypertension in heart failure withpreserved ejection fraction: a target ofphosphodiesterase-5 inhibition in a 1-year study.Circulation. 2011;124(2):164-174.75. Redfield MM, Chen HH, Borlaug BA, et al;

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RELAX Trial. Effect of phosphodiesterase-5 inhi-bition on exercise capacity and clinical status inheart failure with preserved ejection fraction: a ran-domized clinical trial. JAMA. 2013;309(12):1268-1277.76. Borlaug BA, Lewis GD, McNulty SE, et al.Effects of sildenafil on ventricular and vascularfunction in heart failure with preserved ejectionfraction. Circ Heart Fail. 2015;8(3):533-541.77. Califf RM, Adams KF, McKenna WJ, et al.A randomized controlled trial of epoprostenoltherapy for severe congestive heart failure: TheFlolan International Randomized SurvivalTrial (FIRST). Am Heart J. 1997;134(1):44-54.78. Mulder P, Richard V, Derumeaux G, et al.Role of endogenous endothelin in chronic heart fail-ure: effect of long-term treatment with anendothelin antagonist on survival, hemodynamics,and cardiac remodeling. Circulation. 1997;96(6):1976-1982.79. Sutsch G, Kiowski W, Yan XW, et al.Short-term oral endothelin-receptor antagonisttherapy in conventionally treated patients withsymptomatic severe chronic heart failure. Circu-lation. 1998;98(21):2262-2268.80. Packer M, McMurray J, Massie BM, et al.Clinical effects of endothelin receptor antagonismwith bosentan in patients with severe chronic heartfailure: results of a pilot study. J Card Fail. 2005;11(1):12-20.81. Andersen MJ, Hwang SJ, Kane GC, et al.Enhanced pulmonary vasodilator reserve and

abnormal right ventricular: pulmonary artery cou-pling in heart failure with preserved ejectionfraction. Circ Heart Fail. 2015;8(3):542-550.82. Abraham WT, Adams KF, Fonarow GC,et al; ADHERE Scientific Advisory Committeeand Investigators; ADHERE Study Group.In-hospital mortality in patients with acute decom-pensated heart failure requiring intravenousvasoactive medications: an analysis from the AcuteDecompensated Heart Failure National Registry(ADHERE). J Am Coll Cardiol. 2005;46(1):57-64.83. Fawzy ME, Hegazy H, Shoukri M, El ShaerF, ElDali A, Al-Amri M. Long-term clinical andechocardiographic results after successful mitralballoon valvotomy and predictors of long-termoutcome. Eur Heart J. 2005;26(16):1647-1652.84. Fawzy ME, Hassan W, Stefadouros M,Moursi M, El Shaer F, Chaudhary MA. Preva-lence and fate of severe pulmonary hypertension in559 consecutive patients with severe rheumaticmitral stenosis undergoing mitral balloon val-votomy. J Heart Valve Dis. 2004;13(6):942-947.85. Mubeen M, Singh AK, Agarwal SK, Pillai J,Kapoor S, Srivastava AK. Mitral valve replacementin severe pulmonary arterial hypertension. AsianCardiovasc Thorac Ann. 2008;16(1):37-42.86. Bishu K, Suri RM, Nkomo VT, et al. Prog-nostic impact of pulmonary artery systolic pressurein patients undergoing transcatheter aortic valvereplacement for aortic stenosis. Am J Cardiol. 2014;114(10):1562-1567.87. Patlolla B, Beygui R, Haddad F. Right-ventricular failure following left ventricle assist

device implantation. Curr Opin Cardiol. 2013;28(2):223-233.88. Kirklin JK, Naftel DC, Pagani FD, et al.Sixth INTERMACS annual report: a 10,000-patient database. J Heart Lung Transplant. 2014;33(6):555-564.89. Mandarino WA, Morita S, Kormos RL,et al. Quantification of right ventricular shapechanges after left ventricular assist device implan-tation. ASAIO J. 1992;38(3):M228-M231.90. Moon MR, Castro LJ, DeAnda A, et al.Right ventricular dynamics during left ventricularassistance in closed-chest dogs. Ann Thorac Surg.1993;56(1):54-66.91. Farrar DJ, Compton PG, Hershon JJ, FongerJD, Hill JD. Right heart interaction with themechanically assisted left heart. World J Surg. 1985;9(1):89-102.92. Farrar DJ. Ventricular interactions duringmechanical circulatory support. Semin ThoracCardiovasc Surg. 1994;6(3):163-168.93. Raina A, Vaidya A, Gertz ZM, SusanChambers, Forfia PR. Marked changes in rightventricular contractile pattern after cardiothoracicsurgery: implications for post-surgical assessment ofright ventricular function. J Heart Lung Transplant.2013;32(8):777-783.94. Houston BA, Kalathiya RJ, Maltais S, et al.Right Ventricular Adaptation to AfterloadWorsens Up to 6 Months After LVAD Implan-tation But Improves Over Time. J Heart LungTransplant. 2015;34(4):S63-S64.

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Pulmonary Hypertension Due to Heart Failure With PreservedEjection Fraction: Clinical Relevance, Management, andFuture Directions

Rebecca Cogswell, MDCardiovascular DivisionDepartment of MedicineUniversity of Minnesota Medical SchoolMinneapolis, MN

Thenappan Thenappan, MDCardiovascular DivisionDepartment of MedicineUniversity of Minnesota Medical SchoolMinneapolis, MN

There are currently 6 million Americans with heart failure, and this number is pro-jected to increase to 8.5 million by 2030. One-half of patients with heart failure havepreserved ejection fraction (HFpEF), and the prevalence is increasing. HFpEF canlead to secondary pulmonary hypertension (PH-HFpEF) and is associated with aworsened disease trajectory when present. It is unclear, however, whether PH is amarker of disease severity or a target of treatment in HFpEF. As PH-HFpEF andpulmonary arterial hypertension share several clinical characteristics, the distinctionbetween these 2 syndromes can be difficult. New classification schemes have beenproposed to separate those with passive elevations in pulmonary artery pressures fromthose with more significant pulmonary vascular remodeling. While these classifi-cations have limitations, they are necessary such that pathophysiology, disease tra-jectory, and pharmacologic therapies can be studied in specific patient subgroups. Inthis article, we will review the epidemiology of HFpEF, current definitions for bothHFpEF and PH in HFpEF, treatment options, and ongoing clinical trials.

EPIDEMIOLOGY OF HEARTFAILURE WITH PRESERVEDEJECTION FRACTIONThe economic cost of heart failure in theUnited States is estimated to be $24billion in 2015, and is expected todouble to $47 billion by 2030.1 One-halfof patients with heart failure have pre-served ejection fraction (HFpEF), and incommunity studies, HFpEF is now theleading cause of heart failure hospital-ization.2,3 Increasing age, obesity,metabolic syndrome, female gender,hypertension, and atrial fibrillation areknown to be highly associated withdevelopment of this syndrome.4,5 Whilehistorically it has been reported that theprevalence of coronary artery disease(CAD) in HFpEF is lower than heartfailure with reduced ejection fraction(HFrEF), recent data suggest that signif-icant CAD can be identified in morethan 50% of patients with HFpEF.6,7

PATHOPHYSIOLOGY OF HFPEFThe comorbidities that have been associatedwith the development of HFpEF have beendemonstrated to create a systemic pro-

inflammatory state.8,9 This inflammationthen leads to coronary microvasculatureinflammation, impairment of endothelial-cardiomyocyte nitric oxide signaling, andproduction of fibrosis-inducing cytokines.These pathologic changes contribute tomyocyte function and myocardial fibrosis,which cause both increased stiffness andabnormal relaxation during diastole.10-15

Additionally, left ventricular (LV) systolicfunction is impaired on echocardiographicstrain imaging in HFpEF, suggesting thatwhile the calculated LV ejection fraction(LVEF) is normal, the contractility may beimpaired.16,17 Patients with HFpEF canalso have chronotropic incompetence,abnormal endothelial function, ischemia,pulmonary hypertension (PH), and rightventricular (RV) dysfunction—all of whichcan contribute to abnormal fluid handlingand exercise intolerance.18-22 The dominantpathologic finding during exercise can varyfrom patient to patient.23

DEFINITION AND DIAGNOSISOF HFPEFGiven the complex pathophysiology andsignificant heterogeneity within the syn-

drome,24 HFpEF can be challenging todiagnose. Comorbidities that also causedyspnea (obesity, chronic kidney disease,chronic obstructive pulmonary disease)are common in this patient group25 andmay delay the recognition of volumeoverload. Natriuretic peptides may notbe elevated, especially in obese patientsand subjects who are clinically stable.26,27

As filling pressures are known to fluc-tuate between times of decompensationto euvolemia, and even from one day tothe next,28 an echocardiogram or rightheart catheterization may not reveal ele-vated filling pressures unless additionalmaneuvers are performed. Normal fillingpressures, therefore, do not exclude thediagnosis.

Other conditions that mimic HFpEFbut are treated differently need to beconsidered in the initial evaluation, suchas valvular heart disease, infiltrative car-diomyopathies, or constrictivepericarditis. The suspicion of an infil-trative process such as amyloidosis,sarcoidosis, and hemochromatosis isincreased when there are clues in thehistory (carpel tunnel for amyloid, dia-betes, or arthritis and family history forhemochromatosis, mediastinal lymph-adenopathy for sarcoidosis) or when theechocardiogram, electrocardiogram(ECG), or laboratory findings suggest

Key Words—heart failure with preserved ejection fraction, pulmonary hypertensionCorrespondence: cogsw014@umn.eduDisclosures: Dr Cogswell has nothing to disclose. Dr Thenappan has received institutional grant/researchsupport from Lillehei Heart Institute and the American Heart Association.

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these diagnoses. A septal bounce onechocardiogram with normal natriureticpeptides along with a history of chestradiation, recurrent pericarditis, andprior tuberculosis may indicate thatfurther evaluation for pericardial con-striction is warranted.

Because of the complexity of theHFpEF diagnosis, algorithms have beenproposed to both unify the definitionand help clinicians establish the diag-nosis. Guidelines from large cardiologysocieties vary29; however, the EuropeanSociety of Cardiology proposed that thediagnosis of HFpEF can be made byfulfilling the following 3 criteria: 1) signsand symptoms of heart failure, 2) pre-served ejection fraction (LVEF �50%),and 3) evidence of diastolic dysfunctioneither by invasive hemodynamics (leftventricular end diastolic pressure�16 mm Hg or pulmonary artery wedge

pressure [PAWP] �12 mm Hg) or bynoninvasive myocardial tissue Dopplermeasures (E/E’ �15). If myocardialtissue Doppler is indeterminate (15�E/E’ �8), one of the following addi-tional noninvasive diagnostic modalitiescan be used to diagnose HFpEF: mitralflow Doppler pattern (E/A ratio anddeceleration time), LV mass or left atrialvolume index, serum N-terminal prob-type natriuretic peptide (NT-proBNP)or BNP levels, and/or the presence ofatrial fibrillation (Figure 1).9 Additionaltools when the PAWP at the time ofright heart catheterization is �12 mmHg include saline loading or exercise.While there is no consensus on theexact pulmonary capillary wedgepressure (PCWP) elevation needed forthe diagnosis of HFpEF, it has beensuggested that an increase in thePAWP to �25 mm Hg with exercise30

or �15 mm Hg with a 1 L fluid chal-lenge31 is consistent with HFpEF.

PH IN HFpEFHeart failure with preserved ejectionfraction and all conditions that thatcause left-sided heart failure can alsocause secondary PH. The most recentWorld Health Organization (WHO)classification system categorizes PH dueto left heart disease into 4 different cate-gories: PH secondary to HFrEF, PHresulting from HFpEF, PH due to left-sided valve disease, and PH associatedwith congenital/acquired left heartinflow/outflow obstruction and con-genital cardiomyopathies.32 Amongthese, PH-HFpEF is the most common.

The true prevalence of PH in patientswith HFpEF is unknown as the defini-tions of both HFpEF and PH inHFpEF continue to evolve. Most of the

Figure 1: Algorithm for diagnosis of HFpEF. LVEF � left ventricular ejection fraction; LVEDVI � left ventricular end diastolic volume index;mPCWP � mean pulmonary capillary wedge pressure; LVEDP � left ventricular end diastolic pressure; BNP � brain natriuretic peptide; DT �deceleration time. Adapted from Paulus WJ, et al. Eur Heart J. 2007;28:2539-2550.

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prevalence data are based on echocardio-graphic estimation of the systolicpulmonary artery pressure (PAP) ratherthan invasive hemodynamic assessment.The reported prevalence of PH-HFpEFamong the overall HFpEF populationvaries widely depending on the groupstudied and the cutoff value of estimatedsystolic PAP used to define PH. In apopulation-based study from OlmstedCounty, Minnesota, 83% of the patientshad estimated systolic PAP �35 mmHg.33 In a UK-based study of around350 HFpEF patients referred to a heartfailure clinic, only 18% had an estimatedsystolic PAP of �45 mm Hg.34

Regardless of the underlying left heartpathology, the presence of PH in leftheart disease is associated with a worsedisease trajectory and overall prognosis.Every 10 mm Hg increase in estimatedsystolic PAP by echocardiography isassociated with a 1.2-fold increased riskof death independent of age.33 Theobserved survival in patients withPH-HFpEF may be worse than in thosewith pulmonary arterial hypertension(PAH) despite having less severe PHand RV dysfunction.

DIFFERENTIATION OFPH-HFpEF AND PAHPulmonary hypertension in HFpEF andPAH share several clinical featuresincluding signs and symptoms of heartfailure and normal LVEF, making thedistinction between these 2 entities dif-ficult. The distinction is important as thesafety and efficacy of PAH-specific vaso-dilator therapies is unclear in patientswith PH-HFpEF. These therapies havebeen shown to be either ineffective or toincrease mortality in patients with LVsystolic dysfunction.35,36

Several clinical, echocardiographic,and hemodynamic characteristics canhelp differentiate PH-HFpEF fromPAH. Compared to PAH, patients withPH-HFpEF are older, more oftenfemale, and more frequently have othercardiovascular comorbidities includinghypertension, diabetes, obesity, and cor-onary artery disease.37 In a multivariatemodel, simple clinical characteristicswithout echocardiographic or hemody-namic data were able to differentiatePH-HFpEF from PAH with an area

under the curve of 0.92.37 On echocardi-ography, patients with PH-HFpEFoften have left atrial enlargement andless frequently have a midsystolicnotching pattern on the RV outflowtract Doppler signal (Figure 2).38

Cardiac MRI derived left atrial volume�43 mL/m2 can also help to differen-tiate PH-HFpEF from PAH with anarea under the receiver-operating charac-teristic curve of 0.99.39

On hemodynamic evaluation, patientswith PH-HFpEF have only a moderateelevation in PAP and pulmonary vascularresistance (PVR).37 Since the distinctionbetween PAH and PH-HFpEF reliesmainly on the accurate measurement ofPAWP, meticulous efforts must be made

to obtain an accurate PAWP measure-ment. The wedge pressure should bemeasured manually at end expiration40

instead of relying on the digital wedgepressure, and it should be confirmedwith a good wedge pressure wave tracingand by checking an oxygen saturationwith the catheter in the wedge position(�94% confirms wedge pressure). Partialballoon inflation should be used whenoverestimation of wedge pressure is sus-pected due to partial wedging. If theaccuracy of wedge pressure measurementcannot be verified, LV end diastolicpressure should be measured by left heartcatheterization.41,42

In addition, provocative measures suchas saline loading or exercise can help

Figure 2: Representative right ventricular outflow tract pulse-wave Doppler tracing with andwithout notching. RVOT � right ventricular outflow tract.

90 Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

elicit an abnormal response as patientswith the HFpEF syndrome can have anormal resting PAWP or are clinicallyeuvolemic to dry. In a retrospectivestudy of 207 patients, 22% of patientswho had PAWP �15 mm Hg at restwere noted to have PAWP �15 mmHg after 500 cc of acute saline bolus.31

These patients had very similar clinical,echocardiographic, and hemodynamiccharacteristics to those with an estab-lished diagnosis of PH-HFpEF.

Exercise has also been shown toidentify PH-HFpEF in patients withnormal resting PAWP. A recent studysuggests that exercise may be more sen-sitive than saline loading for diagnosingPH-HFpEF.13 A PCWP �25 mm Hgwith exercise has been suggested to beconsistent with HFpEF.30

CURRENT NOMENCLATUREPulmonary hypertension in HFpEF isdefined as mean PAP �25 mm Hg inthe presence of PAWP �15 mm Hg,signs and symptoms of heart failure,LVEF �50%, and absence of significantleft-sided valvular heart disease.41 Thecut point of 15 mm Hg for the PAWPin this definition comes from the long-standing definition of WHO Group2 PH, which splits a normal from anabnormal PAWP at 15 mm Hg.43 Inthe European Society of Cardiologyalgorithm, however, a PAWP of 12 mmHg or more is needed to diagnoseHFpEF. The 12–15 PAWP rangeremains a gray area but is likelyabnormal. With implantable hemody-namic monitoring devices, it is clear thatpatients who have PAWP �15 mm Hgon one day can change their filling pres-sures by the next day,28 suggesting theremay be a fair amount of misclassificationoccurring using our present definitions.Despite these limitations, however, thesePH hemodynamic definitions allowed for

the advancement of the PH field and forthe dramatic improvement in survivalthat has been observed. This is also whysuch effort is currently being put forth totry to further classify PH in left heartdisease such that meaningful subgroupswith shared pathophysiology can beidentified.

The working definitions of PH in leftheart disease will be reviewed here. Pul-monary hypertension due to left heartdisease including PH-HFpEF is clas-sified into 2 broad categories dependingon the presence or absence of intrinsicpulmonary vascular disease, otherwiseknown as the “precapillary” component.These definitions presently rely on a fewkey invasive hemodynamics variablesdefined in Table 1.

ISOLATED POSTCAPILLARYPH-HFpEFIsolated postcapillary PH-HFpEF ischaracterized by passive increase in PAPwithout significant pulmonary vasocon-striction or remodeling of the smallpulmonary arteries. Due to the absenceof a precapillary component, the increasein PAP is proportional to the increasein the left-sided filling pressure andtherefore normalizes completely with areduction in the left-sided fillingpressure. At this stage, due to theabsence of a precapillary component,both the transpulmonary gradient (TPG:the difference between mean PAP andPAWP) and the PVR typically remainwithin normal limits (TPG �12–15 mmHg and PVR �2.5–3 Wood units).44

COMBINED POST- ANDPRECAPILLARY PH OR“MIXED PH”Combined post- and precapillaryPH-HFpEF is characterized by thepresence of precapillary small pulmonaryartery remodeling and alveolar wall

thickening in addition to the passiveincrease in PAP. Chronic elevation inleft-sided filling pressure triggers pul-monary arterial vasoconstriction andlater intrinsic pulmonary arteriolarremodeling.45,46 In addition, elevatedleft-sided filling pressure causes alveolarwall injury, leading to fibrosis and extra-cellular matrix deposition. This results inalveolar wall thickening, which has alsobeen proposed to contribute to the pre-capillary component and restrictivelung syndrome with impaired gasexchange.47 The superimposed precap-illary component increases the PAPdisproportionate to the left-sided fillingpressure and does not normalize with anacute reduction in the left-sided fillingpressure. Hemodynamically, combinedpost- and precapillary PH has beendefined as mean PAP �25 mm Hg andPVR �2.5–3 Wood units (or TPG�12–15 mm Hg) in the presence ofPAWP �15 mm Hg.44 However, asdescribed below, the entity of combinedpost- and precapillary PH is currentlybeing redefined based on the diastolicpulmonary gradient (DPG).

DIASTOLIC PULMONARYPRESSURE GRADIENTCombined post- and precapillaryPH-HFpEF is differentiated from iso-lated postcapillary PH-HFpEF by thepresence of elevated TPG (�12–15 mmHg) or PVR (�2.5–3 Wood units).44

However, both TPG and PVR havebeen demonstrated to be flow-dependentand may not accurately reflect thepresence of intrinsic pulmonary arteriolarremodeling.48 As DPG is not flow-dependent, this has been proposed as asuperior measure of the precapillary pul-monary arteriolar remodeling. Hence, atthe most recent Fifth World Symposiumon PH, new classification and hemody-namic definition for PH due to left heart

Table 1. Hemodynamic Variable Abbreviations, Definitions, and Respective Normal Values.

Abbreviation Long Terminology Definition Normal Values

PAM Mean pulmonary artery pressure (PA systolic pressure � 2[PA diastolic pressure])/3 �25 mm Hg

PAWP Pulmonary artery wedge pressure A surrogate of left-sided filling pressures �12 mm Hg*

TPG Transpulmonary gradient PAM – PAWP �12–15 mm Hg

PVR Pulmonary vascular resistance TPG/cardiac output �2.5–3 Wood units

DPG Diastolic pulmonary gradient PA diastolic pressure – PAWP �7 mm Hg

*A cut point of 12 mm Hg is used for PAWP based on the most current consensus definition of HFpEF by the AHA/ACC.

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disease was proposed based on DPG:isolated postcapillary (mean PAP �25mm Hg, PAWP �15 mm Hg, andDPG �7 mm Hg) and combined post-capillary and precapillary PH (meanPAP �25 mm Hg, PAWP �15 mmHg, and DPG �7 mm Hg).42 Since thisnomenclature was put forth, however,the DPG variable has not performedwell as a prognostic marker,49 callinginto question the clinical utility andrepeatability of DPG in real-worldpractice.

LIMITATIONS OF CURRENTDEFINITIONSSome speculation as to why the DPGmay not be as reliable as an indicator asinitially hoped for is due to the lowabsolute number of this measure, whichincreases its susceptibility to mea-surement error and its variability withheart rate. Dichotomization at one spe-cific point to split normal from abnormalalso leads to loss of information andmisclassification. Some of these limita-tions, however, apply to all hemo-dynamic definitions. Whether or nothemodynamic classification by DPG willbe clinically meaningful remains to beproven. It may be that optimal classifi-cation will include hemodynamicvariables after provocative testing,repeated hemodynamic measures overtime, and perhaps clinical variables aswell.

The take-home point regarding thecurrent nomenclature is that “mixed PH”is suspected when the PVR, TPG,and/or DPG is elevated beyond whatwould be expected for passive congestiononly and not corrected with acutePAWP reduction in the catheterizationlab: these are the patients for whom pul-monary vascular pathology is likely. Inaddition, a PAWP of �12 is likelyabnormal and in the right clinicalcontext is consistent with HFpEF.

TREATMENTPresently, the management of PH-HFpEF consists of treating the under-lying HFpEF. While guidelines forHFpEF treatment support diuretics andsystemic blood pressure control, no spe-cific therapies have been demonstrated todecrease mortality or reduce heart failure

hospitalizations in a large randomizedclinical trial.50 Spironolactone wasrecently shown to decrease hospital-ization in patients with HFpEF;however, there was no effect on mor-tality.25 Revascularization in patientswith HFpEF and concomitant signif-icant CAD was associated withpreservation of ejection fraction and areduction in mortality in one retro-spective single-center study.6 While thiswas not a randomized clinical trial, itunderscores the importance of evaluatingfor ischemia if within the goals of care.

ROLE OF PULMONARYVASODILATOR THERAPIESIN PH-HFpEFPulmonary arterial vasodilator therapiesimprove functional capacity, time toclinical worsening, and survival inpatients with PAH. The efficacy ofPAH-specific therapies in PH-HFpEFis unclear, and there is a theoreticalconcern that these therapies may causeworsening pulmonary edema byincreasing pulmonary blood flow in thepresence of elevated left-sided fillingpressures.35,51-53 Endothelin receptorantagonists and parenteral prostacyclin(intravenous epoprostenol) therapy havebeen shown to be either neutral orincrease mortality in patients with LVsystolic dysfunction.35,52 Only a limitednumber of clinical trials have thus farevaluated the safety and efficacy of pul-monary arterial vasodilator therapies inPH-HFpEF. These trials are eitherneutral or small single-center studies;therefore, PAH-specific therapies arecurrently not approved for the treatmentof PH-HFpEF.

Phosphodiesterase Type 5 InhibitorsOf all the various PAH-specific ther-apies, phosphodiesterase type 5 (PDE5)inhibitors have been studied the most inPH-HFpEF. In a single-center ran-domized clinical trial, 44 patients wererandomized to either placebo or silde-nafil 50 mg 3 times per day for12 months.54 Cardiac hypertrophy andelevated DPG (�9 mm Hg) wererequired for trial entry, consistent withcombined post- and precapillary PH inthe setting of HFpEF. After 6 months,there were significant improvements in

RV function as demonstrated bydecreased right atrial pressure (10.6 �3.6 mm Hg vs 22.0 � 5.2 mm Hg),increased tricuspid annular plane systolicexcursion (19.2 � 2.3 mm vs 10.6 � 2.3mm), and increased RV mean systolicejection rate (276 � 25.1 mL/s vs231 � 24.2 mL/s) in the sildenafil-treated group compared to placebo.There were also significant changes inthe pulmonary vasculature as mean PAP(22.3 � 3.7 mm Hg vs 37.8 � 4.9 mmHg) and PVR (1.18 � 0.50 Wood unitsvs 3.42 � 1.02 Wood units) decreasedsignificantly with sildenafil therapy com-pared to placebo at 6 months. Thebeneficial effects of sildenafil persisted at12 months and sildenafil was associatedwith improvement in quality of life. Col-lectively, these data suggest sildenafilmay be a useful treatment in PH-HFpEF patients. However, this studydid not include hospitalization for heartfailure or mortality given its small size. Itis unclear whether these hemodynamicand echocardiographic improvementswill translate to a meaningful clinicalimprovement.

In contrast, the positive effects ofsildenafil were not observed in theRELAX study, a multicenter clinicaltrial that assessed sildenafil in HFpEFpatients.55 Pulmonary hypertension wasnot required for trial entry and the trialdid not specifically investigate pulmonaryhemodynamics and RV function.Another trial assessing sildenafil inPH-HFpEF has recently been com-pleted in Germany (NCT01726049) andthe results are pending. This trial willdetermine how 12 weeks of treatmentwith sildenafil affects invasive hemody-namics and peak VO2.

Soluble Guanylate Cyclase StimulatorsThe DILATE-1 trial assessed riociguat,a soluble guanylate cyclase activator,in the PH-HFpEF population.56

DILATE-1 compared varying doses ofriociguat: 0.5 mg in 8 patients, 1 mg in7 patients, and 2 mg in 10 patientscompared to placebo (in 11 patients) todetermine the short-term effects oninvasive hemodynamics 6 hours afteradministration of the study drug. Therewas no difference in the change in meanPAP between baseline and 6-hour time

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points in the riociguat 2 mg (n�10) vsplacebo (n�11) groups. Vericiguat,another soluble guanylate cyclase stimu-lator, is currently being evaluated forHFpEF in SOCRATES-HFpEF, a12-week, double-blind, randomized,parallel-group, placebo-controlled, Phase2 clinical trial (clinicaltrials.gov:NCT01951638).

Endothelin Receptor AntagonistsIn a randomized placebo-controlled trialof 192 patients, 6 months of sitaxsentan,a selective endothelin A receptor antag-onist, treatment improved treadmillexercise time compared to placebo(90 seconds vs 30 seconds).57 However,there was no change in LV mass ortrans-mitral diastolic parameters. Thepresence of PH was not a prerequisitefor inclusion in this trial, and the effectof sitaxsentan on pulmonary hemody-namics was not assessed. TheBADDHY trial is assessing the impactof 12 weeks of bosentan treatment on6-minute walk test, hemodynamics viaechocardiography, and symptomaticburden (NCT00820352).

CONCLUSIONIn summary, the incidence of HFpEF isincreasing rapidly. The diagnosis can bedifficult to make and the definition ofthe HFpEF syndrome is still evolving.Pulmonary hypertension secondary toHFpEF is very common and associatedwith a worsened disease trajectory whenpresent. Treatments targeting not onlyHFpEF but also PH associated withHFpEF are urgently needed. The classi-fication scheme describing the varioushemodynamic profiles of PH related toleft heart disease has limitations, but hasrecently evolved to try to help categorizepatients in meaningful ways. Severalnovel treatments for PH-HFpEF andHFpEF are currently being tested,giving hope to the prospect of new treat-ments for these challenging syndromesin the near future.

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15. Bowden MA, Tesch GH, Julius TL, Rosli S,Love JE, Ritchie RH. Earlier onset of diabesity-Induced adverse cardiac remodeling in femalecompared to male mice. Obesity (Silver Spring).2015;23(6):1166-1177.16. Kraigher-Krainer E, Shah AM, Gupta DK,et al; PARAMOUNT Investigators. Impaired sys-tolic function by strain imaging in heart failurewith preserved ejection fraction. J Am Coll Cardiol.2014;63(5):447-456.17. Tan YT, Wenzelburger F, Lee E, et al. Thepathophysiology of heart failure with normalejection fraction: exercise echocardiography revealscomplex abnormalities of both systolic and diastolicventricular function involving torsion, untwist, andlongitudinal motion. J Am Coll Cardiol. 2009;54(1):36-46.18. van Empel VP, Mariani J, Borlaug BA, KayeDM. Impaired myocardial oxygen availability con-tributes to abnormal exercise hemodynamics inheart failure with preserved ejection fraction. J AmHeart Assoc. 2014;3(6):e001293.19. Borlaug BA, Melenovsky V, Russell SD, etal. Impaired chronotropic and vasodilator reserveslimit exercise capacity in patients with heart failureand a preserved ejection fraction. Circulation. 2006;114(20):2138-2147.20. Brubaker PH, Joo KC, Stewart KP, Fray B,Moore B, Kitzman DW. Chronotropic incompe-tence and its contribution to exercise intolerance inolder heart failure patients. J Cardiopulm Rehabil.2006;26(2):86-89.21. Melenovsky V, Hwang SJ, Lin G, RedfieldMM, Borlaug BA. Right heart dysfunction inheart failure with preserved ejection fraction. EurHeart J. 2014;35(48):3452-3462.22. Melenovsky V, Hwang SJ, Redfield MM,Zakeri R, Lin G, Borlaug BA. Left atrial remod-eling and function in advanced heart failure withpreserved or reduced ejection fraction. Circ HeartFail. 2015;8(2):295-303.23. Borlaug BA. Mechanisms of exercise intol-erance in heart failure with preserved ejectionfraction. Circ J. 2014;78(1):20-32.24. Anjan VY, Loftus TM, Burke MA, et al.Prevalence, clinical phenotype, and outcomes asso-ciated with normal B-type natriuretic peptide levelsin heart failure with preserved ejection fraction.Am J Cardiol. 2012;110(6):870-876.25. Pitt B, Pfeffer MA, Assmann SF, et al;TOPCAT Investigators. Spironolactone for heartfailure with preserved ejection fraction. N EnglJ Med. 2014;370(15):1383-1392.26. Bayes-Genis A, Lloyd-Jones DM, van Kim-menade RR, et al. Effect of body mass index ondiagnostic and prognostic usefulness of amino-terminal pro-brain natriuretic peptide in patientswith acute dyspnea. Arch Intern Med. 2007;167(4):400-407.27. Kim H, Jun DW, Cho YK, et al. The corre-lation of left atrial volume index to the level ofN-terminal pro-BNP in heart failure with a pre-served ejection fraction. Echocardiography. 2008;25(9):961-967.28. Raina A, Abraham WT, Adamson PB,Bauman J, Benza RL. Limitations of right heartcatheterization in the diagnosis and risk stratifi-cation of patients with pulmonary hypertension

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related to left heart disease: insights from a wirelesspulmonary artery pressure monitoring system.J Heart Lung Transplant. 2015;34(3):438-447.29. Yancy CW, Jessup M, Bozkurt B, et al;American College of Cardiology Foundation;American Heart Association Task Force onPractice Guidelines. 2013 ACCF/AHA guidelinefor the management of heart failure: a report of theAmerican College of Cardiology Foundation/American Heart Association Task Force onPractice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-e239.30. Borlaug BA, Nishimura RA, Sorajja P, LamCS, Redfield MM. Exercise hemodynamicsenhance diagnosis of early heart failure with pre-served ejection fraction. Circ Heart Fail. 2010;3(5):588-595.31. Robbins IM, Hemnes AR, Pugh ME, et al.High prevalence of occult pulmonary venoushypertension revealed by fluid challenge in pul-monary hypertension. Circ Heart Fail. 2014;7(1):116-122.32. Simonneau G, Gatzoulis MA, Adatia I, et al.Updated clinical classification of pulmonary hyper-tension. J Am Coll Cardiol. 2013;62(25 Suppl):D34-D41.33. Lam CS, Borlaug BA, Kane GC, EndersFT, Rodeheffer RJ, Redfield MM. Age-associatedincreases in pulmonary artery systolic pressure inthe general population. Circulation. 2009;119(20):2663-2670.34. Damy T, Goode KM, Kallvikbacka-BennettA, et al. Determinants and prognostic value of pul-monary arterial pressure in patients with chronicheart failure. Eur Heart J. 2010;31(18):2280-2290.35. Califf RM, Adams KF, McKenna WJ, et al.A randomized controlled trial of epoprostenoltherapy for severe congestive heart failure: TheFlolan International Randomized Survival Trial(FIRST). Am Heart J. 1997;134(1):44-54.36. Packer M, McMurray J, Massie BM, et al.Clinical effects of endothelin receptor antagonismwith bosentan in patients with severe chronic heartfailure: results of a pilot study. J Card Fail. 2005;11(1):12-20.37. Thenappan T, Shah SJ, Gomberg-MaitlandM, et al. Clinical characteristics of pulmonaryhypertension in patients with heart failure and pre-served ejection fraction. Circ Heart Fail. 2011;4(3):257-265.38. Opotowsky AR, Ojeda J, Rogers F, et al. Asimple echocardiographic prediction rule for hemo-dynamics in pulmonary hypertension. CircCardiovasc Imaging. 2012;5(6):765-775.39. Crawley SF, Johnson MK, Dargie HJ,

Peacock AJ. LA volume by CMR distinguishesidiopathic from pulmonary hypertension due toHFpEF. JACC Cardiovasc Imaging. 2013;6(10):1120-1121.40. Ryan JJ, Rich JD, Thiruvoipati T, Swamy R,Kim GH, Rich S. Current practice for determiningpulmonary capillary wedge pressure predisposes toserious errors in the classification of patients withpulmonary hypertension. Am Heart J. 2012;163(4):589-594.41. Hoeper MM, Bogaard HJ, Condliffe R, et al.Definitions and diagnosis of pulmonary hyper-tension. J Am Coll Cardiol. 2013;62(25 Suppl):D42-D50.42. Vachiery JL, Adir Y, Barbera JA, et al. Pul-monary hypertension due to left heart diseases.J Am Coll Cardiol. 2013;62(25 Suppl):D100-D108.43. McLaughlin VV, Archer SL, Badesch DB, etal; American College of Cardiology FoundationTask Force on Expert Consensus Documents;American Heart Association; American Collegeof Chest Physicians; American Thoracic Society,Inc; Pulmonary Hypertension Association.ACCF/AHA 2009 expert consensus document onpulmonary hypertension a report of the AmericanCollege of Cardiology Foundation Task Force onExpert Consensus Documents and the AmericanHeart Association developed in collaboration withthe American College of Chest Physicians;American Thoracic Society, Inc.; and the Pul-monary Hypertension Association. J Am CollCardiol. 2009;53(17):1573-1619.44. Fang JC, DeMarco T, Givertz MM, et al.World Health Organization Pulmonary Hyper-tension group 2: pulmonary hypertension due toleft heart disease in the adult–a summary statementfrom the Pulmonary Hypertension Council of theInternational Society for Heart and Lung Trans-plantation. J Heart Lung Transplant. 2012;31(9):913-933.45. Givertz MM, Colucci WS, LeJemtel TH, etal. Acute endothelin A receptor blockade causesselective pulmonary vasodilation in patients withchronic heart failure. Circulation. 2000;101(25):2922-2927.46. Moraes DL, Colucci WS, Givertz MM. Sec-ondary pulmonary hypertension in chronic heartfailure: the role of the endothelium in pathophysi-ology and management. Circulation. 2000;102(14):1718-1723.47. Azarbar S, Dupuis J. Lung capillary injuryand repair in left heart disease: a new target fortherapy? Clin Sci (Lond). 2014;127(2):65-76.48. Naeije R, Vachiery JL, Yerly P, VanderpoolR. The transpulmonary pressure gradient for the

diagnosis of pulmonary vascular disease. Eur RespirJ. 2013;41(1):217-223.49. Tedford RJ, Beaty CA, Mathai SC, et al.Prognostic value of the pre-transplant diastolic pul-monary artery pressure-to-pulmonary capillarywedge pressure gradient in cardiac transplant recip-ients with pulmonary hypertension. J Heart LungTransplant. 2014;33(3):289-297.50. Yancy CW, Jessup M, Bozkurt B, et al. 2013ACCF/AHA guideline for the management ofheart failure: executive summary: a report of theAmerican College of Cardiology Foundation/American Heart Association Task Force onpractice guidelines. Circulation. 2013;128(16):1810-1852.51. Humbert M, Maitre S, Capron F, Rain B,Musset D, Simonneau G. Pulmonary edema com-plicating continuous intravenous prostacyclin inpulmonary capillary hemangiomatosis. Am J RespirCrit Care Med. 1998;157(5 Pt 1):1681-1685.52. Palmer SM, Robinson LJ, Wang A, GossageJR, Bashore T, Tapson VF. Massive pulmonaryedema and death after prostacyclin infusion in apatient with pulmonary veno-occlusive disease.Chest. 1998;113(1):237-240.53. Preston IR, Klinger JR, Houtchens J, NelsonD, Mehta S, Hill NS. Pulmonary edema caused byinhaled nitric oxide therapy in two patients withpulmonary hypertension associated with theCREST syndrome. Chest. 2002;121(2):656-659.54. Guazzi M, Vicenzi M, Arena R, GuazziMD. Pulmonary hypertension in heart failure withpreserved ejection fraction: a target ofphosphodiesterase-5 inhibition in a 1-year study.Circulation. 2011;124(2):164-174.55. Redfield MM, Chen HH, Borlaug BA, et al;RELAX Trial. Effect of phosphodiesterase-5 inhi-bition on exercise capacity and clinical status inheart failure with preserved ejection fraction: a ran-domized clinical trial. JAMA. 2013;309(12):1268-1277.56. Bonderman D, Pretsch I, Steringer-Mascherbauer R, et al. Acute hemodynamic effectsof riociguat in patients with pulmonary hyper-tension associated with diastolic heart failure(DILATE-1): a randomized, double-blind,placebo-controlled, single-dose study. Chest. 2014;146(5):1274-1285.57. Zile MR, Bourge RC, Redfield MM, ZhouD, Baicu CF, Little WC. Randomized, double-blind, placebo-controlled study of sitaxsentan toimprove impaired exercise tolerance in patientswith heart failure and a preserved ejection fraction.JACC Heart Fail. 2014;2(2):123-130.

94 Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

Pulmonary Hypertension Due to Valvular Heart Disease:Aortic and Mitral

Ryan Karl Kaple, MDFellow in Cardiovascular MedicineNew York Presbyterian HospitalWeill Cornell Medical CenterNew York, NY

Evelyn M. Horn, MDProfessor of Clinical Medicine, Weill

CornellDirector of Advanced Heart Failure,

Mechanical Assist & PulmonaryHypertension Programs

Perkin Heart Failure CenterWeill Cornell Medical CenterDivision of CardiologyNew York, NY

Pulmonary hypertension (PH) can be due to a primary pulmonary vasculature abnor-mality, but is more often secondary to lung, cardiac, or environmental insults, and isfrequently multifactorial. Most commonly, left heart disease is at fault, a subset ofwhich is valvular heart disease (VHD). With sufficient time, most chronic left-sidedvalve lesions will result in some element of PH. Long-standing PH causes pulmonaryvascular remodeling and progressive PH due to reduced vascular compliance. Carefulmonitoring of VHD progression is critical, both through screening imaging andpatient education, in order to properly time intervention to prevent the developmentor worsening of PH. The primary diagnostic tool in PH due to VHD is echocardi-ography, while invasive hemodynamic evaluation can be helpful to determine PHetiology or severity when echocardiography is not adequate. The presence of PH inVHD is often an indication for intervention, but it also increases procedural risk.Severe PH, however, has not been proven to preclude safe intervention, but rathershould prompt full preprocedural evaluation and close intra- and postprocedural mon-itoring. Valve replacement or repair can be viewed as a treatment for PH secondaryto the valvular lesion. Percutaneous alternatives to surgical interventions are availablefor some mitral and aortic valve conditions. Though in relatively early stages of devel-opment, these less invasive procedures may improve the safety profile of valveinterventions. Pulmonary hypertension that fails to improve after intervention shouldraise suspicion for procedural failure or underlying pulmonary vascular disease (eitherprecapillary possibly in association with interstitial lung disease or scleroderma or sec-ondary to combined pre-/postcapillary PH due to long-standing pulmonary venoushypertension). This review is focused on the pathophysiology, treatment options, andoutcomes in patients with PH due to mitral and aortic valve lesions.

PREVALENCE ANDPATHOPHYSIOLOGYPulmonary hypertension (PH) due toleft-sided heart disease (LHD), classifiedby the World Health Organization asGroup 2 (WHO 2), is secondary to leftventricular (LV) systolic dysfunction(heart failure with reduced ejectionfraction – HFrEF), LV diastolic dys-function (heart failure with preservedejection fraction – HFpEF), or valvularheart disease (VHD).1 The principleinsult in this class of PH is elevated leftventricular end diastolic pressure(LVEDP, and/or left atrial pressures),which is transmitted to the pulmonaryvasculature, raising pulmonary arterypressure (PAP).2 This PH physiology is

postcapillary and defined as a mean PAP(mPAP) �25 mm Hg and the pul-monary capillary wedge pressure(PCWP) is �15 mm Hg.3 Other hemo-dynamic features of postcapillary PHinclude increased left atrial pressure(�15 mm Hg) and/or increasedLVEDP (�15 mm Hg). When the dif-ference between mPAP and PCWP(known as transpulmonary gradient,TPG) is �12 mm Hg, pulmonary dia-stolic gradient (PDG) �7, and/or thepulmonary vascular resistance (PVR) is�3 Wood units, the elevated PAP isattributable to left heart disease and isconsidered passive pulmonary venoushypertension. If the TPG is �12 mmHg or the PVR is �3 Wood units, the

PH is described as combinedprecapillary-postcapillary PH (CPpPH).This previously described “postcapillaryreactive” or exaggerated PH can have avariety of mechanisms and comorbidities,particularly in the aging population.Most often, this is due to long-standingpulmonary venous hypertension causingsignificant vascular remodeling anddecreased pulmonary circulation com-pliance. Repetitive and sustained injuryto the pulmonary vasculature results inpathologic changes at the cellular level(increased neurohormonal feedback,endothelin-1 and cytokine activation,decreased nitric oxide and brain natri-uretic peptide).4,5 But complicating theprimary insult of pulmonary venoushypertension, other common comor-bidities include: lung disease that can beabnormal lung physiology from sleepapnea, aging-related decreased lungfunction, anemia, atrial fibrillation, andrenal failure may all play a role in thecombined pre-/postcapillary phenotype.

Key Words—aortic stenosis, congenital heart disease, echocardiography, mitral valve, valvular heart diseaseCorrespondence: horneve@med.cornell.eduDisclosures: Dr Kaple has nothing to disclose. Dr Horn has served as a consultant/advisory board/steeringcommittee member for Ikaria, Novartis Pharmaceuticals, and Janssen. She has received institutional grant/research support from Actelion Pharmaceuticals, St. Jude Medical, Gilead Sciences, Ikaria, SunshineHeart, and CardioKinetics.

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WHO 2 PH – HFrEF, an inde-pendent risk factor for increasedmortality in HFrEF, is an essential partof the evaluation with respect to pul-monary vascular reactivity for hearttransplant. In this population, PH maybe reversible with appropriate use of adurable left ventricular assist device(LVAD) to improve the left-sidedhemodynamics and lead to reversibilityover several months. WHO 2 PH inHFpEF may be more complicated giventhat the disease itself includes differentphenotypes. The disease is often multi-factorial, with mixed etiologies andneeding a multidisciplinary approach toaddress treatable underlying causes. Pul-monary hypertension in VHD requirescareful analysis to choose the rightpatient for appropriate valvular interven-tions inasmuch as valvular repair/replacement is the treatment of choicefor the valvular-related WHO 2 PH.

Aortic and mitral valve disease, bothinsufficiency and stenosis, can lead to thedownstream development of PH. Theprevalence of PH-VHD is difficult todetermine due to varying cutoff valuesand methods of assessment in the pub-lished literature. Furthermore, limitationsof echocardiographic and invasive hemo-dynamic measurements of PAP addfurther limitations. Echocardiographymay over- or underestimate PAP andrequires an adequate jet of tricuspidregurgitation (TR), while invasive mea-surements are often subject to referralbias.6,7 Elevated PAP has long been rec-ognized as a complication of mitralstenosis (MS).8 Hart et al reported 73%of 317 patients with severe MS under-going percutaneous mitral balloonvalvuloplasty (PMBV) had mPAP�25 mm Hg.9 Roughly two-thirds ofpatients with severe aortic stenosis havePH.10-12 By comparison, the devel-opment of PH in mitral regurgitation(MR) is dependent on the valvularabnormality and chronicity. Barbieri et aldemonstrated that degenerative MR dueto a flail leaflet causes PH at baseline in23% of patients.13 The prevalence of PHin functional MR is up to 44%, and isdependent on LV loading conditions aswell as left atrial compliance andfunction.14 Patients with a greateramount of MR are more likely to have

PH, as demonstrated in a cohort studyof 1541 patients with HFrEF.15 Thisstudy also demonstrated that patientswith a precapillary component to PH orworse LV diastolic dysfunction had moresevere MR.16

ASSESSMENTA new diagnosis of PH should prompt adetailed evaluation of the left heart,including assessment of valvular function.One should obtain a detailed history,focusing on risk factors for LHD(assessment for risk factors, prior con-genital heart disease, known cardiacmurmurs or valvular heart disease, cor-onary artery disease) and symptoms(especially effort tolerance, orthopnea,and paroxysmal nocturnal dyspnea).Physical examination findings for rightheart failure due to PH are often non-specific (edema, hypotension, elevatedjugular venous pressure, loud pulmonicvalve closure, right ventricular lift, right-sided S3). Signs of pulmonary edemaand an audible S3 or S4 are more spe-cific for LHD. Cardiac auscultation forclassic findings of aortic and mitralpathologies should be performed, thespecifics of which are beyond the scopeof this review. Electrocardiography canbe useful to demonstrate chamberenlargement and identify conduction andrhythm abnormalities, though mostfindings lack sensitivity for valvularpathologies. Chest radiography with anx-ray or computed tomography (CT)will help demonstrate pulmonary edema,chamber enlargement, and potentiallyvalvular calcification.

Echocardiography is the primary diag-nostic tool for valvular heart disease, as itis a cost-effective method with high sen-sitivity and specificity, providing bothstructural and hemodynamic infor-mation. Pulmonary artery systolicpressure (PASP) can be calculated usingthe modified Bernoulli equation(PASP�4*[tricuspid regurgitation jetvelocity]2 � right atrial pressure). Thismethod can over- and underestimatePAP, and requires a high-qualityDoppler signal from an adequate TR jet,which has been reported to be lacking inup to 89% of ambulatory heart failurepatients.6,7,17 Agitated saline contrast canbe used to determine the presence of

shunts, which are not uncommon in thesetting of PH or congenital heartdisease. Provided there are adequateacoustic windows, echocardiographyallows for accurate assessment of mitraland aortic stenosis and regurgitation(both of native and bioprosthetic valvesusing M-Mode, 2D and 3D imaging).Standardized and validated definitionsfor MS, MR, aortic stenosis (AS), andaortic insufficiency (AI) are providedthrough the American Society of Echo-cardiography.18 Echocardiography alsoallows for evaluation of endocarditislesions, which can cause significant val-vular regurgitation. Mode of failure ofbioprosthetic valves can be determinedby echo, such as regurgitation (perival-vular or central), valve dehiscence, orstenosis (leaflet immobility, calcification,or patient prosthesis mismatch).

Cardiac magnetic resonance imaging(CMR) is an expensive tool, but canprovide accurate assessment of valvularregurgitation (including regurgitantfraction), chamber size and function, jetvelocities through stenotic valves, andcongenital heart disease. Given thattransthoracic echocardiogram (TTE) canunderassess severity of MR, in the rightpatient cohort, use of either CMR ortransesophageal echocardiogram (TEE)is often recommended to detect moresignificant regurgitation.

Invasive right heart catheterization(RHC) with a balloon-directed pul-monary artery catheter is the goldstandard for determining PAP. Whencombined with echocardiographic data,invasive hemodynamics can help differ-entiate the etiology of PH, which isoften multifactorial. Provocative testing(exercise and fluid challenge) and vasodi-lator testing can be performed as well tohelp isolate the pre- and postcapillarycomponents of PH and determine thetrue PH etiology. Data from RHC canalso be useful in optimizing medicaltherapy in PH-VHD. Pressures in eachchamber (right atrium, right ventricle,and pulmonary artery) and PCWPshould be taken at end expiration inspontaneously breathing patients. Fickcardiac output (CO) or thermodilutionCO should be calculated, the latter beingthe preference in low CO patients.19

The PCWP tracing in MR demonstrates

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tall V waves, representing the trans-mitted wave of pressure, which occursduring LV systole. Direct LV pressuremeasurement should be considered ifPCWP is not reliable or yields an unex-pected finding. When echocardiographyfindings are incongruent with clinicalfindings of MS or AS, one should con-sider invasive measurement oftransvalvular gradients.

MANAGEMENTGeneral CommentsTreatment for PH-LHD should beginwith guideline-directed pharmacologictreatment for the underlying HFrEF andHFpEF: diuretics, vasodilators, and neu-rohormonal antagonists.20 In addition,patients should be considered formechanical support and resynchroni-zation therapy when appropriate.Targeted therapies for PH-LHD arelacking, showing only limited benefit insymptomatic improvement withoutaffecting clinical survival. However, thesubset of PH due to VHD is an excep-tion: surgical and percutaneousinterventions for underlying valvularlesions have a meaningful impact onimproving PH.

The development of PH is often anindication for mitral valve (MV) oratrioventricular (AV) intervention, buthas also been well documented to be aprocedural risk factor.21,22 Interventionsfor VHD include surgical approaches,but percutaneous approaches are rapidlybeing adopted for patients who are highor prohibitive risk for surgery (oftenelderly patients with multiple comor-bidities).23 The postcapillary componentof PH will improve after valve inter-vention. The degree to which theprecapillary component of PH (due topulmonary vascular remodeling sec-ondary to long-standing PH) canimprove after intervention remainsunpredictable.24 Patient prosthesis mis-match after valve replacement (especiallyafter MV replacement) must be con-sidered as a cause of persistently elevatedPAP.

Mitral StenosisSevere MS will result in left atrial hyper-tension and some degree of PH overtime, often in the severe range. Roughly

three-fourths of patients will havemPAP �25 mm Hg at the time ofPMBV, and one-quarter in the severerange (defined by PVR �6 Woodunits).9,25 Pulmonary hypertension in thesetting of MS appears to be a functionof poor atrial compliance (defined as(MV area, MVA)/(mitral E wave down-slope) �4 mL/mm Hg), which is inturn a predictor of worse functionalcapacity and the need for MVreplacement or repair.26 Early concernsfor predictable and durable improvementof PH after MV surgery were addressedby Braunwald et al, who reported fullpre- and postoperative hemodynamicchanges in a cohort of 31 patients. Thispivotal trial showed an improvement inPVR (543 to 243 dynes-s-cm5) andincreased pulmonary blood flow inpatients with MV repair for mitralstenosis.27

Severity of MS is based on mean gra-dient, PASP, and valve area (severerange: mean gradient �10 mm Hg,PASP �50 mm Hg, and MV area of�1.0 cm2). Estimated 5-year survival forunrepaired symptomatic MS is 44%.9,28

Echocardiographic assessment will dem-onstrate severity of obstruction, leafletmobility, thickening, calcification, andsubvalvular involvement, all of which areused to calculate the Wilkins score.29

Symptomatic (New York Heart Associ-ation [NYHA] functional class II)patients with a Wilkins score �8 andless than moderate MR can be con-sidered for PMBV. Patients withasymptomatic moderate or severe MScan be considered for PMBV withresting PASP �50 mm Hg, or exercise-induced PASP �60, PCWP �25 mmHg, or MV gradient �15 mm Hg.21

Successful PMBV is defined asincreasing MVA to 1.5 cm2 or �50%increase in MVA with �3� MR.Freedom from death, repeat PMBV, orMV replacement is 50% to 65% at3-7 years (80% to 90% with the mostfavorable valve morphology).30,31 Themost comprehensive assessment of theimpact of PMBV on PH due to MSincluded 559 patients by Fawzy et al.This study demonstrated that PMBVachieved modest immediate reduction inPAP, but normalization of PAP at 6and 12 months follow-up regardless of

pre-PMBV PH severity (mild: 40 � 13to 28 � 8 mm Hg, moderate: 54 � 17to 31 � 9 mm Hg, severe: 92 � 17 to29 � 5 mm Hg).32

Open or closed MV commissurotomysurgical repair for MS continues to havea role in patients who are not candidatesfor or who have failed PMBV.33

Freedom for reoperation with closedcommissurotomy is 50% at 15 years.34

Mitral valve replacement is reserved forthose who require surgery withunsuitable anatomy for repair. Operativemortality for MV replacement is 5% to20%, and correlates with degree of PH(as well as age, functional class, and cor-onary artery disease).35 There is greatinterest in developing a transcatheterMV replacement platform, and severalare in feasibility and early in-man stages.

Mitral RegurgitationWith persistent long-standing MR,eccentric LV hypertrophy develops dueto the reduced afterload conditions. Thisleads to reduced contractility, strokevolume, and CO. Eventually pulmonaryvenous and left atrial pressures increase,resulting in pulmonary edema, PH, andatrial fibrillation. The presence or severityof PH is not part of the quantitative orqualitative assessment of MR severity,though it is an indication for interventionand increases morbidity and mortality.18

As shown in Table 1, there are 2general categories of MR based on theunderlying pathology: degenerative andfunctional. Degenerative MR is mostoften due to myxomatous degenerationand MV prolapse, and can result in aruptured chordae and a flail leafletsegment. Pulmonary hypertension due todegenerative MR complicated by a flailleaflet is an independent predictor ofdeath [all cause, HR 2.03 (1.30-3.18)P�0.002; and cardiovascular, HR 2.21(1.30-3.76) P�0.003; and worseningheart failure, HR 1.70 (1.10-2.62)P�0.018] over a 4-year follow-upperiod.13

Functional MR is due to dilationand/or dysfunction of the left ventricle,causing mitral annular dilation. A dilatedmitral annulus causes papillary muscledisplacement, poor leaflet mobility,tethered leaflets, resulting in poor leafletcoaptation and MR.36 Pulmonary hyper-

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tension in the setting of functional MRincreases mortality, even when con-trolling for the degree of LVdysfunction.37 Acute severe MR is rare,but most often occurs due to rupturedchordae with or without underlyingendocarditis. Acute onset MR results inrapid increase in pulmonary venouspressure and pulmonary edema, oftenaccompanied by systemic hypotensionand tachycardia aimed at compensatingfor acute reduction in afterload.

Medical treatment for chronic degen-erative MR is aimed at lowering LVafterload (angiotensin-converting enzymeinhibitor, ACE; or angiotensin receptorblockers, ARB), but has not been shownto reduce clinical event rates.38 On theother hand, there is a well-establishedsurvival benefit with guideline-directedtherapy for chronic functional MR dueto LV systolic dysfunction or ischemiccardiomyopathy. These medicationsinclude ACE/ARB, beta-blockers, andtreatment for coronary artery diseasewhen applicable. Cardiac resynchroni-zation therapy with biventricular pacingshould also be considered in patientswith reduced ejection fraction, which hasbeen shown to improve PAP in thissubset of patients.39,40

If symptoms persist (NYHA func-tional class II–IV) despite maximalmedical therapy, surgical intervention isindicated for severe degenerative MR. Inasymptomatic severe MR, surgery isindicated when the LV ejection fraction(LVEF) falls below normal (30% to60%), LV dilation develops, new onsetatrial fibrillation appears, or upon devel-opment of PH (PASP �50 mm Hg atrest, or PASP �60 mm Hg with

exercise).21 Surgery for chronic severefunctional MR with an LVEF �30%should only be considered with refractorysevere symptoms (NYHA functionalclass III-IV) despite optimal medicaltherapy.21 The role of MV surgery forfunctional MR is debated, as the under-lying pathology is a poorly functioningdilated LV. In general, repair of the MVis preferred over replacement when valveanatomy is suitable, and should be per-formed in experienced centers.21

Worsening LV function after MVsurgery may be due to the increased LVafterload that develops after eliminatingthe MR, and may necessitate mechanicalcirculatory support (LVAD). Urgentsurgical intervention is the only definitivetreatment for acute severe MR, thoughafterload reduction with nitroprusside orintra-aortic balloon counterpulsation canhelp stabilize patients until surgery.

Several percutaneous options for MVrepair have emerged in recent years. Onetype of device is implanted in the cor-onary sinus. The goal of this device is toreshape the contour of the MV annulusand improve leaflet coaptation in func-tional MR. Several of these devices haveshown encouraging results in the proofof concept and feasibility stages, but havefailed to translate into reproducible anddurable clinical results.41-43 Coronarysinus implants have limited applicationfor 3 primary reasons: 1) variability inthe spatial relationship between the cor-onary sinus, fibrous trigones, and themitral annulus; 2) ongoing mitralannular dilation will likely causerecurrent or worsening MR post pro-cedure; and 3) the implant can causecoronary artery obstruction.

Another percutaneous option is theMitraClip� (Abbott Vascular, SantaClara, CA), which is commerciallyavailable for degenerative (primary) 3 to4� MR in patients who are not candi-dates for surgery. The MitraClip isdelivered anterograde across the MV viatrans-septal approach to achieve an end-to-end repair of the MV leaflets. Thepivotal trial leading to FDA approval ofMitraClip was EVEREST II, whichrandomized patients 2:1 to MitraClip orMV surgery.44 Patients undergoingMitraClip had an improved safetyprofile, but less reduction in MR com-pared to surgery. Clinical outcomes weresimilar (LV size, NYHA functionalclass, quality of life measures) betweenthe 2 groups. A large European registryof 628 patients demonstrated similar1-year mortality rates with both func-tional and degenerative MR (15.3%), butan increased rate of heart failure admis-sions with functional MR (25.8% vs12.0%, P[log-rank]�0.009).45 This studyalso showed a significant reduction inPASP from baseline to discharge andout to 1 year (functional MR: 44.2 mmHg to 39.2 mm Hg and 40.5 mm Hg,respectively; and degenerative MR: 53.5mm Hg to 43.4 mm Hg and 42.9 mmHg, respectively). Matsumoto et al per-formed serial PASP measurements afterMitraClip placement in 48 patients withPH (PASP �50 mm Hg) and 42patients without PH.46 Patients with PHhad a reduction at 30 days (63.5 � 9.0mm Hg to 50.0 � 13.7 mm Hg), whichwas sustained at 1 year (50.8 � 15.3mm Hg). Preexisting PH was a pre-dictor of 1-year mortality (HR 3.731,95% CI 1.653 to 8.475, P�0.002).46 Alarge-scale randomized Phase 3 clinicaltrial for MitraClip is underway(COAPT, NCT01626079), whichincludes both functional and degener-ative MR.

Aortic StenosisEtiologies of AS include calcification ofa trileaflet or bicuspid aortic valve orrheumatic heart disease. The naturalhistory of medically treated symptomaticAS is poor, with a 50% mortality rateover 2 years.47 Roughly two-thirds ofpatients with severe AS have concom-itant PH.11,48,49 Similar to PH related to

Table 1. Mitral Regurgitation Based on Underlying Pathology.

Degenerative Functional

Etiology Myxomatous degenerationMitral value prolapse

Dilation and/ordysfunction of the leftventricle, causingmitral annular dilation

Results Repetured chordaeFlail leaflet segment

Papillary muscledisplacement

Poor leaflet mobilityTether leafletsPoor leaflet coaptation

and mitral regurgitation

Pulmonary hypertensionin this setting

In dependent predictor ofdeath over 4 year follow-up period

Increases mortality

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MV disease, PH in AS increases mor-tality regardless of managementstrategy—medical, surgical, orpercutaneous.50-52 The degree of PHappears to correlate with left atrial dys-function and LV diastolic dysfunction.14

In addition, those who fail to haveimproved PAP after intervention haveworse mortality and heart failuresymptoms.51

Severe AS manifests as angina, heartfailure, or syncope. Echocardiographywill demonstrate a transaortic pressuregradient of 40 mm Hg (or a transaorticjet velocity of �4 m/sec) and an aorticvalve area (AVA) of �1 cm2 (or anindexed AVA of 0.6 cm2/m2 ).21,22

Severe AS may be masked by a low CO(so-called “low-flow, low-gradient AS”)and should not be overlooked. Inter-vention (surgical or percutaneous) isindicated with severe symptomatic AS,severe AS with reduced LVEF, orasymptomatic very severe AS (AVA�0.7 cm2, transaortic jet velocity of�5 m/sec, or transvalvular gradient of�60 mm Hg). Medical managementuntil that point (or in patients deemedunfit for intervention) should focus onguideline-directed treatment of hyper-tension and hyperlipidemia.

The most common method ofassessing operative risk is the Society ofThoracic Surgeons (STS) Predicted Riskof Mortality (PROM), which does notincorporate PH. Alternatively, theEuropean System for Cardiac OperativeRisk Evaluation (EuroSCORE) doesconsider PH in risk calculation.53-55 Ofnote, combined valve disease is notuncommon in this population (namely,concomitant MR). Surgery has longbeen the standard of care for thoserequiring aortic valve replacement(AVR), as valve repair for AS is feasible.Transcatheter aortic valve replacement(TAVR) has now emerged as a commer-cially available option worldwide forpatients who are considered at prohib-itive or high risk for surgical AVR. The2 most widely used valves are theEdwards Sapien XT and S3 valves(balloon expandable) and the MedtronicCoreValve and Evolut R valves (self-expanding).56-58 There are ongoing trialsthat aim to expand the indications forTAVR to include those at moderate risk.

Surgical AVR and TAVR have beenidentified as treatments for PH causedby LV outflow obstruction secondary toAS, both demonstrating a significant anddurable reduction in PAP out to 1year.11,59 The presence of new or worsePH post TAVR has been shown toincrease mortality, a phenomenon that ismost often related to perivalvular regur-gitation.50 Our data have shown theimportance of defining preprocedure PHin this population in order to tailorperiprocedure medication and fluid man-agement. Also, patients with aprecapillary component can be expectedto have less improvement in post-TAVRPH.59

Aortic RegurgitationBoth aortic root and primary aortic valveabnormalities can result in aortic regurgi-tation (AR). Leaflet failure orperivalvular regurgitation of bioprostheticaortic valves can result in AR as well.Chronic AR can be present for manyyears without symptoms or LV com-promise, with the LV increasing totalstroke volume to maintain normal CO.Eventually left atrial pressure increases,causing symptoms, and systolic dys-function will develop, as compensatoryLV hypertrophy is insufficient. As aresult, pulmonary venous pressures willrise, causing PH (defined as PASP�60 mm Hg) in 24% of patients in acase series of 139 patients with severechronic AR.21,62 While mild or mod-erate AR carries a good prognosis, severeAR will result in symptoms or LV dys-function at a rate of 4.3% per year.21

Echocardiography remains the centraltool for evaluation, which, in addition toPAP estimation, provides quantitativeassessment such as regurgitation volume,regurgitant fraction, and effective regur-gitant orifice area.61 Whenechocardiography is suboptimal, mag-netic resonance imaging (MRI) can beconsidered.

Vasodilators (nifedipine, ACE) are theprimary medical intervention for patientswith AR and diastolic hypertension,while beta blockade should be avoided.21

The benefit of vasodilators in asymp-tomatic patients with severe AR is notclear.62,63 Central to the management ofAR is root or valve intervention prior to

development of irreversible LV dys-function. Aortic valve replacement inchronic AR has been shown to effec-tively reduce PVR (4.7 � 3.5 to 1.5 �0.8 Wood units) and normalize PASP ina series of 139 patients from Naidoo etal.60 While chronic AR can be moni-tored until symptoms or LV dysfunctiondevelop, acute severe AR requiresemergent surgical intervention.

CONCLUSIONWith an aging population, VHD andWHO 2 PH are increasingly prevalentand warrant an experienced team inaddressing the specifics of intervention.This patient population carries a higherprocedural risk, but intervention is theonly chance for improvement. Our datashow the feasibility and importance ofapproaching this cohort with a multidis-ciplinary team pre- and postintervention.One should identify those patients thatneed targeted pulmonary vasodilators,either due to existence of precapillaryPH from systemic scleroderma or lungdisease, or due to the more severeCPpPH. Postprocedural management ofPH must be guided by defining compo-nents of prior interventions.

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6. Arcasoy SM, Christie JD, Ferrari VA, et al.Echocardiographic assessment of pulmonary hyper-tension in patients with advanced lung disease.Am J Respir Crit Care Med. 2003;167(5):735-740.7. Fisher MR, Forfia PR, Chamera E, et al.Accuracy of Doppler echocardiography in thehemodynamic assessment of pulmonary hyper-tension. Am J Respir Crit Care Med. 2009;179(7):615-621.8. Ward C, Hancock BW. Extreme pulmonaryhypertension caused by mitral valve disease.Natural history and results of surgery. Br Heart J.1975;37(1):74-78.9. Hart SA, Krasuski RA, Wang A, Kisslo K,Harrison JK, Bashore TM. Pulmonary hyper-tension and elevated transpulmonary gradient inpatients with mitral stenosis. J Heart Valve Dis.2010;19(6):708-715.10. Melby SJ, Moon MR, Lindman BR, BaileyMS, Hill LL, Damiano RJ Jr. Impact of pul-monary hypertension on outcomes after aortic valvereplacement for aortic valve stenosis. J Thorac Car-diovasc Surg. 2011;141(6):1424-1430.11. Ben-Dor I, Goldstein SA, Pichard AD, et al.Clinical profile, prognostic implication, andresponse to treatment of pulmonary hypertensionin patients with severe aortic stenosis. Am JCardiol. 2011;107(7):1046-1051.12. Silver K, Aurigemma G, Krendel S, Barry N,Ockene I, Alpert J. Pulmonary artery hypertensionin severe aortic stenosis: incidence and mechanism.Am Heart J. 1993;125(1):146-150.13. Barbieri A, Bursi F, Grigioni F, et al; MitralRegurgitation International DAtabase (MIDA)Investigators. Prognostic and therapeutic implica-tions of pulmonary hypertension complicatingdegenerative mitral regurgitation due to flail leaflet:a multicenter long-term international study. EurHeart J. 2011;32(6):751-759.14. Saraiva RM, Yamano T, Matsumura Y, et al.Left atrial function assessed by real-time3-dimensional echocardiography is related to rightventricular systolic pressure in chronic mitral regur-gitation. Am Heart J. 2009;158(2):309-316.15. Miller WL, Mahoney DW, Michelena HI,Pislaru SV, Topilsky Y, Enriquez-Sarano M. Con-tribution of ventricular diastolic dysfunction topulmonary hypertension complicating chronic sys-tolic heart failure. JACC Cardiovasc Imaging. 2011;4(9):946-954.16. Luo C, Ramachandran D, Ware DL, MaTS, Clark JW Jr. Modeling left ventricular dia-stolic dysfunction: classification and key indicators.Theor Biol Med Model. 2011;8:14.17. Kalogeropoulos AP, Siwamogsatham S,Hayek S, et al. Echocardiographic assessment ofpulmonary artery systolic pressure and outcomes inambulatory heart failure patients. J Am Heart Assoc.2014;3(1):e000363.18. Zoghbi WA, Enriquez-Sarano M, Foster E,et al; American Society of Echocardiography. Rec-ommendations for evaluation of the severity ofnative valvular regurgitation with two-dimensionaland Doppler echocardiography. J Am Soc Echocar-diogr. 2003;16(7):777-802.19. Hoeper MM, Maier R, Tongers J, et al.Determination of cardiac output by the Fickmethod, thermodilution, and acetylene rebreathing

in pulmonary hypertension. Am J Respir Crit CareMed. 1999;160(2):535-541.20. Writing Committee Members, Yancy CW,Jessup M, et al; American College of CardiologyFoundation/American Heart Association TaskForce on Practice Guidelines. 2013 ACCF/AHAguideline for the management of heart failure: areport of the American College of CardiologyFoundation/American Heart Association TaskForce on practice guidelines. Circulation. 2013;128(16):e240-e327.21. Bonow RO, Carabello BA, Chatterjee K, etal; American College of Cardiology/AmericanHeart Association Task Force on Practice Guide-lines. 2008 focused update incorporated into theACC/AHA 2006 guidelines for the managementof patients with valvular heart disease: a report ofthe American College of Cardiology/AmericanHeart Association Task Force on Practice Guide-lines (Writing Committee to revise the 1998guidelines for the management of patients withvalvular heart disease). Endorsed by the Society ofCardiovascular Anesthesiologists, Society for Car-diovascular Angiography and Interventions, andSociety of Thoracic Surgeons. J Am Coll Cardiol.2008;52(13):e1-e142.22. Vahanian A, Alfieri O, Andreotti F, et al;ESC Committee for Practice Guidelines (CPG);Joint Task Force on the Management of ValvularHeart Disease of the European Society of Cardi-ology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Guidelines on themanagement of valvular heart disease (version2012): the Joint Task Force on the Managementof Valvular Heart Disease of the European Societyof Cardiology (ESC) and the European Associ-ation for Cardio-Thoracic Surgery (EACTS). EurJ Cardiothorac Surg. 2012;42(4):S1-S44.23. Nkomo VT, Gardin JM, Skelton TN, Gott-diener JS, Scott CG, Enriquez-Sarano M. Burdenof valvular heart diseases: a population-based study.Lancet. 2006;368(9540):1005-1011.24. Guazzi M, Galie N. Pulmonary hypertensionin left heart disease. Eur Respir Rev. 2012;21(126):338-346.25. Semler HJ, Shepherd JT, Wood EH. Therole of vessel tone in maintaining pulmonary vas-cular resistance in patients with mitral stenosis.Circulation. 1959;19(3):386-394.26. Kim HK, Kim YJ, Hwang SJ, et al. Hemo-dynamic and prognostic implications of netatrioventricular compliance in patients with mitralstenosis. J Am Soc Echocardiogr. 2008;21(5):482-486.27. Braunwald E, Braunwald NS, Ross J Jr,Morrow AG. Effects of mitral-valve replacementon the pulmonary vascular dynamics of patientswith pulmonary hypertension. N Engl J Med. 1965;273:509-514.28. Horstkotte D, Niehues R, Strauer BE.Pathomorphological aspects, aetiology and naturalhistory of acquired mitral valve stenosis. EurHeart J. 1991;12 Suppl B:55-60.29. Wilkins GT, Weyman AE, Abascal VM,Block PC, Palacios IF. Percutaneous balloon dila-tation of the mitral valve: an analysis ofechocardiographic variables related to outcome andthe mechanism of dilatation. Br Heart J. 1988;

60(4):299-308.30. Cohen DJ, Kuntz RE, Gordon SP, et al.Predictors of long-term outcome after percutaneousballoon mitral valvuloplasty. N Engl J Med. 1992;327(19):1329-1335.31. Palacios IF, Sanchez PL, Harrell LC,Weyman AE, Block PC. Which patients benefitfrom percutaneous mitral balloon valvuloplasty?Prevalvuloplasty and postvalvuloplasty variables thatpredict long-term outcome. Circulation. 2002;105(12):1465-1471.32. Fawzy ME, Hassan W, Stefadouros M,Moursi M, El Shaer F, Chaudhary MA. Preva-lence and fate of severe pulmonary hypertension in559 consecutive patients with severe rheumaticmitral stenosis undergoing mitral balloon val-votomy. J Heart Valve Dis. 2004;13(6):942-947;discussion 947-948.33. Choudhary SK, Dhareshwar J, Govil A,Airan B, Kumar AS. Open mitral commissurotomyin the current era: indications, technique, andresults. Ann Thorac Surg. 2003;75(1):41-46.34. Carabello BA. Modern management of mitralstenosis. Circulation. 2005;112(3):432-437.35. Birkmeyer JD, Siewers AE, Finlayson EV, etal. Hospital volume and surgical mortality in theUnited States. N Engl J Med. 2002;346(15):1128-1137.36. O’Gara P, Sugeng L, Lang R, et al. The roleof imaging in chronic degenerative mitral regurgi-tation. JACC Cardiovasc Imaging. 2008;1(2):221-237.37. Trichon BH, Felker GM, Shaw LK, CabellCH, O’Connor CM. Relation of frequency andseverity of mitral regurgitation to survival amongpatients with left ventricular systolic dysfunctionand heart failure. Am J Cardiol. 2003;91(5):538-543.38. Dujardin KS, Enriquez-Sarano M, BaileyKR, Seward JB, Tajik AJ. Effect of losartan ondegree of mitral regurgitation quantified by echo-cardiography. Am J Cardiol. 2001;87(5):570-576.39. Healey JS, Davies RA, Tang AS.Improvement of apparently fixed pulmonary hyper-tension with cardiac resynchronization therapy.J Heart Lung Transplant. 2004;23(5):650-652.40. Shalaby A, Voigt A, El-Saed A, Saba S.Usefulness of pulmonary artery pressure by echo-cardiography to predict outcome in patientsreceiving cardiac resynchronization therapy heartfailure. Am J Cardiol. 2008;101(2):238-241.41. Kaye DM, Byrne M, Alferness C, Power J.Feasibility and short-term efficacy of percutaneousmitral annular reduction for the therapy of heartfailure-induced mitral regurgitation. Circulation.2003;108(15):1795-1797.42. Liddicoat JR, Mac Neill BD, Gillinov AM,et al. Percutaneous mitral valve repair: a feasibilitystudy in an ovine model of acute ischemic mitralregurgitation. Catheter Cardiovasc Interv. 2003;60(3):410-416.43. Maniu CV, Patel JB, Reuter DG, et al.Acute and chronic reduction of functional mitralregurgitation in experimental heart failure by per-cutaneous mitral annuloplasty. J Am Coll Cardiol.2004;44(8):1652-1661.44. Feldman T, Foster E, Glower DD, et al;EVEREST II Investigators. Percutaneous repair or

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surgery for mitral regurgitation. N Engl J Med.2011;364(15):1395-1406.45. Nickenig G, Estevez-Loureiro R, Franzen O,et al; Transcatheter Valve Treatment Sentinel Reg-istry Investigators of the EURObservationalResearch Programme of the European Society ofCardiology. Percutaneous mitral valve edge-to-edgerepair: in-hospital results and 1-year follow-up of628 patients of the 2011-2012 Pilot EuropeanSentinel Registry. J Am Coll Cardiol. 2014;64(9):875-884.46. Matsumoto T, Nakamura M, Yeow WL, etal. Impact of pulmonary hypertension on outcomesin patients with functional mitral regurgitationundergoing percutaneous edge-to-edge repair. Am JCardiol. 2014;114(11):1735-1739.47. Kelly TA, Rothbart RM, Cooper CM, KaiserDL, Smucker ML, Gibson RS. Comparison ofoutcome of asymptomatic to symptomatic patientsolder than 20 years of age with valvular aortic ste-nosis. Am J Cardiol. 1988;61(1):123-130.48. Kapoor N, Varadarajan P, Pai RG. Echocar-diographic predictors of pulmonary hypertension inpatients with severe aortic stenosis. Eur J Echocar-diogr. 2008;9(1):31-33.49. Enriquez-Sarano M, Rossi A, Seward JB,Bailey KR, Tajik AJ. Determinants of pulmonaryhypertension in left ventricular dysfunction. J AmColl Cardiol. 1997;29(1):153-159.50. Lucon A, Oger E, Bedossa M, et al. Prog-nostic implications of pulmonary hypertension inpatients with severe aortic stenosis undergoingtranscatheter aortic valve implantation: study fromthe FRANCE 2 Registry. Circ Cardiovasc Interv.2014;7(2):240-247.51. Sinning JM, Hammerstingl C, Chin D, et al.Decrease of pulmonary hypertension impacts onprognosis after transcatheter aortic valvereplacement. EuroIntervention. 2014;9(9):1042-

1049.52. Malouf JF, Enriquez-Sarano M, Pellikka PA,et al. Severe pulmonary hypertension in patientswith severe aortic valve stenosis: clinical profile andprognostic implications. J Am Coll Cardiol. 2002;40(4):789-795.53. Vahanian A, Otto CM. Risk stratification ofpatients with aortic stenosis. Eur Heart J. 2010;31(4):416-423.54. Shahian DM, O’Brien SM, Filardo G, et al;Society of Thoracic Surgeons Quality Mea-surement Task Force. The Society of ThoracicSurgeons 2008 cardiac surgery risk models: part3–valve plus coronary artery bypass graftingsurgery. Ann Thorac Surg. 2009;88(1 Suppl):S43-S62.55. Le Tourneau T, Pellikka PA, Brown ML, etal. Clinical outcome of asymptomatic severe aorticstenosis with medical and surgical management:importance of STS score at diagnosis. Ann ThoracSurg. 2010;90(6):1876-1883.56. Reardon MJ, Adams DH, Coselli JS, et al;CoreValve US Clinical Investigators. Self-expanding transcatheter aortic valve replacementusing alternative access sites in symptomaticpatients with severe aortic stenosis deemed extremerisk of surgery. J Thorac Cardiovasc Surg. 2014;148(6):2869-2876.e1-7.57. Leon MB, Smith CR, Mack M, et al;PARTNER Trial Investigators. Transcatheteraortic-valve implantation for aortic stenosis inpatients who cannot undergo surgery. N EnglJ Med. 2010;363(17):1597-1607.58. Popma JJ, Adams DH, Reardon MJ, et al;CoreValve United States Clinical Investigators.Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severeaortic stenosis at extreme risk for surgery. J AmColl Cardiol. 2014;63(19):1972-1981.

59. Kaple RK, Kampaktsis P, Pawar S, et al.Impact of etiology of pulmonary hypertension onpost-procedural management and outcomes inpatients undergoing transcatheter aortic valvereplacement. Paper presented at: American Collegeof Cardiology Annual Meeting; March 30, 2014;Washington, DC.60. Naidoo DP, Mitha AS, Vythilingum S,Chetty S. Pulmonary hypertension in aortic regur-gitation: early surgical outcome. Q J Med. 1991;80(291):589-595.61. American College of Cardiology; AmericanHeart Association Task Force on Practice Guide-lines (Writing Committee to revise the 1998guidelines for the management of patients withvalvular heart disease); Society of CardiovascularAnesthesiologists; Bonow RO, Carabello BA,Chatterjee K, et al. ACC/AHA 2006 guidelinesfor the management of patients with valvular heartdisease: a report of the American College ofCardiology/American Heart Association TaskForce on Practice Guidelines (writing Committeeto Revise the 1998 guidelines for the managementof patients with valvular heart disease) developed incollaboration with the Society of CardiovascularAnesthesiologists endorsed by the Society for Car-diovascular Angiography and Interventions and theSociety of Thoracic Surgeons. J Am Coll Cardiol.2006;48(3):e1-e148.62. Scognamiglio R, Rahimtoola SH, Fasoli G,Nistri S, Dalla Volta S. Nifedipine in asymp-tomatic patients with severe aortic regurgitationand normal left ventricular function. N Engl J Med.1994;331(11):689-694.63. Bonow RO, Dodd JT, Maron BJ, et al.Long-term serial changes in left ventricularfunction and reversal of ventricular dilatation aftervalve replacement for chronic aortic regurgitation.Circulation. 1988;78(5 Pt 1):1108-1120.

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ASK THE EXPERT

Is Cardiac Magnetic Resonance Imaging Underutilized in theDiagnosis of Pulmonary Hypertension?

Section EditorSean M. Studer, MD, MSc

Jordan Ray, MDDivision of Cardiovascular DiseasesMayo Clinic

Charles Burger, MDDivision of Pulmonary DiseasesMayo Clinic

Joseph Blackshear, MDDivision of Cardiovascular DiseasesMayo Clinic

Robert Safford, MD, PhDDivision of Cardiovascular DiseasesMayo Clinic

Patricia Mergo, MDDepartment of RadiologyMayo Clinic

Brian Shapiro, MDDivision of Cardiovascular DiseasesMayo Clinic

Cardiac magnetic resonance imaging(CMR) provides an important andcomplementary role to conventionalimaging in the evaluation of patientswith pulmonary hypertension (PH).Echo-cardiography remains vital givenits ability to quickly assess cardiac mor-phology, function, and hemodynamics.It is also portable, readily available, andrelatively inexpensive. However, certainlimitations of echocardiography dooccur in PH patients such as inabilityto fully or accurately characterize theright ventricle (RV), which remainscrucial for therapeutic decision makingand prognostic determination. Giventhe geometric complexity of the RV aswell as patient-specific factors such asobesity, echocardiography may fail toadequately depict the RV. Conversely,CMR is well suited for PH imaging forvarious reasons, not least of which is itsability to fully characterize RV mor-phology and function. In addition,CMR provides various components

during a PH examination, includingassessment of pulmonary artery (PA)flow and stiffness, ventricular functionand strain, shunt, emboli, and tissuecharacterization.

Generally, echocardiography providesa detailed and accurate assessment ofthe RV in many PH patients.1

However, in those instances whereaccuracy or visualization is limited, orwhere more precise determination isrequired, CMR should be strongly con-sidered as it remains the referencestandard for RV assessment.2,3 On atypical CMR examination, a series orstack of short- and long-axis cineimages are performed and post-processed using commercially availablesoftware. Left and right ventricles aretraced from systolic and diastolic stillframes providing volumetric data,allowing for calculations of end-diastolicand systolic volumes, ejection fraction,mass, and stroke volume. As theseverity of PH progresses, the RV

thickens, enlarges (Figure 1), and willsubsequently fail demonstrated by aprogressive decline in ejection fraction.These changes to RV size and functionare tightly coupled with mortality.4

Also, as pulmonary pressures rise, thereis a characteristic flattening of the inter-ventricular septum leftward. The degreeof flattening can be quantified by com-paring the curvatures of theinterventricular septum to left ven-tricular free wall, a value that is stronglycorrelated to the degree of PH.5 Evalu-ation of myocardial strain usingconventional tagging or other novelsequences may also accurately charac-terize the RV, but at this point islargely relegated to research protocols.

The ability to accurately assess PAstiffness presents an exciting new avenuefor CMR. The development of adversepulmonary vascular remodeling is thehallmark feature, which begins thecascade of pulmonary arterial hyper-tension (PAH). With the use of specificflow sequences, CMR can accuratelymeasure cross-sectional phasic changesto the PA, thereby providing a meansCorrespondence: Shapiro.Brian@mayo.edu

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Figure 1: Four-chamber long axis cine images. A) Normal RV, normal curvature of the interventricular septum (arrows). B) Significant RV dila-tation and hypertrophy as seen in severe PH. The curvature of the interventricular septum is lost (arrows) and presents as a “D”-shaped leftventricle. Also notice the presence of pericardial effusion and dilated right atrium: both are markers of poor prognosis in PH.

Figure 2: Short axis flow images of the pulmonary artery and aorta in normal, mild, and severe PH.

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to calculate indices of PA stiffnessincluding pulsatility [(PA areamax – PAareamin)/PA areamin] (Figure 2). As PHprogresses, the PA typically dilates andthe degree of pulsatility declines,reflecting loss of elasticity and worseningstiffness.6,7 This technique may provide ameans to detect pulmonary vascularremodeling at an earlier stage of devel-opment, and may also ultimately beconsidered a target for PH-specific ther-apies. One potential role of CMR isdetection in those patients who are “atrisk” (ie, scleroderma patients) or haveclinical findings suggestive of early pul-monary vascular remodeling, but exhibitnegligible pulmonary pressure elevationsabove normal during right heart cathe-terization. Pulmonary arterialmeasurements from CMR can also becoupled with invasive catheterization,yielding additional characterization ofcompliance, capacitance, and distensi-bility and may hold promise in assessingventricular-vascular coupling.8,9

The use of magnetic resonanceangiography (MRA) or pulmonary per-fusion to assess for World HealthOrganization Group 4 chronic throm-boembolic PH (CTEPH) andpulmonary blood flow is also a part ofroutine PH CMR protocols. Whilelacking the sensitivity of traditionaltesting such as ventilation perfusionlung scans or computed tomographyangiography, MRA may be useful inselected cases to aid in the diagnosis. Inaddition to CTEPH, conventional cineand flow sequences may also identifyother potential causes for PH that maynot have been previously recognizedsuch as atrial septal defects and shunts,patent ductus arteriosus, and anomalouspulmonary veins. Following perfusionimaging, delayed imaging post-contrastis performed to assess whether late gad-

olinium enhancement is present in themyocardium, a finding suggestive ofcardiac pathology such as with fibrosis,scar, infarction, or infiltrative cardiomy-opathy. In the case of PAH, lategadolinium enhancement is often pic-tured in the RV insertion sites, which isa finding suggestive of increased walltension and strain. An appearance ofscar in the interventricular septum RVinsertion sites may reflect worsened PHand may be linked to poor prognosis.10

While it is highly unlikely that CMRwould replace conventional echocardiog-raphy or right heart catheterization,there is little doubt regarding its value inselected patients with PH where thediagnosis or cause remains unclear or theRV is poorly characterized. Newer tech-niques and data will be necessary todetermine the usefulness of othersequences that measure such things suchas myocardial strain, pulmonary vascularremodeling, and tissue characterization.Certainly, CMR is not without its limi-tations such as cost, limited availability,expertise, and study time. Patient-relatedlimitations include claustrophobia andpotential contrast reactions. However,the superb tissue characterization com-bined with important morphologic andphysiologic data afforded by CMR makeit an extremely useful and promisingmeans for assessment of pertinent changesto the pulmonary circulation and RV inthe setting of PH. No other technique atpresent provides such a comprehensivemeans of assessment of important mor-phologic changes to the heart andvasculature in this patient population.While we cannot definitively statewhether CMR is presently underutilizedin PH, its value and appreciation coupledwith new advancements and research willlikely increase the proportion of CMRused in PH in the future.

References1. Rudski LG, Lai WW, Afilalo J, et al. Guide-lines for the echocardiographic assessment of theright heart in adults: a report from the AmericanSociety of Echocardiography endorsed by theEuropean Association of Echocardiography, a reg-istered branch of the European Society ofCardiology, and the Canadian Society of Echocar-diography. J Am Soc Echocardiogr. 2010;23(7):685-713.2. Mooij CF, de Wit CJ, Graham DA, PowellAJ, Geva T. Reproducibility of MRI measure-ments of right ventricular size and function inpatients with normal and dilated ventricles.J Magn Reson Imaging. 2008;28(1):67-73.3. Grothues F, Moon JC, Bellenger NG, SmithGS, Klein HU, Pennell DJ. Interstudy reproduc-ibility of right ventricular volumes, function, andmass with cardiovascular magnetic resonance.Am Heart J. 2004;147(2):218-223.4. Moledina S, Pandya B, Bartsota M, et al.Prognostic significance of cardiac magnetic reso-nance imaging in children with pulmonaryhypertension. Circ Cardiovasc Imaging. 2013;6(3):407-414.5. Marcus JT, Vonk Noordegraaf A, RoeleveldRJ, et al. Impaired left ventricular filling due toright ventricular pressure overload in primary pul-monary hypertension: noninvasive monitoring usingMRI. Chest. 2001;119(6):1761-1765.6. Sanz J, Kariisa M, Dellegrottaglie S, et al.Evaluation of pulmonary artery stiffness in pul-monary hypertension with cardiac magneticresonance. JACC Cardiovasc Imaging. 2009;2(3):286-295.7. Lankhaar JW, Westerhof N, Faes TJ, et al.Pulmonary vascular resistance and compliance stayinversely related during treatment of pulmonaryhypertension. Eur Heart J. 2008;29(13):1688-1695.8. Champion HC, Michelakis ED, HassounPM. Comprehensive invasive and noninvasiveapproach to the right ventricle-pulmonary circu-lation unit: state of the art and clinical and researchimplications. Circulation. 2009;120(11):992-1007.9. Ibrahim El-SH, Shaffer JM, White RD.Assessment of pulmonary artery stiffness usingvelocity-encoding magnetic resonance imaging:evaluation of techniques. Magn Reson Imaging.2011;29(7):966-974.10. Bradlow WM, Assomull R, Kilner PJ, GibbsJS, Sheppard MN, Mohiaddin RH. Understandinglate gadolinium enhancement in pulmonary hyper-tension. Circ Cardiovasc Imaging. 2010;3(4):501-503.

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PULMONARY HYPERTENSION ROUNDTABLE

Pulmonary Hypertension Due to Left Heart Disease

Guest editor Teresa De Marco, MD, along with Brian Shapiro, MD, Mayo Clinic, Jacksonville, FL, convened a panel of expertsto discuss the challenges in diagnosis and treatment and the emerging science regarding pulmonary hypertension due to left heartdisease. Contributing to the engaging discussion were James Fang, MD, University of Utah School of Medicine; Barry Borlaug,MD, Mayo Clinic, Rochester, MN; and Srinivas Murali, MD, Allegheny Health Network, Pittsburgh, PA.

Dr De Marco: Thank you for joiningDr Shapiro and me for a roundtable dis-cussion to explore salient topics inpulmonary hypertension (PH) due to leftheart disease. As experienced thoughtleaders, your perspective on the majorissues and challenges we face in dealingwith this entity will be valuable to ourreaders. In recent years, there have beenmultiple review publications on thetopic. Recently, the Fifth World Sym-posium Task Force on PH and LeftHeart Disease published a proposal forthe hemodynamic definition, classifi-cation, and nomenclature for PH andleft heart disease. I would like to startthe discussion with you, Dr Fang, as youwere the primary author for a summarystatement on the topic published in theJournal of Heart and Lung Transplan-tation. What are your thoughts on thediastolic pulmonary gradient, the trans-pulmonary gradient, and pulmonaryvascular resistance (PVR) in the defi-nition for PH in left heart disease?Which hemodynamic parameter orparameters would you advocate utilizingin the hemodynamic definition and why?

Dr Fang: Thank you, Dr De Marco;that’s a great question. We traditionallyoften have used things like transpul-monary gradient and PVR, despite alltheir limitations, because of the nature ofthe methods in clinical practice of col-lecting those data. The issue of thediastolic gradient is an interesting one.The evidence to date has been somewhatcontroversial. There are studies thatsuggest that the diastolic gradient is areflection of pulmonary vascular disease.And other studies have not been able tofind that that correlates adequately withoutcomes. In terms of the best mea-surement to make, I still think that our

traditional ways of doing it are what wehave the largest evidence base for. Thisidea of mixed PH is an important issueto sort out, because we really don’tunderstand why people get mixed PH.That being said, I think work by BarryBorlaug and others, looking at com-pliance of the vascular bed, may in factbe a much stronger and better deter-minant of right ventricular (RV) vascularcoupling as we look into the future. AndI do think that these measurements canbe made clinically and then integratedinto the routine evaluation of patientswith secondary PH.

Dr De Marco: Would you like toprovide your perspective, Barry?

Dr Borlaug: Yes, I agree with every-thing Jim is saying. After the initial sortof embrace of the diastolic pressure gra-dient (DPG) as the way to go, therehave been a number of studies in heartfailure patients really questioning howuseful it is. And we’ve looked at this.We published a paper a couple of yearsago looking at different ways to definepulmonary vascular disease and left heartfailure. And at that time, DPG wasn’treally out there, so we didn’t eveninclude it, but it really didn’t predictoutcome. Whereas, as Jim mentioned,things like pulmonary artery (PA) com-pliance were the most robust. Whichmakes sense, because PA compliancestarts to fall off, even when the PVRabnormalities are pretty minor, becauseof the hyperbolic relationship betweenresistance and compliance. So I thinkthat compliance is probably going to bea better way to do it. And whether thatis from problems with the DPG itself orwhether that’s just more logistical issueswith getting a good DPG in terms of

where you’re assessing diastolic pressureand wedge pressure in the respiratorycycle, whip or ringing artifact on thecatheters, these are important sort ofdevil-in-the-detail issues that probablycontribute to why it’s not a real goodpredictor. So, I’m not enthusiastic aboutusing DPG to define pulmonary vas-cular disease in patients with heartfailure.

Dr De Marco: Agreed. More andmore data are coming forth that, in fact,the diastolic pulmonary gradient is notrelated to outcome. Although it makespathophysiologic sense, since the dia-stolic pulmonary pressure and, hence,the diastolic pulmonary gradient isindependent of stroke volume, reflectingabnormalities of the pulmonary vascu-lature itself not driven by cardiacoutput. However, it is ventricularfunction and cardiac output that is tiedto prognosis; therefore, the pulmonaryartery systolic pressure and the transpul-monary gradient, which are dependenton stroke volume, may be more pre-dictive of outcomes as is the PVR,which takes into account the cardiacoutput reflective of ventricular functionin the calculation.

So, Dr Murali, why is the presenceof PH in the setting of left heart diseaseimportant in clinical practice?

Dr Murali: Pulmonary hypertension,when it coexists with left heart disease,irrespective of the particular kind of leftheart disease—whether it is a muscledisease or if it’s a valve disease—is asso-ciated with a significantly highermorbidity and mortality. As we con-tinue to find novel ways to improvemorbidity and mortality in left heartdisease, we have to tackle the man-

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agement of PH, since it is such animportant driver of bad outcomes.

Dr De Marco: Thank you. So Brian,would you like to take it from here?

Dr Shapiro: You got it. So this one’sto Dr Borlaug. And the question is, howdoes one differentiate those patients withGroup 1 pulmonary arterial hypertension(PAH) from those patients with PHwith left heart disease secondary to heartfailure with preserved ejection fraction(HFpEF), based clinically, based onsymptoms and signs, as well as echocar-diography.

Dr Borlaug: The only way to really doit definitely obviously is with a catheter,because it’s a hemodynamic definition,based on the presence or absence of highleft heart filling pressures. But you canprobably get a very good sense clinically,as you suggest, Brian. The things youwould look for would be typical riskfactors that would be associated withGroup 2 HFpEF-related PH, whichwould be older people, so probably above65, at least 60, with common comor-bidities that we see in HFpEF, likesystemic hypertension, which is in thevast majority, along with other thingslike diabetes or metabolic syndrome,obesity, female sex, though of coursemany women also have Group 1 PH, sothe discrimination there probably isn’t asgood. In terms of ventricular function inechocardiography, typical things thatwe’d see in patients with HFpEF-relatedPH would be left atrial enlargement,concentric ventricular remodeling orhypertrophy, though that’s not necessary,of course—and echo Doppler estimatesindicative of high left heart filling pres-sures, though again those are veryimperfect measures. In studies that havelooked at this, they don’t seem to dis-criminate real well. But those are thethings that I would look for ahead oftime. And in people where you reallycan’t tell, obviously you need to do ahemodynamic assessment.

Dr Shapiro: Yes.

Dr De Marco: I have a question foryou, Barry. What’s the value of assessing

“notching” of the Doppler signal in theright ventricular outflow tract? Whatabout other novel parameters? Is there arole for that or are they too difficult toascertain on a regular echo?

Dr Borlaug: That’s a great, great point,Teresa. You know, Paul Forfia’s grouphas published a number of papers onthis. I think in the right hands, ingroups that have a lot of expertise, itseems to be a pretty good indicator.People with a lot of pulmonary vasculardisease get this big reflected wave, whichdecelerates flow or causes this notch. Inour hands, we don’t tend to see it quiteas often, but I can tell you sort of anec-dotally. I haven’t looked at it reallysystematically in our reports, but I thinkthe people that we do tend to see it inmore are the people with really moreadvanced Group 1 PH or maybe chronicthromboembolic PH. We don’t tend tosee it as often in patients with left heartdisease-related PH. Whether that’s justthat they don’t have such profound pul-monary vascular disease or not, I don’tknow. I think if you see it, that’s veryuseful. I think if you don’t see it, thequestion then is: is it an issue with thequality of the echo or the severity of thepulmonary vascular disease, or somethingelse?

Dr De Marco: And do you differen-tiate between a midsystolic notch versusa late systolic notch? Have you foundthat useful in clinical practice?

Dr Borlaug: I have not. In my practice,which is mostly heart failure patients,not non-heart failure-related PH, I havenot found it to be a real helpful thing tolook for.

Dr Shapiro: So Barry, if there are oneor two things that you would look for onthe echo that would help convince youmore it was HFpEF, what would yousay would be your most reliable findings?

Dr Borlaug: I think the presence of leftatrial enlargement would be very helpful.I think that if there is profound diastolicdysfunction, that would be helpful. So ifthe ratio of transmitral flow to tissueDoppler early diastolic velocity, or the

so-called E/E prime ratio, is reallyhigh—greater than 15 or 20—thatwould be helpful. If there is really pro-found abnormal mitral filling pattern,you know, a restrictive or at least Group2 type pattern there, I think those wouldalso be helpful. The old thinking used tobe that you almost had to have con-centric hypertrophy or at least concentricremodeling, which we would define byan increase in wall thickness relative toend diastolic dimension. We see a lot ofpeople these days with HFpEF that havenormal geometry. So I’m not sure thatthat is as useful as we used to think itwas. I think the indicators of either highleft heart filling pressures at the time ofthe study, namely the Doppler and tissueDoppler parameters, and then themarkers of more chronic, sustained ele-vation of left heart pressures, like leftatrial enlargement, would probably bethe most useful.

Dr Shapiro: I know a lot of programsare also starting to do these exercise echohemodynamics, where you get exercisepulmonary pressures and exercise E/Eprime, suggestive of increased fillingpressures. Would you trust those or doyou rely on those, or how do you findthose fit in your clinical practice?

Dr Borlaug: I don’t trust them a greatdeal. I mean, the Pearson R value forE/E prime versus directly measuredwedge pressure usually runs in the rangeof 0.4 to 0.5. So there’s a lot of scatter.We’ve looked at this. We have unpub-lished data from a very large populationof patients that had simultaneous assess-ments. And they’re definitely correlatedwith one another, but not really strong.In particular, the change in E to Eprime is not a very robust indicator ofthe change in wedge pressure. So whatwe typically see, for example, in HFpEFor heart failure with reduced ejectionfraction (HFrEF) patients is the wedgepressures going from maybe 17 to 35.And the E/E prime is maybe going from14 to 15 or something like that. Sothere’s not this nice linear relationshipbetween the two. And I don’t have a lotof confidence in that personally. There’sa number of studies now. I think one inCirculation Heart Failure recently sup-

106 Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

ports the problems with E/E primeexercise as an indicator. The PA systolicpressure, if you can get a good Dopplerenvelope, I think is good. An old studyfrom years back indicated that when theydid it with agitative saline, that doesappear to help and gets you a little bitbetter signal, but it makes it a little bitmore of a pain to do. In our study, againthis is unpublished, we were able to geta PA systolic pressure estimate duringexercise about 50% of the time. So notgreat, but we got one about 50% of thetime. And in that case, we saw a verygood correlation with invasively mea-sured PA pressures. The correlationweakens with exercise because your PApressure estimate obviously is based onthe tricuspid regurgitation (TR) velocity,which is telling you the gradient betweenthe RV and the right atrium (RA). Weoften make this assumption that the RApressure is just 5 or 10 in everybody. Butin reality, in heart failure patients withexercise, we see RA pressures that varyfrom 0 to 50 or 60 mm Hg. So duringthe exercise, we can substantially under-estimate the true PA systolic pressure,even if you’re able to get a goodenvelope. Now, if the velocity is high, atleast you know that it’s probably verysignificant. You just have to keep inmind that you might be underestimatingit. And if you don’t have a good signal,you’re still kind of left wondering.

Dr Borlaug: One more point I wouldmake on that. And I don’t mean tocome out anti-echo. It’s certainly a veryuseful test. But as a person whosepractice is largely doing invasive exercisetests, a lot of the referrals I get arepeople that already had a noninvasiveand sort of echo exercise test that endedup being kind of abnormal or equivocal.And then you just sort of wonder, howoften they should have just been referreddirectly to the cath lab in the first placeto save a little bit of money. Of course,it’s a referral population, so that mightbe a little biased.

Dr Shapiro: I tend to agree with youon the exercise echoes. Interpreting theE or the TR envelope can be so difficult,particularly with the scatter that you geton the TR signal and so forth, that can

make it very difficult to get an accuratemeasurement.

Dr Murali: I agree with both yourcomments on that. You know, I thinkwhen you ask the question, what is thebest way to recognize early PH relatedto left heart disease in a communitysetting, I think an exercise echo wouldnot be the test of choice.

Dr De Marco: So with that regard,how would you differentiate PAH fromPH with left heart disease in the settingof HFpEF based on invasive hemody-namics? Do you have a set invasiveprotocol, Srinivas, that you can rec-ommend to us?

Dr Murali: Well, again, I think unfor-tunately, this is one of the gaps in ourknowledge at this point in time. Clearly,there is a dire need to have a stan-dardized protocol in making thisassessment, and different institutions anddifferent investigators have adopted pro-tocols that they find and that they feel ismost appropriate. In our institution, wedo have an exercise hemodynamic labo-ratory, where we are able to do supinebicycle exercise, with the catheters placedin the neck. And we typically follow aramp protocol, increasing workload by10 every minute. We certainly measurePA pressures and around the time thepatient gets to peak exercise, we wouldquickly measure the wedge pressures, aswell, and do a mixed venous oxygen sat-uration and do thermodilution cardiacoutputs at that setting. We are notequipped in our laboratory to measureoxygen consumption simultaneously,which some laboratories are able to do aVO2 assessment, as well, which I thinkis extremely useful.

Dr De Marco: What do you do, Barry?

Dr Borlaug: So we do both supine andupright exercise. We tend to do moresupine because it’s just easier, it’s morefeasible. It’s a little trickier to get cath-eters in, have everything zeroed at thephlebostatic access and then get themback up again, especially in older people,and get them onto the upright bike. Butwe can certainly do both. So what we’ll

do is get access in the radial artery andin the jugular. We’ll put a 9-Frenchsheath in the neck, so we can measurethe right atrial pressure throughout thecase. And I think that’s very important,as well. Then we put a balloon wedgecatheter to get samples and high fidelitypressure data at rest and during exercise.We do expired gas analysis during thetest and, you know, there is a bit moreexpense there. There is a bit moretraining. There is calibration needed ona daily basis. But we find it to beextremely useful, because I think mostpeople would agree that direct Fickoutputs to measure cardiac output at restand exercise would be considered thegold standard. If you look at how muchthe oxygen consumption goes up duringexercise, you can accurately say whetherthe cardiac output reserve was appro-priate or not. That’s because it’s wellknown in humans that for every 1 mLincrease in oxygen consumption, thereshould be a 6 mL increase in cardiacoutput, if the heart is doing its job, tomeet the body’s metabolic needs. So inthese PAH patients, we can see if theyhave high filling pressures obviously, butthis really gives us a good sense for theadequacy of their cardiac output reserve,which is very often abnormal in patientswith PH and left heart disease. Havingthe right heart pressures, their RApressure and the wedge pressure or thePA pressure together is useful, becausesometimes you see these people wherethe 2 go up in tandem and they almostequalize. And while not well-studied,that suggests that those people arehaving more pericardial restraint andthey might have a somewhat differentkind of disease compared to somebodywhose wedge pressure goes up to 35 buttheir RA pressure stays at 10. So again,that’s not well-studied, but we think thatthat’s probably useful to understand that.

Dr Shapiro: What do you do forvolume loading and things of that naturein the cath lab or how often does onehave to perform that?

Dr Borlaug: We do volume loading.We published a paper earlier in 2015where we compared volume loading andexercise in the same patients. They did

107Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

exercise first; everything came back torecovery. And then they got a veryaggressive volume load, 10 cc/kg, wideopen, over 5 minutes. So it’s about 150 cca minute, prewarmed so we don’t droptheir core temperature. And we see thatfilling pressures go up. But the increase inheart failure patients with saline is notnearly what we see with exercise. And, infact, it’s not statistically different fromwhat we see in normal people, in whomalso it’s not uncommon to have anincrease in wedge pressure above 15. Sothe saline loading, it’s better thannothing, but it’s not as sensitive or spe-cific as exercise. Another group fromVanderbilt published a paper where theirpractice has just been to give 500 ccmuch slower, I think over 10 minutes,and they do see a number of people thathad an elevation in wedge pressure above15 mL. Again, as I mentioned, we do seethis not uncommonly in some of thenormal people, maybe 20% of the time.So I think that there are some issuesthere with the specificity of that finding.

Dr Shapiro: I would have to believethat nationally and internationally, youknow, the rate of a program having theability to exercise, do exercise-invasivehemodynamics must be low. There maybe a number out there, I don’t know,but I would expect it to be low. But forthose programs or those practices out inthe community that, you know, want tomake this diagnosis invasively, but onlyhave the ability to do baseline-typehemodynamics, is that accurate? Is that agood way to go? Or what could they bedoing to enhance that?

Dr Borlaug: Well, I think saline isbetter than nothing. I mean, any sort ofprovocative maneuver, any sort of stress,is going to help to bring out abnormal-ities. So I still think there’s value todoing it. I think that if the wedgepressure goes above—probably above 18with the saline load—that would bepretty good evidence that they probablydo have significant left ventricular (LV)diastolic dysfunction. It’s just not quiteas good as what we see with exercise.

Dr Borlaug: But it’s better thannothing.

Dr Shapiro: How about simpleweights, if they wanted to do curls orwhatever kind of exercise in the cath lab;would that be helpful?

Dr Borlaug: You can do it. Theproblem is, a lot of people when they dosort of these butterflies or whatever typeof weightlifting that is, they involuntarilydo a Valsalva maneuver, which thenincreases intrathoracic pressure. So thenbasically all pressures are going up, evenin the absence of a true change in dis-tending intracardiac pressures. So you canget this false-positive because they’re sortof bearing down as they’re doing the lift.

Dr De Marco: Or maybe the bestapproach is just to go ahead and referthem to a specialized center, which cando the study appropriately.

Dr Murali: Yes, that’s true, Teresa. ButI think saline loading is something thatcan be done in the community. I agree.We use 500 cc over 5 minutes. If youcan do that, a rise in wedge pressure togreater than 18 will have a fairly smallpercentage of risk of being a false-positive result. I think that’s a goodthing, which can easily be done in acommunity setting. I agree with the armexercise, using light weights or salinebags or anything like that almost alwaysresults in the elevation of all pressures.

Dr De Marco: So I have a question forSrinivas. What is the role of vasoreac-tivity testing in WHO Group 1 versusWHO Group 2 PH? What agents doyou use? What are you looking for?What is the purpose of the testinginduced in these 2 clinical scenarios?

Dr Murali: So vasoreactivity testing inWHO Group 1 is recommended for thesubgroup of patients who have idiopathicPAH, where a vasoresponder status isassociated with markedly better short-and long-term clinical outcomes. Andnot to mention the data that support theuse of a less expensive calcium channelblocker treatment strategy for thosepatients who are vasoresponsive. Its rolein other forms of WHO Group 1 PAHis less clear and less well-defined and notwidely clinically applied. As far as

WHO Group 2 patients are concerned,I think the only scenario when vasore-activity is being done at this time iswhen you are evaluating patients forlisting for cardiac transplantation. Inthose patients with HFrEFs who havea very high pulmonary artery pressure,very wide transpulmonary gradient,usually greater than 15, and high PVRs,you want to do vasoreactivity testing todetermine if they would be suitable forlisting for transplant.

Dr De Marco: And what agents doyou use in the various scenarios? Forexample, with WHO Group 1 or WHOGroup 2?

Dr Murali: Our institution uses inhalednitric oxide. So our protocol goes from10 parts per million, all the way to 40parts per million, for both scenarios, forboth groups.

Dr De Marco: Even for patients withPAH and left heart disease? Have yourun into elevations in wedges and pul-monary edema in the WHO Group 2?

Dr Murali: We haven’t quite gotteninto pulmonary edema, but we have seenelevations in wedge pressure in WHOGroup 2 patients. So that’s one of thethings to keep in mind when you testthem. But it is quite valuable. The otheragent—which is not an acute vasoreac-tivity testing agent—we have used insome patients—especially if their cardiacindices are low, is to start them on mil-rinone infusion and then bring themback to the cath lab after a few days ofmilrinone therapy to see if the numbershave improved.

Dr De Marco: And Jim, what do youdo in these scenarios for WHO Group2? What’s your protocol?

Dr Fang: We do also use inhaled nitricoxide. Probably most commonly, we useNipride, if the systemic vascular resis-tance (SVR) is elevated. And we titratethe Nipride to potentially hypotension orjust short of that. We do know patientswho get very hypotensive from Nipridefrom the old Stanford experience don’tdo well. Secondly, if the SVR is low and

108 Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

the PVR is high, we will sometimes justtry nitrates. And then, like Srinivas, wealso are a big fan of using milrinone. Weuse the protocol of the bolus of mil-rinone, 50 mccs per kilo over a minuteor two. You see the peak effect some-where between 5 and 15 minutes. Thisprimarily lowers the PVR by increasingthe output, at least from the calculatedpoint of view.

Dr De Marco: And for both of you,what do you feel are the important con-siderations relevant to PAH and leftheart disease, in the context of hearttransplantation and left ventricular assistdevice (LVAD) implantation? So youwant to start, Srinivas?

Dr Murali: I think transplantationcriteria are a little bit stricter. Wewould, in our program, have certainlywanted to see the transpulmonary gra-dient be less than 12 and thepulmonary vascular distance to be asclose to 3 Wood units as possible beforethey are listed for transplantation. Asfar as LVAD is concerned, it’s a slightlydifferent approach. I think that we havegenerally not excluded patients for con-sideration for LVAD implantation onthe basis of transpulmonary gradientand/or PVR. It’s been our experiencethat in many of those patients with thecurrently used LVADs in clinicalpractice, both the HeartMate II axialflow pump, as well as the HVAD cen-trifugal pump, we have been able tounload the left ventricle with improve-ments in hemodynamics, as it relates topulmonary pressures, transpulmonarygradient, and PVR over a variableperiod of time. So for transplant, wewant to see the numbers come downbefore re-enlisting them. But forLVADs, we would proceed with theLVAD, as long as we feel comfortablewith respect to the risk of right heartfailure postoperatively and then followtheir hemodynamics on LVAD andwait until they improve to the levels Ialluded to before listing for transplant.

Dr De Marco: I agree. In fact, we’reusing VADs at our institution, againprovided the RV function is in a rea-sonable range, as a bridge to transplant.

And over time, the PVR markedlyimproves in virtually all of these patientsand then they do become transplant can-didates. And oftentimes, we may, inaddition, add phosphodiesterase inhib-itors to those patients where we haven’tattained a PVR that would allow themto go to transplant. So these are 2 strat-egies that we’ve employed. What aboutyou, Jim?

Dr Fang: Well, I would concur andecho everything that both you andSrinivas have said. From a pathophysio-logic standpoint, I think a great exampleof how they’re really 2 componentsphysiologically to the elevation in PVRand the PH: one, of course, is a dynamiccomponent that we tend to try to affectacutely with vasodilators, diuretics, etc.And, of course, there is the more ana-tomic part of the equation that obviouslyrequires a, for lack of a better word(laughs), putting down the rage of acti-vation, so you can get the positiveremodeling that you want to see in thepulmonary circulation. And I think theVADs help to provide that.

Dr Shapiro: Absolutely. I think, Barry,we were going to switch gears a little bitto treatments. In terms of the comor-bidities, what are the most importantcomorbidities that one looks for in atypical patient with HFpEF, PH withleft heart disease? And, in our expe-rience, what are the ones that are mostsuccessfully treated and make a dif-ference in a positive outcome?

Dr Borlaug: Well, I’m afraid I don’thave real good experience versus realpositive outcomes. It’s such a challengingdisease. I mean, I think that the peoplewith PH and HFpEF in general are justthe people with more advanced HFpEF.So there are some people that have highfilling pressures and PH that’s justrestricted to exercise. These people areprofoundly limited. They have very bad,lifestyle-limiting symptoms. I mean,many of them are crying literally in theoffice. They are miserable. But they’renot getting admitted for pulmonaryedema or peripheral edema; they’re notgoing into the hospital. It’s more lifestylechanges. The people with more

advanced disease who have high fillingpressures at rest, these are the peoplethat tend to have more PH. And we’vestarted to look at what distinguishesthese people. It’s probably more pro-longed heart failure, more comorbidities,so they tend to have more hypertension,more diabetes and metabolic syndrome,greater age, and worse kidney function,which is probably not surprising. Whenthe kidneys are not able to excrete thesolute anymore, that seems to acceleratethe progression. You know, in terms ofmanaging the comorbidities, we oftenlook at good blood pressure control,weight loss, treating sleep apnea: ofcourse you’re going to do all this. Theevidence that that is going to lead toclinically meaningful improvements intheir heart failure is slim and none. Wedo have some data now on single-centerretrospective data from Mayo that wepublished last year, looking at coronarydisease as a comorbidity in HFpEF,regardless of the presence or absence ofPAH. And the patients with coronarydisease have worse outcomes. And revas-cularization was associated with betteroutcomes. We don’t know what that’sdoing in terms of the hemodynamics andthe filling pressures and the pulmonaryartery pressures, but that’s one comor-bidity that in these, at least in HFpEFpatients with PAH, I have a very lowthreshold to look for.

Dr Shapiro: So provided that all thecomorbidities are being addressed andyou’ve got a patient who is in your officewith severe HFpEF and secondaryPAH, what are your favorite go-to bothpharmacologic and nonpharmacologictreatments that have been most suc-cessful for you?

Dr Borlaug: We said for years thatthere’s “no evidence for diuretics in heartfailure.” But, of course, we’ve alwaysknown that’s not the case. And nowwith the evidence from the Championstudy of the PA pressure sensor device,we know that when you manage peoplewith heart failure based on their hemo-dynamics and modify their diuretics, thatyou can reduce hospitalizations. Andthat’s been shown even stronger inHFpEF, in another analysis from that

109Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

trial. So yeah, good old loop diuretics Ithink are the only thing that I’m con-vinced really works. People talk aboutnitrates. We will have data onthat soon. There was a large, or prettygood-sized, phase 2 trial of isosorbidemononitrate, which has now been com-pleted and will be reported in HFpEF.We know from the RELAX trial thatPDE-5 inhibitors were not effective,though there was a small single-centerstudy that showed benefits in a veryatypical HFpEF population that hadmuch more advanced PH. Beta-blockers, not good evidence. Same thingwith calcium channel blockers. Andthen other people are using off-labelthings, like ranolazine and such, butthere’s really no good data to supportany of those. So, for me, it’s diuretics. Ilook forward to what the others think.

Dr De Marco: Okay. I have one finalquestion for Jim. From your perspective,what are the most important diagnosticand treatment gaps that remain in theknowledge base for PAH due to left

heart disease? And what does the futurehold?

Dr Fang: Well, great question. I thinkone of the basic knowledge gaps that isstill one of the elephants in the room iswhether or not it’s a disease marker or arisk factor. It does fall out often in mul-tivariate analyses as an independentpredictor, which would suggest that it’s afactor. But one of the unexplored areas ishow much of that is really just a sur-rogate for time. Time in most heartfailure studies is poorly controlled for,primarily because the onset of the diseaseis very difficult to quantify or to haveany precision about. If we think aboutthe pathophysiology of PH, clearly theupregulation of growth factors and otherfactors, like endothelium that lead topulmonary vascular remodeling, aretime-dependent issues. So I think thatstill remains a very important issue thatreally outlines a whole field. Because, infact, if it’s simply a risk marker, thenwe need to be a little bit more proximalin our targeting of PH. Number 2 is

that if we agree that it’s a separate issueunto itself and not simply an unrecog-nized surrogate of something else, theissue is to find drugs that are selectivefor the pulmonary bed or methods ofdelivery that are selective for the pul-monary bed. One of the things thatcomplicate the treatment of pulmonaryvascular disease, of course, is trying tofind specificity for that organ bedwithout producing systemic and off-target effects. So that’s sort of verybrief, but I think the two mostimportant issues.

Dr Shapiro: On behalf of Dr DeMarco and myself, I really want to thankDrs Fang, Murali, and Borlaug for thisexcellent discussion on PH and left heartdisease. I am confident that your insightswill be a huge asset to those who carefor patients with this common disease.And once again, I want to thank you somuch for your help.

Dr De Marco: Thank you, everyone.

110 Advances in Pulmonary Hypertension Volume 14, Number 2; 2015

median improvement in 6MWD with Tyvaso at week 12 (P<0.001)Background

therapy

20 m peak*

median improvement in 6MWD with Tyvaso at week 12

14 m trough*

Tyvaso improved 6MWD at week 121,2

For the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability.

WANT TO IMPROVE YOUR PAH PATIENTS’ EXERCISE ABILITY? TYVASO MAY HELP.

Consider adding Tyvaso, an inhaled prostacyclin analogue, studied solely as add-onto oral background monotherapy (sildena� l or bosentan)

6MWD=6-minute walk distance. * Peak measured 10-60 minutes after dosing at week 12; trough measured ≥4 hours after dosing at week 12.

Study Design: TRIUMPH I was a 12-week, randomized, double-blind, placebo-controlled, multicenter study of patients (N=235) with PAH who were receiving a stable dose of bosentan or sildena� l for 3 months before study initiation. Patients were administered either placebo or Tyvaso in 4 daily treatment sessions with a target dose of 9 breaths (54 mcg) over the course of the 12-week study.

• Tyvaso is intended for oral inhalation only. Tyvaso is approved for use only with the Tyvaso Inhalation System

• The safety and e� cacy of Tyvaso have not been established in patients with signi� cant underlying lung disease (such as asthma or chronic obstructive pulmonary disease) and in patients under 18 years of age. Patients with acute pulmonary infections should be carefully monitored to detect any worsening of lung disease and loss of drug e� ect

• Tyvaso may increase the risk of bleeding, particularly in patients receiving anticoagulants

• In patients with low systemic arterial pressure, Tyvaso may cause symptomatic hypotension. The concomitant use of Tyvaso with diuretics, antihypertensives, or other vasodilators may increase the risk of symptomatic hypotension

• Hepatic or renal insu� ciency may increase exposure to Tyvaso and decrease tolerability. Tyvaso dosage adjustments may be necessary if inhibitors of CYP2C8, such as gem� brozil, or inducers of CYP2C8, such as rifampin, are added or withdrawn

• There are no adequate and well-controlled studies with Tyvaso in pregnant women. It is not known whether treprostinil is excreted in human milk

• The most common adverse events seen with Tyvaso in ≥4% of PAH patients and more than 3% greater than placebo in the placebo-controlled clinical study were cough (54% vs 29%), headache (41% vs 23%), throat irritation/pharyngolaryngeal pain (25% vs 14%), nausea (19% vs 11%), � ushing (15% vs <1%), and syncope (6% vs <1%)6MWD=6-minute walk distance; NYHA FC=New York Heart Association Functional Class; TRIUMPH=TReprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension; WHO=World Health Organization.References: 1. Tyvaso [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2014. 2. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010;55(18):1915-1922.

Please see brief summary of Full Prescribing Information on following page. For more information, please see Full Prescribing Information, Patient Package Insert, and Tyvaso Inhalation System Instructions for Use manual. These items are available at www.tyvaso.com. For additional information about Tyvaso, visit www.tyvaso.com or call 1-877-UNITHER (1-877-864-8437).

IMPORTANT SAFETY INFORMATION FOR TYVASO

INDICATIONTyvaso is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) toimprove exercise ability. Studies establishing e� ectiveness included predominately patients with NYHA Functional Class IIIsymptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%).The e� ects diminish over the minimum recommended dosing interval of 4 hours; treatment timing can be adjusted forplanned activities.While there are long-term data on use of treprostinil by other routes of administration, nearly all controlled clinical experience with inhaled treprostinil has been on a background of bosentan (an endothelin receptor antagonist) or sildena� l (a phosphodiesterasetype 5 inhibitor). The controlled clinical experience was limited to 12 weeks in duration.

Tyvaso is a registered trademark of United Therapeutics Corporation.© 2015 United Therapeutics Corporation. All rights reserved. US/TYV/MAY15/331a

BRIEF SUMMARY

The following is a brief summary of the full prescribing information for TYVASO® (treprostinil) Inhalation Solution. Please review the full prescribing information prior to prescribing TYVASO.

INDICATIONS AND USAGE

TYVASO is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%). The effects diminish over the minimum recommended dosing interval of 4 hours; treatment timing can be adjusted for planned activities. While there are long-term data on use of treprostinil by other routes of administration, nearly all controlled clinical experience with inhaled treprostinil has been on a background of bosentan (an endothelin receptor antagonist) or sildenafil (a phosphodiesterase type 5 inhibitor). The controlled clinical experience was limited to 12 weeks in duration.

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

Patients with Pulmonary Disease or Pulmonary Infections–The safety and efficacy of TYVASO have not been established in patients with significant underlying lung disease (e.g., asthma or chronic obstructive pulmonary disease). Patients with acute pulmonary infections should be carefully monitored to detect any worsening of lung disease and loss of drug effect.

Risk of Symptomatic Hypotension– Treprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treatment with TYVASO may produce symptomatic hypotension. Patients with Hepatic or Renal Insufficiency–Titrate slowly in patients with hepatic or renal insufficiency, because such patients will likely be exposed to greater systemic concentrations relative to patients with normal hepatic or renal function. Risk of Bleeding–Since TYVASO inhibits platelet aggregation, there may be an increased risk of bleeding, particularly among patients receiving anticoagulant therapy. Effect of Other Drugs on Treprostinil–Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) may increase exposure (both Cmax and AUC) to treprostinil. Co-administration of a CYP2C8 enzyme inducer (e.g., rifampin) may decrease exposure to treprostinil. Increased exposure is likely to increase adverse events associated with treprostinil administration, whereas decreased exposure is likely to reduce clinical effectiveness.

ADVERSE REACTIONS

The following potential adverse reactions are described in Warnings and Precautions:

• Decrease in systemic blood pressure • Bleeding

Adverse Reactions Identified in Clinical Trials–Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a 12-week placebo-controlled study (TRIUMPH I) of 235 patients with PAH (WHO Group 1 and nearly all NYHA Functional Class III), the most commonly reported adverse reactions to TYVASO included: cough and throat irritation; headache, gastrointestinal effects, muscle, jaw or bone pain, flushing and syncope. Table 1 lists the adverse reactions that occurred at a rate of at least 4% and were more frequent in patients treated with TYVASO than with placebo.

The safety of TYVASO was also studied in a long-term, open-label extension study in which 206 patients were dosed for a mean duration of 2.3 years with a maximum exposure of 5.4 years. Eighty-nine (89%) percent of patients achieved the target dose of nine breaths, four times daily. Forty-two (42%) percent achieved a dose of 12 breaths four times daily. The adverse events during this chronic dosing study were qualitatively similar to those observed in the 12-week placebo controlled trial. Adverse Events Associated with Route of Administration–Adverse events in the treated group during the double-blind and open-label phase reflecting irritation to the respiratory tract included: cough, throat irritation, pharyngeal pain, epistaxis, hemoptysis and wheezing. Serious adverse events during the open-label portion of the study included pneumonia in 15 subjects. There were three serious episodes of hemoptysis (one fatal) noted during the open-label experience. Adverse Reactions Identified in Post-Marketing Experience–The following adverse reaction has been identified during the postapproval use of Tyvaso. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure: Angioedema

DRUG INTERACTIONS

Pharmacokinetic/pharmacodynamic interaction studies have not been conducted with inhaled treprostinil (TYVASO); however, some of such studies have been conducted with orally (treprostinil diolamine) and subcutaneously administered treprostinil (Remodulin®).Pharmacodynamics–Antihypertensive Agents or Other Vasodilators– Concomitant administration of TYVASO with diuretics, antihypertensive agents or other vasodilators may increase the risk of symptomatic hypotension. Anticoagulants–Since treprostinil inhibits platelet aggregation, there may be an increased risk of bleeding, particularly among patients receiving anticoagulants. Pharmacokinetics–Bosentan– In a human pharmacokinetic study conducted with bosentan (250 mg/day) and an oral formulation of treprostinil (treprostinil diolamine), no pharmacokinetic interactions between treprostinil and bosentan were observed. Sildenafil– In a human pharmacokinetic study conducted with sildenafil (60 mg/day) and an oral formulation of treprostinil (treprostinil diolamine), no pharmacokinetic interactions between treprostinil and sildenafil were observed. Effect of Cytochrome P450 Inhibitors and Inducers– In vitro studies of human hepatic microsomes showed that treprostinil does not inhibit cytochrome P450 (CYP) isoenzymes CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A. Additionally, treprostinil does not induce cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A. Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diolamine) indicated that co-administration of the cytochrome P450 (CYP) 2C8 enzyme inhibitor gemfibrozil increases exposure (both Cmax and AUC) to treprostinil. Co-administration of the CYP2C8 enzyme inducer rifampin decreases exposure to treprostinil. It is unclear if the safety and efficacy of treprostinil by the inhalation route are altered by inhibitors or inducers of CYP2C8. Effect of Other Drugs on Treprostinil–Drug interaction studies have been carried out with treprostinil (oral or subcutaneous) co-administered with acetaminophen (4 g/day), warfarin (25 mg/day), and fluconazole (200 mg/day), respectively in healthy volunteers. These studies did not show a clinically significant effect on the pharmacokinetics of treprostinil.

Treprostinil does not affect the pharmacokinetics or pharmacodynamics of warfarin. The pharmacokinetics of R- and S-warfarin and the INR in healthy subjects given a single 25 mg dose of warfarin were unaffected by continuous subcutaneous infusion of treprostinil at an infusion rate of 10 ng/kg/min.

USE IN SPECIFIC POPULATIONS

Pregnancy—Pregnancy Category B–There are no adequate and well controlled studies with TYVASO in pregnant women. Animal reproduction studies have not been conducted with treprostinil administered by the inhalation route. However, studies in pregnant rabbits using continuous subcutaneous (sc) infusions of treprostinil sodium at infusion rates higher than the recommended human sc infusion rate resulted in an increased incidence of fetal skeletal variations associated with maternal toxicity. Animal reproduction studies are not always predictive of human response.Labor and Delivery–No treprostinil treatment-related effects on labor and delivery were seen in animal studies. The effect of treprostinil on labor and delivery in humans is unknown. Nursing Mothers–It is not known whether treprostinil is excreted in human milk. Pediatric Use–Safety and effectiveness in pediatric patients have not been established. Clinical studies of TYVASO did not include patients younger than 18 years to determine whether they respond differently from older patients. Geriatric Use–Clinical studies of TYVASO did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of hepatic, renal, or cardiac dysfunction, and of concomitant diseases or other drug therapy. Patients with Hepatic Insufficiency–Plasma clearance of treprostinil, delivered subcutaneously, was reduced up to 80% in subjects with mild-to-moderate hepatic insufficiency. Uptitrate slowly when treating patients with hepatic insufficiency because of the risk of an increase in systemic exposure which may lead to an increase in dose-dependent adverse effects. Treprostinil has not been studied in patients with severe hepatic insufficiency. Patients with Renal Insufficiency–No studies have been performed in patients with renal insufficiency. Since treprostinil and its metabolites are excreted mainly through the urinary route, patients with renal insufficiency may have decreased clearance of the drug and its metabolites and consequently, dose-related adverse outcomes may be more frequent.

OVERDOSAGE

In general, symptoms of overdose with TYVASO include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Provide general supportive care until the symptoms of overdose have resolved.

Tyvaso manufactured for: United Therapeutics Corporation Research Triangle Park, NC 27709

Rx only February 2015

www.tyvaso.com

Table 1: Adverse Events in ≥4% of PAH Patients Receiving TYVASO and More Frequent* than Placebo

Adverse Event Treatment n (%)

TYVASO n = 115

Placebo n = 120

Cough 62 (54) 35 (29)

Headache 47 (41) 27 (23)

Throat Irritation/ Pharyngolaryngeal Pain 29 (25) 17 (14)

Nausea 22 (19) 13 (11)

Flushing 17 (15) 1 (<1)

Syncope 7 (6) 1 (<1)

*More than 3% greater than placebo

PHA Support Groups

Help your pulmonary hypertension patients gain the knowledge, confidence and hope

vital to coping and managing their disease.

Let them know about their local PHA support group.

The Pulmonary Hypertension Association provides “medicine for the soul” in the form of patient support groups. PHA wants to work with you to put patients in touch with each other.

Find Your Local Groupwww.PHAssociation.org/FindASupportGroup

No Group?Web and phone support can help.Connect online:www.PHAssociation.org/Community

Toll-free Patient-to-Patient Support: 800-748-7274

Starting a support group has never been easier: From a how-to manual to phone support, PHA works with doctors, nurses and other medical professionals to help start successful groups.

For more information on support groups or to request PHA materials for your office, contact Debbie Drell at DebbieD@PHAssociation.org or 301-565-3004 x755.

awareness | education | support | advocacy | hope

PHA offers financial support for food provided at support group meetings. Through the Support Group Central Fund program, PHA support group leaders can secure refreshment and meal sponsorships

for their group meetings. For further details, email SupportGroups@PHAssociation.org

Important Safety InformationCONTRAINDICATIONS

Nitrates:

Hypersensitivity Reactions:

WARNINGS AND PRECAUTIONSCardiovascular:

Cardiovascular:

Cardiovascular:

Potential Drug Interactions:

Special Populations:

Potential Drug Interactions:

Vision/Hearing:

A diagnosis of pulmonary arterial hypertension (PAH)

CAN STOP A PATIENT IN THEIR TRACKSTake the fi rst step forward to a solid foundation with ADCIRCA® (tadalafi l), a fi rst-line therapy for PAH.

Prolonged Erection:

ADVERSE REACTIONSAdverse Reactions:

References: 1.2.

Circulation 3.

www.adcirca.com 1-877-UNITHER

Every Step Matters

†

US/ADC/JAN14/134a

ADCIRCA® (tadalafi l) is a phosphodiesterase 5 inhibitor (PDE-5i) indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability. Studies establishing eff ectiveness included predominately patients with NYHA Functional Class IIIII symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%).

For patients taking ADCIRCA in comparison to patients on placebo at 16 weeks, the average increase from baseline in 6-minute walk distance was 33 meters (108 feet) for all patients* and 44 meters (144 feet) for those on ADCIRCA monotherapy1,2

Clinically proven to reduce risk of clinical worsening vs placebo at 16 weeks1,2†

The recommended dose of ADCIRCA is 40 mg (two 20-mg tablets) taken once-daily, with or without food. Dividing the dose is not recommended

The only once-daily PDE-5 inhibitor for PAH1

The most common (reported by ≥ 13% of patients) treatment-emergent side eff ects of ADCIRCA (headache, myalgia, nasopharyngitis, fl ushing, and respiratory infection) were transient and mild to moderate in intensity1

$20 co-pay for eligible patients on commercial/private insurance plans‡

Help your patients move forward with ADCIRCA—one step at a time.

Please see Brief Summary of Full Prescribing Information on following page. Please see Full Prescribing Information and Patient Information available at www.adcirca.com, or call 1-800-545-5979.

ADCIRCA® (tadalafil) tabletsBRIEF SUMMARYThe following is a brief summary of the Full Prescribing Information on ADCIRCA (tadalafil). Please review the Full Prescribing Information prior to prescribing ADCIRCA.INDICATIONS AND USAGEPulmonary Arterial Hypertension: ADCIRCA is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%).CONTRAINDICATIONSConcomitant Organic Nitrates: Do not use ADCIRCA in patients who are using any form of organic nitrate, either regularly or intermittently. ADCIRCA potentiates the hypotensive effect of nitrates. This potentiation is thought to result from the combined effects of nitrates and ADCIRCA on the nitric oxide/cGMP pathway. Hypersensitivity Reactions: ADCIRCA is contraindicated in patients with a known serious hypersensitivity to tadalafil (ADCIRCA or CIALIS). Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis.WARNINGS AND PRECAUTIONSCardiovascular Effects: Discuss with patients the appropriate action to take in the event that they experience anginal chest pain requiring nitroglycerin following intake of ADCIRCA. At least 48 hours should elapse after the last dose of ADCIRCA before taking nitrates. If a patient has taken ADCIRCA within 48 hours, administer nitrates under close medical supervision with appropriate hemodynamic monitoring. Patients who experience anginal chest pain after taking ADCIRCA should seek immediate medical attention. PDE5 inhibitors, including tadalafil, have mild systemic vasodilatory properties that may result in transient decreases in blood pressure. Prior to prescribing ADCIRCA, carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. Patients with severely impaired autonomic control of blood pressure or with left ventricular outflow obstruction, (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) may be particularly sensitive to the actions of vasodilators, including PDE5 inhibitors. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of ADCIRCA to patients with veno-occlusive disease, administration of ADCIRCA to such patients is not recommended. Should signs of pulmonary edema occur when ADCIRCA is administered, the possibility of associated PVOD should be considered. There is a lack of data on safety and efficacy in the following groups who were specifically excluded from the PAH clinical trials:

disease

cardiomyopathy

dysfunction

uncontrolled hypertension

Use with Alpha Blockers and Antihypertensives — PDE5 inhibitors, including ADCIRCA, and alpha–adrenergic blocking agents are vasodilators with blood pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly, which may lead to symptomatic hypotension (e.g., fainting). Safety of combined use of PDE5 inhibitors and alpha blockers may be affected by other variables, including intravascular volume depletion and use of other antihypertensive drugs. Use with Alcohol — Both alcohol and tadalafil are mild vasodilators. When mild vasodilators are taken in combination, blood pressure-lowering effects are increased. Use with Potent CYP3A Inhibitors or Inducers:Co-administration of ADCIRCA in Patients on Ritonavir — In patients receiving ritonavir for at least one week, start ADCIRCA

individual tolerability. Co-administration of Ritonavir in Patients on ADCIRCA — Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one

week following the initiation of ritonavir, resume ADCIRCA at

individual tolerability. Other Potent Inhibitors of CYP3A — Tadalafil is metabolized predominantly by CYP3A in the liver. In patients taking potent inhibitors of CYP3A such as ketoconazole and itraconazole, avoid use of ADCIRCA. Potent Inducers of CYP3A — For patients chronically taking potent inducers of CYP3A, such as rifampin, avoid use of ADCIRCA. Use in Renal Impairment: In patients with mild or moderate renal impairment

In patients with severe renal impairment — Avoid use of ADCIRCA because of increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis. Use in Hepatic Impairment: In patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) — Because of limited clinical experience in patients with mild to moderate hepatic

In patients with severe hepatic cirrhosis (Child-Pugh Class C) — Patients with severe hepatic cirrhosis have not been studied. Avoid use of ADCIRCA. Visual Loss: Physicians should advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non–arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision that has been reported postmarketing in temporal association with the use of all PDE5 inhibitors. An observational study evaluated whether recent episodic use of PDE5 inhibitors, as a class, typical of erectile dysfunction treatment, was associated with acute onset of NAION. The results suggest an approximate 2-fold increase in the risk of NAION within 1 to 4 days of PDE5 inhibitor use. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors. Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended. Hearing Impairment: Physicians should advise patients to seek immediate medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including ADCIRCA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Combination with Other PDE5 Inhibitors: Tadalafil is also marketed as CIALIS. The safety and efficacy of taking ADCIRCA together with CIALIS or other PDE5 inhibitors have not been studied. Inform patients taking ADCIRCA not to take CIALIS or other PDE5 inhibitors.Prolonged Erection: There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. ADCIRCA should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease). Effects on Bleeding: PDE5 is found in platelets. When

not prolong bleeding time, relative to aspirin alone. ADCIRCA has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although ADCIRCA has not been shown to increase bleeding times in healthy subjects, use in patients with bleeding disorders or significant active peptic ulceration should be based upon a careful risk-benefit assessment.ADVERSE REACTIONSThe following serious adverse reactions are discussed elsewhere in the labeling:

Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Tadalafil was

worldwide. In trials of ADCIRCA, a total of 311 and 251

days, respectively. The overall rates of discontinuation because of an adverse event (AE) in the placebo-controlled trial were

discontinuation because of AEs, other than those related to

was 4% compared to 5% in placebo-treated patients. In the placebo-controlled study, the most common AEs were generally transient and mild to moderate in intensity. Table 1presents treatment-emergent adverse events reported by ≥

frequently than with placebo.TABLE 1: Treatment-Emergent Adverse Events Reported by ≥9% of Patients in ADCIRCA and More Frequent than Placebo by 2%

EVENT Placebo (%) ADCIRCA ADCIRCA (N=82) 20 mg (%) 40 mg (%) (N=82) (N=79)Headache 15 32 42

Nasopharyngitis 7 2 13Flushing 2 6 13Respiratory Tract Infection (Upper and Lower) 6 7 13Pain in Extremity 2 5 11

Nasal Congestion (Including sinus

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of tadalafil. These events have been chosen for inclusion either because of their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. The list does not include adverse events that are reported from clinical trials and that are listed elsewhere in this section. Cardiovascular and cerebrovascular — Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported postmarketing in temporal association with the use of tadalafil. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of tadalafil without sexual activity. Others were reported to have occurred hours to days after the use of tadalafil and sexual activity. It is not possible to determine whether these events are related directly to tadalafil, to sexual activity, to the patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors.Body as a whole — Hypersensitivity reactions including urticaria, Stevens–Johnson syndrome, and exfoliative dermatitis. Nervous — Migraine, seizure and seizure recurrence, and transient global amnesia. Ophthalmologic — Visual field defect, retinal vein occlusion, and retinal artery occlusion. Non–arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 inhibitors, including tadalafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to:

hypertension, coronary artery disease, hyperlipidemia, and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a

combination of these factors, or to other factors. Otologic — Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including tadalafil. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of tadalafil, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors. Urogenital — Priapism.DRUG INTERACTIONSPotential for Pharmacodynamic Interactions with are using any form of organic nitrate. In clinical pharmacology studies ADCIRCA potentiated the hypotensive effect of nitrates. In a patient who has taken ADCIRCA, where nitrate administration is deemed medically necessary in a life–threatening situation, at least 48 hours should elapse after the last dose of ADCIRCA before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring. Alpha-Blockers — PDE5 inhibitors, including ADCIRCA, and alpha–adrenergic blocking agents are both vasodilators with bloodpressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with coadministration of tadalafil with doxazosin, alfuzosin or tamsulosin. Antihypertensives — PDE5 inhibitors, including ADCIRCA, are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of tadalafil on the potentiation of the blood–pressure–lowering effects of selected antihypertensive medications (amlodipine, angiotensin II receptor blockers, bendroflumethiazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo. Alcohol — Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood pressure–lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with ADCIRCA can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood

did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations. Potential for Other Drugs to Affect ADCIRCA: Ritonavir — Ritonavir initially inhibits and later induces CYP3A, the enzyme involved in the metabolism of tadalafil. At steady state of ritonavir (about 1 week), the exposure to tadalafil is similar as in the absence of ritonavir.Other Potent Inhibitors of CYP3A — Tadalafil is metabolized predominantly by CYP3A in the liver. In patients taking potent inhibitors of CYP3A such as ketoconazole, and itraconazole, avoid use of ADCIRCA. Potent Inducers of CYP3A — For patients chronically taking potent inducers of CYP3A, such as rifampin, avoid use of ADCIRCA. Potential for ADCIRCA to Affect Other Drugs:

— Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance

theophylline, warfarin, midazolam, lovastatin, bosentan).

potentiate the increase in bleeding time caused by aspirin. P-lycoprotein (e.g., digoxin) — Coadministration of tadalafil

pharmacokinetics in healthy subjects.USE IN SPECIFIC POPULATIONSPregnancy: Pregnancy Category B — Animal reproduction studies in rats and mice revealed no evidence of fetal harm. There are, however, no adequate and well-controlled studies of tadalafil in pregnant women. Because animal reproduction studies are not always predictive of human response, tadalafil should be used during pregnancy only if clearly needed.Non–teratogenic effects — Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at unbound tadalafil exposures up to 7 times the maximum

organogenesis. In one of two perinatal/postnatal developmental studies in rats, postnatal pup survival decreased following maternal exposure to unbound tadalafil concentrations greater than 5 times the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 8 times the MRHD based on AUC. Surviving offspring had normal development and reproductive performance. Nursing Mothers: It is not known whether tadalafil is excreted into human milk. While tadalafil or some metabolite of tadalafil

was excreted into rat milk, drug levels in animal breast milk may not accurately predict levels of drug in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when ADCIRCA is administered to a nursing woman. Pediatric Use: Safety and effectiveness of ADCIRCA in pediatric patients have not been established.Geriatric Use: Of the total number of subjects in the clinical study of tadalafil for pulmonary arterial hypertension, 28 percent were 65 and over, while 8 percent were 75 and over. No overall differences in safety were observed between subjects over 65 years of age compared to younger subjects or those over 75 years of age. No dose adjustment is warranted based on age alone; however, a greater sensitivity to medications in some older individuals should be considered. Renal Impairment: For patients with mild or moderate renal

with severe renal impairment, avoid use of ADCIRCA because of increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis. Hepatic Impairment: Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class

Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied, thus avoid use of ADCIRCA in such patients.OVERDOSAGE

given to male patients with erectile dysfunction. Adverse reactions were similar to those seen at lower doses. Doses

pulmonary arterial hypertension. In cases of overdose, standard supportive measures should be adopted as needed. Hemodialysis contributes negligibly to tadalafil elimination.Marketed by: Lung Biotechnology Inc., a wholly-owned subsidiary of United Therapeutics CorporationRx only www.adcirca.com

ADCIRCA (package insert). Indianapolis, IN: Eli Lilly and

BS.HCP.KCGLUNGLLC-4-72.v2

Please see additional Important Safety Information, including Boxed Warning, throughout and Brief Summary of Prescribing Information at end of advertisement.

WARNING: EMBRYO-FETAL TOXICITYDo not administer Adempas (riociguat) tablets to a pregnant female because it may cause fetal harm.Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly duringtreatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception. For all female patients, Adempas is available only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program.

INDICATIONS• Adempas (riociguat) tablets are indicated for

the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class.

• Adempas is indicated for the treatment of adults with pulmonary arterial hypertension (PAH), (WHO Group 1), to improve exercise capacity, WHO functional class and to delay clinical worsening.*

Efficacy was shown in patients on Adempas monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominantly patients with WHO functional class II–III and etiologiesof idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%).

*Time to clinical worsening was a combined endpoint defined as death (all-cause mortality), heart/lung transplantation, atrial septostomy, hospitalization due to persistent worsening of pulmonary hypertension, start of new PAH-specific treatment, persistent decrease in 6MWD and persistent worsening of WHO functional class

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONSAdempas is contraindicated in:

• Pregnancy. Adempas may cause fetal harm when administered to a pregnant woman. Adempas was consistently shown to have teratogenic effects whenadministered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of thepotential hazard to the fetus

• Co-administration with nitrates or nitric oxide donors (such as amyl nitrite) in any form.

• Concomitant administration with specificphosphodiesterase-5 (PDE-5) inhibitors (such assildenafil, tadalafil, or vardenafil) or nonspecific PDE inhibitors (such as dipyridamole or theophylline).

WARNINGS AND PRECAUTIONSEmbryo-Fetal Toxicity. Adempas may cause fetal harm when administered during pregnancy and is contraindicatedfor use in women who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, advise use of acceptable contraception and obtain monthly pregnancy tests. For females, Adempas is only available through a restricted program under the Adempas REMS Program.

Adempas REMS Program. Females can only receive Adempas through the Adempas REMS Program, a restricted distribution program.Important requirements of the Adempas REMS program include the following: • Prescribers must be certified with the program by

enrolling and completing training. • All females, regardless of reproductive potential, must

enroll in the Adempas REMS Program prior to initiating Adempas. Male patients are not enrolled in the Adempas REMS Program.

Multiple patient types moving forward, one Adempas

Randomized, multicenter, placebo-controlled clinical study of443 adult PAH patients with predominantly WHO Functional Class II-III. The primary endpoint was change from baseline in 6MWD at 12 weeks.

Randomized, multicenter, placebo-controlled clinical study of 261 adult patients with persistent/recurrent CTEPH aftersurgery or who were inoperable. The primary endpoint waschange from baseline in 6MWD at 16 weeks.

In pulmonary arterial hypertension (PAH), (WHO Group 1)

In inoperable and persistent/recurrent chronic thromboembolic hypertension (CTEPH), (WHO Group 4)

improvement (mean) in 6MWD over placebo at Week 16 (95% CI: 25m-67m; p<0.0001)

improvement (mean) in 6-minute walk distance (6MWD) over placebo at Week 12 (95% Confidence Interval (CI): 20m-52m; p<0.0001)

36m 46m

• Female patients of reproductive potential must comply with the pregnancy testing and contraceptionrequirements.

• Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Adempas.

Further information, including a list of certified pharmacies, is available at www.AdempasREMS.com or 1-855-4ADEMPAS.

Hypotension. Adempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflowobstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP inhibitors. Consider a dose reduction if patient develops signs or symptoms of hypotension.

Bleeding. In the placebo-controlled clinical trials, serious bleeding occurred in 2.4% of patients taking Adempas compared to 0% of placebo patients. Serious hemoptysis occurred in 5 (1%) patients taking Adempas compared to 0 placebo patients, including one event with fatal outcome. Serious hemorrhagic events also included 2 patients with vaginal hemorrhage, 2 with catheter site hemorrhage, and 1 each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage.

Pulmonary Veno-Occlusive Disease. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of Adempas to such patients is not recommended. Should signs of pulmonary edema occur, the possibility of associated PVOD should be considered and if confirmed, discontinue treatment with Adempas.

MOST COMMON ADVERSE REACTIONS• The most common adverse reactions occurring

more frequently (≥3%) on Adempas than placebo were headache (27% vs 18%), dyspepsia/gastritis (21% vs.8%), dizziness (20% vs 13%), nausea (14% vs 11%), diarrhea (12% vs 8%), hypotension(10% vs 4%), vomiting (10% vs 7%), anemia (7% vs 2%), gastroesophageal reflux disease (5% vs 2%), and constipation (5% vs 1%).

• Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were: palpitations, nasal congestion, epistaxis, dysphagia, abdominal distension and peripheral edema.

For important risk and use information, please see the Brief Summary of the full Prescribing Information, including Boxed Warning, on the next page.

Bayer HealthCare LLC100 Bayer Boulevard, Whippany, NJ 07981 USA©2015 Bayer HealthCare Inc.PP-400-US-1451 January 2015

BAYER, the Bayer Cross, and Adempas are registered trademarksof Bayer.

††See what Adempas could do for your patients. VisitAdempas-US.com

WARNINGS AND PRECAUTIONS (continued)

PAH (WHO Group 1) CTEPH (WHO Group 4)

Treatment Naïve CombinationTherapy– ERA

CombinationTherapy– PCA

Inoperable Recurrent after Surgery

†Soluble Guanylate Cyclase

Stimulating

It means different things to different people.

ADEMPAS (riociguat) tablets, for oral useInitial U.S. Approval: 2013

BRIEF SUMMARY of PRESCRIBING INFORMATIONFor additional information, please see the full Prescribing Information at

www.adempas-us.com.WARNING: EMBRYO-FETAL TOXICITY

See full prescribing information for complete boxed warning• Do not administer Adempas to a pregnant female because it may cause

fetal harm. (4.1, 5.1, 8.1)• Females of reproductive potential: Exclude pregnancy before start of

treatment, monthly during treatment, and 1 month after treatmentdiscontinuation. Prevent pregnancy during treatment and for onemonth after treatment discontinuation by use of acceptable methods ofcontraception. (2.3, 5.1, 5.2, 8.6)

• For females, Adempas is available only through a restricted programcalled the Adempas REMS Program. (5.1, 5.2).

1 INDICATIONS AND USAGE1.1 Chronic-Thromboembolic Pulmonary Hypertension Adempas is indicated for the treatment of adults with persistent/recurrentchronic thromboembolic pulmonary hypertension (CTEPH), (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class [see Clinical Studies (14.1)].1.2 Pulmonary Arterial Hypertension Adempas is indicated for the treatment of adults with pulmonary arterial hypertension (PAH), (WHO Group 1), to improve exercise capacity, WHOfunctional class and to delay clinical worsening.Efficacy was shown in patients on Adempas monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominately patients with WHO functional classII–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%) [see Clinical Studies (14.2)]. 4 CONTRAINDICATIONS 4.1 PregnancyAdempas may cause fetal harm when administered to a pregnant woman. Adempas is contraindicated in females who are pregnant. Adempas wasconsistently shown to have teratogenic effects when administered to animals.If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].4.2 Nitrates and Nitric Oxide DonorsCo-administration of Adempas with nitrates or nitric oxide donors (such asamyl nitrite) in any form is contraindicated [see Drug Interactions (7.1) and Clinical Pharmacology (12.2)].4.3 Phosphodiesterase InhibitorsConcomitant administration of Adempas with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) or nonspecific PDE inhibitors (such as dipyridamole or theophylline) is contraindicated [see Drug Interactions (7.1)and Clinical Pharmacology (12.2)].5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal ToxicityAdempas may cause fetal harm when administered during pregnancy and is contraindicated for use in women who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, advise use of acceptable contraception and obtain monthly pregnancy tests. For females, Adempas is only available through a restricted programunder the Adempas REMS Program [see Dosage and Administration (2.3),Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.6)].5.2 Adempas REMS ProgramFemales can only receive Adempas through the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program, a restricted distribution program [see Warnings and Precautions (5.1)].Important requirements of the Adempas REMS Program include the following:• Prescribers must be certified with the program by enrolling and completing

training.• All females, regardless of reproductive potential, must enroll in the

Adempas REMS Program prior to initiating Adempas. Male patients are not enrolled in the Adempas REMS Program.

• Female patients of reproductive potential must comply with the pregnancytesting and contraception requirements [see Use in Specific Populations (8.6)].

• Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Adempas.

Further information, including a list of certified pharmacies, is available at www.AdempasREMS.com or 1-855-4 ADEMPAS.5.3 HypotensionAdempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular

outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/ BCRP inhibitors [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. Consider a dose reduction if patient develops signs or symptomsof hypotension. 5.4 BleedingIn the placebo-controlled clinical trials, serious bleeding occurred in 2.4%of patients taking Adempas compared to 0% of placebo patients. Serious hemoptysis occurred in 5 (1%) patients taking Adempas compared to 0 placebo patients, including one event with fatal outcome. Serious hemorrhagic events also included 2 patients with vaginal hemorrhage, 2 with catheter site hemorrhage, and 1 each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage. 5.5 Pulmonary Veno-Occlusive DiseasePulmonary vasodilators may significantly worsen the cardiovascular statusof patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of Adempas to such patients is not recommended. Should signs of pulmonary edema occur, the possibility of associated PVOD should be considered and, if confirmed, discontinue treatment with Adempas.6 ADVERSE REACTIONSThe following serious adverse reactions are discussed elsewhere in the labeling:• Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Hypotension [see Warnings and Precautions (5.3)]• Bleeding [see Warnings and Precautions (5.4)]

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions,adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety data described below reflect exposure to Adempas in two, randomized, double blind, placebo-controlled trials in patients with inoperable or recurrent/persistent CTEPH (CHEST-1) and treatment naive or pre-treated PAH patients (PATENT-1). The population (Adempas: n = 490;Placebo: n = 214) was between the age of 18 and 80 years [See Clinical Studies (14.1, 14.2)].The safety profile of Adempas in patients with inoperable or recurrent/ persistent CTEPH (CHEST-1) and treatment naive or pre-treated PAH (PATENT-1) were similar. Therefore, adverse drug reactions (ADRs) identified from the 12 and 16 week placebo-controlled trials for PAH and CTEPH respectively were pooled, and those occurring more frequently on Adempas than placebo (≥3%) are displayed in Table 1 below. Most adverse reactions in Table 1 can be ascribed to the vasodilatory mechanism of action of Adempas.The overall rates of discontinuation due to an adverse event in the pivotalplacebo-controlled trials were 2.9% for Adempas and 5.1% for placebo (pooled data).Table 1: Adverse Reactions Occurring More Frequently (≥3%) on Adempas than Placebo (Pooled from CHEST-1 and PATENT-1)Adverse Reactions Adempas % Placebo %

(n=490) (n=214)Headache 27 18Dyspepsia and Gastritis 21 8 Dizziness 20 13 Nausea 14 11Diarrhea 12 8Hypotension 10 4 Vomiting 10 7Anemia (including laboratory parameters) 7 2 Gastroesophageal reflux disease 5 2 Constipation 5 1

Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were: palpitations, nasal congestion, epistaxis, dysphagia, abdominal distension and peripheral edema. With longer observation in uncontrolled long-term extension studiesthe safety profile was similar to that observed in the placebo controlled phase 3 trials.7 DRUG INTERACTIONS7.1 Pharmacodynamic Interactions with AdempasNitrates: Co-administration of Adempas with nitrates or nitric oxide donors:(such as amyl nitrite) in any form is contraindicated because of hypotension [see Contraindications (4.2) and Clinical Pharmacology (12.2)].PDE Inhibitors: Co-administration of Adempas with specific PDE-5 inhibitors :(such as sildenafil, tadalafil, or vardenafil) and nonspecific PDE inhibitors (such as dipyridamole or theophylline), is contraindicated because of hypotension [see Contraindications (4.3) and Clinical Pharmacology (12.2)]. Clinical experience with co-administration of Adempas and

other phosphodiesterase inhibitors (for example, milrinone, cilostazole,roflumilast) is limited.7.2 Pharmacokinetic Interactions with AdempasSmoking: Plasma concentrations in smokers are reduced by 50-60%compared to nonsmokers. Based on pharmacokinetic modeling, for patients who are smokers, doses higher than 2.5 mg three times a day may be considered in order to match exposure seen in nonsmoking patients. Safety and effectiveness of Adempas doses higher than 2.5 mg three times a day have not been established. A dose reduction should be considered in patients who stop smoking [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].Strong CYP and P-gp/BCRP inhibitors: Concomitant use of riociguat:with strong cytochrome CYP inhibitors and P-gp/BCRP inhibitors such as azole antimycotics (for example, ketoconazole, itraconazole) or HIV protease inhibitors (such as ritonavir) increase riociguat exposure and may result in hypotension. Consider a starting dose of 0.5 mg 3 times a day when initiating Adempas in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effectof riociguat [see Dosage and Administration (2.5), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].Strong CYP3A inducers: Strong inducers of CYP3A (for example, rifampin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may significantly reduce riociguat exposure. Data are not available to guide dosing of riociguat when strong CYP3A inducers are co-administered [see Clinical Pharmacology (12.3)].Antacids: Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption and should not be taken within 1 hour oftaking Adempas [see Clinical Pharmacology (12.3)].8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category XRisk SummaryAdempas may cause fetal harm when administered to a pregnant womanand is contraindicated during pregnancy. Adempas was teratogenic and embryotoxic in rats at doses with exposures to unbound drug that were approximately 8 times and 2 times, respectively, the human exposure. In rabbits, riociguat led to abortions at 4 times the human exposure and fetal toxicity with exposures approximately 13 times the human exposure. IfAdempas is used in pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Boxed Warning and Contraindications (4.1)].Animal DataIn rats administered riociguat orally (1, 5, and 25 mg/kg/day) throughout organogenesis, an increased rate of cardiac ventricular-septal defect wasobserved at the highest dose tested. The highest dose produced evidence of maternal toxicity (reduced body weight). Post-implantation loss was statistically significantly increased from the mid-dose of 5 mg/kg/day. Plasmaexposure at the lowest dose in which no adverse effects were observed isapproximately 0.4 times that in humans at the maximally recommendedhuman dose (MRHD) of 2.5 mg three times a day based on area under the time-concentration curve (AUC) for unbound drug in rat and humans.Plasma exposure at the highest dose (25 mg/kg/day) is approximately 8times that in humans at the MRHD while exposure at the mid-dose (5 mg/kg/day) is approximately 2 times that in humans at the MRHD. In rabbits given doses of 0.5, 1.5 and 5 mg/kg/day, an increase in spontaneous abortions was observed starting at the middle dose of 1.5 mg/kg, and an increase inresorptions was observed at 5 mg/kg/day. Plasma exposures at these doses were 4 times and 13 times, respectively, the human exposure at the MRHD.8.3 Nursing MothersIt is not known if Adempas is present in human milk. Riociguat or its metabolites were present in the milk of rats. Because many drugs are presentin human milk and because of the potential for serious adverse reactions innursing infants from riociguat, discontinue nursing or Adempas.8.4 Pediatric UseSafety and effectiveness of Adempas in pediatric patients have not beenestablished [see Nonclinical Toxicology (13.2)].8.5 Geriatric UseOf the total number of subjects in clinical studies of Adempas, 23% were 65 and over, and 6% were 75 and over [see Clinical Studies (14)]. No overall differences in safety or effectiveness were observed between these subjectsand younger subjects, and other reported clinical experience has not identifieddifferences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.Elderly patients showed a higher exposure to Adempas [see Clinical Pharmacology (12.3)].8.6 Females and Males of Reproductive PotentialPregnancy Testing: Female patients of reproductive potential must have a:negative pregnancy test prior to starting treatment with Adempas, monthly during treatment, and one month after discontinuation of treatment with

Adempas. Advise patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant. Counsel patients on the risk to the fetus [see Boxed Warning, Dosage and Administration (2.3) and Use in Specific Populations (8.1].Contraception: Female patients of reproductive potential must use acceptable:methods of contraception during treatment with Adempas and for 1 month after treatment with Adempas. Patients may choose one highly effective form of contraception (intrauterine devices [IUD], contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner’s vasectomy is the chosenmethod of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [See Boxed Warning].8.7 Renal ImpairmentSafety and efficacy have not been demonstrated in patients with creatinine clearance <15 mL/min or on dialysis [see Clinical Pharmacology (12.3)].8.8 Hepatic ImpairmentSafety and efficacy have not been demonstrated in patients with severehepatic impairment (Child Pugh C) [see Clinical Pharmacology (12.3)].10 OVERDOSAGEIn cases of overdose, blood pressure should be closely monitored and supported as appropriate. Based on extensive plasma protein binding, riociguat is not expected to be dialyzable.17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Medication Guide).Embryo-Fetal ToxicityInstruct patients on the risk of fetal harm when Adempas is used during pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. Instruct females of reproductive potential to use effective contraception and to contact her physician immediately if they suspect they may be pregnant. Female patients must enroll in the Adempas REMS Program. Adempas REMS ProgramFor female patients, Adempas is available only through a restricted program called the Adempas REMS Program [see Warnings and Precautions (5.2)].Male patients are not enrolled in the Adempas REMS Program. Inform female patients (and their guardians, if applicable) of the followingimportant requirements:

• All female patients must sign an enrollment form.• Advise female patients of reproductive potential that she must comply

with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)].

• Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure.

• Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber.

Review the Medication Guide and REMS educational materials with female patients.Other Risks Associated with Adempas• Inform patients of the contraindication of Adempas with nitrates or nitric

oxide donors or PDE-5 inhibitors. • Advise patients about the potential risks/signs of hemoptysis and to report

any potential signs of hemoptysis to their physicians.• Instruct patients on the dosing, titration, and maintenance of Adempas.• Advise patients regarding activities that may impact the pharmacology of

Adempas (strong multi pathway CYP inhibitors and P-gp/BCRP inhibitors and smoking). Patients should report all current medications and newmedications to their physician.

• Advise patients that antacids should not be taken within 1 hour of taking Adempas.

• Inform patients that Adempas can cause dizziness, which can affect the ability to drive and use machines [see Adverse Reactions (6.1)]. They should be aware of how they react to Adempas, before driving or operatingmachinery and if needed, consult their physician.

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