Journal of the American College of Cardiology

Volume 62, Issue 25, Supplement, Pages A1-A8, D1-D128 (24 December 2013)

Updates in Pulmonary Hypertension

Edited by Gerald Simonneau and Nazzareno Galiè

INTRODUCTION

1 The Fifth World Symposium on Pulmonary Hypertension Review Article Pages D1-D3 Nazzareno Galiè, Gerald Simonneau Show preview | PDF (98 K) | Recommended articles | Related reference work articles STATE-OF-THE-ART PAPERS

2 Relevant Issues in the Pathology and Pathobiology of Pulmonary Hypertension Review Article Pages D4-D12 Rubin M. Tuder, Stephen L. Archer, Peter Dorfmüller, Serpil C. Erzurum, Christophe Guignabert, Evangelos Michelakis, Marlene Rabinovitch, Ralph Schermuly, Kurt R. Stenmark, Nicholas W. Morrell Show preview | PDF (601 K) | Recommended articles | Related reference work articles

3 Genetics and Genomics of Pulmonary Arterial Hypertension Review Article Pages D13-D21 Florent Soubrier, Wendy K. Chung, Rajiv Machado, Ekkehard Grünig, Micheala Aldred, Mark Geraci, James E. Loyd, C. Gregory Elliott, Richard C. Trembath, John H. Newman, Marc Humbert Show preview | PDF (267 K) | Recommended articles | Related reference work articles

4 Right Heart Adaptation to Pulmonary Arterial Hypertension: Physiology and Pathobiology Review Article Pages D22-D33 Anton Vonk-Noordegraaf, François Haddad, Kelly M. Chin, Paul R. Forfia, Steven M. Kawut, Joost Lumens, Robert Naeije, John Newman, Ronald J. Oudiz, Steve Provencher, Adam Torbicki, Norbert F. Voelkel, Paul M. Hassoun Show preview | PDF (953 K) | Recommended articles | Related reference work articles 5 Updated Clinical Classification of Pulmonary Hypertension Review Article Pages D34-D41 Gerald Simonneau, Michael A. Gatzoulis, Ian Adatia, David Celermajer, Chris Denton, Ardeschir Ghofrani, Miguel Angel Gomez Sanchez, R. Krishna Kumar, Michael Landzberg, Roberto F. Machado, Horst Olschewski, Ivan M. Robbins, Rogiero Souza Show preview | PDF (221 K) | Recommended articles | Related reference work articles

6 Definitions and Diagnosis of Pulmonary Hypertension Review Article Pages D42-D50 Marius M. Hoeper, Harm Jan Bogaard, Robin Condliffe, Robert Frantz, Dinesh Khanna, Marcin Kurzyna, David Langleben, Alessandra Manes, Toru Satoh, Fernando Torres, Martin R. Wilkins, David B. Badesch Show preview | PDF (688 K) | Recommended articles | Related reference work articles

7 Pulmonary Arterial Hypertension: Epidemiology and Registries Review Article Pages D51-D59 Michael D. McGoon, Raymond L. Benza, Pilar Escribano-Subias, Xin Jiang, Dave P. Miller, Andrew J. Peacock, Joanna Pepke-Zaba, Tomas Pulido, Stuart Rich, Stephan Rosenkranz, Samy Suissa, Marc Humbert Show preview | PDF (228 K) | Recommended articles | Related reference work articles

8 Updated Treatment Algorithm of Pulmonary Arterial Hypertension Review Article Pages D60-D72 Nazzareno Galiè, Paul A. Corris, Adaani Frost, Reda E. Girgis, John Granton, Zhi Cheng Jing, Walter Klepetko, Michael D. McGoon, Vallerie V. McLaughlin, Ioana R. Preston, Lewis J. Rubin, Julio Sandoval, Werner Seeger, Anne Keogh Show preview | PDF (1226 K) | Recommended articles | Related reference work articles

9 Treatment Goals of Pulmonary Hypertension Review Article Pages D73-D81 Vallerie V. McLaughlin, Sean Patrick Gaine, Luke S. Howard, Hanno H. Leuchte, Michael A. Mathier, Sanjay Mehta, Massimillano Palazzini, Myung H. Park, Victor F. Tapson, Olivier Sitbon Show preview | PDF (228 K) | Recommended articles | Related reference work articles

10 New Trial Designs and Potential Therapies for Pulmonary Artery Hypertension Review Article Pages D82-D91 Mardi Gomberg-Maitland, Todd M. Bull, Rajeev Saggar, Robyn J. Barst, Amany Elgazayerly, Thomas R. Fleming, Friedrich Grimminger, Maurizio Rainisio, Duncan J. Stewart, Norman Stockbridge, Carlo Ventura, Ardeschir H. Ghofrani, Lewis J. Rubin Show preview | PDF (280 K) | Recommended articles | Related reference work articles

11 Chronic Thromboembolic Pulmonary Hypertension Review Article Pages D92-D99 Nick H. Kim, Marion Delcroix, David P. Jenkins, Richard Channick, Philippe Dartevelle, Pavel Jansa, Irene Lang, Michael M. Madani, Hitoshi Ogino, Vittorio Pengo, Eckhard Mayer Show preview | PDF (485 K) | Recommended articles | Related reference work articles

12 Pulmonary Hypertension Due to Left Heart Diseases Review Article Pages D100-D108 Jean-Luc Vachiéry, Yochai Adir, Joan Albert Barberà, Hunter Champion, John Gerard Coghlan, Vincent Cottin, Teresa De Marco, Nazzareno Galiè, Stefano Ghio, J. Simon R. Gibbs, Fernando Martinez, Marc Semigran, Gerald Simonneau, Athol Wells, Werner Seeger Show preview | PDF (455 K) | Recommended articles | Related reference work articles

13 Pulmonary Hypertension in Chronic Lung Diseases Review Article Pages D109-D116 Werner Seeger, Yochai Adir, Joan Albert Barberà, Hunter Champion, John Gerard Coghlan, Vincent Cottin, Teresa De Marco, Nazzareno Galiè, Stefano Ghio, Simon Gibbs, Fernando J. Martinez, Marc J. Semigran, Gerald Simonneau, Athol U. Wells, Jean-Luc Vachiéry Show preview | PDF (242 K) | Recommended articles | Related reference work articles

14 Pediatric Pulmonary Hypertension Review Article Pages D117-D126 D. Dunbar Ivy, Steven H. Abman, Robyn J. Barst, Rolf M.F. Berger, Damien Bonnet, Thomas R. Fleming, Sheila G. Haworth, J. Usha Raj, Erika B. Rosenzweig, Ingram Schulze Neick, Robin H. Steinhorn, Maurice Beghetti Show preview | PDF (952 K) | Recommended articles | Related reference work articles

Journal of the American College of Cardiology Vol. 62, No. 25, Suppl D, 2013 Ó 2013 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2013.10.030

INTRODUCTION

The Fifth World Symposium on Pulmonary Hypertension

Nazzareno Galiè, MD,* Gerald Simonneau, MDy Bologna, Italy; and Paris, France

Sometimes pivotal events can be identified in the history of The well-known National Institutes of Health Registry on a disease that mark the borders of different eras in the primary pulmonary hypertension was launched after this first diagnosis or treatment. One of these pivotal events in the symposium (4). history of pulmonary arterial hypertension (PAH) was the The second WSPH was held 25 years later in 1998 in publication in 1996 of the paper of Barst et al. (1) on Evian, France. There were multiple reasons for starting the continuous intravenous epoprostenol therapy for primary modern series of WSPH, including the availability of 2 very pulmonary hypertension. For the first time, a medical therapy effective treatments such as epoprostenol (1) and high doses was shown to reduce substantially the mortality of a disease of calcium channel blockers in patients responding to acute defined as the “kingdom of the near dead” (2). In her out- vasoreactivity tests (5). A more comprehensive clinical standing career, Dr. Barst made considerable contributions to classification, including 5 groups, was proposed for the first the additional pivotal events in the PAH history, which can time at the symposium, and this facilitated both clinical be identified in the World Symposia on Pulmonary Hyper- practice and the clinical research. tension (WSPH) that has been held since 1973. The influ- In fact, in the third WSPH, which was held in Venice, ence of Dr. Barst spanned every aspect of the disease from Italy, in 2003, there were already 3 classes of drugs effective pediatrics to adulthood and from genetics to randomized, in the treatment of PAH (prostanoids, endothelin receptor controlled trials (RCTs). Her interventions in the discussions antagonists, and phosphodiesterase type 5 inhibitors), and were unmistakable and full of energy and passion, and this a specific treatment algorithm was proposed (6). The clinical passion also characterized her last days when the energy was classification was refined, including the familial form char- fading. We miss her, and we would like to remember her with acterized by the BMPR2 gene mutations (7). the last gift she has left us: the example of a physician and The fourth WSPH was held in Dana Point, California, in a scientist fully engaged in her activity until the end of her life. 2008. New management strategies were introduced such as Even if she was not able to personally attend the meeting, we the treatment of mildly symptomatic patients and the dedicate the 5th WSPH to her memory. combination and goal-oriented treatment strategies (8). The The achievements of the different WSPH have marked the RCT design was also discussed, including the need to use progress made on this condition. The first WSPH was held in time to clinical worsening as primary endpoint in phase III Geneva, Switzerland, in 1973 and was organized by the registration studies (9). World Health Organization because of an epidemic of PAH The fifth WSPH was held in Nice, France, from February 27 cases due to the use of aminorex, an anorexigen drug (3).A to March 1, 2013; the findings and recommendations of 129 simple clinical classification was proposed at this meeting worldwide experts divided into 12 task forces operating for (primary, secondary, and associated pulmonary hypertension 12 months were discussed in front of an audience of w1,000 [PH]) together with the hemodynamic definition of the physicians and representatives of the industry, patient asso- disease as a mean pulmonary arterial pressure 25 mm Hg. ciations, and regulatory agencies. The main conclusions of the task forces and the meeting discussions are reported in the 13 articles published in From the *Department of Experimental, Diagnostic and Specialty Medicine-DIMES, this supplement of the Journal of the American College of Bologna University Hospital, Bologna, Italy; and the yAssistance Publique-Hôpitaux Cardiology. de Paris, Service de Pneumologie, Hôpital Universitaire de Bicêtre, Université Paris- Sud, Laboratoire d’excellence en Recherche sur le Médicament et Innovation Thér- The Pathology and Pathobiology Task Force reports the apeutique, INSERM, Unité 999, Le Kremlin Bicêtre, Paris, France. Dr. Galiè has increasingly recognized importance of venous disease in served on the advisory boards of and received lecture fees from Eli Lilly, Actelion, PH as well as the disordered metabolism and mitochondrial Pfizer, Bayer-Schering, GlaxoSmithKline, and Novartis; and has received institutional fl grant support from Actelion, Pfizer, Bayer-Schering, GlaxoSmithKline, and Novartis. structure, in ammation, and dysregulation of growth factors Dr. Simonneau has served on the advisory boards of Eli Lilly, Actelion, Pfizer, Bayer- leading to a proliferative, apoptosis-resistant state of the Schering, GlaxoSmithKline, and Novartis; has received lecture fees from Eli Lilly, pulmonary vascular cells (10). Pfizer, Bayer-Schering, and GlaxoSmithKline; and has received institutional grant fi support from Actelion, Pfizer, Bayer-Schering, GlaxoSmithKline, and Novartis. The Genetics and Genomics Task Force con rms a 75% Manuscript received October 18, 2013; accepted October 22, 2013. mutation detection rate for the known genes (BMPR2, ALK1, D2 Galiè and Simonneau JACC Vol. 62, No. 25, Suppl D, 2013 The 5th World Symposium on Pulmonary Hypertension December 24, 2013:D1–3

Endoglin, SMAD-9, CAV1) in familial PAH patients (11). The Task Force on PH due left heart disease and due to New-generation sequencing techniques have allowed the lung diseases recommends that the term “out of proportion” identification of a new recently reported gene encoding the PH should be abandoned in both conditions (27,28). A new potassium channel KCNK3 (12). The importance of genetic nomenclature for PH due to left heart disease and the use of testing and counseling and genomic studies is also discussed. the diastolic gradient (diastolic pulmonary pressure mean The clinical and prognostic importance of the right pulmonary artery wedge pressure) for the identification of ventricle adaptation to the increased afterload in PH patients patients with a pre-capillary PH component is reported (27). is outlined by the Task Force on Pathophysiology: “adaptive” Similarly, new definitions are provided for PH due to lung and a “maladaptive” right ventricle phenotypes are described diseases (28). Targeted therapies have not provided with specific molecular, structural, and hemodynamic char- convincing benefits in both conditions (27,28). acteristics (13). The Task Force on Pediatric PH proposes new diagnostic An updated clinical classification, for the first time the and treatment algorithms adapted for this group of patients same for adult and pediatric patients, is proposed by the (29). The general structure is similar to the algorithms used specific Task Force (14). Changes includes the individual in the adults but takes into consideration the specific char- categorization of the persistent PH of neonates; the addition acteristics and requirements of the pediatric patient of congenital diseases in groups 2, 3, and 5; and the shifting population. of PH associated with chronic hemolytic anemias from In conclusion, this supplement of the Journal of the group 1 to group 5. New drugs potentially inducing PH are American College of Cardiology provides the cutting-edge also listed. knowledge in the different fields of PH, as discussed in The Task Force for Definitions and Diagnosis provides the fifth WSPH. a new hemodynamic definition of PAH, including pulmonary vascular resistance, and a more accurate and standard- Reprint requests and correspondence: Dr. Nazzareno Galiè, ized zero level for the transducer at right heart catheterization University of Bologna, via Massarenti 9, 40138 Bologna, Italy. (15). The term “borderline PH” is discouraged and the E-mail: [email protected] OR Dr. Gerald Simonneau, definition of PH on exercise is still considered not possible. University Hospital Bicêtre, AP-HP, 78 Avenue du Général Indications for screening strategies in asymptomatic patients Leclerc 92275, Le Kremlin Bicêtre, France. E-mail: gerald. and an updated diagnostic algorithm are also provided. [email protected]. The Task Force on Epidemiology and Registries describes the basic methodology by which PAH registries have been conducted and review key insights provided by REFERENCES registries (16). An analysis on the utility of data to predict 1. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous the survival outcomes is also discussed. intravenous epoprostenol (prostacyclin) with conventional therapy for An updated treatment algorithm is provided by the Task primary pulmonary hypertension: the Primary Pulmonary Hyperten- sion Study Group. N Engl J Med 1996;334:296–302. Force on Standard of Care including new published data 2. Robin ED. The kingdom of the near-dead: the shortened unnatural life concerning rehabilitation, combination therapy, new history of primary pulmonary hypertension. Chest 1987;92:330–4. compounds (17–19), and lung transplantation (20,21). The 3. Luthy E. Proceedings: the epidemic of primary pulmonary hypertension in Europe. Pathol Microbiol (Basel) 1975;43:246–7. importance of the effect of the drugs on patient outcome is 4. DAlonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with also outlined (22). primary pulmonary hypertension: results from a national prospective The Task Force on Treatment Goals for PH confirms the registry. Ann Intern Med 1991;115:343–9. fi 5. McLaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in need to analyze multiple goals for de ning the success of pulmonary vascular resistance with long-term epoprostenol (prostacy- therapy including symptoms, exercise capacity and the right clin) therapy in primary pulmonary hypertension. N Engl J Med 1998; ventricular function (23). Specific absolute values for the 338:273–7. 6. Galie N, Seeger W, Naeije R, Simonneau G, Rubin LJ. Comparative relevant parameters are also provided. analysis of clinical trials and evidence-based treatment algorithm in The Task Force on New Trial Designs and Potential pulmonary arterial hypertension. J Am Coll Cardiol 2004;43 Suppl:S81–8. Therapies for PAH confirms the need to adopt a morbidity 7. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43 Suppl:S5–12. and mortality primary endpoint in future phase 3 random- 8. Barst R, Gibbs J, Ghofrani A, et al. Updated evidence-based treatment ized, controlled trials (24). No surrogate endpoints are algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2009; identified in PAH and correlates may be included in phase 2 54 Suppl:S78–84. 9. McLaughlin VV, Badesch DB, Delcroix M, et al. End points and studies. Different novel drugs in very early stages of devel- clinical trial design in pulmonary arterial hypertension. J Am Coll opment are also reported. Cardiol 2009;54 Suppl:S97–107. The Task Force on Chronic Thromboembolic Pulmonary 10. Tuder RM, Archer SL, Dorfmüller P, et al. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Hypertension provides new diagnostic and treatment algo- Cardiol 2013;62 Suppl:D4–12. rithms for this condition (25). Pulmonary endoarterectomy is 11. Soubrier F, Chung WK, Machado R, et al. Genetics and genomics of confirmed as the treatment of choice for the affected patients, pulmonary arterial hypertension. J Am Coll Cardiol 2013;62 Suppl: D13–21. and medical therapy is used in nonoperable ones and in those 12. Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in with persistent PH after surgery (26). pulmonary arterial hypertension. N Engl J Med 2013;369:351–61. JACC Vol. 62, No. 25, Suppl D, 2013 Galiè and Simonneau D3 December 24, 2013:D1–3 The 5th World Symposium on Pulmonary Hypertension

13. Vonk-Noordegraaf A, Haddad F, Chin KM, et al. Right heart adap- Lung and Heart-Lung Transplant Report 2012. J Heart Lung tation to pulmonary arterial hypertension: physiology and pathobiology. Transplant 2012;31:1073–86. J Am Coll Cardiol 2013;62 Suppl:D22–33. 22. Galiè N, Corris PA, Frost A, et al. Updated treatment algorithm of 14. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classi- pulmonary arterial hypertension. J Am Coll Cardiol 2013;62 Suppl: ﬁcation of pulmonary hypertension. J Am Coll Cardiol 2013;62 Suppl: D60–72. D34–41. 23. McLaughlin VV, Gaine SP, Howard LS, et al. Treatment goals 15. Hoeper MM, Bogaard HJ, Condliffe R, et al. Deﬁnitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013;62 Suppl: of pulmonary hypertension. J Am Coll Cardiol 2013;62 Suppl:D42–50. D73–81. 16. McGoon MD, Benza RL, Escribano-Subias P, et al. Pulmonary 24. Gomberg-Maitland M, Bull TM, Saggar R, et al. New trial designs arterial hypertension epidemiology and registries. J Am Coll Cardiol and potential therapies for pulmonary artery hypertension. J Am Coll 2013;62 Suppl:D51–9. Cardiol 2013;62 Suppl:D82–91. 17. Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on 25. Kim NH, Delcroix M, Jenkins DP, et al. Chronic thromboembolic therapy for pulmonary arterial hypertension: results of the randomized pulmonary hypertension. J Am Coll Cardiol 2013;62 Suppl:D92–9. IMPRES study. Circulation 2013;127:1128–38. 26. Ghofrani HA, D’Armini AM, Grimminger F, et al. Riociguat for the 18. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treat- treatment of chronic thromboembolic pulmonary hypertension. N Engl ment of pulmonary arterial hypertension. N Engl J Med 2013;369: J Med 2013;369:319–29. 330–40. 27. Vachiery J-L, Adir Y, Barberà JA, et al. Pulmonary hypertension due to 19. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity left heart diseases. J Am Coll Cardiol 2013;62 Suppl:D100–8. and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 28. Seeger W, Adir Y, Barberà JA, et al. Pulmonary hypertension in 369:809–18. chronic lung diseases. J Am Coll Cardiol 2013;62 Suppl:D109–16. 20. de Perrot M, Granton JT, McRae K, et al. Outcome of patients with 29. Ivy DD, Abman SH, Barst RJ, et al. Pediatric pulmonary hypertension. pulmonary arterial hypertension referred for lung transplantation: J Am Coll Cardiol 2013;62 Suppl:D117–26. a 14-year single-center experience. J Thorac Cardiovasc Surg 2012;143: 910–8. 21. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the Key Words: Fifth World Symposium - pulmonary arterial International Society for Heart and Lung Transplantation: 29th Adult hypertension - pulmonary hypertension. Journal of the American College of Cardiology Vol. 62, No. 25, Suppl D, 2013 2013 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2013.10.025

STATE-OF-THE-ART PAPERS

Relevant Issues in the Pathology and Pathobiology of Pulmonary Hypertension

Rubin M. Tuder, MD,* Stephen L. Archer, MD,y Peter Dorfmüller, MD, PHD,z Serpil C. Erzurum, MD,x Christophe Guignabert, PHD,k Evangelos Michelakis, MD,{ Marlene Rabinovitch, MD,# Ralph Schermuly, PHD,** Kurt R. Stenmark, MD,yy Nicholas W. Morrell, MDzz Aurora, Colorado; Kingston, Ontario, and Edmonton, Alberta, Canada; Le Plessis-Robinson and Kremlin-Bicêtre, France; Cleveland, Ohio; Stanford, California; Giessen, Germany; and Cambridge, United Kingdom

Knowledge of the pathobiology of pulmonary hypertension (PH) continues to accelerate. However, fundamental gaps remain in our understanding of the underlying pathological changes in pulmonary arteries and veins in the different forms of this syndrome. Although PH primarily affects the arteries, venous disease is increasingly recognized as an important entity. Moreover, prognosis in PH is determined largely by the status of the right ventricle, rather than the levels of pulmonary artery pressures. It is increasingly clear that although vasospasm plays a role, PH is an obstructive lung panvasculopathy. Disordered metabolism and mitochondrial structure, inﬂammation, and dysregulation of growth factors lead to a proliferative, apoptosis-resistant state. These abnormalities may be acquired, genetically mediated as a result of mutations in bone morphogenetic protein receptor-2 or activin-like kinase-1, or epigenetically inherited (as a result of epigenetic silencing of genes such as superoxide dismutase-2). There is a pressing need to better understand how the pathobiology leads to severe disease in some patients versus mild PH in others. Recent recognition of a potential role of acquired abnormalities of mitochondrial metabolism in the right ventricular myocytes and pulmonary vascular cells suggests new therapeutic approaches, diagnostic modalities, and biomarkers. Finally, dissection of the role of pulmonary inﬂammation in the initiation and promotion of PH has revealed a complex yet fascinating interplay with pulmonary vascular remodeling, promising to lead to novel therapeutics and diagnostics. Emerging concepts are also relevant to the pathobiology of PH, including a role for bone marrow and circulating progenitor cells and microribonucleic acids. Continued interest in the interface of the genetic basis of PH and cellular and molecular pathogenetic links should further expand our understanding of the disease. (J Am Coll Cardiol 2013;62:D4–12) ª 2013 by the American College of Cardiology Foundation

The specific field of pathobiology of pulmonary hypertension past 110 years (3), several important paradigms have taken (PH) has undergone impressive growth since the last world center stage, including the role of metabolic reprogramming meeting in Dana Point, California, in 2008 (1,2). Building on and inflammation, with promising insights that may lead to a remarkable list of significant accomplishments realized in the novel therapeutic and diagnostic targets. Notwithstanding this

From the *Program in Translational Lung Research, Department of Medicine, received speaker fees for meetings supported by Actelion Pharmaceuticals. Dr. University of Colorado School of Medicine, Aurora, Colorado; yDepartment of Erzurum is supported by NIH-RO1-HL071115, 1RC1HL099462SLAHL115008, Medicine, Queen’s University, Kingston, Ontario, Canada; zDepartment of and HL60917. Dr. Guignabert is supported by the French National Agency for Pathology, Marie Lannelongue Hospital, University Paris-Sud, Le Plessis-Robinson, Research ANR_12_JSV1_0004_01. Dr. Michelakis has served on steering committees France; xLerner Research Institute and Respiratory Institute, Cleveland Clinic, for Medtelligence (Young Investigators Selection Committee) and Bayer (Clinical Trial Cleveland, Ohio; kINSERM UMR 999, LabEx LERMIT, Marie Lannelongue Steering Committee), both of which totaled <$10,000 in the past 2 years. Dr. Schermuly Hospital and University Paris-Sud, School of Medicine, Kremlin-Bicêtre, France; is supported by LOEWE Center Universities of Giessen and Marburg Lung Center {Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; (UGMLC-LOEWE), Excellence Cluster Cardio-Pulmonary System (ECCPS), and #Cardiovascular Institute and Department of Pediatrics and The Vera Moulton Wall German Center for Lung Research (DZL); and has received research grants from Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Actelion, Bayer-Healthcare, Novartis, Noxxon, and Pﬁzer. Dr. Stenmark is supported by Stanford, California; **Excellence Cluster Cardio-Pulmonary System, German Lung NIH/NHLBI Axis Grant, 1R01HL114887, NIH PPG 5P01HL014985, and NIH/ Center, Universities of Giessen and Marburg Lung Center, Justus-Liebig-University, NHLBI SCCOR 5P50HL084923; and has received unrestricted research grants from Giessen, Germany; yyCardiovascular Pulmonary Laboratory, Department of Pediat- Actelion, Bayer-Healthcare, Novartis, Noxxon, and Pﬁzer. Dr. Morrell is supported by rics, University of Colorado School of Medicine, Aurora, Colorado; and the NIHR Cambridge Biomedical Research Centre and the British Heart Foundation (BHF). zzDepartment of Medicine, University of Cambridge School of Clinical Medicine, All other authors have reported that they have no relationships relevant to the contents of Cambridge, United Kingdom. Dr. Tuder is supported by the Cardiovascular this paper to disclose. Drs. Tuder and Morrell are joint corresponding authors. Medical Research and Education Fund and RC1 HL 10084. Dr. Dorfmüller has Manuscript received October 15, 2013; accepted October 22, 2013. JACC Vol. 62, No. 25, Suppl D, 2013 Tuder et al. D5 December 24, 2013:D4–12 Issues in the Pathology and Pathobiology of Pulmonary Hypertension

fi remarkable progress, central questions remain related to the The dif culty in studying the Abbreviations fundamental aspects of pulmonary vascular pathology in PH. pathology of pulmonary venous and Acronyms When choosing the particular areas of emphasis in the remodeling is compounded by the ALK = activin receptor-like context of the World Symposium, the Pathology and lack of distinct molecular markers kinase Pathobiology Working Group opted to continue focusing on that allow for their identification BMPR2 = bone morphogenetic the pathologic alterations of pulmonary veins in PH, largely (as compared with the pulmonary protein type II receptor inspired by the pressing questions in this particular area that arterial bed) when immersed in DC = dendritic cell arose from the last world meeting (1). This was complemented alveolar tissue. Normal veins can ER = endoplasmic reticulum by 3 additional topics, due to their timeliness and overall be recognized by the lack of importance: the molecular determinants of mild versus severe a double elastic lamina and rela- HIF = hypoxia inducible factor PH; the role of metabolic reprogramming underlying cellular tively thin muscular media; how- IPAH = idiopathic pulmonary responses in pulmonary vascular disease; and recent insights ever, when remodeled, pulmonary arterial hypertension into the role of inflammation as a trigger and modifier of PH. veins become “arterialized,” ma- LHF = left heart failure Furthermore, many pathogenetic processes operational in king their distinction from pul- fi PAH = pulmonary arterial mild disease appear to have roles in more severe PH, but how monary arteries more dif cult. hypertension molecular processes determine the progression and ultimately The only distinctive feature, PH = pulmonary the severity of the disease remains unclear. To start addressing which is often not present in bio- hypertension this complex yet central questiondperhaps one of the most psies, is the presence of pul- vexing challenges in the fielddthe integration of pathology monary veins in interlobular septae. Moreover, molecular and pathogenetic mechanisms should provide insights into markers of veins, such as the ephrin B4 receptor, are often this topic in the years to come. difficult to identify in human (and rat) lungs. The venous The group members acknowledge that the chosen coaxial structure includes layers of cardiomyocytes arrayed discussion topics did not allow for an all-inclusive dissection externally around a subendothelial layer of typical smooth of established and emerging areas of investigation. These muscle cells, thus forming sphincter-like structures. In disease include, among others, specific signaling pathways shown to states, this cardiac muscle layer extends further into the lung, affect pulmonary vasoconstriction and remodeling (such as and its role in Group 2 PH merits investigation. epidermal growth factor [4], fibroblast growth factor [5], Given the limitations in recognizing veins histologically, platelet-derived growth factor [6,7], and transforming most studies rely on their identification in selected regions growth factor-b [8,9]) or are protective (such as bone of explant specimens. In subsets of PAH patients with morphogenetic proteins), and evolving knowledge on the scleroderma-associated PAH, pulmonary veno-occlusive involvement of pathogenic (10) or protective (11) micro- disease-like remodeling may predominate over arterial ribonucleic acids in pulmonary arterial hypertension (PAH). remodeling. The venous remodeling, if present, entails a In addition, emerging areas of investigation, including the worse prognosis associated with decreased 6 min-walk potential role of progenitor or stem cells in pulmonary distance, partial pressure of oxygen in the blood, and vascular remodeling (12), were not addressed. Notwith- diffusion capacity (14). However, in a recent pathologic standing these limitations, when fitting, we emphasize the study of PAH, including lungs with scleroderma-associated potential role of circulating cells derived from the bone PAH, no correlations between vein remodeling and intima marrow, as documented in recent human studies (13). and media thickness in arteries could be identified (15). Recent studies have highlighted the pattern of pulmonary Does the Pulmonary Venous System Play an vein remodeling in patients with left heart failure (LHF). Important Role in PAH and to What Extent Are PAH Lung samples obtained from patients with LHF placed on and PVOD Part of the Same Spectrum of Disease? a ventricular assist device showed increased pulmonary vein and artery media thickening. Of interest, some patients who It is apparent that the different forms of PH present with improved on the assist device and underwent repeat lung either a predominance of pulmonary arterial remodeling or biopsy had a significant improvement of pulmonary vein vein remodeling or a variable contribution of both. Para- remodeling (16). The molecular drivers of these processes digmatic of the former is idiopathic pulmonary arterial remain largely unknown. hypertension (IPAH), whereas pure pulmonary veno- We continue to lack the availability of unique molecular occlusive disease and PH due to left heart dysfunction markers that allow the specific identification of pulmonary are characterized predominantly by venous remodeling. veins. Consequently, the prevalence of venous pathology in Virtually all forms of PH, including thromboembolic PH, the various forms of PH remains unknown. This is despite sarcoid PH, and those caused by interstitial lung disease the potential for deleterious effects of prostacyclin and and hypoxia, may involve elements of both arterial and agents that increase bioavailability of nitric oxide in the venous remodeling. However, more precise documen- context of elevated capillary pressures. Finally, little is known tation, including morphometric analysis of pulmonary vein about pathogenetic pathways involved in pulmonary vein remodeling, is still lacking in most of these conditions. remodeling and how they correlate with arterial remodeling D6 Tuder et al. JACC Vol. 62, No. 25, Suppl D, 2013 Issues in the Pathology and Pathobiology of Pulmonary Hypertension December 24, 2013:D4–12 in both LHF and in forms of PH with pre-capillary unused donor “control” lungs revealed substantial neointimal predominance. formation, inflammation, and venous changes (15), features usually judged to be “pathological.” This suggests a spectrum Are There Distinct Pathways in Vascular Cells in from pristine vessels (which are observed primarily in the Mild Versus Severe PH? younger controls) to vascular changes reminiscent of PH that may be present as a function of normal aging, including fi Although PH is de ned as a mean pulmonary arterial inflammation and left ventricular stiffening. Because > pressure at right heart catheterization 25 mm Hg with a description of the pathology in mild forms of PH is largely a normal pulmonary capillary wedge pressure, it is well unavailable, it is difficult to discern whether the pathological known that, on the basis of clinical and hemodynamic features we observe in “controls” are similar but still less fi ndings, PH can range from mild to severe, even in the severe than in patients with “mild” PH. Perhaps a better presence of the same stimulus (e.g., hypoxia). This spectrum definition of severity would also incorporate the extent of the of severity raises several critical pathogenetic and clinical reduction in cross-sectional area of the pulmonary vascular questions in terms of the distinctive features that differen- bed. In this summary, we confine our discussion of severity tiate the severity stages. to the extent of the pulmonary vascular remodeling process, Increased pulmonary artery pressures occur due to sus- although in clinical practice, the assessment of severity will tained vasoconstriction, excessive pulmonary vascular also consider the function of the right ventricle. Below, we remodeling, and in situ thrombosis, which ultimately lead to expand on how genetic factors influence with cellular and increased pulmonary vascular resistance. However, the molecular pathogenetic processes to possibly account for the factors responsible for the aggravation or acceleration of PH severity of pulmonary vascular disease (Fig. 1). fi remain poorly de ned (Fig. 1). The contributing factors Mutations in bone morphogenetic protein type II receptor likely involve accumulation of multiple events on a back- (BMPR2) or activin receptor-like kinase-1 (ALK-1) are ground of genetic predisposition. These factors involve the emerging as determinants of severity of PAH. Mutations in action of vasoconstrictive and pro-remodeling processes, BMPR2 (19) have been reported in more than 70% of subjects fl including the action of in ammatory, procoagulant, anti- with 1 or more affected relatives (heritable PAH) and 11% to – – apoptotic, and autoimmune mediators, cell cell and cell 40% of those with idiopathic PAH (20,21). Mutations in matrix interactions, and environmental factors over time several other genes have been found, including mutations in (Fig. 2) (17). Although the pulmonary artery bed appears the ALK1 gene (22), the endoglin gene (23), the SMAD9 gene unreactive to vasodilators in advanced disease, vasoreactivity (24), the Caveolin-1 gene (25), and recently, the KCNK3 and remodeling possibly interact in disease evolution (18). gene (26). Patients with BMPR2 or ALK-1 mutations present Whether the severity of pulmonary vascular disease with higher pulmonary vascular resistance (27). There is also involves a constellation of pathobiological processes or is evidence that these patients present and die at a younger age fi fi de ned pathologically, with the hallmark nding of reduc- and with more severe disease compared with PAH patients tion of the pulmonary vascular lumen, remains unclear. The without mutations, and they are less likely to respond acutely fi de nition of the severity of PH on the basis of histopath- to vasodilators (28). Recent evidence suggests that the degree fi ological ndings is complicated by the lack information on of pulmonary vascular remodeling is greater in patients with “ ” what constitutes normal. Surprisingly, recent analysis of BMPR2 mutations compared with non-BMPR2–related disease at the time of transplantation (4). In addition to these causal rare sequence variants, variable expressivity of PAH might be explained by genetic modifiers. For example, single nucleotide polymorphisms in several genes, such as the angiotensin-converting enzyme gene, the KCNA5 gene, the serotonin transporter gene, and the serotonin 5-HT2B receptor gene have been reported to influence disease penetrance or progression. In addition, microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in idiopathic PAH (29), as well as somatic chromosome abnormalities (30), have been described. Most cases of PH do not have known genetic triggers; moreover, vascular cells isolated from experimental PH maintain their in vivo Proposed Multifactorial Factors Influencing characteristics when placed in culture, suggesting epigenetic Figure 1 Progression of Pulmonary Hypertension abnormalities. An example of such a contributing factor is the silencing of mitochondrial superoxide dismutase-2, which alters In a suitable genetic background, the interplay of epigenetics and pathobiological injurious events may amplify the severity of the disease, often associated with redox signaling and, therefore, activates hypoxia inducible more pronounced remodeling and worse clinical outcome. factor (HIF)-1a, leading to the aerobic glycolysis seen in PH (31,32). However, further studies, particularly focused on JACC Vol. 62, No. 25, Suppl D, 2013 Tuder et al. D7 December 24, 2013:D4–12 Issues in the Pathology and Pathobiology of Pulmonary Hypertension

Figure 2 Emerging Paradigms in PH Research

Research involving the broad effects of metabolic programming of intima and media pulmonary vascular cells (endothelial and smooth muscle cells) and the immediate perivascular microenvironment. The perivascular region is dominated by fibroblasts and migrating circulating cells, including inflammatory and progenitor cells. Shown in the center is the impact of these factors in the intima and media of pulmonary arteries. The metabolic plasticity involves all cells involved in the pulmonary hypertension (PH) panvasculopathy and is itself modified by inflammation and infiltrating progenitor cells (these paradigms are examined in more detail in Archer et al. [17]). Ca ¼ calcium; Th2 ¼ t-helper lymphocytes; Treg ¼ T regulatory cells. epigenetic control of additional key genes, are required to arteries in the SU5416/hypoxia rat model (37,40),which verify their contribution to the pathogenesis of PH. evolves over time (40), do not fully recapitulate the large Apart from major effects of rare sequence variants in heri- plexogenic lesions seen in patientsdits potential reversibility table forms of PAH, interindividual differences in response may also indicate the model may not be fully reflective of the to the same stimulus are well documented in subjects exposed largely irreversible nature of the human disease. Indeed, recent to environmental hypoxia at high altitude or in the context studies indicate that the long telomeres present in mice may of high pulmonary blood flow or pulmonary venous hyper- limit the extent to which animal model can phenocopy tension. This variable expressivity most certainly involves human disease. the impact of unknown genetic influences regulating the Several genetic, molecular, biochemical, and environ- pulmonary vascular response; this variation in response to mental factors may explain the variable expressivity of PH hypoxia is also seen in different strains of rat (33) and bovines and may contribute to its aggravation or acceleration. Severe exposed to high altitude (34). Elegant studies demonstrated PAH seems to represent the far end of a spectrum, in which that this response is inherited (35), though the identification there is an augmented burden of vascular injury and dysre- of the genetic basis is the subject of ongoing research (36). gulated repair (Fig. 1). Further studies, which likely require The variable expressivity of PH might also be due to a “systems biology-like” approach, are needed to establish exposure to different environmental influences or comor- which key signaling pathways in pulmonary vascular cells bidities including: inflammation, auto-immunity, viral lead to severe disease. Factors that contribute to this accel- infection, and hormonal mediators. The specific topic of erated pathology include genetic abnormalities that may inflammation is addressed in the following text. Further- affect: 1) the exuberance of the cellular response; 2) the more, accumulating evidence indicates that metabolic dys- chronicity of an inflammatory stimulus; and 3) the severity function may also contribute to variability in susceptibility of the altered metabolic state and cumulative DNA damage. and expressivity of PH (Fig. 2). Although in general, animal models of PH do not recapit- What Are the Differences and Similarities Between ulate the severe pathology of human disease, these experi- Cell Proliferations in PAH When Compared With mental models support the idea that PH can be triggered by Traditional Neoplastic Disease? different stimuli and that the structural changes observed in the pulmonary vasculature vary depending on the nature of the The concept of a neoplastic-like pathobiology of PH (in injurious stimulus (37). Several studies have underlined the particular in PAH) (41) has its origins in the finding that importance of different signaling pathways in PH, including endothelial cells in IPAH plexiform lesions are clonal when elastase inhibitors (38), antagonists of epidermal growth factor compared with similar lesions in lungs of patients with (4), or dietary copper restriction (39). The lack of animal model congenital heart disease (42), coupled with somatic instability fidelity to the human pathology needs to be critically analyzed. in PAH lesions (29) and cultured lung endothelial cells (30). The obliterative changes in the most distal pre-capillary Similar to the concept of an uncontrolled cell growth in PAH, D8 Tuder et al. JACC Vol. 62, No. 25, Suppl D, 2013 Issues in the Pathology and Pathobiology of Pulmonary Hypertension December 24, 2013:D4–12 early data emphasized the up-regulation of HIF-1a in plexi- mitochondria fission in PH smooth muscle cell growth, form lesions and pulmonary arteries in PAH (43) and survivin inhibition of dynamin-related protein-1 with the peptide in IPAH (44). These findings, largely centered on the angle of Mdiv-1 blocks cell proliferation in cultured cells as well as disorganized cell growth, favored the emergence of an PH caused by in vivo administration of cobalt and chronic apoptosis-resistant phenotype, a selection process that char- hypoxia (57). Conversely, overexpression of mitofusin-1, acterizes neoplastic processes (45). In the past 8 years, further which leads to mitochondria fusion, counteracts the mito- experimental evidence emerged of metabolic plasticity and chondria phenotype in PH smooth muscle cells (58). altered cell energetics in the pathogenesis of PAH (46,47). The paradigm of metabolic plasticity and adaption of PH Metabolic reprogramming (Fig. 2), along with genomic cells has wider implications, interfacing with controls of instability and mutations, immune escape, and cell-growth cellular stresses and protein misfolding and protein sorting in promoting inflammation, is one of the so-called “emerging cytoplasmic compartments (59). In line with these paradigms, hallmarks” pertinent to the pathogenesis of cancer (48). Recent there is evidence of an altered endoplasmic reticulum (ER) studies have delineated that cancer cells use these hallmarks as stress response in PH (60), which may ultimately contribute to driving forces leading to cell growth and co-option of the both adverse remodeling and elevation of pulmonary artery surrounding stroma for their aggressiveness (49). pressures (61). Moreover, ER stress can lead to activation of Supporting documentation of metabolic adaption of the stress-related kinase activating transcription factor-6, pulmonary vascular cells derived from studies in rat smooth which increases the expression of Nogo-B. This contributes muscle cells from the fawn-hooded model of PH (46) and to an abnormal distancing and signaling coupling (via calcium cultured human IPAH cells (31). In both experimental fluxes) between the ER and the mitochondria (62). These settings, the hypertensive vascular cells would preferentially events would lead to an increase in glycolysis, favoring use aerobic glycolysis (instead of mitochondrial metabolism). vascular cell proliferation and ultimately PH. The preferential use of aerobic glycolysis by proliferating The inroads made by the metabolic-related studies in PH are cells (including cancer cells) would endow a selective growth starting to bear translational fruits. There is increased metabolic advantage to pulmonary vascular cells: glucose and glycolytic labeling of glucose uptake with 18-fluorodeoxyglucose of intermediates provide key substrates for the pentose phos- IPAH lungs and right ventricle when compared with controls phate shunt to generate reducing equivalents in the form of (31,63), which has also been observed in animal models of PH reduced nicotinamide adenine dinucleotide phosphate and (64,65). Pharmacologic targeting of the preferential use of nucleotides, essential for cell growth (50). glycolysis by PH cells is being tested in humans with the small The preferential utilization of aerobic glycolysis appears to be molecule dichloroacetate (NCT01083524), which improves related to up-regulation of several glycolytic genes and increased PH in animals by blocking pyruvate dehydrogenase kinase, expression of the subunit 4.2 of cytochrome oxidase in the a negative regulator of pyruvate import into the mitochondria mitochondrial respiratory chain, all events driven by expression (66). of HIF-1a (51). In human PAH lungs, HIF-1a appears to be We are at the beginning of deciphering the role of cellular expressed by endothelial cells (43) and smooth muscle cells metabolism in the pathogenesis of PH and how this (46). The source of stabilization of HIF-1a remains unclear, fundamental process relates to inflammation, remodeling, but it appears to be related to altered cellular oxidant/antioxi- therapeutic response, and so on. Genetic modifications that dant balance (46,52) present in hypertensive cells. Moreover, favor glycolysis in multiplying cells would certainly HIF-1a could also account for the increased mobilization of contribute to part of the process of remodeling. However, hematopoietic precursors in PAH (53–55), which might many of the vascular cells in established human PH are promote further injury to the pulmonary endothelium (13) and quiescent, long-lived, and probably resistant to apoptosis. possibly to contribute to the remodeled cell population (Fig. 2). These quiescent cells would have substantially different In addition to playing roles in the metabolic adaption and metabolic requirements from those of proliferating cells. mobilization of bone marrow precursors, HIF-1a also Clarifying this metabolic heterogeneity and how it contrib- participates in the regulation of mitochondria dynamics. utes to remodeling and vasoconstriction will be critical HIF-1a accounted for decreased numbers of mitochondria moving forward. The interface of cell metabolism with the and decreased nitric oxide availability in IPAH cells when genetic basis of PAH and inflammation will certainly compared with control cells (43); of interest, these alter- constitute key areas of future investigation. ations also correlate with increased IPAH endothelial cell proliferation when compared with normal endothelial cells What Is the Role of Inflammation in the Initiation in culture (56). HIF-1a–dependent mitochondria plasticity and Progression of Different PAH Types? also pertains to PH smooth muscle cells. Activation of HIF- 1a activity with cobalt or desferrioxamine leads to mito- Inflammation has been long recognized as an important chondria fission (mediated by activation of dynamin related pathogenetic element in PH (67). Expanding on prior protein-1) in human PAH and rodent PH smooth muscle observations of accumulation of inflammatory cells in PAH, cells; this is driven by activation of dynamin-related protein-1 it was documented for the first time that the amount of by active cyclin B1 (57). Finally, consistent with the role of perivascular inflammatory infiltrate, largely of lymphocytes, JACC Vol. 62, No. 25, Suppl D, 2013 Tuder et al. D9 December 24, 2013:D4–12 Issues in the Pathology and Pathobiology of Pulmonary Hypertension correlated with parameters of pulmonary vascular remodel- displayed the canonical cellularity and structure of bona fide ing and hemodynamics in PAH (15).Inflammation consists tertiary follicles, whereas lymphoid organogenic chemo- of a complex series of interactions among soluble factors and kines, such as CXCL13 and CCL19/CCL21, were over- immunologically specialized cells triggered in response to expressed. These data provide a structural basis for a local traumatic, infectious, post-ischemic, toxic, or autoimmune autoimmune response in this disease (81–83). Finally, injury (68). It is increasingly clear that early and persistent inflammation is closely associated with pulmonary vascular inflammation is present and contributes to pulmonary disease in the setting of autoimmune diseases, such as vascular disease, as documented in tissue-based studies and scleroderma, and paradigmatic of the interplay of inflam- studies of circulating inflammatory cells and chemical mation and PH is its link with the infection with the mediators. parasite Schistosoma mansoni (the most frequent cause of The presence of elevated levels of circulating inflamma- PAH worldwide [84]) and human immunodeficiency virus tory cytokines, such as interleukin-1a, in PAH is well infection (85). recognized (69). More recently, a wide range of cytokines Vascular inflammation in general and PH in particular has has been shown to be elevated and to correlate with surviv- traditionally been considered an “inside-out” response al in PAH (70). At the tissue level, traditional cellular centered on leukocyte/monocyte recruitment to the intima of components of inflammation are described in the hyperten- blood vessels driven by the endothelium-expressed adhesion sive pulmonary circulation (71,72). More specifically, cellular molecules. Growing experimental evidence, however, inflammation involves increases in the number of peri- supports an alternative paradigm of an “outside-in” hypoth- vascular macrophages (CD68þ), macrophages/monocytes esis, in which vascular inflammation is initiated in the (CD14þ), mast cells, dendritic cells (DCs) (CD209þ), adventitia and progresses inward toward the media and T cells (CD3þ), cytotoxic T cells (CD8þ), and helper intima, coupled with the activation of the remodeling process. T cells (CD4þ) in the walls of PAH vessels compared with In support of the “outside-in” hypothesis of adventitial regu- control subjects (73). FoxP3(þ) cells have been shown to be lation of inflammation are observations that, in a wide variety significantly decreased, suggesting a reduction in the local of vascular injuries, including PH, there is a rapid influx of number of T regulatory (Treg) cells (73). Although increased leukocytes into the adventitial compartment (86). The numbers of circulating Treg cells has been reported in immediate perivascular environment in PH becomes popu- patients with idiopathic PAH (74,75), the reduced numbers lated by inflammatory/progenitor cells, in a niche dominated of Treg in lung tissue may reflect decreased tissue recruit- by adventitia fibroblasts (37,71,86–90). These adventitial ment of these cells. Given their immune soothing role, fibroblasts and recruited monocytes, particularly under a diminished negative regulation on other active immune/ hypoxia, express in a time-dependent and pulmonary artery– inflammatory cells may trigger or amplify pulmonary vascular specific manner several cytokines/chemokines, their receptors, remodeling and PH. and adhesion molecules; these cells, therefore, appear to The innate inflammatory system appears to also partici- initiate and perpetuate the inflammatory response in an pate in PAH. Natural killer cells, which target stressed, “outside-in” fashion, possibly mediated by nuclear factor virally infected, or oncogenically transformed cells inde- kappa B signaling (91,92). Therefore, temporal-spatial dys- pendent of antigen recognition, are dysfunctional, with regulation and/or failure in the normal “switch-off signal” in reduced number and cytolytic capacity, in patients with fibroblasts and/or macrophages/DCs may directly contribute idiopathic PAH and in mouse and rat models of PH (76). to the persistence of a chronic inflammatory immune Neutrophils may have potentially unrecognized roles as response. These adventitia processes are more evident in sources of powerful proteases, including elastases, which nonmouse models and in the lungs of patients with PH, have recognized roles in pulmonary vascular remodeling possibly due to the presence of bronchial circulation. (38,77). Because hypoxia exerts profound effects on The action of secreted cytokines, including TGF-b, in the neutrophil function (e.g., resistance to apoptosis [78]), adventitia mediates specific homing for leukocytes in this further evaluation of the role of the neutrophil in PAH is vascular compartment, leading to their inappropriate/path- overdue. The complement system, which bridges innate and ologic retention and survival (92). These homing/recruit- adaptive immunity, is also activated in PAH, and deficiency ment cytokines include up-regulated adhesion molecules, of complement C3 protects mice from hypoxia-induced PH including intercellular adhesion molecule 1 and vascular (79). Mechanistic studies focusing on the innate immune adhesion molecule-1, and stromal derived factor-1/CXCR4, system are needed for a better appreciation of its role in PH. which promotes adhesion of leukocytes and bone marrow However, recent insights highlighted a potential role precursor cells, respectively. The adventitia is, therefore, for acquired immunity, suggesting that the pathogenesis suited to harbor canonical innate immune cells, specifically of PH may involve specific and targeted immune cellular macrophages and DCs, which with adventitial fibroblasts, responses. A recent study identified a large number of are all equipped with the necessary machinery (e.g., toll-like tertiary lymphoid follicles in lungs from patients with receptors and inflammasome components [like the nod-like idiopathic PAH when compared with control lungs (80). receptors]) to potently respond to a variety of exogenous and These lymphoid follicles in idiopathic PAH patients endogenous danger signals. D10 Tuder et al. JACC Vol. 62, No. 25, Suppl D, 2013 Issues in the Pathology and Pathobiology of Pulmonary Hypertension December 24, 2013:D4–12

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Genetics and Genomics of Pulmonary Arterial Hypertension

Florent Soubrier, MD, PHD,* Wendy K. Chung, MD, PHD,y Rajiv Machado, PHD,z Ekkehard Grünig, MD,x Micheala Aldred, PHD,k Mark Geraci, MD,{ James E. Loyd, MD,# C. Gregory Elliott, MD,** Richard C. Trembath, MD,yy John H. Newman, MD,# Marc Humbert, MD, PHDzz Paris and Le Plessis Robinson, France; New York, New York; Lincoln and London, United Kingdom; Heidelberg, Germany; Cleveland, Ohio; Aurora, Colorado; Nashville, Tennessee; and Salt Lake City, Utah

Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). Among them, the identification of bone morphogenetic protein receptor type 2 (BMPR2)asthe major predisposing gene and activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) as the major gene when PAH is associated with hereditary hemorrhagic telangiectasia. The mutation detection rate for the known genes is approximately 75% in familial PAH, but the mutation shortfall remains unexplained even after careful molecular investigation of these genes. To identify additional genetic variants predisposing to PAH, investigators harnessed the power of next-generation sequencing to successfully identify additional genes that will be described in this report. Furthermore, common genetic predisposing factors for PAH can be identified by genome-wide association studies and are detailed in this paper. The careful study of families and routine genetic diagnosis facilitated natural history studies based on large registries of PAH patients to be set up in different countries. These longitudinal or cross-sectional studies permitted the clinical characterization of PAH in mutation carriers to be accurately described. The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counseling for a severe disease, taking into account that the major predisposing gene has a highly variable penetrance between families. Molecular information can be drawn from the genomic study of affected tissues in PAH, in particular, pulmonary vascular tissues and cells, to gain insight into the mechanisms leading to the development of the disease. High-throughput genomic techniques, on the basis of next-generation sequencing, now allow the accurate quantification and analysis of ribonucleic acid, species, including micro-ribonucleic acids, and allow for a genome-wide investigation of epigenetic or regulatory mechanisms, which include deoxyribonucleic acid methylation, histone methylation, and acetylation, or transcription factor binding. (J Am Coll Cardiol 2013;62:D13–21) ª 2013 by the American College of Cardiology Foundation

Genetics of Pulmonary Hypertension apparently sporadic cases have now unequivocally established defects in this gene as the major genetic determinant underlying Hereditary predisposition to pulmonary arterial hyper- PAH (1). Pathogenic mutations in the type I receptor ACVRL1 tension: from major genes to associated single nucleotide and, at a signiﬁcantly lower frequency, the type III receptor polymorphisms. Over 300 independent BMPR2 mutations endoglin in multiple kindreds cause PAH associated with (coding for a type II receptor member of the transforming growth hereditary hemorrhagic telangiectasia (HHT) (2). Together, factor [TGF]-b family) have been identiﬁed that account for these observations support a prominent role for TGF-b family approximately 75% of patients with a known family history of members in the development of PAH. Consequently, a series of pulmonary arterial hypertension (PAH), and up to 25% of

From the *Genetics Department, Hospital Pitié-Salpêtrière, Assistance Publique Vanderbilt University Medical Center North, Nashville, Tennessee; **Departments of Hôpitaux de Paris (APHP), Unité Mixte de Recherche en Sante (UMRS) 956 Institut Medicine at Intermountain Medical Center and the University of Utah, Salt Lake National de la Sante et de la Recherche Medicale INSERM, Université Pierre et City, Utah; yyDivision of Genetics and Molecular Medicine, Kings College, London, Marie Curie Paris 06 (UPMC), and Institute of Cardiometabolism and Nutrition United Kingdom; and the zzCentre de Référence de l’Hypertension Pulmonaire (ICAN), Paris, France; yDepartments of Pediatrics and Medicine, Columbia Sévère, Service de Pneumologie, Hôpital de Bicêtre, APHP, Le Kremlin Bicêtre, University Medical Center, New York, New York; zUniversity of Lincoln, School of Université Paris-Sud, Faculté de Médecine, Le Kremlin Bicêtre; Département Life Sciences, Lincoln, United Kingdom; xCentre for Pulmonary Hypertension at Hospitalo-Universitaire (DHU) thorax Innovation, AP-HP, Le Kremlin Bicêtre; University Hospital Heidelberg, Heidelberg, Germany; kGenomic Medicine Institute, UMR_S 999, INSERM and Université Paris-Sud, LabEx LERMIT, Centre Chir- Cleveland Clinic, Cleveland, Ohio; {Division of Pulmonary Sciences and Critical urgical Marie Lannelongue, Le Plessis Robinson, France. Dr. Machado has received Care Medicine, University of Colorado Denver, Aurora, Colorado; #Pulmonary institutional grant support from Actelion and United Therapeutics; and is on the Hypertension Center, Division of Allergy, Pulmonary and Critical Care Medicine, advisory board of United Therapeutics and Gilead. Dr. Grünig has served on the D14 Soubrier et al. JACC Vol. 62, No. 25, Suppl D, 2013 Genetics and Genomics of Pulmonary Arterial Hypertension December 24, 2013:D13–21

Abbreviations studies have adopted a candidate and require further investigation on the functional level. Austin and Acronyms gene approach to delineate novel et al. (8) used whole exome sequencing to study a 3-generation genetic variants by examining family with multiple affected family members with PAH but no BMP = bone morphogenetic b fi protein TGF- receptors and effectors identi able mutation in the known heritable pulmonary arterial in patient cohorts without muta- hypertension (HPAH) genes and identified a novel gene for CHD = congenital heart fi disease tions in the known PAH genes. HPAH: Caveolin-1 (CAV1). They also identi ed a de novo

GINA = Genetic Information With conventional analytical frameshift mutation in a child with IPAH. CAV1 encodes Non-Discrimination Act techniques, Shintani et al. (3) a membrane protein of caveolae abundant in the endothelium ﬁ GSD = glycogen storage identi ed a truncating mutation and other cells of the lung. Caveolae are rich in cell surface disease in the bone morphogenetic protein receptors critical to initiation of a cellular signaling cascade such b HDAC = histone deacetylase (BMP)-responsive gene SMAD9 as the TGF superfamily, nitric oxide pathway, and G-protein

HHT = hereditary (p.C202X) in a panel of 23 Japa- coupled receptors. Aberrant signaling at the plasma membrane hemorrhagic telangiectasia nese cases. A second truncating might be the mechanism for PAH pathogenesis. Their study

HPAH = heritable pulmonary mutation (p.R294X) has since demonstrates that mutations in CAV1 are associated in rare arterial hypertension been identified in another pa- cases with familial PAH and IPAH, and it could provide new IL = interleukin tient of Asian descent (4).A insight into the pathogenesis of PAH. fi IPAH = idiopathic pulmonary similar screen of the BMP-speci c Exome sequencing in another family with multiple arterial hypertension SMADs and SMAD4 described affected family members without identifiable HPAH muta- mRNA = messenger a series of 4 variants in 198 idio- tions was found to have a heterozygous novel missense ribonucleic acid pathic pulmonary arterial hyper- variant in the potassium channel KCNK3 (9). Analysis for miRNA = micro ribonucleic tension (IPAH) patients. These additional familial PAH cases and IPAH cases identified acid variants in SMAD1 (p.V3A), 5 additional heterozygous novel missense variants. All 6 PAEC = pulmonary artery SMAD4 (p.N13S; c.1448-6T>C), variants are located in highly conserved amino acids and are endothelial cell and SMAD9 (p.K43E) were des- predicted to be damaging by in silico analysis. With transient PAH = pulmonary arterial cribed as being of unknown sig- transfection in COS-7 cells, whole patch clamp procedures hypertension nificance due to their moderate demonstrated that each of the 6 mutations resulted in loss of PASMC = pulmonary artery effects on canonical downstream function. Some, but not all, mutations were rescued by the smooth muscle cell BMP-mediated signaling out- phospholipase inhibitor, ONO RS-082. KCNK3 encodes SNP = single nucleotide comes (5).TheSMAD9 variants a pH-sensitive potassium channel in the 2-pore domain polymorphism are more compelling, because superfamily (10). It has been reported that this potassium TGF = transforming growth these data are supported by the channel is sensitive to hypoxia and plays a role in the regu- factor development of clinical and his- lation of resting membrane potential and pulmonary vascular topathological features of pulmonary hypertension in a Smad9 tone (11–13). Identification of this gene as a cause of HPAH knock-out mouse model (6). More recently, 2 missense and IPAH and the possibility of rescuing specific mutations mutations of the type I receptor BMPR1B (p.S160N and might provide a new target for PAH treatment. p.F392L) were reported in a cohort of 43 IPAH patients. Childhood-onset PAH shows some clinical and genetic Subsequent functional and reporter assays suggested that these differences from adult-onset PAH. The frequency of variants generated an induction of SMAD9 and augmentation BMPR2 mutations found in sporadic cases is far lower than in of transcriptional activity indicative of a gain-of-function adult-onset PAH (14–16). Pulmonary hypertension is an mechanism. Because the preceding studies, in conjunction uncommon complication in many genetic disorders, although with the Smad9 mutant mouse model, suggest a molecular in certain syndromes such as Down syndrome, PAH is more mechanism of haploinsufficiency for this gene, the observations common (17). The increased risk for PAH with Down described by Chida et al. (7) would seem to be contradictory syndrome is due to left-to-right cardiac shunts; in addition, upper airway obstruction associated with obstructive sleep apnea might promote non-PAH pulmonary hypertension advisory board of Bayer Healthcare, Actelion, GlaxoSmithKline, Eli Lilly, Novartis, (18). Genetic syndromes more commonly but not necessarily United Therapeutics, Alexion, and Pfizer; and has received consultancy and lecture associated with congenital heart disease (CHD) and fees from Bayer Healthcare Pharmaceuticals, Actelion, GlaxoSmithKline, Eli Lilly, pulmonary hypertension include DiGeorge syndrome, Novartis, United Therapeutics, Pfizer, and Alexion. Dr. Geraci has served on the Medical Advisory Board for Flight Attendants Medical Research Institute. Dr. Elliott VACTERL syndrome, CHARGE syndrome, Scimitar is employed by Intermountain Healthcare, which has received research grants from syndrome (19), Noonan syndrome (20), and chromosomal Actelion, Bayer, GeNO, Gilead, National Institutes of Health, and United Thera- anomalies associated with congenital diaphragmatic hernia. peutics for which he has acted as Principal Investigator; and he has received honoraria and/or consulting fees from Ikaria, CoTherix, and Boehringer Ingelheim. Dr. Genetic syndromes associated with pulmonary hypertension Humbert has served on the scientific advisory board of and as an investigator for trials usually not associated with CHD include Adams-Oliver involving Actelion, Aires, Bayer, GlaxoSmithKline, Novartis, and Pfizer. All other syndrome (21,22), neurofibromatosis type 1 (23,24), long authors have reported that they have no relationships relevant to the contents of this paper to disclose. QT syndrome, hypertrophic cardiomyopathy, Cantu Manuscript received October 15, 2013; accepted October 22, 2013. syndrome (25), autoimmune polyendocrine syndrome (26), JACC Vol. 62, No. 25, Suppl D, 2013 Soubrier et al. D15 December 24, 2013:D13–21 Genetics and Genomics of Pulmonary Arterial Hypertension mitochondrial disorders including mitochondrial encepha- influence the penetrance of the BMPR2 mutations. They lopathy lactic acidosis and stroke-like episodes (27), Gaucher proposed that the TGF-b1 polymorphism modulates the disease (28), and glycogen storage diseases (GSDI and age at diagnosis and penetrance of the BMPR2 mutations. GSDIII) (29). The mechanism for development of pulmo- West et al. (35) used another approach by studying gene nary hypertension has not been definitely demonstrated for expression in immortalized B-lymphocyte cell lines of most genetic syndromes but could involve increased pulmo- BMPR2 mutation carriers, either affected or unaffected. The nary blood flow with left-to-right shunts with CHD, upper most striking expression difference was observed for the airway obstruction, dysfunctional vascular smooth muscle CYP1B1 gene, with nearly 10-fold lower expression, but cells with hyperproliferation leading to pulmonary vessel only in female patients (36). CYP1B1 is in the synthetic stenosis and remodeling (Adams Oliver syndrome [21,22] pathway of 2-OH estradiol metabolites that have anti- and neurofibromatosis type 1) (24,30), pulmonary venous proliferative effects on pulmonary vascular smooth muscle obstruction (Cantu syndrome) (25), or production of cells and attenuate pulmonary hypertension in animal diffusible hepatic factors increasing the pulmonary pressures models (37,38). In contrast, when CYP1B1 is inhibited, (Gaucher disease and GSD) (29). Notably, pulmonary 16b-OH-estradiol and -estrone are synthesized, which have hypertension in patients with Gaucher disease has been re- proinflammatory, proangiogenic, and promitogenic effects ported to respond well to treatment of the primary metabolic (reviewed in Paulin and Michelakis [39]). However, mice disorders with enzyme replacement therapy (28). with a disrupted Cyp1b1 gene do not exhibit differences in Nimmakayalu et al. (31) reported a microdeletion the development of experimental pulmonary hypertension, encompassing TBX2 and TBX4 in a case of syndromic indicating an environmental context for the gene-effect (40). pulmonary hypertension associated with microcephaly These results show the complexity of hormonal influences thyroid and sensorineural abnormalities. Recently, Kerstjens- that might explain female predominance of PAH, which is Frederikse et al. (32) studied 3 children with idiopathic or observed in HPAH as well as in IPAH (41). With the same familial PAH associated with mental retardation and dys- type of approach in cultured cells from patients carrying morphic features by comparative genomic hybridization to BMPR2 mutations leading to destruction of the mutated identify deletions encompassing the same locus. They found messenger ribonucleic acid (mRNA) by nonsense mediated 3 overlapping deletions at 17q23.2 involving also the TBX2 ribonucleic acid (RNA) decay, Flynn et al. (42) have and TBX4 genes. These genes were subsequently sequenced proposed a PAH penetrance signature on the basis of in the 20 children, and 3 additional mutations were found in expression profiling of mRNAs in lymphocytes, and this the TBX4 gene, which is responsible for the small patella profile suggests that reactive oxygen species formation would syndrome. All patients with the TBX4 mutations present play an important role in the development of the disease. with signs of small patella syndrome. Inversely, careful Concurrent inflammation can modify pathologic effects of investigation of patients known to have small patella the mutated BMPR2 gene (43,44). syndrome did not reveal pulmonary hypertension. Clinical presentation of HPAH. In approximately 75% of Another approach for identifying genes predisposing for patients with a family history of PAH, a mutation in known PAH is to perform association studies using polymorphic PAH-causing genes has been identified (1,15,45,46) corre- markers (single nucleotide polymorphisms [SNPs]) distrib- sponding mostly with BMPR2 mutations. In patients uted throughout the whole genome. This approach requires without known family history (sporadic or idiopathic cases), a large number of patients and control subjects to compare approximately 20% harbor a germ-line mutation. In patients the genotype frequencies in the 2 groups and look for with a personal or familial history of HHT, ACVRL1 a significant difference that can indicate association between mutations were the major cause identified. Similar propor- the disease and the marker. With such an approach, Ger- tions of mutation carriers were observed in anorexigen- main et al. (33) identified an SNP associated with IPAH induced PAH. By contrast, BMPR2 mutations are not and the familial form of PAH not caused by BMPR2 found in associated PAH (scleroderma and connective tissue mutations. The risk allele of the SNP is associated with an diseases, portal hypertension, human immunodeficiency odds ratio for PAH of 1.97 (95% confidence interval: 1.59 to virus infection), with the exception of some reports in 2.45; p ¼ 7.47 10 10) and is close to the Cerebellin 2 CHDs. Of note, familial cases of pulmonary veno-occlusive (CBLN2) gene on Chr 18q22.3. diseases are rarely associated with a BMPR2 mutation The molecular basis of the variation in penetrance (47–49). observed for BMPR2 mutations has been addressed by Retrospective analysis from registries (1,15,45,46) and 1 several studies. The question is made difficult by the limited prospective study (50) revealed that HPAH patients carrying number of patients who can be included in this type of a BMPR2 mutation, irrespective of the family history, study, which requires large series of patients to reach develop PAH at a younger age than mutation-negative statistical significance. Different approaches have been used. IPAH patients. Furthermore, HPAH patients have a more Philips et al. (34) studied a functional polymorphism of the severe clinical and hemodynamic phenotype at diagnosis TGF-b1 gene to investigate a possible disequilibrium (less response to acute vasodilator challenge, lower cardiac between the BMPs and TGF signaling pathways that might index, and higher pulmonary vascular resistance), and they D16 Soubrier et al. JACC Vol. 62, No. 25, Suppl D, 2013 Genetics and Genomics of Pulmonary Arterial Hypertension December 24, 2013:D13–21 are more likely to progress to death or lung transplantation childless, to have no genetic pre-natal testing (reproductive (at a younger age than noncarriers) (46,50–53). However, chance), to undergo pre-natal or pre-implantation genetic the number of analyzed gene-carriers is so far relatively low. diagnosis, to use gamete donation, or to adopt. Pre-natal Further studies are needed to evaluate whether genetic diagnosis allows the detection of an in utero fetus carrying testing might be helpful for risk stratification and clinical a mutation predisposing to PAH. Pre-natal diagnosis management. Similar findings are observed with ACVRL1 requires that the familial mutation has been identified mutations with a significant number of pediatric cases and molecularly. If the familial mutation is identified, a medical a dismal prognosis (50). Of note, ACVRL1 mutation carriers abortion is an option. might develop both PAH and HHT. Because HHT has Another option is pre-implantation genetic diagnosis, nearly complete penetrance at the age of 60 years, some medically-assisted reproduction with selection and implan- ACVRL1 mutation carriers might not have clinical evidence tation of embryos that do not carry the familial mutation, of HHT at very young ages. Collecting information of thus avoiding the distress of a medical abortion. Pre- personal and familial history of HHT, including “forme implantation genetic diagnosis requires in vitro fertilization fruste,” seems important, especially in pediatric cases. and might require multiple cycles before leading to A more extensive evaluation of the Vanderbilt Pulmonary successful delivery of a baby. Pre-implantation genetic Hypertension Registry casts doubt on the likelihood of diagnosis is not available in all countries and is not a covered genetic anticipation in BMPR2-related familial PAH (54). insurance benefit in all countries or by all insurers. These Analysis of families with sibships that have lived at least 57 methods are used in many other diseases but are contro- years from first family diagnosis allows >85% of mutation versial in conditions in which penetrance is incomplete, such carriers to express disease. In these families, the apparent as HPAH. Due to the psychological impact of abortion on effect of lower age of onset in earlier generations disappears, prospective parents, especially in the setting of an incom- because the time it takes for penetrance to occur in this pletely penetrant genetic disease, many patients prefer pre- illness can be up to 75 years of age in an apparently unaf- implantation genetic diagnosis in selected HPAH families fected carrier. Thus, genetic anticipation is no longer sup- after multidisciplinary discussion when it is financially ported by current data. feasible and medically available. In France, pre-implantation The penetrance of disease in the Vanderbilt Pulmonary genetic diagnosis is currently offered to selected families Hypertension Registry has been re-evaluated (54): of a total with highly-penetrant BMPR2 mutations causing HPAH number of 1,683 siblings, assuming a 50% carriage rate of (57,58). Because pregnancy is a risk factor of PAH, pre- the mutation, there were 232 affected individuals of 842 implantation genetic diagnosis is currently proposed in carriers (one-half of 1,683 siblings), or a 27% overall pene- couples where the future father carries the causal mutation. trance. There were 177 female subjects and 59 male subjects. Genetic testing allows identification of pre-symptomatic The female/male ratio of PAH was 3:1, which was similar to carriers of PAH-causing mutations who are at high risk of previous estimates. The female penetrance was approxi- developing PAH. However, because of incomplete pene- mately 42%, and the male penetrance was approximately trance of mutations in PAH-predisposing genes, it is 14%. These sex differences should have an impact on disease currently not possible to identify which carriers of a muta- and genetic counseling in families. tion will develop PAH. There are currently no proven Genetic counseling and testing. Two consensus guide- effective interventions or medications available to prevent lines recommend that physicians offer professional genetic disease in mutation carriers. Associated genetic or environ- counseling and genetic testing to patients with a history that mental factors modifying penetrance of PAH in these suggests HPAH (55,56). In addition, the authors of these mutation carriers to improve risk stratification are still guidelines have recommended that patients with IPAH be unknown. Thus, genetic testing in relatives will effectively advised about the availability of genetic testing and coun- identify mutation noncarriers who have no increased risk of seling, because of the strong possibility that they carry the heritable disease and potentially provide significant a disease-causing mutation. The guidelines recommend that relief; however, mutation carriers currently face many professionals offer counseling and testing to the affected uncertainties, because physicians cannot determine which IPAH patient before approaching other family members. patients will develop the disease or when. Such patients are The identification of a disease-causing mutation in an currently offered yearly screening echocardiography with affected family member allows less expensive testing of other Doppler as well as immediate evaluation for symptoms such family members, if they want such testing. as exercise dyspnea. Because of the psychological impact of Affected individuals and “at risk” family members might the positive or negative genetic results in asymptomatic want to know their mutation status for family planning relatives, pre-symptomatic genetic testing should be purposes. Pre-natal screening or pre-implantation diagnosis provided in the setting of a multidisciplinary team with and management are possible. Reproductive medicine allows availability of pulmonary hypertension specialists, genetic several options for preventing transmission of HPAH to the counselors, geneticists, psychologists, and nurses. next generation. Indeed, current reproductive options for In France, up to 200 relatives of mutation carriers have couples with a BMPR2 mutation carrier are to remain volunteered for pre-symptomatic genetic testing. This led to JACC Vol. 62, No. 25, Suppl D, 2013 Soubrier et al. D17 December 24, 2013:D13–21 Genetics and Genomics of Pulmonary Arterial Hypertension the identification of dozens of asymptomatic BMPR2 muta- cases showed that endothelial cells have a monoclonal tion carriers. An ongoing study is currently evaluating the pattern of X-inactivation (62,64). Some lesions also showed efficacy of pre-symptomatic screening and follow-up in this microsatellite instability, a hallmark of hereditary non- cohort. In this study, all carriers have yearly complete evalua- polyposis colon cancer, and mutations of the apoptosis tion, including exercise testing, Doppler echocardiography, regulator BAX (65). Many of the abnormal properties and measurement of circulating biomarkers (and rest observed in pulmonary artery endothelial cells (PAECs) and and exercise right heart catheterization) (NCT01600898). pulmonary artery smooth muscle cells (PASMCs) are Long-term follow-up might allow investigators to identify analogous to cancer, including increased proliferation, predictors of progression to PAH in pre-symptomatic BMPR2 decreased apoptosis, activation of hypoxia-inducible factor- mutation carriers. This active screening approach remains 1-alpha, mitochondrial abnormalities, and a shift from investigational and should help to refine future guidelines. oxidative to glycolytic metabolism (66–72). In the United States, physicians, PAH patients, and their Use of SNP arrays or comparative genomic hybridization family members have rarely embraced pre-symptomatic array data to assess copy number variations can provide genetic testing for several reasons. First, genetic testing is important information in PAH. Analysis of hyper- relatively expensive. Second, the psychological impact of proliferative PAECs and PASMCs from patients with PAH either a positive test (anxiety and depression) or a negative test identified large-scale genomic alterations in the endothelial (survivor guilt) is important for some individuals. These cells, which were confirmed in patient lung tissue by fluo- effects might have unintended consequences for other family rescent in-situ hybridization (73). Abnormalities were members who do not wish to know their mutational state. detected across heritable, idiopathic, and associated cases of Third, in the United States, concerns about discrimination PAH, providing the first evidence for a second genetic hit in remain, in spite of the passage of the Genetic Information patients with germline BMPR2 mutations and also sug- Non-Discrimination Act (GINA) (HR 493). Although gesting that somatic changes might represent a shared GINA protects against discrimination by insurers and em- feature across different types of the disease. However, there ployers, there are gaps in GINA protections (e.g., when is no evidence for direct loss of heterozygosity at the BMPR2 applying for life, disability, or long-term insurance). In locus (74). In some cases, PAECs seem to be clonal even contrast, the French Network of Pulmonary Hypertension before the acquisition of the cytogenetically abnormal sub- has launched a genetic counseling clinic with more than 1,000 clone (73). This suggests that another underlying genetic subjects volunteering for “free” genetic counseling in the last mutation or other population bottleneck precedes the 10 years (M. Humbert, personal communication, June 2013). chromosome rearrangement, a finding that fits well with In a German proof of concept approach (59) and the hypothesis that endothelial apoptosis in the early stages a subsequent larger study in the European Union, screening of PAH leads to subsequent selection of proliferative, of family members with echocardiography at rest and during apoptosis-resistant endothelial cells (75). exercise and hypoxia revealed a significantly higher The PASMC proliferation is also a critical component of frequency of an elevated tricuspid regurgitation velocity vascular remodeling in PAH, yet the incidence of chromo- response to exercise and to prolonged hypoxia than in some abnormalities seems to be much lower than in PAECs. control subjects, especially in those relatives who shared PASMCs are also usually polyclonal (62). The reasons for a BMPR2 mutation with the index patients (60). This these differences are presently unclear. suggests that elevated estimated pulmonary artery pressure One limitation of these studies is their reliance on explant response to exercise and hypoxia might be genetically or autopsy lung tissue, which by definition represents end- determined with a familial clustering. Further studies are stage disease. However, it is not feasible to obtain tissue needed to analyze the clinical value of noninvasive screening by lung biopsy in the earlier stages of PAH. Another assessments in relatives of IPAH and HPAH patients and important consideration is to demonstrate that these to develop an algorithm for early diagnosis in this cohort. abnormalities are not simply artifacts of in vitro cell culture. Several lines of evidence argue against this, including Genomics of PAH confirmation of 2 chromosome deletions in uncultured lung tissue by fluorescent in-situ hybridization and the absence of Besides the investigation of constitutional genetic variations any detectable abnormalities in multiple control subjects or or mutations underlying PAH, molecular investigation of cells from explant lungs of patients with cystic fibrosis or lung tissue or specific cell types when possible or surrogate chronic obstructive pulmonary disease (73). blood cells can provide important information concerning mRNA expression studies. Early expression studies on the mechanisms of the disease. lung tissue were limited by small sample sizes. Alternative Somatic genetic changes in PAH lungs. Considerable strategies with surrogate tissue (peripheral blood) have sug- evidence has accumulated over the past decade to advance gested the utility of transcriptional profiling (76). The effec- the hypothesis that the pathogenesis of PAH is a neoplastic- tiveness of expanding cohort sizes and using well-defined like process (61–63). Microdissection of plexiform lesions phenotypes for array-based classification was demons- from the lungs of idiopathic and anorexigen-induced PAH trated with blood and examining markers that differentiate D18 Soubrier et al. JACC Vol. 62, No. 25, Suppl D, 2013 Genetics and Genomics of Pulmonary Arterial Hypertension December 24, 2013:D13–21

“scleroderma only” from “systemic sclerosis-associated PAH” conserved and functional STAT3-binding site in the patients (77). There is a clear benefit to using large, well- promoter region of miR17/92 was found, and persistent characterized cohorts when examining lung tissue gene activation of STAT3 leads to repressed protein expression of expression profiles. Several newer efforts have focused on BMPR2 (91). this approach. A larger sample of lung tissue array analysis The BMP/TGF-b signaling itself regulates multiple demonstrates similar pathway disruption between pulmo- different miRNAs through an interaction between Smads nary hypertension and pulmonary fibrosis (78). Perhaps the and the primary miRNA transcript, which leads to up- largest study to date using lung tissue microarray profiling regulation of mature miRNAs in response to BMP ligand demonstrated that, in patients with pulmonary fibrosis, the (92). This response was lost in lung vascular cells from presence of pulmonary hypertension is characterized by a patients with BMPR2 or SMAD9 mutations, suggesting that specific gene expression profile in both a training and testing abnormal miRNA regulation plays an important role in algorithm (79). HPAH (4). A systems biology approach supports a central Cell-based expression studies have been useful in char- role for miR-21, 1 of the miRNAs regulated by this BMP- acterizing selected pathways as well as determining mediated pathway (93). Abnormalities of miRNA process- differences in selected cell populations. For systemic ing in HPAH cells can be corrected by increasing the amount sclerosis-associated PAH, pulmonary fibroblasts and lung of BMPR-II protein at the cell surface or by promoting tissue from patients with PAH and those from systemic readthrough of nonsense mutations in BMPR2 or SMAD9 sclerosis patients without PAH demonstrate characteristic (94,95). These approaches have the advantage of correcting gene expression signatures (80). Several studies have used the levels of multiple different miRNAs as well as other global gene expression signatures to determine a more robust aspects of BMP signaling and, therefore, could represent pathway analysis, including the effects of BMPR2 deficiency promising therapeutic approaches in HPAH. Other studies (81). The novel role of interleukin (IL)-13 in PAH in human tissues and animal models of pulmonary hyper- pathobiology has been investigated, on the basis of array- tension have implicated additional miRNAs, including the generated data (82) and mouse model studies (83). Poten- miR-17-92 cluster and miR-145 (91,96,97). tial new therapeutic targets, such as apelin and peroxisome There are several methods to assess global miRNA proliferator-activated receptor-gamma, have been extensively expression, and both array-based and polymerase chain studied with array-based platforms (84,85). reaction-based methods represent biased approaches, relying One significant challenge to all genomic approaches is on “known” miRNA sequences. Because miRNA processing leveraging data into novel systems-based analysis ap- can result in changes of miRNA sequences, the most proaches. Putting all of the relevant information into unbiased approach and one that is increasingly adopted is a systems model of pulmonary vascular disease might provide the use of massively parallel sequencing strategies targeting unique insights (86). small RNA species. Role of miRNAs in PAH. Microribonucleic acids (miR- Epigenetic modifications and pulmonary hypertension. NAs) are small non-coding sequences of RNA that have the Epigenetic traits are stably heritable phenotypes resulting capacity to regulate many genes, pathways, and complex from changes in a chromosome without alterations in biological networks within cells, acting either alone or in deoxyribonucleic acid sequence (98). Epigenetic changes are concert with one another (87). In diseases such as cancer and thought to lead to cellular reprogramming, the process by cardiac disease, the role of miRNAs in disease pathogenesis which a differentiated cell type can be induced to adopt an has been well-documented (88). The application of miRNA alternate cell fate. This idea seems to be consistent with technologies and their therapeutic potential in cardiovascular observations in pulmonary hypertension, in which PAECs, diseases is most elegantly summarized by Small and Olson PASMCs, and adventitial fibroblasts have all been demon- (89). The most extensive global investigation, leading to strated to acquire significantly altered characteristics, in- mechanistic studies and potential therapeutic implications cluding stable increases in proliferation, resistance to for miRNAs in PAH centers, was performed on miR-204 apoptosis, metabolic switching, and pro-inflammatory gene (90). In this study, the investigators provided a comprehen- expression. Recent studies have documented that down- sive model linking abnormal miRNA expression to already regulation of superoxide dismutase-2 in the fawn-hooded rat known pathophysiologic processes in PAH, including model of pulmonary hypertension results from tissue- nuclear factor of activated T cells activation, BMPR-II specific hypermethylation of just 2 CpG positions in the down-regulation, IL-6 production, the Rho pathway, SOD2 promoter and an intronic enhancer (99). Another PASMC proliferation, and resistance to apoptosis. This candidate for epigenetic study is BMPR2, with significantly study not only demonstrates the importance of miRNAs in down-regulated expression in many PAH lungs, even in the PAH but also suggests that re-establishing normal miR-204 absence of a germline mutation (78,100). levels might represent a novel therapeutic approach for Histone deacetylases (HDACs) catalyze removal of acetyl human PAH (90). Brock et al. (91) showed that BMPR2 is groups from lysine residues in a variety of proteins. The directly targeted by miR-17-5p and miR-20a and that IL-6 HDACs have mainly been studied in the context of induces miR-17/92 through STAT3 induction. A highly chromatin, where they regulate gene transcription by JACC Vol. 62, No. 25, Suppl D, 2013 Soubrier et al. D19 December 24, 2013:D13–21 Genetics and Genomics of Pulmonary Arterial Hypertension deacetylating nucleosomal histones. The 18 mammalian REFERENCES HDACs are grouped into 4 classes (101). Dysregulation of 1. 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Right Heart Adaptation to Pulmonary Arterial Hypertension Physiology and Pathobiology Anton Vonk-Noordegraaf, MD,* François Haddad, MD,y Kelly M. Chin, MD,z Paul R. Forﬁa, MD,x Steven M. Kawut, MD,k Joost Lumens, PHD,{ Robert Naeije, MD,# John Newman, MD,** Ronald J. Oudiz, MD,yy Steve Provencher, MD,zz Adam Torbicki, MD,xx Norbert F. Voelkel, MD,kk{{ Paul M. Hassoun, MDz Amsterdam and Maastricht, the Netherlands; Stanford and Torrance, California; Dallas, Texas; Philadelphia, Pennsylvania; Brussels, Belgium; Nashville, Tennessee; Chemin Sainte-Foy, Québec, Canada; Otwock, Poland; Richmond, Virginia; and Baltimore, Maryland

Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the underlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation. (J Am Coll Cardiol 2013;62:D22–33) ª 2013 by the American College of Cardiology Foundation

Pulmonary arterial hypertension (PAH) is a progressive patients, however, these compensatory mechanisms are disorder that affects both the pulmonary vasculature and the insufﬁcient, and RV dysfunction occurs. In this report, we heart (1–6). Although the initial insult in PAH involves the highlight current understanding of RV pathobiology in pulmonary vasculature, survival of patients with PAH is PAH and brieﬂy outline the evidence underlying the closely related to right ventricular (RV) function (7–19). The management of right heart failure (RHF) in PAH. Future right ventricle adapts to the increased afterload by increasing directions and priorities of research in RV research in PAH its wall thickness and contractility. In the vast majority of are also discussed. Although the majority of the report

From the *Department of Pneumology, VU University Medical Center, Amsterdam, committee for Actelion, Bayer, and Pfizer. Dr. Chin has received research grants the Netherlands; yDivision of Cardiovascular Medicine, Department of Medicine, from Actelion, Bayer, Gilead, GlaxoSmithKline, Novartis, United Therapeutics, Stanford University, Stanford, California; zDepartment of Internal Medicine, GeNO, and the National Institutes of Health; and honoraria for service on advisory Pulmonary Division, University of Texas Southwestern Medical Center, Dallas, boards for Actelion, Bayer, and Gilead. Dr. Forfia is a consultant for Actelion and Texas; xPulmonary Hypertension and Right Heart Failure Program, Temple United Therapeutics. Dr. Lumens has received a research grant within the framework University Hospital, Philadelphia, Pennsylvania; kPerelman School of Medicine, of the Dr. E. Dekker Program of the Dutch Heart Foundation (NHS-2012T010). University of Pennsylvania, Philadelphia, Pennsylvania; {CARIM School for Dr. Oudiz has received grants and research funding, consulting and speaking fees, Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands; and honoraria from Actelion, AIRES, Bayer, Gilead, Ikaria, Lung LLC, Pfizer, #Department of Pathophysiology, Faculty of Medicine, Free University of Brussels, United Therapeutics. Dr. Provencher has received consulting fees from Actelion, Brussels, Belgium; **Department of Medicine, Division of Allergy, Pulmonary and GlaxoSmithKline, Pfizer, and Unither Biotech; research grants from Actelion, Bayer, Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Ten- and GlaxoSmithKline; and speaker fees from Actelion. Dr. Torbicki has received nessee; yyThe David Geffen School of Medicine at UCLA, Liu Center for Pulmonary research grants and speaker’s honoraria from Actelion, Bayer, AOP, United Thera- Hypertension, Division of Cardiology, Biomedical Research Institute at Harbor- peutics, and GlaxoSmithKline; and has served on advisory boards and scientific UCLA Medical Center, Torrance, California; zzPulmonary Hypertension Research committees for Actelion, Bayer, AOP, and GlaxoSmithKline. Dr. Voelkel has Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneu- received grant support for pre-clinical studies from Actelion and United Therapeu- mologie de Québec, Chemin Sainte-Foy, Québec, Canada; xxDepartment of tics. Dr. Hassoun has participated on advisory boards for Gilead, Merck, Bayer, and Pulmonary Circulation and Thromboembolic Diseases, Centre of Postgraduate Novartis; has received research funding from United Therapeutics for the Registry to Medical Education, ECZ, Otwock, Poland; kkDivision of Pulmonary and Critical Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Care Medicine and Victoria Johnson Lab for Lung Research, Virginia Common- Management; and his research was supported by grants P50 HL084946 and R01 wealth University, Richmond, Virginia; and the {{Johns Hopkins University, Balti- HL114910 from the National Heart, Lung, and Blood Institute. All other authors more, Maryland. Dr. Vonk-Noordegraaf has received lecture fees from Actelion, have reported that they have no relationships relevant to the contents of this paper to Bayer, GlaxoSmithKline, United Therapeutics, Lilly, Pfizer, and Novartis; is on the disclose. Drs. Vonk-Noordegraaf and Haddad contributed equally to this manuscript. industry advisory board from Actelion and Bayer; and serves on the steering Manuscript received October 15, 2013; accepted October 22, 2013. JACC Vol. 62, No. 25, Suppl D, 2013 Vonk-Noordegraaf et al. D23 December 24, 2013:D22–33 The Right Ventricle in Pulmonary Hypertension

“ ” focuses on RHF in the setting of PAH, the committee also failure (stage A), asymptomatic Abbreviations wants to emphasizes that RV function is also a strong heart dysfunction (stage B), symp- and Acronyms predictor of outcomes in patients with left heart failure, tomatic heart failure (stage C), and BNP = B type natriuretic advanced lung disease, and congenital heart disease (20). end-stage heart failure (stage D) peptide (34).Thisclassification could CO = cardiac output Definition of the Right Heart Failure Syndrome potentially be applied to patients Ea = arterial elastance with RHF, with the caveat that RHF in patients with PAH can be defined as a complex the majority of patients with Ees = ventricular elastance clinical syndrome due to suboptimal delivery of blood and/or advanced RHF (stage D) have LV = left ventricular elevated systemic venous pressure at rest or exercise as the ability to reverse remodel MHC = myosin heavy chain a consequence of elevated RV afterload. after lung transplantation. Also MPAP = mean pulmonary The cardinal clinical manifestations of RHF are exercise importantly, although we often arterial pressure limitation and fluid retention. Exercise limitation is the consider the right ventricle and PAC = pulmonary arterial earliest symptom of RHF and is a strong predictor of the left ventricle as separate en- compliance survival in patients with PAH (8,14,21). Exercise limitation tities, this distinction is some- PAH = pulmonary arterial is related to a decrease in flow reserve during exercise what artificial, because both hypertension (decreased peak cardiac index) (22–24). In addition, ventricles are interconnected th- PH = pulmonary a reduction in peripheral blood flow can increase lactate rough the interventricular sep- hypertension production, further contributing to muscle fatigue and tum, shared myofibers, and the PVR = pulmonary vascular resistance exercise limitation. Supraventricular tachycardia, which can pericardium. Because of ventric- occur in approximately 12% of patients with PAH or ular interdependence, patients RAP = right atrialpressure inoperable thromboembolic pulmonary hypertension, can with RHF will often have relax- RHF = right heart failure also lead to clinical deterioration and reduced exercise ation abnormalities of the left RNA = ribonucleic acid capacity (25). Syncope, a less common symptom of PAH, ventricle and, in severe cases, RV = right ventricular often indicates severe limitations in flow reserve. As in left- even left ventricular systolic RVEF = right ventricular sided heart failure, RHF can also lead to chronic kidney dysfunction (2,20,35).Recentstu- ejection fraction disease and hyponatremia (26). Shah et al. (27) showed that dies have also emphasized electro- chronic kidney disease in patients with PAH is associated physiological remodeling in the left ventricle in patients with increased right atrial pressure and a higher likelihood of with PAH (36). death or transplantation. Similarly, acute kidney injury has also been associated with worse outcomes after acute RHF Pathobiology of Right Heart Failure Syndrome in (28). Although congestive hepatopathy is often observed in Pulmonary Arterial Hypertension patients with RHF and PAH, cirrhosis is a late complication of severe RHF. In patients with worsening hypoxemia and The continuum of RV remodeling in PAH. RV adap- PAH, right-to-left shunting through a patent foramen ovale tation and ventricular remodeling in PAH is a complex must be considered. process that depends not only on the severity of pulmonary Patients with PAH may also present with acute heart vascular disease but also on the interplay between neuro- failure. Recent studies have shown that the short-term hormonal activation, coronary perfusion, and myocardial mortality in patients with PAH and acute RHF may be as metabolism (Fig. 1) (6,20,37–45). Other factors that may high as 40% in patients who require admission to the hospital influence RV adaptation include the rate and time of onset (29–32). Although the majority of patients with acute RHF of pulmonary hypertension, its underlying etiology, and, are admitted with congestive symptoms requiring diuretic although not yet well defined, genetic and epigenetic therapy, a smaller proportion of patients will have low–cardiac factors. output syndrome requiring inotropic or vasopressor support Although ventricular remodeling in PAH represents (29,30). Although the most common cause of death in a continuum, experimental studies often differentiate 2 patients with PAH is progressive RHF, sudden and unex- patterns of ventricular remodeling on the basis of morpho- pected death may also occur (33). In a study by Hoeper et al. metric and molecular characteristics: adaptive and malad- (33), sudden death explained 17% of cardiopulmonary arrest aptive remodeling (Table 1). Adaptive remodeling is for which resuscitation was attempted. Among all patients characterized by more concentric remodeling (higher mass- who had cardiopulmonary arrest (not just those with sudden to-volume ratio) and preserved systolic and diastolic func- death), the initial electrocardiogram at the time of cardio- tion (e.g., ventricular remodeling observed in patients with pulmonary resuscitation showed bradycardia in 45%, elec- Eisenmenger syndrome), whereas maladaptive remodeling is tromechanical dissociation in 28%, asystole in 15%, associated with more eccentric hypertrophy and worse ventricular fibrillation in 8%, and other rhythms in 4% (33). systolic and diastolic function (e.g., remodeling observed in In patients with chronic left heart failure, heart failure is patients with PAH associated with connective tissue disease usually classified into 4 stages of development: at risk for heart or idiopathic PAH) (9,46). Tricuspid regurgitation, which is D24 Vonk-Noordegraaf et al. JACC Vol. 62, No. 25, Suppl D, 2013 The Right Ventricle in Pulmonary Hypertension December 24, 2013:D22–33

Figure 1 Pathophysiology of RV Dysfunction in PAH

Increased right ventricular (RV) wall stress, neurohormonal activation, inﬂammation, and altered bioenergetics contribute to RV remodeling in pulmonary arterial hypertension (PAH). Adaptive remodeling is associated with minimally altered ventriculoarterial coupling. Progressive RV dilation with maladaptive remodeling further contributes to RV stress. Adapted, with permission, from Champion et al. (5), Benza et al. (8), and Rudski et al. (99).

often secondary to annular dilation, may also lead to ad- RV wall stress is greater for a comparable pressure increase verse ventricular remodeling and decreased flow reserve. because of the smaller thickness of the right ventricle. Second, Right-to-left shunting through a patent foramen ovale is fibrosis is much less extensive in patients with RV pressure also observed more frequently in patients with maladaptive overload (often <10% of ventricular volume) and often remodeling and more severe RHF (47). Recent studies also limited to the RV-septal insertion points compared with suggest that RV dyssynchrony is a marker of maladaptive myocardial fibrosis observed in patients with aortic stenosis or remodeling and more severe dysfunction (48–54). In PAH, severe systemic hypertension (56–59). This explains why the the RV free wall is still contracting while the left ventricle is majority of patients with severe RHF recover their ventricular already in its early diastolic phase, leading to late systolic function after lung transplantation, even if right ventricular leftward septal movement (55). Because myocytes under ejection fraction (RVEF) is severely reduced at the time of mechanical stress prolong their contraction time and action transplantation (60–63). Identifying which patients would potential duration, right-to-left ventricular dyssynchrony not recover right heart function after lung transplantation will increase in the failing right ventricle with increased wall alone and therefore would benefit from heart-lung trans- stress, explaining why measures of dyssynchrony are asso- plantation remains a subject of ongoing investigation (64). ciated with prognosis. The concept of ventriculoarterial coupling and the When comparing ventricular remodeling with pressure cardiopulmonary unit in PAH. Recent focus in PAH overload, several differences emerge between the right and left research has shifted from looking at the pulmonary vascu- ventricles. First, ventricular enlargement occurs much earlier lature and the right heart as separate entities to analyzing the in the course of PAH compared with the pressure-overloaded cardiopulmonary unit as a system (5). This is valid not only left ventricle (e.g., in systemic hypertension or aortic stenosis). from the physiological perspective but also from a thera- Mechanically, this can be partially explained by the fact that peutic aspect. Several studies have shown that RV adaptation JACC Vol. 62, No. 25, Suppl D, 2013 Vonk-Noordegraaf et al. D25 December 24, 2013:D22–33 The Right Ventricle in Pulmonary Hypertension

Table 1 Continuum of Adaptive Versus Maladaptive Remodeling of the Right Ventricle

Characteristic Adaptive Remodeling Maladaptive Remodeling Remodeling RV size Normal size to mild dilation RV enlargement Mass/volume ratio Higher Lower Function VA coupling Usually preserved or mildly decreased Lower RVEF at rest Normal to mildly decreased Decreased CPET Usually better preserved exercise Decreased exercise capacity and capacity and ventilatory efficiency increased ventilatory inefficiency Ventricular/flow reserve Probably decreased early Decreased BNP or NT-BNP Normal Elevated Perfusion Normal or mildly impaired Decreased Metabolism Normal glucose uptake Increased glucose uptake Molecular (selected) Micro-RNA 133a Normal Decreased Apelin Increased Severely reduced Insulin-like growth factor-1 Increased No increase Vascular endothelial growth factor Increased Normal/reduced Hexokinase-1 Decreased Increased Alcohol dehydrogenase-7 Normal Decreased

Most of the molecular data are based on experimental studies. Ventricular reserve refers to either the contractile response of the right ventricle or the dynamic change in diastolic RV end-diastolic pressures during exercise or pharmacological stress. BNP ¼ B-type natriuretic peptide; CPET ¼ cardiopulmonary exercise testing; NT-BNP ¼ N-terminal B-type natriuretic peptide; RNA ¼ ribonucleic acid; RV ¼ right ventricular; RVEF ¼ right ventricular ejection fraction; VA ¼ ventriculoarterial. to PAH depends on the right ventricle’s ability to increase its corresponding to an optimal balance between RV mechan- contractility in response to the increased afterload (43,65). ical work and oxygen consumption (5,43,66). Kuehne et al. “Ventriculoarterial coupling” speciﬁcally refers to the rela- previously showed that chronic RV pressure overload in PAH tionship between ventricular contractility and afterload was associated with reduced RV pump function despite (Fig. 2). Its most objective metric is the ratio between enhanced RV myocardial contractility. Using ventriculoarterial ventricular elastance and arterial elastance. Although the measures, recent studies have also conﬁrmed worse ven- idea is based mainly on research involving the left ventricle, triculoarterial coupling in patients with scleroderma-associated it is assumed that the normal ratio of ventricular to arterial PAH compared with those with afterload-matched idiopathic elastance for the right ventricle is also between 1.5 and 2.0, PAH (67).

Figure 2 Describing Right Ventricular Function

(A) Pressure-volume relation, illustrating the concepts of ventricular elastance (Ees), arterial elastance (Ea), and the maximal isovolumic pressure used to estimate single-beat Ees. (B) Pump function graph, illustrating that when baseline pulmonary vascular resistance (PVR) is high, a decrease in PVR mainly causes an increase in stroke volume, while at lower baseline PVR, pressure is more affected. D26 Vonk-Noordegraaf et al. JACC Vol. 62, No. 25, Suppl D, 2013 The Right Ventricle in Pulmonary Hypertension December 24, 2013:D22–33

Table 2 Measures of Ventricular and Pulmonary Load

Component of Load Equation or Deﬁnition Comment PVR PVR ¼ TPG/CO Most commonly used clinical measure of resistive load PAC PAC ¼ SV/PP Most commonly used clinical measure of pulsatile load Ea Ea ¼ RVESP/SV Common measure of load used in pressure-volume loop analysis Pulmonary impedance Fourier transformation yields impedance and Used in experimental and research settings; cannot be summarized by a phase according to harmonics single number DPPG DPPG ¼ DPAP mean PCWP New markers to assess out-of-proportion heart failure with left heart disease

Mean pulmonary arterial distensibility (Areasystole Areadiastole)/Areasystole Assessed with MRI; may be useful in detecting early PH Mean PAP-CO slope Slope of mean PAP to CO relationship or main The slope represents a more dynamic concept of resistance to flow; may slope of TPG-CO relationship be a more physiological way to define exercise-induced PH RV afterload Estimated by RV wall stress: RVESWS ¼ Simplified formula, as RV geometry is more difficult to assess

(0.5 RVSP rRVES)/RVES wall thickness

PVR can be indexed to BSA. Usually PAC is not indexed, because it represents a measure of ﬂow and pressure. CO ¼ cardiac output; DPAP ¼ diastolic pulmonary arterial pressure; DPPG ¼ diastolic pulmonary pressure gradient; Ea ¼ pulmonary arterial elastance; MRI ¼ magnetic resonance imaging; PAC ¼ pulmonary arterial capacitance; PAP ¼ pulmonary arterial pressure; PCWP ¼ pulmonary capillary wedge pressure; PH ¼ pulmonary hypertension; PP ¼ pulmonary pressure; PVR ¼ pulmonary vascular resistance; rRVES ¼ right ventricular end-systolic radius; RV ¼ right ventricular; RVES ¼ right ventricular end-systolic; RVESP ¼ right ventricular end-systolic pressure; RVESWS ¼ right ventricular end-systolic wall stress; RVSP ¼ right ventricular systolic pressure; SV ¼ stroke volume; TPG ¼ transpulmonary gradient.

Clinically, RV afterload is estimated using simple steady or resistive component accounts for approximately measures of load such as arterial elastance, pulmonary 77% of total hydraulic RV power and that the remaining vascular resistance, and pulmonary arterial compliance 23% is used for the pulsatile component (68). This relatively (Table 2). Arterial elastance is the metric of afterload used constant distribution follows from the unique properties of during pressure-volume loop analysis, while pulmonary the pulmonary circulation compared with the systemic vascular resistance and pulmonary arterial compliance are circulation. In contrast to the systemic circulation, in the used to describe the resistive and pulsatile load of the pulmonary circulation, resistance and compliance are pulmonary circulation. The resistive and pulsatile compo- inversely related to each other over time and after therapy nents of pulmonary load are also useful to describe the work (Fig. 3) (69,70). This is because the resistive vessels in the of the right ventricle. Recent studies have found that the pulmonary circulation also contribute to the compliance of

Figure 3 Molecular Pathways Involved in RV Remodeling in PAH

The figure outlines the importance of cardiomyocyte remodeling involving altered metabolism, increased reactive oxygen species (ROS) production, decreased oxidative metabolism, and endothelial reticulum stress. PAH ¼ pulmonary arterial hypertension; RV ¼ right ventricular. JACC Vol. 62, No. 25, Suppl D, 2013 Vonk-Noordegraaf et al. D27 December 24, 2013:D22–33 The Right Ventricle in Pulmonary Hypertension the system (71). Recent studies have showed, however, that susceptibility loci in PAH, identifying a susceptibility locus elevated pulmonary capillary wedge pressure can decrease the to RHF will require larger sample sizes and matching for resistance-compliance time constant in the pulmonary degree according to ventricular dysfunction and afterload. system, thus enhancing net RV afterload by elevating Several mechanisms contribute to maladaptive remodeling pulsatile, relative to resistive, load (72). of the pressure-overloaded ventricle, including increased Although the previously mentioned indexes of afterload levels of reactive oxygen species, activation of myocardial are clinically useful, a more physiological definition of RV apoptotic pathways, and neurohormonal activation (e.g., afterload would need to take into account all factors that adrenergic and angiotensin pathways) (80–82). Importantly, contribute to total myocardial wall stress (or tension) during cardiomyocyte hibernation and growth arrest contrast with systole, such as ventricular pressure, chamber enlargement, the resistance to apoptosis seen in the pulmonary vasculature wall thickness, and ventricular geometry. Moreover, tricuspid in PAH (Table 3, Fig. 3) (83). regurgitation and right-to-left shunting (i.e., through When comparing the failing right and left ventricles, both a patent foramen ovale, septal defect, or atrial septostomy) overlapping and varying expression in transcription factors, can also decrease afterload by offering an alternative, less messenger ribonucleic acid (RNA), and micro-RNA are resistive path (73–75). More comprehensive models of observed. The differences between the right and left ven- afterload may better predict the course of RHF. Research tricles originate in part from their different embryologic groups are currently working on developing biophysical origins as well as their different mechanical boundary con- models linking local cardiac myofiber mechanics to global ditions, the right ventricle being exposed to lower impedance cardiovascular system dynamics and adaptation are currently post-partum. From an embryologic point of view, the right being developed. These models provide novel insights into ventricle arises from the anterior heart field, whereas the left the mechanisms of cardiac adaptation to PAH (76,77). ventricle develops from the posterior heart field (84). These Similarly, pre-load can be defined as the combination of the differences may explain the lack of Iroquois homeobox and factors that contribute to passive end-diastolic ventricular atrial natriuretic peptide expression in the normal right wall stress (or tension). Optimal pre-load is the pre-load that ventricle (41,85,86). Although B-type natriuretic peptide is leads to maximal cardiac output without causing significant also expressed in the failing right ventricle, the responsive- systemic congestion or renal impairment (27). This is espe- ness to recombinant B-type natriuretic peptide may be cially important in tailoring pre-load in patients with acute different in the failing right heart; whether this is due to RHF and is discussed in the section on management. differences in loading conditions still requires further Molecular insights into RV remodeling and failure. In study (87,88). As in the left ventricle, down-regulation of recent reviews, the different pathways involved in remodel- fast alpha–myosin heavy chain and synchronous over- ing of the pressure-overloaded right ventricle have been expression of slow beta-isoform are also observed in the summarized (40,78). The different animal models used to pressure-overloaded right ventricle (89). The long-term study the pressure-overloaded right ventricle were recently consequences of alpha–cardiac actin down-regulation on reviewed by Guihaire et al. (79). More recent investigations contractile performance remain unknown (40). Because are using induced pluripotent stem cells for screening of alpha–myosin heavy chain requires larger amounts of aden- novel molecules in PAH and RHF; proof-of-concept results osine triphosphate to generate force, a decreased alpha- for these novel strategies should be available within the next myosin/beta-myosin ratio may provide an energy-sparing few years. Although genetic studies are identifying novel profile that may have some advantages for long-term

Comparative Remodeling of Right Ventricle and Pulmonary Circulation in Patients With PAH: Table 3 Main Cellular and Interstitial Features (19–22)

Pulmonary Circulation Right Ventricle Differences Cellular changes Resistance to apoptosis and aberrant proliferation Growth arrest apoptosis (CMs) (PAECs and PASMCs), hyperplasia, and migration (PASMCs) Microcirculation changes Dysregulated angiogenesis Decreased capillary density Similarities Extracellular matrix Increased interstitial fibrosis Increased interstitial fibrosis Mitochondrial remodeling Decreased number abnormal shape and size, Decreased number abnormal shape and size, increased oxidative capacity decreased oxidative capacity Metabolic transformation Glycolytic shift Glycolytic shift Controversies Inflammation Increased mononuclear cells and inflammatory cytokines Increased mast cells and inflammatory cytokines Neurohormonal modulation Increased ACE activity (PAECs); down-regulation of Impairment of AT-R1 signaling pathway

b1-adrenergic receptor (PASMCs)

ACE ¼ angiotensin-converting enzyme; AT-R1 ¼ angiotensin II receptor type 1; CM ¼ cardiomyocyte; PAEC ¼ pulmonary artery endothelial cell; PAH ¼ pulmonary arterial hypertension; PASMC ¼ pulmonary artery smooth muscle cells. D28 Vonk-Noordegraaf et al. JACC Vol. 62, No. 25, Suppl D, 2013 The Right Ventricle in Pulmonary Hypertension December 24, 2013:D22–33 compensation of the right ventricle. Studies using microarray method for evaluating ventricular elastance, arterial ela- gene chips have highlighted that 1 of the pathways that stance, and ventriculoarterial coupling (5,43). appears to be more activated in the pressure-overloaded right The American Society of Echocardiography guidelines ventricle compared with the pressure overloaded left ventricle offer the most comprehensive review of normative echo- is the Wnt pathway, which regulates glycogen synthase cardiographic values of the right heart (99). The guideline kinase–3b activity, a serine/threonine protein kinase involved also highlights the need for future scaled echocardiographic in cell proliferation, migration, inflammation, glucose regu- references for right heart dimensions as well as references lation, and apoptosis (90). Chamber-specific expression of adjusted for age, sex, and race. Using a large cohort of 4,204 phosphodiesterase type 5 in the pressure-overloaded right participants, the MESA (Multi-Ethnic Study of Athero- ventricle has also been demonstrated in experimental and sclerosis) investigators were able to develop these normative human studies (91,92). Although most expressed micro- equations for RV mass and systolic function on the basis of RNA is similar in right and left heart failure, Reddy et al. age, sex, and race (100). Kawut et al. (100) demonstrated (93) showed that 4 micro-RNAs (34a, 28, 148a, and 93) are that in general, younger age, male sex, and Hispanic upregulated in RHF/RV hypertrophy that are down- ethnicity are associated with higher RV mass, while older regulated or unchanged in left heart failure/left ventricular age and female sex are associated with higher RVEF. hypertrophy. More recently, several investigators are working on defining A change in myocardial metabolism is a prominent dynamic right heart and pulmonary circulation measures. feature of RHF. A switch from fatty acid oxidation to These dynamic measures include themean pulmonary arterial glycolysis is presumably a protective response of the stressed pressure–cardiac output slope as well as RV reserve, usually left heart, as carbohydrate metabolism requires less oxygen defined either as peak RVEF, peak stroke volume, or peak amount than fatty acid oxidation (81). Decreased mito- cardiac index after exercise or pharmacological stress (101,102). chondrial activity resulting in a switch from aerobic to In controls, mean pulmonary arterial pressure–cardiac output anaerobic metabolism might also be involved in the transi- slope is usually <1.5 to 2.5 mm Hg$min/l, with older healthy tion from compensated RV hypertrophy to maladaptive subjects having higher average slope values (22,103–113). remodeling (81). Insufficient adaptation of the capillary The committee wants to emphasize that the commonly network and myocardial ischemia may also impair vascular used indexes of RV systolic performance, such as RVEF endothelial growth factor signaling and the hypertrophic and tricuspid annular plane systolic excursion, are markers response (94). Increased rate of myocardial fibrosis has been of ventriculoarterial coupling rather than ventricular con- reported in RV failure and may contribute to decreased tractility, which is increased in PAH (65). Another caveat the ventricular compliance (56,95). committee members want to emphasize is that the reduction in Recent animal and human studies support a role of tricuspid annular plane systolic excursion after cardiac surgery inflammation in the pressure-overloaded right ventricle does not reflect corresponding changes in RVEF, because (82,96). Studies by Watts et al. (97) have shown that annular plane motion is preferentially compromised (114). neutrophils are found in the RV myocardium early after an acute increase in afterload, whereas macrophages may be Prediction of Outcomes in Patients With involved during progressive remodeling in the setting of Pulmonary Arterial Hypertension: chronic pulmonary hypertension (97). Ongoing studies are The Importance of the Right Heart investigating the role of macrophages, T-regulatory cells, and leukotriene in the development of RHF in patients with PAH. Outcome prediction in patients with PAH has been extensively studied using large-cohort designs as well as in smaller Evaluation of Right Heart Size and Function: studies incorporating imaging parameters (7,8,10,12,13, From Resting Parameters to Dynamic Evaluation 16–19,115–123). One consistent finding among studies is that survival in PAH is closely related to RV adaptation to The assessment of the right heart plays an essential the increased pressure overload. Hemodynamic studies have part in managing patients with PAH (98). Although echo- demonstrated the predictive value of right atrial pressure and cardiography is the mainstay in the evaluation of the right cardiac index (7,14,117,118,124). Echocardiographic studies heart in clinical practice, magnetic resonance imaging has have highlighted the predictive value of tricuspid annular emerged as the most accurate method for evaluating RV plane systolic excursion, RV myocardial performance in- mass, RV volume, and RVEF. In addition, magnetic reso- dex, atrial size, and pericardial effusion (10,12,13,17,125). nance imaging offers the possibility to quantify regurgitant Magnetic resonance imaging studies have emphasized volumes; delayed enhancement, a marker for focal scar the predictive value of stroke volume index, RVEF, and burden; myocardial strain; coronary perfusion; and pulmo- indexed RV end-diastolic and end-systolic volumes nary pulsatility (98). Positron emission tomography is used (18,115,116,122,126). Although delayed enhancement has experimentally to assess RV and pulmonary metabolism and, been associated with the severity of PAH, its independent at specialized centers, for apoptosis imaging. Finally predictive value has not yet been proved (127). More recent conductance catheterization represents the gold-standard studies have shown the potential predictive value of RV strain JACC Vol. 62, No. 25, Suppl D, 2013 Vonk-Noordegraaf et al. D29 December 24, 2013:D22–33 The Right Ventricle in Pulmonary Hypertension

(17). In terms of cardiac biomarkers, B-type natriuretic ongoing, on the basis of early clinical and experimental peptide (and N-terminal B-type natriuretic peptide) and studies showing promising results (48,49). At this time, the troponin have been the most investigated cardiac biomarkers role of angiotensin-converting enzyme inhibitors, angio- in PAH and have both been found to be predictive tensin or aldosterone blockade, myosin activators, implant- of outcomes (8,119,128–132). More recent studies are also able defibrillator or destination RV assist device highlighting the role of high-sensitivity troponin assays in implantation has not been comprehensively investigated in PAH (129,130). Exercise testing has highlighted the value patients with RHF and PAH. of maximal oxygen consumption, right-to-left shunting, For novel targeted RV drug therapy, the most promising maximal cardiac index with exercise, and the pulmonary data are for metabolic modulation. On the basis of the pressure–cardiac output slope (48,101). metabolic changes that are observed in the right heart and Particularly with regard to the right heart, future outcome pulmonary vasculature in patients with PAH, investigators studies in PAH will have 2 main objectives. First, studies are have at this time completed phase 1 and 2 clinical trials using needed to evaluate the role of novel imaging biomarkers, mitochondrial modulators such as dichloroacetate in PAH such as right atrial function, ventricular strain, and (37,138). At this time, stem cell therapy or gene therapy myocardial acceleration during isovolumic contraction, as specifically targeting the right heart in PAH still needs to be well as more recent reported biomarkers such as ST2 and investigated. cystatin C. Second, multivariate studies will be needed to In managing acute RHF in patients with PAH, the com- validate a simplified predictive score incorporating imaging mittee wants to emphasize 3 important aspects. First, volume parameters of the right heart. loading should be avoided in patients with evidence of increased filling pressures (right atrial pressure >10 to 15 mm Hg) Management of Right Heart Failure because this can worsen ventricular performance by further From Pulmonary Vasodilation to distending the right ventricle and increasing septal shift and Targeted Right Ventricular Therapy pericardial constraint through ventricular interdependence. Second, every effort should be made to avoid the vicious In addition to their effects on exercise capacity and circle of hypotension and ventricular ischemia and further pulmonary vascular resistance, approved therapies for PAH hemodynamic compromise; this can include prompt car- lead to reverse remodeling of the right heart. This is dioversion of atrial arrhythmias, early initiation of inotropic mediated mainly through their vasodilatory or afterload- or vasopressor support, and avoiding hypercapnia or reducing effects (133). Nagendran et al. (91) demonstrated increased intrathoracic pressure, as well consideration of that the vasodilator sildenafil may in addition have direct extracorporeal membrane oxygenation when appropriate. inotropic effects. Whether this will translate into long-term Third, it remains unclear which agent is the inotrope or clinical benefits compared with endothelin receptor blockers vasopressor of choice; the most commonly used agents still requires further study. Digoxin is the other oral into- include dobutamine, dopamine, norepinephrine, and levo- tropic agent occasionally used in symptomatic patients with simendan (2,139–141). PAH; a small study of 17 patients has suggested the acute hemodynamic effects of digoxin use in PAH (134). Role of Right Heart Investigation Targeted right heart therapy has been the focus of recent in the Development of Novel investigation in PAH. These usually fall into 2 categories, Pulmonary Arterial Hypertension Therapy the first being the investigation of medication proved to be beneficial in left heart failure with decreased ejection fraction Because medications affecting the pulmonary vasculature and the second being the investigation of novel and poten- may be detrimental to the right heart, the task force tially specific targets of RHF. Because of the embryologic recommends that any new drug developed for PAH should and molecular differences between the right and left heart, therefore be experimentally tested for its effects on the results for chronic left heart failure cannot be directly pressure-overloaded right heart. For example, imatinib, extrapolated to RHF. Moreover, a pressure-overloaded which was shown to be promising for pulmonary vascular ventricle may respond differently than a non-pressure- remodeling, was shown to have potential cardiotoxic effects overloaded ventricle. Although recent experimental studies (142,143). The variable effects can be explained by the fact have suggested beneficial effects of carvedilol or bisoprolol that although the remodeled lung in PAH vasculature is on ventricular remodeling in PAH, these beneficial effects characterized by angiogenesis, apoptosis resistance, and cell may be mitigated in patients with severe PAH, in whom proliferation, the failing right ventricle may be subject to contractile reserve is significantly reduced (135,136). In fact, ischemia, capillary rarefaction, and cardiomyocyte apoptosis. a small clinical study by Provencher et al. (137) showed detrimental effects of nonselective and selective beta- Future Directions blockade on exercise capacity in patients with portopulmonary PAH. Clinical trials regarding the effects of resynch- In this report, we have outlined the recent progress made in ronization therapy in patients with PAH are currently understanding of the RHF syndrome, identifying key areas D30 Vonk-Noordegraaf et al. JACC Vol. 62, No. 25, Suppl D, 2013 The Right Ventricle in Pulmonary Hypertension December 24, 2013:D22–33 of future investigation. Areas of research priority are diverse hypertension in the modern management era. Circulation 2010;122: – and include refining the definition of normal right heart 156 63. 15. Mahapatra S, Nishimura RA, Sorajja P, Cha S, McGoon MD. structure and function; investigating novel genetic, epige- Relationship of pulmonary arterial capacitance and mortality in idio- netic, and molecular pathways of RHF; and developing pathic pulmonary arterial hypertension. J Am Coll Cardiol 2006;47: – more effective management strategies for refractory RHF. 799 803. 16. Raymond RJ, Hinderliter AL, Willis PW, et al. 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Updated Clinical Classification of Pulmonary Hypertension

Gerald Simonneau, MD,* Michael A. Gatzoulis, MD, PHD,y Ian Adatia, MD,z David Celermajer, MD, PHD,x Chris Denton, MD, PHD,k Ardeschir Ghofrani, MD,{ Miguel Angel Gomez Sanchez, MD,# R. Krishna Kumar, MD,** Michael Landzberg, MD,yy Roberto F. Machado, MD,zz Horst Olschewski, MD,xx Ivan M. Robbins, MD,kk Rogiero Souza, MD, PHD{{ Le Kremlin-Bicêtre and Paris, France; London, United Kingdom; Edmonton, Alberta, Canada; Sydney, Australia; Marburg, Germany; Madrid, Spain; Kerala, India; Boston, Massachusetts; Chicago, Illinois; Graz, Austria; Nashville, Tennessee; and São Paulo, Brazil

In 1998, a clinical classification of pulmonary hypertension (PH) was established, categorizing PH into groups which share similar pathological and hemodynamic characteristics and therapeutic approaches. During the 5th World Symposium held in Nice, France, in 2013, the consensus was reached to maintain the general scheme of previous clinical classifications. However, modifications and updates especially for Group 1 patients (pulmonary arterial hypertension [PAH]) were proposed. The main change was to withdraw persistent pulmonary hypertension of the newborn (PPHN) from Group 1 because this entity carries more differences than similarities with other PAH subgroups. In the current classification, PPHN is now designated number 1. Pulmonary hypertension associated with chronic hemolytic anemia has been moved from Group 1 PAH to Group 5, unclear/multifactorial mechanism. In addition, it was decided to add specific items related to pediatric pulmonary hypertension in order to create a comprehensive, common classification for both adults and children. Therefore, congenital or acquired left-heart inflow/outflow obstructive lesions and congenital cardiomyopathies have been added to Group 2, and segmental pulmonary hypertension has been added to Group 5. Last, there were no changes for Groups 2, 3, and 4. (J Am Coll Cardiol 2013;62:D34–41) ª 2013 by the American College of Cardiology Foundation

Pulmonary hypertension (PH) was previously classified into classification was established in order to individualize 2 categories: 1) primary pulmonary hypertension; or 2) different categories of PH sharing similar pathological secondary pulmonary hypertension according to the presence findings, similar hemodynamic characteristics and, similar of identified causes or risk factors (1). management. Five groups of disorders that cause PH were Since the second World Symposium on pulmonary identified: pulmonary arterial hypertension (Group 1); hypertension held in Evian, in 1998 (2), a clinical pulmonary hypertension due to left heart disease (Group 2);

From the *Assistance publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital has received grant support from Actelion, Pfizer, Bayer-Schering, GlaxoSmithKline, Universitaire de Bicêtre, Université Paris-Sud, Laboratoire d’excellence en recherche and Novartis. Dr. Gatzoulis has served on advisory boards of Actelion UK and Global, sur le médicament et innovation thérapeutique, and INSERM, Unité 999, Le Kremlin Pfizer UK, and GlaxoSmithKline; and has received unrestricted educational grants Bicêtre, France; yAdult Congenital Heart Centre and Centre for Pulmonary Hyper- from Actelion and Pfizer UK. Dr. Adatia is a member of Critical Events Committee tension, Royal Brompton Hospital and the National Heart and Lung Institute, for the tadalafil study in pediatrics with Eli Lilly. Dr. Celermajer is a member of the Imperial College, London, United Kingdom; zUniversity of Alberta, Stollery Chil- speakers’ bureau, serves on the advisory board of, and receives travel and research dren’s Hospital and Mazankowski Alberta Heart Institute, Edmonton, Alberta, support from Actelion. Dr. Denton has received payment for consultancy and speaker’s Canada; xHeart Research Institute, Royal Prince Alfred Hospital, University of fees from Actelion, Pfizer, GlaxoSmithKline, Digna, Sanofi Aventis, Boehringer Sydney, Sydney, Australia; kCentre for Rheumatology and Connective Tissue Ingelheim, Roche, CSL Behring, and Genzyme; has received grant funding from Diseases, Division of Medicine, Royal Free Campus, UCL Medical School, London, Encysive, Actelion, Novartis, and Genzyme; and has served as clinical trial investigator United Kingdom; {University of Giessen and Marburg Lung Center, Geissen, Hesse, and steering committee member for Pfizer, Actelion, Sanofi-Aventis, MedImmune, Germany; #Cardiology Service, Hospital Universitario 12 de Octubre, Madrid, Spain; Digna, United Therapeutics, Novartis, and Celgene. Dr. Denton has received **Pediatric Cardiology, Amrita Institute of Medical Sciences, Cochin, Kerala, India; consultancy and speaker fees from Actelion, Pfizer, GlaxoSmithKline, Digna, Sanofi- yyChildrens’ Hospital, Boston, Massachusetts; zzUniversity of Illinois, Chicago, Illi- Aventis, Boehringer Ingelheim, Roche, CSL Behring, and Genzyme. Dr. Ghofrani nois; xxInstitute for Lung and Vascular Research, Medical University of Graz, Graz, has received support from Actelion, Bayer, GlaxoSmithKline, Merck, Novartis, and Austria; kkVanderbilt University Medical Center, Nashville, Tennessee; and the Pfizer. Dr. Gomez Sanchez has received honoraria for consultations and speaking at {{Pulmonary Department, Heart Institute, University of São Paulo, Medical School, conferences from Actelion, Bayer, GlaxoSmithKline, Novartis, Pfizer, United Ther- São Paulo, Brazil. Dr. Simonneau has served on advisory boards of Eli Lilly, Actelion, apeutics, and Ferrer Pharma. Dr. Landzberg has received research grants from Pfizer, Bayer-Schering, GlaxoSmithKline, and Novartis; has received payment for Actelion, Myogen, and the NHLBI; and is on the steering committee for Actelion. lectures by Eli Lilly, Pfizer, Bayer-Schering, and GlaxoSmithKline; and his institution Dr. Machado has received institutional grant support (without salary support) from JACC Vol. 62, No. 25, Suppl D, 2013 Simonneau et al. D35 December 24, 2013:D34–41 Classification of Pulmonary Hypertension pulmonary hypertension due to chronic lung disease and/or new gene mutations have been Abbreviations hypoxia (Group 3); chronic thromboembolic pulmonary identified: a mutation in cav- and Acronyms hypertension (Group 4); and pulmonary hypertension due to eolin-1 (CAV1) which encodes CHD = congenital heart unclear multifactorial mechanisms (Group 5). During the a membrane protein of caveolae, disease successive world meetings, a series of changes were carried abundant in the endothelial cells fl HAART = highly active out, re ecting some progresses in the understanding of the of the lung (10), and KCNK3, a antiretroviral therapy disease. However, the general architecture and the philosophy gene encoding potassium channel HIV = human of the clinical classification were unchanged. The current super family K member-3 (11). immunodeficiency virus fi fi clinical classi cation of pulmonary hypertension (3) is now The identi cation of these new IFN = interferon well accepted and, widely used in the daily practice of genes not intimately related to b PAH = pulmonary arterial pulmonary hypertension experts. It has been adopted by the TGF signaling may provide new hypertension

Guidelines Committee of the Societies of Cardiology and, insights into the pathogenesis of PAP = pulmonary arterial Pneumology (4,5). Moreover, this classification is currently PAH. pressure used by the U.S. Food and Drug Administration and the PH = pulmonary European Agency for Drug Evaluation for the labelling of Drug- and Toxin-Induced hypertension new drugs approved for pulmonary hypertension. Pulmonary Hypertension POPH = portopulmonary During the Fifth World Symposium held in 2013 in hypertension Nice, France, the consensus was to maintain the general A number of drugs and toxins PPHN = persistent disposition of previous clinical classification. Some have been identified as risk fac- pulmonary hypertension of modifications and updates, especially for Group 1, were tors for the development of PAH the newborn proposed according to new data published in the last and were included in the previous PVR = pulmonary vascular years. It was also decided in agreement with the Task classification (3). Risk factors resistance Force on Pediatric PH to add some specificitemsrelated were categorized according to SCD = sickle cell disease to pediatric pulmonary hypertension in order to have the strength of evidence, as defi- Sch-PAH = schistosomiasis- a comprehensive classification common for adults and nite, likely, possible, or unlikely associated PAH children (Table 1). (Table 2). TGF = tumor growth factor Adefinite association is de- TKI = tyrosine kinase inhibitor Group 1: Pulmonary Arterial Hypertension (PAH) fined as an epidemic or large multicenter epidemiologic studies Since the second World Symposium in 1998, the nomen- demonstrating an association between a drug and PAH. A clature of the different subcategories of Group 1 have likely association is defined as a single case-control study markedly evolved and, additional modification were made in demonstrating an association or a multiple-case series. the Nice classification. Possible is defined as drugs with similar mechanisms of action as those in the definite or likely category but which have not Heritable Pulmonary Hypertension yet been studied. Last, an unlikely association is defined as one in which a drug has been studied in epidemiologic studies In 80% of families with multiple cases of pulmonary arterial and an association with PAH has not been demonstrated. hypertension (PAH), mutations of the bone morphogenic Over the last 5 years, new drugs have been identified or protein receptor type 2 (BMPR2), a member of the tumor suspected as potential risk factors for PAH. growth factor (TGF)-beta super family, can be identified Since 1976, Benfluorex (MEDIATOR, Laboratories (6). In addition, 5% of patients have rare mutations in other Servier, Neuilly-Sur-Seine, France) has been approved in genes belonging to the TGFb super family: activin-like Europe as a hypolipidemic and hypoglycemic drug. This fl receptor kinase-1 (ALK1) (7), endoglin (ENG) (8), drug is in fact a fen uramine derivative, and its main and mothers against decapentaplegic 9 (Smad 9) (9). metabolite is norfenfluramine, similar to Isomeride. Ben- Approximately 20% of families have no detectable mutations fluorex, due to its pharmacological properties, was within currently known disease-associated genes. Recently two drawn from the market in all European countries after 1998 (date of the worldwide withdrawal of fenfluramine derivatives), except in France where the drug was marketed until Actelion and United Therapeutics; and has served on advisory boards of Gilead and United Therapeutics. Dr. Olschewski has received consultancy and lecture fees from 2009 and was frequently used between 1998 and 2009 as Actelion, Bayer, Lilly, Gilead, GlaxoSmithKline, Pfizer, and Unither; and consultancy a replacement for Isomeride. The first case series reporting fees from NebuTec. Dr. Robbins has received honoraria from United Therapeutics, benfluorex-associated PAH was published in 2009. In Gilead, and Actelion for attending advisory board meetings; has received honoraria from Actelion, Gilead, United Therapeutics, and Bayer; and he has been the primary addition to 5 cases of severe PAH, 1 case of valvular disease investigator on industry-sponsored studies from Actelion, Gilead, United Therapeu- was also reported (12). Recently, Savale et al. (13) reported tics, GeNO, Novartis, and Aires in which payment was made to Vanderbilt University. 85 cases of PAH associated with benfluorex exposure, Dr. Souza has received consultancy/lecture fees from Bayer. All other authors report fi that they have no relationships relevant to the contents of this paper to disclose. identi ed in the French national registry from 1999 to 2011. Manuscript received October 15, 2013; accepted October 22, 2013. Of these cases, 70 patients had confirmed pre-capillary D36 Simonneau et al. JACC Vol. 62, No. 25, Suppl D, 2013 Classification of Pulmonary Hypertension December 24, 2013:D34–41

Table 1 Updated Classification of Pulmonary Hypertension* Updated Classification for Drug- and Toxin-Induced Table 2 PAH* 1. Pulmonary arterial hypertension 1.1 Idiopathic PAH Definite Possible 1.2 Heritable PAH Aminorex Cocaine 1.2.1 BMPR2 Fenfluramine Phenylpropanolamine 1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3 Dexfenfluramine St. John’s wort 1.2.3 Unknown 1.3 Drug and toxin induced Toxic rapeseed oil Chemotherapeutic agents 1.4 Associated with: Benfluorex Interferon a and b 1.4.1 Connective tissue disease SSRIsy Amphetamine-like drugs 1.4.2 HIV infection 1.4.3 Portal hypertension Likely Unlikely 1.4.4 Congenital heart diseases Amphetamines Oral contraceptives 1.4.5 Schistosomiasis L-Tryptophan Estrogen 10 Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis Methamphetamines Cigarette smoking 100. Persistent pulmonary hypertension of the newborn (PPHN) Dasatinib 2. Pulmonary hypertension due to left heart disease 2.1 Left ventricular systolic dysfunction *Nice 2013. ySelective serotonin reuptake inhibitor (SSRIs) have been demonstrated as a risk 2.2 Left ventricular diastolic dysfunction factor for the development of persistent pulmonary hypertension in the newborn (PPHN) in preg- 2.3 Valvular disease nant women exposed to SSRIs (especially after 20 weeks of gestation). PPHN does not strictly 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and belong to Group 1 (pulmonary arterial hypertension [PAH]) but to a separated Group 1. Main fi fi congenital cardiomyopathies modi cation to the previous Danapoint classi cation are in bold. 3. Pulmonary hypertension due to lung diseases and/or hypoxia 3.1 Chronic obstructive pulmonary disease Montani et al. (16) recently published incidental cases of 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern dasatinib-associated PAH reported in the French registry. 3.4 Sleep-disordered breathing Between November 2006 and September 2010, 9 cases 3.5 Alveolar hypoventilation disorders treated with dasatinib at the time of PH diagnosis were 3.6 Chronic exposure to high altitude fi 3.7 Developmental lung diseases identi ed. At diagnosis, patients had moderate to severe pre- fi 4. Chronic thromboembolic pulmonary hypertension (CTEPH) capillary PH con rmed by heart right catheterization. No 5. Pulmonary hypertension with unclear multifactorial mechanisms other PH cases were reported with other TKIs at the time 5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative of PH diagnosis. Interestingly, clinical, functional, and disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, hemodynamic improvements were observed within 4 months lymphangioleiomyomatosis of dasatinib discontinuation in all but 1 patient. However, 5.3Metabolicdisorders: glycogenstorage disease,Gaucher disease,thyroiddisorders after a median follow-up of 9 months, most patients did not 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH demonstrate complete recovery, and 2 patients died. Today, more than 13 cases have been observed in France among *5th WSPH Nice 2013. Main modifications to the previous Dana Point classification are in bold. BMPR ¼ bone morphogenic protein receptor type II; CAV1 ¼ caveolin-1; ENG ¼ endoglin; 2,900 patients treated with dasatinib for CML during the HIV ¼ human immunodeficiency virus; PAH ¼ pulmonary arterial hypertension. same period, giving the lowest estimate incidence of dasatinib-associated PAH of 0.45%. Finally, notifications of pulmonary hypertension (PH) with a median ingestion almost 100 cases of PH have been submitted for European duration of 30 months and a median delay between start of pharmaceutical vigilance. Dasatinib is considered a likely risk exposure and diagnosis of 108 months. One-quarter of factor for PH (Table 2). patients in these series showed coexisting PH and mild to Few cases of PAH associated with the use of interferon moderate valvular heart diseases (14). (IFN)-a or -b (17,18) have been published so far. Recently, Chronic myeloproliferative (CML) disorders are a rare cause all cases of PAH patients with a history of IFN therapy of PH, involving various potential mechanisms (Group 5) notified in the French PH registry were analyzed (19). Fifty- including high cardiac output, splenectomy, direct obstruc- three patients with PAH and a history of IFN use were tion of pulmonary arteries, chronic thromboembolism, identified between 1998 and 2012. Forty-eight patients were portal hypertension, and congestive heart failure. The treated with IFN-a for chronic hepatitis C, most of them prognosis of CML has been transformed by tyrosine kinase had an associated risk factor for PH such as human inhibitors (TKIs) such as imatinib, dasatinib, and nilotinib. immunodeficiency virus (HIV) infection and/or portal Although, TKIs are usually well tolerated, these agents are hypertension. Five other cases were treated with IFNb for associated nevertheless with certain systemic side effects multiple sclerosis; those patients did not have any associated (edema, musculoskeletal pain, diarrhea, rash, pancytopenia, risks factor for PAH. The mean delay between initiation of elevation of liver enzymes). It is also well established IFN therapy and PAH diagnosis was approximately 3 years. that imatinib may induce cardiac toxicity. Pulmonary Sixteen additional patients with previously documented complications and specifically pleural effusions have been PAH were treated with IFN-a for hepatitis C and showed reported more frequently with dasatinib. In addition, case a significant increase in pulmonary vascular resistance (PVR) reports suggested that PH may be a potential complication of within a few months of therapy initiation; in half of them, dasatinib use (15). withdrawal of IFN resulted in a marked hemodynamic JACC Vol. 62, No. 25, Suppl D, 2013 Simonneau et al. D37 December 24, 2013:D34–41 Classification of Pulmonary Hypertension improvement. Regarding a potential mechanism, several patients with a mean pulmonary artery pressure (PAP) experimental studies have found that IFN-a and INF-b between 21 and 24 mm Hg are at high risk for the devel- induced the release of endothelin-1 by pulmonary vascular opment of overt PH within 3 years and should be closely cells (20). followed (34). In summary, this retrospective analysis of the French registry together with experimental data suggested that IFN PAH Associated With HIV Infection therapy may be a trigger for PAH. However, most of the patients exposed to IFN also had some other risk factors for The prevalence of PAH associated with HIV infection has PAH, and a prospective case control study is mandatory to remained stable within the last decade, estimated to be 0.5% definitively establish a link between IFN exposure and (35). Before the era of highly active antiretroviral therapy fi development of PAH. At this time, IFN-a and -b are (HAART) and the development of speci c PAH drugs, the considered possible risks factors of PH. prognosis for HIV-PAH was extremely poor, with a Persistent PH of the newborn (PPHN) is a life- mortality rate of 50% in 1 year (36). The advent of HAART threatening condition that occurs in up to 2 per 1,000 and the wide use of PAH therapies in HIV patients have live-born infants. During the past 15 years, many studies dramatically improved their prognosis, and the current have specifically assessed the associations between use of survival rate at 5 years in the French cohort is more than serotonin reuptake inhibitors (SSRIs) during pregnancy and 70% (37). Interestingly, approximately 20% of these cases the risk of PPHN with discordant results from no associa- experience a normalization of hemodynamic parameters after tion to 6-fold increased risk (21–26). several years of treatment (38). A recent study involving nearly 30,000 women who had PAH Associated With Portal Hypertension used SSRIs during pregnancy found that every use in late pregnancy increased the risk of PPHN by more than Hemodynamic studies have shown that PAH is confirmed 2-fold. Based on this large study, SSRIs can be considered in 2% to 6% of patients with portal hypertension, so called fi ade nite risk factor for PPHN (27). Whether exposure to portopulmonary hypertension (POPH) (39,40). The risk of SSRIs is associated with an increased risk of PAH in adults developing POPH is independent of the severity of the liver is unclear. disease (41). Long-term prognosis is related to the severity Although presently there is no demonstrated association of cirrhosis and to cardiac function (41). There is wide with PAH, several drugs with mechanisms of actions similar discrepancy in the published survival estimates of patients to amphetamines, used to treat a variety of conditions with POPH. In, the U.S. REVEAL registry (42) patients including obesity (fentermine/topiramate [Qsiva]), attention with POPH had a poor prognosis, even worse that those fi ’ de cit disorder (methylphenidate) (28), Parkinson s disease with idiopathic PAH with a 3-year survival rate of 40% (ropinirole), and narcolepsy (mazindol), need to be moni- versus 64%, respectively. In the French registry, the 3-year tored closely for an increase in cases of PAH. survival rate of POPH was 68%, slightly better than that In summary, several new drugs have recently been iden- of idiopathic PAH (43). These discordant results are likely fi fi ti ed as de nite, likely, or possible risk factors for PAH. In explained by important differences with respect to the order to improve detection of potential drugs that induce severity of liver disease. In the U.S. REVEAL registry, PAH, it is important to outline the critical importance of most of these patients were referred from liver trans- obtaining a detailed history of current and prior exposure in plantation centers, whereas in the French cohort, most every PAH patient. The proliferation of national and patients had mild cirrhosis (39–43). international registries should provide the unique opportunity to collect these data prospectively. In addition, one must PAH Associated With emphasize the need to report all side effects of drugs to local Congenital Heart Disease in Adults pharmaceutical agencies and pharmaceutical companies. Increasing numbers of children with congenital heart di- PAH Associated With Connective Tissue Diseases sease (CHD) now survive to adulthood. This reflects improvement in CHD management in recent decades, and The prevalence of PAH is well established only in sclero- both the number and complexity of adults with CHD derma, and rate of occurrence is estimated between 7% and continue to increase. It is estimated that 10% of adults with 12% (29,30). The prognosis for patients with PAH associ- CHD may also have PAH (44). The presence of PAH in ated with scleroderma remains poor and worse compared to CHD has an adverse impact on quality of life and outcome other PAH subgroups. The 1-year mortality rate in patients (45,46). with idiopathic PAH is approximately 15% (31) versus 30% A well-recognized clinical phenotype of patients with in PAH-associated with scleroderma (32). Recent data volume and pressure overload (i.e., with large ventricular or suggest that in scleroderma, early diagnosis and early arterial shunts) are at much higher risk of developing early intervention may improve long-term outcome (33). Inter- PAH than patients with volume overload only (i.e., with estingly, it has been recently demonstrated that scleroderma atrial shunts). Nevertheless, there are some exceptions, and D38 Simonneau et al. JACC Vol. 62, No. 25, Suppl D, 2013 Classification of Pulmonary Hypertension December 24, 2013:D34–41

we speculate that a permissive genotype might place some Criteria for Closing Cardiac Shunts in PAH Patients Table 4 patients with CHD at higher risk of developing PAH. Associated With Congenital Heart Defects* Given the prevalence of PAH among adults with CHD, we 2 y suggest that every patient with CHD merits an appropriate PVRi, Wood units/m PVR, Wood units Correctable < < assessment in a tertiary setting to determine whether PAH is 4 2.3 Yes >8 >4.6 No present. While it is anticipated that the number of patients 4-8 2.3–4.6 Individual patient evaluation with Eisenmenger syndrome, the extreme end of the PAH/ in tertiary centers

CHD spectrum, complicated also by chronic cyanosis, will *Criteria: the long-term impact of defect closure in the presence of pulmonary arterial hypertension decrease in the coming years and there will be an increasing (PAH) with increased PVR is largely unknown. There are a lack of data in this controversial area, and caution must be exercised. yCorrectable with surgery or intravascular nonsurgical procedure. number of patients with complex and/or repaired CHD PVR ¼ pulmonary vascular resistance; PVRi ¼ pulmonary vascular resistance index. surviving to adulthood with concomitant PH (47). The present clinical subclassification of PAH associated with CHDs has evolved sensibly from 2008. It remains clinical ventricle” type hearts), who do not fulfill standard criteria for and simple, thus widely applicable. Importantly, it is now PH but may have an increased PVR. There are very limited fi aligned with the Nice Pediatric classi cation, as PAH in surgical alternatives for this group of patients with complex association with CHD is a lifelong disease (Table 3). We anatomy/physiology. There has been some recent evidence have proposed criteria for shunt closure in patients with net of potential clinical response to specific PAH therapies in left to right shunting who may represent a management Fontan patients, which needs further exploration before dilemma (Table 4). Other types of PH in association with therapeutic recommendations can been made (48,49). CHD who do not belong to Group 1 (PAH) are included in fi different groups of the general clinical classi cation (i.e., PAH Associated With Schistosomiasis congenital or acquired left heart inflow/outflow obstructive lesions and congenital cardiomyopathies in Group 2). Schistosomiasis-associated PAH (Sch-PAH) was included Segmental PH (PH in one or more lobes of one or both in Group 1 in 2008. Previously it was in Group 4 (chronic lungs) is included in Group 5. In addition, some patients thromboembolism disease). Today, Sch-PAH is potentially with PH associated with CHD are difficult to classify, such the most prevalent cause of PAH worldwide. Schistosomi- as patients with transposition of great arteries and those asis affects over 200 million people, of whom 10% develop with PH following atrial redirection surgery or following hepatosplenic schistomiasis (50). PAH occurs almost neonatal arterial switch operation. This reinforces the need exclusively in this population, and 5% of patients with to delineate the underlying cardiac anatomy/physiology and hepatosplenic schistosomiasis may develop PAH (51). The severity of PAH/PVR in every single patient. Here we make hemodynamic profile of Sch-PAH is similar to that of specific reference to patients with the Fontan circulation POPH (52). Its mortality rate may reach up to 15% at 3 (atrio- or cavopulmonary connections as palliation for “single years (52). Recent uncontrolled data indicate that PAH therapies may benefit patients with Sch-PAH (53).

Updated Clinical Classiﬁcation of Pulmonary Arterial Chronic Hemolytic Anemia Table 3 Hypertension Associated With Congenital Heart Disease* Chronic hemolytic anemia such as sickle cell disease, thal-

1. Eisenmenger syndrome assemia, spherocytosis, and stomatocytosis are associated Includes all large intra- and extra-cardiac defects which begin as systemic-to- with an increased risk of PH. The cause of PH is unclear pulmonary shunts and progress with time to severe elevation of pulmonary and often multifactorial, including chronic thromboembo- vascular resistance (PVR) and to reversal (pulmonary-to-systemic) or bidirectional shunting; cyanosis, secondary erythrocytosis and multiple organ lism, splenectomy, high cardiac output, left-heart disease, involvement are usually present. and hyperviscosity; the role of an inactivation of nitric oxide 2. Left-to-right shunts by free plasma hemoglobin due to chronic hemolysis is Correctabley controversial (54,55). Noncorrectable Include moderate to large defects; PVR is mildly to moderately increased The prevalence and characteristic of PH in chronic systemic-to-pulmonary shunting is still prevalent, whereas cyanosis is not hemolytic anemia has been extensively studied only in sickle a feature. cell disease (SCD). In SCD, PH confirmed by right-heart 3. Pulmonary arterial hypertension (PAH) with coincidental congenital heart disease fi Marked elevation in PVR in the presence of small cardiac defects, which catheterization and de ned as a mean PAP 25 mm Hg themselves do not account for the development of elevated PVR; the clinical occurs in 6.2% (56) to 10% of patient (57). Post-capillary picture is very similar to idiopathic PAH. To close the defects in contraindicated. PH due to left-heart disease represents the most frequent 4. Post-operative PAH cause, with a prevalence of 3.3% (56) to 6.3% (57). The Congenital heart disease is repaired but PAH either persists immediately after surgery or recurs/develops months or years after surgery in the absence of prevalence of pre-capillary PH is lower but not rare: 2.9% significant postoperative hemodynamic lesions. The clinical phenotype is often (56) to 3.7% (57). The classification of pre-capillary PH aggressive. associated with SCD has evolved during the successive *Nice 2013. world meetings, revealing uncertainties in potential causes. JACC Vol. 62, No. 25, Suppl D, 2013 Simonneau et al. D39 December 24, 2013:D34–41 Classification of Pulmonary Hypertension

Hemodynamic Characteristics in Patients With vascular injuries are quite common in patients with SCD; Table 5 PH Associated With SCD in 3 Different Cohorts: however, not a single case with plexiform lesions could be France, Brazil, and United States found (61). Three recent hemodynamic studies provided baseline French Brazilian U.S. Cohort (56) Cohort (57) Cohort (62) hemodynamic data in patients with SCD and PH (56–62). Characteristic (n ¼ 24) (n ¼ 8) (n ¼ 56) Findings were similar among the 3 cohorts, with a high d RAP, mm Hg 10 6 10 5 cardiac output between 8 and 9 l/min and moderate eleva- mPAP, mm Hg 30 6 33.1 8.9 36 9 tion in mean PAP (from 30 to 60 mm Hg) (Table 5). SCD PCWP, mm Hg 16 7 16.0 5.7 16 5 CO, l/min–CI, l/min/m2* 8.7 1.9 5.00 1.36* 8 3 patients with a pre-capillary PH had a modest elevation in PVR, dyn$s$cm5 138 58 179 120 229 149 PVR that was 3 or 4 times less than PVR observed in other PAH subgroups (Table 6). Among the 11 patients of the *Cardiac index use instead of cardiac output in the Brazilian cohort. fi CI ¼ cardiac index; CO ¼ cardiac output; mPAP ¼ mean pulmonary artery pressure; French SCD cohort with a con rmed pre-capillary PH PCWP ¼ pulmonary capillary wedge pressure; PH ¼ pulmonary hypertension; PVR ¼ pulmonary (mean pulmonary artery pressure [mPAP] 25 mm Hg and vascular resistance; RAP ¼ right atrial pressure; SCD ¼ sickle cell disease. pulmonary capillary wedge pressure 15 mm Hg), no patient fulfilled the hemodynamic criteria for PAH, defined > $ $ 5 fi as PVR 250 dyn s cm (56). In the Evian classi cation (2), it was placed in Group 4 Specific therapies approved for the treatment of PAH (chronic thromboembolism). In the Venice and Dana Point fi include prostacyclin derivatives, endothelin receptor antago- classi cations (3), it was shifted to Group 1 (PAH). Pre- nists, and phosphodiesterase-5 inhibitors. However, none of capillary PHs belonging to Group 1 share some character- fi these agents is currently approved for the treatment of istics: 1) histological ndings of major proliferation of the PH associated with SCD due to the lack of data in this specific wall of pulmonary arteries including plexiform lesions; population. Recently, the effect of bosentan was assessed in 2) severe hemodynamic impairment, with PVR >3 Woods a randomized double-blind placebo-controlled trial of units (240 dyn$s$cm 5); and 3) well-documented response fi patients with sickle cell disease and PH (63). Overall, to PAH-speci c therapies. bosentan appeared to be well tolerated, although the small In SCD, autopsy studies providing insight into the sample size precluded an analysis of its efficacy. Another characteristics of pulmonary vascular lesions are limited. randomized, double-blind, placebo-controlled study designed The best-documented study (58) reported 20 cases and to evaluate the safety and efficacy of sildenafil was prematurely obtained photomicrographs of the lesions; among them, halted after interim analysis showed that sildenafil-treated 12 patients were considered having plexiform lesions. In patients were likely to have more acute sickle cell pain crises fact, 8 of these 12 cases had histological evidence of hepatic (35%) than placebo-treated patients (14%) (64). Furthermore, cirrhosis, which is a major confounding factor. Moreover, there was no evidence of treatment-related improvement at the picture of the pulmonary vascular changes considered the time of study termination (64). plexiform lesions were not typical and may correspond to In summary, pre-capillary PH associated with SCD recanalyzed thrombi (P. Dorfmüller, personal communica- appears significantly different from other forms of PAH in tion, February 2013). Another autopsy study of 21 cases regard to pathological findings, hemodynamic characteris- (59) reported 66.6% of microthrombotic and/or thrombo- tics, and response to PAH-specific therapies. Therefore, it embolic lesions, whereas mild moderate or severe pulmonary was decided to move PH associated with SCD from Group 1 vasculopathy was observed in only one-third of this (PAH) to Group 5 (unclear multifactorial mechanisms). population. A larger autopsy study of 306 cases of SCD patients with a clinical suspicion of PH found thrombo- Other PH Groups embolic lesions in 24% but no cases of pulmonary vasculopathy lesions (60). A recent review of autopsy cases in Persistent PH of the newborn has been withdrawn from a single tertiary center in Brazil found that pulmonary Group 1 (PAH) because this entity carries more

Table 6 Comparison of Hemodynamics at Diagnosis in Different PAH Subgroups and in Pre-Capillary PH Associated With SCD

IPAH (43) CTD-PAH (43) POPH (43) CHD-PAH (43) HIV-PAH (38) PH-SCD (43,56) Hemodynamic (n ¼ 288) (n ¼ 157) (n ¼ 127) (n ¼ 35) (n ¼ 58) (n ¼ 11) RAP, mm Hg 8 57 58 67 58 55 2 mPAP, mm Hg 49 13 41 947 12 51 16 49 10 28 4 PCWP, mm Hg 9 48 49 04 8 49 510 3 Cardiac index, l/min/m2 2.4 0.8 2.8 0.9 3.0 1.0 3.0 1.0 2.9 0.7 5.8 1.3 PVR, dyn$s$cm5 831 461 649 379 611 311 753 370 737 328 178 55

Values are mean SD. CHD ¼ congenital heart disease; CTD ¼ connective tissue disorders; HIV ¼ human immunodeficiency virus; IPAH ¼ idiopathic pulmonary arterial hypertension; mPAP ¼ mean pulmonary artery pressure; PCWP ¼ pulmonary capillary wedge pressure; PH ¼ pulmonary hypertension; POPH ¼ portopulmonary hypertension; PVR ¼ pulmonary vascular resistance; RAP ¼ right atrial pressure; SCD ¼ sickle cell disease. D40 Simonneau et al. JACC Vol. 62, No. 25, Suppl D, 2013 Classification of Pulmonary Hypertension December 24, 2013:D34–41 differences than similarities with other PAH subgroups. In 17. Caravita S, Secchi MB, Wu SC, et al. Sildenafil therapy for interferon- b the current classification, PPHN is designated 1. In 1-induced pulmonary arterial hypertension: a case report. Cardiology 2011;120:187–9. agreement with the pediatric classification (65),congenital 18. Dhillon S, Kaker A, Dosanjh A, et al. Irreversible pulmonary hyper- or acquired left-heart inflow/outflow obstructive lesions tension associated with the use of interferon alpha for chronic hepatitis – and congenital cardiomyopathies have been added to C. Dig Dis Sci 2010;55:1785 90. 19. Savale L, Gunther S, Chaumais M-C, et al. Pulmonary arterial hyper- Group 2. There is no change for Group 3 (PH due to lung tension in patients treated with interferon. Available at: https://www. diseases and/or hypoxia) and for Group 4 (chronic ersnetsecure.org/public/prg_congres.abstract?ww_i_presentation=63109. thromboembolism). In Group 5 (unclear multifactorial Accessed November 2013. 20. George PM, Badiger R, Alazawin, et al. Pharmacology and therapeutic mechanisms) chronic hemolytic anemia and segmental PH potential of interferons. Pharmacol Ther 2012;135:44–53. (pediatric classification) have been included. An update for 21. Chambers CDE, Johnson KA, Dick LM, et al. 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Definitions and Diagnosis of Pulmonary Hypertension

Marius M. Hoeper, MD,* Harm Jan Bogaard, MD,y Robin Condliffe, MD,z Robert Frantz, MD,x Dinesh Khanna, MD,jj Marcin Kurzyna, MD,{ David Langleben, MD,# Alessandra Manes, MD,** Toru Satoh, MD,yy Fernando Torres, MD,zz Martin R. Wilkins, MD,xx David B. Badesch, MDjjjj Hannover, Germany; Amsterdam, the Netherlands; Shefﬁeld and London, United Kingdom; Rochester, Minnesota; Ann Arbor, Michigan; Warsaw, Poland; Montreal, Quebec, Canada; Bologna, Italy; Tokyo, Japan; Dallas, Texas; and Denver, Colorado

Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure 25 mm Hg at rest, measured during right heart catheterization. There is still insufficient evidence to add an exercise criterion to this definition. The term pulmonary arterial hypertension (PAH) describes a subpopulation of patients with PH characterized hemodynamically by the presence of pre-capillary PH including an end-expiratory pulmonary artery wedge pressure (PAWP) 15 mm Hg and a pulmonary vascular resistance >3 Wood units. Right heart catheterization remains essential for a diagnosis of PH or PAH. This procedure requires further standardization, including uniformity of the pressure transducer zero level at the midthoracic line, which is at the level of the left atrium. One of the most common problems in the diagnostic workup of patients with PH is the distinction between PAH and PH due to left heart failure with preserved ejection fraction (HFpEF). A normal PAWP does not rule out the presence of HFpEF. Volume or exercise challenge during right heart catheterization may be useful to unmask the presence of left heart disease, but both tools require further evaluation before their use in general practice can be recommended. Early diagnosis of PAH remains difficult, and screening programs in asymptomatic patients are feasible only in high-risk populations, particularly in patients with systemic sclerosis, for whom recent data suggest that a combination of clinical assessment and pulmonary function testing including diffusion capacity for carbon monoxide, biomarkers, and echocardiography has a higher predictive value than echocardiography alone. (J Am Coll Cardiol 2013;62: D42–50) ª 2013 by the American College of Cardiology Foundation

Diagnosis and assessment of patients with pulmonary arte- on Pulmonary Hypertension (WSPH) held in 2008 in Dana rial hypertension (PAH) have been major topics at all Point, California (1). The recommendations from that previous world meetings on pulmonary hypertension (PH), conference were incorporated into the most recent interna- with the last update coming from the 4th World Symposium tional guidelines (2–4). During the 5th WSPH in 2013 in

From the *Department of Respiratory Medicine and German Center for Lung United Therapeutics; and has received research funding from the National Institutes of Research, Hannover Medical School, Hannover, Germany; yDepartment of Pulmo- Health and the Scleroderma Foundation. Dr. Kurzyna has received speaker and/or nary Medicine, VU University Medical Center, Amsterdam, the Netherlands; conference travel fees from and/or served on advisory boards for Bayer, AOP Orphan, zPulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, United Actelion, Pfizer, and GlaxoSmithKline. Dr. Langleben has received speaker and/or Kingdom; xCollege of Medicine, Mayo Clinic, Rochester, Minnesota; jjUniversity of consulting fees from, has served on advisory boards for, and/or has been an investigator in Michigan Scleroderma Program, Ann Arbor, Michigan; {Department of Pulmonary clinical trials for Actelion, Bayer, GlaxoSmithKline, Eli Lilly, Myogen, Northern Circulation and Thromboembolic Diseases, Medical Centre of Postgraduate Medi- Therapeutics, Novartis, Pfizer, and United Therapeutics. Dr. Manes has received speaker cation, Warsaw, Poland; #Center for Pulmonary Vascular Disease, Division of fees from Actelion, Bayer, and GlaxoSmithKline. Dr. Satoh has received speaker fees Cardiology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; from Actelion. Dr. Torres has received grant funding from GENO, Medtronic, Acte- **Department of Experimental, Diagnostic and Specialty MedicinedDIMES, lion/CoTherix, Gilead, Pfizer, United Therapeutics/Lung Rx, Eli Lilly/ICOS, Bayer, Bologna University Hospital, Bologna, Italy; yyDivision of Cardiology, Kyorin Novartis, Akaria, and ARIES; has served as a consultant (often in the role of steering University School of Medicine, Tokyo, Japan; zzPulmonary Hypertension Program, committee or advisory board member) for Actelion/CoTherix, Gilead, Novartis, Pfizer, University of Texas Southwestern Medical Center, Dallas, Texas; xxExperimental United Therapeutics/Lung Rx, GlaxoSmithKline, and Bayer; and is a speaker/advisory Medicine, Imperial College London, London, United Kingdom; and the jjjjDivision board member of Gilead, Actelion, United Therapeutics, Bayer, and Novartis. Dr. of Pulmonary Sciences and Critical Care Medicine and Cardiology, University of Wilkins has received speaker and/or consulting fees from Bayer, GlaxoSmithKline, Colorado, Denver, Colorado. Dr. Hoeper has received speaker and/or consulting fees Pfizer, and Novartis; and has received research funding from the British Heart Foun- from Actelion, Bayer, Gilead, GlaxoSmithKline, Eli Lilly, Lung Rx, Pfizer, and dation, Wellcome Trust, and the National Institutes of Health. Dr. Badesch has received Novartis. Dr. Bogaard has received speaker fees from and served on advisory boards for grant funding from Actelion/CoTherix, Gilead, Pfizer, United Therapeutics/Lung Rx, Pfizer and United Therapeutics. Dr. Condliffe has received speaker and/or conference Eli Lilly/ICOS, Bayer, Novartis, Ikaria, and ARIES; has served as a consultant (often in travel fees from and/or served on advisory boards for Actelion, Bayer, Pfizer, Glaxo- the role of steering committee or advisory board member) for Actelion/CoTherix, SmithKline, and Eli Lilly. Dr. Frantz has received consulting fees from Pfizer; and has Gilead, Pfizer, Mondo-Biotech/Mondogen, United Therapeutics/Lung Rx, Glax- received research funding from United Therapeutics. Dr. Khanna has received speaker oSmithKline, Eli Lilly/ICOS, Bayer, Ikaria, Reatta, and Arena; and has provided advice and/or conference travel fees from and/or served on advisory boards for Actelion, Bayer, in a legal matter to Actelion. Bristol-Myers Squibb, Digna, Intermone, Gilead, Pfizer, Roche, Sanofi-Aventis, and Manuscript received October 11, 2013; accepted October 22, 2013. JACC Vol. 62, No. 25, Suppl D, 2013 Hoeper et al. D43 December 24, 2013:D42–50 Definition and Diagnosis of PH

Nice, France, the working group on diagnosis and assess- manifest PAH (9). The thera- Abbreviations ment did not attempt to fully revise previous recommen- peutic consequences of such and Acronyms dations but proposed changes only where strong new findings, however, are unknown. CO = cardiac output evidence has been generated to support new proposals. CTD = connective tissue RECOMMENDATIONS. disease Definitions, Limitations, Uncertainties, The general definition of DLCO = diffusion capacity for and Controversies PH should remain un- carbon monoxide changed. PH is defined by fi HFpEF = heart failure with Some aspects of the de nitions and recommendations PAPm 25 mm Hg at rest preserved ejection fraction derived from the 4th WSPH have remained controversial. measured by right heart HPAH = heritable pulmonary Debates are still ongoing, especially regarding the following catheterization (RHC). arterial hypertension fi fi questions. 1) Should PH be de ned by a resting mean There are still insuf cient IPAH = idiopathic pulmonary pulmonary artery pressure (PAPm) 25 mm Hg as is data to introduce the term arterial hypertension > “ ” currently the case or by a resting PAPm 20 mm Hg and borderline PH for patients LVEDP = left ventricular end- should the term “borderline PH” be introduced for patients with PAPm levels between diastolic pressure with a PAPm between 21 and 24 mm Hg? 2) Should 21 and 24 mm Hg, espe- NT-proBNP = N-terminal pro– exercise-induced PH be reintroduced as part of the PH cially because the prognostic B-type natriuretic peptide definition? 3) Should pulmonary vascular resistance (PVR) and therapeutic implica- PAH = pulmonary arterial be included in the PH/PAH definition? 4) Is pulmonary tions remain unknown. hypertension artery wedge pressure (PAWP) of 15 mm Hg appropriate to Patients with PAPm values PAPm = mean pulmonary distinguish between pre-capillary and post-capillary PH and between 21 and 24 mm Hg artery pressure how should PAWP be measured? 5) Should fluid or exercise should be carefully fol- PAWP = pulmonary artery challenge be used to distinguish patients with PAH from lowed, in particular when wedge pressure patients with PH due to left ventricular (LV) dysfunction? they are at risk for devel- PH = pulmonary Should PH be defined by a resting PAPm ‡25 mm Hg as oping PAH (e.g., patients hypertension is currently the case or by a resting PAPm >20 mm Hg with CTD, family mem- PVR = pulmonary vascular resistance and should the term “borderline PH” be introduced for bers of patients with idio- patients with a PAPm between 21 and 24 mm Hg? A pathic pulmonary arterial RHC = right heart catheterization resting PAPm >25 mm Hg has been the cutoff value for hypertension [IPAH] or a diagnosis of manifest PH since the 1st WSPH. However, heritable pulmonary arterial SSc = scleroderma the upper level of normal for resting PAPm is 20 mm Hg (5), hypertension [HPAH]). WU = Wood units and it is unclear how to classify and manage patients with PAPm levels between 21 and 24 mm Hg. Most of the Should exercise-induced PH be reintroduced as part of relevant epidemiological and therapeutic studies in the field the PH definition? Before the 4th WSPH, PH was defined of PAH have used the 25 mm Hg threshold, and little is by resting PAPm >25 mm Hg or PAPm with exercise known about patients with PAPm levels between 21 and >30 mm Hg. Potential weaknesses of that definition included 24 mm Hg. the fact that the level, type, and posture of exercise had not Several studies have suggested that even mildly elevated been specified. Furthermore, the normal exercise PAP varies PA pressures may be of prognostic significance, particularly with age. In a systematic review of the available literature (5), in patients with lung disease or connective tissue disease there were no significant differences in PAP at rest according (CTD) (6,7). Introduction of the term “borderline PH” for to age groups; however, during exercise, PAPm was signifi- patients with a PAPm ranging from 21 to 24 mm Hg was cantly higher in older patients (>50 years of age). Based on discussed in Dana Point and in Nice (8). This term could be these data, a task force at the 4th WSPH concluded that it was used to avoid labeling patients with PAPm values between impossible to define a cutoff value for exercise-induced PH 21 and 24 mm Hg as manifest PH/PAH but at the same and recommended eliminating this criterion (1). time would ensure that such values are not labeled “healthy.” Since 2008, several studies have shed more light on In some circumstances, “borderline” PH might indicate early exercise-induced PH (10,11), but there is still uncertainty pulmonary vascular disease, especially when PAWP is low about the most suitable exercise protocol and cutoff levels. In and transpulmonary gradient and PVR are elevated. addition, prognostic value and therapeutic consequences of However, the term “borderline PH” would not be useful in exercise-induced PH in the setting of normal resting patients with left heart disease and elevated PAWP levels. hemodynamics have not been elucidated. The natural history of patients with PAPm values between 21 and 24 mm Hg has not been widely studied. One RECOMMENDATIONS ON EXERCISE-INDUCED PH. exception are patients with the scleroderma spectrum of Because of the lack of a suitable definition, an exercise disease, in whom the presence of “borderline” pressures criterion for PH should not be reintroduced at the is associated with a high risk of future development of present time. D44 Hoeper et al. JACC Vol. 62, No. 25, Suppl D, 2013 Definition and Diagnosis of PH December 24, 2013:D42–50

Further studies are needed to define which levels of setting the cutoff for PAPm at 25 mm Hg, despite the exercise-induced elevations in PAPm and PVR have upper limit of normal being 20 mm Hg). prognostic and therapeutic implications. Is PAWP of 15 mm Hg appropriate to distinguish be- Should PVR be included in the definition of PH/PAH? tween pre-capillary and post-capillary PH and how should d HARMONIZATION OF PVR UNITS. PAWP be measured? PAWP/PAOP/PCWP HARMONIZTION Although PA is always given as mm Hg, various units OF TERMINOLOGY. are used for PVR, most frequently dyn∙s∙cm 5 and The term pulmonary capillary wedge pressure Wood units (mm Hg/l∙min). Consistency would be (PCWP) is widely used in the medical literature. For useful, and the working group suggested using Wood measurement of this pressure, balloon occlusion occurs units (WU), which can be directly derived from PAP in the pulmonary arteries, and the obtained value is not and cardiac output (CO) measurements without equal to the pulmonary capillary pressure in non- multiplication with the factor 80. The use of SI units is occluded areas. Thus, the term PCWP is misleading. not endorsed because they are not commonly being Better terms are pulmonary artery occlusion pressure used for hemodynamics in clinical practice. (PAOP) and PAWP. The working group prefers the latter term because the short versions “wedge” and According to a recent analysis (12), normal PVR at rest is “wedge pressure” are well established in daily clinical > to some extent age dependent, but PVR 2 WU can be practice, even in non–English-speaking countries. considered elevated in all age populations. In the current U.S. guidelines, PVR >3 WU is used as part of the Current guidelines recommend using a PAWP (or fi hemodynamic definition of PAH (3). LVEDP) 15 mm Hg to de ne pre-capillary PH. Higher The working group members unanimously agreed that the PAWP values are commonly viewed as indicators of left general definition of PH should be kept as simple and as heart disease. However, patients with the diagnosis of heart broad as possible. Some PH populations (for instance, failure with preserved ejection fraction (HFpEF) can have < patients with elevated PAWP levels or patients with high a resting PAWP 15 mm Hg and patients with features pulmonary blood flow) may have elevated PAP but normal otherwise indicating the presence of PAH may present with PVR. Thus, PVR should not be part of the general defini- higher PAWP values (13). In addition, PAWP measure- tion of PH. ments vary between centers, and standardization is necessary However, the working group members proposed to to ensure comparisons of patient populations. include PVR in the hemodynamic definition of PAH for the following reasons: 1) including PVR underscores the need STANDARDIZATION OF PAWP MEASUREMENTS. PAWP mea- to base the definition of PH on invasive measurements surements may be largely affected by swings in the intra- (i.e., RHC); 2) including PVR makes PAWP (or left thoracic pressure, especially in patients with lung disease. ventricular end-diastolic pressure [LVEDP]) measurements This effect is least pronounced at the end of a normal mandatory; 3) including PVR requires measurements of expiration, which is the point at which PAWP should be CO, which would be a substantial advantage because it is determined. Many available devices do not provide end- current practice in many nonexpert centers to perform expiratory but digitized mean PAWP and therefore tend RHCs without measuring CO; 4) including PVR will to underestimate the PAWP. For standardization of PAWP exclude high flow conditions with normal PVR and without measurements, values should be determined at the end of pulmonary vasculopathy from the PAH definition; and normal expiration (breath holding is not required). Ideally, fi 5) including PVR will lower the likelihood of patients with high- delity tracings on paper should be used, rather than left heart disease of being labeled as having PAH. small moving tracings on a cardiac monitor. Normal PAWP values have been explored since the RECOMMENDATIONS ON PVR. advent of cardiac catheterization and have been found to To avoid the use of various units, PVR should be given range from 5 to 12 mm Hg in healthy volunteers. However, in WU. these data were generated in younger patients, and it remains PVR should not become part of the general PH unclear whether there is a physiological increase in PAWP definition. with aging. In a comprehensive analysis of the medical PVR should be included in the hemodynamic char- literature, Kovacs et al. (12) found that PAWP at rest was acterization of patients with PAH as follows: patients independent of age, with values of 9 2 mm Hg found in with PAH are characterized by pre-capillary PH (i.e., patients ranging from <24 to 70 years. Of note, the data PAPm 25 mm Hg, PAWP 15 mm Hg, and of the oldest patient population were derived from 17 elevated PVR [>3 WU]). patients only. Prasad et al. (14) performed a small but Although the upper level of normal PVR is approxi- meticulous study comparing hemodynamics and LV func- mately 2 WU, the PVR cutoff value for PAH should tion in elderly patients with and without HFpEF, demon- be kept at 3 WU because patients with lower PVR strating that the normal PAWP slightly increased with age, levels are unlikely to have PAH (this is consistent with although usually not beyond 15 mm Hg. Most importantly, JACC Vol. 62, No. 25, Suppl D, 2013 Hoeper et al. D45 December 24, 2013:D42–50 Definition and Diagnosis of PH

PAWP levels 15 mm Hg did not rule out the presence of coronary heart disease or HFpEF. In addition, the finding of HFpEF. On the basis of these and other data, it has been an elevated PAWP in a patient when this is unexpected suggested to lower the PAWP cutoff for pre-capillary PH to (normal left atrial size, absence of echocardiographic markers 12 mm Hg. Reasons to reduce the PAWP threshold to of elevated LV filling pressures, absence of risk factors for 12 mm Hg include the notion that PAWP of 15 mm Hg is HFpEF) should prompt the performing physician to associated with a higher chance of misclassifying patients measure LVEDP to avoid misclassification. with HFpEF as PAH and that the use of 15 mm Hg has probably contributed to the labeling of patients with HFpEF RECOMMENDATIONS FOR PAWP AT REST. as PAH with consequences for medical therapy as well as The working group does not recommend lowering the inclusions in clinical trials. threshold to 12 mm Hg in clinical practice. On the other hand, PAWP 15 mm Hg has a high The cutoff for pre-capillary PH should remain at sensitivity to identify patients with pre-capillary PH, and 15 mm Hg because this value has been used in this cutoff value has been used for decades and has been almost all clinical trials generating evidence for the fi widely memorized among physicians. Almost all PAH trials safety and ef cacy of PAH-targeted therapies in fi have included patients with PAWP 15 mm Hg, which patients ful lling these criteria. means that the safety and efficacy of PAH drugs have been Invasive hemodynamics need to be placed in clinical evaluated in this patient population. Lowering the PAWP and echocardiographic context with regard to proba- threshold to 12 mm Hg decreases the likelihood of falsely bility of existence of left heart disease. labeling patients with PH due to HFpEF as PAH but at the The current evidence does not support recommending same time increases the rate at which the presence of PAH is left heart catheterization in all patients with PAH. mistakenly excluded. Should fluid or exercise challenge be used to distinguish There is no single PAWP value that allows for correct patients with PAH from patients with PH due to LV classification of all patients. PAWP is not a constant number dysfunction? SHOULD FLUID CHALLENGE BE USED TO but a biological variable that is affected by various factors, UNMASK LV DIASTOLIC DYSFUNCTION? The effect of volume fl including uid balance, intrathoracic pressure, and others. In challenge on left-sided end-diastolic pressure has been many patients with left heart disease, it will be possible to at a subject of interest for some time. Studies in healthy indi- least temporarily lower PAWP below 15 mm Hg with viduals have shown that administration of 1 liter of saline over meticulous afterload reduction and diuretic medication (15). 6 to 8 min raised the PAWP by a maximum of 3 mm Hg ’ A comprehensive assessment of the patient s medical history but not to >11 mm Hg (18). In contrast, in a population at and risk factors together with echocardiographic assessment high risk for diastolic dysfunction, administration of 500 ml will provide a more reliable diagnosis than a single PAWP of saline over 5 min was able to reveal patients in whom the (or LVEDP) measurement. The presence of clinical risk PAWP increased to >15 mm Hg (19). factors (systemic hypertension, older age, obesity, diabetes Thus, fluid challenge may identify patients with HFpEF mellitus, obstructive sleep apnea, coronary artery disease), but normal PAWP at baseline and may help reduce the fi fi atrial brillation, and echocardiographic ndings such as left number of inappropriate diagnoses of PAH in patients atrial enlargement or LV hypertrophy indicate a high like- with LV diastolic dysfunction. A fluid bolus of 500 ml lihood of HFpEF (16). administered over a period of 5 to 10 min appears to be A recent study showed that more than 50% of the patients safe and seems to discriminate patients with PAH from with PH and PAWP 15 mm Hg had LVEDP values those with LV diastolic dysfunction (20). Larger volumes, > 15 mm Hg during simultaneous right and left heart in contrast, may cause the PAWP to rise even in healthy catheterization (17). These data raised a debate as to volunteers (21). The diagnostic performance (sensitivity, fi whether the hemodynamic classi cation as pre- or post- specificity, and positive and negative predictive values) of capillary PH might be improved with routine LVEDP fluid challenge has not yet been sufficiently evaluated, and measurements. The additional risks and costs associated thesameistrueforthesafetyoffluid challenge in patients with routine left heart catheterizations are considerable but with severe PH as well as in patients with HFpEF. In might be offset by a more accurate diagnosis and the addition, fluid challenge adds another layer of complexity avoidance of the expensive and potentially harmful use of to RHC. PAH medications in patients with HFpEF. The working group felt that the current evidence does not support rec- RECOMMENDATION ON FLUID CHALLENGE FOR UNMASKING ommending left heart catheterization in all patients with HFPEF. PAH, especially when neither the patient’s history nor Fluid challenge may be useful in identifying patients clinical and echocardiographic findings suggest the presence with occult HFpEF, but this technique requires of LV dysfunction. However, the threshold to perform meticulous evaluation and standardization before its use left heart catheterization should be low in patients with in clinical practice can be recommended. echocardiographic signs of systolic and/or diastolic LV Current evidence suggests that administration of 500 dysfunction as well as in patients with risk factors for ml of fluid over 5 to 10 min is safe and may help to D46 Hoeper et al. JACC Vol. 62, No. 25, Suppl D, 2013 Definition and Diagnosis of PH December 24, 2013:D42–50

distinguish patients with PAH from those with occult complications (26). Thus, this invasive diagnostic LV diastolic dysfunction. The results of this test, procedure should be performed in expert centers. however, must be interpreted with caution and should Every RHC should include a comprehensive hemo- not be used alone to discard a diagnosis of PAH. dynamic assessment, including measurements of pressures in the right atrium, right ventricle, and PA; “ ” SHOULD HEMODYNAMICS BE ASSESSED AT EXERCISE TO in the wedge position; and CO and mixed-venous UNMASK LV DIASTOLIC DYSFUNCTION? Exercise, with wide oxygen saturation. swings in airway and pleural pressures, poses particular The zero level of the pressure transducer varies among technical challenges in recording and interpreting cardiac centers and should be standardized for future research pressures, and few studies have systematically analyzed the because the level of the transducer has an important PAWP changes during exercise. In a study of healthy non- impact on the hemodynamic results, especially on right athletes, the mean wedge pressure rose by up to 5 mm Hg atrium pressure and PAWP (27). The working group with exercise but did not exceed 15 mm Hg (22). In well- recommends zeroing the pressure transducer at the trained athletes, recumbent exercise significantly increased midthoracic line in a supine patient halfway between the PAWP, reaching 20 to 25 mm Hg in several individuals the anterior sternum and the bed surface. This repre- (23). In a more recent study on exercise-induced PH, Tolle sents the level of the left atrium. fl et al. (11) found PAWP values >15 mm Hg in approxi- The balloon should be in ated in the right atrium mately half of the healthy control group as well as in patients from where the catheter should be advanced until it fl with exercise-induced or resting PH. reaches the PAWP position. Repeated de ations and fl Borlaug et al. (24) studied the effects of exercise on in ations of the catheter should be avoided because hemodynamics in patients with exertional dyspnea and this has been associated with ruptures of PAs (26). presumed HFpEF but normal resting PAWP levels. At rest, The PAWP should be recorded as the mean of 3 patients with HFpEF had slightly higher PAWP (11 2 vs. measurements at end-expiration. 9 3 mm Hg in controls without cardiac disease). During The gold standard for CO measurement is the direct exercise, end-expiration PAWP rose to 32 6mmHgin Fick method, which requires direct measurement of patients with HFpEF compared with 13 5mmHgin the oxygen uptake, a technique that is not widely controls (24). In addition, a recent study suggested that available. Therefore, it has become common practice in exercise hemodynamics may be useful in distinguishing many centers to use the indirect Fick method, which between PAH and PH associated with LV diastolic uses estimated values for oxygen uptake derived from dysfunction in patients with the scleroderma (SSc) spectrum tables. This approach is acceptable but lacks reliability. of disease (25). Therefore, the preferred method of measuring CO is Thus, exercise hemodynamics may identify patients with thermodilution, which has been shown to provide HFpEF with normal PAWP at rest. However, it is reliable measurements even in patients with very low cumbersome and time consuming to exercise patients with CO and/or severe tricuspid regurgitation (28). a catheter in place, reading of the PAWP during exercise is Oximetry (i.e., stepwise assessment of oxygen satura- difficult, and there has been no standardization on the level tion) should be performed in every patient with a PA > of exercise, type of exercise, position at exercise, and normal oxygen saturation 75% and whenever a cardiac left- values for various ages. to-right shunt is suspected. Pulmonary vasoreactivity testing for identification of RECOMMENDATION ON EXERCISE CHALLENGE TO UNMASK calcium channel blocker “responders” is recommended HFPEF. only for patients with IPAH. In all other forms of It is likely that exercise hemodynamics will be useful in PAH or PH, pulmonary vasoreactivity testing is not uncovering HFpEF. However, further evaluation, recommended unless it is completed for scientific standardization, and comparison with volume chal- purposes because “responders” are exceedingly rare lenge are necessary before their use in clinical practice among these patients and the results can be misleading can be endorsed. (29). Inhaled nitric oxide at 10 to 20 parts per million is the gold standard for pulmonary vasoreactivity testing (30); intravenous epoprostenol (2 to 12 ng/kg/min), Additional Recommendations for RHC intravenous adenosine (50 to 350 mg/min), and inhaled iloprost (5 mg) can be used as alternatives (31,32). The Although current guidelines and textbooks recommend use of oxygen, calcium channel blockers, phosphodi- RHC for the diagnostic evaluation of patients with PH, esterase 5 inhibitors, or other vasodilators for acute specific recommendations on how to perform this procedure pulmonary vasoreactivity testing is discouraged. are rare. The following points should be noted. Pulmonary angiography can be part of the RHC but RHC in patients with PH can be technically demanding should be performed after all hemodynamic assess- and has been associated with serious, sometimes fatal, ments have been completed. JACC Vol. 62, No. 25, Suppl D, 2013 Hoeper et al. D47 December 24, 2013:D42–50 Definition and Diagnosis of PH

Figure 1 Diagnostic Approach to Pulmonary Hypertension

BGA ¼ blood gas analysis; CHD ¼ congenital heart disease; CTD ¼ connective tissue disease; CTEPH ¼ chronic thromboembolic pulmonary hypertension; DLCO ¼ diffusion capacity of the lung for carbon monoxide; ECG ¼ electrocardiogram; HR-CT ¼ high-resolution computed tomography; PA ¼ pulmonary angiography; PAH ¼ pulmonary arterial hypertension; PAPm ¼ mean pulmonary artery pressure; PAWP ¼ pulmonary arterial wedge pressure; PCH ¼ pulmonary capillary hemangiomatosis; PEA ¼ pulmonary endarterectomy; PFT ¼ pulmonary function testing; PH ¼ pulmonary hypertension; PVOD ¼ pulmonary veno-occlusive disease; PVR ¼ pulmonary vascular resistance; RHC ¼ right heart catheter; RV ¼ right ventricle; V/Q ¼ ventilation/perfusion; x-ray ¼ chest radiograph.

Diagnostic Approach in Patients With and/or signs of right ventricular dysfunction. Transthoracic Clinical Suspicion of PH/PAH echocardiography continues to be the most important noninvasive screening tool to assess the possibility of PH, The most fundamental principles in the diagnostic workup but RHC remains mandatory to establish the diagnosis. A of patients with clinical suspicion of PH/PAH remain diagnosis of PAH requires the exclusion of other causes of unchanged. PH/PAH should be suspected in any patient PH, and the working group proposes a slightly modiﬁed with otherwise unexplained dyspnea on exertion, syncope, version of the diagnostic algorithm proposed in the 2009 D48 Hoeper et al. JACC Vol. 62, No. 25, Suppl D, 2013 Definition and Diagnosis of PH December 24, 2013:D42–50

European guidelines (2,4) as shown in Figure 1. This revised early detection. These include patients with CTD, congenital version has been simplified and, in some aspects, is more heart disease, chronic liver disease, and HIV infection. specific. The pathway leading from ventilation/perfusion Except for patients with the SSc spectrum of disease, no new scintigraphy to pulmonary veno-occlusive disease has been evidence has been generated; therefore, previous recom- deleted (33), and diffusing capacity of the lung for carbon mendations have not been modified. monoxide (DLCO) measurements have been added to the Screening for PAH in patients with the SSc spectrum of initial assessment because spirometry alone does not always disease. Current guidelines recommend regular screening reveal parenchymal lung disease, for instance, in patients by echocardiography in patients with SSc spectrum of with combined pulmonary fibrosis and emphysema (34–36). diseases (defined as patients with systemic sclerosis, mixed A comprehensive workup for PH requires expertise and connective tissue disease, or other CTDs with prominent should be performed at expert centers (2). scleroderma features such as sclerodactyly, nail fold capillary abnormalities, SSc-specific autoantibodies) (2,4). No such Early Identification of Patients With PAH guidelines exist for other CTDs. The DETECT (Evidence-based detection of pulmonary Sporadic cases (IPAH). Despite increasing awareness, arterial hypertension in systemic sclerosis) study recently there is often considerable delay between onset of symptoms evaluated a 2-step approach in patients with SSc spectrum and diagnosis of IPAH. In the recent REVEAL (Registry to disorders with DLCO 60% and disease duration of >3 years Evaluate Early and Long-Term PAH Disease Manage- (52). The first step used a simple screening test, such as the > ment) registry, 21% of patients had symptoms for 2 years presence of telangiectasia, anticentromere antibodies, right- before diagnosis (37,38). The vast majority of patients axis deviation on electrocardiogram, and low DLCO and diagnosed with IPAH are in World Health Organization serum biomarkers (urate and N-terminal pro–B-type natri- – functional classes III and IV (37,39 41), which have been uretic peptide [NT-proBNP]), which gave a sensitivity of shown to predict poorer survival (42,43). The nature of 97% (i.e., a low likelihood of falsely excluding PAH). Step 2 patients formally diagnosed with IPAH has also changed was echocardiography (tricuspid regurgitation jet and right over recent years, at least in the Western world, with atrium area) in patients at risk, followed by RHC. With this fi a signi cant increase in age and number of comorbidities algorithm, the number of missed PAH cases was 4%, (41,44,45). Identifying patients with IPAH earlier in the compared with 29% with the echocardiography-based fi disease process is likely to be bene cial, allowing targeted approach recommended in the current European Respiratory fi therapies to be started before the development of signi cant Society/European Society of Cardiology guidelines, suggest- fi right heart failure (46). Screening is possible in well-de ned ing that using a broader panel of diagnostic tools provides patient groups at high risk of developing PAH, but this more reliable information than echocardiography alone. approach is not feasible in the wider population. Identifying The DETECT algorithm is not yet validated in patients patients with IPAH earlier relies on health care professionals with DLCO >60%. Other choices include a combination of having awareness of the condition. echocardiogram, NT-proBNP, and pulmonary function Hereditary cases (HPAH). Approximately 20% of patients testing (PFT) parameters, which is summarized in the with sporadic IPAH and 70% of patients with HPAH have recently published recommendations on screening and early a mutation in bone morphogenetic protein receptor 2 detection of CTD-associated PAH (53,54). (BMPR2), and additional genes associated with HPAH have recently been identified (47,48), which raises the possibility of Recommendations on screening of high-risk populations family screening (49). However, because of reduced pene- for PAH. trance, the lifetime risk of developing PAH is approximately Annual screening for PAH is recommended in 20% in BMPR2 mutation carriers (50). The benefits of (cardiopulmonary) asymptomatic patients with the SSc genetic testing are therefore not certain. A negative test in the spectrum of diseases, although there is a lack of context of a known mutation in a family member is reassur- evidence-based data. ing, whereas a positive test can create significant psycholog- Screening of patients with the SSc spectrum of diseases ical issues (51). Furthermore, the approach to monitoring without clinical signs and symptoms of PH should known mutation carriers for the development of PAH is not include a 2-step approach using clinical assessment for clear. Interval echocardiography of mutation carriers has been the presence of telangiectasia, anticentromere anti- suggested (53), although in the absence of evidence for bodies, PFT and DLCO measurements, electrocar- benefit of targeted therapies in truly asymptomatic patients, it diogram, and biomarkers (NT-proBNP and uric acid) could be argued that echocardiography should be reserved in the initial stage, followed by echocardiography and only for symptomatic carriers. Most importantly, expert consideration of RHC in patients with abnormal find- counseling should accompany any family screening program. ings, although there is a lack of data with DLCO >60%. Detection of PAH and screening in high-risk populations. The above mentioned screening programs for patients Various other groups of patients may be considered at high with SSc should be part of a scientific protocol, or risk of developing PAH and, as such, may be candidates for a registry, whenever possible. JACC Vol. 62, No. 25, Suppl D, 2013 Hoeper et al. D49 December 24, 2013:D42–50 Definition and Diagnosis of PH

Patients with SSc and other CTDs with clinical signs 3. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 and symptoms of PH should be evaluated by RHC. expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, Summary and Conclusions American Thoracic Society, Inc., and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009;53:1573–619. The diagnostic approach to PH proposed at the 4th WSPH 4. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the has proved useful and largely successful. The general hemo- Diagnosis and Treatment of Pulmonary Hypertension of the European dynamic definition of PH (PAPm 25 mm Hg at rest) should Society of Cardiology (ESC) and the European Respiratory Society not be changed. Patients with PAPm values between 21 and (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493–537. 24 mm Hg should be carefully followed, but the term 5. Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial “borderline PH” should be avoided because these patients pressure during rest and exercise in healthy subjects: a systematic do not have PH. PVR >3 WU has been added as a hemo- review. Eur Respir J 2009;34:888–94. 6. Kovacs G, Maier R, Aberer E, et al. Borderline pulmonary arterial dynamic criterion for PAH, in an attempt to provide a clearer pressure is associated with decreased exercise capacity in scleroderma. distinction from other forms of PH. RHC remains an Am J Respir Crit Care Med 2009;180:881–6. essential tool for the diagnostic workup of patients with PH, 7. Hamada K, Nagai S, Tanaka S, et al. Significance of pulmonary arterial pressure and diffusion capacity of the lung as prognosticator in patients and the working group has made several proposals for further with idiopathic pulmonary fibrosis. Chest 2007;131:650–6. standardization of this procedure. Reintroducing exercise 8. Hoeper MM. The new definition of pulmonary hypertension. Eur criteria for patients with normal hemodynamics at rest but Respir J 2009;34:790–1. 9. Bae S, Saggar R, Bolster MB, et al. Baseline characteristics and follow- elevated PA pressures during exercise is not recommended up in patients with normal haemodynamics versus borderline mean because it is currently impossible to define appropriate cutoff pulmonary arterial pressure in systemic sclerosis: results from the levels and there have been few studies assessing what is path- PHAROS registry. 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Eur Respir J 2012;39:945–55. right heart catheterization - screening. Journal of the American College of Cardiology Vol. 62, No. 25, Suppl D, 2013 2013 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2013.10.023

Pulmonary Arterial Hypertension Epidemiology and Registries Michael D. McGoon, MD,* Raymond L. Benza, MD,y Pilar Escribano-Subias, MD,z Xin Jiang, MD,x Dave P. Miller, MS,k Andrew J. Peacock, MD,{ Joanna Pepke-Zaba, MD,# Tomas Pulido, MD,** Stuart Rich, MD,yy Stephan Rosenkranz, MD,zz Samy Suissa, PHD,xx Marc Humbert, MD, PHDkk Rochester, Minnesota; Pittsburgh, Pennsylvania; Madrid, Spain; Beijing, China; San Francisco, California; Glasgow and Cambridge, United Kingdom; Mexico City, Mexico; Chicago, Illinois; Cologne, Germany; Montreal, Quebec, Canada; and Le Kremlin Bicêtre, France

Registries of patients with pulmonary arterial hypertension (PAH) have been instrumental in characterizing the presentation and natural history of the disease and provide a basis for prognostication. Since the initial accumulation of data conducted in the 1980s, subsequent registry databases have yielded information about the demographic factors, treatment, and survival of patients and have permitted comparisons between populations in different eras and environments. Inclusion of patients with all subtypes of PAH has also allowed comparisons of these subpopulations. We describe herein the basic methodology by which PAH registries have been conducted, review key insights provided by registries, summarize issues related to interpretation and comparison of the results, and discuss the utility of data to predict survival outcomes. Potential sources of bias, particularly related to the inclusion of incident and/or prevalent patients and missing data, are addressed. A fundamental observation of current registries is that survival in the modern treatment era has improved compared with that observed previously and that outcomes among PAH subpopulations vary substantially. Continuing systematic clinical surveillance of PAH will be important as treatment evolves and as understanding of mechanisms advance. Considerations for future directions of registry studies include enrollment of a broader population of patients with pulmonary hypertension of all clinical types and severity and continued globalization and collaboration of registry databases. (J Am Coll Cardiol 2013;62:D51–9) ª 2013 by the American College of Cardiology Foundation

Registries provide information about deﬁned cohorts of impact of the disease (outcome) is the primary goal of patients who are intended to represent the population with clinical observational PH registries. Constellations of similar disease characteristics. Description of patients with circumstances (risks) may be elucidated that are associated pulmonary hypertension (PH), or a subset of PH, and the with various probabilities of outcome. Registries provide the

From the *Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota; Dr. Escribano-Subias reports that the Spanish registry of PH is sponsored by a Bayer yDivision of Cardiovascular Diseases, Allegheny General Hospital, Pittsburgh, Schering Pharma educational grant; has received honoraria for sitting on advisory Pennsylvania; zCardiology Department and Spanish Cardiovascular Research boards and taking at sponsored symposia from Actelion, GlaxoSmithKline, United Network, Hospital Universitario, Madrid, Spain; xThrombosis Medicine Center, Therapeutics, Pfizer, Bayer and Ferrer; and has received institutional grants for per- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Peking Union forming RCTs by the same companies. D. P. Miller is an employee of Icon Clinical Medical College and Chinese Academy Medical Science, Beijing, China; kICON Research, which receives research funding from pharmaceutical and biotechnology Clinical Research, Medical Affairs Statistical Analysis, San Francisco, California; companies. Dr. Peacock has received honoraria for speaking at meetings (non- {Scottish Pulmonary Vascular Unit, Regional Heart and Lung Center, Glasgow, promotional) from Actelion, Bayer, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, and United Kingdom; #Pulmonary Vascular Diseases Unit, Papworth Hospital, Cam- United Therapeutics; travel assistance to conferences from Actelion, Bayer, Eli Lilly, bridge, United Kingdom; **Cardiopulmonary Department, National Heart Institute, GlaxoSmithKline, Novartis, Pfizer, and United Therapeutics; research grants Mexico City, Mexico; yySection of Cardiology, University of Chicago, Chicago, (educational only) from Actelion and Bayer; and has served on the advisory boards of Illinois; zzClinic III for Internal Medicine, Department of Cardiology, Heart Center Actelion, Bayer, Eli Lilly, GlaxoSmithKline, Novartis, and Pfizer. Dr. Pepke-Zaba at the University of Cologne, Cologne, Germany; xxCentre for Clinical Epidemiology, has received reimbursement of travel expenses to congresses and speakers’ fees from Jewish General Hospital, Department of Epidemiology and Biostatistics, McGill Actelion, Pfizer, GlaxoSmithKline, Bayer; has served on the advisory boards of University, Montreal, Quebec, Canada; and the kkUniversite Paris-Sud, Inserm U999, Actelion, Bayer, and GlaxoSmithKline; and has received funds for research and LabEx LERMIT, AP-HP, DHU Thorax Innovation, Service de Pneumologie, education from Actelion, Pfizer, GlaxoSmithKline, and Bayer. Dr. Pulido has received Hôpital Bicêtre, Le Kremlin Bicêtre, France. Dr. McGoon has received institutional honoraria for serving as a consultant for Actelion, Bayer, and Pfizer; has received grants for studies in which he was the primary investigator from and Medtronic and research grants (institutional) from Actelion, Bayer, Gilead, Lilly, Pfizer, and United Gilead; participated in speaking activities for Actelion, Gilead (funded conferences, Therapeutics; has received honoraria for serving on the advisory boards of Actelion and not speakers’ bureaus); was a consultant for Actelion; was the chair of the REVEAL Bayer; and has received lecture fees from Actelion, Bayer, and Pfizer. Dr. Rosenkrantz Registry and on the data adjudication committees; on the Data Safety Monitoring has received speaker fees and/or renumerations for consulting from Acetelion, Bayer, Board of Gilead and GlaxoSmithKline; and is on the Advisory Committee of Lung GlaxoSmithKline, Lilly, Novartis, Pfizer, and United Therapeutics; and research LLC. Dr. Benza has contracted research for Acetlion, Bayer, Gilead, GeNO, Ikaria, grants from Actelion, Bayer, Novartis, Pfizer, and United Therapeutics. Dr. Suissa has and United Therapeutics; and is a consultant for Bayer and United Therapeutics. participated in advisory meetings or as a conference speaker for Actelion, AstraZeneca, D52 McGoon et al. JACC Vol. 62, No. 25, Suppl D, 2013 Registries of Pulmonary Arterial Hypertension December 24, 2013:D51–9

Abbreviations foundation of knowledge upon structure and process of data collection; and 3) as noted and Acronyms which other important clinical in the GRACE (Good Research for Comparative Effec- research, such as clinical drug tiveness) principles (3), identiﬁcation of the most likely 6MWD = 6-min walk distance studies, may be constructed. sources of bias. Survival, bias, and missing data. Survival is one of the CRF = case report form most common outcomes in registries. The survival curve’s CTEPH = chronic Methods of Registries thromboembolic pulmonary time frame must be clear. Survival from time of enrollment hypertension Deﬁnitions. The Agency for in a prevalent cohort can lead to biased results if generalized

NIH = National Institutes of Healthcare Research and Quality to newly diagnosed patients. Conversely, survival from Health in the United States defines diagnosis can lead to biased estimates if those results are “ PAH = pulmonary arterial a patient registry as an organized generalized to a cohort of prevalent patients at a typical hypertension system that uses observational clinic. Additionally, survival estimates from one incident PH = pulmonary study methods to collect uniform cohort may not be generalizable to another incident cohort if hypertension data (clinical and other) to eval- diagnosis methods or time from symptom onset to diagnosis PPH = primary pulmonary uate specified outcomes for a differ between cohorts. hypertension population defined by a particular It is never appropriate to define an at-risk period that disease, condition, or exposure, includes the time during which patients were not in the and that serves one or more predetermined scientific, clinical, study. Doing so leads to immortal time bias (4) because or policy purposes” (1). The European Medicines Agency patients are guaranteed to have survived the pre-study defines a registry as “a list of patients presenting with the same period. An important difference between immortal time characteristic(s). This characteristic may be a disease or an bias and survivor bias is that there does not exist any outcome (disease registry) or a specific exposure (exposure or appropriate population to whom analyses with immortal drug registry)” (2). time bias may be correctly generalized. On the other hand, The European Medicines Agency defines cohort studies survivor bias, a form of selection bias, does not prevent as involving “a population-at-risk for an event of interest accurate generalization so long as the results are not incau- followed over time for the occurrence of that event” while tiously generalized to incident patients. allowing that a registry may, itself, represent a cohort (2). Due to the lack of randomization, confounding, rather The Agency for Healthcare Research and Quality defines than selection bias, is often the Achilles heel of registries, cohort studies as a specific category of registry distinct from whereas generalizability to a broad cohort is often one of the case-control studies. The term cohort may also be used to greatest strengths. As a result, the guidelines do not suggest define a subpopulation of interest within a registry. For specific rules for inclusion/exclusion criteria, instead sug- instance, if a registry enrolls both incident and prevalent gesting that the target population, the study objectives, and patients, analyses may be conducted on one or both of these avoidance of bias should guide study design decisions. cohorts depending on the objective. Missing data are a common methodological problem in The term prevalent may be applied to patients who have registries because specific clinical tests are generally not previously received a diagnosis and who may enter a study mandated. Casewise deletion of patients with missing data when returning for follow-up visits or follow-up treatments. can lead to selection bias. If most patients in real practice do The term incident is generally used to indicate patients who not have complete batteries of testing at regular intervals, the have just received a diagnosis as opposed to those patients results of analyses using casewise deletion cannot be gener- who have just experienced onset of symptoms. These alized to them. Alternative approaches include multiple patients are considered incident on the day of diagnosis and imputation (5) or treating missingness as a distinct category. prevalent the day after. When outcomes data, rather than risk factor data, are None of the guidelines propose limiting inclusion criteria missing, casewise deletion could lead to even greater biases, in registries to incident patients, although neither of them but imputation of outcomes is generally not desirable. explicitly suggest that such a restriction would be ill-advised. Patients who are lost to follow-up should be censored at the The guidelines do address 3 important issues that should point in time that they are lost. Care should be taken to lead to a study-specific decision about inclusion/exclusion define the time of last follow-up to ensure that it includes criteria: 1) generalizability and carefully defined target the time period in which an event would have been reported populations; 2) the need for clear objectives to define the and excludes the time period in which an event would not have been reported. Current pulmonary arterial hypertension registries. Pul- Bayer, Boehringer- Ingelheim, GlaxoSmithKline, Merck, Novartis, and Pfizer. Dr. monary arterial hypertension (PAH) (group 1 PH) registries Humbert has been a consultant for and a member of the advisory board of Actelion, have used different inclusion and exclusion criteria with Aires, Bayer, GlaxoSmithKline, Novartis, Pfizer, and United Therapeutics as well as respect to the enrollment of newly and previously diagnosed being an investigator in trials involving these companies. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. patients. Lee et al. (6) argue in favor of restricting survival Manuscript received October 10, 2013; accepted October 22, 2013. analyses to incident patients, as in the United Kingdom and JACC Vol. 62, No. 25, Suppl D, 2013 McGoon et al. D53 December 24, 2013:D51–9 Registries of Pulmonary Arterial Hypertension

Ireland registry, whereas Miller et al. (7) argue that risk objectives. Major costs include funding for site coordinators, stratification or a delayed entry model accounting for left project management, in-person meetings, data management, truncation is preferable to excluding prevalent patients from and statistical analysis. When studies receive industry PAH registries. A population is said to be left truncated if sponsorship, the relationship of the sponsor and advisors patients may have been excluded from a cohort due to events must be clearly delineated, and it is similarly important for that occurred before the study. Patients who die before study data ownership and data access rules to be specified initiation are excluded, whereas patients who survive to study contractually. Disclosing conflict of interest is critical, but initiation are included from the point in their survival at there are many important scientific objectives with which the which they were enrolled. An approach to analyzing survival interests of industry, patients, and the scientific community from diagnosis, using both newly diagnosed and previously are fully aligned. diagnosed patients, was used in the U.S. REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Manage- Characteristics of Major Registries ment) protocol, as well as in the French Registry (8–10). Survival from time of diagnosis, using data from both Baseline. The characteristics of 11 major registries are incident and prevalent patients, was estimated both by shown in Table 1 (17–39). Six countries are represented. All Humbert et al. (9) and Benza et al. (10) and are comparable registries enrolled patients with idiopathic and heritable to survival estimates that are restricted to incident patients PAH, 7 included PAH, and 1 also included chronic (11). Of note, inclusion of patients with nonconforming thromboembolic pulmonary hypertension (CTEPH) (PH high wedge pressures (pulmonary artery pulmonary wedge Group 4). The number of patients in each registry ranged pressure ranging from 16 to 18 mm Hg) has been contro- from 72 to 3,515, and the number of participating centers versial; however, these patients may be excluded or included ranged from 1 to 55. Table 2 provides the basic presenting in individual analyses and differences may be evaluated (12). characteristics of patients enrolled in each registry. Analysis: what can be done with the data and what is not Outcome. Table 3 shows survival over the duration of possible? Although literature on design and conduct of reported follow-up. In general, survival improved as treat- registries is not as extensive as the literature on clinical trials, ment options increased. Data from the U.S. REVEAL observational researchers must begin by reviewing recent suggests that current median survival is 7 years for patients guidelines (3,13,14). Registry data are useful for describing with PAH (10) compared with 2.8 years for patients with practice patterns, characterizing populations, assessing primary pulmonary hypertension (PPH, now referred to as burden of illness, and developing risk stratification tools. idiopathic/heritable PAH) in the U.S. National Institutes of The use of registry data for comparative effectiveness is Health (NIH) Registry (17). probably the most controversial study aim (15,16). Because aggressive treatments will generally be reserved for the The Changing Phenotype of PAH sickest patients, the worst outcomes will occur frequently in the Modern Management Era among these patients, thereby confounding assessment of efficacy. A variety of methods exist to adjust for confound- Registries have provided important information about ing. Matching, multivariable risk-adjusted models of the epidemiology and phenotype of patients with PAH. outcomes and propensity scores can be effective if all con- Of note, considerable changes in the PAH phenotype founding variables have been identified and measured. In have been observed over the past decades. These include PAH, it is plausible that most, but not all, important substantial changes in age, sex, comorbidities, and survival potential confounders have been successfully identified due (Tables 2 and 4) (6,9,19,27,34,37,40). Although the mean to the extensive research that has been published in the past age of patients with idiopathic PAH in the first registry decade on risk factors. Nonetheless, it is unlikely that all created in 1981 (U.S. NIH Registry) was 36 15 years (18), important confounders have been measured at the time of PAH is now more frequently diagnosed in elderly patients, treatment selection. Variable time lags between treatment resulting in a mean age at diagnosis between 50 14 and 65 decision and treatment initiation can also increase the 15 years in current registries (Table 2). Furthermore, the potential for immortal time bias to enter into a comparative female predominance is quite variable among registries and effectiveness analysis. may not be present in elderly patients (39), and survival Funding. A number of factors can make observational appears to have improved over time (Table 3). To know studies less expensive than randomized trials. Patients can whether these differences reflect a change in the disease generally be recruited faster due to broad inclusion criteria itself, one must determine all of the biases that affect PH and few barriers to participation. There are usually no registries and how they differ between registries before any mandated treatments or tests. A risk-based site monitoring conclusion can be made that the phenotype of PAH is approach reduces the need for full source document verifi- actually changing (41). When looking at any registry, cation. Some aspects of registries can also make them differences need to be identified between the target pop- more expensive. These include long-term follow-up and ulation, the accessible population, the intended population, analysis requirements associated with having multiple study and the population actually studied. How representative the D54 eitiso umnr reilHypertension Arterial Pulmonary of Registries McGoon tal et .

Table 1 General Information of PAH Registries From Different Countries and Time Periods

Study Design Predominant Etiologies Registry (Ref. #) Study Cohort and Time Period No. of Centers No. of Patients Incidence/Prevalence of PAH U.S. NIH (17,18) IPAH Prospective, 1981–1985 32 187 NA NA U.S. PHC (19) Group 1 PH, age >18 yrs Retrospective, 1982–2004; 3 578 NA IPAH, 48%; CTD-PAH, 30%; prospective, 2004–2006 CHD-PAH, 11% Scottish-SMR (20) Group 1 PH (IPAH, CHD-PAH, Retrospective, 1986–2001 NA 374 PAH, 7.6/26 cases/MAI; IPAH, 47%; CTD-PAH, 30%; and CTD-PAH), age 16–65 yrs IPAH, 2.6/9 cases/MAI CHD-PAH, 23% French (9,21,22) Group 1 PH, age >18 yrs Prospective, 2002–2003 17 674 PAH, 2.4/15 cases/MAI; IPAH, 39%; CTD-PAH, 15% (SSc, 76%); IPAH, 1.0/5.9 cases/MAI CHD-PAH, 11% Chinese (23) IPAH and HPAH Prospective, 1999–2004 1 72 NA NA U.S. REVEAL (8,24–33) Group 1 PH Prospective, 2006–2009 55 3,515 (age >3 months) PAH, 2.0/10.6 cases/MAI IPAH, 46%; CTD-PAH, 25% (SSc, 62%); IPAH, 0.9 cases/MAI CHD-PAH, 10% Spanish (34) Group 1 PH and CTEPH, Retrospective, 1998–2006; 31 PAH, 866; CTEPH, 162 PAH, 3.2/16 cases/MAI; IPAH, 30%; CTD-PAH, 15% (SSc 61%); age >14 yrs prospective, 2007–2008 IPAH, 1.2/4.6 cases/MAI CHD-PAH, 16% UK (6,35) IPAH, HPAH, and anorexigen- Prospective, 2001–2009 8 482 1.1/6.6 cases/MI NA associated PAH New Chinese Registry (36,37) Group 1 PH, age >18 yrs Prospective, 2008–2011 9 956 NA CHD-PAH, 43%; IPAH, 35%; CTD-PAH, 19% (SLE, 51%; SSc, 9%) Mayo (38) Group 1 PH Prospective, 1995–2004 1 484 NA IPAH, HPAH 56%; CTD-PAH, 24%, other, 20% Compera (39) IPAH, age >18 yrs Prospective, 2007–2011 28 587 NA IPAH, 100%

CHD ¼ congenital heart disease; CTD ¼ connective tissue disease; CTEPH ¼ chronic thromboembolic pulmonary hypertension; HPAH ¼ heritable pulmonary arterial hypertension; IPAH ¼ idiopathic pulmonary arterial hypertension; MAI ¼ million adult inhabitants; MI ¼ million inhabitants; NA ¼ not available; NIH ¼ National Institutes of Health; PAH ¼ pulmonary arterial hypertension; PHC ¼ pulmonary hypertension connection; SMR ¼ Scottish morbidity record; SSc ¼ systemic sclerosis. ACVl 2 o 5 up ,2013 D, Suppl 25, No. 62, Vol. JACC eebr2,2013:D51 24, December – 9 JACC Vol. 62, No. 25, Suppl D, 2013 McGoon et al. D55 December 24, 2013:D51–9 Registries of Pulmonary Arterial Hypertension

actual population is of the target population will determine . 12 10 11 10 14 how generalizable the registry is. 2 Table 1 m A potential explanation for the change of phenotype may $ be the increased awareness for PAH in the modern 14 27 13 23 10 23 management era, as effective therapies are now available. Because PPH was considered a rare disease that affected young women at the time of the initial U.S.-NIH registry, it is likely that older patients and men were often not 12 NA NA 12 NA NA 15 25 14 NA 23 13 21 19 NA NA 15 NA NA 14 21 1813 NA NA 26 NA considered for the diagnosis at that time. Other factors contributing to biased enrollment include lack of awareness of this registry among nonexperts in the community and unavailability of widespread screening tools such as Doppler 13 55 20 63 14 52 16 55 15 56 14 56 echocardiography. Nowadays, PAH may indeed be detected

World Health Organization; other abbreviations as in more frequently in elderly patients, as the population of most ¼ Western countries is aging. However, one should also be 5NA44 653 6NA54 663 6NA69 651 554 555 6NA60 752 cautious about possible misclassifications between PAH and non-PAH PH (particularly post-capillary PH due to heart failure with preserved ejection fraction [HFpEF]), which 613 58 610 58 59 711 may occur, particularly in elderly patients as a consequence of uncertainties in the current definitions and difficulties in

Scottish morbidity record; WHO the measurement of the pulmonary arterial wedge pressure. ¼ Registries from China and other developing countries 126 NA 8 125 13 127 8 123 NA 10 129 9 117 9 112 8 demonstrate demographics and characteristics similar to the early studies of the U.S. NIH Registry (23), suggesting that some differences in phenotype are related to the healthcare environment rather than to different expressions of the disease. Nonetheless, speciﬁc sources of systematic bias in 125 344 125 353 120 382 126 374 109 328 PAH registries include the following: 1) changes in the mean right atrial pressure; SMR

¼ classiﬁcation of PH that have led to the inclusion of a varying spectrum of patients in modern registries; 2) changing interest in PH by academic physicians producing more development and dissemination of information; 3) increased awareness of PH by clinicians due to availability and marketing of effective therapy, with associated education from pharmaceutical representatives (42); 4) easier access to medical information by patients who may then inﬂuence their referral to specialized care; and 5) widespread use of pulmonary vascular resistance index; RAP

¼ noninvasive techniques (Doppler echocardiography), which allow for disease detection even in the absence of previous suspicion, thereby leading to a perception of increased disease prevalence (43). Thus, it appears that the changing 15 NA 60 NA 91 NA 293 15 75 76 55 56 329 13 70 70 54 66 378 17 NA 70 NA 84 NA 292 18 71 73 69 70 363 15 80 83 56 55 366 12 NA 71 NA 61 NA NA NA 13 15 65 62 75 81 329 1411 77 70 75 62 80 NA 80 NA NA NA NA NA 11 NA NA NA NA NA NA 15 NA 63 NA 75 NA NAphenotype NA of 10 patients with PH in modern registries is SD (age, 6WMD, and hemodynamic variables). potentially inﬂuenced by factors that are independent of the disease itself. Age, yrs Female, % WHO III/IV, % 6MWD, m RAP, mm Hg mPAP, mm Hg PVRI, U 15 52 13 38 17 46 14 50 15 52 14 45 12 49 Prediction and Prognosis Based on NA 65 NA 50 NA 36 NA 36 mean pulmonary arterial pressure; PVRI PAH IPAH PAH IPAH PAH IPAH PAH IPAH PAH IPAH PAH IPAH PAH IPAH ¼ 52 36 45 50 50 48 52 Relevant Registry Data

The U.S. NIH Registry was the ﬁrst to develop a prognostic equation. Use of this equation in the current treatment era (36,37) 33)

– has limitations; it provides information only on the natural history of untreated PPH rather than on group 1 PH (20) Demographic, Clinical, and Hemodynamic Characteristics of PAH Registries From Different Countries and Time Periods (8,24 ﬁ

(39) (PAH). More recent registries (Tables 1 to 3)haveidenti ed (19) (17,18) (34) 6-min walking distance; mPAP (23) (9,21,22) ¼ (38) Registry (Ref. #) predictors of outcome (Table 4), which show surprising (6,35) homology between studies, including disease etiology, patient Compera Mayo New Chinese registry Spanish U.S. REVEAL UK Chinese U.S. PHC Scottish-SMR French U.S. NIH 6MWD Table 2 ﬂ Values are frequency (female, WHO functional class) and mean sex, and factors re ective of right heart function. D56 McGoon et al. JACC Vol. 62, No. 25, Suppl D, 2013 Registries of Pulmonary Arterial Hypertension December 24, 2013:D51–9

Prognostic equations and calculators. In 4 of the registries (U.S. REVEAL, U.S. Pulmonary Hypertension Connection Registry, French registry, and U.K. registry), multivariable analyses led to the development of prognostic equations (U.S. REVEAL, U.S. Pulmonary Hypertension Connection Registry, French registry) (Table 5) or calcula- NA NA NA NA tors (U.S. REVEAL, U.K. registry). Despite the U.S. REVEAL equation’s derivation in a combined incident and prevalent cohort at the time of enrollment, the equation demonstrated equal prognostic power when tested at the time of diagnosis and was validated in an entirely incident 73 NA 61 Inc 55 Ent 58 Prev 69

65 yrs, 83 65 yrs, 68 population (40) and in distinct PH populations at other > institutions (38,44,45). The U.K. prognostic score was validated in a second set of incident patients taken retro- spectively from the U.K. registry only (derivation was from the Scottish registry only). The French registry and U.S. *

NA Ent 74 REVEAL equations have shown adequate predictive power Ent 67 Prev 71 Inc 51 when tested in matched patients from the U.S. REVEAL and French registries, respectively (46,47). However, the French registry equation had lower calibration than the U.S. REVEAL equation when tested in respective matched populations from each registry. The U.S. REVEAL equa- 84 57 . Inc 68 Ent 67 tion was also noted to have good calibration in both the U.K. Prev 77 65 yrs, 91 65 yrs, 79 > and Spanish registries, whereas the French registry equation Table 1 appears to slightly overestimate the risk of death in these respective registries. One explanation for this is that the French registry equation, as opposed to the U.S. REVEAL

* equation, was calculated in a cohort of patients recruited in NA Ent 83

Ent 76 Prev 79 Inc 65 the 2002/2003 period that partially preceded widespread and early use of oral therapies for PAH. It is also apparent that the earlier discussions and concerns about the relative contribution to mortality risk of newly and previously diagnosed patients is minimized and overshadowed by the

93 68 overall contribution of individual risk proﬁles in each of Inc 89 Ent 83 Prev 89 65 yrs, 96 65 yrs, 90

> these populations, respectively. In other words, a newly diagnosed patient is not “independently” at risk of dying by

1 yr, % 2 yrs, %the mere 3 yrs, % fact of newly receiving 5 yrs, % a diagnosis, but rather because they have a larger proportion of at-risk factors than prevalent or previously diagnosed patients; other abbreviations as in Data for U.S. REVEAL is from the time of diagnostic right heart catheterization. y ¼ * those who previously received a diagnosis (7,21). PAH IPAH PAH IPAH PAH IPAH PAH IPAH Inc 88 Prev 88 Future Directions

Broadening to other PH groups and novel entry criteria. Although patients belonging to group 2 (PH due to left heart diseases) and group 3 (PH due to chronic lung diseases and/or hypoxia) of the PH classiﬁcation represent IncPrev and IncPrev and Inc 84 Ent 87 NA NA 68 NA NA NA NA 67 NA NA 48 58 NA NA 34 Prev and Inc 85 91 NA NA 68 74 57 65 Prev and IncIncPrev and IncInc NA 81 79 NA 89 NA Ent 92 NA NA NA NA NA 61 77 NA NA 48 68 NA Inc NAan 68 increasing part NA of the clinic 57al practice, there NA is dispro- 39 NA 21

incident or newly diagnosed patients; Prev portionately little information about the demographic ¼ factors and clinical course of this segment of the PH pop-

y ulation. This suggests that registry database methodology 33)

– maybeusefulforthesegroups.Thestructureofpotential registries incorporating “non-PAH” PH is problematic. Survival Data of PAH Registries From Different Countries and Time Periods (8,24 (39)

(19) Asingleregistrycouldinclude all patients with any type (17,18) (34) (23) (9,21,22) ﬁ (38)

entire study population; Inc of PH from which de ned subgroups (i.e., PH associated (6,35) Registry (Ref. #) Study Cohort ¼ with interstitial lung disease, chronic obstructive pulmonary U.S. PHC French Spanish UK Compera Mayo U.S. NIH U.S. REVEAL Chinese Ent Table 3

*Survival data calculated only from patients with IPAH and patients with CTD-PAH. disease, left ventricular systolic dysfunction, or left JACC Vol. 62, No. 25, Suppl D, 2013 McGoon et al. D57 December 24, 2013:D51–9 Registries of Pulmonary Arterial Hypertension

Table 4 Multivariate Predictors of Survival

Category Increase Risk Decrease Risk Demographics Sex (male) and age interaction (>65 yrs) (9,27,33,40) Age (6,19) Male (6,9,27,34) Etiology: CTD, (6,19,27,34,37,40) PoPH, (6,34,40); HPAH, (27,40); PVOD (6,34) Functional capacity Higher NYHA/WHO class (23,40,19,27,34,37) Lower NYHA/WHO class (19,27) Lower 6MWD (6,9,27,40) Higher 6MWD (6,9,27) Laboratory and biomarkers Higher BNP or NT-proBNP (27,40) Lower BNP or NT-proBNP (27) Higher creatinine (27,40) Imaging Echo: pericardial effusion (27,37,40) Lung function studies Lower predicted DLCO (27,37,40) Higher predicted DLCO (27,40) Hemodynamics Higher mRAP (6,19,27,34,40) Higher CO or CI (19) Lower CO or CI (6,9,34) Higher PVR or PVRI (27,40)

BNP ¼ B-type natriuretic peptide; CI ¼ cardiac index; CO ¼ cardiac output; DLCO ¼ diffusing capacity of the lung for carbon monoxide; Echo ¼ echocardiography; HPAH ¼ heritable pulmonary arterial hypertension; mRAP ¼ mean right atrial pressure; NT-proBNP ¼ N-terminal pro– B-type natriuretic peptide; NYHA ¼ New York Heart Association; PoPH ¼ portopulmonary hypertension; PVOD ¼ portopulmonary hypertension; PVR ¼ pulmonary vascularresistance;PVRI¼ pulmonary vascular resistance index; other abbreviations as in Tables 1 and 2. ventricular HFpEF) could be extracted for analyses. An CRFs at a less anticipated cost. This has been successfully advantage of this model is that all patients would be enrolled proposed for CTEPH (50). from the same sites and would permit direct comparisons Regardless of the disease area of interest, one question between cohorts with minimal adjustment for differences in that should be addressed during registry design is whether enrollment patterns, location, and follow-up. Disadvan- the purpose is to obtain information about a precisely tages are that many patients would need to be enrolled to defined disease (option 1) or to examine a more ambigu- provide sufficient cohort size for characterization of all ously delineated study population to determine what groups, and a single case report form (CRF) may not be defines a cohesively defined disease entity in terms of appropriate for all cohorts. The ASPIRE (Assessing the presentation and natural history (option 2). Option 1 is Spectrum of Pulmonary Hypertension Identified at most appropriate for diseases in which the criteria for a Referral Centre Registry) has attempted to assess the disease are definitive, whereas option 2 may be appropriate spectrum of PH across the 5 PH groups encountered in for circumstances in which the definition of the dise- a single specialist referral center, allowing specificdescrip- ase depends on multiple continuous parameters. PH fits tions of PH patients with associated diseases such as chronic within the second category; 1 registry (U.S. REVEAL) was obstructive pulmonary disease and other comorbidities constructed to examine whether there is true inhomoge- (48,49). However, this approach describes only the neity of presentation and course between patients meeting subgroup of patients seen at a referral center and may differ classic definitions of disease versus those outside the defi- from the characteristics of patients in the community. An nition (12). This approach has the potential for providing alternative model would be to develop separate registries insightintowhattheclinically meaningful delimiters of around specific disease entities of interest, using focused the disease are. At-risk population cohorts. Unless all patients who have PH within a population are enrolled in a registry, estimates fi Table 5 Prognostic Equations for Probability of Survival in PAH of incidence or prevalence of disease in a pre-speci ed population are not possible. To understand the chances of Registry (Ref. #) Equation C Index PH developing in a population requires that the population U.S. NIH* (17) P(t) ¼ H(t)A(x,y,z) 0.588 at risk be observed systematically over time to detect the y ¼ French (21) P(t;x,y,z) H(t)A(x,y,z) 0.57 occurrence of PH. Examples of populations of interest in PHCz (19) P(t) ¼ e A(x,y,z)t Not calculated g whom the risk of the development of PH makes systematic REVEALx (27) P(1-year) ¼ S0(1)exp(Z0b ) 0.772 data collection likely to yield clinically useful information *H(t) ¼ 0.88 – 0.14t þ 0.01t2; A(x,y,z) ¼ e(0.007325x þ 0.0526y 0.3275z), where x ¼ mean pulmonary artery pressure; y ¼ mean right-sided atrial pressure; and z ¼ cardiac index. yH(t) ¼ baseline include patients with known BMPR2 mutations, with 2 survival ¼ e(a þ b$t), where a and b are parameters estimated from the multivariate Cox family members with PH, with systemic sclerosis, with proportional hazards model, and t is the time from diagnosis measured in years; A(x,y,z) ¼ where x is the distance walked (m) at diagnosis, y ¼ 1 if female, y ¼ 0 if male, and z is the cardiac output cirrhosis and portal hypertension, with past or present (l/min) at diagnosis; A(x,y,z) ¼ e((c $ x þ d $ y þ e $ z)), where c and d were parameters obtained from methamphetamine use, with mean pulmonary artery pres- the Cox proportional hazards model. zP(t) is the probability of survival, t is the time interval in years, A(x,y,z) ¼ e(1.270 0.0148x þ 0.0402y 0.361z), x ¼ mean pulmonary artery pressure, sure of 20 to 25 mm Hg, or with PH observed only during y ¼ mean right atrial pressure, z ¼ cardiac index. xS0(1) is the baseline survivor function (0.9698), exercise. 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Hansmann G, Hoeper MM. Registries for paediatric pulmonary 2012:85–93. hypertension. Eur Respir J 2013;42:580–3. 37. Zhang R, Dai LZ, Xie WP, et al. Survival of Chinese patients with 55. Humbert M, Sega lES, Kiely DG, Carlsen J, Schwierin B, pulmonary arterial hypertension in the modern management era. Chest Hoeper MM. Results of European post-marketing surveillance of 2011;140:301–9. bosentan in pulmonary hypertension. Eur Respir J 2007;30:228–44. 38. Kane GC, Maradit-Kremers H, Slusser JP, Scott CG, Frantz RP, McGoon MD. Integration of clinical and hemodynamic parameters in the prediction of long-term survival in patients with pulmonary arterial Key Words: databases - epidemiology - pulmonary hypertension - hypertension. Chest 2011;139:1285–93. registries. Journal of the American College of Cardiology Vol. 62, No. 25, Suppl D, 2013 2013 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2013.10.031

Updated Treatment Algorithm of Pulmonary Arterial Hypertension

Nazzareno Galiè, MD,* Paul A. Corris, MD,y Adaani Frost, MD,z Reda E. Girgis, MD,x John Granton, MD,k Zhi Cheng Jing, MD,{ Walter Klepetko, MD,# Michael D. McGoon, MD,** Vallerie V. McLaughlin, MD,yy Ioana R. Preston, MD,zz Lewis J. Rubin, MD,xx Julio Sandoval, MD,kk Werner Seeger, MD,{{ Anne Keogh, MD## Bologna, Italy; Newcastle, England; Houston, Texas; Grand Rapids and Ann Arbor, Michigan; Rochester, Minnesota; Toronto, Canada; Beijing, China; Vienna, Austria; Boston, Massachusetts; La Jolla, California; Mexico City, Mexico; Giessen/Bad Nauheim, Germany; and Sydney, Australia

The demands on a pulmonary arterial hypertension (PAH) treatment algorithm are multiple and in some ways conﬂicting. The treatment algorithm usually includes different types of recommendations with varying degrees of scientiﬁc evidence. In addition, the algorithm is required to be comprehensive but not too complex, informative yet simple and straightforward. The type of information in the treatment algorithm are heterogeneous including clinical, hemodynamic, medical, interventional, pharmacological and regulatory recommendations. Stakeholders (or users) including physicians from various specialties and with variable expertise in PAH, nurses, patients and patients’ associations, healthcare providers, regulatory agencies and industry are often interested in the PAH treatment algorithm for different reasons. These are the considerable challenges faced when proposing appropriate updates to the current evidence-based treatment algorithm.The current treatment algorithm may be divided into 3 main areas: 1) general measures, supportive therapy, referral strategy, acute vasoreactivity testing and chronic treatment with calcium channel blockers; 2) initial therapy with approved PAH drugs; and 3) clinical response to the initial therapy, combination therapy, balloon atrial septostomy, and lung transplantation. All three sections will be revisited highlighting information newly available in the past 5 years and proposing updates where appropriate. The European Society of Cardiology grades of recommendation and levels of evidence will be adopted to rank the proposed treatments. (J Am Coll Cardiol 2013;62:D60–72) ª 2013 by the American College of Cardiology Foundation

The complexity of the treatment algorithm for pulmonary channel blockers (CCBs) for vasoreactive patients, the only arterial hypertension (PAH) has progressively increased since approved therapy was epoprostenol administered by continuous the 2nd World Symposium on Pulmonary Hypertension intravenous infusion (1). Five years later at the 3rd WSPH held (WSPH) in Evian, France in 1998 when, apart from calcium in Venice, Italy, in 2003, the treatment algorithm had expanded

From the *Department of Experimental, Diagnostic and Specialty Medicine and Novartis. Dr. Corris has received grant support from Bayer and Actelion; and (DIMES), Bologna University Hospital, Bologna, Italy; yInstitute of Cellular Medi- honoraria for speaking and chairing meetings for Actelion, Bayer, Pfizer, and Glaxo- cine Newcastle University and The Newcastle Hospitals NHS Foundation Trust, SmithKline. Dr. Frost has received clinical research grants from Gilead, Actelion, Newcastle, United Kingdom; zBaylor College of Medicine, Houston, Texas; Pfizer, GlaxoSmithKline, InterMune, Eli Lilly, United Therapeutics, AIRES, xMichigan State University, College of Human Medicine, Grand Rapids, Michigan; Novartis, Bayer, and IKARIA; has received honoraria for speakers’ bureau presenta- kDivision of Respirology, University of Toronto, Toronto, Canada; {Fu Wai Hospital tions from Actelion, Gilead, United Therapeutics, Bayer, and Pfizer; has served on the & National Center for Cardiovascular Disease Peking Union Medical College and steering committee for AIRES, AMBITION (Gilead, GlaxoSmithKline, Eli Lilly); Chinese Academy of Medical Science, Beijing, China; #Department of Thoracic has served on the advisory boards for Bayer, Gilead, and Actelion; has served on the Surgery, Medical University Vienna/Vienna General Hospital, Vienna, Austria; steering committee for AIRES, IKARIA, Gilead/GlaxoSmithKline, and United **Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota; yyCardiovascular Therapeutics/Lung LLC; and has served as a committee member for Entelligence and Medicine, The University of Michigan, Ann Arbor, Michigan; zzPulmonary, Critical REVEAL funded by Actelion. Dr. Girgis has served on the speakers’ bureau for Bayer; Care and Sleep Division, Tufts Medical Center, Tufts University School of Medicine, and is a consultant for Gilead. Dr. Granton has received support for investigator-led Boston, Massachusetts; xxMedical School, University of California, San Diego, La research from Actelion, Bayer, GlaxoSmithKline, Lilly, United Therapeutics, Ikaria, Jolla, California; kkClinical Research, National Institute of Cardiology of Mexico, and Pfizer; has received honoraria directed to his institution for consultant work from Mexico City, Mexico; {{Max Planck Institute for Heart and Lung Research, Actelion, Eli Lilly, GlaxoSmithKline, Ikaria, and Bayer; his institution has received Universities of Giessen and Marburg Lung Center, Giessen/Bad Nauheim, Germany; support for their foundation from Actelion, Bayer, and Lilly; and has received unre- and the ##Heart Transplant Unit, St Vincent’s Hospital, Sydney, Australia. Dr. Galiè stricted support for investigator-led research from Actelion and Pfizer/CIHR grant has served on the advisory boards of and received paid lectures from Eli Lilly, Actelion, (Canadian Institute for Health Research). Dr. Jing has served as a consultant, member Pfizer, Bayer-Schering, GlaxoSmithKline, and Novartis; has been paid lectures for Eli of scientific advisory boards, and investigator and speaker in trials for Actelion, Bayer Lilly and Company, Pfizer, Bayer-Schering, and GlaxoSmithKline; and received Schering, Pfizer, GlaxoSmithKline, and United Therapeutics. Dr. McGoon has institutional grant support from Actelion, Pfizer, Bayer-Schering, GlaxoSmithKline, received grant support directed at his institution for investigator-led research from JACC Vol. 62, No. 25, Suppl D, 2013 Galiè et al. D61 December 24, 2013:D60–72 Treatment Algorithm of Pulmonary Arterial Hypertension

General Measures, to 5 compounds belonging to 3 pharmacological classes, pro- Abbreviations stanoids, endothelin receptor antagonists (ERA), and phos- Supportive Therapy, and Acronyms phodiesterase type 5 inhibitors (PDE-5i), and included 4 Referral Centers, and Vasoreactivity Test APAH = associated different routes of administration (oral, inhaled, subcutaneous, pulmonary arterial and intravenous) (2). In 2008 the 4th WSPH was held in Dana hypertension General measures. In this Point, California, and the treatment algorithm included 4 section new information is BAS = balloon atrial additional compounds (1 of them, the ERA sitaxentan, was septostomy provided for pregnancy, rehabil- eventually withdrawn) (3,4). Although this progress in phar- itation, and exercise training. CCB = calcium channel macotherapy has been associated in different meta-analyses blocker with a reduction of morbidity and mortality (5,6),limiting PREGNANCY. Pregnancy remains ERA = endothelin receptor symptoms and poor outcome still characterize patients with associated with a substantial antagonist PAH. Further advances observed in different areas of PAH mortality rate in PAH. However, PAH = pulmonary arterial treatment in the past 5 years and the evolution of the treatment a recent report indicates that the hypertension algorithm discussed and updated at the 5th WSPH held in outcome of pregnancies in PAH PVR = pulmonary vascular Nice, France, from February 27 to March 1, 2013, will be has improved, at least when PAH is resistance presented here. well controlled and particularly in RCT = randomized controlled The current treatment algorithm may be divided into 3 long-term responders to CCBs (7). trials main areas: 1) general measures (rehabilitation/exercise and During a 3-year period, the 13 6MWD = 6-min walk distance exercise training, psychosocial support, pregnancy, vaccina- participating centers reported 26 tions), supportive therapy (anticoagulants, diuretics, digitalis, pregnancies. Three women (12%) WHO-FC = World Health Organization Functional oxygen), the roles of referral centers, acute vasoreactivity died and 1 (4%) developed right Class testing, and chronic CCB therapy; 2) information about the heart failure requiring urgent heart- initial therapy and includes all drugs approved in any country lung transplantation. There were 8 abortions: 2 spontaneous and according to the World Health Organization functional 6 induced. Sixteen pregnancies (62%) were successful (i.e., the class (WHO-FC) of the patients and the grade of recom- women delivered healthy babies without complications). These mendation and level of evidence of each individual compound; data must be confirmed by larger series before the general and 3) the clinical response to the initial therapy and in case recommendation to avoid pregnancy in all patients with PAH is of inadequate results, the recommendations/role of combi- reconsidered (grade of recommendation I, Level of Evidence: C). nations of approved drugs and additional interventional procedures such as balloon atrial septostomy and lung REHABILITATION AND EXERCISE TRAINING. The 2009 transplantation. pulmonary hypertension (PH) guidelines suggested that PAH All 3 sections will be revisited, highlighting the new patients should be encouraged to be active within symptom information collected in the past 5 years and proposing limits (4). It was recommended that patients should avoid updates where appropriate. excessive physical activity that leads to distressing symptoms, The European Society of Cardiology grades of recom- but when physically deconditioned may undertake supervised mendation and levels of evidence will be adopted to score exercise rehabilitation. This was based on a randomized the proposed treatments (Tables 1 and 2) (4). controlled trial (RCT) that demonstrated an improvement in The new proposed treatment algorithm is shown in exercise and functional capacity and in quality of life in patients Figure 1. with PH who took part in a training program as compared with a control untrained group (8). Since then, additional uncon- Medtronic and Gilead; has participated in speaking activities for Actelion and Gilead trolled experiences have supported these data utilizing different (funded conferences, not speakers’ bureaus); has served as a consultant to Pharma and models of exercise training (9–13). Two additional RCTs have Actelion; has served as the chair of the REVEAL Registry; on the data adjudication committees for Gilead; and on the advisory committee for Lung LLC and Glaxo- also been published reports that trained PAH patients reached SmithKline. Dr. McLaughlin has served on the speakers’ bureau for Gilead and United higher levels of physical activity, had decreased fatigue severity, Therapeutics; has served as a consultant or member of the advisory board/steering showed improved 6-min walk distance (6MWD), cardiore- committee for Actelion, Bayer, Gilead, United Therapeutics; and has received institutional grant/research support from Actelion, Bayer, Lkana, and Novartis. Dr. Preston spiratory function, and patient-reported quality of life as has received research grants from Actelion, Bayer, Gilead, United Therapeutics, compared with untrained controls (14,15). The sample size of Novartis, GeNO, and AIRES; and has served as a consultant for Actelion, Bayer, all these studies is quite small (ranging from 19 to 183 Gilead, and United Therapeutics. Dr. Rubin has a relationship with United Thera- peutics, Bayer, GeNO, NHLBI, FDA, Actelion, Lung LLC, Gilead, Reata Phar- patients), and all or initial training was highly supervised and in maceuticals, Arena Pharmaceuticals, and AIRES. Dr. Sandoval has received honoraria some instances conducted in an in-patient setting. Despite and lecture fees from Bayer Schering. Dr. Seeger has received speaker fees from Pfizer these limitations, however, the concordance of the results and and Bayer HealthCare; and is a consultant for Bayer Pharma AG. Dr. Keogh has served as a clinical trialist for Actelion, Aires, Bayer, GlaxoSmithKline, Pfizer, Novartis, the overall publication of 3 RCTs suggest the upgrading of the Arena, and United Therapeutics; has served on the advisory board for Actelion, Bayer, recommendation for rehabilitation and exercise training to and GlaxoSmithKline; and has served on the speakers’ bureau for Actelion, Bayer, and Class I with a Level of Evidence: A. GlaxoSmithKline. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The limitations of this recommendation are based on the Manuscript received October 11, 2013; accepted October 22, 2013. gaps in knowledge of the optimal method, intensity, and D62 Galiè et al. JACC Vol. 62, No. 25, Suppl D, 2013 Treatment Algorithm of Pulmonary Arterial Hypertension December 24, 2013:D60–72

Table 1 Classes of Recommendations

Class of Suggested Wording Recommendations Definition to Use Class I Evidence and/or general agreement that a given treatment or Is recommended, procedure is beneficial, useful, effective. Is indicated Class II Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure. Class IIa Weight of evidence/opinion is in favor of usefulness/efficacy. Should be considered Class IIb Usefulness/efficacy is less well established by evidence/opinion. May be considered Class III Evidence or general agreement that the given treatment or Is not recommended procedure is not useful/ effective, and in some cases may be harmful. duration of the training. In addition, neither the character- Individual compounds. A summary of the RCTs per- istics of the supervision and the mechanisms for the formed in PAH for each compound is shown in Tables 3–6 improvement of symptoms, exercise, and functional capacity on the basis of the related pathobiological pathway. The nor the possible effects on prognosis are clear. Exercise table also includes nonapproved drugs for PAH or drugs still training programs should be implemented by centers expe- under regulatory consideration at the time of this publica- rienced in both PAH patient care and rehabilitation of tion. Pharmacological classes and drugs are listed in alpha- compromised patients. betical order. Only compounds approved for PAH or under Supportive therapy. No major new information is available regulatory approval process are included in the treatment on anticoagulants, diuretics, digitalis, and oxygen, and no algorithm and are listed in alphabetical order (Fig. 1). changes in the recommendations are proposed (4). Long- A brief description of the compounds, according to their term oxygen therapy is suggested to maintain arterial pharmacological class, is provided subsequently. blood O2 pressure 8 kPa (60 mm Hg). Endothelin pathway. Activation of the endothelin system Referral centers and vasoreactivity testing. PAH is a rare has been demonstrated in the plasma and lung tissue of chronic progressive condition that is lethal, disabling, costly, PAH patients (20). Although it is not clear if the increases and treatable. High-volume specialized centers have been in endothelin plasma levels are a cause or a consequence of recurrently shown to obtain the best outcomes for patients PH (21), these data support a prominent role for the in different areas of medicine while maintaining greatest endothelin system in the pathogenesis of PAH (22). patient satisfaction, lowest complication rates, shortest length Endothelin receptor antagonists. Endothelin exerts of hospital stay and best value for healthcare payers (16). vasoconstrictor and mitogenic effects by binding to 2 Suggestions on possible models of emergency treatments (17) distinct receptor isoforms in the pulmonary vascular smooth and a survey on PAH care organization in developed coun- muscle cells, endothelin-A and -B receptors. Endothelin-B tries have been published (18). The recommendation to refer receptors are also present in endothelial cells, and their patients after PAH diagnosis to expert centers is maintained. activation leads to release of vasodilators and antiproliferative Acute vasoreactivity testing remains mandatory in patients substances such as NO and prostacyclin that may counter- with idiopathic PAH to identify subjects that will respond balance the deleterious effects of endothelin-1. Despite favorably to long-term treatment with high doses of potential differences in receptor isoform activity, the efficacy calcium-channel blockers. Inhaled nitric oxide (iNO) is the in PAH of the dual endothelin-A and -B receptor antago- compound of choice for the acute test and, on the basis of nist drugs and of the selective endothelin-A receptor previous experience, intravenous epoprostenol or adenosine antagonist compounds appear to be comparable. may also be used as an alternative (but with a risk of systemic vasodilator effects) (4). More recently, inhaled iloprost has AMBRISENTAN. Ambrisentan is a nonsulfonamide, propanoic been able to identify patients who may benefit from long- acid class, ERA that is selective for the endothelin-A receptor. term therapy with CCBs (19). Ambrisentan has been evaluated in a pilot study (23) and

Initial Therapy With PAH-Approved Drugs Table 2 Levels of Evidence

Therapy with PAH-approved drugs needs to be initiated in Level Definition PAH patients who are not vasoreactive or are vasoreactive but A Data derived from multiple randomized clinical trials or meta-analyses not responding appropriately to CCBs (Fig. 1). For the initial B Data derived from a single randomized clinical trial or large fi nonrandomized studies therapy, drugs are classi ed according to the grade of C Consensus of opinion of the experts and/or small studies, recommendation (Table 1) and the level of evidence (Table 2) retrospective studies, registries on the basis of published RCTs. In addition, initial drug Results on the basis of post-hoc and subgroup analyses of clinical trials most often do not meet the therapies are also stratified according to WHO-FC. criteria of a level of evidence A. JACC Vol. 62, No. 25, Suppl D, 2013 Galiè et al. D63 December 24, 2013:D60–72 Treatment Algorithm of Pulmonary Arterial Hypertension

Figure 1 Evidence-Based Treatment Algorithm

APAH ¼ associated pulmonary arterial hypertension; BAS ¼ balloon atrial septostomy; CCB ¼ calcium channel blockers; ERA ¼ endothelin receptor antagonist; sGCS ¼ soluble guanylate cyclase stimulators; IPAH ¼ idiopathic pulmonary arterial hypertension; i.v. ¼ intravenous; PDE-5i ¼ phosphodiesterase type-5 inhibitor; s.c. ¼ subcutaneous; WHO-FC ¼ World Health Organization functional class. in 2 large RCTs (ARIES [Ambrisentan in pulmonary hemodynamics, and time to clinical worsening of patients arterial hypertension, Randomized, double-blind, placebo- with idiopathic PAH and PAH associated with connective controlled, multicentre, Efficacy Study]-1 and -2), which tissue disease and human immunodeficiency virus infection have demonstrated efficacy on symptoms, exercise capacity, (24). Ambrisentan has been approved for the treatment of D64 Galiè et al. JACC Vol. 62, No. 25, Suppl D, 2013 Treatment Algorithm of Pulmonary Arterial Hypertension December 24, 2013:D60–72

Characteristics of Randomized Controlled Trials With Pulmonary Arterial Hypertension Drugs Interfering With the Table 3 Endothelin Pathway (See Text for References)

Drug(s) Tested Study Background Primary Endpoint Outcome (Secondary Endpoint) Duration (weeks) No. of Patients Ambrisentan ARIES-1 No 6MWD TTCW (NS) 12 202 ARIES-2 No 6MWD TTCW 12 192 Bosentan Study-351 No 6MWD TTCW 12 32 BREATHE-1 No 6MWD TTCW 16 213 BREATHE-2* No PVR d 12 33 EARLY No Sildenaﬁl (16%) PVR, 6MWD TTCW 24 185

BREATHE-5 No SaO2, PVR d 12 54 Macitentany SERAPHIN No, PDE5i or Inhal iloprost TTCW Safety 100 742

*Bosentan þ epoprostenol versus placebo þ epoprostenol. yApproved by the FDA for PAH patients and has obtained at the time of printing the positive opinion of the Committee for Medicinal Products for Human Use of the the EMA for this indication.

6MWD ¼ 6-min walk distance; inhal ¼ inhalation; NS ¼ not statistically signiﬁcant; PDE5i ¼ phosphodiesterase type-5 inhibitors; PVR ¼ pulmonary vascular resistance; SaO2 ¼ ﬁnger oxygen saturation; TTCW ¼ time to clinical worsening.

WHO-FC II and III patients. The incidence of abnormal MACITENTAN. The dual ERA macitentan was developed liver function tests range from 0.8% to 3%. No tendency for by modifying the structure of bosentan to increase efficacy development of abnormal liver function tests was observed in and safety. Macitentan is characterized by sustained receptor patients who had previously demonstrated abnormalities binding and enhanced tissue penetration. In the event- while on other ERA, and monthly liver function assessment is driven SERAPHIN (Study with an Endothelin Receptor not mandated in the United States (25). An increased inci- Antagonist in Pulmonary Arterial Hypertension to Improve dence of peripheral edema has been reported with ambri- Clinical Outcome) study (31), 742 PAH patients were sentan use. Ambrisentan is approved for PAH patients. treated with 3 or 10 mg macitentan as compared with placebo for an average of 100 weeks. The primary endpoint BOSENTAN. Bosentan is an oral active dual endothelin-A and -B was the time from the initiation of treatment to the first receptor antagonist and the first molecule of its class to be occurrence of a composite endpoint of death, atrial septos- synthesized. Bosentan has been evaluated in PAH (idio- tomy, lung transplantation, initiation of treatment with pathic, associated with connective tissue disease and Eisen- intravenous or subcutaneous prostanoids, or worsening of menger’s syndrome) in 5 RCTs (Study-351, BREATHE PAH. Macitentan significantly reduced this composite [Bosentan Randomised trial of Endothelin Antagonist endpoint of morbidity and mortality among patients with THErapy]-1, BREATHE-2, BREATHE-5, and EARLY PAH and also increased exercise capacity. Benefits were [Endothelin Antagonist tRial in mildLY symptomatic shown both for patients who had not received treatment pulmonary arterial hypertension patients]), which showed previously and for those receiving background therapy for improvement in exercise capacity, functional class, hemody- PAH. While no liver toxicity was shown, reduction in blood namics, echocardiographic and Doppler variables, and time hemoglobin 8 g/dl was observed in 4.3% of patients to clinical worsening (26–30). Increases in hepatic amino- receiving 10 mg of macitentan. Macitentan is approved transferases occurred in approximately 10% of the subjects but by the U.S. Food and Drug Administration (FDA) for PAH were found to be dose-dependent and reversible after dose patients and has obtained at the time of printing the positive reduction or discontinuation. For these reasons, liver function opinion of the Committee for Medicinal Products for testing should be performed monthly in patients receiving Human Use of the European Medicines Agency (EMA) for bosentan. Bosentan is approved for PAH patients. this indication.

Characteristics of Randomized Controlled Trials With Pulmonary Arterial Hypertension Drugs Interfering With the Table 4 Nitric Oxide Pathway (See Text for References)

Drug(s) Tested Study Background Primary Endpoint Outcome (Secondary Endpoint) Duration (weeks) No. of Patients Soluble Guanylate Cyclase Stimulators Riociguat* PATENT No bosentan or prostanoids 6MWD TTCW 12 443 Phosphodiesterase Type-5 Inhibitors Sildenafil SUPER-1 No 6MWD TTCW (NS) 12 277 Sastry No TT d 12 22 Singh No 6MWD d 620 PACES Epoprostenol 6MWD TTCW 16 264 Iversen Bosentan 6MWD d 12 20 Tadalafil PHIRST No or bosentan (54%) 6MWD TTCW 16 405 Vardenafily EVALUATION No 6MWD TTCW 12 66

*Approved by the FDA for PAH and CTEPH patients and is currently undergoing the regulatory approval process by the EMA for both indications. yNot approved for pulmonary arterial hypertension. TT ¼ treadmill test; other abbreviations as in Table 3. JACC Vol. 62, No. 25, Suppl D, 2013 Galiè et al. D65 December 24, 2013:D60–72 Treatment Algorithm of Pulmonary Arterial Hypertension

Characteristics of Randomized Controlled Trials With Pulmonary Arterial Hypertension Drugs Interfering With the Table 5 Platelet-Derived Growth Factor Pathway (See Text for References)

Drug(s) Outcome Duration No. of Tested Study Background Primary Endpoint (Secondary Endpoint) (weeks) Patients Tyrosine kinase inhibitor imatinib* Phase 2 Bosentan and/or sildenaﬁl and/or 6MWD (NS) d 24 59 prostanoids IMPRES Bosentan and/or sildenaﬁl and/or 6MWD TTCW (NS) 24 202 prostanoids

*Not approved for pulmonary arterial hypertension. Abbreviations as in Table 3.

Nitric oxide pathway. Impairment of NO synthesis and common serious adverse event in the placebo group and signaling through the NO–soluble guanylate cyclase (sGC)– the 2.5 mg group was syncope (4% and 1%, respectively). cyclic guanosine monophosphate (cGMP) pathway is The combination of riociguat and PDE-5i is contra- involved in the pathogenesis of pulmonary hypertension. indicated due to hypotension and other relevant side effects Soluble guanylate cyclase stimulators. While PDE-5is, detected in the open-label phase of the PATENT-plus such as sildenafil, tadalafil, and vardenafil, enhance the study (34). Riociguat is approved by the FDA for PAH NO–cGMP pathway, slowing cGMP degradation, sGC and chronic thromboembolic pulmonary hypertension stimulators enhance cGMP production and are potentially (CTEPH) patients and is currently undergoing the regu- effective also in conditions in which endogenous NO is latory approval process by the EMA for both indications. depleted (32). Pre-clinical studies with sGC stimulators PDE-5is. Inhibition of the cyclic guanosine mono- have shown antiproliferative and antiremodeling properties phosphate degrading enzyme PDE-5 results in vasodilation in various animal models. through the NO/cGMP pathway at sites expressing this enzyme. Because the pulmonary vasculature contains RIOCIGUAT. Riociguathasadualmodeofaction,acting substantial amounts of PDE-5 the potential clinical benefit in synergy with endogenous NO and also directly stimu- of PDE-5ì has been investigated in PAH. In addition, lating sGC independent of NO availability. An RCT PDE-5i exerts antiproliferative effects (35,36). All 3 PDE- (PATENT [Pulmonary Arterial Hypertension Soluble 5is approved for the treatment of erectile dysfunction, sil- Guanylate Cyclase–Stimulator Trial]-1) (33) in 443 PAH denafil, tadalafil, and vardenafil cause significant pulmonary patients (44% and 6% on background therapy with ERA vasodilation with maximum effects observed after 60, 75 to or prostanoids, respectively) treated with riociguat up to 90, and 40 to 45 min, respectively (37). 2.5 mg 3 times daily has shown favorable results on exercise capacity, hemodynamics, WHO-FC, and time to clinical SILDENAFIL. Sildenafil is an orally active, potent, and worsening. The increase in exercise capacity was also selective PDE-5i. Five RCTs in PAH patients treated with demonstrated in patients on background therapy. The most sildenafil have confirmed favorable results on exercise

Characteristics of Randomized Controlled Trials With Pulmonary Arterial Hypertension Drugs Interfering With the Table 6 Prostacyclin Pathway (See Text for References)

Primary Outcome Duration No. of Drug(s) Tested Study Background Endpoint (Secondary Endpoint) (weeks) Patients Prostanoids Beraprost ALPHABET No 6MWD d 12 130 Barst No CW (NS) d 52 116 Epoprostenol Rubin No 6MWD d 12 23 Barst No 6MWD Survival 12 81 Badesch No 6MWD d 12 111 Iloprost AIR No 6MWD and FC d 12 203 STEP Bosentan 6MWD TTCW 12 67 COMBI Bosentan 6MWD (NS) d 12 40 Treprostinil SC- Simonneau No 6MWD d 12 470 Inhal TRIUMPH Bosentan or Sildenafil 6MWD d 12 235 PO- Freedom M No 6MWD d 16 185 PO- Freedom C1 Bosentan and/or sildenafil 6MWD (NS) d 16 354 PO- Freedom C2 Bosentan and/or sildenafil 6MWD (NS) d 16 310 Prostacyclin IP-receptor Agonists Selexipag* Phase 2 Bosentan and/or sildenafil PVR 6MWD (NS) 17 43

*Not approved for pulmonary artery hypertension. CW ¼ clinical worsening; FC ¼ Functional Class; inhal ¼ inhalation; PO ¼ oral; SC ¼ subcutaneous; other abbreviations as in Table 3. D66 Galiè et al. JACC Vol. 62, No. 25, Suppl D, 2013 Treatment Algorithm of Pulmonary Arterial Hypertension December 24, 2013:D60–72

may be efficacious in PAH. Two RCTs on PAH patients treated with imatinib (all of them on background therapy Survival After Lung Transplantation in Patients With Table 7 Pulmonary Arterial Hypertension with at least 2 PAH-approved drugs) have shown positive results on exercise capacity and hemodynamics (data possibly 1 year 5 years 10 years influenced by the drop-out rate in the treated group), but Pittsburgh (Toyoda et al., 2008 [74]) 86 75 66 failed to show favorable effects on time to clinical worsening Paris (Fadel et al., 2010 [75]) 79 52 43 (46,47). In addition, an increased incidence of subdural Toronto (de Perrot et al., 2012 [76]) 78 60 45 Vienna (Klepetko, unpublished 73 71 d hematoma was observed in PAH patients treated with both data, 2011) imatinib and oral anticoagulants. Regulatory consideration of imatinib for the PAH indication has recently been halted. Prostacyclin pathway. Prostacyclin is produced predomi- capacity, symptoms, and/or hemodynamics (38–41). The nantly by endothelial cells and induces potent vasodilation of PACES (Pulmonary Arterial hypertension Combination all vascular beds and in addition is an inhibitor of platelet study of Epoprostenol and Sildenafil) trial addressing the aggregation and it also appears to have both cytoprotective effects of adding sildenafil to epoprostenol showed and antiproliferative activities (48). Dysregulation of the improvements after 12 weeks in 6MWD and time to clinical prostacyclin metabolic pathways has been shown in patients worsening. Of note, 7 deaths occurred in this trial, all in the with PAH as assessed by reduction of prostacyclin synthase placebo group (42). The approved dose of sildenafilis20mg expression in the pulmonary arteries and of urinary metab- three times daily. Most side effects of sildenafil are mild to olites of prostacyclin (49,50). moderate and mainly related to vasodilation (headache, Prostanoids. The clinical use of prostacyclin in patients flushing, epistaxis). On the basis of pharmacokinetic data an with PAH has been extended by the synthesis of stable intravenous formulation of sildenafil (43) has been approved analogues. by the FDA and EMA as a bridge for PAH patients on BERAPROST. Beraprost is the first chemically stable and long-term oral treatment who are temporarily unable to orally active prostacyclin analogue. The RCT ALPHABET fi ingest tablets. Sildena l is approved for PAH patients. (Arterial Pulmonary Hypertension And Beraprost Euro- TADALAFIL. Tadalafil is a once daily dispensed, selective pean Trial) (51) in Europe and a second study in the United PDE-5i. An RCT (PHIRST [Pulmonary arterial Hyper- States (52) with this compound have shown an improvement tension and ReSponse to Tadalafil] trial) in 406 PAH in exercise capacity, which unfortunately persists only up to patients (53% on background bosentan therapy) treated 3 to 6 months. There were no hemodynamic benefits. The with tadalafil 2.5, 10, 20, or 40 mg once daily has shown most frequent adverse events were headache, flushing, favorable results on exercise capacity, symptoms, hemody- jaw pain, and diarrhea. Beraprost is approved for PAH in namics, and time to clinical worsening at the highest dose Japan and South Korea. (44). The side effect profile was similar to that of sildenafil. EPOPROSTENOL. Epoprostenol (synthetic prostacyclin) has Tadalafil is approved for PAH patients. a short half-life (3 to 5 min) and is stable at room temper- VARDENAFIL. Vardenafil is a twice daily dispensed PDE-5i. ature for only 8 h requiring cooling, continuous adminis- An RCT (EVALUATION [Efficacy and Safety of Varde- tration by means of an infusion pump and a permanent nafil in the Treatment of Pulmonary Arterial Hypertension]) tunneled catheter. The efficacy of continuous intravenous in 66 treatment naive PAH patients treated with vardenafil (IV) administration of epoprostenol has been tested in 3 5 mg twice daily has shown favorable results on exercise unblinded RCTs in patients with idiopathic PAH (53,54) capacity, hemodynamics, and time to clinical worsening and in those with PAH associated with the scleroderma (45). The side effect profile was similar to that of sildenafil. spectrum of diseases (55). Epoprostenol improves symp- Vardenafil is currently not approved for PAH patients. toms, exercise capacity, and hemodynamics in both clinical Platelet-derived growth factor pathway. Proliferation of conditions, and is the only treatment shown to reduce endothelial cells and vascular smooth muscle cells with mortality in idiopathic PAH in a randomized study (54). narrowing or occlusion of the vessel lumen is a histopatho- The meta-analysis for total mortality of the 3 epoprostenol logical hallmark of the distal pulmonary arteries in PAH RCTs (53–55) performed with the Mantel–Haenszel and patients. Evidence from animal models and human disease the Peto fixed-effect methods showed a relative risk suggest that platelet-derived growth factor and c-KIT (RR) reduction of 70% (z ¼ 2.35, p ¼ 0.019, heterogeneity signaling are important in vascular smooth muscle cell p ¼ 0.182) and 68% (z ¼ 2.52, p ¼ 0.012, heterogeneity proliferation and hyperplasia. p ¼ 0.153), respectively (Fig. 2). Serious adverse events Tyrosine kinase inhibitors. IMATINIB. Imatinib is an related to the delivery system include pump malfunction, antiproliferative agent developed to target the Bcr-Abl local site infection, catheter obstruction, and sepsis. Intra- tyrosine kinase in patients with chronic myeloid leukemia. venous epoprostenol is approved for PAH patients. A In addition, the inhibitory effects of imatinib on platelet- thermostable formulation of epoprostenol is approved in the derived growth factor receptors and c-KIT suggest that it United States, Canada, Japan and in most of the European JACC Vol. 62, No. 25, Suppl D, 2013 Galiè et al. D67 December 24, 2013:D60–72 Treatment Algorithm of Pulmonary Arterial Hypertension countries and does not require cooling packs to maintain TREPROSTINIL. Treprostinil is a tricyclic benzidine analogue stability beyond 8 to 12 h. of epoprostenol, with sufficient chemical stability to be administered at ambient temperature. These characteristics ILOPROST. Iloprost is a chemically stable prostacyclin allow administration of the compound by the IV as well analogue available for intravenous, oral, and inhaled as the subcutaneous and oral route. The subcutaneous administration. Inhaled iloprost has been evaluated in 1 administration of treprostinil can be accomplished by a RCT (AIR [Aerosolized Iloprost Randomized] study) in microinfusion pump and a small subcutaneous catheter. which daily repetitive iloprost inhalations (6 to 9 times, 2.5 The effects of treprostinil in PAH were studied in an RCT to 5 mg/inhalation, median 30 mg daily) were compared and showed improvements in exercise capacity, hemody- with placebo inhalation in patients with PAH and CTEPH namics, and symptoms (60). Infusion site pain was the most (56). The study showed an increase in exercise capacity and common adverse effect of treprostinil, leading to discon- improvement in symptoms, pulmonary vascular resistance tinuation of the treatment in 8% of cases on active drug and (PVR) and clinical events in enrolled patients. Two addi- limiting dose increase in an additional proportion of patients tional RCTs (STEP [Safety and pilot efficacy Trial of (60). An RCT was performed with intravenous treprostinil inhaled iloprost in combination with bosentan for Evalua- in PAH patients (TRUST [Multicenter, Randomized, tion in Pulmonary arterial hypertension] and COMBI Double-Blind, Placebo-Controlled Trial Compared Con- [COMbination therapy of Bosentan and aerosolized Iloprost tinuous IV Treprostinil to Placebo in PAH Patients]) but in idiopathic pulmonary arterial hypertension]) of patients the enrollment of this trial was closed after 45 (36%) of the already treated with bosentan have shown conflicting results planned 126 patients had been randomized because of safety of the addition of inhaled iloprost (57,58). Overall, inhaled considerations (61). The data generated from 31 (25%) iloprost was well tolerated with flushing and jaw pain being survivors after the randomized phase (23 active and 8 the most frequent side effects. Continuous IV administra- placebo) are not considered reliable and the study is not tion of iloprost appears to be as effective as epoprostenol in included in Table 6. a small uncontrolled series of patients with PAH and An RCT (TRIUMPH [inhaled TReprostInil sodiUM CTEPH (59). Inhaled iloprost is approved for PAH. The in Patients with severe Pulmonary arterial Hypertension]) IV formulation is approved for PAH in New Zealand. with inhaled treprostinil in PAH patients on background

Meta-Analysis of Published Randomized Controlled Studies (Identiﬁed by First Author and Year of Publication) Figure 2 With Epoprostenol in Pulmonary Arterial Hypertension by Mantel–Haenszel and Peto Methods

The analysis included 215 patients in 3 trials. The figure shows the cumulative relative risk (RR) estimate of death in active treatment groups when compared with control groups. An overall reduction of the risk of mortality of 70% (p ¼ 0.019) and 68% (o ¼ 0.012) is shown with Mantel–Haenszel and Peto methods, respectively. CI ¼ confidence interval; OR ¼ odds ratio. D68 Galiè et al. JACC Vol. 62, No. 25, Suppl D, 2013 Treatment Algorithm of Pulmonary Arterial Hypertension December 24, 2013:D60–72 therapy with either bosentan or sildenafil showed improve- combination therapy. The experience with combination ments in 6MWD by 20 m at peak dose, N-terminal pro– therapy is therefore growing and a recent meta-analysis on 6 B-type natriuretic peptide (NT-proBNP) and quality-of-life RCTs with combination therapy including 858 patients has measures (62). been published (67): compared with the control group, Oral treprostinil has been evaluated in 2 RCTs in PAH combination therapy reduced the risk of clinical worsening patients on background therapy with bosentan and/or sil- (RR: 0.48; 95% confidence interval: 0.26 to 0.91; p ¼ denafil (FREEDOM [Multicenter, Double-101 Blind, 0.023), increased the 6MWD significantly by 22 m, and Randomized, Placebo-Controlled Study of the Efficacy and reduced mean pulmonary arterial pressure, right atrial Safety of Oral treprostinil Sustained Release Tablets in pressure, and PVR. The incidence of serious adverse events Subjects With Pulmonary Arterial Hypertension] C1 and was similar in the 2 groups (RR: 1.17; 95% confidence C2) and in both the primary endpoint 6MWD did not reach interval: 0.40 to 3.42; p ¼ 0.77). The reduction on all-cause statistical significance (63,64). An additional RCT in PAH mortality was not statistically significant. However, the naive patients showed improvement in 6MWD by 26 m at incidence of mortality in RCTs with PAH medications is peak dose (65). Subcutaneous treprostinil is approved for relatively low and to achieve statistical significance a sample PAH. Intravenous treprostinil is approved in the United size of several thousands of patients may be required (67). States and European Union in patients with PAH who The patterns to apply combination therapy may be cannot tolerate the subcutaneous administration (based on sequential or initial (upfront). bioequivalence). Inhaled treprostinil is approved for PAH in Sequential combination therapy is the most widely the United States. Oral treprostinil is currently not approved utilized strategy both in RCTs (12 of 13 of the RCTs with for PAH. combination therapy) (Tables 3 to 6) and in clinical prac- Prostacyclin IP-receptor agonists. SELEXIPAG. Selexipag tice: From monotherapy there is addition of a second and is an orally available, selective prostacyclin IP receptor agonist. then third drug in cases of inadequate clinical results or in Although selexipag and its metabolite have modes of action cases of deterioration. A structured prospective program to similar to that of endogenous prostacyclin (IP receptor ago- evaluate the adequacy of clinical results is the so-called nism), they are chemically distinct from prostacyclin with “goal-oriented therapy,” a treatment strategy that uses a different pharmacology. In a pilot RCT in PAH patients known prognostic indicators as treatment targets. The (receiving stable ERA and/or a PDE-5i therapy) selexipag therapy is considered adequate only if the targets are met. reduced PVR after 17 weeks (66). A large event-driven phase The key difference between goal-oriented therapy and 3 RCT (GRIPHON [Prostocyclin (PGI2) Receptor Agonist nonstructured approaches is that patients who are stabi- in Pulmonary Arterial Hypertension] trial) is currently lized, or even those who improve slightly, can still receive ongoing. Selexipag is currently not approved for PAH. additional therapy if treatment goals are not met. The goal- oriented treatment strategy has been endorsed by recent Clinical Response, Combination Therapy, PAH guidelines proposing different targets including and Interventional Procedures WHO-FC I or II and the near normalization of resting cardiac index and/or of NT-proBNP plasma levels (4).A After initial therapy, the next steps are based on the clinical recent study has confirmed a better prognosis in patients response, which is usually reassessed at 3 to 6 months after achieving these goals as compared with the patients who treatment start. did not (68). Sequential combination therapy has been The clinical response is based on the evaluation of allocated a grade of recommendation I and level of evidence different parameters including WHO-FC, exercise capacity, A in PAH patients with inadequate clinical response to cardiac index, right atrial pressure, NT-proBNP plasma initial monotherapy. levels, echocardiographic parameters, and perceived need The rationale for initial or upfront combination therapy for additional/change of therapy. The exact definition of is based on the known mortality of PAH that is reminiscent clinical response is addressed in another paper of this of many malignancies and the fact that malignancies and supplement and is beyond the scope of this paper. critical medical illnesses (heart failure, malignant hyperten- If the clinical response is considered not adequate, sion) are not treated with a stepwise approach to therapy combination therapy is considered. but rather with pre-emptive combination therapy. The Combination therapy. Combination therapydusing 2 or experience on RCTs with initial combination therapy is more classes of drugs simultaneouslydhas been used limited to the small BREATHE-2 study, which failed to successfully in the treatment of systemic hypertension and demonstrate any significant difference between patients heart failure. It is also an attractive option for the manage- treated initially with the combination epoprostenol and ment of PAH, because 3 separate signaling pathways are bosentan as compared with epoprostenol alone (28).In known to be involved in the disease: the prostacyclin a more recent experience, 23 treatment naive PAH patients pathway, the endothelin pathway, and the NO pathway. were treated with the initial combination of epoprostenol In Tables 3 to 6, 13 (43%) of the RCTs performed in and bosentan and compared with a matched historical PAH patients included at least 1 subgroup treated with control group treated with epoprostenol (69). The study JACC Vol. 62, No. 25, Suppl D, 2013 Galiè et al. D69 December 24, 2013:D60–72 Treatment Algorithm of Pulmonary Arterial Hypertension showed a statistically significantly greater decrease in PVR Eisenmenger’s syndrome due to simple shunts have been in the initial combination therapy group but this hemody- treated by isolated lung-transplantation and repair of the namic benefit did not translate into a statistically significant cardiac defect or by heart-lung transplantation (73). difference in survival, or in transplant-free survival. A mul- While registry data initially supported a survival benefitof ticenter, multinational blinded placebo controlled trial heart-lung transplantation for patients with pulmonary (AMBITION [A Randomized, Multicenter Study of First- hypertension associated with a ventricular septal defects (78) Line Ambrisentan and Tadalafil Combination Therapy in experience with isolated bilateral lung transplantation has Subjects with Pulmonary Arterial Hypertension]) comparing grown and more recent data supports a role for this approach first line monotherapy with tadalafil, monotherapy with combined with repair of the defect (79). ambrisentan and combination therapy with tadalafil and Recent reports indicate that venoarterial extracorporeal ambrisentan in de novo WHO-FC II and III PAH patients membrane oxygenation may be employed in awake end- was underway at the time of this publication to address the stage PH patients for bridging to lung transplantation (80). efficacy to safety ratio of initial combination therapy. Initial combination therapy has been allocated a grade of recom- BALLOON ATRIAL SEPTOSTOMY. The creation of an interatrial mendation IIb and level of evidence C in WHO-FC IV right-to-left shunt can decompress the right heart chambers, PAH patients in case of nonavailability of IV prostanoids. and increase left ventricle pre-load and cardiac output Interventional procedures. LUNG TRANSPLANTATION. The (81,82). In addition, this improves systemic O2 transport advent of disease targeted therapy for severe PAH has despite arterial O2 desaturation (81) and decreases sympa- reduced and delayed patients referral for lung transplant thetic hyperactivity. The recommended technique is graded programs (70). The long-term outcomes of medically treated balloon dilation atrial septostomy, which produces equiva- patients remain uncertain and transplantation should lent improvements in hemodynamics and symptoms but continue to be an important option for those who fail on reduced risk compared with the original blade technique. such therapy and remain in WHO-FC III or IV (71,72). Other techniques are considered experimental (83). Delayed referral in combination with the length of the A careful pre-procedure risk assessment ensures reduced waiting time, due to the shortage of organ donors, may mortality. Balloon atrial septostomy (BAS) should be increase the mortality on the waiting list and clinical severity avoided in end-stage patients presenting with a baseline > at the time of transplantation. mean right atrial pressure of 20 mm Hg and O2 satura- The overall 5-year survival following transplantation for tion at rest of <85% on room air. Patients should be on PAH was considered to be 45% to 50% with evidence of optimal medical therapy, which may include precondition- continued good quality of life (73). More recent data show ing with IV inotropic drugs, prior to considering BAS. that survival is increased to 52% to 75% at 5 years and to Published reports suggest a benefit in patients who are in 45% to 66% at 10 years (Table 7) (74–76). WHO-FC IV with right heart failure refractory to medical Considering together the previous information, it seems therapy or with severe syncopal symptoms (81,82). It may reasonable to consider eligibility for lung transplantation also be considered in patients awaiting transplantation or after an inadequate clinical response to the initial mono- when medical therapy is not available. Studies show therapy and to refer the patient soon after the inadequate improvements in cardiac index and decreases in right atrial clinical response is confirmed on maximal combination pressure with improvement in 6MWD (81,82). The impact therapy (Fig. 1). of BAS on long-term survival has not been established in Also the etiology of PAH may help the decision making RCTs (81,82). BAS should be regarded as a palliative or because the prognosis varies according to the underlying bridging procedure to be performed only by centers with condition. In fact, PAH associated with connective tissue experience in the method (70). disease has a worse prognosis than idiopathic PAH even Treatment algorithm principles and description. when treated with prostanoids, while patients with PAH PRINCIPLES. associated with congenital heart disease have a better The treatment algorithm for PAH patients is shown in survival. The worst prognosis is seen in patients with pul- Figure 1. The definitions of the grades of recom- monary veno-occlusive disease and pulmonary capillary mendation and the levels of evidence are reported in hemangiomatosis because of the lack of effective medical Tables 1 and 2. treatments and these patients should be listed for trans- The different treatments have been evaluated by RCTs plantation at diagnosis. mainly in idiopathic PAH, heritable PAH, PAH due Both heart-lung and double-lung transplantation have to anorexigen drugs, and in PAH associated with been performed for PAH, although the threshold for connective tissue disease or with congenital heart unrecoverable right ventricle systolic dysfunction and/or left disease (surgically corrected or not). The grades of ventricle diastolic dysfunction is unknown. Currently the recommendation and levels of evidence for the other vast majority of patients worldwide receive bilateral lungs associated PAH conditions may be lower. However, as evidenced by the International Society for Heart and the treatment algorithm is applicable to associated Lung Transplantation Registry figures (77). Patients with PAH conditions without substantial changes. D70 Galiè et al. JACC Vol. 62, No. 25, Suppl D, 2013 Treatment Algorithm of Pulmonary Arterial Hypertension December 24, 2013:D60–72

PAH is a rare disease and regulatory agencies may adequate response should be confirmed after 3 to 4 require only 1 RCT with pre-specified characteristics months of treatment. (e.g., size, duration, endpoint, level of statistical Nonresponders to acute vasoreactivity testing who are significance) to grant the approval for the use. For in WHO-FC II should be treated with an oral these reasons approved drugs with level of evidence A compound. (more than 1 RCT or meta-analysis) and approved Nonresponders to acute vasoreactivity testing, or drugs with Level of Evidence: B (1 RCT) have been responders who remain in (or progress to) WHO-FC grouped together. III, should be considered candidates for treatment The treatment algorithm does not apply to patients in with any of the approved PAH drugs. other clinical groups, and in particular not to patients As head-to-head comparisons among different with PH associated with left heart disease (group 2) or compounds are not available, no evidence-based first- with lung diseases (group 3). line treatment can be proposed (see previous) for either Only the compounds officially approved for PAH or WHO-FC II or III patients. under regulatory approval process in at least 1 country Continuous IV epoprostenol is recommended as first- are included. Single compounds are listed by alpha- line therapy for WHO-FC IV PAH patients because betical order according with the pharmacological of the survival benefit in this subset. In absence of IV name. epoprostenol all other compounds may be utilized. As head-to-head comparisons among different Although ambrisentan, bosentan, and sildenafil are compounds are not available, no evidence-based first- approved in WHO-FC IV patients in the United line treatment can be proposed. In this case the choice States, only a small number of these patients were of the drug may depend on a variety of factors included in the RCTs of these agents. Accordingly, including the approval status, the labeling, the route of most experts consider these treatments as a second line administration, the side effect profile, patients prefer- in severely ill patients. ences, physician experience, and the cost. In WHO-FC IV patients initial combination therapy A 4-level hierarchy for endpoints in RCT has been may also be considered. proposed by experts according to level of evidence In case of inadequate clinical response, sequential regarding efficacy (84,85): Level 1 is a true clinical combination therapy should be considered. Combi- efficacy measure; Level 2 is a validated surrogate (for nation therapy can either include an ERA plus a specific disease setting and class of interventions); a PDE-5i or a prostanoid plus an ERA or a prostanoid Level 3 is a nonvalidated surrogate, yet 1 established to plus a PDE-5i. Upon regulatory approval the sGC be reasonably likely to predict clinical benefit (for stimulator riociguat can be considered as a potential a specific disease setting and class of interventions); alternative to PDE-5i in the different types of double and Level 4 is a correlate that is a measure of biological combinations. The combination of riociguat and activity but that has not been established to be so at PDE-5is is contraindicated. a higher level. All-cause death and morbidity and In case of inadequate clinical response with double mortality endpoints for PAH have been included in combination therapy, triple combination therapy Level 1 (84) whereas 6MWD is not considered should be attempted. a validated surrogate in PAH (86) and it may be It seems reasonable to consider eligibility for lung included either at Level 3 or 4. According to this transplantation after an inadequate clinical response to hierarchy, drugs with morbidity and mortality as the initial monotherapy and to refer the patient for primary endpoint in RCTs or drugs with demon- lung transplantation soon after the inadequate clinical strated reduction in all-cause mortality (prospectively response is confirmed on maximal combination defined) have been highlighted. therapy. Balloon atrial septostomy should be regarded as DESCRIPTION. a palliative or bridging procedure in patients deterio- The suggested initial approach after the diagnosis of rating despite maximal medical therapy. PAH is the adoption of the general measures, the initiation of the supportive therapy, and referral to an expert center. Reprint requests and correspondence: Dr. Nazzareno Galiè, Acute vasoreactivity testing should be performed in all University of Bologna, Institute of Cardiology, via Massarenti 9, 40138-Bologna, Italy. E-mail: [email protected]. patients with PAH (group 1), although patients with idiopathic PAH, heritable PAH, and PAH associated with anorexigen use are the most likely to exhibit an acute positive response and to benefit from high-dose REFERENCES CCB therapy. Vasoreactive patients should be treated 1. McLaughlin VV, Rich S. Pulmonary hypertensiondadvances in medical with high and optimally tolerated doses of CCBs; and surgical interventions. 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Efficacy and safety of oral tre- Cardiol 2012;60:1192–201. prostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation 2013;127:624–33. 66. Simonneau G, Torbicki A, Hoeper MM, et al. Selexipag, an oral, Key Words: endothelin receptor antagonists - guanylate cyclase selective IP receptor agonist for the treatment of pulmonary arterial stimulators - hypertension, pulmonary - lung transplantation hypertension. Eur Respir J 2012;40:874–80. - phosphodiesterase type-5 inhibitors - prostanoids - pulmonary. Journal of the American College of Cardiology Vol. 62, No. 25, Suppl D, 2013 2013 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2013.10.034

Treatment Goals of Pulmonary Hypertension

Vallerie V. McLaughlin, MD,* Sean Patrick Gaine, MD, PHD,y Luke S. Howard, DPHIL,z Hanno H. Leuchte, MD,x Michael A. Mathier, MD,k Sanjay Mehta, MD,{ Massimillano Palazzini, MD,# Myung H. Park, MD,** Victor F. Tapson, MD,yy Olivier Sitbon, MD, PHDzz Ann Arbor, Michigan; Dublin, Ireland; London, United Kingdom; Munich, Germany; Pittsburgh, Pennsylvania; London, Ontario, Canada; Bologna, Italy; Baltimore, Maryland; Durham, North Carolina; and Le Kremlin-Bicêtre, France

With significant therapeutic advances in the field of pulmonary arterial hypertension, the need to identify clinically relevant treatment goals that correlate with long-term outcome has emerged as 1 of the most critical tasks. Current goals include achieving modified New York Heart Association functional class I or II, 6-min walk distance >380 m, normalization of right ventricular size and function on echocardiograph, a decreasing or normalization of B-type natriuretic peptide (BNP), and hemodynamics with right atrial pressure <8 mm Hg and cardiac index >2.5 mg/kg/ min2. However, to more effectively prognosticate in the current era of complex treatments, it is becoming clear that the “bar” needs to be set higher, with more robust and clearer delineations aimed at parameters that correlate with long-term outcome; namely, exercise capacity and right heart function. Specifically, tests that accurately and noninvasively determine right ventricular function, such as cardiac magnetic resonance imaging and BNP/N-terminal pro–B-type natriuretic peptide, are emerging as promising indicators to serve as baseline predictors and treatment targets. Furthermore, studies focusing on outcomes have shown that no single test can reliably serve as a long-term prognostic marker and that composite treatment goals are more predictive of long-term outcome. It has been proposed that treatment goals be revised to include the following: modified New York Heart Association functional class I or II, 6-min walk distance 380 to 440 m, cardiopulmonary exercise test–measured peak oxygen consumption >15 ml/min/kg and ventilatory equivalent for carbon dioxide <45 l/min/l/min, BNP level toward “normal,” echocardiograph and/or cardiac magnetic resonance imaging demonstrating normal/near-normal right ventricular size and function, and hemodynamics showing normalization of right ventricular function with right atrial pressure <8 mm Hg and cardiac index >2.5 to 3.0 l/min/m2. (J Am Coll Cardiol 2013;62:D73–81) ª 2013 by the American College of Cardiology Foundation

As the ﬁeld of pulmonary arterial hypertension (PAH) has Lessons from the past 2 decades provide the basis for matured, there has been a shift in our focus from short-term deﬁning important treatment goals in the hope of improving functional changes to improvements in long-term outcomes. long-term survival. Indeed, the quest for clinically relevant

From the *Division of Cardiovascular Medicine, University of Michigan Health Novartis and United Therapeutics. Dr. Howard has received honoraria for speaking from System, Ann Arbor, Michigan; yDepartment of Pulmonology, Mater Misericordiae Actelion, GlaxoSmithKline, Pfizer, and Bayer; consultancy fees from Actelion, Glax- University Hospital, Dublin, Ireland; zNational Heart and Lung Institute, National oSmithKline, Pfizer, Eli Lilly and Company, and Bayer; support for congress attendance Pulmonary Hypertension Service, Hammersmith Hospital, London, United from Actelion, GlaxoSmithKline, Eli Lilly and Company, and Bayer; and research grants Kingdom; xDivision of Pulmonary Diseases, Ludwig-Maximilians-University, Klini- from Actelion, Pfizer, and Bayer. Dr. Leuchte has received fees for lectures and consulting kum Grosshadern, Munich, Germany; kPulmonary Hypertension Program, Heart and from Actelion, Bayer Vital, Bayer Healthcare, GlaxoSmithKline, Pfizer, United Thera- Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; peutics, Lilly, and Novartis. Dr. Mehta has received research grants from Actelion; {Division of Respirology, London Health Sciences Centre–Victoria Hospital, investigator fees for participation in pharmaceutical clinical trials from Actelion, Bayer, Western University, London, Ontario, Canada; #Department of Experimental, Gilead, GlaxoSmithKline, Ikaria, Lilly, and United Therapeutics; and consulting and Diagnostic, and Specialty Medicine, Bologna University Hospital, Bologna, Italy; speaking fees from Actelion, Bayer, and GlaxoSmithKline. Dr. Palazzini has received **University of Maryland School of Medicine, Division of Cardiology, Baltimore, speaker fees from Actelion, GlaxoSmithKline, Bayer, and United Therapeutics. Dr. Park Maryland; yyDuke University Medical Center, Durham, North Carolina; and the has served as a consultant/adviser to Actelion Pharmaceuticals, Bayer, Gilead Sciences, zzUniversité Paris-Sud, AP-HP, CHU de Bicêtre, INSERM U999, Le Kremlin- and United Therapeutics. Dr. Tapson has received research grants/funding from Acte- Bicêtre, France. Dr. McLaughlin has served on the speakers’ bureau of Gilead and lion, Bayer, Ikaria, Gilead, Novartis, and United Therapeutics; consulting fees from United Therapeutics (ended); has acted as a consultant or member of advisory board/ Actelion, Bayer, Gilead, Lung LLC, and United Therapeutics; and speaking honoraria steering committees of Actelion, Bayer, Gilead, and United Therapeutics; and has from Actelion, Bayer, Gilead, and United Therapeutics. Dr. Sitbon has acted as received institutional grant/research support from Actelion, Bayer, lkana, and Novartis. a consultant for Actelion Pharmaceuticals Ltd., Bayer HealthCare, Eli Lilly and Dr. Gaine has served on advisory boards and received speaker/consulting fees from Company, GlaxoSmithKline, Pfizer, and United Therapeutics. All other authors have Actelion, GlaxoSmithKline, Pfizer, and United Therapeutics; and has received investi- reported that they have no relationships relevant to the contents of this paper to disclose. gator feed for participation in pharmaceutical trials from Actelion, GlaxoSmithKline, Manuscript received October 15, 2013; accepted October 22, 2013.

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Abbreviations prognostic predictors has been area. The French Registry characterized survival and im- and Acronyms a key goal for clinicians involved in portant prognostic indicators in patients with idiopathic, the care of patients with pulmo- familial, and anorexigen-induced PAH. The registry BNP = B-type natriuretic peptide nary hypertension (PH). The demonstrated that the survival of this cohort of PAH National Institutes of Health patients has improved compared with the predicted CHD-PAH = pulmonary ﬁ arterial hypertension related (NIH) registry was the rst to survival on the basis of the NIH registry, although it is to congenital heart disease show the impact of baseline stillsuboptimal,with1-,2-,and3-yearsurvivalof85.7%, CI = cardiac index hemodynamic parameters on out- 69.5%, and 54.9%, respectively, for incident cases (3).

CMR = cardiac magnetic come, demonstrating that factors Important predictors of survival included sex, FC, exercise resonance which govern right heart function tolerance as measured by using the 6MWD, and hemo- ﬁ EqCO2 = ventilatory can also determine the prognosis dynamics, speci cally RAP and cardiac output. Similarly, equivalent for carbon dioxide in patients with PAH (1).Uti- in the large, U.S.-based REVEAL (Registry to Evaluate FC = functional class lizing these parameters, a survival Early and Long-Term Pulmonary Arterial Hypertension

HIV-PAH = pulmonary arterial equation was derived that was Disease Management) registry, key predictors of outcome hypertension related to the first attempt to use baseline included etiology of PAH, FC, sex, exercise tolerance, human immunodeficiency hemodynamic factors to predict and hemodynamics that reflect right ventricular (RV) virus infection outcome. The formula included function (4). IPAH = idiopathic pulmonary measurements of right atrial pres- arterial hypertension sure (RAP), cardiac index (CI), Modified New York Heart Association NIH = National Institutes of and mean pulmonary artery pres- Health Functional Class sure (PAP), each of which was NT-proBNP = N-terminal pro–B-type natriuretic shown to contribute indepen- Baseline FC is an important correlate and predictor of peptide dently toward the prediction of survival. This assertion has been found in single-center fi NYHA = New York Heart risk of death. cohorts from many countries, the rst U.S. NIH registry of Association With the advent of multiple idiopathic pulmonary arterial hypertension (IPAH) patients, fi PAH = pulmonary arterial clinical trials and the success of and, most recently, con rmed in the REVEAL registry, hypertension demonstrating better outcome which enrolled 2,716 PAH patients of all subtypes (4).It PAP = pulmonary artery through improvements achieved should be recognized that some studies have found no pressure in exercise parameters, the utility association between FC and survival, and in other studies, PH = pulmonary of noninvasive prognostic markers FC was found to correlate with survival in univariate analyses, hypertension as surrogates for hemodynamic but this association was lost in multivariate analyses (1,5–8). PoPH = pulmonary arterial indices has been explored. In During the follow-up assessment of treated PAH hypertension related to particular, the finding that the patients, repeated assessment of FC provides important portal hypertension 6-min walk distance (6MWD) information regarding the severity of PAH and the response 6MWD = 6-min walk test correlated with hemodyna- to therapy, as well as the prognosis for survival. After distance mics established its role as a new institution of effective PAH therapy, clinical improvement RAP = right atrial pressure baseline prognostic marker and as from initial FC III/IV to FC II is associated with improved RV = right ventricular a treatment goal. Subsequently, a prognosis. RVEDVI = right ventricular growing number of publications There are limitations to the clinical use of modified New end-diastolic volume index have identified other prognostic York Heart Association (NYHA) FC, including poor SSc-PAH = pulmonary factorsinpatientswithPAH, interobserver reliability and effects of demographic charac- arterial hypertension related fi to scleroderma which include assessment of func- teristics (e.g., age, sex, ethnicity) (9). Nevertheless, modi ed tional class (FC), parameters of NYHA FC is a simple, reproducible, and clinically impor- SLE-PAH = pulmonary arterial hypertension related exercise tolerance, hemodynamics, tant assessment tool and prognostic measure in PAH to systemic lupus echocardiographic parameters, and patients, both at the time of diagnosis and at follow-up erythematosus biomarkers. However, investiga- during PAH treatment.

SvO2 = mixed venous tors have recently begun to analyze oxygenation the utility of these markers as 6-Min Walk Distance Test prognostic indicators with the availability of long-term data, in particular the 6MWD. It The 6MWD is a simple, noninvasive test that is inex- is becoming clear that no single parameter can fulﬁll the role pensive, reproducible, and well tolerated in patients of a reliable prognostic indicator. Composite treatment goals with PAH. Initial studies have shown signiﬁcant correla- have been shown to have more meaningful correlation with tions between the baseline 6MWD and hemodynamic outcome, both as baseline predictors and as treatment targets (2). parameters,aswellassurvival(10).Furthermore,the More recently, 2 large registries have shed light on the 6MWD has been used as the primary endpoint for almost prognosis of patients with PAH in the current therapeutic all pivotal clinical trials of PAH treatments, and it is

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Variables Used in Clinical Practice to Determine performed a study to determine the minimal important Table 1 Response to Therapy and Prognosis in Patients difference from analyzing the 6MWD results of the tadalafil With PAH clinical trial. From their analysis using both distributional and anchor-based methods, the estimated minimal impor- Functional class IorII tant difference in the 6MWD for PAH patients is Echocardiography/CMR approximately 33 meters. The results of the 2 studies suggest Normal/near-normal RV size and function that the differences in the 6MWD seen in the recent Hemodynamics combination trials may not indicate clinically meaningful Normalization of RV function (RAP <8 mm Hg and CI >2.5 to 3.0 l/min/m2) changes. 6-min walk distance There remain several relevant important questions in >380 to 440 m; may not be aggressive enough in young individuals using 6MWD. These questions include which distance Cardiopulmonary exercise testing best correlates with exercise capacity and right heart > < Peak VO2 15 ml/min/kg and EqCO2 45 l/min/l/min function, and whether this should be measured as an B-type natriuretic peptide level absolute value of 6MWD that is associated with improved Normal survival in PAH (e.g., >380 m, as suggested from Sitbon ¼ ¼ ¼ CI cardiac index; CMR cardiac magnetic resonance; EqCO2 ventilatory equivalent for carbon > dioxide; PAH ¼ pulmonary arterial hypertension; RAP ¼ right atrial pressure; RV ¼ right ventricular; et al. [18],or 440 m, as shown by the REVEAL ¼ VO2 peak oxygen consumption. registry [4]). Also, should the distance be assessed based on percent predicted according to patient parameters (i.e., age, sex, height) (19)? Another question that remains to viewed by regulatory agencies as an acceptable surrogate be answered is how improvement(s) in distance translate endpoint because it has been shown to serve as a useful into meaningful change in quality of life or survival. marker of treatment outcome during the pre-defined trial There is evidence to suggest that incorporating other durations (11). measurements obtained during the test, such as heart rate The 6MWD is widely used by clinicians as an integral recovery time, may enhance the usefulness in interpreting component for assessing prognosis at baseline and treat- 6MWD (20). ment effect at follow-up. However, there are many The current treatment goal for 6MWD is >380 m. limitations to 6MWD, including the learning effect, day- However, we propose to increase this to 380 to 440 m; for to-day variation, and impact of demographic characteris- some patients, using percent predicted may better reflect an tics and comorbidities. A meta-analysis recently reported appropriate goal of therapy. on the usefulness of 6MWD in determining outcome in PAH. Savarese et al. (12) evaluated the results in 3,112 Cardiopulmonary Exercise Testing patients from 22 clinical trials, and they concluded that pharmacological treatments resulted in significant reduc- Cardiopulmonary exercise testing provides an integrative tion of all-cause death, hospitalization for PAH, trans- approach to assessing cardiac function, gas exchange, and plant, initiation of rescue therapy, and composite outcome, muscular physiology. Peak oxygen consumption has been but the favorable effects on clinical events were not pre- shown to be predictive of survival in PH, with 3 studies dicted by changes in 6MWD. providing cutoff values of 10.4 ml/min/kg (21),11.5ml/ The other weakness of 6MWD relates to the difficulty min/kg (22),and13.2(23) ml/min/kg below which in assessing what is a true meaningful difference in walk mortality is increased, as well as being established as distance, beyond achieving statistical significance. An a prognostic marker in other conditions, such as heart example of this is the “ceiling effect,” which refers to the lack failure (24). of sensitivity to detect changes with treatment in patients The development of a right-to-left shunt on exercise has with early stage PAH and relatively high 6MWD at base- been shown to be significantly and strongly associated with line. A similar limitation is shown by the inability to detect worse survival; in patients without a shunt, in FC III/IV, meaningful changes in 6MWD with the use of combination ventilatory equivalent for carbon dioxide (EqCO2)atan treatment as add-on therapy (13–15). Gabler et al. (16) anaerobic threshold <40 l/min/l/min was associated with investigated whether changes in 6MWD in the 12-week excellent survival (25). treatment period correlated with clinical events. The Peak oxygen consumption has been suggested as a goal authors reported findings from the pooled analysis that the of therapy, with <10 ml/min/kg indicating poor prognosis change in 6MWD accounted for only 22.1% of the treat- and a need to escalate treatment and with >15 ml/min/kg ment effect; the average difference in 6MWD across the indicating better prognosis. In young patients, this may trials was 22.4 m, and the significant threshold effect was be a limited approach, and percent predicted peak oxygen calculated to be 41.8 m. Thus, the study concluded that the consumption may provide a better indication in this change in 6MWD does not explain a large proportion of the group (26); this theory requires further evaluation. EqCO2 treatment effect and that, as a surrogate endpoint for clinical is less age-dependent, and values <45 l/min/l/min and events, it can claim only a modest validity. Mathai et al. (17) >55 l/min/l/min would seem appropriate goals/warning

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Variables Used in Clinical Practice to Determine relevance of B-type natriuretic peptide (BNP) has been Table 2 Response to Therapy and Prognosis in Patients With demonstrated in outcome studies and as a secondary Pulmonary Arterial Hypertension endpoint in some PAH treatment trials. Current guidelines suggest a “normal” BNP level as Prognostic Prognostic Implications Implications a potential treatment goal. Therefore, it has to be taken into at Baseline at Follow-Up account that both BNP and N-terminal pro–B-type natri- (Ref. #) (Ref. #) Comments Exercise tolerance uretic peptide (NT-proBNP) are age- and sex-dependent, NYHA FC (2,4,9,10) (2,9,10) leading to higher normal values (especially with age). Indi- 6MWD (2–4,10,61) vidual normal values are given by the manufacturer. An

Peak VO2 (24) attempt to individualize BNP values has been suggested by Hemodynamics dividing the measured BNP values by the age- and sex- RAP (2,9,10,24,40,50,61,62) (9) In some specific normal values. This BNP ratio would be increased PAPm (1,4) studies, > higher whenever 1 (27,28). PVR (24) (9) PAPm was BNP levels have been shown to parallel hemodynamic CO/CI (2,3,9,24,40,50,61) (2,9) associated and functional responses to PAH therapies in most clinical SvO2 (2,24,64) (2,64) with better survival trials. Recent data support the hypothesis that the change (10,63) in NT-proBNP levels carries prognostic information. Echocardiographic Independently of baseline values, follow-up NT-proBNP variables levels <1,800 pg/ml indicated better survival in a cohort TAPSE (40) of 84 PAH patients in the current treatment era (2). RV strain (65) An open question remains the position of BNP in the RA area (40) rank order of various therapy goals. When the goal-oriented Pericardial (4,40) effusion therapy approach was initially proposed for IPAH, natri- Biomarkers uretic peptides (as many others) were not included as BNP/NT-proBNP (2,4,5,62) (2,5,66) therapy goals (29). However, because RV failure is the main Troponin (62) cause of death in IPAH, it seems reasonable to have an Uric acid (24,67,68) observer- and effort-independent, broadly available para- CRP (69) meter of RV dysfunction as a main therapeutic goal. An PaCO2 (61) (61) attempt could be made when treatment of PAH is initiated MRI parameters to reach the “lowest possible” or “personal best” BNP and/or SV index (8) NT-proBNP. Comparable attempts have been made in RVEDVI (8) LVEDV (8) congestive heart failure. In this context, a meta-analysis RVEF (44) (44) found that usage of cardiac peptides to guide pharmaco- RVAC (70) logical therapy significantly reduced mortality and heart – BNP ¼ B-type natriuretic peptide; CI ¼ cardiac index; CO ¼ cardiac output; CRP ¼ C-reactive failure related hospitalization in patients with chronic heart protein; LVEDV ¼ left ventricular end-diastolic volume; MRI ¼ magnetic resonance imaging; NYHA failure (30). There is no evidence that such an approach FC ¼ New York Heart Association functional class; NT-proBNP ¼ N-terminal pro–B-type natriuretic would work in PAH, however, and it is questionable if peptide; 6MWD ¼ 6-min walk distance; PaCO2 ¼ partial arterial pressure of carbon dioxide; PAPm ¼ mean pulmonary artery pressure; PVR ¼ pulmonary vascular resistance; RA ¼ right atrial; a study size comparable to that used in congestive heart RAP ¼ right atrial pressure; RVEDVI ¼ right ventricular end-diastolic volume index; RVEF ¼ right ventricular ejection fraction; RVFAC ¼ right ventricular fractional area change; SV ¼ stroke volume; failure could be achieved in this rare condition. However, as ¼ ¼ ¼ SvO2 mixed venous oxygen saturation; TAPSE tricuspid annular plane systolic excursion; VO2 mentioned, on the basis of the parallel development of oxygen consumption. hemodynamics and BNP/NT-proBNP levels (31) and the prognostic value of the change and follow-up values signs for evaluation of the exercise response in relation to of BNP/NT-proBNP levels (2,5), as well as on the expe- treatment and prognosis. The presence of a right-to-left rience from other disease states, this approach has some shunt opening on exercise should be regarded as an justification. ominous sign. Echocardiography Biomarkers Echocardiography is widely used as an initial diagnostic Research on biomarkers has tremendously increased the test to confirmthepresenceofPHand/orRVabnormal- understanding of different pathophysiological processes of ities in patients suspected clinically to have PH. However, PAH, including pulmonary vascular disease (e.g., endothe- its use as a tool to provide prognostic information is based lial dysfunction, in situ thrombosis, oxidative stress), RV on a relatively small amount of data, specifically regarding dysfunction, and end-organ failure (e.g., renal failure). echocardiographic assessments of RV function, which is However, only a small minority of the investigated para- the key determinant of outcome. The Tei index, although meters have been shown to be clinically relevant. The it has been shown to be predictive of outcome, is not as

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reliable because it is affected by loading conditions and Wolferen et al., there were no deaths in patients with degree of tricuspid regurgitation (32). The other parameter RVEDVI <84 ml/m2. Furthermore, RV mass index <59 g/m2 of RV function that reportedly correlates with survival is showed a trend toward better survival in IPAH, and in measurement of tricuspid annular plane systolic excursion, a cohort of patients with suspected scleroderma PAH, the recently shown to be predictive of survival in patients with ratio of RV to left ventricular end-diastolic mass >0.7 PAH-associated scleroderma; these findings need further predicted worse survival (40). Ejection fraction has also study for confirmation (33,34). Right atrial and ventricular been assessed and a value <35% shown to be predictive of enlargement and the eccentricity index have also been mortality (38). Importantly, even in patients with falling shown to correlate with outcome among patients with pulmonary vascular resistance, a decrease in ejection fraction IPAH (6). The right atrial area at baseline seems to be 1 was significantly associated with worse prognosis. Pulmo- of the most robust echocardiographic determinants of nary artery stiffness increases afterload on the right ventricle outcome, but it is unclear whether this variable is also and, when measured by using the relative pulmonary artery useful for guiding treatment decisions during follow-up area change throughout the cardiac cycle, has also been (6,35). Furthermore, presence of a pericardial effusion to associated with increased mortality (41,42). any extent has been shown to be a strong predictor of Although CMR seems to hold promise for evaluation and mortality (36). follow-up of patients with PH, data are currently limited. It The major limitations in using echocardiographic is not in widespread use for serial follow-up of patients with parameters for prognostic assessments, especially as a follow- PH, and its main role currently resides in baseline diagnosis. up marker to guide treatment, relate to the lack of consistent It should not be assumed that myocardial indices are method of reporting the RV size and function and the conserved across the different PH classifications, and further technical difficulties in obtaining reproducible right-sided evaluation is required before it is considered part of routine chamber measurements. There is also variability stemming clinical use. from differing skill levels of the technician performing the test. Furthermore, there is no consensus defining the Hemodynamic Parameters severity of PH as assessed by echocardiographic estimates of RV systolic pressure that correlates with right heart Hemodynamic parameters are considered to be the gold catheterization–derived parameters. standard indices of outcome in PAH. The NIH registry We recommend maintaining the current recommenda- demonstrated that increased mean PAP, increased mean tions regarding echocardiographic goals of treatment, RAP, and decreased CI were associated with an increased specifically normal/near-normal RV size and function. The mortality (1). Since then, hemodynamics (specifically, RA fi fi need to further de ne and con rm reliable quantitative pressure, CI, and mixed-venous oxygen saturation [SvO2] measurements that can be measured, which reflect RV but not mean PAP) have been confirmed in numerous function (i.e., tricuspid annular plane systolic excursion, RA studies as robust independent prognostic factors (4,43,44). size) require further study. However, there are several caveats and limitations in using hemodynamic parameters to assess prognosis. First, as PAH Cardiac Magnetic Resonance progresses and the right ventricle dilates and fails, the mean PAP declines, which is why survival estimates use mean Cardiac magnetic resonance (CMR) is the gold standard for RAP and CI in the equations. Obtaining hemodynamic the investigation of right heart structure and volumes (37). measurements require an invasive procedure that is not Given that right heart function is accepted as the main widely available, and the associated risks, albeit small in determinant of survival in PAH, this modality would be experienced centers, limit the ability to obtain follow-up or expected to provide reliable information regarding prog- serial hemodynamic parameters on treatment. Hemody- nosis; however, few studies are available that have assessed namic measurements also illustrate the physiological state at this variable’s role in predicting survival (8,38,39).In a single time point at rest, in a supine position, which does response to chronic PH, the right ventricle hypertrophies not account for changes associated with activity. Although and dilates with reducing function and stroke volume. The exercise-related hemodynamic effects are currently under- interventricular septum bows in to the left ventricle in going active research, there is no consensus regarding the diastole and systole. Commensurate with this action, right method of performing exercise right heart catheterization or ventricular end-diastolic volume index (RVEDVI) <84 ml/m2, interpretation of the hemodynamic effects of exercise in left ventricular end-diastolic volume index >40 ml/m2, and PAH. Furthermore, the effects of systemic processes such as a stroke volume index >25 ml/m2 are associated with better anxiety, hypertension, and sedation can markedly affect the survival in patients with IPAH (8). RVEDVI was parameters. also shown to be an independent predictor of mortality The current recommendation advises normalization by another group of researchers, but the number of events of RV function for treatment goal, which is defined as was too small to generate a threshold value for worse sur- RAP <8mmHgandCI>2.5 l/min/m2. There is a vival (39). However, according to the study by van proposal to increase the CI to >3.0 l/min/m2, and the

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discussions include the following points. First, there is no baseline evaluation. Table 1 summaries the variables used in strong evidence for the current recommendation of CI >2.5 clinical practice to determine response to therapy and l/min/m2 as a hemodynamic goal; it was derived mainly progress in patients with PAH. from studies evaluating patients with left heart failure. The Notably, use of 1 parameter is not sufficient to reflect the definition of normal CI for healthy subjects varies widely status of RV function; multiple variables must be inter- in the literature, from 2.4 to 4.2 l/min/m2, depending on preted in the context of each individual patient. A proposal the sources cited (44–47). There are no direct data from to rank the parameters has been suggested, with prioriti- PAH patients to guide this recommendation. The opinions zation of markers (i.e., objective parameters such as in favor of this measure are based on the fact that we need to hemodynamics ranked first/highest or categorize variables establish more ambitious goals in PAH, with clear manda- into major versus minor criteria); this proposal warrants tes to “raise the bar” with the common goal of improving further consideration, but current data are insufficient to outcome. Clearly, there are patients who have improved validate such a ranking system. Table 2 reviews the clinical symptoms and exercise capacity with treatments that result observations on specific variables. from an increase in cardiac outputs. Thus, given the lack of Risk scores and prognostic equations have served as evidence supporting 2.5 l/min/m2 as the best goal, the useful predictors of survival on a population basis, but question is whether to increase the recommended CI to 3.0 currently, none has been adequately studied or validated as l/min/m2. The concerns raised from the panel members agoaloftherapy.Howanindividual’s change in score regarding this change include that there is no evidence reflects that individual’s subsequent prognosis has not yet that just raising the CI limit translates into better outcome, been adequately studied. In addition, some risk scores and that some physicians may feel compelled to augment (e.g., REVEAL) include a number of variables that cannot treatments and/or increase doses just to reach the 3.0 l/min/ change, even when the response to therapy is favorable m2 target, with more risk to patients. Furthermore, from (i.e., age, sex, etiology). We advocate for a multiparameter a physiological standpoint, there is a potential to increase approach to treatment goals and hope that data from large the workload of the right ventricle in inappropriate settings registries may aide in developing a scoring system that and the possibility of incurring damaging effects to the RV canbeusedtoassessresponsetotherapy,andtoestablish myocardium from detrimental effects of increased cate- goals of therapy using the modifiable parameters as cholamine release. variables. Given the lack of data regarding the optimal CI in the PAH population, there seems to be support to recommend Are Treatment Goals Different in that the target CI as a hemodynamic treatment goal be Different PAH Subgroups? adjusted for the individual patient to >2.5 to 3.0 l/min/m2. The CI is just 1 measure in the evaluation process, however, PAH is a heterogeneous group of diseases with numerous and it must be interpreted in the context of all other subgroups defined according to associated or causative hemodynamic variables as well as clinical parameters. conditions. Common examples include PAH related to connective tissue disease, including PAH related to sclero- Current Status of Prognostic Predictors in PAH derma (SSc-PAH) and systemic lupus erythematosus (SLE-PAH); PAH related to congenital heart disease Recently, Nickel et al. (2) reported a systemic evaluation of (CHD-PAH); PAH related to human immunodeficiency prognostic markers at baseline and follow-up in a series of virus infection (HIV-PAH); and PAH related to portal patients with IPAH. They identified 4 variables that were hypertension (PoPH). It is relevant to ask whether treat- independently associated with survival at baseline as well ment goals should differ for these various subgroups. as at follow-up: NYHA FC, NT-proBNP, CI, and The paucity of published data addressing this question < SvO2. NYHA FC I and II, NT-proBNP 1,800 ng/l, makes it impossible to provide clear answers in most cases. 2 CI 2.5l/min/m , and SvO2 65% during follow-up were Although the prognosis for patients with SSc-PAH associated with a better survival. Of note, the follow-up remains poor, it has improved, as shown in recent reports assessments were found to be better outcome predictors (48–50). The current treatment goals for patients with SSc- than the baseline evaluations; in fact, the outcome was PAH are not well defined and are generally similar to those almost entirely determined by the variables obtained at used in other types of PAH. However, functional goals (e.g., follow-up rather than by using the baseline measurements. FC, 6MWD) and biomarkers (e.g., BNP) may be unreliable Thus, both baseline and follow-up assessments are im- in SSc-PAH because of the systemic nature of scleroderma portant when assessing the risk of patients with PAH. The (51,52). Given the poor prognosis in SSc-PAH, it is baseline evaluation will determine disease severity at important to explore whether more aggressive treatment presentation, providing important information for choosing goals will result in improved outcomes in the future. Out- the initial therapy. Follow-up assessments are crucial for comes for patients with SLE-PAH seem to be better than assessing the response to treatment, and they seem to those for SSc-PAH patients (48). Intensive immunosup- provide a more reliable prognostic estimation than the pression may enhance the benefit of PAH-specific

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therapies in SLE-PAH and improve outcomes (53). Thus, improve long-term outcomes in patients with this previously optimal treatment of inflammation can be considered a fatal disease. unique treatment goal in SLE-PAH. Patients with CHD-PAH have a better prognosis than Reprint requests and correspondence: Dr. Vallerie V. other subgroups (54), and bosentan was shown to be safe McLaughlin, Department of Internal Medicine, University of and effective in a study performed specifically in this pop- Michigan Health System, 1500 East Medical Center Drive, SPC ulation (55). Patients with HIV-PAH have a worse prog- 5853, Ann Arbor, Michigan 48109-5853. E-mail: vmclaugh@ nosis than other subgroups, although outcomes have umich.edu. improved (56). There are no data currently to suggest that treatment goals in CHD-PAH or HIV-PAH should differ from those in other PAH subgroups. REFERENCES Patients with PoPH have a worse prognosis than other 1. D’Alonzo GE, Barst RJ, Ayres SM, et al. 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Downloaded From: http://content.onlinejacc.org/ on 12/21/2013 Journal of the American College of Cardiology Vol. 62, No. 25, Suppl D, 2013 2013 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2013.10.026

New Trial Designs and Potential Therapies for Pulmonary Artery Hypertension

Mardi Gomberg-Maitland, MD, MSC,* Todd M. Bull, MD,y Rajeev Saggar, MD,z Robyn J. Barst, MD,x Amany Elgazayerly, MD, PHD,k Thomas R. Fleming, PHD,{ Friedrich Grimminger, MD, PHD,# Maurizio Rainisio, PHD,** Duncan J. Stewart, MD,yy Norman Stockbridge, MD, PHD,zz Carlo Ventura, MD, PHD,xx Ardeschir H. Ghofrani, MD,# Lewis J. Rubin, MDkk Chicago, Illinois; Aurora, Colorado; Phoenix, Arizona; New York, New York; London, United Kingdom; Seattle, Washington; Giessen, Germany; San Remo and Bologna, Italy; Ottawa, Ontario, Canada; White Oak, Maryland; and San Diego, California

A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to signiﬁcant advances, but the disease remains fatal. Treatment options are neither universally available nor always effective, underscoring the need for development of novel therapies and therapeutic strategies. Clinical trials to date have provided evidence of efﬁcacy, but were limited in evaluating the scope and duration of treatment effects. Numerous potential targets in varied stages of drug development exist, in addition to novel uses of familiar therapies. The pursuit of gene and cell-based therapy continues, and device use to help acute deterioration and chronic management is emerging. This rapid surge of drug development has led to multicenter pivotal clinical trials and has resulted in novel ethical and global clinical trial concerns. This paper will provide an overview of the opportunities and challenges that await the development of novel treatments for PAH. (J Am Coll Cardiol 2013;62:D82–91) ª 2013 by the American College of Cardiology Foundation

A greater understanding of the epidemiology, pathogenesis, relatively short in duration and were comprised of small and pathophysiology of pulmonary artery hypertension populations of affected patients. These studies provided (PAH) has led to significant advances over the past 2 evidence of efficacy, but were limited in evaluating the scope decades in treatment of this disorder. However, these and duration of treatment effects. Accordingly, clinical treatment options are neither universally available nor always development of novel therapies for PAH in the future will effective, underscoring the need for development of novel require trials of larger and perhaps more diverse patient therapies and therapeutic strategies. Because PAH is cohorts who are studied for longer periods and with more considered an orphan disease that is uniformly progressive robust and meaningful efficacy endpoints. The challenges and fatal, prior clinical trials evaluating novel therapies were posed by these requirements are substantial, and include

From the *Section of Cardiology, Department of Medicine, University of Chicago, committees, scientific advisory boards, or data safety monitoring for Actelion, Gilead, Chicago, Illinois; ySection of Pulmonary and Critical Care, Department of Medicine, Medtronic, Merck, and Ikaria. Dr. Bull has received an investigator initiated grant University of Colorado, Aurora, Colorado; zHeart and Lung Institute, Phoenix, from United Therapeutics; and has served on the advisory board of Actelion. Dr. Arizona; xColumbia University, New York, New York; kEuropean Medicine Agency, Saggar has a relationship with EvoLung LLC; has served on the advisory board of London, England; {Department of Biostatistics, University of Washington, Seattle, Gilead; and is a United Therapeutics employee as of September 1, 2013. Dr. Fleming Washington; #Section of Pulmonary, Department of Medicine, Department of has served as a consultant to Actelion and Pfizer. Dr. Grimminger has received Medical Oncology, University Hospital Giessen, Giessen, Germany; **AbaNovus, San research grants from Bayer Schering, Pfizer, Ergonex, and Encysive; has received Remo, Italy; yySection of Cardiology, Department of Medicine, Ottawa Hospital honoraria payments from Bayer Schering, Pfizer, Actelion, Encysive, and Novartis Research Institute, Ottawa, Ontario, Canada; zzFood and Drug Administration, Pharmaceuticals; and has a consultancy and/or advisory board relationship with White Oak, Maryland; xxSection of Cardiology, Department of Medicine, University Nycomed (Altana Pharma). Dr. Stewart has had relationships with Northern Ther- of Bologna, Bologna, Italy; and the kkSection of Pulmonary and Critical Care, apeutics and United Therapeutics. Dr. Ghofrani has relationships with Actelion, Department of Medicine, University of California San Diego, San Diego, California. Bayer, GlaxoSmithKline, Merck, Novartis, and Pfizer. Dr. Rubin has relationships Dr. Saggar contributed to the manuscript until September 1, 2013, when he became with United Therapeutics, Bayer, GeNO, the National Heart, and Blood Institute, the an employee of United Therapeutics. Dr. Barst is deceased. The opinions expressed U.S. Food and Drug Administration, Actelion, Lung LLC, Gilead, Reata Pharma- herein might not reflect the official opinions of the Food and Drug Administration or ceuticals, Arena Pharmaceuticals, and Aires Pharmaceuticals; and has served as the European Medical Agencies. Dr. Gomberg-Maitland has received institutional a consultant for Aires Pharmaceuticals and GeNO. All other authors have reported grant support from Actelion, Gilead, Medtronic and Novartis as principal investigator that they have no relationships relevant to the contents of this paper to disclose. through the University of Chicago; and has served as a consultant to and/or on steering Manuscript received October 13, 2013; accepted October 22, 2013. JACC Vol. 62, No. 25, Suppl D, 2013 Gomberg-Maitland et al. D83 December 24, 2013:D82–91 New Trial Designs and Therapies for Pulmonary Arterial Hypertension greater global access to patients and experienced investiga- active control regimen, the eligi- Abbreviations tors, industry partners who are willing and able to invest bility criteria, and supportive care and Acronyms in drug development for a rare disease, and collaboration regimens, and these may be dif- fi 6MWD = 6-min walk with regulators to ensure that the trials can both provide cult to justify in settings such distance evidence of sufficient safety and efficacy to support regula- as PAH where these factors are – ECMO = extracorporeal tory approval while, at the same time, can be realistically rapidly changing (6 8). A cross- membrane oxygenation carried out in a diverse clinical environment. This paper will over design can test for short- eNOS = endothelial nitric provide an overview of the opportunities and challenges that term differences in 2 different oxide synthase await the development of novel treatments for PAH. treatment approaches; however, EPC = endothelial progenitor such designs assume that a short cell Designs and Endpoints for PAH Trials time to wash out the therapeutic FAO = fatty acid oxygenation is adequate and that there are no LV = left ventricle/ Clinical trial designs. The objective of clinical trials is to “carry-over” treatment effects (3). ventricular determine, in a selected population, if a treatment is both safe Crossover trials for PAH are of MSC = mesenchymal stem and effective and whether the findings in the study can be concern as a washout may cause cell translated to the larger population of affected individuals. rebound clinical worsening. NO = nitric oxide “ ” The proof of concept or phase 2 stage of clinical develop- Clinical trial endpoints. PAH = pulmonary arterial ment can generate critical information regarding dosing and CHARACTERISTICS OF APPRO- hypertension safety and can provide insight into whether a full-scale phase PRIATE PRIMARY ENDPOINTS IN PDGF = platelet-derived 3 study is likely to be successful (1). Virtually all of the REGISTRATION TRIALS. The se- growth factor currently approved PAH therapies underwent phase 2 studies lection of the primary endpoint PH = pulmonary prior to phase 3, whereas none of the drugs that have gone for a registration trial is one of the hypertension straight to pivotal trials has met with regulatory approval. most important steps in study PRO = patient-reported Nonetheless, the limitations of phase 2 trials include: small design at any phase of develop- outcome sample size, heterogeneity of the study population, selection of ment. There are several charac- PVR = pulmonary vascular an appropriate endpoint, and competition for patients teristics of outcome measures that resistance between multiple trials. Some of these issues can be addressed should be considered when RAAS = renin-angiotensin- by using enrichment strategies, as recently highlighted in the choosing the primary endpoint. aldosterone system Food and Drug Administration’s strategies for successful This endpoint should be consis- RV = right ventricle/ drug trials (2). One of the challenges arising from our relative tently and reliably measureable, ventricular success in developing therapies for PAH is that future ther- because missing data meaning- TTCW = time to clinical worsening apies can no longer be studied as de novo treatments with fully impacts the interpretability placebo-treated comparator groups. One solution to this VEGF = vascular endothelial of results and because ethical growth factor dilemma is to implement creative adaptive designs. For issues might arise when outcome example, a factorial design allows for testing more than assessments are based on invasive procedures that are not 1 novel element in a single trial (3). routinely conducted as part of clinical practice. These ethical A second creative approach that could be used for PAH issues are particularly important in pediatric settings. Due to therapies, which is known to be effective during the short these considerations, endpoints that require right heart term but without potential utility over a longer term, is the catheterizations or histologic measures that require invasive randomized discontinuation trial. Although PAH clinicians biopsy procedures might be problematic. The outcome have expressed concern about implementing this approach measure also should be distinct and reliable, with properly in a population that is hemodynamically fragile, the stan- established content validity. Content validity is “the extent to dardized use of background therapy should help minimize the which an instrument measures the important aspects of risk without compromising the quality of information. This concepts most significant and relevant to the patient’s trial design utilizes predictive enrichment techniques by condition and its treatment” (9,10). selecting subjects for study who, on the basis of their prior The most important characteristic of the primary response, have the greatest chance of benefit (4). Of course, outcome measure in a registration trial is that it should be concern remains that withdrawal of a treatment could result a clinically meaningful endpoint, defined by Temple (11) to in acute clinical deterioration (5). Additionally, it is prob- beadirectmeasureofhowapatient“feels, functions or lematic that the population studied in this type of trial design survives,” where “function” refers to the ability of a patient may not be representative of the larger affected population (4). to carry out normal daily activities. Examples of clinically Noninferiority and crossover designs are difficult to meaningful endpoints in PAH are death, lung trans- implement in an orphan disease. A noninferiority trial plantation, initiation of parenteral prostanoid therapy, utilizing current endpoints could require large sample sizes hospitalization for worsening PAH, or symptoms of PAH (6). Acceptable margins for such studies would be depen- such as cough, breathlessness, chest pain, or syncope. PAH dent on many factors, including the selected endpoint, the symptoms can be utilized as primary endpoints in D84 Gomberg-Maitland et al. JACC Vol. 62, No. 25, Suppl D, 2013 New Trial Designs and Therapies for Pulmonary Arterial Hypertension December 24, 2013:D82–91

Table 1 Future Therapeutics potential surrogate endpoints because they are thought to be related to disease progression and because they are known to be Pathway/Targets Therapy correlated with clinically meaningful endpoints. As correlates, Vasodilation Nitric oxide, nitrite they can be very useful for diagnosis or assessing prognosis, as Sympathetic nervous Selective > nonselective beta-adrenergic blockade endpoints in phase 2 trials, or as parameters that support the system Renin-angiotensin- Aldosterone antagonist, vasopressin receptor meaningfulness of changes in the primary endpoint. In addi- aldosterone system antagonist, catheter-guided ablation tion, measurement of biomarkers may provide insights into Vascular remodelingd Dichloroacetate, ranolazine the mechanisms of action of novel treatments. metabolic alterations It is important, however, to distinguish between showing Anti-inflammation Rho-kinase inhibitors, rituximab, vasoactive intestinal that a biomarker value is strongly correlated with the risk peptide Selective and Tyrosine kinase inhibitors of achieving clinically meaningful endpoints and demon- multikinase strating that changes in biomarker values reliably predict inhibition comparable directional changes on clinically meaningful Stem cells outcomes; in other words, a “correlate does not a surrogate Gene therapy make” (14). There are multiple reasons for this apparent Cell therapy Endothelial, mesenchymal, and – gene-enhancing cells paradox (13 15). First, even if a biomarker does not Devices Cardiac resynchronization, extracorporeal life contribute to causation of the disease, it may nevertheless be support: venoarterial, venovenous, and pumpless correlated with a clinically meaningful endpoint if both the arteriovenous extracorporeal lung assist endpoint and biomarker are impacted by the disease’s true cause. Second, the magnitude of change and duration of effect on the biomarker that translates to clinically registration trials if the effects on these outcomes are meaningful endpoints may be unknown, or there may be assessed using appropriate patient-reported outcome other pathways that are not represented by the biomarker. (PRO) measures. The December 2009 Food and Drug Third, even if the biomarker captures the effects of the Administration’s Guidance to Industry for Patient- intervention on all important causal pathways of the disease Reported Outcomes provides valuable insights into the process, interventions often have off-target effects that are proper development of such measures, including confir- not captured by the biomarker, yet may have a meaningful mation of reliability, sensitivity, content and construct impact on the net treatment effect (14). The Institute of validity, interpretability, and clinical relevance (12).To Medicine provided a detailed discussion of rigorous steps, ensure integrity of the evaluation of the effect of entitled “analytical validation,”“qualification,” and “utiliza- an intervention on symptoms of PAH, it is important that tion,” that are needed before a biomarker is used as a this be done using randomized blinded clinical trials with replacement endpoint in any registration clinical trial (15). efforts to minimize the occurrence of missing data. In Unfortunately, it is very uncommon to have biomarkers that pediatric settings, it might be necessary to restrict trials to are properly validated surrogate endpoints, and it is apparent children 7 years of age when conducting a PRO-based that there are currently none in the setting of PAH. assessment of treatment effects on PAH symptoms. INDIRECT OUTCOME MEASURES. Some indirect measures that SURROGATE ENDPOINTS: DEFINITION AND VALIDATION. In are dependent on patient motivation or clinical judgment have order to reduce the size and duration of registration clinical been used as primary endpoints in registration trials. These trials, there often is interest in using indirect outcome include the 6-min walk distance (6MWD), the 3-min stair measures, such as biomarkers that are measurements of climb, and handgrip strength or treadmill testing. These tests biological processes, as replacement or “surrogate” end- are conducted in artificial settings and thus provide only points. A surrogate endpoint is an outcome measure “used as indirect assessments of the effect of the intervention on how a substitute for a clinically meaningful endpoint” (11).Itis a patient feels, functions, or survives (13). What is the minimal acceptable to use an indirect outcome measure if it is clinically meaningful effect of treatment on 6MWD, that is, a properly validated surrogate for a clinically meaningful the treatment-induced change that can be translated to endpoint. Establishing an indirect measure to be a valid a patient’s ability to carry out daily activities that are relevant to surrogate endpoint “requires providing an evidence based him or her? As trials in the future will primarily assess the justification, often from randomized controlled clinical trials, effects of add-on therapy to background therapies, the that achievement of substantial effects on the surrogate magnitude of incremental changes in 6MWD will be nar- endpoint reliably predicts achievement of clinically impor- rower than studies in treatment-naïve patients, making tant effects on a clinically meaningful endpoint” (13). interpretation more challenging. In pediatric settings, these Biomarkers that are based on laboratory assessments (such indirect measures might also require an age restriction, as as brain natriuretic peptide or the N-terminal pro-brain younger subjects may not be able to cooperate sufficiently. natriuretic peptide) or hemodynamic measures (such as pulmonary vascular resistance [PVR], PVR index, mean THE ROLE AND INTERPRETABILITY OF COMPOSITE ENDPOINTS. pulmonary arterial pressure, or cardiac output) are of interest as Composite endpoints may more comprehensively reflect JACC Vol. 62, No. 25, Suppl D, 2013 Gomberg-Maitland et al. D85 December 24, 2013:D82–91 New Trial Designs and Therapies for Pulmonary Arterial Hypertension clinically meaningful treatment effects. This approach is first clinical event. For example, this TTCW composite particularly appealing in rare diseases such as PAH and, in might be defined as: particular, in subsets of rare diseases such as PAH in children. 1. Death All of the components of a composite endpoint should be of 2. Lung transplantation similar clinical relevance, thereby strengthening the mean- 3. Hospitalization for worsening PAH (including atrial ingfulness of the treatment effect. For example, the major septostomy) cardiovascular endpoint is a composite endpoint comprised of 4. Initiation of intravenous therapy due to worsening cardiovascular death, stroke, and myocardial infarction that is PAH used frequently as the primary endpoint in registration trials 5. Worsening of function (i.e., worsening functional for the treatment of acute coronary syndrome. The mean- class and exercise capacity) ingfulness of changes in this composite endpoint is enhanced 6. Worsening of PAH symptoms (i.e., worsening of at because each component is an independent measure of irre- least 2 of the 4 symptoms: dyspnea, chest pain, versible morbidity or mortality. dizziness/syncope, fatigue/activity level) In PAH, the composite endpoint of time to clinical worsening (TTCW) has been used as a secondary, or reinforcing, endpoint in prior registration trials. As defined at Future Targets for Therapeutics the Fourth World Symposium in PH at Dana Point, Cal- ifornia, components of this composite include death, The future of clinical research in PAH will likely consist of lung transplantation, hospitalization for worsening PAH 3 major approaches. First, the identifying and testing of (including atrial septostomy), initiation of intravenous newly identified targets of pathogenesis. Of these, vaso- therapy due to worsening PAH, and worsening of function constriction, inflammation, abnormal growth, and angio- (i.e., worsening World Health Organization functional class genesis are the most extensively studied at present. Second, and a decrease in 6MWD). Recently completed trials in optimization of treatment targeting pathways known to be PAH suggest that “clinical worsening” may be a more important in PAH, for example, developing more potent, suitable and meaningful primary endpoint than 6MWD, less toxic drugs that target the endothelin, nitric oxide, and particularly as new trials will be studying patients on back- prostacyclin pathways, or establishing whether combination ground therapies and for longer periods of observation. therapy is more efficacious than monotherapy and, if so, determining the timing and choice of agents. Third, the ALTERNATIVE ENDPOINTS FOR ADULT AND PEDIATRIC PAH development of devices aimed at improving or supporting TRIALS. Individual measures that are potential phase 3 trial right ventricular (RV) function. The next section will discuss primary endpoints include: these in more detail (Table 1). Vasodilators. NITRIC OXIDE. Nitric oxide (NO) is a potent 1. Overall survival (all-cause mortality); vasodilator and an inhibitor of platelet activation and 2. Hospitalization for worsening PAH and death caused vascular smooth muscle proliferation. Intact NO signaling is by PAH; critical to maintaining the appropriate pulmonary vascular 3. Exercise capacity measures; tone both before and after birth (16). There are 3 isoforms of 4. Functional class; and the NO synthase family of enzymes: endothelial nitric oxide 5. PROs synthase (eNOS), inducible NO synthase, and neuronal NO Level of successful social interactions with peers synthase; all are expressed in the lung (17). Both eNOS and 36-Item Short Form Health Survey inducible NO synthase deficiency are associated with Borg Dyspnea Score elevated basal pulmonary vascular tone in animal models Days of work (or “school” in pediatric setting) (18,19). missed for health-related reasons. Inhaled NO is a familiar agent that is an effective pulmonary Composite measures are of interest in both adult and vasodilator. Inhaled NO works well in the setting of increased pediatric PAH settings. For example, changes in 4 symptom pulmonary vascular tone due to pulmonary vasoconstriction categories comprising the endpoint could be: dyspnea, chest and has minimal effects in healthy subjects (20). Inhaled NO pain, dizziness/syncope, and fatigue/activity level. Properly is potentially useful for PAH by limiting RV hypertrophy developed instruments would be needed for the assessment and enhancing downstream signaling targets, such as soluble of these symptoms, and the appropriate time post- guanylate cyclase and cyclic guanosine monophosphate, to randomization for endpoint assessment would also need to attenuate pulmonary vascular remodeling (21–23). Nitrite is be defined. a physiological signaling molecule with roles in intravascular The Dana Point TTCW composite endpoint, which is endocrine NO transport, hypoxic vasodilation, signaling, and the time to the first event, could be enhanced to include cytoprotection after ischemia-reperfusion. Evaluation of a component that would be based on these same 4 PAH inhaled nitrite for PAH is in progress as well (NCT01431313), symptoms cited in the previous text. These symptom vari- understanding that rebound after withdrawal of inhaled ables are especially important as, for PAH, death is rarely the NO and inhaled nitrite is a concern. D86 Gomberg-Maitland et al. JACC Vol. 62, No. 25, Suppl D, 2013 New Trial Designs and Therapies for Pulmonary Arterial Hypertension December 24, 2013:D82–91

Beta-blockers. Unlike left-sided heart failure, the effects of Vascular remodeling. METABOLIC ALTERATIONS: DICHLORO- beta-blocker therapy on PAH-induced right heart failure ACETATE. The vascular remodeling in PAH is partially charac- have not been thoroughly investigated (24). Concern terized by a state of apoptosis resistance. As in cancer, a switch regarding the use of beta-blockers in PAH is based primarily from the antiapoptotic glycolytic metabolism to the pro- on their potential to produce negative inotropic effects; apoptotic oxidative phosphorylation metabolism causes additionally, PAH patients are dependent on heart rate to regression of vascular remodeling in several PH animal maintain cardiac output, and these agents are likely to affect models (39–41). Mitochondrial-metabolic abnormalities this compensatory mechanism (25,26). However, many of have been proposed in PAH, including disruption in the original studies used first-generation, nonselective beta- pyruvate dehydrogenase kinase-mediated inhibition of blockers that have more bronchial and myocardial depressive pyruvate dehydrogenase, which increases aerobic glycolysis effects than currently available more selective agents (26,27). in the lungs and RV (42). By inhibiting mitochondrial In support of further study of their use in PAH is the pyruvate dehydrogenase kinase and pyruvate dehydrogenase, demonstration that chronic adrenergic overdrive, which is dichloroacetate increases pyruvate entry into the mitochon- present in PAH, can result in myocardial depression and dria, promotes glucose oxidation over glycolysis (39),and cardiac compromise (28). restores Kv channel function and expression in pulmonary In animal models of PH, selective beta-blockers appear artery smooth muscle cells, leading to the inhibition of to improve RV function and myocardial remodeling (29,30). voltage-gated calcium channels, a decrease in intracellular For example, carvedilol (a1/b1/b2-adrenergic receptor an- calcium, an inhibition of vasoconstriction, and a reduction tagonist) improved RV contractility and hemodynamics in in pulmonary artery smooth muscle cell proliferation (43–45). the Su-5416 (sugen)/hypoxia derived PAH-rat model (30), Based on PH regression in animal models (43,44), and bisoprolol (cardioselective b1-adrenergic receptor a phase 1, safety and tolerability, 2-center study of antagonist) delayed progression toward right heart failure by dichloroacetate in functional class III to IV PAH patients preventing RV inflammation and decreased RV fibrosis in on background therapy is ongoing in Canada and in the monocrotaline PAH rat model (31). A phase 2 clinical England (NCT01083524). study to investigate the safety and efficacy of bisoprolol in METABOLIC ALTERATIONS:RANOLAZINE. Reactivation of pyruvate PAH patients (NCT01246037) has been initiated. dehydrogenase kinase to promote glucose oxidation can be Sympathetic nervous system and renin-angiotensin- achieved by activating the Randle cycle, using inhibitors of aldosterone system. The sympathetic nervous system and fatty acid oxidation (FAO) (42). FAO is increased in RV renin-angiotensin-aldosterone system (RAAS) are hypertrophy produced by pulmonary arterial banding in both activated in PAH patients, but the value of these animals (46). Accordingly, it has been proposed that agents systems as therapeutic targets is unclear (32,33). Hypona- that inhibit FAO could improve RV hemodynamics in tremia is an indirect marker of RAAS activation and may PAH. Ranolazine, an FAO inhibitor approved to treat be a useful surrogate biomarker of disease severity (33). refractory angina, improves cardiac work by inhibiting FAO Aldosterone inhibition reduces pulmonary pressure and through activation of pyruvate dehydrogenase and stimu- pulmonary vascular resistance without systemic hypotension lating glucose oxidation (47,48). An acute, randomized, fi in the Su-5416/hypoxia and monocrotaline animal models placebo-controlled, single-center safety and ef cacy study (34). These studies provide support for the evaluation of with ranolazine for PAH is currently enrolling in the United aldosterone antagonist therapy in PAH (NCT01712620). States (NCT01757808). fl fl The release of arginine vasopressin is an additional factor Anti-in ammatory agents. In ammation occurs in PAH contributing the sodium and water retention that is common in with different levels of severity dependent on the subtype. PAH. In patients with heart failure, plasma arginine vaso- Mononuclear cells, including T cells, B cells, and macro- pressin levels are elevated out of proportion to serum osmo- phages, surround plexiform lesions in pathologic specimens. larity, resulting in water retention and hyponatremia (35,36). Clinically, PAH patients have elevated cytokine levels of Conivaptan, a vasopressin receptor antagonist, improves signs interleukin-1B, -6, and -8 and chemokines CCL2/MCP-1, of left heart failure and is being studied in the treatment of CCL5/RANTES CX3CCL-1, and CXC3CL1/fractalline – PAH-induced right heart failure (NCT00811486). (49 54). Catheter-guided ablation to alter the RAAS pathway is RHO-KINASE INHIBITORS. A wide variety of cellular actions, also being investigated for PAH. Pulmonary vein ablation including proliferation, apoptosis, motility, migration, has been used to treat resistant atrial fibrillation, and more inflammation, and vasoconstriction, are influenced and recently, renal sympathetic nerve ablation has shown pro- regulated by the Rho/Rho-kinase signaling pathway (55,56), mise in the treatment of refractory systemic hypertension a pathway that appears to play an important pathogenetic (37). A recent pilot study from China demonstrated marked role in PH (57). Rho/Rho-kinase inhibitors, such as fasudil reductions in pulmonary artery pressure and vascular resis- and Y-27632, effectively inhibit the development of PH tance in 13 PAH patients after catheter-based denervation when administered to animals prior to the induction of PH; of the pulmonary artery (38), but this has not yet been when given to animals with established PH, these agents confirmed by other investigators. improve endothelial cell function, decrease arterial JACC Vol. 62, No. 25, Suppl D, 2013 Gomberg-Maitland et al. D87 December 24, 2013:D82–91 New Trial Designs and Therapies for Pulmonary Arterial Hypertension neomuscularization, and improve RV function (58–60). differences in TTCW or survival between groups; but, of Small studies evaluating fasudil in PAH thus far have particular concern, subdural hematomas occurred in 8 demonstrated a nonselective reduction in both pulmonary patients in the treatment arm (2 in the core study and 6 in and systemic vascular resistances (58,61,62). This potential the extension study). As a result, development of imatinib decrease in systemic blood pressure is of concern and for PAH has been discontinued. requires careful consideration during its drug development. The multikinase inhibition, by definition, can add to the off-target effects of these drugs, which may be unpredictable RITUXIMAB. Rituximab is a chimeric monoclonal antibody and devastating (78). Sorafenib, a Raf-1, VEGF-R2, and that binds the B-cell surface protein CD20. It has proven PDGF receptor-b inhibitor evaluated in a phase 1 dosing efficacy in a number of diseases characterized by increased safety study, demonstrated some improvement in exercise B-cell numbers or aberrant function, including lymphomas, capacity but no improvement in cardiac output (79), and leukemias, and autoimmune disorders (63,64). The potential development of sunitinib for PAH was halted after drug- role of autoimmune and inflammatory mechanisms in PAH induced cardiotoxicity was observed in oncology trials. has raised interest in the use of rituximab in PAH, and Cardiotoxicity with TKIs is a serious concern, with reports specifically in the treatment of sclerodema-associated PAH. of cardiac ischemia, left ventricular (LV) dysfunction, and Since infusion of rituximab can result in hypotension, this hypertension occurring with VEGF inhibition and as an off- will be a closely watched potential adverse event in a trial target consequence (80–87). LV dysfunction is potentially currently in progress (NCT01086540). fatal in a PAH patient, and is difficult to diagnose prior to VASOACTIVE INTESTINAL PEPTIDE. Vasoactive intestinal symptoms. Research of the oncology data demonstrates often peptide (VIP) is a neuropeptide in the glucagon growth idiosyncratic, nondose-dependent decreases in cardiac func- hormone-releasing factor secretion superfamily with a wide tion with sunitinib, sorafenib, and imatinib (81,83–87). range of effects, including anti-inflammatory and immune- Adding to this concern are case reports implicating the multi- modulatory roles as well as vasodilation of the pulmonary TKI dasatinib as a potential inducer of PAH (88). vasculature and inhibition of pulmonary artery smooth Stem cells. Regeneration of lung microvasculature is muscle cell proliferation (65–67). Administration of VIP to a novel therapeutic strategy for restoring pulmonary hemo- patients with PAH by inhalation improved hemodynamics dynamics in patients with advanced PAH. Evidence in and exercise tolerance in a small, uncontrolled 3-month experimental models of lung vascular disease has suggested study (68). However, a randomized, placebo-controlled, that, as in systemic arterial beds, stem cells may also induce double-blinded phase 2 trial showed no effects of inhaled the regeneration of pulmonary microvessels. The adminis- VIP in the doses studied (69,70). tration of mesenchymal stem cells (MSCs) may be a thera- Tyrosine kinase inhibitors. Tyrosine kinase inhibitors peutic option for PAH. Despite the progress in stem cell (TKIs) are pharmaceutical agents derived to inhibit tyrosine biology, a number of hurdles still need to be overcome, kinases, and a number of these agents have proven to be including the difficulty of ex vivo expansion, the poor markedly effective antitumor and antileukemic treatments delivery efficiency (<5% of transplanted cells are retained (71). PAH and cancer share elements of pathophysiology. after transplantation), and their uncertain fate in vivo. As part of the pulmonary vascular remodeling, endothelial Gene therapy. The pulmonary endothelium is accessible cells in a monoclonal expansion form plexiform lesions through the pulmonary and bronchial circulations, whereas that express angiogenic vascular endothelial growth factor the epithelial linings of alveoli can be accessed through the (VEGF) and VEGF receptors. The cells become resistant to airways. The pathology of PH suggests several distinct apoptosis and contribute to the microvascular obstruction. genetic targets; gene therapy delivered through either the Thus, cross-purposing anticancer therapies for PAH is an airway or vasculature may be feasible. opportunity for novel therapeutics. Cell therapy. Both endothelial progenitor cells (EPCs) and Imatinib is an example of such an agent that has completed MSCs have been evaluated in pre-clinical studies as therapy phase 3 development for advanced PAH. It is a well- for PAH on the basis of their abilities to repair and regen- established inhibitor of the kinase BCR-ABL, the receptor erate damaged pulmonary vasculature. A small clinical trial for the stem cell factor c-KIT and the platelet derived growth using autologous EPCs showed improvements of both factor (PDGF) receptor (72), and it is approved for the pulmonary hemodynamics and clinical performance treatment of chronic myelogenous leukemia and gastroin- (6MWD) (89). MSCs allow for allogeneic cell therapy testinal stromal tumors (73,74). Because of the putative role because they are considered immune privileged. However, in of PDGF in the development of PAH, this agent has been contrast to EPCs, there have been no human studies eval- investigated as a possible therapeutic agent for PH (75,76). uating MSC transplantation in established PAH. In the IMPRES (Imatinib in Pulmonary Arterial Hypertension, a Randomized Efficacy Study) (77),a GENE-ENHANCED CELL THERAPY. MSCs may represent multicenter, randomized, placebo-controlled trial of ima- a more convenient platform for cell-based gene therapy as tinib for the treatment of PAH, patients had modest a result of their potential for allogeneic transplantation as improvements in 6MWD and reductions in PVR with no well as their ability to expand in culture. D88 Gomberg-Maitland et al. JACC Vol. 62, No. 25, Suppl D, 2013 New Trial Designs and Therapies for Pulmonary Arterial Hypertension December 24, 2013:D82–91

The use of syngeneic bone marrow–derived early- with the need for bypass stabilization, and the risk outgrowth EPCs engineered to overexpress eNOS may of bleeding, thromboembolism, and infection (94,95). represent an innovative approach to improving the function of pulmonary endothelium. Early outgrowth EPCs over- Ethical/Global Issues in Drug Development expressing eNOS not only prevented the progression of for an Orphan Disease PAH, but also reversed established disease in the MCT rat model, even when delivered 3 weeks after MCT injury (90). Multicenter pivotal clinical trials in PAH are now being These studies provided evidence to support a phase 1 clinical conducted worldwide. Training of centers in less-developed trial using autologous EPC-based eNOS gene therapy, nations on the standards of clinical practice is challenging, PHACeT (Pulmonary Hypertension and eNOS Cell not only because of language barriers, but also due to Therapy Trial; NCT00469027). differences in political climates and regulatory practices. In Devices. CARDIAC RESYNCHRONIZATION THERAPY. Ven- addition, standard of care, facilities, and quality of care is tricular dyssynchrony is seen in progressive stages of PAH- quite diverse. Clinical trial sites must have sufficient induced right heart failure. PAH patients with severe disease manpower and training to ensure that patients’ rights and have interventricular mechanical asynchrony, evidenced by safety are not compromised by trial enrollment (101,102). delayed peak shortening and prolonged duration of short- Many countries have limited funds for treating patients with ening of the RV free wall compared with LV free wall (91). orphan diseases and, thus, cannot approve all therapeutics. This pattern of interventricular dyssynchrony in PAH is associated with impaired RV systolic function (RV overload) Summary and LV underfilling. Recent work performed in experimental models of PAH suggest that RV free wall pacing There is an ongoing need to develop new treatment strate- improves right heart function (increased maximal rate of rise gies for PAH. Advancements in molecular biology and fi of RV pressure) and diminishes adverse interventricular therapeutics have identi ed novel targets, but not all of these diastolic interaction (without detrimental effects on LV or can realistically be studied, given the small number of PAH coronary perfusion), thereby potentially delaying develop- patients worldwide. New trial designs may enhance the ment of RV failure (92). These acute changes have recently development of new therapies without compromising the fi been confirmed in a pilot study of patients with right heart adequate assessments of both safety and ef cacy. Many of fi failure and ventricular asynchrony due to chronic thrombo- the potential new targets have been identi ed using animal embolic PH (93). models of PAH, but these models have thus far not proven to be reliable models of human disease. Other study EXTRACORPOREAL LIFE SUPPORT. Cardiogenic shock in approaches, such as ex vivo studies of cellular and molecular PAH patients is an acute decompensation of their under- events from tissue obtained from affected patients, may be lying chronic RV failure. The use of extracorporeal life more productive in generating new disease pathways to support as a bridge to recovery and/or as a bridge to lung target with new drugs. transplantation is now clinically utilized (94). The 3 most common extracorporeal life support approaches include: 1) Acknowledgment venoarterial extracorporeal membrane oxygenation The authors thank all the participants at the Nice 5th World (ECMO) for hypoxia or hemodynamic failure; 2) venove- symposium for help on the task force. nous ECMO for hypercapnia or hypoxemia; and 3) pumpless arteriovenous extracorporeal lung assist (Nova- Reprint requests and correspondence: Dr. Mardi Gomberg- lung, Hechingen, Germany). ECMO is predominantly used Maitland, University of Chicago, Pulmonary Hypertension for intubated patients, but it can be used in awake, non- Program, Department of Medicine, Section of Cardiology, 5841 intubated patients as a bridge to transplantation (95–97).A South Maryland Avenue, MC5403, Chicago, Illinois 60611. venovenous ECMO experience early in acute RV failure E-mail: [email protected]. may prove beneficial and, with the Avalon Elite Bicaval Dual Lumen catheter (Avalon Laboratories, Los Angeles, California) allowing a single cannulation site, can avoid REFERENCES multiple access sites and the need for ECMO (98,99). The 1. Sheiner LB. Learning versus confirming in clinical drug development. Novalung assist device is a pumpless, low resistance Clin Pharmacol Ther 1997;61:275–91. oxygenator designed for pulsatile blood flow drive by the 2. The American Society for Pharmacology and Experimental Thera- ’ patient’s cardiac output (100). The Novalung device is peutics. 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Chronic Thromboembolic Pulmonary Hypertension

Nick H. Kim, MD,* Marion Delcroix, MD,y David P. Jenkins, MB BS,z Richard Channick, MD,x Philippe Dartevelle, MD,k Pavel Jansa, MD,{ Irene Lang, MD,# Michael M. Madani, MD,* Hitoshi Ogino, MD, PHD,** Vittorio Pengo, MD,yy Eckhard Mayer, MDzz La Jolla, California; Leuven, Belgium; Cambridge, United Kingdom; Boston, Massachusetts; Le Plessis Robinson, France; Prague, Czech Republic; Vienna, Austria; Tokyo, Japan; Padova, Italy; and Bad Nauheim, Germany

Since the last World Symposium on Pulmonary Hypertension in 2008, we have witnessed numerous and exciting developments in chronic thromboembolic pulmonary hypertension (CTEPH). Emerging clinical data and advances in technology have led to reinforcing and updated guidance on diagnostic approaches to pulmonary hypertension, guidelines that we hope will lead to better recognition and more timely diagnosis of CTEPH. We have new data on treatment practices across international boundaries as well as long-term outcomes for CTEPH patients treated with or without pulmonary endarterectomy. Furthermore, we have expanded data on alternative treatment options for select CTEPH patients, including data from multiple clinical trials of medical therapy, including 1 recent pivotal trial, and compelling case series of percutaneous pulmonary angioplasty. Lastly, we have garnered more experience, and on a larger international scale, with pulmonary endarterectomy, which is the treatment of choice for operable CTEPH. This report overviews and highlights these important interval developments as deliberated among our task force of CTEPH experts and presented at the 2013 World Symposium on Pulmonary Hypertension in Nice, France. (J Am Coll Cardiol 2013;62:D92–9) ª 2013 by the American College of Cardiology Foundation

Chronic thromboembolic pulmonary hypertension (CTEPH) reinforce best practice guidelines, and to discuss and stimu- is a potentially curable cause of pulmonary hypertension late future directions. To facilitate these goals, this panel (PH). In the previous 4th World Symposium on Pulmonary proposed and explored 4 key clinical topics germane to Hypertension at Dana Point, California, in 2008, this topic CTEPH at the present time. was addressed in 2 overlapping task forces: 1) Interventional and Surgical Modalities of Treatment in Pulmonary Hyper- CTEPH Diagnosis tension; and 2) Diagnosis, Assessment, and Treatment of Non-PAH Pulmonary Hypertension (1,2). For the current Over the years, there have been numerous and evolving symposium, a separate dedicated task force consisting of versions of diagnostic algorithms for the evaluation of PH. experts from both medical and surgical specialties was estab- These algorithms have consistently recommended the use of lished to focus on this unique and important cause of PH. a radionuclide ventilation/perfusion (VQ) scan to screen for The goals of this task force were to provide key updates, chronic thromboembolic disease (3–6). Despite advances in

From the *University of California San Diego, La Jolla, California; yPneumology adjudicator and steering committee member from Actelion, Bayer, GlaxoSmithKline, Department, University Hospitals of Leuven, Leuven, Belgium; zCardiothoracic and Pfizer. Dr. Channick has received research grants from and/or consulted for Surgery, Papworth Hospital, Cambridge, United Kingdom; xPulmonary and Critical companies that have treatments for pulmonary hypertension, including Actelion Care Medicine, Massachusetts General Hospital, Boston, Massachusetts; Pharmaceuticals, Bayer, United Therapeutics, and Gilead. Dr. Jansa has received fees kCardiothoracic Surgery, Paris-Sud University, Le Plessis Robinson, France; {Charles for serving as investigator, consultant, and speaker from Actelion, Bayer, United University, Prague, Czech Republic; #Cardiology, Medical University of Vienna, Therapeutics, AOP Orphan Pharmaceuticals, Pfizer, and GlaxoSmithKline. Dr. Lang Vienna, Austria; **Cardiac Surgery, Tokyo Medical University, Tokyo, Japan; has received fees for serving as investigator, speaker, consultant, or steering committee yyCardiac, Thoracic, and Vascular Sciences, University of Padova, Padova, Italy; and member from Actelion, Bayer, GlaxoSmithKline, Novartis, Pfizer, AOP Orphan the zzThoracic Surgery, Kerckhoff-Klinik, Bad Nauheim, Germany. Dr. Kim has Pharmaceuticals, and United Therapeutics; educational grants from Actelion; and received consultancy fees for work on steering committees for Actelion and Bayer; and research grants from Actelion, AOP Orphan Pharmaceuticals, Bayer, and United research support from Actelion, Aires, Gilead Sciences, Lung LLC, and United Therapeutics. Dr. Madani has served as consultant for Bayer and GlaxoSmithKline; Therapeutics. Dr. Delcroix has received fees for serving as investigator, speaker, and received fees as speaker for Bayer. Dr. Pengo is on the advisory board of Daiichi- consultant, or steering committee member from Actelion, Bayer, GlaxoSmithKline, Sankyo; and has received lecture fees from Bayer AG and Roche Diagnostics. Dr. Novartis, Pfizer, and United Therapeutics; educational grants from Actelion, Glaxo- Mayer received fees for serving as speaker, consultant, or steering or adjudication SmithKline, and Pfizer; research grants from Actelion, Pfizer, and GlaxoSmithKline; committee member from Actelion, Bayer, GlaxoSmithKline, Pfizer, and AOP and she is also holder of the Actelion Chair for Pulmonary Hypertension and of the Orphan Pharmaceuticals. All other authors have reported that they have no rela- GlaxoSmithKline chair for research and education in pulmonary vascular pathology at tionships relevant to the contents of this paper to disclose. the KU Leuven. Dr. Jenkins has received fees for lecturing and/or serving as a trial Manuscript received October 18, 2013; accepted October 22, 2013. JACC Vol. 62, No. 25, Suppl D, 2013 Kim et al. D93 December 24, 2013:D92–9 Chronic Thromboembolic Pulmonary Hypertension computed tomography (CT) and magnetic resonance of CTPA in detecting CTEPH, Abbreviations imaging (MRI), the VQ scan remains the preferred test for some of these patients presumed and Acronyms screening for chronic thromboembolic disease, and it should to have PAH may in fact have ACP = antegrade cerebral be viewed as an initial step in the diagnosis of CTEPH CTEPH. The report also dis- perfusion (Fig. 1). The limitations of using computed tomography closed that roughly one-third of CT = computed tomography pulmonary angiogram (CTPA) for detecting chronic these cases without a VQ scan were CTEPH = chronic thromboembolic disease were highlighted in the report from because the provider reported that thromboembolic pulmonary Tunariu et al. (7). They reported a sensitivity rate of de- the scan was not relevant. There- hypertension tecting chronic thromboembolic disease of just 51% with fore, in addition to the technical CTPA = computed CTPA versus >96% with a VQ scan. and interpretive limitations of tomography pulmonary VQ scan remains the preferred test for screening for CTPA over VQ scans in the angiogram additional reasons. Compared with CTPA, a VQ scan screening for CTEPH, there is DHCA = deep hypothermic requires less radiation exposure, avoids potential com- a need for ongoing physician circulatory arrest plications related to intravenous contrast, and offers poten- education and general emphasis of ECMO = extracorporeal tial cost benefits with less likelihood for detection of best practice for the evaluation of membrane oxygenation incidental findings (8). In addition, interpretation requires PH. MRI = magnetic resonance less additional training beyond what is currently demanded These limitations notwith- imaging for interpreting a VQ scan. In other words, perfusion defects standing, CTPA has some bene- PAH = pulmonary arterial hypertension on VQ scan appear identical for either pulmonary embolism or fits over conventional pulmonary chronic disease (9). However, with CTPA, the defects in angiography in the evaluation of PAP = pulmonary artery pressure chronic disease usually have a different appearance than CTEPH. With an abnormal PEA = pulmonary pulmonary embolism, hence requiring additional training and screening VQ scan, the next endarterectomy attention to detect such differences (10). An additional imaging step in diagnostic algo- PH = pulmonary concern regarding reliance on CTPA for screening PH rithms recommends pulmonary hypertension fi includes false-positive cases from conditions mimicking angiography for disease con r- PTPA = percutaneous chronic thromboembolic disease. These conditions include mation (Fig. 1). With improving transluminal pulmonary proximal lining thrombi associated with pulmonary arterial generations of CT scanners, the angioplasty hypertension (PAH) or congenital heart defects (11). higher-resolution images provide PVR = pulmonary vascular Pulmonary artery sarcoma can also be mistaken for chronic additional details such as vascular resistance thrombus (12). Therefore, overreliance on CTPA may lead to wall thickness and surrounding RCTs = randomized a false-positive diagnosis of chronic thromboembolic disease. structures not appreciated by con- controlled trials Another important concern regarding the reliance on ventional angiography (15,16). VQ = ventilation/perfusion CTPA for screening and diagnosis of CTEPH has to do with Furthermore, CTPA avoids the operability assessment. CTPA detects chronic thromboem- need for direct catheter access and the associated expertise bolic disease in vessels often deemed accessible for experienced and capability to perform selective angiograms. Accordingly, pulmonary endarterectomy (PEA) surgeons (segmental, lobar, high-quality CTPA, especially at centers experienced with or main pulmonary arteries). Disease confined to the very chronic thromboembolic disease, may be a reasonable alter- distal segmental or subsegmental pulmonary arteries (locations native to pulmonary angiography in the evaluation of more likely to be deemed inoperable) may be missed if screened CTEPH. CT also has the advantage of revealing associated by using CTPA. Indeed, even with the latest 320-slice CT findings suggestive of chronic thromboembolic disease such as technology, the sensitivity for detecting chronic disease in the bronchial artery collaterals and a mosaic perfusion pattern, and segmental vessels was reportedly lower compared with it may also serve to screen for underlying mediastinal disease or detection rates for disease found in the main or lobar branches other conditions mimicking chronic thromboembolic disease (86% vs. 97%, respectively) (13). Accordingly, for experienced (17). Lastly, with promising modalities such as dual-energy or higher-volume endarterectomy centers, CTEPH diag- CT and lung perfusion MRI, the innovation and growth nosed by using CTPA will often be deemed technically potential in pulmonary vascular imaging seem assured (18,19). operable. Furthermore, reliance on CTPA for screening alone Despite these advances in CT and MRI scans, catheter- may miss potentially inoperable patients with CTEPH who based selective pulmonary angiography (particularly incor- should be considered for a trial of medical therapy or could porating digital subtraction angiography to improve vessel participate in an appropriate clinical investigation. contrast) remains the gold standard for diagnosis and Underutilization of VQ scans in screening PH invites confirmation of chronic thromboembolic disease, and it is potential misdiagnosis of PAH. In the recent report from the reference technique by which other imaging modalities the Pulmonary Arterial Hypertension Quality Enhancement are compared in CTEPH (20,21).Amajoradvantage Research Initiative registry, we learned that 43% of patients with catheter-based pulmonary angiogram is the ability to in the registry with PAH never had a VQ scan leading up to combine the imaging with assessment of hemodynamic their diagnosis (14). When considering the lower sensitivity parameters by using right heart catheterization. The D94 Kim et al. JACC Vol. 62, No. 25, Suppl D, 2013 Chronic Thromboembolic Pulmonary Hypertension December 24, 2013:D92–9

Updates on Surgical Therapy

The standard surgical technique for PEA has not changed in the last 5 years. It is based on the principles established by the group from San Diego (24). A median sternotomy is essential to approach both lungs and cardiopulmonary bypass and cooling to 20 C to allow arrest of the circulation. Deep hypothermic circulatory arrest (DHCA) is necessary to provide a clear operating field to enable a complete endarterectomy with dissection into subsegmental branches. This technique has proven safe and reproducible and is used at most centers performing PEA surgery. Indeed, the latest series from San Diego reported an in-hospital mortality of 2.2% in the last 500 consecutive patients (25). In the European CTEPH registry, with 17 surgical centers, the in-hospital mortality was 4.7% despite some centers having low volumes and less experience (26). However, there have been a series of reports, from Europe, indicating that PEA is possible without complete DHCA Figure 1 Diagnosis of CTEPH Leads to Operative Assessment and another recommending multiple episodes of brief – Diagnosis and treatment of CTEPH occur in a stepwise process, starting with an DHCA (27 31). These have served to stimulate debate echocardiogram and ventilation-perfusion scan. Diagnostic confirmation requires about the technique and question if they can be improved high quality pulmonary angiogram and right heart catheterization to assess the further. Can DHCA be reduced or even avoided? Is there location of chronic thromboembolism and severity of PH, respectively. The pulmonary endarterectomy operability assessment depends on numerous factors subtle cognitive injury with DHCA, and is there any which contribute to overall risk assessment. CTEPH ¼ chronic thromboembolic benefit in attempting to maintain some brain perfusion? pulmonary hypertension; CTPA ¼ computed tomography pulmonary angiogram; More fundamentally, the purpose of the procedure is to MRA ¼ magnetic resonance angiogram; VQ ¼ ventilation/perfusion. reduce pulmonary vascular resistance (PVR), and it is not certain whether a complete endarterectomy is feasible in all patients without DHCA. amount of contrast can be tailored by using cardiac output The PEACOG (Circulatory Arrest Versus Cerebral measurement to produce optimum image quality while Perfusion During Pulmonary Endarterectomy Surgery) minimizing contrast exposure. The angiographic appear- study attempted to answer these questions (32). In this ance and distribution, such as subpleural perfusion score prospective controlled trial, patients were randomized to (i.e., qualitative measurement of pulmonary angiographic undergo the PEA operation with DHCA or antegrade “pruning”), has been associated with postoperative cerebral perfusion (ACP) with maintained brain blood flow. outcomes (22). The comparison of radiographic burden of Cognitive function was assessed with multiple tests by disease with hemodynamics is a critical exercise in deter- a blinded independent observer before surgery and at miningoperabilityaswellassurgicalriskbeforePEA(23). 3 months and 1 year after surgery. This trial was the first Ultimately, however, the overall operability assessment also direct comparison of DHCA and ACP in any surgical needs to incorporate patient factors such as comorbidities procedure, the largest trial involving DHCA in adults, and and the experience level of the PEA surgeon and supporting the most complete evaluation of cognitive function after CTEPH team. PEA. Seventy-four patients were randomized to receive Recommendations regarding CTEPH diagnosis are thus treatment, with only 1 death in the hospital (1.4%), and as follows: 1-year survival was 96%. The findings with respect to VQ scan is the preferred and recommended screening cognitive function were unexpected. At 3 months and 1 year, test for chronic thromboembolic disease in patients there was no difference between the groups and, more with PH. CTPA for screening may lead to potential importantly, the mean scores in both groups for the main misdiagnosis of PAH and underdiagnosis of CTEPH, parameters actually improved after surgery. This finding was including patients with distal disease. probably a result of improved cardiac output. The results did Pulmonary angiography (digital subtraction angiog- not change when analyzed on a per-protocol or intention- raphy) remains the gold standard for confirmation of to-treat basis. Importantly, 9 patients had to cross over chronic thromboembolic disease and evaluation of from the ACP to the DHCA group to complete the PEA operability. because vision in the operating field was compromised High-quality multidetector CTPA may be a suitable without complete circulatory arrest. Therefore, patients and alternative to pulmonary angiography in centers with referring physicians can be reassured that the current PEA experience in CTEPH. procedure is safe and does not cause impairment of cognitive JACC Vol. 62, No. 25, Suppl D, 2013 Kim et al. D95 December 24, 2013:D92–9 Chronic Thromboembolic Pulmonary Hypertension function despite the long cardiopulmonary bypass times and beneficial results. The reported hemodynamic results are DHCA. Surgeons can be confident that the standard impressive and represent hemodynamic improvements of DHCA procedure is the best technique to allow a complete the magnitude obtained with PEA by experienced centers. endarterectomy, and this remains the recommended proce- Furthermore, improvements in 6-min walk distance and in dure. Any further modifications should be compared directly World Health Organization functional class have also been with this standard, preferably in a randomized controlled observed (43). setting. However, there are numerous concerns and unanswered Despite the improvements in outcome, there are specific questions about this technique for the treatment of complications that account for the majority of deaths after CTEPH. First, clarification is needed to address the patient surgery: residual PH and reperfusion lung injury. The 2 are selection process for this therapy over established and often present in combination, and when severe, conventional potentially curative PEA. This technique also requires therapy has proved ineffective. As the technology of extra- multiple procedures, each with risks of complications, the corporeal membrane oxygenation (ECMO) support has most severe being vessel rupture and reperfusion lung injury. improved in the last few years, it has been used for PEA In addition, the procedure is currently limited, with a rela- patients. Venoarterial ECMO is necessary if there is tively short follow-up compared with PEA. The durability hemodynamic instability, and the rationale is uniquely of the procedure and the risk of restenosis need to be appropriate for the pathophysiology. It can be used both systematically evaluated and established. Hence, based on centrally with cannulation of the heart or peripherally with the evidence to date, the role of percutaneous pulmonary cannulation of the femoral vessels. Blood is diverted away angioplasty in CTEPH remains uncertain and requires from the right heart and lungs, allowing reduction in further evaluation before it can be recommended as an pulmonary artery pressure, offloading the right ventricle; at established treatment for CTEPH. the same time, the ECMO circuit provides cardiac output Recommendations regarding updates on surgical therapy and gas exchange. For reperfusion injury alone, veno-venous are thus as follows: ECMO support is sufficient. The important principle for PEA with DHCA remains the standard and recom- ECMO use is fulfilled as recovery can occur within the mended operative technique for the treatment of time frame of potential support. To date, 3 publications CTEPH. have reported on ECMO after PEA. Some have reserved ECMO can be helpful as a supportive measure for ECMO for patients with severe reperfusion lung injury patients with severe postendarterectomy complications who have had a good hemodynamic result from PEA (33). and should be a standard of care in PEA centers. Other groups have used ECMO for hemodynamic support The role of percutaneous pulmonary angioplasty needs in patients with right ventricular failure (34,35). Average to be further evaluated and should not replace PEA for support duration is a median of 5 days in most series, and the treatment of CTEPH. reported survival is up to 57% (35). In the last 2 years, there A CTEPH team, consisting of an experienced PEA have been 4 additional case reports of ECMO use (36–39). surgeon and CTEPH physicians, should assess oper- It is estimated that many of the patients described in these ability before alternative treatments are considered. series would have died without ECMO, and it is therefore Close working collaboration between community recommended as a standard of care for PEA centers to have providers and CTEPH centers is required. salvaging ECMO capability for the most severe complications after PEA. The primary treatment for patients with CTEPH Role of Medical Therapy remains surgical. However, since the original publication on percutaneous pulmonary angioplasty in 2001, there had There are compelling reasons for considering PAH- been no further reports until 2012 when 3 reports emerged targeted therapies in CTEPH. The histopathological from Japan (40–43).Intotal,therearenowdatapublished examination of distal arteries in CTEPH patients reveals on 127 patients. In some reports, the procedure was reserved vascular changes similar to those in patients with idio- for patients who were not felt to be surgical candidates, but pathic PAH (44).AsinPAH,plasmalevelsof in others a surgical opinion was not documented. Some endothelin-1 closely correlate with the hemodynamic and reports indicated that patients had “distal” disease and some clinical severity of disease (45,46);asignificant number of had “operable” disease, but comorbidity precluded PEA. operated patients have persistent PH; and there are Some of the images within the publications demonstrate CTEPH patients whose condition is inoperable (47).In that the vessels opened were of a size that arguably could be the large European CTEPH registry, 17% of the patients treated surgically with PEA. The patients studied were had persistent PH defined by a mean PAP >25 mm Hg more likely to be female (>78%), whereas CTEPH typically at the last measurement in the intensive care unit, and has no sex predilection, thus suggesting selection bias. 37% of patients referred to the participating centers were Common to all the series is the need for multiple angio- considered inoperable, mainly because of anatomically plasty procedures within the same patient to achieve peripheral disease deemed inaccessible, comorbidities, and D96 Kim et al. JACC Vol. 62, No. 25, Suppl D, 2013 Chronic Thromboembolic Pulmonary Hypertension December 24, 2013:D92–9 discrepancy between PH severity and morphological up-titration scheme to offset systemic vasodilatory effects. lesions. At the end of 16 weeks, the treatment group was observed to There is mounting evidence that PAH-targeted medical have a 46-m improvement in the primary endpoint of 6-min therapy may have a role in the treatment of select CTEPH walk distance (95% confidence interval: 25 to 67; p < 0.001). patients. Patients deemed inoperable due to peripheral In addition, PVR was the first in a series of hierarchical disease and patients with residual or persistent PH after secondary endpoints and saw a placebo-adjusted treatment PEA are in need of effective therapy. Numerous open-label effect of –31% with therapy (p < 0.001). Additional positive and several randomized controlled trials (RCTs) of 3 to secondary endpoints included N-terminal pro–B-type 6 months’ duration have reported varying degrees of efficacy natriuretic peptide and World Health Organization func- with medical therapy (Table 1) (48–60). Recognizing that tional class. However, no significant effect on time to clinical the treatment of choice and the only potential for cure worsening was observed. In the subgroup analysis, the remains PEA, the 2 largest RCTs to date devoted to treatment effects were less pronounced in patients with CTEPH included an operability adjudication process. persistent PH after PEA. The safety profile seems satisfac- The first large-scale RCT in CTEPH was the BENEFiT tory even if an increased incidence of hemoptysis was (Bosentan Effects in Inoperable Forms of Chronic observed in the double-blind period and in the open-label Thromboembolic Pulmonary Hypertension) study with continuation study. Riociguat is approved by the U.S. bosentan (58). A total of 157 patients with inoperable Food and Drug Administration for PAH and CTEPH CTEPH, including 28% with previous PEA, were ran- patients and is currently undergoing the regulatory approval domized to receive either placebo or bosentan and were process by the European Medicines Agency for both studied for 16 weeks. The study observed mixed results in indications. its 2 co-primary endpoints: 6-min walk distance in meters As with previous guidelines, medical therapy in CTEPH was unchanged, with a treatment effect of 2 m (95% should not be considered as a replacement for PEA. The confidence interval: –22 to 27; p ¼ 0.5449), whereas PVR evidence for medical therapy has all specifically focused reduction was achieved with a treatment effect of –24% on a subset of CTEPH patients with either peripheral disease (95% confidence interval: –32 to –16; p < 0.0001). that PEA specialists deemed inoperable or those patients with In the most recent and largest RCT of medical therapy recurrent or residual PH after PEA. Accordingly, the critical in CTEPH to date, the CHEST-1 (Chronic Thomboem- step in the CTEPH treatment algorithm remains the opera- bolic Pulmonary Hypertension Soluble Guanylate Cyclase- bility assessment by a CTEPH team (Fig. 2). Because the Stimulator Trial-1) study with riociguat became the first to operability assessment remains complex, we recommend that achieve clinically meaningful primary endpoints (60). only an experienced CTEPH team should determine that Riociguat is an oral therapy taken 3 times a day and belongs a case of CTEPH is inoperable. Furthermore, recognizing the to a novel class of soluble guanylate cyclase stimulators. In subjective nature of the operability assessment process, we CHEST-1, a total of 261 patients with prospectively adju- encourage a re-evaluation of operability by a second experi- dicated, inoperable CTEPH, including 27% with previous enced CTEPH center, whenever feasible, in cases initially PEA, were randomized 2:1 to receive either riociguat or deemed inoperable. In cases of operable CTEPH, medical placebo, respectively. The study used a cautious drug treatment is associated with delays with PEA, and it adds no

Table 1 Short-Term (3 to 6 Months) Effects of Medical Treatment in CTEPH

Study First Author (Ref. #), Year Design Duration n NYHA 6MWD* Effect PVR Effect Epoprostenol (IV) Cabrol et al. (48), 2007 – 3 months 23 III–IV 280 112 66 (T) 29 7y21% Treprostinil (SC) Skoro-Sajer et al. (49), 2007 – 6 months 25 III–IV 260 111 59 924 347 13% Iloprost (inh) Olschewski et al. (50), 2002 RCT 3 months 57 III–IV NA NS NA NS Sildenafil (PO) Ghofrani et al. (51), 2003 – 6 months 12 NA 312 30 54 1,935 228z 30% Sildenafil (PO) Reichenberger et al. (52), 2007 – 3 months 104 II–IV 310 11 51 863 38 12% Sildenafil (PO) Suntharalingam et al. (53), 2008 RCT 3 months 19 II–III 339 58 18 (NS) 734 363 27% Bosentan (PO) Hoeper et al. (54), 2005 – 3 months 19 II–IV 340 102 73 914 329 33% Bosentan (PO) Hughes et al. (55), 2005 – 3 months 20 II–IV 262 106 45 (T) 1,165 392 21% Bosentan (PO) Bonderman et al. (56), 2005 – 6 months 16 II–IV 299 131 92 712 213 NA Bosentan (PO) Seyfarth et al. (57), 2007 – 6 months 12 III 319 85 72 1,008 428 NA Bosentan (PO) Jais et al. (58), 2008 RCT 4 months 157 II–IV 342 84 2 (NS) 783 (703–861) 24% Riociguat (PO) Ghofrani et al. (59), 2010 – 3 months 41 II–III 390 (330–441) 55 691 (533–844) 29% Riociguat (PO) Ghofrani et al. (60), 2013 RCT 4 months 261 II–IV 347 80 46 787 422 31%

*Mean SD or median (interquartile range) in meters. Pulmonary vascular resistance (PVR) dyn$s/cm5 in yWoods unit, dyn$s/cm5/m2. This table summarizes the results from published reports of medical treatment effects for select CTEPH patients, including the four randomized controlled trials noted under study design. CTEPH ¼ chronic thromboembolic pulmonary hypertension; inh ¼ inhaled; IV ¼ intravenous; NYHA ¼ New York Heart Association functional class; 6MWD ¼ 6-min walk distance; NA ¼ not applicable; PO ¼ per os; RCT ¼ randomized controlled trial; SC ¼ subcutaneous; T ¼ total pulmonary resistance (mean SD or median). JACC Vol. 62, No. 25, Suppl D, 2013 Kim et al. D97 December 24, 2013:D92–9 Chronic Thromboembolic Pulmonary Hypertension

Figure 2 CTEPH: Treatment Algorithm

Once the diagnosis of CTEPH is made, all patients should receive life-long anticoagulation therapy unless contraindicated. All patients with CTEPH should be referred for operability assessment by an experienced CTEPH team to determine if the patient is operable and candidate for pulmonary endarterectomy. If a patient is deemed non-operable, we recommend consideration for a second opinion by an experienced CTEPH team. This recommendation is in recognition of operability deﬁnition being subjective and dependent on center experience, and mirroring the operability adjudication process utilized in recent randomized controlled trials of medical therapy. For patients deemed non- operable, or patients after pulmonary endarterectomy with persistent symptomatic PH, treatment with PH targeted medical therapy is recommended. Other treatment options in select cases may include lung transplantation or percutaneous transluminal pulmonary angioplasty. PTPA ¼ percutaneous transluminal pulmonary angioplasty; other abbreviations as in Figure 1.

benefit (61). Therefore, PAH-targeted medical therapy in in-hospital mortality (62). With increases in global aware- operable cases of CTEPH is not recommended. In addition ness and clinical activity in PH, we have witnessed a parallel to the delay for definitive treatment with PEA, the potential growth in the science and clinical experience of CTEPH. effectsandrisksofPAH-targetedtherapiesonthechronic New centers have begun performing PEA surgery, in part to thromboembolic material or surgery have not been keep up with a growing demand of patients diagnosed with adequately evaluated. CTEPH (63). At the same time, the experienced and Recommendations regarding the role of medical therapy established centers are performing more surgeries, gaining are thus as follows: more experience, and, as a result, are improving their postoperative outcomes (25). In anticipation and recognition of The determination of operability is critical in CTEPH this growth and trend, at the 4th World Symposium on and should only be conducted by an experienced Pulmonary Hypertension in Dana Point, California, the CTEPH team. consensus recommendation was for PEA centers to achieve For inoperable CTEPH and residual disease after and target a <7% in-hospital mortality rate (1). At this PEA, medical therapy is recommended. Riociguat is point, we recommend revisiting these targets and endorse the first drug therapy to show positive primary additional treatment goals and expectations. endpoints in an RCT for those indications. The European CTEPH registry has contributed valuable Operable CTEPH cases should be referred for PEA information to help guide the field of CTEPH going forward without delay. The role of bridging with medical (26,47). This registry combined 679 incident cases of therapy has not been sufficiently studied and should be CTEPH diagnosed from 1 Canadian center and 26 European reserved for controlled investigation. centers (including 17 PEA centers). The registry reinforced the importance of PEA in the treatment of CTEPH and Treatment Outcome Considerations improved surgical outcome based on center experience as measured according to PEA cases performed per year. The In the early years of PEA for CTEPH, reasonable alterna- outcome data after PEA importantly went beyond the typical tive treatments did not exist. In addition, PEA operative in-hospital mortality and captured long-term mortality. The mortality was significantly higher than seen in the modern difference in observed survival at 3 years was 89% for operated era. Accordingly, early or traditional focus has been with CTEPH versus 70% for the nonoperated group (p < 0.0001) immediate postoperative hemodynamic improvement and (64). Similarly favorable long-term survival rates after PEA D98 Kim et al. JACC Vol. 62, No. 25, Suppl D, 2013 Chronic Thromboembolic Pulmonary Hypertension December 24, 2013:D92–9 have been reported by Archibald et al. (65), and these results 6. Wilkens H, Lang I, Behr J, et al. Chronic thromboembolic pulmonary re-emphasize the importance of surgical evaluation and hypertension (CTEPH): updated recommendations of the Cologne Consensus Conference 2011. Int J Cardiol 2011;154:S54–60. treatment for all patients with CTEPH. 7. Tunariu N, Gibbs SJ, Win Z, et al. Ventilation-perfusion scintigraphy Although long-term survival is of critical importance, it is more sensitive than multidetector CTPA in detecting chronic may not be adequate without additional considerations. thromboembolic pulmonary disease as a treatable cause of pulmonary hypertension. J Nucl Med 2007;48:680–4. For the individual patient with CTEPH, efficacy of any 8. Freeman JM. Don’t bury the V/Q scan: it’s as good as multidetector treatment should also demonstrate durability of benefit CT angiograms with a lot less radiation exposure. J Nucl Med 2007;49: – and improved quality of life. For the patient who undergoes 5 8. 9. Wartski M, Collignon MA. Incomplete recovery of lung perfusion after PEA, freedom from PAH-targeted therapy, oxygen sup- 3 months in patients with acute pulmonary embolism treated with plementation, or lung transplantation represents an impor- antithrombotic agents. J Nucl Med 2000;41:1043–8. tant measure of treatment success beyond in-hospital or 10. Bergin CJ, Sirlin S, Hauschildt J, et al. Chronic thromboembolism: diagnosis with helical CT and MR imaging with angiographic and long-term survival. For cases of inoperable CTEPH, both surgical correlation. Radiology 1997;204:695–702. affected patients and treating clinicians want effective 11. Perloff JK, Hart EM, Greaves SM, Miner PD, Child JS. 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Pulmonary Hypertension Due to Left Heart Diseases

Jean-Luc Vachiéry, MD,* Yochai Adir, MD, MHA,y Joan Albert Barberà, MD, PHD,z Hunter Champion, MD,x John Gerard Coghlan, MD,k Vincent Cottin, MD, PHD,{ Teresa De Marco, MD,# Nazzareno Galiè, MD,** Stefano Ghio, MD,yy J. Simon R. Gibbs, MD,zz Fernando Martinez, MD,xx Marc Semigran, MD,kk Gerald Simonneau, MD,{{ Athol Wells, MD, MBSHB,## Werner Seeger, MD, PHD*** Brussels, Belgium; Haifa, Israel; Barcelona, Spain; London, United Kingdom; Lyon, France; San Francisco, California; Bologna and Pavia, Italy; Ann Arbor, Michigan; Boston, Massachusetts; Le Kremlin Bicêtre, France; and Giessen/Bad Nauheim, Germany

Pulmonary hypertension (PH), a common complication of left heart diseases (LHD), negatively impacts symptoms, exercise capacity, and outcome. Although the true prevalence of PH-LHD is unknown, a subset of patients might present significant PH that cannot be explained by a passive increase in left-sided filling pressures. The term “out-of-proportion” PH has been used to identify that population without a clear definition, which has been found less than ideal and created confusion. We propose a change in terminology and a new definition of PH due to LHD. We suggest to abandon “out-of-proportion” PH and to distinguish “isolated post-capillary PH” from “post-capillary PH with a pre-capillary component” on the basis of the pressure difference between diastolic pulmonary artery pressure and pulmonary artery wedge pressure. Although there is no validated treatment for PH-LHD, we provide insights into management and discuss completed and randomized trials in this condition. Finally, we provide recommendations for future clinical trials to establish safety and efficacy of novel compounds to target this area of unmet medical need. (J Am Coll Cardiol 2013;62:D100–8) ª 2013 by the American College of Cardiology Foundation

Pulmonary hypertension (PH) is a common complication of results in more severe symptoms and worse exercise toler- left heart disease (LHD), frequently occurring as a “symptom” ance and exerts a negative impact on outcome (1–3).Over of the underlying condition (1,2) and often related to disease the past 10 years, PH-LHD has been recognized as a growing severity. Pulmonary hypertension LHD is most common in problem in terms of deﬁnition and differential diagnosis but patients with heart failure (HF), with preserved or reduced also of inﬂuence on outcome and therapy. Indeed, the ejection fraction (EF) (1–3). When present, PH-LHD differential diagnosis between pre- and post-capillary PH is

From the *Department of Cardiology, Hôpital Erasme, Université Libre de Bruxelles, Lung Research, Giessen/Bad Nauheim, Germany. Dr. Vachiéry is a consultant for Brussels, Belgium; yPulmonary Division, Lady Davis Carmel Medical Center, Faculty Actelion Pharmaceuticals, BayerSchering, Eli Lilly, Merck, and GlaxoSmithKline; has of Medicine, The Technion, Institute of Technology, Haifa, Israel; zHospital Clínic- received speaker fees from Actelion, Bayer Schering, and GlaxoSmithKline; and has IDIBAPS, University of Barcelona, Network Center of Biomedical Research on received a research grant from Actelion. Dr. Barberà has received honoraria and Respiratory Diseases (CIBERES), Barcelona, Spain; xUniversity of Pittsburgh consultancy fees from Actelion, Bayer, GlaxoSmithKline, and Pfizer; his institution has Medical Center Montefiore Hospital, Pittsburgh, Pennsylvania; kDepartment of received research grants from Actelion, Bayer, GlaxoSmithKline, Novartis, and Pfizer. Cardiology Royal Free Hospital, London, United Kingdom; {Hospices Civils de Dr. Champion has served as a consultant to Bayer, Gilead, and Pfizer; and has received Lyon, Louis Pradel Hospital, Department of Respiratory Diseases, National Reference research funding from Aires Pharmaceuticals. Dr. Coghlan has received consultancy fees, Center for Rare Pulmonary Diseases, Regional Competence Center for Severe lecture fees, and honoraria from Actelion, GlaxoSmithKline, Bayer, GenenTech, and Pulmonary Arterial Hypertension; Claude Bernard University Lyon 1, Lyon, France; United Therapeutics; and equipment support from Actelion. Dr. Cottin has received fees #University of California, San Francisco, San Francisco, California; **Department of from Actelion, GlaxoSmithKline, and Pfizer for speaking, advisory boards, meetings, Experimental, Diagnostic and Specialty Medicine-DIMES, Bologna University and clinical trials. Dr. De Marco has received honoraria and consultancy fees from Hospital, Bologna, Italy; yyDivisione di Cardiologia, Fondazione IRCCS Policlinico Actelion and Gilead; and has received research grants from United Therapeutics, San Matteo, Pavia, Italy; zzNational Heart and Lung Institute, Imperial College Novartis, and Pfizer. Dr. Galiè has served on the advisory boards of Eli Lilly, Actelion, London and Department of Cardiology, National Pulmonary Hypertension Service, Pfizer, Bayer-Schering, GlaxoSmithKline, and Novartis; has received speaker fees from Hammersmith Hospital, London, United Kingdom; xxDivision of Pulmonary and Eli Lilly and Company, Pfizer, Bayer-Schering, and GlaxoSmithKline; and has received Critical Care, University of Michigan Medical Center, Ann Arbor, Michigan; institutional grant support from Actelion, Pfizer, Bayer-Schering, GlaxoSmithKline, kkMGH Heart Failure and Cardiac Transplantation Center, Massachusetts General and Novartis. Dr. Ghio has consultancies with Actelion and Pfizer. Dr. Gibbs has Hospital, Boston, Massachusetts; {{Service de Pneumologie, Hôpital Universitaire de received consultancy fees from Gilead, Novartis, and Actelion; has served on the advisory Bicêtre, APHP, Université Paris-Sud, Laboratoire d’excellence en recherche sur le board and received speaker fees from Actelion, Bayer, GlaxoSmithKline, Pfizer, and médicament et innovation thérapeutique, and INSERM, Le Kremlin Bicêtre, France; United Therapeutics; and research funding from United Therapeutics. Dr. Martinez has ##Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom; served on the advisory boards of Amgen, Boehringer Ingelheim, Carden Jennings, Forest and the ***University of Giessen and Marburg Lung Center (UGMLC), member of Pharmaceuticals, GlaxoSmithKline, Ikaria, Jannsens, MedImmune, Merck, Nycomed/ the German Center for Lung Research (DZL), Max-Planck Institute for Heart and Takeda, Pfizer, and Vertex; has served on steering committees or data and safety JACC Vol. 62, No. 25, Suppl D, 2013 Vachiéry et al. D101 December 24, 2013:D100–8 Pulmonary Hypertension Due to Left Heart Diseases often challenging in patients with heart failure with preserved (10,11). The resulting increase in Abbreviations ejection fraction (HF-pEF). Compared with pulmonary PAWP might be enhanced by and Acronyms arterial hypertension (PAH), patients with PH-LHD are exercise-induced mitral regurgi- CO = cardiac output more often older, female, with a history of systemic hyper- tation, together with a loss of tension (4), and most, if not all, of the features of the metabolic left atrial compliance (12).The Cpc-PH = combined post- capillary and pre-capillary PH syndrome (5). pulsatile load imposed by a chron- DPD = diastolic pressure The true prevalence of PH-LHD in HF remains unknown, ically elevated PAWP might also difference due at least in part to the following: 1) current data are derived play a role in the development of EF = ejection fraction from either epidemiological studies in community-based HF PH (13). In some patients, these populations (6–8) or tertiary HF referral centers (3); 2) the purely mechanical components of HF = heart failure definition of PH was based on echocardiography, with venous congestion might trigger HF-pEF = heart failure with preserved ejection fraction a variety of cutoff values (6–8); 3) populations have been a superimposed component, heterogeneous, in terms of symptoms, age, and level of EF; combining pulmonary vasocon- LHD = left heart disease and 4) measurements of pulmonary arterial and left atrial striction, decreased nitric oxide LV = left ventricle/ ventricular filling pressures were not assessed by right (RHC) and/or left (NO) availability, increased heart catheterization, with the exception of single-center endothelin expression, desensiti- mPAP = mean pulmonary artery pressure reports (3–5). As a result, the prevalence of PH in LHD has zation to natriuretic peptide been reported to range between 25% and 100% of the patients induced vasodilation, and vascular NO = nitric oxide studied (Table 1). remodeling (2,14).Atthisstage, PAH = pulmonary arterial hypertension This paper provides new hemodynamic definitions, mPAP increases further, and this terminology, and treatment insights of PH-LHD. increase seems to be in excess of PCWP = pulmonary capillary wedge pressure the elevation of PAWP (10,11). PAWP = pulmonary artery Definitions and Terminology Finally, these changes might lead wedge pressure to pulmonary vascular disease, fi PDE5 = phosphodiesterase The current hemodynamic de nition of PH-LHD combines a increased right ventricle (RV) type 5 afterload, and RV failure (Fig. 1). mean pulmonary artery pressure (mPAP) 25 mm Hg, PH = pulmonary a pulmonary artery wedge pressure (PAWP) >15 mm Hg, and Heterogeneity in terms of hypertension fi a normal or reduced cardiac output (CO) (9).Thetrans- de nition and terminology. PVD = pulmonary vascular pulmonary pressure gradient (TPG) (i.e., the difference Many legitimate attempts to disease between mPAP and PAWP) is commonly used to distinguish distinguish the mechanical from PVR = pulmonary vascular “passive” PH (TPG 12 mm Hg) from “reactive” PH (TPG the active component have been resistance >12 mm Hg). However, this definition and the associated made, by using different terms RCT = randomized controlled terminology have been unsatisfactory, to such extent that “out- such as passive versus reactive, trial of-proportion” PH-LHD has been often used to characterize fixed versus irreversible, unre- RHC = right heart a subset of patients with significant changes in the pulmonary sponsive versus responsive, and catheterization circulation. out of proportion versus propor- RV = right ventricle There are several reasons why we need a simple and tionate (1). These lead to unclear sGC = soluble guanylate workable definition for “out-of-proportion” PH in the definitions, especially because the cyclase context of LHD. current definition of “passive” SV = stroke volume “ ” Understanding the determinants of PH-LHD. Irres- versus reactive PH (9) has been TPG = transpulmonary pective of the origin of left heart disease, the first event leading progressively substituted by “out- gradient fi ” to PH is a passive backward transmission of lling pressures, of-proportion PH. This term VO2 = oxygen consumption mainly driven by left ventricular (LV) diastolic function has never been defined by any clear hemodynamic criteria, although it has been assumed that PH develops “out-of-proportion” to the raised PAWP. monitoring boards of Centocor, Forest, Gilead, GlaxoSmithKline, Jannsens, Nycomed/ Takeda, and Stromedix; has served on teleconferences of American Institute for Areas of confusion with PAH/pre-capillary PH. The lack Research, Axon, Grey Healthcare, and Sudler and Hennessey; has received speaking fees of a clear definition of “out-of-proportion” PH causes from Bayer, Forest, GlaxoSmithKline, Nycomed/Takeda CME programs for CME confusion with PAH. As a result, it might encourage Incite, Foundation for Improving Patient Care, Inova Health System, MedScape/ WebMD, National Association of Colleges and Employers, National Conference on physicians to treat some patients suffering from PH-LHD Medical Education, Peer Voice, Projects in Knowledge, St. John’s Hospital, St. Mary’s with PAH-approved therapies, despite the lack of evidence Hospital, University of Illinois/Chicago, University of Texas Southwestern, UpToDate, (9). In contrast, complex surgery (transplantation, LV assist and Wayne State University; and has received royalties from Informa. Dr. Simonneau has relationships with Eli Lilly, Actelion, Bayer, Novartis, Pfizer, and GlaxoSmithKline. device, valve surgery) might be considered too high risk Dr. Wells has received consultancy fees and fees for delivering lectures from Actelion. because of significant PH. Finally, vasoreactivity testing in Dr. Seeger has received speaker fees from Pfizer and Bayer HealthCare; and is a PH-LHD is often performed without clear guidelines about consultant for Bayer Pharma AG. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. which vasodilator should be used to perform testing and the Manuscript received October 12, 2013; accepted October 22, 2013. expected changes in pulmonary vascular resistance (PVR) D102 Vachiéry et al. JACC Vol. 62, No. 25, Suppl D, 2013 Pulmonary Hypertension Due to Left Heart Diseases December 24, 2013:D100–8

Table 1 Prevalence of PH in HF (Selected Studies)

First Author % Measurable Prevalence Corrected (Ref. #) n Type Deﬁnition of PH Population EF TRV of PH Prevalence of PH Bursi (8)* 1,049 Echocardiography TTGþRAP Epidemiological 91% 79% 72% 35 mm Hg Damy (51)* 1,380 Echocardiography TTG 35 mm Hg Hull HF clinic 26% preserved 26% 25% 7% Lam (7)y 244 Echocardiography TTGþRAP Olmsted County Only EF 50% 83% 83% 69% 35 mm Hg HF survey Leung (52)y 455 Invasive mPAP 25 Cath lab 52% LVEF 15% Robbins (5)y 122 Invasive mPAP 25 PH reference Mixed NA 23% 20% PAWP >15 center

See text for references. *All-comer patients with heart failure (HF); ypatients from HF/pulmonary hypertension (PH) specialized centers. Cath lab ¼ catheterization laboratory; EF ¼ ejection fraction; mPAP ¼ mean pulmonary artery pressure; PAWP ¼ pulmonary artery wedge pressure; RAP ¼ right atrial pressure (estimated from the inferior vena cava); TRV ¼ tricuspid regurgitant jet velocity; TTG ¼ transtricuspid gradient. and/or TPG. As a consequence this might lead to the 2) it must be less dependent on (or as independent as inappropriate use of PAH drug therapies. possible of) the change in PAWP; 3) it should be minimally Identification of different hemodynamic presentations. influenced by changes in blood flow and stroke volume (SV); A simple way to clarify the definition would be to rely on and 4) it should reflect changes in compliance and take a simple description of the potential hemodynamic presen- into account the distensibility of the pulmonary arteries. tations, as follows: 1) an elevated PAWP, but no significant Pulmonary vascular resistance, TPG, and the diastolic change in the pulmonary circulation (i.e., absence of pressure difference (DPD) (defined as diastolic PAPdmean pulmonary vascular disease or vascular remodeling) (PVD); PAWP) have the advantage of being easily obtained from 2) an elevated PAWP, with PVD; 3) a previously elevated RHC. They might not all be suitable to describe the pre- but meanwhile normalized PAWP, with persistence of capillary component of PH-LHD. The PVR is commonly PVD. The latter can be found in patients who have used in clinical practice. It has the disadvantage of being undergone forced diuresis in the presence of HF-pEF, atrial a composite variable, with an interdependent numerator and fibrillation and corrected valve disease. denominator (changes in flow influence pressure in the A key issue is how to best describe “pulmonary vascular pulmonary circulation). Therefore, it is highly sensitive to disease” or the “pre-capillary remodeling component” (and changes in both flow and filling pressures but does not possibly also a “post-capillary remodeling component”)ofan reflect changes in the pulmonary circulation at rest (11,15). initially purely passive phenomenon. In other words, how At a constant SV, an increase of PAWP has a more can we define a change in the pulmonary circulation that pronounced effect on systolic PAP and mPAP than diastolic is not in relation with the increase in PAWP and that is PAP (Fig. 2). This impact is even greater when SV measurable by RHC? Some key characteristics of such increases. As a result, TPG is influenced by all determinants variables include the following: 1) it should reflect changes of mPAP, including flow, resistance, and left heart filling of the pulmonary circulation and be a clear marker of PVD; pressure (11,15). In contrast, diastolic PAP when compared with systolic pulmonary artery pressure and mPAP is less influenced by PAWP, which might be explained by a lower sensitivity to vessel distensibility (10,11). This is illustrated by a less steep slope of the diastolic pulmonary artery pressure/PAWP line compared with the same relationship with systolic and mPAP at any level of SV (Fig. 2). When reported as pressure differences, DPD seems to best approach the characteristics required to determine PVD. In normal subjects, DPD lies in the 1-mm Hg to 3-mm Hg range, and in patients evaluated for cardiac disease (excluding shunts), the DPD remains 5 mm Hg in most cases (11,16). In a retrospective study, 406 patients with PVR 200 dynes/s/cm 5 were compared with 406 subjects presenting with PVR <200 dynes/s/cm 5. Patients were catheterized for evaluation of HF (n ¼ 367), valvular regurgitation (n ¼ 177), valvular stenosis (n ¼ 244), and possible Mechanism of Pulmonary Hypertension Due to Figure 1 ¼ Left Heart Disease constrictive/restrictive physiology (n 24) (16). In patients with PVR <200, PAPd and PAWP were similar, and JACC Vol. 62, No. 25, Suppl D, 2013 Vachiéry et al. D103 December 24, 2013:D100–8 Pulmonary Hypertension Due to Left Heart Diseases

Figure 2 Effect of PAWP and SV on Pulmonary Pressures

Pulmonary artery wedge pressure (PAWP) is transmitted in a 1:1 ratio to diastolic pulmonary artery pressure (dPpa) and PAWP, both pressures being within a 3-mm Hg range. If PAWP is directly transmitted to dPpa, there is a non-proportional increase in systolic (sPpa) and mean (mPpa) pulmonary artery pressure, depending on (SV) (left graph). The transpulmonary gradient (TPG) increases, but the dPpa-PAWP gradient is independent of both PAWP and SV (right graph). If dPpa increases more than PAWP, the TPG increases. The dPpa-Ppw gradient increases linearly but slightly with PAWP but is independent of SV. Reproduced with permission from Naeije et al. (11).

DPD remained 5 mm Hg in 94% of the cases. When limitations, including its retrospective nature, a bias in the PVR increased, approximately one-half had DPD >5mmHg; population with patients presenting a negative DPD, and however, a PAP 40 mm Hg was associated with an the unknown number of patients with a TPG <12 mm Hg increased DPD >5mmHgin<20%. but a DPD 7mmHg. This suggests that, when PH develops in heart diseases, Recommendations. The term “out-of-proportion” PH DPD increases >5 mm Hg in one-half of the cases and that should be abandoned in patients with post-capillary hemo- the increase in PAPd is somehow unrelated to the changes dynamic status, while recognizing the importance of in PAWP. Therefore, the DPD might be seen as a potential describing the presence of a pre-capillary component in marker of changes in the pulmonary circulation. some cases of PH-LHD, without further implications in TheroleoftheDPDinpredictingoutcomehasrecently terms of reactivity, remodeling, or changes in the pulmonary been explored in a large cohort of patients referred to circulation that cannot be assessed clinically. a single center for PH evaluation (17). In this retrospective We propose 2 types of PH-LHD, on the basis of the study on 3,107 patients, the population was separated level of the DPD: “isolated post-capillary PH” (PAWP according to the current definition of “passive” versus >15 mm Hg and DPD <7 mm Hg) and “combined post- “reactive” PH, the latter being referred to as “out-of- capillary PH and pre-capillary PH” (PAWP >15 mm Hg proportion” PH. Pulmonary hypertension due to LHD and DPD 7 mm Hg. Cutoff values and the definition are accounted for 35% of all cases of PH. More than one-half shown in Table 2. (55%) presented passive with PH-LHD, and 45% had Gaps in evidence. Although based on a strong patho- “reactive” PH. By receiver-operating characteristic analysis, physiological reasoning, the respective value of the TPG aDPD7 mm Hg has been identified to independently and the DPD should be further explored, including their predict outcome. The authors subsequently defined “out- role in predicting outcome. Multicenter data collection of-proportion” PH as a TPG >12 mm Hg and a DPD and analysis of established databases might be helpful to >7 mm Hg, which represented 16% of the patients with address the issue in an acceptable timeframe. A joint PH-LHD. Patients with a TPG >12 mm Hg and a initiative with the International Society for Heart and DPD 7 mm Hg had a worse median survival (78 months) Lung Transplantation might help to establish a common compared with patients who presented with a DPD nomenclature and develop this in the specificcontextof <7mmHg(101months;p¼ 0.010). Survival in patients heart transplantation and LV assist devices. This pop- with an elevated TPG and DPD was similar to that re- ulation is of interest, because patients with advanced HF ported for PAH (class I) patients. In addition, an elevated are at much higher risk of presenting with a pre-capillary DPD was associated with more advanced pulmonary component of their PH. vascular remodeling in a small sample of patients who The standardization and the relevance of testing the had lung biopsies. However, this study has important vasoreactivity of PH-LHD could be addressed in the context D104 Vachiéry et al. JACC Vol. 62, No. 25, Suppl D, 2013 Pulmonary Hypertension Due to Left Heart Diseases December 24, 2013:D100–8

Table 2 Proposed Definition and Classification of PH-LHD impaired NO-dependent vasodilation (24). In addition, direct LV myocardial effects might be more important Terminology PAWP Diastolic PAP – PAWP in PH-LHD. For example, endothelin 1 has positive Isolated post-capillary PH >15 mm Hg <7mmHg myocardial inotropic and lusitropic effects that might be Combined post-capillary >15 mm Hg 7mmHg blocked by receptor antagonists. In contrast, inhibition of and pre-capillary PH phosphodiesterase type 5 (PDE5) attenuates LV remodeling Hemodynamic measurements are taken under resting conditions. LHD ¼ left heart disease; other abbreviations as in Table 1. and improves vascular, renal, and neuroendocrine function (25–27). The rationale to use PAH therapies in PH-LHD of the new nomenclature and be included in the previously has been supported by acute or short-term studies using described proposals. In line with the previous comments, prostanoids, endothelin receptor antagonists, and PDE5 this topic is of critical importance in the context of heart inhibitors. Most of these studies consistently reported transplantation and mechanical circulatory support. Its improvements in hemodynamic status, exercise capacity, and relevance in other fields of cardiology (i.e., valvular heart symptoms (28). However, the methodology (small sample disease, management of HF) is unknown. size, single-center, unclear or no randomization process) The importance of fluid loading and exercise in uncov- does not provide enough evidence to support the use of ering PH due to LHD requires standardization and vali- these drugs in clinical management of patients. dation. Recent advances suggest that these tools might play Clinical trials with prostanoids and endothelin-1 antagonists. a role in the differential diagnosis of PH, which has been Several randomized controlled trials (RCTs) (Table 3)have discussed elsewhere and is beyond the scope of this been conducted with PAH-approved therapies (bosentan manuscript. [29,30], epoprostenol [31]) or drugs acting on a pathway The importance of the failing RV in the context of PH- involved in the development of PH (darusentan [32,33]). LHD should be further explored. We believe that there These studies have the following in common: 1) almost all might be a spectrum of clinical phenotypes in PH-LHD studies were performed in HF with systolic dysfunction, that might evolve from one to the other, from isolated leading to disappointing results; 2) few required optimization post-capillary PH with little effect on the RV to more of patient volume status before initiating therapy, which advanced disease where the failing RV is the key determi- potentially led to drug-induced adverse events; 3) patients with nant of outcome. valvular heart diseases were excluded; and 4) none of the studies stratified patients for the presence of PH, although some re- Treatment Insights ported on invasive hemodynamic status (31,33).Theresultsof these trials in HF were all negative (Table 3). Two RCTS The primary goal of therapy of PH-LHD must be to (with epoprostenol [31] and high doses of bosentan [29])had improve global management of the underlying condition to be terminated before completion, due to either a trend before considering specific measures to treat PH. This toward higher mortality rate (31) or increased side effects (29) includes repair of valvular heart disease and aggressive observed in the treated group. therapy for HF with reduced systolic function (18). Some Two RCTs assessed the safety and efficacy of bosentan on patients might also benefit from nonspecific vasodilators outcome in patients with systolic dysfunction (29,30). The such as nitrates and hydralazine, although evidence sup- REACH 1 (Research on Endothelin Antagonism in porting this strategy is limited (18). In severe HF, opti- Chronic Heart Failure) trial (29) was interrupted due to an mizing volume status is of critical importance and might elevated rate of liver function test abnormalities, likely due to require invasive monitoring (19). In addition, the implan- the high dose of bosentan used in the trial (500 mg bid). tation of an LV assist device has been shown to lower The second trial failed to demonstrate a benefit on mortality pulmonary pressures through LV unloading without and hospital stay (30). increasing the risk of post-implantation RV failure (20,21). Two RCTs assessed the safety and efficacy of darusentan Risk factors for cardiovascular diseases and features of the on invasive hemodynamic status (33) and outcome (32) in metabolic syndrome should be controlled (18). Concomitant HF with systolic dysfunction. Although the study drug disorders leading to PH should be identified and treated, seemed to increase CO but not pulmonary capillary wedge including chronic obstructive pulmonary disease, sleep apnea pressure (PCWP) (33), it failed to reach the primary syndrome, and pulmonary embolism. In contrast, there is no endpoint of decreasing clinical events and improving strong evidence-based recommendation for the treatment magnetic resonance imaging-derived indexes of LV func- for HF-pEF (18). tion (32). The potential use of PAH therapies in PH-LHD is based Clinical trials with PDE5 inhibitors. Before their use as on a sound pathobiological rationale. In patients with HF, part of the treatment regimen of HF, PDE5 inhibitors had endothelial dysfunction has been proposed as a cause of PH been used to treat erectile dysfunction, with an encouraging and hence as a target for treatment (14), supported by the safety profile (34). Acutely, sildenafil 25 to 50 mg has presence of increased endothelin 1 activity (22,23) and been shown to decrease PVR in the pre-transplant setting JACC Vol. 62, No. 25, Suppl D, 2013 Vachiéry et al. D105 December 24, 2013:D100–8 Pulmonary Hypertension Due to Left Heart Diseases

Table 3 Completed RCTs Using Prostanoids and Endothelin Receptor Antagonists in HF

Drug/Author Primary Year Study Acronym (Ref. #) Patients Design Endpoint Results Epoprostenol FIRST (31) n ¼ 471 1:1 randomization Survival Early termination (trend to decreased Califf 1996 Severe HF event-driven survival in treated group) mean dose 4 ng/kg/min Bosentan REACH-1 (29) n ¼ 174 2:1 randomization Change in clinical state Early termination (drug-induced ﬂuid Packer Severe HF 26-week duration retention in the treated group) 500 mg bid Kalra 2002 ENABLE (30) n ¼ 1,613 1:1 randomization Mortality þ hospital stays No effect Severe HF 18-month duration 125 mg bid Darusentan HEAT (33) n ¼ 179 3:1 randomization Hemodynamic (changes Increased CO Lüscher 2002 NYHA III 3-week duration in PAWP/CO) No change in PAWP doses of 30, 100, 300 mg Anand 2004 EARTH (32) n ¼ 642 5:1 randomization LV changes by MRI þ No effect NYHA II–IV 6-month duration clinical events doses 10, 25, 50, 100, 300 mg

See text for references. CO ¼ cardiac output; HF ¼ heart failure; LV ¼ left ventricular; MRI ¼ magnetic resonance imaging; NYHA ¼ New York Heart Association functional class; PAWP ¼ pulmonary artery wedge pressure; RCT ¼ randomized controlled trial.

(35–37), to improve hemodynamic variables at rest (34,38) of NO (44). Its vasodilatory effects might be associated with and exercise (38) and to improve peak oxygen consumption anti-fibrotic, anti-proliferative, and anti-inflammatory – fi (VO2) (34,38 40). The vasodilator capacities of sildena l effects (44). Riociguat has recently been shown to improve seem to be superior to prostaglandin E1. In a case-controlled 6-min walking distance in PAH (45) and chronic throm- prospective study, 22 patients with PVR >200 dynes/s/cm 5 boembolic pulmonary hypertension (46). received a single dose of 40 mg of sildenafil, compared In a multicentric placebo-controlled trial (47), 201 with 24 matched control subjects (41). Acute administra- patients with PH due to systolic HF were randomized in 4 tion of sildenafil was associated with a greater improvement arms comparing 3 doses of riociguat (0.5, 1, and 2 mg tid) in PVR and compliance compared with prostaglandin E1. with placebo during 16 weeks. No effect on the primary Chronic administration of sildenafil has also been shown endpoint (a change in mPAP after 16 weeks) was observed to improve pulmonary hemodynamic status before trans- at any dose of riociguat compared with placebo. plantation (37). A proof-of concept study to test the effects of riociguat in In a placebo-controlled study performed in patients with patients with PH associated with diastolic dysfunction decreased LVEF, sildenafil has been shown to improve (NCT01172756) has recently been completed, but results hemodynamic status and exercise tolerance after 12 weeks at are not yet available (Table 4). a dose of 25 to 75 mg tid (38). The 20% decrease in PVR HF with preserved EF. Heart failure with preserved ejec- was mostly accounted for by an improvement in CO, tion fraction (HF-pEF) is a common cause of PH (1,2,7,9), whereas mPAP remained unchanged. Similar improvements and the latter is also associated with a worse outcome (7).In in exercise tolerance were sustained up to 6 months with contrast with systolic HF, exposure of patients with HF- sildenafil 50 mg tid (42). pEF to vasodilators is associated with a greater blood pres- Although encouraging, the results of these RCTs should sure reduction, a modest increase in CO, and a greater be treated with caution, because the studies were single- likelihood to decrease SV (48). Thus, there are fundamental center and used a range of doses of sildenafil (from 25 to differences in the 2 HF phenotypes, and this suggests 75 mg tid) that were consistently higher than the doses that more pathophysiologically targeted therapies are needed approved to treat PAH. in this setting. Therefore, it is anticipated that PAH ther- Two multicenter clinical trials in PH-LHD are currently apies might have a different effect in patients with HF-pEF underway (Table 4), with sildenafil(NCT01616381) (43) compared with other forms of HF. and tadalafil(NCT01910389). Although these trials plan Data on the use of PAH therapies in the context of HF- to include a well-defined population with PH due to systolic pEF with or without PH are scarce. HF, the absence of RHC validation of PH might represent The effects of sildenafil on exercise capacity and a significant limitation. clinical status have been studied in a recently published pha- Guanylate cyclase stimulators. Riociguat is a novel soluble se II trial (49). A total of 216 patients with HF-pEF guanylate cyclase (sGC) stimulator that sensitizes sGC to were randomized to receive sildenafil(n¼ 113) or placebo endogenous NO and directly stimulates sGC independently (n ¼ 103) administered orally at 20 mg tid for 12 weeks, D106 Vachiéry et al. JACC Vol. 62, No. 25, Suppl D, 2013 Pulmonary Hypertension Due to Left Heart Diseases December 24, 2013:D100–8

Table 4 Current Phase II/III Placebo-Controlled Randomized Trials in PH With LHD

Drug Trial (Ref. #) Primary Secondary Trial Number n Start End Duration Endpoint Endpoints HF With Reduced EF Riociguat 201 Published (50) 16 W Mean PAP AE, PK, PVR, NT-pro BNP LEPHT (47) (BAY63-2521) Tadalaﬁl 2102 Up to 54 months Time to CV death or 1st HF Biomarkers, exercise PITCH-HF hospital stay capacity, QoL (NCT01910389) Sildenaﬁl 210 9/2012 6/2014 24 W Patient Global Assessment Qol, Kansas City Sil-HF (43) and 6MWT questionnaire, AE (NCT01616381) HF With Preserved EF Riociguat 48 Recruitment completed 16 W mPAP AE, PK, PVR, NT-pro BNP DILATE (BAY63-2521)

Available from ClinicalTrials.gov; accessed July 27, 2013. AE ¼ adverse events; CV ¼ cardiovascular; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide; PK ¼ pharmacokinetics; PVR ¼ pulmonary vascular resistance; QoL ¼ quality of life; 6MWT ¼ 6-min walk test; other abbreviations as in Table 1.

followed by 60 mg tid for 12 weeks. In line with previous patients with isolated post-capillary PH and patients with RCTs in HF due to reduced EF, there was no stratification for combined post-capillary with a pre-capillary component. PH. After 24 weeks on a therapy regimen, there was no The latter is felt to be the population of interest for future difference between groups in the primary endpoint, the studies. Finally, the question of the most appropriate change in peak VO2. In addition, there was no difference in endpoint to assess for any intervention in the setting of other relevant secondary endpoints, including outcome PH-LHD is critical. It is acceptable and necessary for measurements. a proof-of-concept to assess safety first together with In 1 placebo-controlled study that was performed in evidence of an efficacy signal based on a measurable clin- patients with PH induced by HF-pEF, sildenafil 50 mg tid ical, exercise capacity, and/or hemodynamic improvement improved exercise capacity and hemodynamic status after 6 only. This would prompt larger, event-driven RCT with months, with beneficial effects up to 1 year (50). robust endpoints in event-driven trials for regulatory Recommendations. Vasoreactivity testing in PH-LHD approval. should not be performed with selective pulmonary vasodi- Recommendations for RCTs. POPULATION. Patients with lators (e.g., IV prostacyclin) in patients with PCWP PH due to HF-pEF and PH due to HF with reduced EF >15 mm Hg, due to the risk of increased PCWP and should be studied separately. Patients with uncorrected pulmonary edema. The role of vasoreactivity testing remains valvular heart diseases should be excluded. Patients with to be explored further. corrected valvular heart diseases might be studied as well. There is no new evidence supporting the use of PAH Patients should be on optimal regimens of HF therapy therapies in PH-LHD, due to the absence of studies and fluid balance before randomization. specifically stratifying patients for PH and/or targeting this Patients with combined post-capillary and pre-capillary specific condition. PH should represent the target population. Recruitment RCTs in PH due to left heart diseases. The history of should be based on RHC, although pre-screening by trials to treat PH-LHD has yielded little evidence of echocardiography might be considered. clinical efficacy. In addition, much of the available evi- ENDPOINT. A proof-of-concept study, including a placebo dence applies to HF (in which many drugs efficacious for arm, should be conducted first to assess safety and record an PAH have failed) and without specific focus of the efficacy signal (preferably hemodynamic and/or exercise subgroup of patients with PH-LHD (for which data are capacity assessment). The latter could be either a change in fi fi scarce). Many reasons might explain why this eld seems DPD and/or peak VO2 or ventilatory ef ciency and/or to be stagnant. Firstly, the population of HF is more increase in 6-min walking distance. heterogeneous than in PAH and more male, with older The population should ideally be similar in proof- patients, and extensive background therapy resulting in of-concept and phase III studies (i.e., identified by complex polypharmacy. Secondly, the target population invasive hemodynamic status, performed in the same has not been properly defined. If all patients meeting clinical setting in patients on a regiment of optimized the definition of PH-LHD were to be included in a trial, and stable therapy), although this approach might be heterogeneity would be further increased by mixing challenging. JACC Vol. 62, No. 25, Suppl D, 2013 Vachiéry et al. D107 December 24, 2013:D100–8 Pulmonary Hypertension Due to Left Heart Diseases

An outcome study should then be conducted, and 9. Galiè N, Hoeper MM, Humbert M, et al., ESC Committee for a composite endpoint should be considered (a combination Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and of cardiovascular mortality, hospital stay for worsening HF, Treatment of Pulmonary Hypertension of the European Society of and/or PH). Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Trans- CHALLENGES. An invasive approach for recruiting in these plantation (ISHLT). Eur Heart J 2009;30:2493–537. trials is challenging, because many HF patients are not 10. Harvey RM, Enson Y, Ferrer MI. A reconsideration of the origins of – necessarily seen in highly specialized PH centers. It is of pulmonary hypertension. Chest 1971;59:82 94. 11. Naeije R, Vachiery JL, Yerly P, Vanderpool R. The transpulmonary critical importance to properly characterize patients who pressure gradient for the diagnosis of pulmonary vascular disease. Eur might best benefit from the intervention. Respir J 2013;41:217–23. In addition, invasive hemodynamic assessments are not 12. Magne J, Lancellotti P, Piérard LA. Exercise pulmonary hypertension in asymptomatic degenerative mitral regurgitation. Circulation 2010; part of standard of care in HF irrespective of EF, and right 122:33–41. heart catheterization is even discouraged (18,19). 13. Tedford RJ, Hassoun PM, Mathai SC, et al. Pulmonary capillary wedge pressure augments right ventricular pulsatile loading. Circulation Recruitment might be delayed by the increasing off-label – fi 2012;125:289 97. use of PDE5 inhibitors, the dif culties in performing 14. Moraes DL, Colucci WS, Givertz MM. 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Pulmonary Hypertension in Chronic Lung Diseases

Werner Seeger, MD,* Yochai Adir, MD,y Joan Albert Barberà, MD,z Hunter Champion, MD, PHD,x John Gerard Coghlan, MD,k Vincent Cottin, MD,{ Teresa De Marco, MD,# Nazzareno Galiè, MD,** Stefano Ghio, MD,yy Simon Gibbs, MD,zz Fernando J. Martinez, MD,xx Marc J. Semigran, MD,kk Gerald Simonneau, MD,{{ Athol U. Wells, MD,## Jean-Luc Vachiéry, MD*** Giessen/Bad Nauheim and Brussels, Germany; Haifa, Israel; Barcelona, Spain; Pittsburgh, Pennsylvania; London, United Kingdom; Lyon and Clamart, France; San Francisco, California; Bologna and Pavia, Italy; Ann Arbor, Michigan; and Boston, Massachusetts

Chronic obstructive lung disease (COPD) and diffuse parenchymal lung diseases (DPLD), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis, are associated with a high incidence of pulmonary hypertension (PH), which is linked with exercise limitation and a worse prognosis. Patients with combined pulmonary fibrosis and emphysema (CPFE) are particularly prone to the development of PH. Echocardiography and right heart catheterization are the principal modalities for the diagnosis of COPD and DPLD. For discrimination between group 1 PH patients with concomitant respiratory abnormalities and group 3 PH patients (PH caused by lung disease), patients should be transferred to a center with expertise in both PH and lung diseases for comprehensive evaluation. The task force encompassing the authors of this article provided criteria for this discrimination and suggested using the following definitions for group 3 patients, as exemplified for COPD, IPF, and CPFE: COPD/IPF/CPFE without PH (mean pulmonary artery pressure [mPAP] <25 mm Hg); COPD/IPF/CPFE with PH (mPAP 25 mm Hg); PH-COPD, PH-IPF, and PH-CPFE); COPD/IPF/CPFE with severe PH (mPAP 35 mm Hg or mPAP 25 mm Hg with low cardiac index [CI <2.0 l/min/m2]; severe PH-COPD, severe PH-IPF, and severe PH-CPFE). The “severe PH group” includes only a minority of chronic lung disease patients who are suspected of having strong general vascular abnormalities (remodeling) accompanying the parenchymal disease and with evidence of an exhausted circulatory reserve rather than an exhausted ventilatory reserve underlying the limitation of exercise capacity. Exertional dyspnea disproportionate to pulmonary function tests, low carbon monoxide diffusion capacity, and rapid decline of arterial oxygenation upon exercise are typical clinical features of this subgroup with poor prognosis. Studies evaluating the effect of pulmonary arterial hypertension drugs currently not approved for group 3 PH patients should focus on this severe PH group, and for the time being, these patients should be transferred to expert centers for individualized patient care. (J Am Coll Cardiol 2013;62:D109–16) ª 2013 by the American College of Cardiology Foundation

From the *University of Giessen and Marburg Lung Center (UGMLC), member of of Cardiology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. Dr. the German Center for Lung Research, Max-Planck Institute for Heart and Lung Seeger has received speaker fees from Pfizer and Bayer HealthCare; and consultant fees Research, Giessen/Bad Nauheim, Germany; yPulmonary Division, Lady Davis Car- from Bayer Pharma AG. Dr. Barberà has received honoraria and consultancy fees from mel Medical Center, Faculty of Medicine, The Technion, Institute of Technology, Actelion, Bayer, GlaxoSmithKline, and Pfizer; and his institution has received research Haifa, Israel; zHospital Clínic-IDIBAPS, University of Barcelona, Network Center of grants from Actelion, Bayer, GlaxoSmithKline, Novartis, and Pfizer. Dr. Champion has Biomedical Research on Respiratory Diseases, Barcelona, Spain; xUPMC Montefiore served as a consultant to Bayer, Gilead, and Pfizer; and has received research funding Hospital, Pittsburgh, Pennsylvania; kDepartment of Cardiology, Royal Free Hospital, from Aires Pharmaceuticals. Dr. Coghlan has received consultancy and lecture fees and London, United Kingdom; {Hospices civils de Lyon, Louis Pradel Hospital, honoraria from Actelion, GlaxoSmithKline, Bayer, and United Therapeutics; and Department of Respiratory Diseases, National Reference Center for Rare Pulmonary equipment support from Actelion. Dr. Cottin has received speaker’s fees, funding for Diseases, Regional Competence Center for Severe Pulmonary Arterial Hypertension, meetings, a grant to his institution for participation in trials, and fees as an advisory board Claude Bernard University Lyon 1, INRA, Lyon, France; #University of California member and consultant from Actelion, GlaxoSmithKline, and Pfizer. Dr. De Marco has San Francisco, San Francisco, California; **Department of Experimental, Diagnostic, received honoraria and consultancy fees from Actelion and Gilead; and has received and Specialty Medicine, DIMES, Bologna University Hospital, Bologna, Italy; research grants from United Therapeutics and Novartis. Dr. Galiè has served on advisory yyDivisione di Cardiologia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; boards of Eli Lilly, Actelion, Pfizer, Bayer-Schering, GlaxoSmithKline, and Novartis; zzNational Heart and Lung Institute, Imperial College London, and Department of has received speaker’s fees from Eli Lilly, Pfizer, Bayer-Schering, and GlaxoSmithKline; Cardiology, National Pulmonary Hypertension Service, Hammersmith Hospital, and his institution has received grants from Actelion, Pfizer, Bayer-Schering, Glaxo- London, United Kingdom; xxDivision of Pulmonary and Critical Care, University of SmithKline, and Novartis. Dr. Ghio has consulted for Actelion and Pfizer. Dr. Gibbs has Michigan Medical Center, Ann Arbor, Michigan; kkHeart Failure and Cardiac consulted for Gilead, Novartis, and Actelion; has served as an advisory board member Transplantation Center, Massachusetts General Hospital, Boston, Massachusetts; with and received speaker’s fees from Actelion, Bayer, GlaxoSmithKline, Pfizer, and {{Centre National de Référence des Maladies Vasculaires Pulmonaires, Université United Therapeutics; and has received research funding from United Therapeutics. Dr. Paris-Sud, Hôpital Antoine Béclère, Clamart, France; ##Royal Brompton and Martinez has served on advisory boards of Amgen, Boehringer Ingelheim, Carden Harefield NHS Foundation Trust, London, United Kingdom; and the ***Department Jennings, Forest Pharmaceuticals, GlaxoSmithKline, Ikaria, Jannsens, MedImmune, D110 Seeger et al. JACC Vol. 62, No. 25, Suppl D, 2013 Pulmonary Hypertension in Chronic Lung Diseases December 24, 2013:D109–16

Epidemiology and Clinical Abbreviations predictor of mortality in COPD, with an inverse correla- and Acronyms Relevance of Pulmonary tion between mPAP and/or pulmonary vascular resistance Hypertension in Lung (PVR) values and survival (2,6,7). A 5-year survival rate of 6MWD = 6-min walk Disease distance only 36% was reported for COPD patients with mPAP values >25 mm Hg, with pulmonary hemodynamics being BNP = brain natriuretic Chronic obstructive pulmonary a far stronger predictor of survival than the forced expira- peptide disease. The prevalence of pul- tory volume in 1 s (FEV1) or gas exchange variables (7).In CI = cardiac index monary hypertension (PH) in addition, enlarged pulmonary artery diameter, as detected COPD = chronic obstructive chronic obstructive pulmonary by computed tomography (CT) scan, predicts hospitaliza- pulmonary disease disease (COPD) depends on the tion caused by acute COPD exacerbation (8). CPFE = combined pulmonary severity of the disease and the fibrosis and emphysema fi de nition of PH (see discussion Idiopathic pulmonary fibrosis and diffuse parenchymal CT = computed tomography in the following text). Several lung disease. In idiopathic pulmonary fibrosis (IPF), which DLCO = diffusing capacity of studies in patients with the has a survival range of only 2.5 to 3.5 years, mPAP values of lung for carbon monoxide previous GOLD (Global Initia- >25 mm Hg were reported in 8.1% and 14.9% of patients, DPLD = diffuse parenchymal tive for Chronic Obstructive respectively, upon initial workup (9,10). Higher percentages lung disease Lung Disease) stage IV showed are found in advanced (30% to 50%) and end-stage (>60%) ERA = endothelin receptor that up to 90% of these patients – antagonist IPF cases (11 13). Among these, a small percentage may have a mean pulmonary artery present with mPAP values >40 mm Hg (w9% [14]). There FEV1 = forced expiratory pressure (mPAP) of >20 mm Hg, volume in 1 s is only a poor or even no correlation between PH severity and with most ranging between 20 lung function impairment (14) or high-resolution CT FVC = forced vital capacity w and 35 mm Hg and 3% to 5% fibrosis score (15). Increased dyspnea, deterioration of gas IPAH = idiopathic pulmonary patients with mPAP >35 to 40 arterial hypertension exchange at rest, low capacity of lung to diffuse carbon mm Hg (1,2). The morphological monoxide (DLCO) values, rapid desaturation upon exercise, IPF = idiopathic pulmonary appearance of vascular lesions in fibrosis high brain natriuretic peptide (BNP) levels, gross right heart COPD patients correlates with mPAP = mean pulmonary dilation on chest radiography, and limitation of exercise artery pressure the severity of PH, which is capacity caused by circulatory impairment have been linked to similar to idiopathic pulmonary PH development in IPF (12,16,17).Doppler-defined PH PaCO2 = partial pressure of carbon dioxide in arterial arterial hypertension (IPAH) in (systolic PAP >50 mm Hg [16]) and even invasive mPAP blood severe cases (3).Evenundermod- values of >17 mm Hg (9) were associated with impaired erate exercise conditions, COPD PaO2 = partial pressure of survival in IPF, with mPAP and forced vital capacity (FVC) oxygen in arterial blood patients typically show a rapid being independent predictors of survival (10).Rapid PH = pulmonary further rise in mPAP values, indi- progression of PH was reported in late stage diffuse paren- hypertension cating loss of lung vascular disten- chymal lung disease (DPLD)/IPF patients (13). In some PH-SA = pulmonary sibility and/or vessel recruitment studies, the prognosis of PH in lung fibrosis is not linked to the hypertension in sarcoidosis capability (4).TherateofPH mPAP values but to PVR (18) or cardiac index (CI), with CI PVR = pulmonary vascular progression in COPD is nor- values <2.4 l/min/m2 being correlated with survival of only resistance < mally slow (an increase of 1 a few months (19). RHC = right heart mm Hg per year [5]). Never- Combined pulmonary fibrosis and emphysema and other catheterization theless, the presence of (even lung diseases. Combined pulmonary fibrosis and emphy- moderate) PH is a strong sema (CPFE) patients are particularly prone to PH development, with estimates approaching 30% to 50% (19,20). Here, severe PH and markedly impaired DLCO may Merck, Nycomed/Takeda, Pfizer, and Vertex; has participated on steering committees or data and safety monitoring boards of Centocor, Forest, Gilead, GlaxoSmithKline, contrast with normal or mildly subnormal lung volumes and Jannsens, Nycomed/Takeda, and Stromedix; has participated in advisory teleconfer- absence of airflow obstruction. PH apparently contributes to ences with American Institute for Research, Axon, Grey Healthcare, and Sudler and the functional profile of CPFE (severe dyspnea, severely Hennessey; has served as a speaker for Bayer, Forest, GlaxoSmithKline, Nycomed and Takeda; has consulted in continuing medical education programs for Incite, Foun- impairment of gas transfer, and hypoxemia upon exercise) dation for Improving Patient Care, Inova Health System, MedScape/WebMD, and is associated with poor survival (19–21). At right heart NACE, NCME, Peer Voice, Projects in Knowledge, St. John’s Hospital, St. Mary’s catheterization (RHC), PH was hemodynamically severe in Hospital, University of Illinois/Chicago, University of Texas Southwestern, UpTo- > Date, and Wayne State University; and has received royalties from Informa. Dr. approximately one-half of the patients (mPAP 35 mm Hg Simonneau has financial relationships with Actelion, Bayer, Eli Lilly, Novartis, Pfizer, in 68%, >40 mm Hg in 48%), and the CI was the most and GlaxoSmithKline; and has received consultancy and lecture fees from Actelion. accurate prognostic determinant (19). Dr. Vahiery has received lecture fees from and served as an advisory board member for Actelion Pharmaceuticals, Bayer Schering Eli Lilly, GlaxoSmithKline, and Pfizer; and Several case reports and published series suggest a role for has received consultancy fees from Actelion Pharmaceuticals, Merck, Bayer Schering, PH, for example, in advanced sarcoidosis (22,23), severe GlaxoSmithKline, and Pfizer. All other authors have reported that they have no kyphoscoliosis, obesity-hypoventilation syndrome (24), relationships relevant to the contents of this paper to disclose. Manuscript received October 12, 2013; accepted October 22, 2013. Langerhans cell histiocytosis (25,26), and to a lesser extent, JACC Vol. 62, No. 25, Suppl D, 2013 Seeger et al. D111 December 24, 2013:D109–16 Pulmonary Hypertension in Chronic Lung Diseases in advanced lymphangioleiomyomatosis (27). Moreover, the virtually any PAP value of >25 mm Hg may be considered incidence of adult bronchopulmonary dysplasia (28) and out of proportion. cystic fibrosis (29) patients with PH is apparently increasing. Recommendations Assessment and definition of PH due to chronic lung “ ” diseases (group 3). Echocardiography is the initial It is suggested that the term out of proportion be aban- fi modality for noninvasive diagnosis of PH in COPD and doned and that the following de nitions for COPD, IPF, DPLD. Comparing echo cardiographic data with RHC in and CPFE (measurements undertaken at rest with supple- lung disease patients, positive predictive values of 32% and mental oxygen if needed) be used: 68%, respectively, and negative predictive values of 93% and 1. COPD/IPF/CPFE without PH (mPAP <25 mm Hg); 67%, respectively, were reported (30,31). Plasma levels of 2. COPD/IPF/CPFE with PH (mPAP 25 mm Hg; BNP or the N-terminal prohormone of BNP are elevated in PH-COPD, PH-IPF, and PH-CPFE); and severe COPD- and DPLD-associated PH, but lack sensi- 3. COPD/IPF/CPFE with severe PH (mPAP 35 tivity in moderate PH and may be confounded by left heart mm Hg or mPAP 25 mm Hg with low CI (<2.0 abnormalities (32). Nevertheless, BNP levels they were l/min/m2); severe PH-COPD, severe PH-IPF, and found to be strongly predictive of mortality in a mixed severe PH-CPFE). DPLD population (33). RHC, the gold standard for PH diagnosis, should be The choice of mPAP 35 mm Hg as a cutoff for severe performed in patients with chronic lung disease when PH is based on the following findings/assumptions, which 1) evaluation for lung transplantation is deemed necessary; 2) should be further addressed and putatively revised in future clinical worsening and progressive exercise limitation is studies: disproportionate to ventilatory impairment; 3) progressive gas 1. The “severe PH group” includes only a minority of exchange abnormalities are disproportionate to ventilatory chronic lung disease patients suspected of having significant/ impairment; 4) an accurate prognostic assessment is deemed severe vascular abnormalities (remodeling) accompanying to be critical; 5) severe PH is suspected by noninvasive the parenchymal disease (40). For COPD, this corresponds measures and further therapy or inclusion in clinical trials or to w1% of the entire population included in the NETT registries are being considered; and 6) there is suspicion of left (National Emphysema Treatment Trial) (41). ventricular systolic/diastolic dysfunction and categorization of 2. This degree of PH in COPD/IPF is assumed to the pulmonary artery occlusion pressure might alter cause circulatory impairment that substantially worsens the management (adapted from Nathan and Cottin [34]). reduced exercise capacity caused by obstructive/restrictive Inhalation of iloprost and NO have been shown to reduce ventilatory impairment. A recent study documented the mPAP and PVR in PH-IPF (35–37) and PH-COPD (38), fact that COPD patients with mPAP 40 mm Hg but there are currently no valid data to support routine use of definitely showed an exhausted circulatory reserve at the acute vasodilator testing in lung disease patients with PH. end of exercise (documented by low mixed venous oxygen Combining RHC with exercise testing in IPF, systolic saturation and reduced slope of the cardiac output/oxygen PAP measured by echocardiography correlated with peak O2 consumption ratio), with breathing reserve maintained uptake, anaerobic threshold, peak O2 pulse, and ventilatory (documented by low arterial PaCO2) (39). In contrast, equivalent for CO2, suggesting that PH has a negative COPD patients without PH and those with moderate PH impact on exercise capacity (17). In COPD, exercise testing (mPAP 31 mm Hg) are limited by ventilatory impairment may discriminate between an exhausted breathing reserve (exhaustion of breathing reserve, arterial PaCO2 increase at caused by airflow limitation and an exhausted circulatory the end of exercise), with circulatory reserve maintained reserve caused by PH, as detailed in the following text (39). (39). Notably, although the FEV1 values were even higher Use of the term “in proportion” PH in lung disease is in the COPD/mPAP 40 mm Hg group than in the based on the assumption that the underlying parenchymal COPD group without PH, the 6-min walk distance remodeling process with accompanying hypoxia causes some (6MWD) values were drastically lower in COPD with “natural” loss of overall vascular cross-sectional area and thus mPAP 40mmHg.Inlinewithpreviousstudies(1), an increase in PVR. “Out of proportion” PH, in contrast, these findings strongly support the view that circulatory signals that the severity of PH is high in relation to the impairment in COPD patients with severe PH markedly degree of lung parenchymal abnormalities. Such a constel- adds to the limitation in exercise capacity. Similarly, lation may reflect the fact that: 1) the chronic parenchymal studies in IPF patients documented the fact that the disease is a trigger of a progressive vascular remodeling development of PH, in particular with mPAP values 35 process, developing independently of lung function impair- mm Hg, resulted in significantly lower values for capacity ment; or 2) the PH appears “by chance” in a patient with of lung to diffuse carbon monoxide and arterial oxygena- lung disease at some stage but independently of this tion at rest, lower exercise capacity, and decline of arterial comorbidity background. However, given the fact that a loss oxygenation upon exercise, independent of lung function of only >80% of normal lung structure will provoke PH, tests (2,12,17). D112 Seeger et al. JACC Vol. 62, No. 25, Suppl D, 2013 Pulmonary Hypertension in Chronic Lung Diseases December 24, 2013:D109–16

Notably, IPAH patients may also display mild to moderate In DPLD, long-term oxygen treatment is usually recom- ventilatory impairment in the absence of any evidence of mended to maintain arterial oxygen saturation >90%; lung airway or parenchymal disease, mainly in the form of however, this recommendation is not supported by a con- airway obstruction (42–45). In the largest of these studies trolled trial. As for PAH-focused drugs, the current state (171 IPAH patients; mean age 45 years; mean PVR 1,371 may be summarized in the following text. dynes s cm 5), the mean FEV1 was 83% of predicted Vasoactive therapy in lung fibrosis. Any vasodilator may value, and the FEV1/VC (Forced Expiratory Volume in 1 s/ worsen gas exchange in lung-diseased patients because of Vital Capacity) ratio was 76%; in 22% of the total IPAH interference with hypoxic vasoconstriction, which diverts patients, the FEV1/VC ratio was below 70% (45). Against pulmonary blood flow from more seriously to less seriously this background, randomized controlled trials in the field of affected lung segments. However, vasodilators may prefer- PAH set exclusion criteria using pulmonary function testing entially access the better ventilated and oxygenated areas of in the following ranges: total lung capacity <60% to 70% of the fibrotic lung because of their mode of distribution predicted values; FEV1 values <55% to 80% of predicted (inhaled iloprost, treprostinil, or nitric oxide [35,37,47])or values; or FEV1/FVC ratio <50% to 70%. may enhance normoxic vasodilation (the phosphodiesterase Moreover, lung diseases (in particular COPD) are 5 inhibitor sildenafil [36,48]), which may be advantageous in common conditions, and development of PAH in such this respect. Long-term studies using prostanoids in lung patients may not necessarily be the result of these diseases fibrosis-associated PH are missing, however. In IPF, the (definition group 3 PH patients) but may be coincidental. nonselective endothelin receptor antagonist (ERA) bosentan When there is uncertainty in the classification of a patient was well tolerated (49–51), but failed to improve the pre- with lung disease and PH to group 1 (PAH) or group 3 (PH defined endpoint “time to occurrence of lung fibrosis caused by lung disease), the patient should be referred to worsening” in a phase III trial (51). Negative trial results centers with expertise. Some suggested criteria for discrim- were also reported for the selective ERA ambrisentan ination between group 1 and group 3 are summarized (ARTEMIS-IPF [Placebo-Controlled Study to Evaluate in Table 1. Safety and Effectiveness of Ambrisentan in Idiopathic Pulmonary Fibrosis]) and macitentan (MUSIC [Macitentan Treatment of PH Caused by Chronic Lung Disease Use in an Idiopathic Pulmonary Fibrosis Clinical study]) in (Group 3): Evidence for Appropriate IPF. The ARTEMIS-IPF study was terminated because of Benefit/Risk Ratio of PAH-Focused Drugs? an increased rate of disease progression and respiratory hospitalization (52). Within this entire IPF group, 11% of The underlying lung disease should be treated according to patients presented with PH (mPAP 25 mm Hg), which current guidelines. Within these guidelines, none of the did not affect the endpoint estimates. Based on these results, therapeutic measures focuses on the vascular component of the European Medicines Evaluation Agency recently con- the disease, with the exception of long-term oxygen treat- traindicated the use of ambrisentan in IPF patients, ment. In COPD patients with partial pressure of oxygen in regardless of the presence of PH. No results are currently < arterial blood (PaO2) values 60 mm Hg, long-term available from a bosentan trial particularly focusing on IPF- oxygen treatment improved life expectancy, which might associated PH (B-PHIT [Bosentan in PH in Interstitial be related to its retardation of PH development (46). Lung Disease]; NCT00637065).

Table 1 Differential Diagnosis Between Group 1 (PAH) and Group 3 (PH Due to Lung Disease) PH

Criteria Favoring Group 1 (PAH) Parameter Criteria Favoring Group 3 (PH Due to Lung Disease) Normal or mildly impaired Ventilatory function Moderate to very severe impairment FEV1 >60% predicted (COPD) FEV1 <60% predicted (COPD) FVC >70% predicted (IPF) FVC <70% predicted (IPF) Absence of or only modest airway or parenchymal High-resolution CT scan* Characteristic airway and/or parenchymal abnormalities abnormalities Features of exhausted circulatory reserve Features of exhausted ventilator reserve Preserved breathing reserve Reduced breathing reserve Reduced oxygen pulse Normal oxygen pulse

Low CO/VO2 slope Normal CO/VO2 slope Mixed venous oxygen saturation at lower limit Mixed venous oxygen saturation above lower limit

No change or decrease in PaCO2 during exercise Increase in PaCO2 during exercise

*As to CT diagnosis, parenchymal changes linked to PVOD are to be discriminated from those associated with DPLD.y Features of exhausted circulatory reserve are also noted in severe PH-COPD and severe PH-IPF, but are then accompanied by major lung function and CT abnormalities.

CO/VO2 ¼ cardiac output/oxygen consumption ratio; COPD ¼ chronic obstructive pulmonary disease; CT ¼ computed tomography; DPLD ¼ diffuse parenchymal lung disease; FEV1 ¼ forced expiratory volume in 1 s; FVC ¼ forced vital capacity; IPF ¼ idiopathic pulmonary ﬁbrosis; PaCO2 ¼ partial pressure of carbon dioxide in arterial blood; PAH ¼ pulmonary arterial hypertension; PH ¼ pulmonary hypertension; PVOD ¼ pulmonary veno-occlusive disease. JACC Vol. 62, No. 25, Suppl D, 2013 Seeger et al. D113 December 24, 2013:D109–16 Pulmonary Hypertension in Chronic Lung Diseases

Table 2 Management of PH in the Setting of Chronic Lung Disease

Underlying Lung Disease mPAP <25 mm Hg at Rest mPAP 25 and <35 mm Hg at Rest mPAP 35 mm Hg at Rest* COPD with FEV1 60% of predicted No PH PH classification uncertain PH classification uncertain: discrimination IPF with FVC 70% of predicted No PAH treatment No data currently support treatment between PAH (group 1) with concomitant CT: absence of or only very modest airway recommended with PAH-approved drugs lung disease or PH caused by lung or parenchymal abnormalities disease (group 3) Refer to a center with expertise in both PH and chronic lung disease COPD with FEV1 <60% of predicted No PH PH-COPD, PH-IPF, PH-CPFE Severe PH-COPD, severe PH-IPF, severe IPF with FVC <70% of predicted No PAH treatment No data currently support treatment PH-CPFE Combined pulmonary fibrosis and recommended with PAH-approved drugs Refer to a center with expertise in both PH emphysema on CT and chronic lung disease for individualized patient care because of poor prognosis; randomized controlled trials required

*Lower PA pressures may be clinically signiﬁcant in COPD/DPLD patients with depressed cardiac index or right ventricular dysfunction. CPFE ¼ combined pulmonary ﬁbrosis and emphysema; mPAP ¼ mean pulmonary artery pressure; other abbreviations as in Table 1.

In a small open-label study in IPF patients with PH, challenging than in lung fibrosis caused by the presence of sildenafil was noted to improve 6MWD (53). In a controlled low ventilation/perfusion ratio areas (63). Inhaled prosta- trial of sildenafil in advanced IPF, the primary outcome noids may acutely reduce mPAP and PVR while largely variable (proportion of patients with 6MWD increase maintaining gas exchange in PH-COPD (64); however, >20%) was not met, but arterial oxygenation, DLCO, long-term clinical trials have not been reported. In COPD dyspnea, and quality of life improved (STEP-IPF [Sildenafil patients with mild PH, bosentan caused deterioration of gas Trial Of Exercise Performance In Idiopathic Pulmonary exchange with lack of improvement in peak oxygen uptake, Fibrosis]) (48). A pre-specified analysis of the available echo exercise capacity, and quality of life in a small randomized cardiographic data from this trial (119 of 180 patients) controlled trial (65). In 1 small trial, improved exercise showed that sildenafil preserved the 6MWD and improved capacity upon treatment of PH-COPD patients with the St. George’s Questionnaire score compared with placebo bosentan was reported (66). Robust data for the effect of in the subgroup of 22 patients with right ventricular systolic ERAs on pulmonary hemodynamics and exercise tolerance dysfunction (54). Additional evidence is expected from trials in PH-COPD are thus lacking. focusing on the use of sildenafil in IPF patients with asso- Short-term administration of sildenafil in PH-COPD ciated PH (NCT00625079; recruitment status currently improved hemodynamics but deteriorated gas exchange unknown). (67). One month of sildenafil treatment in COPD patients fi Pre-clinical and clinical ndings support the view that without PH did not affect 6MWD and VO2 peak but wors- both endothelin receptor antagonists and phosphodiesterase 5 ened arterial oxygenation and quality of life (68,69). A recent inhibitors possess marked antiproliferative capacity in the randomized controlled trial of sildenafil added to pulmonary pulmonary vasculature in addition to their vasodilatory effects rehabilitation also failed to show improvement in exercise (55). This field is currently extended by the use of direct tolerance in COPD patients without severe PH (70).In stimulators and activators of the soluble guanylate cyclase, contrast, 1 small randomized controlled trial reported working even at sites with inactivated NO axis and exerting a decrease in PAP, accompanied by an increase in 6MWD, strong pulmonary vasodilatory and antiproliferative potency upon long-term use of sildenafil in patients with severe PH- in experimental models of PH (56). Phase II and III trials in COPD (71). Thus, there is definitely a lack of evidence of both PAH and chronic thromboembolic pulmonary hyper- a long-term beneficial effect of sildenafil in COPD patients in tension (CTEPH) patients demonstrated the efficacy of the the absence of severe PH, whereas the impact of this agent on soluble guanylate cyclase stimulator riociguat in improved severe PH-COPD is still not settled. exercise capacity (primary outcome variable) and several When assessing the acute effects of riociguat in PH- secondary endpoints (57–60). A recent phase II trial missed COPD, improvement of pulmonary hemodynamics with- the primary endpoint (reduction in PAP) but demonstrated out major deterioration of gas exchange (multiple inert gas the efficacy of riociguat in decreasing PVR but also systemic elimination technique technology) was noted (H.A. Gho- vascular resistance and in increasing cardiac output and frani et al., nonpublished results, October 2013), thus war- 6MWD in PH-DPLD (61); a randomized controlled trial ranting future studies in this indication. focusing on PH-DPLD is in preparation. Occasional cases of improved hemodynamic data and, Recommendations for COPD and Lung Fibrosis more rarely, clinical improvement with PH-specific therapy in CPFE patients have been reported (19,62). Randomized Long-term randomized controlled trials focusing on patients controlled trials are currently missing. with severe PH and chronic obstructive or restrictive lung Vasoactive therapy in COPD. In COPD, pulmonary diseases are needed. Only such an approach will provide vasodilation without deterioration of gas exchange is more reliable data for the use of PAH-approved drugs in these D114 Seeger et al. JACC Vol. 62, No. 25, Suppl D, 2013 Pulmonary Hypertension in Chronic Lung Diseases December 24, 2013:D109–16 patients. In such studies, obstructive and restrictive lung addition, for the time being, use of a PAH-approved drug on diseases should be investigated separately because of the a compassionate treatment basis may be considered for this major differences in underlying pathophysiology. Based on subpopulation, with thorough monitoring of gas exchange lung function testing, cardiopulmonary exercise testing, and (PaO2, PaCO2) and inclusion in prospective registries. Gas clinical and CT evidence for lung airway or parenchymal exchange may be found to be deteriorated (caused by inter- disease and severity of PH, the following groups of PH ference with the hypoxic vasoconstriction) or improved patients are to be distinguished with respect to classification (caused by normoxic vasodilatation and higher central venous and therapy recommendations (Table 2): oxygen saturation upon drug-induced CI increase). 1. Patients with milder forms of obstructive or restrictive 4. Patients with end-stage obstructive or restrictive lung lung disease and minor impairment of lung function testing, diseases or a combination thereof should be included. In these in whom CT analysis shows no gross parenchymal or airway patients, any use of PAH-approved drugs was hitherto largely abnormalities and who present with clinically relevant discouraged because of limited life expectancy. However, the PH should be specified. Whether such patients have PAH recent finding that bridging to transplantation may include (group 1) with concomitant lung disease or PH caused by the use of “awake extracorporeal membrane oxygenation” lung disease (group 3) is a diagnostic dilemma (see the (extracorporeal membrane oxygenation) (72) and that long- previously mentioned conditions). Therefore, these patients term noninvasive (nocturnal) home mechanical ventilation should be referred to an expert unit, where a comprehensive may substantially prolong the life expectancy of these patients diagnostic workup should be made, including high- challenges this view. Controlled trials should address the resolution CT, hemodynamics, complete lung function question whether PAH-approved drugs may improve exer- testing, and detailed cardiopulmonary exercise testing. cise capacity and quality of life, prolong time to clinical Chance association of PH is much less likely in IPF than in worsening, and improve survival or bridging to trans- COPD. plantation in patients with end-stage obstructive or restrictive 2. Patients with more severe obstructive or restrictive lung diseases and accompanying PH receiving mechanical lung disease (IPF with FVC <70% predicted; COPD with ventilatory or extracorporeal membrane oxygenation support. FEV1 <60% predicted) and accompanying less severe PH (mPAP 25 mm Hg and <35 mm Hg; PH-COPD, PH- Specific Aspects of Sarcoidosis, IPF) and patients with combined pulmonary fibrosis and Systemic Sclerosis, and Rare Lung Diseases emphysema and accompanying PH (mPAP 25 mm Hg and <35 mm Hg; PH-CPFE; lung volumes may be The prevalence of pulmonary hypertension in sarcoidosis preserved in these patients) should be classified. This group (PH-SA) was approximately 5% in the only series of unse- represents the majority of patients presenting with chronic lected patients (73). However, PH was reported in 47% of lung disease and PH. Here, no data currently support sarcoidosis patients with exertional dyspnea disproportionate therapy with PAH-approved drugs. Moreover, as the limi- to pulmonary function test results, with low PaO2 and low tation in exercise capacity in these patients is largely based DLCO levels, indicating the presence of PH (74) and, in up on ventilatory and not circulatory impairment, any benefit to 74% of sarcoidosis patients, listed lung transplantation from PAH treatment is questionable. In addition, vasodi- (75). PH-SA has a 5-year survival of w60% (76), with lators may impair gas exchange, particularly in COPD. PH being an independent, poor prognostic determinant. This does not exclude the fact that vascular changes may PH may occur with little or no evidence of interstitial contribute to disease progression and may become a future lung disease (75),reflecting considerable pathophysiologic therapeutic target from this angle, but controlled clinical heterogeneity. Mechanisms contributing to the pathogenesis trials addressing this topic are currently missing. of PH-SA include fibrotic ablation of the pulmonary 3. Patients with more severe obstructive or restrictive lung vasculature, extrinsic compression of the central pulmonary disease or a combination thereof and severe PH as defined in vessels by lymphadenopathy or mediastinal fibrosis, pul- the previous text (mPAP 35 mm Hg; severe PH-COPD; monary veno-occlusive disease, left ventricular dysfunction, severe PH-IPF; severe PH-CPFE) must be distinguished. portopulmonary hypertension, and an intrinsic sarcoid vas- These patients have a poor prognosis and should be referred culopathy caused by granulomatous invasion of pulmonary to a center with expertise in both PH and chronic lung vessels (76). The management of PH-SA includes treatment disease for individualized patient care. In some of these of the underlying sarcoidosis, reversal of resting hypoxemia, patients, a detailed analysis of hemodynamics may suggest and referral for lung transplantation in selected patients. that a low or low normal cardiac output (baseline conditions) As to vasoactive therapy, acute and chronic improvements in and/or an inadequately increasing cardiac output upon pulmonary hemodynamics and exercise capacity have been exercise testing may substantially contribute to the limitation reported for inhaled NO, intravenous epoprostenol, bosen- of peak oxygen uptake and, thus, physical activity and that tan, sildenafil, and inhaled iloprost (77–79); however, larger the augmented right heart afterload is the main cause for the controlled trials are missing. Referral of patients with hemodynamic compromise. These patients should preferably PH-SA to expert centers is strongly recommended, with be included in randomized controlled trials if available. In treatment decisions made on a case by case basis. JACC Vol. 62, No. 25, Suppl D, 2013 Seeger et al. D115 December 24, 2013:D109–16 Pulmonary Hypertension in Chronic Lung Diseases

Patients with systemic sclerosis occasionally develop both 13. Nathan SD, Shlobin OA, Ahmad S, et al. Serial development of fi pulmonary fibrosis and PH, with hemodynamic character- pulmonary hypertension in patients with idiopathic pulmonary brosis. Respiration 2008;76:288–94. istics generally comparable to that of IPAH (80). Whether 14. Shorr AF, Wainright JL, Cors CS, Lettieri CJ, Nathan SD. Pulmonary PH should be classified as group 1 or 3 in this setting is hypertension in patients with pulmonary fibrosis awaiting lung trans- – often unclear and should be judged in expert centers. Only plant. Eur Respir J 2007;30:715 21. 15. Zisman DA, Ross DJ, Belperio JA, et al. Prediction of pulmonary retrospective studies regarding PAH therapy are available in hypertension in idiopathic pulmonary fibrosis. Respir Med 2007;101: patients with systemic sclerosis, PH, and interstitial lung 2153–9. disease, with unclear benefit (81). 16. Lettieri CJ, Nathan SD, Barnett SD, Ahmad S, Shorr AF. Prevalence and outcomes of pulmonary arterial hypertension in advanced idio- For patients with rare lung diseases, in whom any random- pathic pulmonary fibrosis. Chest 2006;129:746–52. ized controlled trial is very unlikely to be undertaken in the near 17. Boutou AK, Pitsiou GG, Trigonis I, et al. Exercise capacity in idio- fi future, registries are strongly encouraged to provide reliable pathic pulmonary brosis: the effect of pulmonary hypertension. Respirology 2011;16:451–8. data about the prevalence of PH in these populations and to 18. Corte TJ, Wort SJ, Wells AU. Pulmonary hypertension in idiopathic provide a hypothesis as to whether PAH-focused therapy pulmonary fibrosis: a review. Sarcoidosis Vasc Diffuse Lung Dis 2009; – might be of any clinical benefit. Individual responses to treat- 26:7 19. 19. Cottin V, Le Pavec J, Prévot G, et al. 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First acute haemodynamic Key Words: combined pulmonary fibrosis and emphysema - COPD - study of soluble guanylate cyclase stimulator riociguat in pulmonary exhausted circulatory reserve - exhausted ventilatory reserve - lung hypertension. Eur Respir J 2009;33:785–92. fibrosis - pulmonary hypertension in chronic lung disease. Journal of the American College of Cardiology Vol. 62, No. 25, Suppl D, 2013 2013 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2013.10.028

Pediatric Pulmonary Hypertension

D. Dunbar Ivy, MD,* Steven H. Abman, MD,y Robyn J. Barst, MD,z Rolf M. F. Berger, MD,x Damien Bonnet, MD,jj Thomas R. Fleming, PHD,{ Sheila G. Haworth, MD,# J. Usha Raj, MD,** Erika B. Rosenzweig, MD,z Ingram Schulze Neick, MD,# Robin H. Steinhorn, MD,yy Maurice Beghetti, MDzz Aurora, Colorado; New York, New York; Groningen, the Netherlands; Paris, France; Seattle, Washington; London, United Kingdom; Chicago, Illinois; Davis, California; and Geneva, Switzerland

Pulmonary hypertension (PH) is a rare disease in newborns, infants, and children that is associated with signiﬁcant morbidity and mortality. In the majority of pediatric patients, PH is idiopathic or associated with congenital heart disease and rarely is associated with other conditions such as connective tissue or thromboembolic disease. Incidence data from the Netherlands has revealed an annual incidence and point prevalence of 0.7 and 4.4 for idiopathic pulmonary arterial hypertension and 2.2 and 15.6 for pulmonary arterial hypertension, respectively, associated with congenital heart disease (CHD) cases per million children. The updated Nice classiﬁcation for PH has been enhanced to include a greater depth of CHD and emphasizes persistent PH of the newborn and developmental lung diseases, such as bronchopulmonary dysplasia and congenital diaphragmatic hernia. The management of pediatric PH remains challenging because treatment decisions continue to depend largely on results from evidence-based adult studies and the clinical experience of pediatric experts. (J Am Coll Cardiol 2013;62:D117–26) ª 2013 by the American College of Cardiology Foundation

Pulmonary hypertension (PH) can present at any age from children are lacking. Nevertheless, children with PAH are infancy to adulthood. The distribution of etiologies in child- currently treated with targeted PAH drugs and may benefit ren is quite different than that of adults, with a predominance from these new therapies. This review provides an overview of of idiopathic pulmonary arterial hypertension (IPAH) and recent information regarding the current approach and diag- PAH associated with congenital heart disease (APAH-CHD) nostic classification of PAH in children as based on discus- (1–5). In pediatric populations, IPAH is usually diagnosed sions and recommendations from the Pediatric Task Force of in its later stages due to nonspecific symptoms. Without the 5th World Symposium on Pulmonary Hypertension appropriate treatments, median survival rate after diagnosis (WSPH) in Nice, France (2013). of children with IPAH appears worse when compared with that of adults (6). Therapeutic strategies for adult PAH have Definition not been sufficiently studied in children, especially regarding potential toxicities, formulation, or optimal dosing, and The definition of PH in children is the same as that in adults. appropriate treatment targets for goal-oriented therapy in Similar to adults, pulmonary vascular resistance (PVR) is

From *Pediatric Cardiology, Children’s Hospital Colorado, University of Colorado Lilly, Novartis, and Pfizer. Dr. Berger has performed consultancies for Actelion, School of Medicine, Aurora, Colorado; yPediatric Pulmonary Medicine, Children’s Bayer, GlaxoSmithKline, Lilly, Novartis, Pfizer, and United Therapeutics. Dr. Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado; Bonnet has received lecture and consulting honoraria from Actelion, Eli Lilly, Pfizer, zColumbia University, College of Physicians and Surgeons, New York, New York; and Bayer. Dr. Fleming has served as a consultant to Actelion and Pfizer. Dr. xCentre for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children’s Haworth has received consulting fees from GlaxoSmithKline. Dr. Rosenzweig has Hospital, University Medical Center Groningen, University of Groningen, Gronin- received research grant support from Actelion, Gilead, GlaxoSmithKline, Eli Lilly, gen, the Netherlands; kCentre de Référence Malformations Cardiaques Congénitales Bayer, and United Therapeutics; and consulting honoraria from United Therapeutics Complexes, Necker Hospital for Sick Children, Assistance Publique des Hôpitaux de and Actelion. The University of California has received consulting fees for Dr. Paris, Pediatric Cardiology, University Paris Descartes, Paris, France; {Department of Steinhorn from Ikaria and United Therapeutics, and she has served as an unpaid Biostatistics, University of Washington, Seattle, Washington; #Great Ormond Street consultant to Actelion. Dr. Beghetti has served as an advisory board member for Hospital, London, United Kingdom; **Department of Pediatrics, University of Illinois Actelion, Bayer, Eli Lilly, GlaxoSmithKline, Novartis, and Pfizer; has received grants at Chicago, Chicago, Illinois; yyDepartment of Pediatrics, University of California from Actelion and Bayer; has receiving lecture fees from Actelion, Bayer, and Pfizer; Davis Children’s Hospital, Davis, California; and the zzPediatric Cardiology Unit, has developed educational materials for Actelion and Pfizer; and has receiving University Hospital, Geneva, Switzerland. The University of Colorado School of consulting fees from Actelion, Bayer, GlaxoSmithKline, Pfizer, and Novartis. All Medicine has received consulting fees for Dr. Ivy from Actelion, Bayer, Gilead, Eli other authors have reported that they have no relationships relevant to the contents of Lilly, Pfizer, and United Therapeutics. The University Medical Center Groningen this paper to disclose. has received consulting fees for Dr. Berger from Actelion, Bayer, GlaxoSmithKline, Manuscript received October 15, 2013; accepted October 22, 2013. D118 Ivy et al. JACC Vol. 62, No. 25, Suppl D, 2013 Pediatric Pulmonary Hypertension December 24, 2013:D117–26

fi Abbreviations excluded in the de nition of PH. in response to AVT that determines operability with and Acronyms Absolute pulmonary artery pres- adequate sensitivity and specificity to predict a favorable sure falls after birth, reaching long-term outcome. The preponderance of data used for APAH-CHD = pulmonary arterial hypertension levels that are comparable to adult evaluation of operability includes baseline hemodynamics associated with congenital values within 2 months after and clinical characteristics (15). In assessing prognosis in heart disease birth. After 3 months of age in IPAH and repaired CHD, AVT may be predictive. The AVT = acute vasodilator term babies at sea level, PH is Barst and Sitbon criteria have each been shown to be of testing present when the mean pulmo- predictive value in IPAH in children and adults (12,16,17). CHD = congenital heart nary pressure exceeds 25 mm Hg disease in the presence of an equal dis- Classification HPAH = hereditary tribution of blood flow to all pulmonary arterial segments of both lungs. This As a modification of the past Dana Point classification (18), hypertension definition does not carry any the Nice clinical classification of PH further highlights aspects IPAH = idiopathic pulmonary arterial hypertension implication of the presence or of pediatric disorders, especially in regard to childhood absence of pulmonary hyperten- disorders that may be increasingly encountered by specialists PAPm = mean pulmonary artery pressure sive vascular disease (PHVD). treating adults with PH (Table 1). Children with PH who In particular, PVR is important were diagnosed in the neonatal through adolescent age ranges PH = pulmonary fi hypertension in the diagnosis and manage- are now surviving into adulthood; thus, a common classi -

PHVD = pulmonary ment of PHVD in children with cation is required to facilitate transition from pediatric to adult hypertensive vascular CHD. services. In addition, goals for improving pediatric classifica- disease In defining the response to tion systems include the need for clarification of disease PPHN = persistent acute vasodilator testing (AVT), phenotype, encouraging new thinking on causation pulmonary hypertension of it is critical to initially determine and disease pathobiology, enhancement of diagnostic evalu- the newborn the purpose of the test for the ations, improvements in correlations of phenotype and ther- PVR = pulmonary vascular care of the individual child. apeutic responsiveness, and enhancement of clinical trial resistance Three separate situations may be design. As a result, the Pediatric Task Force recommended SVR = systemic vascular evaluated. First, AVT is critical several changes for implementation in the WSPH meeting resistance for determining possible treat- proceedings. ment with calcium channel blockers (CCBs) in patients In particular, the Nice classification now includes addi- with IPAH. Second, AVT may be helpful in the assessment tional novel genetic disorders causing PAH, including those of operability in children with CHD. Third, AVT may aid related to mutations in the following genes: SMAD 9, cav- in assessing long-term prognosis. There is no drug standard eolin 1 (19), potassium channel KCNK3 (20), and T-box 4 for AVT in pediatrics; however, inhaled nitric oxide (dose (small patella syndrome) (21). range 20 to 80 parts per million) has been used most Persistent pulmonary hypertension of the newborn frequently and is advised if available for this purpose (PPHN), due to its particular anatomic and physiological (3,4,7–11). In the child with IPAH, a robust positive nature, has been moved to a separate subcategory in group response during AVT may be used to determine whether or 1 to emphasize unique aspects of its timing of onset not treatment with a CCB may be beneficial. Use of the immediately after birth, time course, and therapeutic strat- modified Barst criteria, which is defined as a 20% decrease egies. In group 2, congenital and acquired left heart inflow in mean pulmonary artery pressure (PAPm) with normal and outflow tract obstruction has been added (22). Lesions or sustained cardiac output and no change or decrease in the in this category include pulmonary vein stenosis, cor tria- ratio of pulmonary to systemic vascular resistance (PVR/ triatum, supravalvular mitral ring, mitral stenosis, subaortic SVR) has been associated with a sustained response to stenosis, aortic valve stenosis, and coarctation of the aorta CCBs (12). Although generally used in adult settings, associated with an increased left ventricular end-diastolic evaluation of the Sitbon criteria (e.g., a decrease in PAPm pressure. In group 3, developmental lung diseases have by 10 mm Hg to a value <40 mm Hg with sustained cardiac been emphasized due to growing recognition of the output) has not been studied adequately in children with important role of abnormal lung vascular growth in the IPAH to determine if these criteria are appropriate, pathogenesis of PH and impaired lung structure in these in particular with regard to long-term response (13).In disorders (Table 2). Congenital diaphragmatic hernia assessing operability in CHD, there is no established (CDH) and bronchopulmonary dysplasia (BPD) (Fig. 1) protocol for AVT or proven criteria for assessing the res- have been highlighted due to their relative frequency and ponse with respect to either operability or long-term the critical role of PH in determining survival and long- outcomes (level C). Although many studies have evaluated term outcomes (23–25). Several other developmental retrospective criteria for operability, such as PVR/SVR disorders, such as surfactant protein deficiencies and alveolar (9,14), there is no solid evidence to support the abso- capillary dysplasia, are now included as relatively rare but lute mean pulmonary pressure, PVR index, or PVR/SVR important causes of PH (Table 2). In the neonate, these JACC Vol. 62, No. 25, Suppl D, 2013 Ivy et al. D119 December 24, 2013:D117–26 Pediatric Pulmonary Hypertension

Table 1 Updated Classification of Pulmonary Hypertension* Developmental Lung Diseases Associated With Table 2 Pulmonary Hypertension 1. Pulmonary arterial hypertension 1.1 Idiopathic PAH Congenital diaphragmatic hernia 1.2 Heritable PAH Bronchopulmonary dysplasia 1.2.1 BMPR2 Alveolar capillary dysplasia (ACD) 1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3 1.2.3 Unknown ACD with misalignment of veins 1.3 Drug and toxin induced Lung hypoplasia (“primary” or “secondary”) 1.4 Associated with: Surfactant protein abnormalities 1.4.1 Connective tissue disease Surfactant protein B (SPB) deficiency 1.4.2 HIV infection SPC deficiency 1.4.3 Portal hypertension 1.4.4 Congenital heart diseases ATP-binding cassette A3 mutation 1.4.5 Schistosomiasis thyroid transcription factor 1/Nkx2.1 homeobox mutation 0 1 Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis Pulmonary interstitial glycogenosis 100. Persistent pulmonary hypertension of the newborn (PPHN) Pulmonary alveolar proteinosis 2. Pulmonary hypertension due to left heart disease Pulmonary lymphangiectasia 2.1 Left ventricular systolic dysfunction 2.2 Left ventricular diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and CHD of any type who develop PHVD. The task force also congenital cardiomyopathies recognized lesions in which pulmonary vascular disease is 3. Pulmonary hypertension due to lung diseases and/or hypoxia likely, but the specific criteria for PH are not met, and thus 3.1 Chronic obstructive pulmonary disease are not included in the Nice clinical classification. This 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern includes patients with single ventricle physiology who have 3.4 Sleep-disordered breathing undergone bidirectional Glenn or Fontan-type procedures 3.5 Alveolar hypoventilation disorders (26). In this setting of nonpulsatile flow to the pulmonary 3.6 Chronic exposure to high altitude > fi 3.7 Developmental lung diseases arteries, PAP may not be 25 mm Hg; however, signi cant 4. Chronic thromboembolic pulmonary hypertension (CTEPH) pulmonary vascular disease can lead to a poor outcome (27). 5. Pulmonary hypertension with unclear multifactorial mechanisms It is anticipated that these recommended changes in the 5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative classification of PH will prove to be useful in the diagnostic disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, evaluation and care of patients and design of clinical trials in lymphangioleiomyomatosis pediatric PH. 5.3Metabolicdisorders: glycogenstorage disease,Gaucher disease,thyroiddisorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH Etiology

*Modified as compared with the Dana Point classification. Reprinted with permission from Simonneau G, Gatzoulis MA, Adatia I. Updated clinical classification of pulmonary hypertension. Current registries have begun to examine the etiology J Am Coll Cardiol 2013;62:D34–41. and outcome of pediatric PH. In children, idiopathic BMPR2 ¼ bone morphogenetic protein receptor type II; CAV1 ¼ caveolin 1; ENG ¼ endoglin; KCNK3 ¼ potassium channel K3; PAH ¼ pulmonary arterial hypertension; PH ¼ pulmonary PAH, heritable PAH, and APAH-CHD constitute the hypertension; PPHN ¼ persistent pulmonary hypertension of the newborn. majority of cases, whereas cases of PAH associated with connective tissue disease are relatively rare (1–4,28).Large latter disorders often present with severe or lethal PH and registries of pediatric PH, including the TOPP (Tracking must be specifically evaluated to provide appropriate diag- Outcomes and Practice in Pediatric Pulmonary Hyper- nosis and management. In group 5, the category of seg- tension) registry (4) and the combined adult and pediatric mental PH has been added to PH with unclear U.S. REVEAL (Registry to Evaluate Early and Long- multifactorial mechanisms. Examples of segmental PAH Term PAH Disease Management) registry, have been include pulmonary atresia with ventricular septal defect described (3). Of 362 patients with confirmed PH in the and major aortopulmonary collateral arteries and branch TOPP registry, 317 (88%) had PAH, of which 57% pulmonary arterial stenosis of variable severity. were characterized as IPAH or hereditary PAH (HPAH) The Nice classification has also been modified with regard and 36% as APAH-CHD (4). PH associated with respi- to PAH associated with CHD (Table 3). Type 1 includes ratory disease was also noted, with BPD reported as the patients with classic Eisenmenger syndrome with right-to- most frequent chronic lung disease associated with PH. left shunting and systemic desaturation. Type 2 includes Only 3 patients had either chronic thromboembolic PH patients with CHD and significant PHVD with normal or miscellaneous causes of PH. Chromosomal anomalies resting saturation. The shunts may be either operable or (mainly trisomy 21) or syndromes were reported in 47 of inoperable but are characterized by increased PVR. Type 3 the patients (13%) with confirmed PH. Many factors may includes PAH with coincidental CHD, which includes contribute to PH associated with Down syndrome, such small atrial or ventricular septal defects that do not cause as lung hypoplasia, alveolar simplification (which may severe PAH and follow a course similar to IPAH. Finally, be worse in the presence of CHD), CHD, changes in post-operative PAH (type 4) includes patients with repaired the production and secretion of pulmonary surfactant, D120 Ivy et al. JACC Vol. 62, No. 25, Suppl D, 2013 Pediatric Pulmonary Hypertension December 24, 2013:D117–26

Figure 1 Pulmonary Vascular Disease in Bronchopulmonary Dysplasia

From Mourani PM, Abman SH. Curr Opinion Pediatr 2013;25:329–37. SMC ¼ smooth muscle cell. elevated plasma levels of asymmetric dimethyl arginine, children with PAH. In the Netherlands registry, the yearly hypothyroidism, obstructive airway disease, sleep apnea, incidence rates for PH were 63.7 cases per million children. reflux, and aspiration (29–31). The annual incidence rates of IPAH and APAH-CHD Another large registry for pediatric PH has been reported were 0.7 and 2.2 cases per million, respectively. The point from the nationwide Netherlands PH Service (32). In this prevalence of APAH-CHD was 15.6 cases per million. The registry, 2,845 of 3,263 pediatric patients with PH incidences of PPHN and transient PH associated with had PAH (group 1), including transient PAH (82%) and CHD were 30.1 and 21.9 cases per million children, progressive PAH (5%). The remaining causes of PH respectively (32). Likewise, the incidence of IPAH in the included lung disease and/or hypoxemia (8%), PH associ- national registries from the United Kingdom was 0.48 cases ated with left heart disease (5%), and chronic thromboem- per million children per year, and the prevalence was 2.1 bolic PH (<1%). The most common causes of transient cases per million (34). pulmonary hypertension were PPHN (58%) and APAH- Prior to the availability of targeted PAH therapies, CHD (42%). In the progressive PAH cases, APAH- a single-center cohort study showed that the estimated CHD (72%) and IPAH (23%) were common causes. median survival of children and adults with IPAH were Down syndrome was the most frequent chromosomal dis- similar (4.12 vs. 3.12 years, respectively) (35). Currently, order (12%), a rate similar to that observed in the TOPP with targeted pulmonary vasodilators, the survival rate has registry. Thus, early registry reports of children with PH continued to improve in pediatric patients with PAH. provide important insights into the spectrum of pediatric Patients with childhood-onset PAH in the combined adult PH; however, these data are likely limited or biased by the and pediatric U.S. REVEAL registry demonstrated 1-, 3-, nature of referrals and the clinical practice of PH centers and 5-year estimated survival rates from diagnostic cathe- participating in the registries (33). terization of 96 4%, 84 5%, and 74 6%, respectively (3). There was no significant difference in 5-year survival Epidemiology and Survival between IPAH/FPAH (75 7%) and APAH-CHD (71 13%). Additionally, a retrospective study from the United Although the exact incidence and prevalence of PH in Kingdom has shown the survival in 216 children with IPAH pediatric population are still not well known, recent regis- and APAH-CHD (1). The survival rates of IPAH were tries have described estimates of incidence and prevalence in 85.6%, 79.9%, and 71.9% at 1, 3, and 5 years, respectively, whereas APAH-CHD survival rates were 92.3%, 83.8%, Clinical Classification of Congenital Heart Disease Table 3 and 56.9% at 1, 3, and 5 years, respectively. In a separate Associated With Pulmonary Arterial Hypertension report of IPAH from the United Kingdom, survival at 1, 3,

1. Eisenmenger Syndrome and 5 years was 89%, 84%, and 75%, whereas transplant-free 2. Left to right shunts survival was 89%, 76%, and 57% (34). Reports from the Operable Netherlands have shown 1-, 3-, and 5-year survival of 87%, Inoperable 78%, and 73%, respectively, for patients with progressive 3. PAH with co-incidental CHD PAH (36). Although overall survival has improved, certain 4. Post-operative PAH patients, such as those with repaired CHD and PHVD, Deﬁnition of PAH based on mean PAP >25 mm Hg and PVR >3 Wood units m2. remain at increased risk (1,32,36,37). JACC Vol. 62, No. 25, Suppl D, 2013 Ivy et al. D121 December 24, 2013:D117–26 Pediatric Pulmonary Hypertension

Figure 2 Pulmonary Arterial Hypertension Diagnostic Work-Up

#If a reliable test cannot be obtained in a young child and there is a high index of suspicion for underlying lung disease, the patient may require further lung imaging. {Children 7 years of age and older can usually perform reliably to assess exercise tolerance and capacity in conjunction with diagnostic work-up. AVT ¼ acute vasodilator testing; CHD ¼ congenital heart disease; CT ¼ computed tomography; CTA ¼ computed tomography angiography; CTD ¼ connective tissue disease; CTEPH ¼ chronic thromboembolic pulmonary hypertension; CXR ¼ chest radiography; DLCO ¼ diffusing capacity of the lung for carbon monoxide; ECG ¼ electrocardiogram; HPAH ¼ heritable pulmonary arterial hypertension; PA ¼ pulmonary artery; PAH ¼ pulmonary arterial hypertension; PAPm ¼ mean pulmonary artery pressure; PAWP ¼ pulmonary artery wedge pressure; PCH ¼ pulmonary capillary hemangiomatosis; PEA ¼ pulmonary endarterectomy; PFT ¼ pulmonary function test; PH ¼ pulmonary hypertension; PVOD ¼ pulmonary veno-occlusive disease; PVR ¼ pulmonary vascular resistance; RHC ¼ right heart catheterization; RV ¼ right ventricular; V/Q ¼ ventilation/perfusion; WU ¼ Wood units.

Diagnosis Treatment Goals

A methodical and comprehensive diagnostic approach is Although many treatment goals and endpoints for clinical important because of the many diseases associated with PH. trials are similar in adults and children, there are also Despite this, recent registries have shown that most children important differences. As in adults, clinically meaningful do not undergo a complete evaluation (38–40). A modified, endpoints include clinically relevant events such as death, comprehensive diagnostic algorithm is shown in Figure 2. transplantation, and hospitalization for PAH. Further Special situations may predispose to the development of parameters that directly measure how a patient feels, func- PAH and should be considered (41). tions, and survives are meaningful and include functional D122 Ivy et al. JACC Vol. 62, No. 25, Suppl D, 2013 Pediatric Pulmonary Hypertension December 24, 2013:D117–26 class and exercise testing; however, there are no acceptable a vasoreactivity has been shown to correlate with survival surrogates in children. Although World Health Organiza- (3,12,16). Indications for repeat cardiac catheterization in tion (WHO) functional class is not designed specifically children with PH include clinical deterioration, assessment for infants and children, it has been shown to correlate of treatment effect, detection of early disease progression, with 6-min walk distance and hemodynamic parameters listing for lung transplant, and prediction of prognosis. (1–3,32,34). Further, WHO functional class has been However, it must be emphasized that cardiac catheterization shown to predict risk for PAH worsening and survival in should be performed in experienced centers able to manage pediatric PH of different subtypes. Although not validated, potential complications such as PH crisis requiring extra- a functional class designed specifically for children has been corporeal membrane oxygenation (40,48–50). Noninvasive proposed (42). Pediatric PAH treatment goals may be endpoints to be further evaluated in children include pediatric divided into those that are for patients at lower risk or functional class as well as z-scores for body mass index (3,34), higher risk for death (Table 4). As in adults, clinical evidence echocardiographic parameters such as the systolic to diastolic of right ventricular failure, progression of symptoms, WHO duration ratio (51), tissue Doppler indexes (52–54), eccen- functional class 3/4 (3,34,36,43), and elevated brain natri- tricity index (52), tricuspid plane annular excursion (52,55), uretic peptide levels (44–46) are recognized to be associated and pericardial effusion. Pediatric reference values for with higher risk of death. In children, failure to thrive has cardiopulmonary exercise testing in association with outcome been associated with higher risk of death (3,34). Abnormal are needed (56,57). Development of assessment tools for daily hemodynamics are also associated with higher risk, but the activity measures may be valuable in determining treatment values found to be associated with higher risk are different goals. Initial magnetic resonance imaging parameters are than those for adults. Additional parameters include the promising (58), and pulsatile hemodynamics such as pulmo- ratio of PAPm to systemic artery pressure, right atrial nary arterial capacitance (59,60) require further validation. pressure >10 mm Hg, and PVR index (PVRI) greater than Novel parameters, such as fractal branching (61), proteomic 20 Wood units m2 (16,43). In recent pediatric PAH approaches (62,63), and definition of progenitor cell pop- outcome studies, baseline 6-min walk distance was not ulations (64–66) are under active study. a predictor of survival, neither when expressed as an absolute distance in meters nor when adjusted to reference values Treatment expressed as z-score or as percentage of predicted value (1,34,36,46,47). Serial follow-up of cardiac catheterization The prognosis of children with PAH has improved in the in pediatric PH may be beneficial. Maintenance of past decade owing to new therapeutic agents and aggressive

Figure 3 World Symposium on Pulmonary Hypertension 2013 Consensus Pediatric IPAH/FPAH Treatment Algorithm*

*Use of all agents is considered off-label in children aside from sildenafil in Europe. **Dosing recommendations per European approved dosing for children. See text for discussion of use of sildenafil in children in the United States. CCB ¼ calcium channel blocker; ERA ¼ endothelin receptor antagonist; HPAH ¼ hereditary pulmonary arterial hypertension; inh ¼ inhalation; IPAH ¼ idiopathic pulmonary arterial hypertension; IV ¼ intravenous; PDE-5i ¼ phosphodiesterase 5 inhibitor; SQ ¼ subcutaneous. JACC Vol. 62, No. 25, Suppl D, 2013 Ivy et al. D123 December 24, 2013:D117–26 Pediatric Pulmonary Hypertension treatment strategies. However, the use of targeted pulmo- and pericardial effusion. Additional hemodynamic parame- nary PAH therapies in children is almost exclusively based ters that predict higher risk include a PAPm to syste- on experience and data from adult studies, rather than mic artery pressure ratio >0.75 (16), right atrial pressure evidence from clinical trials in pediatric patients. Due to the >10 mm Hg, and PVRI greater than 20 Wood units m2 complex etiology and relative lack of data in children with (43). Additional high-risk parameters include failure to PAH, selection of appropriate therapies remains difficult. thrive. In the child with a negative acute vasoreactivity We propose a pragmatic treatment algorithm based on the response and lower risk, initiation of oral monotherapy is strength of expert opinion that is most applicable to children recommended. Treatment of choice is an endothelin with IPAH (Fig. 3). Treatment of PPHN has recently receptor antagonist (bosentan [43,71–77], ambrisentan been reviewed (67,68). [78,79]) or phosphodiesterase 5 (PDE5) inhibitor (sildenafil The ultimate goal of treatment should be improved [80–86], tadalafil [87,88]). The STARTS-1 (Sildenafilin survival and allowance of normal activities of childhood Treatment-Naive Children, Aged 1–17 Years, With without the need to self-limit. The Nice pediatric PH Pulmonary Arterial Hypertension) and STARTS-2 silde- treatment algorithm was modeled from the 2009 consensus nafil trials have received recent regulatory attention and were adult PH treatment algorithm and current pediatric expe- actively discussed at the WSPH meeting. STARTS-1 and rience (69). Background therapy with diuretics, oxygen, STARTS-2 were worldwide randomized (stratified by anticoagulation, and digoxin should be considered on an weight and ability to exercise), double-blind, placebo- individual basis. Care should be taken to not overly decrease controlled studies of treatment-naive children with PAH. In intravascular volume due to the pre-load dependence of the these 16-week studies, the effects of oral sildenafil mono- right ventricle. Following the complete evaluation for all therapy in pediatric PAH were studied (84). Children with causes of PH, AVT is recommended to help determine PAH (1 to 17 years of age; 8 kg) received low- (10 mg), therapy. medium- (10 to 40 mg), or high- (20 to 80 mg) dose sil- In children with a positive AVT response, oral CCBs may denafil or placebo orally 3 times daily. The estimated mean be initiated (12,70). Therapy with amlodipine, nifedipine, or standard error percentage change in pVO2 for the low-, diltiazem has been used. Because CCBs may have negative medium- and high-doses combined versus placebo was inotropic effects in young infants, these agents should be 7.7 4.0% (95% CI: 0.2% to 15.6%; p ¼ 0.056). Thus, avoided until the child is older than 1 year of age. In the the pre-specified primary outcome measure was not statis- child with a sustained and improved response, CCBs may be tically significant. Peak VO2 only improved with the continued, but patients may deteriorate, requiring repeat medium dose. Functional capacity only improved with evaluation and additional therapy. For children with high dose sildenafil. PVRI improved with medium- and a negative acute vasoreactivity response or in the child with high-dose sildenafil, but mean PAP was lower only with a failed or nonsustained response to CCBs, risk stratification medium-dose sildenafil. As of June 2011, 37 deaths had should determine additional therapy (Table 4). Although been reported in the STARTS-2 extension study (26 on the specific number of lower- or higher-risk criteria to drive study treatment). Most patients who died had IPAH/ therapeutic choices is not yet known, a greater proportion of HPAH and baseline functional class III/IV disease; patients either should be considered as justification for therapy. who died had worse baseline hemodynamics. Hazard ratios Similar to adults, determinants of higher risk in children for mortality were 3.95 (95% CI: 1.46 to 10.65) for high include clinical evidence of right ventricular failure, pro- versus low dose and 1.92 (95% CI: 0.65 to 5.65) for gression of symptoms, syncope, WHO functional class III or medium versus low dose (83). Review of these data by the IV, significantly elevated or rising B-type natriuretic peptide U.S. Food and Drug Administration (FDA) and the levels, severe right ventricular enlargement or dysfunction, European Medicines Agency (EMA) resulted in disparate

Table 4 Pediatric Determinants of Risk

Lower Risk Determinants of Risk Higher Risk No Clinical evidence of RV failure Yes No Progression of symptoms Yes No Syncope Yes Growth Failure to thrive I,II WHO functional class III,IV Minimally elevated SBNP/NTproBNP Significantly elevated Rising level Echocardiography Severe RV enlargement/dysfunction Pericardial Effusion Systemic CI >3.0 l/min/m2 Hemodynamics Systemic CI <2.5 l/min/m2 mPAP/mSAP <0.75 mPAP/mSAP >0.75 Acute vasoreactivity RAP >10 mm Hg PVRI >20 WU$m2 D124 Ivy et al. JACC Vol. 62, No. 25, Suppl D, 2013 Pediatric Pulmonary Hypertension December 24, 2013:D117–26 recommendations. Sildenafil was approved by the EMA in REFERENCES < 2011 (10 mg 3 times daily for weight 20 kg and 20 mg 1. Haworth SG, Hislop AA. Treatment and survival in children with 3 times daily for weight >20 kg), with a later warning on pulmonary arterial hypertension: the UK Pulmonary Hypertension avoidance of use of higher doses. In August 2012, the FDA Service for Children 2001–2006. 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