Pulmonary Circulation 1:2 2011 by Pulmonary Vascular Research Institute

www.PulmonaryCirculation.org Volume 1, Number 2 (April‐June 2011)

Pulmonary Circulation • Volume 1 • Issue 2 • April-June 2011 • Pages 133-???

Pulmonary Circulation

ISSN: 2045-8932 E-ISSN: 2045-8940

A multi-dimensional map of forces exerted by endothelial cells during capillary formation (please see COVER PHOTO inside)

A Journal of the Pulmonary Vascular Research Institute

COVER PHOTO: An image showing a multi-dimensional map of the forces that pulmonary artery endothelial cells exert on their matrix while networking during capillary formation.

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Pulmonary Circulation

ISSN 2045-8932, E-ISSN 2045-8940

An official journal of the Pulmonary Vascular Research Institute Editors-in-Chief

Senior Editor

Jason X.-J. Yuan, MD, PhD (Chicago, USA) Nicholas W. Morrell, MD (Cambridge, UK) Harikrishnan S., MD (Trivandrum, India)

Ghazwan Butrous, MD (Canterbury, UK)

Kurt R. Stenmark, MD (Denver, USA) Kenneth D. Bloch, MD (Boston, USA) Stephen L. Archer, MD (Chicago, USA) Marlene Rabinovitch, MD (Stanford, USA) Joe G.N. Garcia, MD (Chicago, USA)

Editors

Executive Editor

Harikrishnan S., MD (Trivandrum, India)

Stuart Rich, MD (Chicago, USA) Martin R. Wilkins, MD (London, UK) Hossein A. Ghofrani, MD (Giessen, Germany) Candice D. Fike, MD (Nashville, USA) Werner Seeger, MD (Giessen, Germany)

Scientific Advisory Board

Sheila G. Haworth, MD (London, UK) Patricia A. Thistlethwaite, MD, PhD (San Diego, USA) Chen Wang, MD, PhD (Beijing, China) Antonio A. Lopes, MD, PhD (Sao Paulo, Brazil)

Robert F. Grover, MD, PhD (Denver, USA) Joseph Loscalzo, MD (Boston, USA) Charles A. Hales, MD (Boston, USA) John B. West, MD, PhD, DSc (San Diego, USA) Magdi H. Yacoub, MD, DSc, FRS (London, UK)

Editorial Board

Steven H. Abman, MD, USA Serge Adnot, MD, France Vera D. Aiello, MD, Brazil Almaz Aldashev, MD, PhD, Kyrgyz Republic Diego F. Alvarez, MD, PhD, USA Robyn J. Barst, MD, USA Evgeny Berdyshev, PhD, USA Michael A. Bettmann, MD, USA Jahar Bhattacharya, MD, PhD, USA Konstantin G. Birukov, MD, USA Murali Chakinala, MD, USA Navdeep S. Chandel, PhD, USA Richard N. Channick, MD, USA Hunter C. Champion, MD, USA Shampa Chatterjee, PhD, USA Xiansheng Cheng, MD, China Naomi C. Chesler, PhD, USA Augustine M.K. Choi, MD, USA Paul A. Corris, MD, UK David N. Cornfield, MD, USA Michael J. Cuttica, MD, USA Hiroshi Date, MD, PhD, Japan Regina M. Day, USA Steven M. Dudek, MD, USA Raed A. Dweik, MD, USA Yung E. Earm, MD, PhD, Korea Jeffrey D. Edelman, MD, USA Oliver Eickelberg, PhD, Germany C. Gregory Elliott, MD, USA Serpil Erzurum, MD, USA A. Mark Evans, PhD, UK Karen A. Fagan, MD, USA Barry L. Fanburg, MD, USA Harrison W. Farber, MD, USA Jeffrey A. Feinstein, MD, USA Jeffrey Fineman, MD, USA Patricia W. Finn, MD, USA Sonia C. Flores, PhD, USA Paul R. Forfia, MD, USA Robert Frantz, MD, USA M. Patricia George, MD, USA Mark W. Geraci, MD, USA Stefano Ghio, MD, Italy Mark N. Gillespie, PhD, USA

Reda Girgis, MD, USA Mark T. Gladwin, MD, USA Mardi Gomberg-Maitland, MD, USA Andy Grieve, PhD, Germany Alison M. Gurney, PhD, UK Elizabeth O. Harrington, PhD, USA C. Michael Hart, MD, USA Paul M. Hassoun, MD, USA Abraham G. Hartzema, USA Jianguo He, MD, China Jan Herget, MD, PhD, Czech Republic Nicholas S. Hill, MD, USA Marius M. Hoeper, MD, Germany Eric A. Hoffman, PhD, USA Yuji Imaizumi, PhD, Japan Dunbar Ivy, MD, USA Jeffrey R. Jacobson, MD, USA Roger Johns, MD, PhD, USA Peter L. Jones, PhD, USA Naftali Kaminski, MD, USA Chandrasekharan C. Kartha, MD, India Steven M. Kawut, MD, USA Ann M. Keogh, MD, Australia Nick H. Kim, MD, USA Sung Joon Kim, MD, PhD, Korea James R. Klinger, MD, USA Stella Kourembanas, MD, USA Michael J. Krowka, MD, USA Thomas J. Kulik, MD, USA R. Krishna Kumar, MD, DM, India Steven Kymes, PhD, USA David Langleben, MD, Canada Timothy D. Le Cras, PhD, USA Normand Leblanc, PhD, USA Fabiola Leon-Velarde, MD, Peru Irena Levitan, PhD, USA Jose Lopez-Barneo, MD, PhD, Spain Wenju Lu, MD, PhD, China Roberto Machado, MD, USA Margaret R. MacLean, PhD, UK Michael M. Madani, MD, USA Ayako Makino, PhD, USA Asrar B. Malik, PhD, USA Jess Mandel, MD, USA

Michael A. Matthay, MD, USA Marco Matucci-Cerinic, MD, PhD, Italy Paul McLoughlin, PhD, Ireland Ivan F. McMurtry, PhD, USA Dolly Mehta, PhD, USA Marilyn P. Merker, PhD, USA Barbara O. Meyrick, PhD, USA Evangelos Michelakis, MD, Canada Omar A. Minai, MD, USA Liliana Moreno, PhD, USA Timothy A. Morris, MD, USA Kamal K. Mubarak, MD, USA Srinivas Murali, MD, USA Fiona Murray, PhD, USA Kazufumi Nakamura, MD, PhD, Japan Norifumi Nakanishi, MD, PhD, Japan Robert Naeije, MD, Belgium Viswanathan Natarajan, PhD, USA John H. Newman, MD, USA Andrea Olschewski, MD, Austria Horst Olschewski, MD, Austria Stylianos E. Orfanos, MD, Greece Ronald J. Oudiz, MD, USA Harold Palevsky, MD, USA Lisa A. Palmer, PhD, USA Myung H. Park, MD, USA Qadar Pasha, PhD, India Andrew J. Peacock, MD, UK Joanna Pepke-Zaba, MD, UK Nicola Petrosillo, MD, Italy Bruce R. Pitt, PhD, USA Nanduri R. Prabhakar, PhD, USA Ioana R. Preston, MD, USA Tomas Pulido, MD, Mexico Soni S. Pullamsetti, PhD, Germany Goverdhan D. Puri, MD, India Rozenn Quarck, PhD, Belgium Deborah A. Quinn, MD, USA J. Usha Raj, MD, USA Amer Rana, PhD, USA Thomas C. Resta, PhD, USA Ivan M. Robbins, MD, USA Sharon I. Rounds, MD, USA Nancy J. Rusch, PhD, USA

Editorial Staff

Tarek Safwat, MD, Egypt Sami I. Said, MD, USA Julio Sandoval, MD, Mexico Maria V.T. Santana, MD, Brazil Bhagavathula K. Sastry, MD., India Anita Saxena, MD, India Marc J. Semigran, MD, USA Ralph T. Schermuly, MD, Germany Dean Schraufnagel, MD, USA Paul T. Schumacker, PhD, USA Pravin B. Sehgal, MD, PhD, USA James S.K. Sham, PhD, USA Steven D. Shapiro, MD, USA Larisa A. Shimoda, PhD, USA Robin H. Steinhorn, MD, USA Troy Stevens, PhD, USA Duncan J. Stuart, MD, Canada Yuchiro J. Suzuki, PhD, USA Victor F. Tapson, MD, USA Merryn H. Tawhai, PhD, New Zealand Dick Tibboel, MD, PhD, The Netherlands Christoph Thiemermann, MD, PhD, UK Mary I. Townsley, PhD, USA Richard C. Trembath, MD, UK Rubin M. Tuder, MD, USA Carmine D. Vizza, MD, Italy Norbert F. Voelkel, MD, USA Peter D. Wagner, MD, USA Wiltz W. Wagner, Jr., PhD, USA Jian Wang, MD, USA Jian-Ying Wang, MD, USA Jun Wang, MD, PhD, China Xingxiang Wang, MD, China Jeremy P.T. Ward, PhD, UK Aaron B. Waxman, MD, USA Norbert Weissmann, PhD, Germany James D. West, PhD, USA R. James White, MD, USA Sean W. Wilson, PhD, USA Michael S. Wolin, PhD, USA Tianyi Wu, MD, China Lan Zhao, MD PhD, UK Nanshan Zhong, MD, China Brian S. Zuckerbraun, MD, USA

Nikki Krol (London, UK), nkrol@imperial.ac.uk Karen Gordon (Chicago, USA), gordonk@uic.edu Paul Soderberg (Phoenix, USA), paulsoderberg@hotmail.com

Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Pulmonary Circulation

| April-June 2011 | Vol 1 | No 2 |

An official journal of the Pulmonary Vascular Research Institute

CONTENTS LEFT TO RIGHT: pages 164, 216, 265, and 229

Zc =

rEh 2p 2r 5

inside front cover

General Information

Editors and Board Members Editorial Our journey continues

Jason X.-J. Yuan, Nicholas W. Morrell, S. Harikrishnan, Ghazwan Butrous

Guest Editorial Classification of pediatric pulmonary hypertensive vascular disease: Does it need to be different from the adult classification? Robyn J. Barst

Review Articles Overview of current therapeutic approaches for pulmonary hypertension Jason A. Stamm, Michael G. Risbano, and Michael A. Mathier

Diagnosis and assessment of pulmonary vascular disease by Doppler echocardiography Justin D. Roberts and Paul R. Forfia

Lung transplantation for pulmonary hypertension

M. Patricia George, Hunter C. Champion, and Joseph M. Pilewski

134

138 160 182

Acute respiratory distress syndrome: A clinical review Michael Donahoe

192

Pulmonary vascular wall stiffness: An important contributor to the increased right ventricular afterload with pulmonary hypertension Zhijie Wang and Naomi C. Chesler

Computational models of the pulmonary circulation: Insights and the move towards clinically directed studies Merryn H. Tawhai, Alys R. Clark, and Kelly S. Burrowes

Research Articles Air travel can be safe and well tolerated in patients with clinically stable pulmonary hypertension Melanie Thamm, Robert Voswinckel, Henning Tiede, Friederike Lendeckel, Friedrich Grimminger, Werner Seeger, and Hossein A. Ghofrani

133

212

224

239

Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

CONTENTS continued

Log-transformation improves the prognostic value of serial NT-proBNP levels in apparently stable pulmonary arterial hypertension Elaine Soon, Natalie J. Doughty, Carmen M. Treacy, Robert M. Ross, Mark Toshner, Paul D. Upton, Karen Sheares, Nicholas W. Morrell, and Joanna Pepke-Zaba

Vasoreactivity to inhaled nitric oxide with oxygen predicts long-term survival in pulmonary arterial hypertension

Rajeev Malhotra, Dean Hess, Gregory D. Lewis, Kenneth D. Bloch, Aaron B. Waxman, and Marc J. Semigran

Hypoxic pulmonary hypertension in mice with constitutively active platelet-derived growth factor receptor-b Bhola K. Dahal, Rainer Heuchel, Soni Savai Pullamsetti, Jochen Wilhelm, Hossein A. Ghofrani, Norbert Weissmann, Werner Seeger, Friedrich Grimminger, and Ralph T. Schermuly

Guidelines and Consensus Functional classification of pulmonary hypertension in children: Report from the PVRI pediatric taskforce, Panama 2011 Astrid E. Lammers, Ian Adatia, Maria Jesus del Cerro, Gabriel Diaz, Alexandra Heath Freudenthal, Franz Freudenthal, S. Harikrishnan, Dunbar Ivy, Antonio A. Lopes, J. Usha Raj, Julio Sandoval, Kurt Stenmark, and Sheila G. Haworth

A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011 Maria Jesus del Cerro, Steven Abman, Gabriel Diaz, Alexandra Heath Freudenthal, Franz Freudenthal, S. Harikrishnan, Sheila G. Haworth, Dunbar Ivy, Antonio A. Lopes, J. Usha Raj, Julio Sandoval, Kurt Stenmark, and Ian Adatia

Snapshot Drugs currently used for treatment of of pulmonary arterial hypertension (PAH) Ankit Desai and Roberto Machado

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Contributions to Pulmonary Circulation

300

Why Become a Pulmonary Circulation Author?

302

Call for Papers

LEFT TO RGHT: pages 288, 188, 207, and 276

Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

inside back cover

iii

Corrigenda In our last issue, in the Review Article by Green et al. (Is peroxisome proliferator-activated receptor gamma (PPARg) a therapeutic target for the treatment of pulmonary hypertension?), there were 3 errors, which are corrected here. 1. On page 44, Citation [18]—Hansmann L, Groeger S, et al. Human monocytes represent a competitive source of interferon-alpha in peripheral blood. Clin Immunol 2008;127(2):252-264—should have been: Hansmann G, de Jesus Perez Vinicio A, et al. An antiproliferative BMP-2/PPARg/apoE axis in human and murine SMCs and its role in pulmonary hypertension.” J Clin Invest 2008;118(5):1846-57. 2. Also, on page 44, Citation [22]—Hansmann G, de Jesus Perez VA, et al. An antiproliferative BMP2/PPARg/apoE axis in human and murine SMCs and its role in pulmonary hypertension. J Clin Invest 2008;118(5):1846-57—should have been: Hansmann, G., Wagner RA, et al. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation. Circulation 2007;115(10): 1275-84. 3. Finally, the reference on page 35 to the paper by Dr. Hansmann et al. should be [18] rather than [22]. iv

Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Edi t ori al

Our journey continues In 2008, when we first envisaged a professional journal dedicated to pulmonary vascular disease, it was our hope that others in our field would share our conviction that such a journal was needed. The response to our inaugural issue, published this past March, has vindicated that hope beyond expectation. From colleagues, trainees and students we received feedback, including suggestions for improvement, many of which we are incorporating. For example, we are premiering a new feature in this issue, at the foot of this page–corrections or clarifications of points in previous issues either by authors (Corrigenda) or by the editors (Errata). This issue also premieres an exciting new type of contribution, the Snapshot. Each of these will be a single page compilation on a particular topic. This issue’s Snapshot is on drugs for pulmonary hypertension.

The lifeblood of any professional journal is the quality of manuscripts it receives. We are now processing a steadily increasing volume of submissions through our web portal (www.journalonweb.com/PC/). The topics of the original research articles in this second issue include the blockade of Ca2+-activated Cl- channels and the role of plateletderived growth factor receptors in hypoxic pulmonary hypertension in mice. The article on safety of air travel for patients with pulmonary hypertension (PH) answers a question clinicians frequently are asked in clinics. Two articles deal with the outcome of patients with PH, one with vasoreactivity to inhaled nitric oxide and its impact on long-term survival, the other describing the use of logtransformed ntBNP in predicting response to therapy. In this issue we also present review articles on clinically focused issues for readers working in the clinical management of pulmonary hypertension patients. These include reviews on the current treatment of pulmonary hypertension, on the Doppler echocardiographic assessment in pulmonary vascular disease, on acute respiratory distress syndrome, on pulmonary vascular wall stiffness, and computational models in the pulmonary circulation and gas exchange. A special highlight in this second issue is the classification of pediatric pulmonary vascular diseases. The Pulmonary Vascular Research Institute (PVRI) initiated a discussion on this topic during its annual meeting in Panama City early this year, and the pediatric pulmonary hypertension taskforce was given the task of proposing a new classification. In this issue we are proud to present two articles on this topic, which put forward both a new diagnostic classification system for pediatric pulmonary vascular disease and a functional classification of PH in children. On the following page is Robyn Barst’s excellent guest editorial that provides the context for both of those articles. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

In the 6th Century BCE the Chinese philosopher Laozi (Lao Tzu) wrote in the Daodejing (Tao Te Ching), “A journey of a thousand miles begins with a single step.” The first step of the journey upon which Pulmonary Circulation is now embarked was taken this past March, with the publication of Volume 1, Number 1, and the present issue is our second step. Where will this journey lead? Inevitably, as authors share their work and discoveries with readers, the journey will lead to advances in our field, as this new journal becomes the primary medium of communication between physicians and researchers in the field of pulmonary vascular diseases worldwide. In particular, we hope, our journey will contribute to easing the enormous burden of pulmonary vascular disease in the so-called developing world. Although the research output in the form of publications from these regions is far less compared to elsewhere, we will endeavor to bring high-quality research outputs from these regions to the attention of the so-called developed world. But in a very real sense, the specific journey that Pulmonary Circulation ends up taking will be determined by you, the clinicians and researchers engaged in this rapidly evolving and exciting field. If you are engaged in clinical, translational or basic science on any aspect of pulmonary vascular disease or physiology, then this journal will provide the ideal home for your research. We encourage you to send in feedback for improvements and, best of all, manuscripts describing your work or the topics you feel of greatest importance to our field. For this all-important feedback, we thank you sincerely in advance.

Jason X.-J. Yuan1, Nicholas W. Morrell2, S. Harikrishnan3, Ghazwan Butrous4

1 Departments of Medicine and Pharmacology, The Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA; 2Department of Medicine, Division of Respiratory Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, UK; 3Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India; 4 University of Kent, Canterbury,

Email: jxyuan@uic.edu Access this article online Quick Response Code:

Website: www.pulmonarycirculation.org DOI: 10.4103/2045-8932.83442

How to cite this article: Yuan JX, Morrell NW, Harikrishnan S, Butrous G. Our journey continues. Pulm Circ 2011;1:133.

133

Guest Edi t o r i al

Classification of pediatric pulmonary hypertensive vascular disease: Does it need to be different from the adult classification? Robyn J. Barst Columbia University, New York, New York USA

CLINICAL CLASSIFICATION The clinical classification of pulmonary hypertension (PH) has gone through a series of changes since the first classification was proposed in 1973 at the World Health Organization international conference on primary pulmonary hypertension (PPH) in Geneva, Switzerland.[1,2] The initial classification designated only two categories, primary pulmonary hypertension (PPH) and secondary PH, depending on the presence or absence of identifiable causes or risk factors. Twenty-five years later, a second World Symposium on Pulmonary Arterial Hypertension (PAH) was held in 1998 in Evian, France. Based on the research that had ensued in studying the pulmonary circulation since 1973, by 1998 significant advances had been made in our understanding of PH. Further, the first drug for PPH was approved during this time, i.e., in 1995. Thus, because the aim of a clinical classification is to individualize different categories sharing similarities in pathobiology, clinical presentation, and therapeutic approaches, the “Evian Classification” was based on defining categories of PH that shared similar histopathology and clinical characteristics. The Evian Classification expanded the prior 1973 classification from 2 groups to 5 major groups with Group 1 PH being the most studied, i.e., PAH.[3] In 2003, during the third World Symposium on PH held in Venice, Italy, the clinical classification was slightly modified,[4] with further modification most recently during the fourth World Symposium held in Dana Point, California in 2008[5] (Table 1). Although not the basis for the modifications, these modifications also permitted clinical investigators to conduct randomized controlled drug trials in patients with a shared underlying pathobiology (resulting in our currently having 8 drugs approved for the treatment of adult subjects with PAH, i.e., Group 1 PH).

Address correspondence to:

Robyn J. Barst MD Professor Emeritus, Columbia University New York, New York USA Email: robyn.barst @gmail.com 134

The classifications were developed, and revised, based on the current understanding of PH, i.e., its etiology, pathobiology, clinical course and response to therapeutic interventions. The majority of the work in this field has focused on PAH, i.e., Group 1 PH. And although these classifications were never specifically limited to adult subjects, utilizing them for all pediatric subjects can be less than ideal. Reasons for this include unique aspects of childhood PH, not the least of which is that PH can start in utero resulting in growth abnormalities that can persist into adulthood. Further, with improvements in our ability to effectively take care of premature infants, children are now living longer with many children not infrequently having various forms of pulmonary vascular disease that did not exist several decades ago (and thus are not included in the most recent Dana Point Classification). Nevertheless, the Dana Point Classification has been, and continues to be, invaluable in our advancing the PH field. It has also been invaluable for adolescent patients and has facilitated obtaining therapy for younger children.

However, the Dana Point Classification has limitations for classifying pulmonary vascular disease in childhood. Thus, at the 2011 Pulmonary Vascular Research Institute (PVRI) meeting in Panama, a new classification for Pediatric Pulmonary Hypertensive Vascular Disease was developed by a group of investigators focused on pulmonary hypertension in childhood.[6,7] The aim was not to replace the Dana Point Classification of 2008 but rather to augment it for specific pediatric disorders. The proposed classification, presented in this issue of Pulmonary Circulation, may be called the “Panama Classification, sponsored by the Pulmonary Vascular Research Institute,” Access this article online

Quick Response Code:

Website: www.pulmonarycirculation.org DOI: 10.4103/2045-8932.83443

How to cite this article: Barst RJ. Classification of pediatric pulmonary hypertensive vascular disease: Does it need to be different from the adult classification?. Pulm Circ 2011;1:134-7.

Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Barst: Pediatric PHVD Classification

or, “the Panama Classification (2011).” This classification now allows those interested in pediatric pulmonary hypertensive vascular disease to more critically identify specific diseases and disorders that we hope will improve our ability to move the field forward. In many aspects, pediatric PH is now where PH in the adult was 2 decades Table 1: Dana Point clinical classification of pulmonary hypertension (2008)

1. Pulmonary Arterial Hypertension 1.1 I diopathic PAH 1.2 H eritable 1.2.1. B MPR2 1.2.2. A LK1, endoglin (with or without hereditary hemorrhagic telangiectasia) 1.2.3. Unknown. 1.3 D rug- and toxin-induced 1.4 A ssociated with 1.4.1. C onnective tissue diseases 1.4.2. H IV infection 1.4.3. P ortal hypertension 1.4.4. C ongenital heart diseases 1.4.5. Schistosomiasis 1.4.6. C hronic hemolytic anemia 1.5 P ersistent pulmonary hypertension of the newborn 1.’ P ulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) 2. P ulmonary hypertension due to left heart disease 2.1 S ystolic dysfunction 2.2 D iastolic dysfunction 2.3 V alvular disease 3. P ulmonary hypertension due to lung diseases and/or hypoxia 3.1 C hronic obstructive pulmonary disease 3.2 I nterstitial lung disease 3.3 O ther pulmonary diseases with mixed restrictive and obstructive pattern 3.4 S leep-disordered breathing 3.5 A lveolar hypoventilation disorders 3.6 C hronic exposure to high altitude 3.7 D evelopmental abnormalities 4. C hronic thromboembolic pulmonary hypertension (CTEPH) 5. PH with unclear multifactorial mechanisms 5.1 H ematologic disorders: myeloproliferative disorders splenectomy 5.2 S ystemic disorders, sarcoidosis, pulmonary Langerhans cell histiocytosis lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 M etabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 O thers: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

ago; including our lagging behind in developing evidencebased treatment guidelines for children with PH with increased pulmonary vascular resistance (PVR). The current consensus-based treatment recommendations for children with PAH are based on extrapolation from the evidence-based adult PAH treatment guidelines. And although due to the similarities between children and adults there is no reason to believe that drugs approved to treat PAH in adults will not be efficacious in pediatric PAH, determining optimal dosing and long-term safety, including potential effects on growth and development, cannot merely be extrapolated from adult data. Children are not “small adults.”

There are also important aspects of neonatal and childhood pulmonary hypertensive vascular disease that are not included in the 2008 Dana Point Classification. These include: (1) fetal origins of pulmonary vascular disease; (2) the potential importance of developmental mechanisms in both childhood and adult onset disease; (3) an inconsistent approach to neonatal pulmonary vascular disease; (4) the importance of perinatal maladaptation, maldevelopment and pulmonary hypoplasia in pulmonary vascular disease; (5) variability in the heterogeneity of factors that contribute to pulmonary vascular disease in children compared with adults; and (6) adult survivors of pediatric pulmonary vascular disease (e.g., children with pulmonary vascular disease who in the past never survived long enough to reach adulthood are now surviving into adulthood). Additionally, there are risk factors that may be significant in children that have not been considered significant in adult PH (Table 2).

The Dana Point Classification Supplements that focus on the specifics of the congenital heart defects are useful but remain less than ideal for use in patients of all ages. For example, a 1-cm defect may be large in an infant but small in an adult (Table 3). Nevertheless, defining the congenital heart defects as accurately as possible is useful. I find the Groups A, B, C and D in patients with congenital systemic to pulmonary shunts very informative and recommend that they be included in the pediatric classification (Table 4). Classifications are useful in medicine because they provide a framework for diagnosis and management, and encourage epidemiological insight. They should also include categories for undiscovered diseases and undiscovered mechanisms of known disease complexes but this is more difficult. As the authors of this new

Table 2: Updated risk factors and associated conditions for PAH Definite

Likely

Possible

Unlikely

Aminorex Fenfluramine Dexfenfluramine Toxic rapeseed oil

Amphetamines L-tryptophan Methamphetamines

Cocaine Phenylpropanolamine St. John’s Wort Chemotherapeutic agents; SSRIs

Oral contraceptives Estrogen Cigarette smoking

Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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Barst: Pediatric PHVD Classification

Table 3: Anatomic-pathophysiologic classification of congenital systemic-to-pulmonary shunts associated with pulmonary arterial hypertension

Table 4: Clinical classification of congenital systemic-to-pulmonary shunts associated with pulmonary arterial hypertension

1. Type 1.1. S imple pre-tricuspid shunts 1.1.1. A trial septal defect (ASD) 1.1.1.1. O stium secundum 1.1.1.2. S inus venosus 1.1.1.3. O stium primum 1.1.2. T otal or partial unobstructed anomalous pulmonary venous return 1.2. S imple post-tricuspid shunts 1.2.1. V entricular septal defect (VSD) 1.2.2. P atent ductus arteriosus 1.3. C ombined shunts Describe combination and define predominant defect 1.4. C omplex CHD 1.4.1. C omplete atrioventricular septal defect 1.4.2. T runcus arteriosus 1.4.3. S ingle ventricle physiology with unobstructed pulmonary blood flow 1.4.4. T ransposition of the great arteries with VSD (without pulmonary stenosis) and/or patent ductus arteriosus 1.4.5. Other 2. Dimension (specify for each defect if more than one congenital heart defect) 2.1. H emodynamic (specify Qp/Qs)* 2.1.1. R estrictive (pressure gradient across the defect) 2.1.2. Nonrestrictive 2.2. Anatomic 2.2.1. S mall to moderate (ASD≤2.0 cm and VSD≤1.0 cm) 2.2.2. L arge (ASD>2.0 cm and VSD>1.0 cm) 3. Direction of shunt 3.1. P redominantly systemic-to-pulmonary 3.2. P redominantly pulmonary-to-systemic 3.3. Bidirectional 4. A ssociated cardiac and extracardiac abnormalities 5. Repair status 5.1. Unoperated 5.2. P alliated (specify type of operation/s, age at surgery)

A. Eisenmenger syndrome Includes all systemic-to-pulmonary shunts resulting from large defects and leading to a severe increase in pulmonary vascular resistance (PVR) and a reversed (pulmonary-to-systemic) or bidirectional shunt. Cyanosis, erythrocytosis, and multiple organ involvement are present. B. P ulmonary arterial hypertension associated with systemic-to-pulmonary shunts Includes moderate to large defects. PVR is mildly to moderately increased, systemic-to-pulmonary shunt is still prevalent, and no cyanosis is present at rest. C. Pulmonary arterial hypertension with small defects Small defects (usually ventricular septal defects <1 cm and atrial septal defect <2 cm of effective diameter assessed by echocardiography). The clinical picture is very similar to idiopathic pulmonary arterial hypertension (PAH). D. P ulmonary arterial hypertension after corrective cardiac surgery Congenital heart disease has been corrected, but PAH is still present immediately after surgery or recurs several months or years after surgery in the absence of significant postoperative residual lesions.

Repaired (specify type of operation/s, age at surgery) * Ratio of pulmonary (Qp) to systemic (Qs) blood flow

proposed pediatric classification point out, the aims are to: Improve diagnostic strategies, promote clinical investigation in pathobiology, pathophysiology and outcomes, provide guidance for human disease modeling in laboratory and animal studies, and serve as an educational resource. However, it is important to note that this new classification was not designed solely to serve as a therapeutic guide. This “Panama Classification (2011)” has been termed “pulmonary hypertensive vascular disease” as opposed to PH to exclude children with PH who do not have increased PVR. A significant number of children have PH without increased PVR, e.g., children with large left to right 136

systemic to pulmonary shunts, in whom the treatment should be closure of the shunts and not treatment for PAH (which by definition requires an increase in PVR in addition to PH). Unfortunately, the term PAH does not immediately equate to PH with increased PVR to the pediatric cardiology community; it never has, and I doubt it ever will regardless of education attempts at conveying this.

This pediatric classification also includes children with an increase in PVR in whom the mean pulmonary artery pressure (PAPm) may be less than 25 mmHg but the children are symptomatic from the increased PVR, e.g. children undergoing staged repair for a single ventricle. And as surgical procedures improve, many of these children will survive into adulthood with symptomatic pulmonary vascular disease due to increased PVR without a mean PAP≥25 mmHg. The proposal for the definition of pediatric pulmonary hypertensive vascular disease is: an increased pulmonary vascular resistance index (PVRI), i.e. ≥3 Wood units times m2 whether or not the PAPm is ≥25 mmHg. No classifications are perfect; their value is if and only if they are used, thereby permitting colleagues in different specialties around the world to communicate with one another using the same language. To balance being allinclusive with adequate simplicity is the challenge. At first review, this new proposal appears overwhelming; however, the 10 divisions are quite straightforward when viewed individually. There will always be overlap Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Barst: Pediatric PHVD Classification

Table 5: Modified NYHA functional classification for PH Class I Patients with pulmonary hypertension but without limitation of physical activity. Ordinary physical activity does not cause undue dyspnea, fatigue chest pain or near syncope. Class II Patients with pulmonary hypertension resulting in slight limitation of physical activity. Comfortable at rest. Ordinary physical activity causes undue dyspnea, fatigue, chest pain or near syncope. Class III Patients with pulmonary hypertension resulting in marked limitation of activity. Comfortable at rest. Less than ordinary activity causes dyspnea or fatigue, chest pain or near syncope. Class IV Patients with pulmonary hypertension resulting in inability to carry out any physical activity without symptoms. These patients manifest symptoms of right heart failure. Dyspnea and/or fatigue may be present even at rest. Discomfort is increased by any physical activity undertaken. Syncope or near syncope can occur.

as there is in the Dana Point Classification, since patients have genetic, epigenetic, environmental and unknown factors triggering the development of pulmonary vascular disease. In the Dana Point Classification, a patient may be considered to have Group 1 PH, i.e., PAH, as his primary diagnosis, but he may also have COPD, left ventricular diastolic dysfunction, etc., that may be contributing in some way to the patient’s PH. Multi-factorial conditions come into play in subjects of all ages. However, in addition to multi-factorial conditions in the pediatric population, pathological insults on the growing lung and pulmonary developmental abnormalities can be quite significant. Additionally, children with chromosomal or genetic syndromes that may not have previously survived to adulthood are surviving longer and not infrequently these syndromes appear to contribute to the development of pulmonary vascular disease. And whether some of these factors will affect the response to various therapies remains unclear but certainly is possible and will require careful study. Utilizing this new pediatric clinical classification will undoubtedly result in modifications; if not, then the classification will not have been successful, as one of its goals is to advance research and further our understanding of pulmonary vascular disease in subjects of all ages.

FUNCTIONAL CLASSIFICATION

What about how we assess patients’ functional capacity? Can we use the same functional classification for children as we do for adults? And what about children of differing ages, e.g. infants, toddlers, school-age children, Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

adolescents? As one of our goals in treating patients is to improve their overall quality of life (in addition to increasing survival), how should we assess children? For adult PH, we modified the NYHA functional classification specifically for PH (Table 5). And although clinicians may vary from one to another in how they classify patients, for a given patient, classification performed by the same clinician appears quite useful in assessing functional capacity. But when we look at this classification for children, there are significant difficulties in using it. The members of the 2011 PVRI pediatric task force therefore also proposed a new functional classification for children with PH. The adult classification was modified based on differences in age, maturity, and motor and language development. Further, how a parent perceives their child is doing is also important and thus assessments from the children (adapted for various aged children) and from their parents were developed. Similar to the pediatric clinical classification, this pediatric functional capacity classification may appear quite complicated when first looking at it, but that is because of the significant changes that occur normally from infancy through adolescence and the inability to have a “one size fits all” functional capacity tool. Thus when you look at the classification specifically for the age child you want to assess, this proposed classification should permit us to accurately assess how a child is coping with his illness and functionally in his family, school and interacting with his peers. I commend these investigators for their dedication to advancing our understanding of pulmonary vascular disease in childhood. As we move forward in the field of PH and pulmonary vascular disease in children and in adults, an increased collaboration between investigators committed to this disease will improve outcomes for all aged patients; life is a continuum.

REFERENCES 1. 2.

3. 4.

Hatano S, Strasser T. Primary pulmonary hypertension. Report on a WHO meeting. October 15-17, 1973, Geneva: WHO; 1975. Wagenvoort CA, Wagenvoort N. Primary pulmonary hypertension: A pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970;42:1163-84. Fishman AP. Clinical classification of pulmonary hypertension. Clin Chest Med 2001;22:385-91, vii. Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:S5-S12. Simonneau G, Robbins IM, Beghetti M, Channick RN, Denton CP, Elliott GE, et al. Updated Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43-54. Del Cerro MJ, Abman S, Diaz G, Freudenthal AH, Freudenthal F, Harikrishnan S, et al. A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011. Pulm Circ 2011;2:286-98. Lammers AE, Adatia I, del Cerro MJ, Diaz G, Freudenthal AH, Freudenthal F, et al. Functional classification of pulmonary hypertension in children: Report from the PVRI pediatric taskforce, Panama 2011. Pulm Circ 2011;2:280-5.

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Review Ar ti cl e

Overview of current therapeutic approaches for pulmonary hypertension Jason A. Stamm1, Michael G. Risbano2, and Michael A. Mathier3 1

Department of Pulmonary, Allergy, and Critical Care Medicine, Geisinger Medical Center, Danville, 2Department of Pulmonary and Critical Care Medicine, University of Pittsburgh Medial Center (UPMC), Pittsburgh, 3UPMC Cardiovascular Institute, Pittsburgh, Pennsylvania

ABSTRACT There have been tremendous strides in the management of pulmonary hypertension over the past 20 years with the introduction of targeted medical therapies and overall improvements in surgical treatment options and general supportive care. Furthermore, recent data shows that the survival of those with pulmonary arterial hypertension is improving. While there has been tremendous progress, much work remains to be done in improving the care of those with secondary forms of pulmonary hypertension, who constitute the majority of patients with this disorder, and in the optimal treatment approach in those with pulmonary arterial hypertension. This article will review general and targeted medical treatment, along with surgical interventions, of those with pulmonary hypertension. Key Words: pulmonary hypertension, pulmonary arterial hypertension, therapy, treatment

BACKGROUND Pulmonary hypertension (PH) is a disorder of the pulmonary vasculature that results in increased pulmonary arterial pressure and is defined as a mean pulmonary arterial pressure (mPAP)≥25 mm Hg at rest.1 Pulmonary arterial hypertension (PAH) is a subset of PH that results from increased vascular resistance in the pulmonary arteries and may ultimately result in right heart failure. PH can be idiopathic or associated with a variety of disorders but is broadly classified into five groups based upon shared pathophysiologic and clinical features: I. pre-capillary or pulmonary arterial hypertension (PAH); II. PH with left heart disease (e.g., left ventricular dysfunction and valvular heart disease); III. PH associated with disorders of the respiratory system; IV. PH caused by chronic thromboembolic disease (CTEPH); and V. PH associated with miscellaneous disorders, such as sarcoidosis (Table 1).[1] A key point in caring for patients with PH is that the correct etiology must be established, and the severity of disease quantified, before treatment can be considered. PAH, which results from intrinsic disease of

Address correspondence to:

Dr. Michael Mathier University of Pittsburgh Medical Center 200 Lothrop Street S553 Scaife Hall Pittsburgh PA 15213 USA Phone (Office): 412/647-3429 Fax: 412/647-0481 E-mail: mathierm@upmc.edu 138

the pulmonary vessels, is amenable to specific medical therapy, while treatment of other forms of PH is generally supportive and aimed at the underlying disorder. While other forms of PH are more prevalent, PAH has garnered much attention over the past several decades due to its frequent occurrence in healthy young to middle-aged adults, and more recently, the explosion of knowledge illuminating disease pathogenesis and of newly available therapies.

The reported prevalence of PAH is 15 per million, with a mean age at diagnosis of 50±15 years; women constitute three-quarters of those affected.[2,3] Notably, the average duration between symptom onset and diagnosis is over 2 years.[3] Idiopathic PAH, that which occurs with neither a family history of PAH nor an identified risk factor or associated clinical condition, accounts for 40% of PAH diagnoses, based on data from a recent U.S. registry.[3] Heritable PAH, caused by somatic mutations in genes of the transforming growth factor β (TGF-β) receptor Access this article online

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Website: www.pulmonarycirculation.org DOI: 10.4103/2045-8932.83444 How to cite this article: Stamm JA, Risbano MG, Mathier MA. Overview of current therapeutic approaches for pulmonary hypertension. Pulm Circ 2011;1:138-59.

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family, accounts for approximately 5% of patients with PAH, although similar mutations have been found in up to 20% of those with apparent idiopathic PAH.[2,4,5] A number of drugs and medications have been associated with the development of PAH; the most notorious of these include the appetite suppressants fenfluramine and dexfenfluramine, although methamphetamine use has been more recently indicted as a cause of drug-related PAH.[6,7]

Associated PAH is that which occurs in the presence of some other systemic disease; approximately 50% of PAH patients fall into this category.[3] While many of the connective tissues diseases have been associated with PAH, the most common etiology is that of the systemic sclerosis spectrum of disease, particularly limited systemic sclerosis.â&#x20AC;&#x2030;[8,9] A significant proportion of patients with uncorrected congenital heart disease, particularly those with systemic to pulmonary shunts, will develop PAH and Eisenmenger syndrome.[1] PAH is also an uncommon but documented complication of HIV infection, chronic hemolytic anemia, and cirrhosis with portal hypertension. [1] Finally, in developing countries, schistosomiasis is a frequent cause of PAH, with an estimated 200 million people infected worldwide. Indeed, chronic schistosomiasis infection may be one of the most common causes of PAH worldwide.[10]

PATHOPHYSIOLOGY

The pathophysiology of PAH has recently been reviewed

and is beyond the scope of this article.[11,12] However, a basic understanding of the normal pulmonary circulation, and of the abnormalities seen in those with PAH, is essential to the discussion and application of therapy. The remarkable progress made in clarifying the molecular pathways that contribute to the pathogenesis of PAH has resulted in the identification of multiple therapeutic targets and forms the basis of both currently available and investigational agents. All of the approved PAH-specific medications target one of three pathways: the prostacyclin pathway, the nitric oxide pathway, and the endothelin pathway.

The normal pulmonary circulation is capable of accommodating the entire cardiac output at perfusion pressures that are approximately 20% those of the systemic circulation, even with conditions of increased cardiac output such as exercise. The pulmonary circulation accomplishes this by dilation of the vasculature already receiving the cardiac output and recruitment of unused vasculature; through these mechanisms the pulmonary circulation minimizes increases in perfusion pressure and maximizes gas exchange surface area. The local production of several humoral mediators, including nitric oxide (NO) and prostacyclin, contribute to the maintenance of a low vasomotor tone. In contrast to normal pulmonary vascular physiology, PH can be caused by either narrowing of the precapillary vessels (arteries and arterioles), loss of vascular surface area, and/or passive pressure from the postcapillary

Table 1: Classification of pulmonary hypertension, Dana Point (2008) PH Group

Subtypes

Group I: Pulmonary Arterial Hypertension

Sporadic or Idiopathic PAH Heritable PAH Drug- and toxin-induced PAH Conditions associated with PAH

Group II: PH owing to left heart disease Group III: PH owing to lung diseases and/or hypoxemia

Group IV: Chronic thromboembolic PH Group V: PH with unclear or multifactorial mechanisms

Associated with significant venous or capillary involvement Systolic or non-systolic dysfunction, valve disease Chronic obstructive pulmonary disease Interstitial lung disease Sleep-disordered breathing and alveolar hypoventilation disorders Chronic exposure to high-altitudes Chronic thromboembolic pulmonary hypertension Hematologic disorders Systemic disorders Metabolic disorders

Specific examples BMPR2, ALK1, others Anorexigens, methamphetamines, others Collagen vascular diseases Congenital systemic to pulmonary shunts Portal hypertension HIV infection Chronic hemolytic anemias Schistosomiasis Pulmonary veno-occlusive disorder Pulmonary capillary hemangiomatosis

OSA, OHS, neuromuscular disorders

Myeloproliferative disorders, splenectomy Sarcoidosis Glycogen storage diseases

ALK1: activin-like kinase, type I; BMPR2: bone morphogenetic protein, type II; HIV: human immunodeficiency virus; OSA: obstructive sleep apnea; OHS: obesity hypoventilation syndrome; PAH: pulmonary arterial hypertension; PH: pulmonary hypertension

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vessels (Table 2). In PAH, the classic histological finding is the plexiform lesion. While neither sensitive nor specific for PAH, the plexiform lesion, a localized proliferation of endothelial cells, smooth muscle cells, fibroblasts and extracellular matrix, is found in pre-capillary and intraacinar pulmonary vessels. Along with medial hypertrophy and intimal thickening by smooth muscle cells and fibroblasts, resistance to blood flow within plexiform lesions is secondary to endothelial-lined channels that narrow the vascular lumen.[13] Activation and expression of adhesion molecules by endothelial cells results in a procoagulant state, with thrombin deposition and platelet adhesion. The sum of these abnormalities in the pulmonary vasculature of those with PAH is unregulated vasoconstriction, smooth muscle cell proliferation out of proportion to apoptosis, and microvascular thrombosis.[12] Studies of the pulmonary vasculature in idiopathic PAH suggest endothelial injury and dysfunction occur early in the process. In idiopathic PAH, expression of pulmonary endothelial nitric oxide synthetase and prostacyclin synthetase are reduced while levels of endothelin-1 and thromboxane are increased.[11,14] Prostacyclin and nitric oxide (NO) are potent vasodilators and inhibitors of platelet activation and vascular smooth muscle proliferation. The effects of prostacyclin are mediated through adenylate cyclase and the 2nd messenger cyclic adenosine monophosphate (cAMP).[15] Nitric oxide is synthesized from L-arginine by NO synthetases; this readily diffusible gas enters smooth muscle cells and mediates vascular relaxation through stimulation of soluble guanylate cyclase, generating the 2nd messenger cyclic guanosine monophosphate (cGMP). cGMP is subsequently regulated by a phosphodiesterase (PDE-5) which metabolizes cGMP and thus inhibits NO-mediated vasodilation. [11] Endothelin-1 and thromboxane are potent pulmonary vasoconstrictors and mitogens. Serotonin, another pulmonary vasoconstrictor, may also play a role.â&#x20AC;&#x2030;[16] Other mechanisms that have been postulated to explain the development of PAH include disordered mitochondrial metabolism in which glucose metabolism is shifted from oxidative phosphorylation to that of glycolysis despite adequate oxygen tension, a property shared with some malignant cells; this pseudohypoxic state fosters cellular proliferation and resistance to apoptosis.[17] Another potential mechanism underlying PAH is decreased expression or function of smooth muscle potassium receptors, which results in membrane depolarization and increased concentrations of intracellular calcium. Calcium is an important regulator of vasomotor tone and proliferation; the sustained increase in intracellular calcium levels promotes smooth muscle proliferation and contributes to vascular remodeling.[18,19] Finally, growth factors and inflammatory mediators are implicated in the abnormal proliferation and migration 140

Table 2: Relationship between vascular lesion location, pathologic process, and corresponding forms of PH Vascular lesion location

Pathologic process

Corresponding form of PH

Pre-capillary

Intravascular obstruction or vascular remodeling

Capillary

Destruction of intra-pulmonary capillary bed Passive pressure from elevated left atrial pressure or LVEDP

Vasculopathy caused by drugs/toxins, connective tissue disease, inherited disorders, or idiopathic PAH; chronic pulmonary emboli Emphysema; interstitial lung disease

Postcapillary

Left ventricular failure with depressed systolic or preserved ejection fraction; valve disease

LVEDP: left ventricular end-diastolic pressure; PAH: pulmonary artery hypertension; PH: pulmonary hypertension

of pulmonary vascular cells. Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) are potent mitogens and chemoattractants for endothelial cells, smooth muscle cells, and fibroblasts; the activity of both VEGF and PDGF are increased in PAH.[20-22] These cellular pathways are not mutually exclusive and likely interact in the development of PAH.

MANAGEMENT: GENERAL PRINCIPLES

Regardless of the etiology of PH, general supportive care is similar for all PH patients and focuses on improving symptoms and quality of life, mitigating disease progression as much as possible, and improving mortality. Most of the following interventions have either not been studied in large randomized trials, or have been restricted to those with idiopathic PAH; the extrapolation to other populations with PH is based on expert recommendation rather than sound evidenced-based medicine.[23-25]

Diuretics and volume status

All patients with pulmonary hypertension should be educated about and adhere to a sodium-restricted diet. Daily monitoring of body weight can help reinforce dietary adherence and alert the patient and physician of early fluid retention. Despite adequate lifestyle measures, diuretics are widely used in those with pulmonary hypertension to control volume status, improve symptoms and decrease RV loading. Although particular agents and doses have not been well-studied, in recent trials of PAH targeted therapies 49-70% of patients received some form of diuretic therapy.[25] Caution must be exercised not to aggressively diurese patients with significant PH Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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as intravascular volume depletion may be accompanied by exertional or orthostatic pre-syncope or frank loss of consciousness due to the preload dependent state of the RV in those with advanced PH.

Oxygen supplementation

Hypoxia is a potent pulmonary vasoconstrictor and can be seen in PAH patients for a number of reasons, including reduced diffusion capacity, right to left shunting, and low cardiac output with resultant low mixed venous oxygen saturation. As a consequence, all patients with PAH should be assessed for resting, nocturnal and exertional hypoxia and supplemental oxygen provided as necessary to maintain normoxia. While oxygen therapy has not been specifically studied in the PAH population, longterm supplemental oxygen is likely beneficial in patients with PAH who have hypoxemia. In older but paradigmsetting studies in those with chronic obstructive lung disease and hypoxia, long-term oxygen therapy improved mortality.[26-28] A subset of these patients had invasive hemodynamics measured at the beginning and end of these trials; supplemental oxygen stabilized or marginally reduced pulmonary artery pressures in those receiving oxygen while those in the untreated control groups had continued progression of their pulmonary vascular disease. A subsequent study found similar results, with a reduction in mean pulmonary artery pressure with the initiation of supplemental oxygen, although no subject had normalization of pulmonary hemodynamics.[29] Notably, the studies that showed the largest improvement in pulmonary vascular pressures involved the longest use of daily oxygen therapy (≥18 hours); therefore, if hypoxia is present, patients should be encouraged to wear their oxygen continuously.[30] Likewise, PAH patients should be cautioned regarding exposure to high altitudes or commercial air travel without supplemental oxygen, either of which could worsen hypoxia and result in increased pulmonary vasoconstriction.

Exercise

While many patients with chronic cardiopulmonary conditions have been found to benefit physically and emotionally from physical rehabilitation programs,[31-33] strenuous exercise has traditionally been avoided in those with PAH due to concerns of worsening pulmonary pressures and precipitating syncope or sudden cardiac death.[34] More recently, a randomized trial of monitored exercise in a small group of patients with clinically stable PAH or CTEPH showed improved six-minute walk distances and quality of life after 15 weeks. Specifically, the patients in the treatment group performed daily interval stationary bicycle training (10-25 min./day), walking on flat surfaces (60 min./day), and low-resistance weight training (30 min./day), along with instruction in breathing Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

techniques and stretching, with a resultant mean increase in the six-minute walk distance of 111 m. Exercise training was well tolerated in this group of PAH patients with no significant adverse effects, although the first 3 weeks of exercise training occurred in an inpatient arena and all exercise sessions occurred in a monitored health-care setting.[35] Therefore, while low-level aerobic and strength training is likely to benefit those with clinically stable PAH, as it does with other cardiopulmonary disorders, prescribed exercise should occur in the context of a formal rehabilitation program with appropriate monitoring and support personnel.

Anticoagulation

Thrombophilia is thought to contribute to the pathogenesis of PAH. Apart from those with CTEPH, in which anticoagulation is mandatory, most guidelines recommend therapeutic anticoagulation only in patients with idiopathic PAH.[23,24] However, this recommendation is based upon on a few studies that are either retrospective or nonrandomized in nature. In an early investigation, Rich and colleagues found that in a non-randomized, prospective study of patients with idiopathic PAH that those receiving warfarin had improved mortality compared to those who did not receive anticoagulation, even while controlling for baseline hemodynamic parameters and vasoreactivity status.[36] Fuster and coworkers subsequently reported in a single-center retrospective review of patients with idiopathic PAH that prescription of warfarin was one of the strongest identified favorable prognostic indicators. [37] Finally, in the most recent and largest report on the topic, Frank et al. found that in a retrospective multi-center review of patients with either idiopathic or anorectic induced PAH that anticoagulation improved symptoms and mortality (mean survival time of 7.2±0.6 years versus 4.9±0.6 years, P≤0.05, in those that did and did not receive anticoagulation).[38] Thus, while there is consistent evidence that anticoagulation improves outcomes in those with PAH, there is as of yet no randomized trial showing a benefit. Moreover, unanswered are the clinically relevant questions of whom to treat, since the available studies included only those with idiopathic or anorectic-related PAH, and when to treat, as no study specifically addressed severity of disease.

Pregnancy

Pregnancy is considered to pose an extreme risk to the health of women with PAH, due to the limited ability of the right heart to compensate for the increased cardiovascular demands of pregnancy and labor, in which cardiac output and blood volume can increase by up to 40%. In the era before specific PAH therapy was available, mortality rates for pregnant women were reported to be as high as 35-50% in those with idiopathic PAH or PAH due to congenital heart disease, with most deaths 141

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occurring in the immediate post-partum period due to refractory right heart failure, sudden cardiac death, or thromboembolism.[39,40] More recently, in retrospective observational studies, women with PAH who elected to continue their pregnancies have had improved outcomes through the use of PAH-targeted therapies and elective induction of labor in specialized centers, although these studies are small in size and uncontrolled in design.[41,42] While neonatal survival in those women who carry their pregnancies to term is greater than 80%, the marked risk of death to the mother is the basis of the recommendation that all women with PAH avoid pregnancy through either effective contraception or elective termination.[24] While pregnancy prevention should be reviewed with all women with PAH of childbearing potential, there is a dearth of evidence upon which to a base contraception decisions. Hormonal contraceptives are convenient and available in many formulations but pose an increased risk of venous thrombosis; consideration should be given to surgical or non-hormonal methods.

Mental health in chronic illness

Finally, as with many chronic medical conditions, patients with PAH suffer from an increased burden of anxiety and depression but only a minority are receiving therapy for these conditions.[43] While most of the relevant literature comes from studies of those with chronic heart and lung disease rather than PAH per se, the prevalence of these disorders, which ranges from 10-45%, is significant.[44,45] Moreover, the presence of mood disorders is associated with lower treatment adherence, higher medical costs, and is an independent predictor of mortality.[44,45] While specific screening and management interventions have not been established for PAH, a recent randomized trial of coping skill education and support group participation in a cohort of patients with chronic left-ventricular heart failure realized significant improvements in depression and anxiety, although there was no effect on the rate of hospitalization or mortality over one year.[46] As PAH remains an incurable disease that, while amenable to medical therapy, often progresses over time, patients with PAH should regularly be assessed for depression and/or anxiety disorders. Through screening and with assistance from mental health professionals, PAH patients can receive both treatment for existing mood disorders and preparation for dealing with a chronic disease and, if the need arises, end of life care.

MANAGEMENT: PULMONARY ARTERIAL HYPERTENSION SPECIFIC

There three major classes of PAH specific therapies include prostanoids, endothelial receptor antagonists (ETRA) and phosphodiesterase-5 (PDE5) inhibitors. 142

Treatment decisions in PH care are centered upon both the underlying etiology and the severity of disease. It is a paradox of PH that while the overwhelming majority of patients with PH have disease secondary to either chronic left heart or lung disease, most of the major clinical trials and therapeutic advances have focused on patients with Group I disease (PAH). Consequently, all of the pulmonary vascular-targeted PH therapies are approved only for use in those with PAH, and it is imperative that an underlying cause, if any, be discovered in the initial evaluation of PH patients. Expert opinion regarding treatment is predicated upon assessment of World Health Organization (WHO) functional class (Table 3) and risk assessment (Table 4 and Fig. 1).[23-25,47]

Vasoreactivity and calcium channel blockers

Determining acute vasodilator response in patients with PAH may help identify long-term responders who have an improved prognosis compared to non-responders and may reduce the need of costlier PAH specific therapies by utilizing the less expensive calcium channel blockers (CCB). Until recently only acute vasodilator responders treated with CCB with idiopathic PAH[36,48] have a survival benefit. Patients with other etiologies of PH have been investigated[49,50,51] but generally, among these patients who are acutely vasoresponsive, there is no survival advantage. However, a recent study[52] did demonstrate a survival advantage not only in idiopathic PAH patients but PH in Groups III-V. Vasodilator testing at the time of diagnostic Table 3: World Health Organization classification of functional capacity in patients with PH WHO functional class I

III

Clinical description Patients with PH with no limitation of usual physical activity; ordinary physical activity does not cause dyspnea, chest pain, or presyncope Patients with PH with mild limitation of physical activity; no discomfort at rest but normal physical activity causes dyspnea, fatigue, chest pain or presyncope Patients with PH with marked limitation of physical activity; no discomfort at rest but less than ordinary activity causes dyspnea, fatigue, chest pain or presyncope Patients with PH who are unable to perform any physical activity; dyspnea and/or fatigue are present at rest and symptoms are worsened with any physical activity. Syncope may occur with exertion

PH: pulmonary Hypertension; WHO: World Health Organization

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Diagnosis of PAH

Throughout PAH Treatment

General supportive care: - Diuretics - Supplemental oxygen - Supervised physical rehabilitation - Anticoagulantion - Screening for depression/anxiety

Referral for transplant evaluation if WHO class III-IV and/or if parenteral therapy required Referral for surgical evaluation if CTEPH diagnosed

RHC with vasoreactivity testing (for those with idiopathic PAH) Positive vasoreactivity test: decrease in mPAP ≥ 10mmHg to less than 40mmHg and with an unchanged or improved cardiac output

Positive vasoreactivity response

Negative vasoreactivity response

Consider oral CCBs (versus PAH specific therapy)

Institute PAH specific monotherapy based on WHO functional class, severity of disease

Close follow up for response

If clinical response sustained, continue

Lower risk PAH

Higher risk PAH

Oral ETRA or PDE5 inhibitor Inhaled iloprost Inhaled treprostinil

Intravenous epoprostenol Intravenous treprostinil Subcutaneous treprostinil

If no sustained response or if fail to reach WHO class I or II, treat with additional PAH therapy

Assess response via changes in WHO functional class, 6MWD, TTE, RHC, natiuretic peptide. Consider combination therapy if inadequate clinical response

Figure 1: Treatment Algorithm for PAH. Lower risk PAH constitutes those patients with no evidence of right heart failure, WHO II or III functional status, preserved 6MWD and minimally elevated natriuretic peptide levels. Higher risk PAH patients have clinical or hemodynamic evidence of right heart failure, WHO class IV functional status, short 6MWD or significantly elevated natriuretic peptide levels. (6MWD: six-minute walk distance; FC: functional class; CCB: calcium channel blocker; ETRA: endothelial receptor antagonist; PAH: pulmonary arterial hypertension; PDE5: phosphodiesterase 5 inhibitor; RHC: Right heart catheterization; TTE: transthoracic echocardiogram; WHO: World Health Organization).

right heart catheterization has been performed with several different agents including intravenous epoprostenol[53] or adenosine[54] and inhaled nitric oxide (NO).[55]

A positive response to acute vasodilator testing is currently defined as a decrease in mPAP of ≥10 mmHg to value <40 mmHg without a decrease in cardiac output. [48,56] While Sitbon et al. found that 12.6% of those with idiopathic PAH demonstrated a positive vasoreactive response at initial evaluation, only 6.8% of this group maintained long-term response to calcium channel blockers. Patients with idiopathic PAH may therefore benefit from acute vasodilator testing for prognostic and treatment purposed. If a vasodilator response is seen and treatment with CCB attempted, close follow up is essential to ensure an appropriate and sustained hemodynamic response. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Prostanoids

The Food and Drug Administration (FDA) has approved prostacyclin analogues for the treatment of Group I PH (PAH). Epoprostenol was approved in 1995 as continuously infused intravenous (IV) therapy for World Health Organization (WHO) functional class (FC) III-IV idiopathic PAH, heritable PAH, and connective tissue disease related PAH (CTD-PAH). Treprostinil has three modes of delivery: continuously infused subcutaneous (SC), IV, and intermittently inhaled. The SC and IV formulations of treprostinil were approved in 2002 for WHO functional classes II-IV idiopathic PAH, heritable PAH, congenital systemic to pulmonary shunts and CTD-PAH. Inhaled treprostinil was FDA approved in 2009 for WHO FC III idiopathic PAH, heritable PAH and CTD-PAH. Inhaled iloprost is FDA approved as inhaled therapy for WHO FC III-IV idiopathic PAH, heritable PAH and CTD-PAH in 2004. 143

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Table 4: WHO group I assessment of PAH severity (REVEAL PAH Registry) Test

Finding

HR 1-y M *

Vital signs

Heart rate>92 beats per minute Systolic blood pressure<110 mmHg Class I†

1.39

Class III†

1.41

Class IV†

3.13

≥440 m

0.58

<165 m

1.68

Pericardial effusion mRAP>20 mmHg

1.35

PVR>32 Wood Units <50 pg/mL

4.08

>180 pg/mL

1.97

≥80% predicted

0.59

≤32% predicted

1.46

WHO functional class

Six-minute walk distance Echocardiography Right heart catheterization

Brain natriuretic peptide DLCO

1.67 0.42

1.79

0.50

*Hazard ratio for 1-year mortality, adjusted for age, gender, and significant comorbidities, †compared to WHO class II, DLCO: diffusion capacity, carbon monoxide; mRAP: mean right atrial pressure; PAH: pulmonary artery hypertension; PVR: pulmonary vascular resistance; REVEAL: registry to Evaluate Early and Longterm Pulmonary Arterial Hypertension Disease Management; WHO: World Health Organization

Prostanoid: Epoprostenol Clinical trials The first and only randomized, controlled trial to demonstrate a mortality benefit with PAH specific therapy was reported in 1996 by Barst et al.[57] This was a prospective, randomized, open label multicenter trial of 81 FC III/IV patients with idiopathic PAH treated with conventional therapy (diuretics, digoxin and warfarin) versus conventional therapy with IV epoprostenol. The primary endpoint was 6-minute walk distance (6MWD) which improved in the therapy group by a mean of 32 meters over a twelve week period, with a mean placebo corrected distance improvement of 47 meters. Secondary endpoints that were met were hemodynamics (decreased mPAP and pulmonary vascular resistance (PVR) and increased cardiac index), quality of life and mortality. Eight patients on conventional therapy died while no treatment subjects died (P=0.003). Additional studies performed validated the survival effect, improved functional class, exercise endurance and improved hemodynamics in IV epoprostenol treated patients with advanced idiopathic PAH when compared to historical controls[58] and to predicted survival based on the National Institutes of Health (NIH) survival equation (see Prognosis section, below).[59] 144

Badesch et al.[60] reported the first large scale open-label, randomized, multicenter trial to evaluate the utility of continuous infusion of epoprostenol in the treatment of 111 moderate to severe scleroderma associated PAH (SSc-PAH) patients. After 12 weeks of therapy, those randomized to the epoprostenol group had improved hemodynamic parameters, functional class, and achieved a 6MWD of 108 meters greater than those in the conventional group. Unlike previous epoprostenol-treated idiopathic PAH patients,[57-59] no survival benefit was found in the SSc-PAH patients treated with epoprostenol, likely related to an underpowered study and a greater complexity of illness and multiorgan involvement in the SSc-PAH subjects. Various other groups of patients have demonstrated symptomatic and hemodynamic benefit from IV epoprostenol therapy but not demonstrated a survival benefit. Congenital heart disease patients[61] have seen improvements in hemodynamics and functional class. Patients with portopulmmonary PAH[62] have improved hemodynamics while those with HIV associated PAH[63] had improved hemodynamics and 6MWD. Finally, those with CTEPH[64] have improved hemodynamics, functional class and 6MWD that sustained at mean follow-up of 19.6 months.

Clinical application and considerations IV epoprostenol is typically reserved for individuals with severe PAH. To date it is the only medication that has a mortality benefit.[57] Objective hemodynamic values are usually the trigger to consider parenteral therapy. A right heart catheterization result that shows a moderate to severe elevation in pulmonary arterial pressures with a reduced cardiac index (<2.0 L/min./m 2) and an elevated RAP (>12 mmHg) should be considered for parenteral therapy. The decision to initiate IV therapy must be individualized, as comorbidities, capabilities, and goals of care for each patient are different.

Epoprostenol use can be challenging. It is continuously infused medication that requires a tunneled central venous catheter, an infusion pump, and ice packs to keep the medication cold; moreover, the drug has an incredibly short half-life. Patients may face complications of thrombosis, line infection and infusion interruptions, the latter of which can result in hemodynamic collapse. Additionally, dose dependent side effects may be intolerable and include headache, jaw pain (trismus), flushing, nausea, diarrhea, skin rash and musculoskeletal pain of a severity requiring narcotic pain management. Individuals must be screened carefully to determine if they are able to commit to long-term use of this medication. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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Prostanoid: Treprostinil Clinical trials Treprostinil, can be administered as a subcutaneous (SC), IV or inhaled therapy; the efficacy of all 3 modes of delivery has been demonstrated in clinical studies.

Subcutaneous: SC treprostinil was evaluated in a 12week multicenter, randomized, double-blind, placebo controlled trial of 470 functional class II-IV PAH subjects with idiopathic PAH, connective tissue disease, and patients with systemic to pulmonary shunts.[65] Enrolled subjects were randomized to conventional therapy (which included oral vasodilators, anticoagulants, diuretics and digoxin) plus SC treprostinil versus conventional therapy plus placebo. The primary endpoint of 6MWD was met with a modest improvement of 16 meters (P=0.006); improvement in 6MWD was found to be dramatically dose-related. Additional statistically significant endpoints were improved hemodynamics, quality of life and dyspnea scores.

secondary endpoints of improved dyspnea score and hemodynamics. Thirty-one WHO FC II and III patients on stable epoprostenol therapy for at least 3 months were transitioned to IV treprostinil[70] over 24-48 hours while hospitalized. The 27 subjects that completed the 12-week study maintained their 6MWD of 439+16 m with a modest increase in mPAP and decrease in cardiac index (CI). Interestingly, upon hospital discharge after the transition was made, the doses of treprostinil and epoprostenol were equivalent at 47+24 ng/kg/min. and 40+4 ng/kg/min., respectively. All subjects on treprostinil subsequently required dose increases. At week 6 the mean dose was 60+23 ng/kg/min. (range: 15-96 ng/kg/min.) and at week 12 the mean dose increased to 83+38 ng/kg/min. (range: 24-180 ng/kg/min.). This finding of IV treprostinil dose being approximately twice that of epoprostenol has been also noted in subsequent publications.[71]

An open-label extension study66 of 860 WHO FC II-IV idiopathic PAH and associated PAH subjects, which included previously enrolled SC treprostinil subjects[65] and de novo treatment subjects, evaluated the long-term outcome and efficacy of SC treprostinil as monotherapy. Follow-up of all subjects for a period of 1-4 years after enrollment, which included 130 subjects treated with additional PAH therapy, compared to those with SC treprostinil as monotherapy (n=730), showed no difference in survival. Idiopathic PAH subjects (n=332) treated with SC treprostinil demonstrated improved survival over the NIH predicted survival equation.

Inhaled: In 2006 Voswinckel et al. [72] published the results of 3 pilot studies evaluating the hemodynamic effects of inhaled treprostinil in a total of 123 patients with idiopathic PAH. The primary study endpoint was a change in PVR. The first study evaluated 44 subjects with moderate-severe PAH in a randomized, open label, single blind, crossover study where the primary objective compared acute hemodynamic effects and systemic side effects of inhaled treprostinil (n=22) with inhaled iloprost (n=22) at comparable doses. The second study evaluated the pharmacodynamic and pharmacokinetic effects of inhaled treprostinil at a dose of 30µg and explored the highest tolerated single dose. The third was a randomized, open-label, single blind study to explore the shortest possible inhalation time for a 15µg dose of treprostinil.

Intravenous: Based upon the bioequivalence with subcutaneous treprostinil [68] the FDA approved IV treprostinil in 2004 for the treatment of WHO FC II, III and IV PAH and in patients requiring transition from epoprostenol therapy. A 12 week, multi-center, prospective, open-label, uncontrolled study of 16 WHO FC III, IV PAH subjects evaluated the safety and efficacy of monotherapy with IV treprostinil.[69] The primary endpoint of improved 6MWD was met with an increase of 82 m (319+22 to 400+26 m; P=0.001) as well as

The TRIUMPH-1 trial evaluated the safety and efficacy of 235 WHO FC III/IV PAH patients with a baseline 6MWD of 200-450m who were randomized to inhaled treprostinil or placebo while on baseline bosentan (70%) or sildenafil (30%).[74] The primary endpoint was met with a placebo adjusted increase in 6 MWD of 20 m (P=0.0004) and secondary endpoints of quality of life and biomarkers. There were no reported improvements in time to clinical worsening, functional class, or dyspnea score.

A post-hoc analysis of a randomized, double blind placebocontrolled study, by Oudiz et al.,[67] evaluated 90 patients with PAH due to connective tissue disease, with almost half of those with SSc (n=45). Patients treated for 12 weeks with SC treprostinil were able to walk a median value of 25 m more than those treated with placebo. Patients also had improved hemodynamic parameters and a trend toward improved quality of life measures. This post-hoc analysis was not powered to detect a difference in mortality between the two groups.

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The study showed that the maximum effects of treprostinil and iloprost on PVR were comparable, however the treprostinil effect lasted longer (P<0.0001). The treprostinil group exhibited a sustained increase in cardiac output with no decrease in systemic arterial pressure. Neither drug had affected gas exchange. The treprostinil dose of 30 µg maximally reduced PVR when compared to the other formulations, without a dose response. The study demonstrated that the optimal dose to be 9 breaths via ultrasonic nebulizer four times daily, which delivers approximately 54 µg of treprostinil.[73]

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Clinical application and considerations SC treprostinil therapy avoids the complications of a permanent central venous catheter and does not require daily mixing and preparation as the drug is dispensed in pre-mixed syringes. In addition, cassettes can be changed every 48 hours and do not require ice packs. The package insert recommends changing the subcutaneous site every 3-4 days; however, if an optimal site is found it can be used for 2-4 weeks.[75] The most common side effects are pain at the SC infusion site. The etiology of pain is unclear and does not appear to be dose related. [65] Management protocols that include pharmacologic (local and systemic) and non-pharmacologic options, as well as physician and patient communication as to optimal site placement, are important aspects of infusion site maintenance.[76]

Pivotal clinical studies may have treated subjects with lower doses than are currently being clinically used. [65,71,79] Post trial experience in poster and abstract form[76] regarding SC treprostinil have indicated that dosing is considerably higher than in clinical studies, with mean doses of 40.6–44 ng/kg/min. (range 26-72 ng/kg/min.) by 12 months. Current expert opinion[76] recommends a goal dose range is 40-80 ng/kg/min. by month 6 of therapy. Site pain and discomfort should not limit dose escalation. In fact, rapid dose escalation has been associated with improved infusion site pain and exercise capacity when compared to slow escalation.[77]

PAH patients who are unable to manage SC treprostinil infusion, or require higher doses of therapy, have the option of IV treprostinil. Although the two formulations are bioequivalent and share similar elimination half lives, initial rapid up-titration of IV treprostinil has been associated with improved dyspnea.[69] There are no proposed guidelines for titration management of IV treprostinil. The dose can be increased several times per week at 1-2 ng/kg/min. increments to a goal of 40 ng/ kg/ min.; the upper limits of IV therapy in previously reported trials have ranged from 62-83 ng/kg/min,[69,70] this is approximately twice the dose seen in epoprostenol use. Regardless of the method of administration, treprostinil produces typical prostanoid side effects of jaw pain, headache, chest pain, flushing, nausea and diarrhea. Patients tend to experience symptoms with medication up-titration with eventual resolution after adjusting to the new dose. Intravenous treprostinil had reports of a significantly higher rate of catheter infections, in particular Gram-negative organisms when compared to epoprostenol.[78] This however has been resolved once a closed-hub system and waterproofing of the catheter hub connections for showering were implemented.[79] 146

Prostanoid: Iloprost Clinical trials Iloprost is a prostacyclin analogue available in inhaled form, with a terminal half-life of 25 minutes. Due to the short half-life, lasting approximately 30-60 minutes, iloprost requires multiple daily inhalations (6-9 inhalation sessions per day).

In the AIR study Olschewski et al. [80] evaluated 203 patients in a 12-week, double blind, randomized, placebocontrolled multicenter trial. Subjects included in the study had idiopathic PAH, CTD-PAH, appetite suppressant associated PAH and inoperable CTEPH and were WHO FC III-IV. Patients were permitted to continue standard conventional therapy. The trial utilized a novel composite endpoint to determine response to therapy. In order to meet the primary endpoint subjects had to increase 6MWD by 10% and improve WHO FC by one class in the absence of clinical deterioration or death. Seventeen percent of subjects on iloprost met the combined endpoint, compared to 4% of those receiving placebo (P<0.05). The mean increase in 6MWD in all subjects was 36m; the subset of those with idiopathic PAH demonstrated a mean increase of 59m. Hemodynamic values were unchanged when comparing pre-inhalation of iloprost to baseline values. Post-inhalation decreases in PVR and pulmonary artery pressure were noted with associated increases in cardiac output and mixed venous O2 saturation. Iloprost monotherapy was evaluated in an open label prospective study of 76 idiopathic PAH patients with WHO FC II-IV symptoms.[81] Subjects were evaluated according to prospectively defined endpoints of death, transplant or a switch to parenteral therapy or addition of oral therapy during a median follow-up period of 383 days. Event free survival at 12, 24, 36, 48 and 60 months was 53, 29, 20, 17 and 13%. Clinical application and considerations Side effects of treatment are related to the vasodilatory properties of the drug with skin flushing, syncope and jaw pain and related to the drug delivery system with increased cough.[80] A potential drawback is the need to perform 6-9 inhalations per day.

Prostanoid pharmacology Epoprostenol is the first synthetic prostanoid to be approved by the FDA. The only formulation available is offered intravenously. Due to vein irritation seen in all prostanoids, epoprostenol needs to be continuously infused through a central venous catheter. The plasma half-life is similar to that of endogenous prostacyclin (3-5 min.). Patients need to mix the powered drug with a highly basic solvent that must be used within 12- 24 hours. The initial in-hospital dose of epoprostenol is 2 ng/ kg/min. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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with an optimal dose range of 22-40 ng/ kg/min. when utilized as monotherapy. Unlike standard epoprostenol, recently marketed room temperature (thermostable) epoprostenol is a chemically stable compound that does not require cooling with ice packs and can be reconstituted with sterile water or sodium chloride rather than highly basic solutions. Thermostable epoprostenol can be mixed days ahead of time and stored until needed. When prescribing epoprostenol, care must be taken to not overdose patients as chronic overdose can result in high output cardiac failure.[82] Treprostinil, as compared to standard epoprostenol, is neutral pH and chemically stable at room temperature with an elimination half-life of 4.6 hours for subcutaneous therapy and 4.4 hours for intravenous therapy.[83] Specific biological effects have been noted in treprostinil. In adult rat cardiomyocytes, treprostinil potentiated the positive inotropic effects of catecholamines. [84] This may be clinically relevant in humans as subjects with right heart failure have increased cathecholamine drive; this effect may theoretically augment cardiovascular performance. Due to the method of administration, inhaled iloprost exhibits selective intrapulmonary activity. Drug deposition relies upon the proximity of the terminal airways to the small pulmonary arteries and acts directly on the pulmonary artery wall.[85] Nebulization of iloprost into small particles[86] results in alveolar deposition and the need for a reduced dose compared to intravenous infusion of iloprost.[80]

Postscript, prostanoids Overall prostanoids are the “go to” therapy for advanced PAH patients. Decision on specific prostanoid therapy depends upon whether the patient capability and preference in regards to SC, IV or inhalation therapy. Our recommendation is to initiate parenteral therapy in subjects who have a hemodynamic profile of moderate to severe elevation in pulmonary arterial pressures with a depressed cardiac index (< 2.0 L/min./m2) and an elevated RAP (>12 mmHg). If patients on oral PAH specific therapy have worsening symptoms and hemodynamics, a step up to inhaled prostaoinds may be initiated, particularly if a patient is not amenable to parenteral therapy.

Endothelin receptor antagonists (ETRA)

Bosentan and ambrisentan are FDA approved endothelial receptor antagonists (ETRA) for the treatment of Group I PAH. Bosentan, approved in 2001, is available as twice daily oral therapy for WHO FC II-IV related to idiopathic PAH, heritable PAH, congenital systemic to pulmonary shunts and CTD-PAH. Ambrisentan was FDA approved in 2007 and is available as once a day oral therapy only for idiopathic PAH, heritable PAH and CTD-PAH. Sitaxentan, Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

a selective endothelial receptor antagonist, was recently withdrawn from the market and ongoing clinical trials were suspended due to fatal liver failure. Sitaxentan will not be reviewed in this article. ETRA: Bosentan Clinical trials Bosentan is a synthetic nonpeptide pyrimidine derivitave that irreversibly binds to the endothelial receptors A and B.[87] It is the first FDA approved oral agent available for the specific treatment of PAH.

In 2001 Channick et al. reported the results of the first oral PAH specific therapy in a double-blind, placebo controlled trial with bosentan in 32 idiopathic PAH and SSc-PAH WHO FC III subjects.[88] The study met its primary endpoints of improved 6MWD and secondary endpoints of improved functional class and hemodynamic values after 12 weeks of treatment. The subsequent larger, multicenter controlled trial, BREATHE-1, studied 213 WHO FC III/IV subjects with idiopathic PAH and CTD-PAH.[89] Patients were randomized to 125mg or 250mg twice daily bosentan or placebo for 16 weeks. There was no difference between the primary endpoint of 6MWD between the 125mg or 250mg groups. The combined placebo adjusted improvement in the 6MWD was 44m (P<0.001). There was an increase in the time to clinical worsening and improvement in WHO FC in the bosentan groups. This study was not adequately powered to detect a difference in mortality. Survival has been shown to be similar in FC III idiopathic PAH subjects treated with bosentan compared to historical subjects treated with epoprostenol.[90] Sitbon et al. noted sustained improvements in exercise capacity, functional class and hemodynamics in subjects with Group I PAH followed for 12 months.[91] Subsequent studies have evaluated bosentan in HIV associated PAH,[92,93] portopulmonary hypertension[94] and inoperable CTEPH[95,96] with favorable results. Most trials treating Group I PAH evaluated subjects with WHO FC III. The issue of whether early medical intervention would be beneficial in those with milder disease (WHO FC II) was the goal addressed by Galiè and colleagues in the Endothelin Antagonist Trial in Mildly Symptomatic PAH Patients (EARLY) trial.[97] This trial was a randomized, double-blind placebo controlled, multicenter study which evaluated treatment with 125 mg twice daily of bosentan versus placebo for 6 months. Individuals treated with PAH specific medications were prohibited with the exception of the PDE5 inhibitor sildenafil. One hundred eighty five WHO FC II subjects with idiopathic PAH, heritable PAH, CTD-PAH, anorexigen-related PAH, HIV-related PAH and congenital heart disease associated PAH were enrolled. Those treated with bosentan met the primary endpoint of a significant decrease in PVR (17% 147

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decrease in bosentan versus an increase of 8% in controls). The decrease in PVR was associated with a decrease in mPAP and an increase in CI. 6MWD was not significantly different between bosentan and placebo groups. This was regarded as a ceiling effect, related to the treatment of PAH patients with mild pulmonary vascular disease. Time to clinical worsening was improved in the bosentan group and more subjects in the bosentan group had lower incidence of worsening functional class. Despite the lack of significant improvement in 6MWD in the bosentan treatment group, the hemodynamic and clinical outcomes of the EARLY trial provided evidence that led to the approval for WHO FC II patients.

A post hoc analysis by Denton et al.[98] of two randomized, double-blind placebo controlled studies evaluated 52 patients with WHO FC III or IV SSc-PAH. After 12-16 weeks of therapy those treated with bosentan had stable 6 MWD and a delay in time to clinical worsening; the authors concluded that treatment with bosentan slowed disease progression. Girgis et al.[99] performed a retrospective evaluation of 17 patients with SSc-PAH versus 19 patients with idiopathic PAH in whom bosentan was the first-line single agent for at least 6 months. Mortality evaluated 1 and 2 years after treatment showed that the idiopathic PAH group had a non-statistically significant increase in survival (100% at years 1 and 2) in comparison to the SSc-PAH group, which had survival was 87% at year 1 and 79% at year 2. Functional status improved by almost one class in the idiopathic PAH group, but remained stable or deteriorated in the SSc-PAH patients. Clinical application and considerations The adverse events associated with bosentan are related to systemic vasodilatation with headache, nasopharyngitis, dizziness and lower extremity edema being most common. None of these events were statistically different between the bosentan and placebo group in the BREATHE-1 trial. The hepatic clearance of bosentan raised concern for serious hepatotoxicity in treated individuals. An increase in liver function tests (LFT) greater than 3 times the upper limit of normal (ULN) was noted in 12 and 14% of subjects who had received 125mg and 250mg of bosentan twice daily, respectively.[89] Although most LFT abnormalities were transient patients treated with bosentan require monthly lab draws. Hepatic function generally normalizes with treatment interruption.

Bosentan induces the cytochrome P450 enzymes CYP3A4 and 2C9. Concomitant administration of bosentan with warfarin may reduce plasma warfarin concentrations.â&#x20AC;&#x2030;[100] Bosentan may increase the metabolism, and therefore reduce drug levels, when co-administered with cyclosporine, erythromycin, amiodarone, diltiazem, HIV protease inhibitors, and the azole antifungals. These drug 148

interactions may require appropriate medication dose adjustments.

ETRA: Ambrisentan Clinical trials A double-blind, randomized dosing strategy study evaluated 64 patients with idiopathic PAH, HIV and anorexigen-associated PAH and CTD-associated PAH. Four doses of ambrisentan (1, 2.5. 5 and 10mg) were evaluated during the 12-week study which had a subsequent 12 week open label extension study, permitting dose adjustment. The initial 12 weeks demonstrated an increase in 6MWD of 34-38m in all 4 dosing groups. By the 24th week further increases in exercise capacity were noted with all subjects experiencing an overall 6MWD increase of 54m.

Two nearly identical concurrent studies, ARIES 1 and 2, evaluated three doses of once-daily oral ambrisentan (2.5, 5 and 10mg) in 394 treatment-naĂŻve subjects diagnosed with idiopathic PAH or associated PAH (HIV, anorexigen and CTD).[101] These multicenter, randomized, doubleblind placebo controlled studies both met their primary endpoint, with a combined drug improvement in 6MWD of 31-59m when comparing baseline to week 12. Secondary endpoints of dyspnea scores and biomarkers were also improved in both studies. Time to clinical worsening was improved only in ARIES-2 study while WHO FC improved only in the ARIES-1 trial.

Subjects who had completed ARIES 1 and 2 were eligible to enroll into the open label safety and efficacy extension study, ARIES-E. At two years of follow-up, subjects in the 5 and 10 mg ambrisentan group maintained 6MWD at 23 and 28m respectively. Twelve subjects experienced increases in hepatic enzymes with two subjects requiring drug discontinuation. [102] More recently Klinger et al. performed a restrospective evaluation of the long-term hemodynamic effects of ambrisentan in the ARIES-E cohort. Sixty-eight subjects had a followup right heart catheterization (RHC) a median time of 60 months after initiating ambrisentan monotherapy. Significant improvements were noted in mPAP, PVR and CI in both the 5 and 10mg treatment groups when compared to baseline values at 2 years of follow-up. This study showed a statistically significant correlation between improvement in 6MWD and decreases in mPAP and PVR. Clinical application and considerations Ambrisentan is well-tolerated. Lower extremity edema, headache and nasal congestion appears to be the drugs main side-effects. The incidence of hepatic injury is much less than bosentan. The ARIES-1 and 2 study had no patients with LFTs >3 times the ULN.[101] Recently the FDA has removed the black box warning related to liver injury Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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based upon post-marketing analysis that showed the risk of hepatotoxicity was low in ambrisentan.

Ambrisentan is eliminated through phase II hepatic glucuronidation and metabolism is through the cytochrome P450 enzyme 3A4, similar to bosentan. However warfarin dose adjustment is not necessary with ambrisentan use. All ETRAs are teratogenic and should not be used during pregnancy. Bosentan, unlike ambrisentan, may decrease the efficacy of oral contraceptives.[103] Therefore it is recommended that two forms of contraception be employed by patients treated with ETRAs.

Pharmacology Endothelin-1 is a vasoconstrictor and smooth muscle mitogen that is overexpressed in the lungs of patients with PAH.[104] Endothelin binds to receptors EndothelinA and EndothelinB (ETA and ETB) which results in deleterious remodeling of the pulmonary vasculature. Endothelin receptor antagonists are either nonselective receptor antagonists (block ET A and ET B) or single receptor antagonists (blocks ETA only). ETA receptors have been isolated predominately in the smooth muscle cells of the pulmonary artery, airways, lung fibroblasts and cardiomyocytes. ETB receptors predominate in pulmonary vascular endothelial cells with a lesser expression in pulmonary artery smooth muscle cells and fibroblasts.â&#x20AC;&#x2030;[87] There is a theoretical benefit of employing specific receptor antagonist over a dual receptor antagonist as blockage of the ETA receptors may promote the production of vasodilatory and antimitogenic substances activated through the ETB pathway. The clinical implication of this difference is currently a debated topic. The mean terminal half-life of bosentan is around 5 hours[105] and takes up to 5 days to reach steady state.[106] Ambrisentan is a nonsulfonamide that selectively antagonizes ETA. Ambrisentan is rapidly absorbed into the systemic circulation with a half-life of approximately 15 hours.â&#x20AC;&#x2030;[107] The longer half-life allows for once daily dosing of ambrisentan. Postscript, ETRAs There is currently no data to establish the benefit of one ETRA over the other. The decision to utilize ambrisentan or bosentan may be, in part, guided by patient preference. Ambrisentan may appeal to patients due to the once daily dosing and additional benefit of a lower incidence of hepatic injury. The decision to follow monthly LFTs may vary with provider preference.

Phosphodiesterase-5 (PDE5) inhibitors

Currently sildenafil and tadalafil are the only FDA approved oral PDE5 inhibitors for the treatment of WHO FC II-III PAH. Sildenafil, approved in 1998, is available as three times daily oral and IV formulations for idiopathic PAH and connective tissue disease associated PAH. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Tadalafil, approved in 2003, is available as once a day oral therapy for idiopathic PAH, heritable PAH and CTDPAH. Vardenafil is not currently FDA approved for PAH but a recent clinical trial has shown its beneficial use in idiopathic PAH, CTD-PAH and congenital systemic to pulmonary shunts.[108]

PDE5 Inhibitor: Sildenafil Clinical trials Oral sildenafil: The Sildenafil Use in Pulmonary Arterial Hypertension (SUPER-1) study evaluated 278 WHO FC IIIII subjects with idiopathic PAH, connective tissue disease and systemic to pulmonary shunts in a 12 week, double blind, placebo controlled trial.[109] The trial compared subjects assigned to placebo and 20, 40 or 80mg of sildenafil in a 1:1:1:1 ratio. Subjects on IV prostanoids, bosentan, treprostinil, iloprost or L-arginine were excluded. The primary endpoint, 6MWD, was met in the 20, 40 or 80mg sildenafil groups (the baseline 6MWD was 339-347m), although a dose-response effect on 6MWD was not demonstrated. The mPAP and PVR decreased significantly in the three groups studied compared to placebo and the reduction in PVR was dose dependent. All doses resulted in an improvement in WHO FC but did not decrease time to clinical worsening.

The open-label, uncontrolled SUPER-1 extension study, SUPER-2[110] followed subjects taking 80mg sildenafil three times daily, for at least 3 years; the majority of which were WHO FC II-III. One hundred seventy subjects completed both studies and were followed for a median of 1,242 days. Sixty percent of these patients maintained or improved their functional status, and a conservative 3-year survival estimate was 68%. A surprisingly low number of subjects, 3%, 10% and 18%, required additional PAH specific therapy at years 1, 2 and 3, respectively. It was notable that patients with baseline 6MWD <325m in SUPER-1 who lacked improvement in 6MWD during the first 12 weeks of sildenafil therapy exhibited worse survival. A follow up post-hoc analysis of 84 subjects from the SUPER-1 study of patients with connective tissue disease associated PAH [111] suggested improved 6MWD and hemodynamics in this subgroup as well.

Sildenafil has been investigated in patients with CTEPH,[112-113] COPD associated PH,[114] and PH related to ILD.[115,116] These studies have suggested potential benefit, but larger studies are needed to draw firm conclusions.

The Sildenafil versus Endothelial Receptor Antagonist for Pulmonary Hypertension (SERAPH) study [117] directly compared sildenafil and bosentan as first line therapy in 26 WHO FC III idiopathic PAH and connective tissue disease associated PAH followed for 16 weeks. 149

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The sildenafil group met its primary outcome in with a decrease in right ventricular mass and both sildenafil and bosentan groups had improvements in 6MWD and CI. The authors conclude that sildenafil and bosentan should be considered equivalent therapies for this patient population. Intravenous (IV): Hospitalized patients on chronic PDE5 inhibitor therapy who cannot tolerate a discontinuation of oral therapy can be transitioned to IV sildenafil. Recently the pharmacokinetic and pharmacodynamic effects of 10mg of IV sildenafil were compared to 20mg of oral sildenafil and were found to be similar in a single center open label study.[118]

Clinical application and considerations The side effect profile for PDE5 inhibitors are generally similar with common side effects of headache, flushing, nasal congestion, dyspepsia and myalgias, primarily attributed to the drugs vasodilatory effects.[109,111,119] These adverse events are often transient, mild to moderate in nature and dose-related. A major concern for patients treated with PDE5 inhibitors is hypotension, especially with the concomitant administration of nitrates. Both nitrates and PDE5 inhibitors increase cGMP via the NO pathway and subsequently lower systemic blood pressure. Nitrates are contraindicated in patients treated with PDE5 inhibitors.

Visual disturbances are noted with sildenafil, including blurry vision, blue-green color changes and light sensitivity, and have been attributed to differences in PDE selectivity. These effects are related to inhibition of a retinal form of PDE, namely PDE6,[120] which does not occur with the more selective PDE5 inhibitor tadalafil. More serious sensory effects have been documented. Nonarteritic anterior ischemic optic neuropathy (NAION)â&#x20AC;&#x2030;[121] and sudden sensorineural hearing loss[122] have been described in case reports of PDE5 inhibitors used in erectile dysfunction. These disturbances were not found in the >3 years of follow-up of chronic sildenafil administration in the SUPER-2 trial.[110]

PDE5 Inhibitor: Tadalafil Clinical trials The Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Trial is a 16-week, randomized, double blind, double dummy, placebo controlled multicenter trial which studied the efficacy and tolerability of 4 doses of tadalafil on 405 PAH subjects with and without background bosentan therapy.[119] Unlike the SUPER-1 study, subjects on 40mg of tadalafil had significantly improved time to clinical worsening when compared to placebo, as well as a reduction in the incidence of clinical worsening (relative risk reduction 68% less than placebo). 150

Exercise capacity was improved with all doses of tadalafil studied in a dose dependent manner. Only the 40mg dose met the pre-specified value for statistical significance of <0.01, with a placebo corrected 6MWD of 33m. The placebo corrected 6MWD was improved in the treatment naĂŻve (no background bosentan) tadalafil subjects moreso than in those on background bosentan. Hemodynamic data available for 93 subjects available showed improved hemodynamics in the 40mg group, with better results noted in tadalafil naĂŻve subjects. Use of tadalafil did not demonstrate significant improvement in other secondary outcomes.

Clinical application and considerations The adverse events related to tadalafil are similar in the SUPER-1 and PHIRST trials, with the most common reactions related to the vasodilatory properties of the drug. Visual disturbances however should not be as prominent with tadalafil, given its more selective PDE5 inhibition.[120] Pharmacology Although the magnitude of hemodynamic effect of sildenafil was dose dependent in the SUPER-1 trial, the FDA recommended 20mg three times daily based upon the absence of dose dependence in 6MWD. The peak vasodilatory effect of sildenafil is 60 minutes[123] with a terminal half-life of 4 hours for sildenafil.[124] Sildenafil is metabolized hepatically through the cytochrome P450 3A4 isoform. Dose adjustment is not necessary mild to moderate hepatic impairment but sildenafil use in severe hepatic impairment has not been studied. Concomitant use of medications metabolized through this pathway, such as HIV protease inhibitors and macrolides, may increase sildenafil levels. No dose adjustment is necessary in renal impairment.[125]

The peak vasodilatory effect for tadalafil is 75-90 minutes[123] and the terminal half-life is 17.5 hours.[124] Like sildenafil, tadalafil is metabolized hepatically through the cytochrome P450 3A4 isoform. Unlike sildenafil, tadalafil needs dose adjustment (from 40mg to 20mg) in the setting of hepatic impairment.[126] Postscript, PDE5 inhibitors Patient preference may dictate the drug selection between tadalafil and sildenafil, with once daily tadalafil therapy as an appealing option. Unlike the SUPER trials, the PHIRST trial showed an increase in time to clinical worsening with tadalafil. A patient that fails tadalafil monotherapy can advance to add-on therapy or switch drug classes. In contrast, sildenafil can be uptitrated from 20mg. The SUPER-2 study demonstrated that nearly all subjects were on maximal dose of 80mg three times daily and only 18% of WHO FC II-III subjects advanced to additional Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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PH specific therapy within 3 years. Hemodynamic improvements are similar in sildenafil and tadalafil; however sildenafil improves areterial oxygenation[123] likely through a favorable impact on ventilation perfusion matching.

II investigation in those with PAH, imatinib was well tolerated and improved pulmonary vascular resistance and cardiac output, although there was no improvement in 6MWD. An additional study evaluating the long term safety and efficacy of imatinib in PAH is ongoing (NCT01117987).

Combination therapy for PAH is a logical step from single drug regimens due to the progressive and incurable nature of the disease in most patients and due to the availability of agents that target different molecular pathways. While the most efficacious combination of medications, along with the issue of sequential versus concurrent initiation, is uncertain and an active area of investigation, several studies are available to guide current therapy. The addition of inhaled iloprost to patients who remained symptomatic despite oral bosentan therapy resulted in improved functional class, 6MWD, and hemodynamics. [127] The addition of high dose sildenafil to symptomatic PAH patients treated with parenteral epoprostenol likewise resulted in improved functional class, 6MWD, and hemodynamics.[128] In a study combining 2 oral agents, the addition of tadalafil to background bosentan therapy, resulted in improved 6MWD and health-related quality of life.[119] Finally, the addition of inhaled treprostinil to either oral bosentan or sildenafil therapy resulted in improved 6MWD, health-related quality of life and natriuretic peptide levels.[74]

The favorable effects of nitric oxide are mediated through soluble guanylate cyclase (sGC) and the 2nd messenger cGMP. [11] Currently targeted by the PDE5 inhibitors, another potential approach to augmenting the nitric oxide pathway is through direct stimulation of sGC. Riociguat, the first of a new class of medication, activates sGC independently of nitric oxide.[130] In a phase II study in those with PAH or CTEPH, riociguat was well tolerated and demonstrated improvements in 6MWD and hemodynamics.[131] Phase III trials are currently ongoing (NCT00863681, NCT00810693).

Combination therapy

Overall these studies, although limited in size and few in number, suggest that combination therapy results in clinical improvement and is well-tolerated. Notably these studies, similar to many other PAH investigations, were brief and were not powered to assess mortality, making assumptions about long-term outcomes difficult. Ongoing combination studies include the addition of bosentan to patients already on therapy with sildenafil (COMPASS 2, NCT00303459), the use of ambrisentan and tadalafil in patients with systemic sclerosis (ATPAHSS, NCT01042158), the addition of sildenafil to background bosentan therapy (NCT00323297), and concurrent initiation of PAH therapy with both ambrisentan and tadafil (AMBITION, NCT01178073). Consideration should be given to enrolling patients into one of these or other studies when using PAH therapy in combination.

INVESTIGATIONAL THERAPIES Imatinib

The platelet derived growth factor (PDGF) signaling pathway is thought to play a causative role in the pathogenesis of PAH.22,129 Imatinib mesylate, a tyrosine kinase inhibitor antagonizes the PDGF pathway and may prove to be efficacious in the treatment of PAH In a phase Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Riociguat

DISEASE PROGRESSION AND MONITORING RESPONSE TO TREATMENT

Once the patient has been diagnosed with pulmonary hypertension and initiated on PAH specific therapy the goal of subsequent visits, set at 3-6 month intervals depending on the severity of disease, is to monitor response to therapy. A general assessment of the patient will elicit whether the patient has improved symptomatically or in activities of daily living. Metrics of interest include functional class, 6MWD, physical exam, and right heart function. Evaluating objective endpoints including exercise capacity, serum biomarkers and right heart function after initiating therapy may also be helpful.[132] The six-minute walk test is a simple, easy to perform evaluation that is a measure of exercise capacity and correlates with peak aerobic capacity.[133] It is a common primary endpoint in clinical trials and is an accepted marker for therapeutic response by regulatory agencies. The six-minute walk test offers prognostic information as it is an independent predictor of death in idiopathic PAH.[134] However reproducibility of the 6MWD can vary depending on the underlying disease state of the patient population being studied.[135-137] Evaluation of non-invasive biomarkers can help determine response to therapy. Natriuretic peptides (BNP and NT-proBNP) are associated with right ventricular dysfunction in PAH.[138,139] Rather than interpreting individual endpoints to assess response to therapy, evaluating a composite endpoint may be beneficial. The AIR study80 evaluated inhaled iloprost and utilized a novel composite endpoint to determine response to therapy. In order to meet the primary 151

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endpoint study subjects had to increase 6MWD by 10% and improve WHO FC by one class in the absence of clinical deterioration or death at any point. In another study, the concept of goal-oriented treatment was evaluated by Hoeper etâ&#x20AC;Żal.[140] in 123 patients with WHO class III or IV PAH that were followed for 3 years. Subjects that did not reach treatment goals while on monotherapy received combination therapy according to a pre-defined strategy. Statistically significant improvement in survival was noted in patients who met the pre-established treatment goals of 6MWD > 380m, peak VO 2 >10.4ml/min./kg while maintaining a systolic blood pressure >120 mmHg when compared to historical controls. Although at this time exercise testing is not commonly performed, this study has established the benefit of using goal-directed treatment goals. There is a paradox in defining severity of PAH hemodynamically by mPAP. Responses to pharmacologic therapy may elicit improvements in exercise capacity but do not always translate into a meaningful reduction in pulmonary artery pressures. Seldom do patients entirely return to normal pulmonary arterial pressures despite improvement in symptoms, biomarkers, right heart function, 6MWD or WHO functional class. This may indicate that improvements and preservation of right heart function and cardiac output are likely the true goals of therapy, with improvements of exercise capacity as mere reflections of these hemodynamic changes. Patients treated with PAH specific therapy have improvements in specific echocardiographic and Doppler parameters.[141] We believe that following changes in right ventricular size and function in patients on therapy is a very useful parameter to trend progression of disease. A repeat right heart catheterization after diagnosis can be helpful in patients with a change in symptoms or an unexpected response to therapy. The authors do not make it a common practice to routinely re-evaluate hemodynamics with heart catheterization, though this can be physician and facility dependent.

MANAGEMENT: SURGICAL THERAPIES FOR PAH

While medical therapy, either general supportive care for non-group I PH and targeted vascular therapy for those with PAH, is the cornerstone of treatment, there are surgical therapies available for those with some forms of PH. Indeed, the only potential cure for PH is via a surgical procedure, as the currently available medical therapies only improve symptoms and do not reverse the underlying pathophysiologic process. The treatment of choice for patients with CTEPH is pulmonary endarterectomy, a procedure that can significantly ameliorate, if not 152

cure, pulmonary vascular disease in selected patients. More generally applicable, patients with refractory or progressive PAH may be candidates for the salvage procedure of atrial septostomy or the curative process of lung transplantation.[142]

Pulmonary endarterectomy

CTEPH is the only cause of PH that is potentially curable; therefore the importance of recognizing and diagnosing this entity is paramount. Several recent reviews provide more in depth discussion of this topic.[143,144] Briefly, CTEPH is a long-term complication of pulmonary embolism; approximately 4% of patients experiencing a pulmonary embolism will subsequently develop CTEPH.[145] However, the majority of patients with CTEPH lack a history of venous thromboembolism. There are about 2500 new cases per year of CTEPH in the US, although the estimated number of unreported or unrecognized cases is likely much higher.[143] The pathophysiology of CTEPH is complex and poorly understood. Obstruction of the proximal pulmonary arteries by organized thromboembolic material and increased resistance to flow is likely the initial insult. Subsequently vascular remodeling occurs in both large and small pulmonary vessels, with intimal thickening, collagen deposition, and calcification. The small vessel arteriopathy seen in CTEPH is similar to that seen in idiopathic PAH and may reflect vascular remodeling in response to increased flow in those parts of the distal pulmonary arterial bed unobstructed by more proximal thrombotic material.[144]

Pulmonary endarterectomy (PEA) is a true endarterectomy that involves stripping the diseased intimal layer from the proximal pulmonary arteries; this procedure differs from embolectomy performed in some cases of acute pulmonary embolism. PEA is performed via median sternotomy on cardiopulmonary bypass with deep hypothermic arrest to minimize blood loss.[146] In most patients, RV afterload reduction by removal of obstructive material from the pulmonary vasculature will result in an immediate and significant decrease in pulmonary artery pressures.[146,147] While PEA is the treatment of choice for CTEPH, not all patients diagnosed with CTEPH are surgical candidates. The decision of whether PEA is feasible for specific patients must be made at a center with expertise in this procedure. General considerations include evidence of surgically accessible thrombi, degree of pulmonary vascular resistance as measured during right heart catheterization, and patient comorbidities.[148] In particular, an elevated pulmonary vascular resistance in the absence of substantial thromboembolic disease on pulmonary angiogram suggests a predominance of small vessel disease that will not benefit from surgical intervention. Unfortunately, there is as of yet no accepted preoperative classification system that reliably Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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defines operable versus non-operable CTEPH disease, reinforcing the recommendation that patients with CTEPH be evaluated at centers that have experience in this procedure.

In a recent publication from the University of California at San Diego Medical Center, the institution with the most experience with PEA, the overall mortality associated with the procedure was 4.7%, with most deaths attributable to residual pulmonary vascular disease and right heart failure.[146] This operative mortality rate has dropped significantly since PEA was first begun in the 1970s, likely due to improved operative technique; during this early period approximately 20% of patients did not survive the procedure.[147]

Patients who successfully undergo PEA have excellent long-term outcomes.[149-151] Most of the hemodynamic improvement associated with PEA occurs within the first 3 months, with reductions in PVR and improved cardiac output.[150,151] Reflective of the improved hemodynamics, functional class likewise improves. One group reports that contrary to the preoperative state, in which 97% of patients were functionally limited (WHO class III-IV), at 3â&#x20AC;Żmonths this prevalence decreased to 12%.[150] At 4 years post-PEA, the same study group had excellent functional status, with 74% in WHO class I and none in class IV.[150] While there is marked improved in hemodynamics and physical stamina in the majority of patients, approximately 25% will have some degree of persistent PAH after PEA. These patients often require targeted PAH medical therapy, although recent publications do not indicate increased mortality in those with persistent PAH who survive the perioperative period. Freed and colleagues report that at 5 years after PEA, survival was 90% in both those with and without residual PAH.[151] Regardless of whether residual PAH is present, all patients who have CTEPH and undergo PEA must remain on lifelong anticoagulation.[146]

Transplant

Transplantation, either lung or heart/lung, is the final treatment option for those with PAH who are failing medical therapy. Most transplant centers now perform double-lung or combined heart-lung transplantation for PAH, due to the high incidence of reperfusion injury and worse outcomes with single lung transplantation.â&#x20AC;&#x2030;[142] The decision of whether to perform double lung or combined heart-lung transplantation for PAH is center specific, but, in general, heart-lung transplantation is performed when there is either significant impairment of cardiac function (inotrope dependence) or in the setting of complex congenital heart disease.[142,152] The International Society for Heart and Lung Transplantation (ISHLT) recommends that patients with PAH be referred for transplant evaluation if they have either WHO functional class III or IV disease, Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

irrespective of ongoing therapy, or if they have rapidly progressive disease.[153] Overall PAH accounts for 3.5% of all lung transplants performed since 1990. Interestingly, the percentage of lung transplants performed for PAH is decreasing over time, with a prevalence of 12% in 1990 compared to 2% in 2008, likely a reflection of improved medical therapy.[154]

Lung organ allocation in the U.S. is currently dictated by the potential recipientâ&#x20AC;&#x2122;s Lung Allocation Score (LAS), a metric devised and implemented by the Organ Procurement and Transplantation Network in 2005. The LAS attempts to equitably assign donor organs based transplant benefit; in particular, a complex calculation is performed that quantifies the urgency of transplant with expected transplant outcome (1 year post-transplant survival).[155] The goals of the LAS are to minimize wait list mortality while maximizing transplant benefit, ensuring efficient allocation of scarce donor organs. Some of the factors included in the LAS calculation include forced vital capacity, functional status, age, six-minute walk distance, serum creatinine, pulmonary artery systolic pressure, and pulmonary capillary wedge pressure.[155] While the goals of the LAS have in general been accomplished, with more transplants occurring in those with more severe disease and a concordant decrease in wait-list mortality, the beneficial effect of those with PAH awaiting transplant has been less clear.[156] Like other groups with lung disease, those with PAH have seen an increased rate of transplants occurring in those on the waitlist. However, unlike other subgroups, those with PAH have not experienced a decline in wait list mortality after implementation of the LAS system. (20% mortality at 12 months on wait list in LAS era, compared to 14% mortality at 12 months on the wait list in the pre-LAS era, p=0.19).[156] While the reasons for the failure of the LAS score to improve wait list mortality in PAH patients is uncertain, one potential explanation is the fact that patients with PAH are listed for double lung transplant; a simple scarcity of donor organs, which may favor those listed for single lung transplant, may account the observed findings. Another possibility is that the LAS does not accurately capture the mortality risk of those with PAH. Of all lung diseases, those patients with PAH have the lowest average LAS (denoting less priority for receiving donor organs).[155,156] The LAS score does not incorporate many of the hemodynamic parameters known to be associated with mortality in PAH, such as right atrial pressure or cardiac index.[157,158] Although successful in regards to lung transplantation as a whole, the LAS system appears to need further refinement to accurately assess mortality risk in those with PAH. The outcomes of those with PAH who undergo lung transplantation are worse in the short term, but better in the long term, compared to all patients who undergo lung 153

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transplantation. According to ISHLT data, which reflects both U.S. and international experience, overall survival for lung transplant recipients is 88% at 3 months and 78% at 1 year, with a median survival of 5.2 years. In comparison, patients with PAH have a 3-month survival rate of only 74% but a median survival of 8.6 years.

Atrial septostomy

Finally, as a palliating or bridging procedure, percutaneous balloon atrial septostomy (AS) decompresses the right ventricle via the creation of a right to left inter-atrial shunt, decreasing right heart filling pressures and improving cardiac output and systemic oxygen delivery at the expense of arterial oxygen saturation. Indications for AS include refractory right heart failure and/or recurrent syncope despite maximum medical therapy, including targeted PAH therapy, or as a bridging procedure while the patient is awaiting transplantation.[142] Despite its conceptual appeal, AS is rarely undertaken, with only approximately 300 procedures performed worldwide; furthermore, there is scant evidence upon which to inform patient care decisions, as most of the available medical literature consists of small case series.[159-161] Expert-based consensus guidelines define as contraindications to AS the following: a mean right atrial pressure > 20 mmHg, a resting arterial oxygen saturation of <90% on room air, or a left ventricular end diastolic pressure (LVEDP) of > 18 mmHg.[142] The expected response to AS is a decrease in mean right atrial pressure with an increase in cardiac output and systemic oxygen delivery. The procedural related mortality of AS ranges from 9-22%. [142,160,161] The most significant procedure-related complication is refractory hypoxemia; while all patients will have an expected reduction in arterial oxygen saturation with AS and require supplemental oxygen, 30-40% of patients can experience refractory hypoxemia. [160] Patients who undergo and survive AS have improved functional status, with most patients improving one WHO functional class.[160,161] Overall, AS may benefit those with progressive right heart failure despite available medical therapies, either as a palliative procedure or as a bridge to transplantation, but it should only be undertaken in centers experienced in the care of PH patients and with a clear understanding of the potential risks of the procedure.

PROGNOSIS

The prognosis of those with PH is dictated by both the etiology of the underlying disorder and the ability of the right ventricle to adapt to the elevated pulmonary vascular pressures. In an early description from the National Institutes of Health (NIH), the 3-year survival rate of those with idiopathic PAH was 48%.[162] In more recent American and French cohorts, 3-year survival 154

rates have increased to 58-72%, likely due to treatment advances.[158,163] Across the spectrum of disorders causing PAH, those due to connective tissue diseases, particularly systemic sclerosis, have a worse prognosis than those with idiopathic PAH; in comparison, those with congenital heart disease related PAH have a better prognosis.[164] Within disease states that are complicated by PH, including left heart disease and chronic lung disease, the presence of PH is usually associated with a worse prognosis compared to disease of similar severity not complicated by PH.[165-167] Despite the observed improvements in population survival, there is great heterogeneity in the outcomes of patients with PH, and clinicians should recognize the functional and hemodynamic characteristics that denote individual prognosis. The factors that impact survival and give insight into a patient’s disease course are outlined below and in Table 5. Most of the available data come from studies in those with PAH; their applicability to those with other forms of PH is unknown. Limited functional status, as assessed via the New York Heart Association (NYHA) classification system, has long been correlated with worse outcomes. [158,162,163] Likewise, objective measures Table 5: Factors associated with worse survival in PAH* Indicator

NIH coFrench American hort cohort cohort (1991)[162] (2010)[158] (2010)[163]

Age

Functional Class (NYHA)

Yes (Class IIIIV) N/A

Exercise Capacity (6MWD)

Yes Yes (≥63 years) (>60 years, men only) Yes Yes (Class (class III-IV) III-IV) Yes Yes (<250 m) (< 165 m)

Hemodynamics- Yes mRAP (≥20 mmHg) HemodynamYes ics- CI (< 2 L/ min∙m2) Hemodynamics- Yes PVR

Yes

Pericardial effusion Natriuretic Peptide

N/A

Yes (>32 Wood Units) Yes

N/A

Yes

Yes No

Yes (> 20 mmHg) No

(BNP>180 pg/mL)

*Clinical factors listed with cutpoints, if available. 6MWD: sixminute walk distance; BNP: brain natiuretic peptide; CI: cardiac index; mRAP: mean right atrial pressure; N/A: not assessed in this particular study; NIH: National Institutes of Health; NYHA: New York Heart Association; PAH: pulmonary artery hypertension; PVR: pulmonary vascular resistance; REVEAL: Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management

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of decreasing exercise tolerance, most commonly sixminute walk distance, have correlated with increased mortality. [57,158,163] Invasively measured hemodynamics allow quantification of right ventricle function and are powerful indicators of survival. In particular, measurements associated with a decompensated right ventricle, including elevated right atrial pressure and decreased cardiac index, are consistent markers of worsened outcomes. [58,59,158,162] Notably, the absolute level of pulmonary artery pressure is not a consistent indicator of prognosis, likely due to the eventual decrease in pulmonary pressure that occurs in association with a failing right ventricle.[24] Assessment of pulmonary vasodilator response is commonly performed via right heart catheterization in the evaluation of those with PH. Although the purpose of vasodilator testing was initially to determine suitability for treatment with calcium channel blockers, the results of vasodilator testing may also have prognostic value. Specifically, those with a positive vasodilator response, variably defined across studies, appear to have better survival compared to those who are not vasodilator responsive. [36,59,168,169] However, these studies are confounded by the fact that patients who displayed vasodilator response were often treated differently than those who did not display vasodilator response, [168,169] and not all studies have found an association between vasodilator response and outcome.[170] Therefore, the prognostic value of vasodilator response in the modern treatment era is uncertain. Echocardiography is a commonly used screening test in the evaluation of PH. While prognostic data from echocardiography are not as well validated compared to the information available from right heart catheterization, the presence of a pericardial effusion on echocardiography has consistently been associated with a shortened survival.[163,171,172] Finally, elevations in several biomarkers, including natiuretic peptides and cardiac troponins, have also been associated with worse prognosis in PAH.[163,173,174] The above clinical factors yield a general impression of an individual’s prognosis and may be sufficient for everyday practice. There are, however, several predictive equations that give a more precise estimate of a patient’s probability of one year survival: the older NIH equation and the newer REVEAL formula.[162,163] The NIH equation, which incorporates only the hemodynamic parameters of mean pulmonary artery pressure, cardiac index, and mean right atrial pressure, was derived from a cohort of PAH patients in the era before widespread targeted PAH treatment and may not be applicable in the modern era. The REVEAL equation was derived in a modern cohort of American patients and incorporates multiple variables, including demographics, hemodynamics, and functional status. Both of these equations are computationally complex and are not easily performed at the bedside. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

The improved survival in those with PAH over the past 2 decades is often attributed to improvements in medical therapy. However, improvements in mortality have not been well documented in the plethora of PAH therapeutic trials as the majority of clinical studies use surrogate endpoints, such as functional status or hospitalizations, rather than survival. Remarkably, only one trial, studying the use of IV epoprostenol, has shown a mortality benefit of targeted PAH therapy.[57] Longer term follow up of PAH patients treated with IV epoprostenol has also demonstrated survival benefit compared to historical controls, with 1- and 3-year survival rates of 88% and 63%, respectively, compared to expected survival rates of 59% and 35% (based on the NIH equation). [59] Likewise, non-controlled observational studies also suggest that other PAH therapies, including bosentan and treprostinil, improve survival.[66,175] More recently, a meta-analysis of major PAH trials (restricted to those trials with placebo controls) reported an aggregate 43% reduction in allcause mortality with the currently available medical therapies (1.54% vs. 3.80% in the treatment and control arms, respectively, RR=0.57, p=0.023).[176,177] Like the aforementioned epoprostenol trial, all but one of the 21 trials included in this analysis enrolled patients with FC III-IV disease, and although the overall mortality rate appears low, the mean study duration was only 14 weeks.

CONCLUSIONS

While the survival of those with PAH has clearly improved over the past 20 years and is likely due to improvements in targeted medical therapy and overall supportive care, there is much research that yet needs to be done. The available literature is mostly limited to those with PAH and the impact of these targeted therapies on the more widely prevalent secondary forms of PH is uncertain. In addition, most study designs utilize surrogate outcomes rather than survival and are short in duration, neither of which are reflective of the outcome of most interest to patients and physicians or that reflect the long-term use of these medications in this chronic, incurable disease. Finally, most studies have assessed the impact of a single agent in comparison to placebo; head to head comparisons of available agents are still few in number and combination therapy, as commonly practiced, is not well defined by the current literature. Studies currently underway should help address these important questions.

REFERENCES 1. 2.

Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43-54. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. Pulmonary arterial hypertension in France: Results from a national

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137. Eaton T, Young P, Milne D, Wells AU. Six-minute walk, maximal exercise tests: reproducibility in fibrotic interstitial pneumonia. Am J Respir Crit Care Med 2005;171:1150-7. 138. Blyth KG, Groenning BA, Mark PB, Martin TN, Foster JE, Steedman T, et al. NT-proBNP can be used to detect right ventricular systolic dysfunction in pulmonary hypertension. Eur Respir J 2007;29:737-44. 139. Tulevski, II, Groenink M, van Der Wall EE, van Veldhuisen DJ, Boomsma F, Stoker J, et al. Increased brain and atrial natriuretic peptides in patients with chronic right ventricular pressure overload: Correlation between plasma neurohormones and right ventricular dysfunction. Heart 2001;86:27-30. 140. Hoeper MM, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J 2005;26:858-63. 141. Galie N, Hinderliter AL, Torbicki A, Fourme T, Simonneau G, Pulido T, et al. Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and doppler measures in patients with pulmonary arterial hypertension. J Am Coll Cardiol 2003;41:1380-6. 142. Keogh AM, Mayer E, Benza RL, Corris P, Dartevelle PG, Frost AE, et al. Interventional and surgical modalities of treatment in pulmonary hypertension. J Am Coll Cardiol 2009;54:S67-77. 143. Lang IM, Klepetko W. Chronic thromboembolic pulmonary hypertension: an updated review. Curr Opin Cardiol 2008;23:555-9. 144. McNeil K, Dunning J. Chronic thromboembolic pulmonary hypertension (CTEPH). Heart 2007;93:1152-8. 145. Pengo V, Lensing AW, Prins MH, Marchiori A, Davidson BL, Tiozzo F, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257-64. 146. Thistlethwaite PA, Kaneko K, Madani MM, Jamieson SW. Technique and outcomes of pulmonary endarterectomy surgery. Ann Thorac Cardiovasc Surg 2008;14:274-82. 147. Jamieson SW, Kapelanski DP, Sakakibara N, Manecke GR, Thistlethwaite PA, Kerr KM, et al. Pulmonary endarterectomy: Experience and lessons learned in 1,500 cases. Ann Thorac Surg 2003;76:1457-62; discussion 1462-4. 148. Kim NH. Assessment of operability in chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc 2006;3:584-8. 149. Condliffe R, Kiely DG, Gibbs JS, Corris PA, Peacock AJ, Jenkins DP, et al. Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2008;177:1122-7. 150. Corsico AG, D‘Armini AM, Cerveri I, Klersy C, Ansaldo E, Niniano R, et al. Long-term outcome after pulmonary endarterectomy. Am J Respir Crit Care Med 2008;178:419-24. 151. Freed DH, Thomson BM, Berman M, Tsui SS, Dunning J, Sheares KK, et al. Survival after pulmonary thromboendarterectomy: Effect of residual pulmonary hypertension. J Thorac Cardiovasc Surg 2011;141:383-7. 152. Toyoda Y, Thacker J, Santos R, Nguyen D, Bhama J, Bermudez C, et al. Long-term outcome of lung and heart-lung transplantation for idiopathic pulmonary arterial hypertension. Ann Thorac Surg 2008;86:1116-22. 153. Orens JB, Estenne M, Arcasoy S, Conte JV, Corris P, Egan JJ, et al. International guidelines for the selection of lung transplant candidates: 2006 update—a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006;25:745-55. 154. Christie JD, Edwards LB, Aurora P, Dobbels F, Kirk R, Rahmel AO, et al. Registry of the International Society for Heart and Lung Transplantation: Twenty-fifth official adult lung and heart/lung transplantation report--2008. J Heart Lung Transplant 2008;27:957-69. 155. Davis SQ, Garrity ER, Jr. Organ allocation in lung transplant. Chest 2007;132:1646-51. 156. Chen H, Shiboski SC, Golden JA, Gould MK, Hays SR, Hoopes CW, et al. Impact of the lung allocation score on lung transplantation for pulmonary arterial hypertension. Am J Respir Crit Care Med 2009;180:468-74. 157. Benza RL, Miller DP, Frost A, Barst RJ, Krichman AM, McGoon MD. Analysis of the lung allocation score estimation of risk of death in patients with pulmonary arterial hypertension using data from the REVEAL Registry. Transplantation 2010;90:298-305. 158. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al.

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Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010;122:156-63. Allcock RJ, O‘Sullivan JJ, Corris PA. Atrial septostomy for pulmonary arterial hypertension. Heart 2003;89:1344-7. Kurzyna M, Dabrowski M, Bielecki D, Fijalkowska A, Pruszczyk P, Opolski G, et al. Atrial septostomy in treatment of end-stage right heart failure in patients with pulmonary hypertension. Chest 2007;131:977-83. Law MA, Grifka RG, Mullins CE, Nihill MR. Atrial septostomy improves survival in select patients with pulmonary hypertension. Am Heart J 2007;153:779-84. D‘Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343-9. Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, et al. Predicting survival in pulmonary arterial hypertension: Insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 2010;122:164-72. McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, et al. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:78S-92S. Grigioni F, Potena L, Galie N, Fallani F, Bigliardi M, Coccolo F, et al. Prognostic implications of serial assessments of pulmonary hypertension in severe chronic heart failure. J Heart Lung Transplant 2006;25:1241-6. Oswald-Mammosser M, Weitzenblum E, Quoix E, Moser G, Chaouat A, Charpentier C, et al. Prognostic factors in COPD patients receiving longterm oxygen therapy. Importance of pulmonary artery pressure. Chest 1995;107:1193-8. Ryu JH, Krowka MJ, Pellikka PA, Swanson KL, McGoon MD. Pulmonary hypertension in patients with interstitial lung diseases. Mayo Clin Proc 2007;82:342-50. Sandoval J, Bauerle O, Palomar A, Gómez A, Martínez-Guerra ML, Beltrán M, et al. Survival in primary pulmonary hypertension. Validation of a prognostic equation. Circulation 1994;89:1733-44. Raffy O, Azarian R, Brenot F, Parent F, Sitbon O, Petitpretz P, et al. Clinical significance of the pulmonary vasodilator response during short-term infusion of prostacyclin in primary pulmonary hypertension. Circulation 1996;93:484-8. Higenbottam T, Butt AY, McMahon A, Westerbeck R, Sharples L. Longterm intravenous prostaglandin (epoprostenol or iloprost) for treatment of severe pulmonary hypertension. Heart 1998;80:151-5. Eysmann SB, Palevsky HI, Reichek N, Hackney K, Douglas PS. Twodimensional and Doppler-echocardiographic and cardiac catheterization correlates of survival in primary pulmonary hypertension. Circulation 1989;80:353-60. Raymond RJ, Hinderliter AL, Willis PW, Ralph D, Caldwell EJ, Williams W, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol 2002;39:1214-9. Fijalkowska A, Kurzyna M, Torbicki A, Szewczyk G, Florczyk M, Pruszczyk P, et al. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest 2006;129:1313-21. Torbicki A, Kurzyna M, Kuca P, Fijałkowska A, Sikora J, Florczyk M, et al. Detectable serum cardiac troponin T as a marker of poor prognosis among patients with chronic precapillary pulmonary hypertension. Circulation 2003;108:844-8. McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galiè N, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J 2005;25:244-9. Galie N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394-403. McGoon M, Gutterman D, Steen V, Barst R, McCrory DC, Fortin TA, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:14S-34S.

Source of Support: Nil, Conflict of Interest: None declared.

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Review Ar ti cl e

Diagnosis and assessment of pulmonary vascular disease by Doppler echocardiography Justin D. Roberts and Paul R. Forfia Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

ABSTRACT Pulmonary hypertension (PH) is a relatively misunderstood disease, partly related to the fact that many perceive PH to be a singular diagnosis. An unintended consequence of this is the misapplication of the role of the Doppler-Echocardiographic (DE) examination, as well as an underappreciation for its ability to help discern PH pathophysiology prior to right heart catheterization. Since DE often serves as the â&#x20AC;&#x153;gatekeeperâ&#x20AC;? to invasive right heart catheterization, misinterpretation of the DE can lead to missed or delayed diagnosis with devastating consequences. Too often, the primary or nearly exclusive focus of the DE examination is placed on the pulmonary artery pressure estimation. Two main issues with this approach are that Doppler pressure estimations can be inaccurate and even when accurate, without integration of additional 2-D and Doppler information, the clinician will often still not appreciate the pathophysiology of the PH nor its clinical significance. This review will focus on the 2-D and Doppler features necessary to assess pulmonary vascular disease (PVD), discern the salient differences between PVD and pulmonary venous hypertension (PVH), and how to integrate these key DE parameters such that PH pathophysiology can be determined noninvasively and early in the patient workup. Overreliance on any single DE metric, and especially PA pressure estimation, detracts from the overall diagnostic potential of the DE examination. Integrating the relative balance of right and left heart findings, along with proper Doppler interpretation provides a wealth of clinical and pathophysiologic insight prior to invasive hemodynamic assessment. The end results are heightened awareness and improved identification of which patients should be referred for further invasive testing, as well the use of the DE information to compliment the findings from invasive testing. Key Words: pulmonary hypertension, right ventricular function, echocardiogram, Doppler

INTRODUCTION This review will focus on the principles and uses of the echo-Doppler examination (DE) in patients with pulmonary vascular disease (PVD). That is, patients whom have pulmonary hypertension that is primarily related to an increase in the pulmonary vascular resistance (PVR) and loss of large pulmonary artery compliance. We will also address the role of DE in the initial assessment of patients with undifferentiated pulmonary hypertension (PH), as the diagnosis of PH typically precedes confirmation or exclusion of PVD as the cause of PH. We will emphasize noninvasive clues that provide insight into the pathophysiology of PH Address correspondence to:

Paul R. Forfia MD Cardiovascular Medicine Division Heart Failure and Transplant Cardiology Pulmonary Hypertension Program Hospital of University of Pennsylvania 3400 Civic Center Blvd, Perelman-2 East, Philadelphia PA 19104 USA Phone: 215/615-0718 Fax: 215/349-8309 Email: paul.forfia@uphs.upenn.edu 160

pulmonary hypertension prior to invasive hemodynamic assessment. To accomplish this, a basic understanding of the right heart and pulmonary circulation is required, then how various forms of pulmonary hypertension, including pulmonary vascular disease, can disrupt the right ventricular-pulmonary artery interaction. Using a more integrated approach helps the clinician avoid some of the pitfalls of the DE examination, especially the overreliance on the Doppler pressure estimation in the initial diagnosis and serial assessment of patients with pulmonary hypertension. This approach also improves the diagnostic sensitivity of the DE examination for PVD and improves patient selection for further invasive hemodynamic testing. Access this article online

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Website: www.pulmonarycirculation.org DOI: 10.4103/2045-8932.83446 How to cite this article: Roberts JD, Forfia PR. Diagnosis and assessment of pulmonary vascular disease by Doppler echocardiography. Pulm Circ 2011;1:160-81.

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ANATOMY AND PHYSIOLOGY OF THE PULMONARY CIRCULATION AND RIGHT HEART The right ventricle is comprised of inflow (sinus) and outflow (conus) regions, separated by a muscular ridge, the crista supraventricularis. The inflow region includes the tricuspid valve (TV), the chordae/papillary muscles as well as the body of the RV.[1,2] The boundaries of the body of the RV are formed by the RV free wall, extending with a radius of curvature approximating that of a large sphere, from the anterior and posterior aspects of the interventricular septum. The normal septal curvature is convexed toward the RV cavity, imparting a crescentic shape to the right ventricle in cross section. The interior surface of the RV is heavily trabeculated; this feature along with the moderator band and more apical insertion of the TV-annulus impart key morphologic differences that distinguish the RV from the LV by echocardiography. In contrast, the infundibulum is a smooth, funnel shaped outflow portion of the RV that ends at the pulmonic valve. Thus, the RV has a complex geometry which largely precludes calculation of RV volume (and thus RV ejection fraction) by 2D echo. However, this limitation does not preclude alternative, non-volumetric methods of RV function assessment (vide infra). Normal RV free wall thickness is 0.3-0.5 cm, imparting greater distensability and larger cavity volumes in the RV versus the LV, despite lower end-diastolic filling pressures. This translates to an RVEF that is typically 35% to 45% (versus 55-65% in the LV) yet generates the identical SV as the LV. Systolic function of the RV, like the LV, is influenced by changes in preload, afterload, and the intrinsic contractility of the ventricle. Differences in RV muscle fiber orientation dictate that the body of the RV shortens symmetrically in the longitudinal and radial planes; thus, longitudinal shortening accounts for a much larger proportion of RV ejection than in the LV.[3] This relatively conspicuous RV shortening along the longitudinal axis can be exploited to measure RV systolic function using relatively simple techniques that do not require geometric assumptions or meticulous endocardial definition, both of which are known limitations to the noninvasive assessment of RV systolic function.[3,4] The right ventricle and the pulmonary circulation function as a coupled unit. In health, a normal pulmonary vasculature couples to an appropriately thin-walled, distensible RV that is designed to generate large amounts of blood flow without a resulting high pressure (‘flow generator’). As long as this normal interaction holds, so Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

will this physiologic paradigm. As pulmonary vascular disease develops, the pulmonary vascular resistance increases and the large arteries stiffen. As a result, the (formerly appropriate) non-muscular RV is typically incapable of completely matching, or coupling its contractile performance to its new afterload.[5,6] This relative RV-PA uncoupling leads to a stereotypical triad of changes that occur at the level of the RV, including RV systolic dysfunction, increased size and altered shape of the RV, as well as varying degrees of systolic and diastolic bowing of the interventricular septum. This triad of changes forms the basis of the echocardiographic diagnosis of PVD. The degree to which these changes occur is contingent upon the degree of RV-PA uncoupling. At a PVR of 5 WU, a patient with depressed RV contractility is far more uncoupled to their vascular load than a patient with an intrinsically normal RV coupled to the same afterload. The RV dysfunction triad helps to adjudicate and assess the physiologic and clinical significance of any given degree of PVD. The greater the RV impairment, the greater the overall significance of the PVD, no matter what the noninvasive pressure estimate is reported to be. Hypertrophy typically denotes chronicity, thus in more chronic forms of PH, RV hypertrophy predominates over RV dilatation. In contrast, in more acute forms such as pulmonary embolism, or even pulmonary arterial hypertension, dilatation of the RV occurs disproportionate to hypertrophy. It also seems that chronicity affects the degree of adaptation of the RV to a given afterload. The RV in Eisenmenger’s syndrome is often massively hypertrophied, not dilated, and maintains relatively normal function despite decades of systemic level afterload; this is the most likely explanation for the more favorable long term prognosis of these patients as compared to other forms of pulmonary arterial hypertension (PAH).[5,6]

Doppler data provides further physiologic and hemodynamic characterization of the varying etiologies of pulmonary hypertension. Importantly, varying degrees of pulmonary hypertension often result from an abnormal RV-PA interaction. However, the increased pulmonary artery pressure is the result, not the cause, of the RVPA mismatch. Thus, a simple, but critically important distinction is that PA pressure is a poor measure of RV afterload, which is why pulmonary artery pressure is also a poor predictor of clinical RV failure and prognosis in PAH.[7] Understanding this physiologic paradigm puts the clinician at a distinct advantage when assessing a patient with known or suspected PH. The presence or absence (whether a true negative or false negative) of elevated pulmonary artery pressure should not necessarily dissuade the clinician from suspecting PVD if there is evidence of RV dysfunction, especially when occurring in the form of the above noted triad. 161

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PRESSURE ASSESSMENT BY DOPPLER Despite its shortcomings as a measure of RV afterload, the pulmonary artery pressure assessment is a central component of the evaluation of patients with known or suspected PVD. This relates to the fact that varying degrees of pulmonary hypertension are nearly always present in patients with PVD, and the workup of these patients typically emanates from the initial noninvasive pressure assessment. A PASP>40 mmHg is generally accepted as the upper limit of normal in most subjects, however the cutoff may be higher in elderly subjects.[[8,9]

The most common method used in Doppler pressure assessment utilizes continuous wave Doppler to determine the peak tricuspid regurgitant jet velocity, which estimates the pressure difference between the right ventricle and right atrium using the modified Bernoulli equation (4v2; v equals the peak velocity of the TR jet),[10,11] as shown in Figure 1. The TV must be interrogated from multiple different views (i.e. RV inflow, short axis, apical four chamber, subcostal views) to ensure that the ultrasound beam is parallel to the regurgitant signal, thus allowing optimal Doppler envelope quality and an accurate peak transtricuspid flow velocity (TTFV). In general, the highest velocity obtained should be used to calculate the peak RV systolic pressure. One exception is the inclusion of a post-extrasystolic beat, which will often have a substantially higher peak velocity than steady state beats, relating to the larger stroke volume generated following the compensatory pause. If pulmonic stenosis is present, the gradient across the pulmonic valve must be subtracted from the peak RV systolic pressure to obtain the peak PA pressure, otherwise, a

Figure 1: Four chamber apical view with continuous wave Doppler interrogation across the tricuspid valve. The peak velocity is 2.7 m/sec, thus estimating a pressure gradient between the right ventricle and right atrium of 29 mmHg. This added to an RA pressure estimate will estimate PA systolic pressure. The high quality Doppler signal with a clearly defined peak lends to more reproducible and reliable pressure estimation. 162

distinction between ‘RV hypertension’ and pulmonary hypertension can be missed and PH medical therapy may be misapplied over mechanical intervention on the stenotic valve. In a technically limited study, agitated saline can be injected intravenously (IV) to enhance the TR jet signal and improve the measurement of the maximum TR jet velocity. [12] The absence of TR precludes pressure assessment via this method. An estimated right atrial pressure (RAP) is then added to the RV-RA pressure gradient to approximate PA systolic pressure. Thus, PASP≈4v2 + estimated RA pressure.

When all “conditions” required for this method are met– namely sufficient TR for interrogation, proper Doppler alignment, optimal visualization of the peak of the TR jet, and accurate RAP estimation–this method indeed correlates strongly with invasive PA systolic pressure assessment.[13,14] However, one or more of these limitations frequently occur in clinical practice leading to varying degrees of discrepancy between Doppler and invasive pressure. Clinicians experienced in assessing patients with PH will attest to the limitations of the Doppler pressure estimate, and recognize that the Doppler PA systolic pressure estimates should not be viewed as synonymous with invasive pressure recordings. Fisher et al. examined the correlation between Doppler estimated and invasively measured PA systolic pressure in a cohort of 65 patients with more severe pulmonary hypertension (62% with pulmonary arterial hypertension). [15] Although the correlation between Doppler and invasive PA systolic pressure measurements was reasonable (r=0.66; P<0.001), Bland-Altman analysis revealed that 48% of patients had a Doppler-estimated PA systolic pressure that was at least 10 mmHg different from the catheterization (16 underestimates, 15 overestimates). Pressure overestimations arose from either overestimation of the peak velocity signal (Fig. 2) or an overestimated RAP arising from IVC diameter and collapsibility assessment (vide infra). The magnitude of underestimation (-30 mmHg) was significantly greater than the degree of overestimation (+19 mmHg), with the underestimates leading to more frequent and marked misclassification of the degree of PH. Subjects with Doppler pressure underestimation had lower quality TR Doppler signals, leading to peak velocity (and thus pressure) underestimation (Fig. 3). Of note, of the 6 subjects in the study with no TR, 4 of these patients had pulmonary hypertension by catheterization. Thus, the absence of TR is not sufficient to exclude significant PH, even though it typically denotes a more compensated right ventricle. Twelve of the 16 patients in whom PA pressure was underestimated by DE had evidence of RV enlargement and/or dysfunction on their DE exam. Multiple studies have now shown a misclassification or improper estimation of PASP ranging from 48-54%.[16,17] Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Roberts and Forfia: Echo in PVD

Figure 2: Example of pulmonary artery systolic pressure overestimation by the continuous-wave Doppler method. The reported peak velocity is 4.4 m/s, estimating a gradient between the RV and the RA of 77 mmHg. However, the true peak velocity (b) is only 3.6 m/s, estimating an RV to RA gradient of only 52 mmHg. This figure highlights the importance of measuring the peak velocity carefully, as the peak velocity is squared, thus amplifying the error. Note the true peak Doppler velocity (single arrow) and the ‘shadow’ (double arrow) above the true peak of the Doppler envelope.

A variety of techniques have been used to estimate RAP, most often using the inferior cava dimensions and/or the degree of IVC collapsibility with inspiration or “sniff.”[18,19] None of these techniques have proved particularly accurate, with RAP overestimation being the more frequently observed limitation.[15] In fact, an overestimated RAP was the primary source of error in nearly 50% of the subjects with an overestimated PASP. [15] The relative inaccuracy of the IVC-estimated RAP relates to a number of factors, including the fact that IVC dilatation and collapsibility are dictated not only by the intravascular distending pressure, but also by the relative compliance of the IVC, the degree of chronic remodeling of the IVC, and also the relative degree and transmission of the fall in pleural pressure to the vena cava. Recently, Utsunomiya et al. compared right atrial pressure estimates obtained via the ratio of tricuspid inflow E wave velocity to the tricuspid annular tissue Doppler E wave velocity (E/Ea) with near simultaneous invasive pressure values in 50 patients with chronic PAH. The echo measured E/Ea had a reasonable correlation to RHC measured mean RAP (r=0.80), with most error arising from echocardiogram overestimation. [20] Given the significant variation in these methods, we prefer to add the clinically estimated right atrial pressure from the jugular venous pressure examination to the Doppler derived transtricuspid gradient in order to obtain the most accurate PA systolic pressure estimate. The Doppler pressure estimate should not be viewed as a “stand alone” test in the assessment of a patient with known or suspected pulmonary vascular disease. Rather, the Doppler pressure estimate should be integrated Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Figure 3: Example of pulmonary artery systolic pressure underestimation by continuous wave Doppler method. Note the Doppler signal dropout and a poorly defined peak TR velocity. The peak velocity is estimated at 3.3 m/sec, estimating an RV to RA gradient of 43mmHg and PA systolic pressure of 53 mmHg. A right heart catheterization within 24 hours of the DE examination revealed a pulmonary artery systolic pressure of 95 mmHg. Note the RV dilation on the above 2-D image; the RV dilatation is an important clue to potential PA systolic pressure underestimation.

into the context of the remainder of the examination; if the Doppler examination estimates mild pulmonary hypertension in the context of moderate RV enlargement and systolic dysfunction, it is more likely that the pressure has been underestimated and a right heart catheterization should be performed. In contrast, borderline or mild pulmonary hypertension in the context of normal RV size, shape and systolic function often is associated with a false positive diagnosis of pulmonary hypertension.

Pulmonary artery diastolic pressure (PADP) can be derived from the end-diastolic point of the pulmonary regurgitation signal, added to an estimate of right atrial pressure[21] (Fig. 4). Alternatively, PADP can be estimated from the velocity obtained from the TR jet at the time of pulmonic valve opening.[22,23] In either case, the accuracy of the method is contingent on the presence of PR or TR and the quality of the respective Doppler envelopes.

The mean pulmonary artery pressure can also be estimated by Doppler. The most common method takes advantage of the inverse correlation between the time to peak velocity (acceleration time; AcT) of the pulsed wave Doppler profile obtained in the RV outflow tract [mPAP=79-0.45 (RVOT AcT)] (Fig. 5). Kitabatake et al. showed that patients with a mean PA pressure of 19 mmHg had an average AcT of 137±24 msec, whereas an AcT of 97±20 msec and 65±14 msec was seen in patients with a mPAP of 20-39 mmHg, and ≥40 mmHg, respectively. [24] This method is relatively easy to perform, highly reproducible, and unlike pressure estimates based on tricuspid regurgitation velocity, Doppler recordings 163

Roberts and Forfia: Echo in PVD

from the RVOT are available in virtually all patients. The AcT can provide very useful corroborative information that aids in the accuracy of PH diagnosis; for example, in the presence of borderline PH by TR jet velocity, a AcT >100 msec would suggest there is no PH, whereas an AcT of <70 ms would greatly increase the likelihood of PH being present. Another method of deriving the mPAP uses the standard formula for mPAP, taken from the Doppler-estimated SPAP and DPAP from tricuspid and pulmonic reguritant flow velocities (mPAP=DPAP+(SPAPâ&#x20AC;&#x201C;DPAP/3), respectively. However, since this method relies on two Doppler pressure estimates, this method is potentially subject to compounding error. Alternatively, the mean PAP can be estimated from the Doppler PA systolic pressure estimate using the Chemla (mPAP=0.61 (sPAP)+2 mmHg) or the Syyed (mPAP=0.65 (sPAP)+0.55 mmHg) formulas.â&#x20AC;&#x2030;[25] These formulas take advantage of the predictable hemodynamic relationship between mean and systolic pulmonary artery pressure in most patients.[26]

As mentioned above, RV geometry does not lend to simple modeling, and thus formulae to estimate RV volumes are not nearly as reliable. As a result, accurate RV ejection fraction assessments have proved elusive, and thus most measures of RV function employ changes in RV dimension or area. Future use of three-dimensional echocardiography should make RVEF assessment more accurate and feasible. The most common and arguably least ideal method of RV function assessment by echocardiography is visual estimation. The echocardiographer visually integrates the relative change in RV cavity area to estimate global RV systolic function, typically reporting RV function as normal, mild, moderate, or severely reduced. However, the inherent limitations of RV imaging combined with

RV FUNCTION ASSESSMENT

Direct measures of RV systolic function

Assessment of right ventricular function is the single most important aspect of the DE examination in patients with known or suspected PVD, given the morbidity and mortality associated with this condition is heavily dependent on the degree of adaptation of the right ventricle to its excessive pulmonary vascular load. Virtually all echocardiographic measures shown to have prognostic significance in PAH are either direct or indirect measures of RV systolic performance.[7]

Figure 4: Continuous wave Doppler interrogation of the right ventricular outflow tract. The end diastolic regurgitant velocity is 1.9 m/sec. When added to an estimate of right atrial pressure of 15 mmHg, this estimates a pulmonary artery diastolic pressure of 30 mmHg.

Figure 5: Pulse wave Doppler interrogation of the right ventricular outflow tract. Panel A represents the time to peak velocity of the Doppler envelope, or Acceleration Time (AcT)=158ms, consistent with normal mean pulmonary artery pressure. Panel B illustrates an AcT=68ms, in a patient with a mean pulmonary artery pressure of 42 mmHg. 164

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reader subjectivity lends to significant inter-observer variability, with unreliable or highly inconsistent reporting of RV function. Thus, one must be very cautious in how to interpret RV function by this method, as one reader’s “severe” may be another reader’s “mild” RV dysfunction.

A more quantitative approach is to measure the total systolic area change of the RV, referred to as the RV fractional area of change (RVFAC). This measure is derived from the planimetered areas of the RV at end-diastole and endsystole ([RVFAC=RV Area ED-RV areaES/RV AreaED] × 100) from the apical four-chamber view. The RVFAC does not require geometric assumptions and correlates with the RV ejection fraction.27 However, incomplete visualization of the RV cavity (more common in the setting of RV enlargement) as well as suboptimal endocardial definition lead to relatively high inter- and intra-observer variablility.[28,29] As mentioned above, differences in muscle fiber orientation of the RV dictate that there is proportionally greater RV longitudinal shortening in the RV than in the LV.[3] In a recent study, longitudinal fractional area change (LFAC) accounted for the majority of total RVFAC (77%) in normal subjects.[30] Others have shown that longitudinal systolic displacement of the RV base toward the RV apex (referred to as tricuspid annular plane systolic excursion, or TAPSE) correlates strongly (r=0.79-0.92) with RV ejection fraction derived from radionuclide angiography. [4,31] The predominantly longitudinal contractile pattern of the RV can be exploited in order to assess RV systolic function.

TAPSE can be derived from 2D echo or M-Mode (Fig. 6a-c), is simple to perform and has been shown to be highly reproducible, owed in part to the lack of reliance on RV endocardial definition or geometric assumptions. [4,29] Evidence from prior studies indicates that a normal TAPSE is 2.4-2.7 cm, with lesser values indicating mild (2.0-2.3 cm), moderate (1.5-1.9 cm) and severe (<1.5 cm) RV dysfunction.[32,33] A TAPSE<1.8 cm predicts a stroke volume index <29 ml/m2 with 87% accuracy, and is associated with increased hospitalization rates for right heart failure and decreased survival in patients with PAH. [29,31] Ghio et al. recently showed in a PAH cohort that a TAPSE≤1.5 cm was associated with a nearly three-fold higher event rate (death or emergent lung transplant) versus subjects with a TAPSE>1.5 cm.[34] Tissue Doppler imaging (TDI) can also be used to measure the velocity of RV contraction in the longitudinal axis (denoted S’ or Sa), correlates with TAPSE (r=0.90), and is another simple and reproducible method of RV function assessment[35] (Fig. 7). An S’ <10 cm/sec predicts a cardiac index <2.0 l/min/m 2 with 89% sensitivity and 87% specificity.[36] In addition, the RV TDI signal can be integrated to measure the longitudinal tissue Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Figure 6: Tricuspid annular plane systolic excursion (TAPSE) in M-mode obtained in the apical four chamber view. The distance between the enddiastolic (a) and end-systolic (b) represents TAPSE (2.7 cm). Panel B represents end-diastolic measurement (7.2 cm) from the apex to the tricuspid valve plane. Panel C represents the end-systolic measurement (5.9 cm) from the apex to the tricuspid valve plane. The difference between these two measurements is the 2-D TAPSE (1.3 cm). M-mode is more commonly used, but the methods yield comparable results.

Figure 7: Right ventricular Tissue Doppler imaging along the basal long axis of the right ventricular free wall. The longitudinal shortening is labeled S’ and is measured at 9cm/sec. Right ventricular myocardial performance index can be obtained from the isovolumic contraction time (IVCT), relaxation time (IVRT), and ejection time (RVET).

displacement.[37] Using ROC curve analysis, an RV tissue displacement >1.5 cm predicted an RV stroke volume index 165

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≥30 ml/m2 (AUC 0.79); changes in RV tissue displacement related strongly to changes in RV stroke volume index in response to intravenous epoprostenol infusion.

The myocardial performance index (MPI or Tei-Doppler index) uses a different approach to RV function assessment, integrating systolic and diastolic function parameters in a single measure, using the formula IVRT+IVCT/RVET, where IVRT is the RV isovolumic relaxation time, IVCT is the isovolumic contraction time, and RVET is the RV ejection time. The time intervals are typically derived from tissue Doppler signals (Fig. 7). Increasing values represent worsening function, with an increased RV MPI associated with decreased survival in PAH.[38] In certain centers, RV MPI is a standard noninvasive measure of global RV function, whereas other centers have found the method somewhat cumbersome and thus is used less often in clinical practice.

All of the clinically used noninvasive methods of RV (and LV) function are load-dependent, and thus will change in response to different loading conditions, most notably RV afterload. The afterload sensitivity of these RV function measures may be viewed as a strength or weakness. A strength, in that the vast majority of RV dysfunction in the setting of PVD is indeed afterload-dependent and thus it is desirable that these measures will track with changes in RV afterload. A weakness, in that a fall in TAPSE, for example, does not indicate the intrinsic, load-independent performance of the RV (RV contractility). This distinction becomes clinically relevant when a patient with PAH is referred for lung vs. heart-lung transplantation, and the question is raised as to whether normalizing RV afterload with lung transplant will be sufficient to allow for RV function recovery.

Indirect measures of RV systolic function

The fundamental response of the relatively non-muscular RV to progressive increases in RV afterload is a fall in RV systolic function. In most forms of PVD (save chronic systemic to pulmonary shunts), the rise in RV afterload occurs relatively quickly, which in turn impedes RV ejection and increases RV wall tension. Due to the relative compliance of the RV and RA, this leads to increased chamber size, which in part, helps restore RV stroke volumes closer to baseline (heterometric autoregulation). As a result, increases in right heart chamber size can be thought of as an important indirect measure of RV systolic dysfunction. The normal RV measures approximately 2.5-3.5 cm at end-diastole, with a planimetered area of 15-18 cm2.[39] Typically, the RV dimension and area are two-thirds that of the LV. Expressing RV size as a ratio of RV:LV dimension is especially practical and is easily derived from the apical four chamber view, where the RV and LV are viewed side-by-side. The normal RV:LV ratio 166

is approximately 0.6-0.8, with increasing RV:LV ratios in patients with mild (0.8-1.0), moderate (1.1-1.4), and severe (≥1.5) RV dilatation. A useful rule of thumb is that the RV:LV ratio should be <1.0, and any value >1.0 is strongly suggestive of RV dilatation, often coinciding with RV dysfunction. Similarly, the angle and position of the RV apex change in response to increased RV afterload, thus leading to an overall change in RV shape. Normally, the RV apex forms a relatively acute angle and does not form, or occupy the apex of the heart. Thus, in the apical four chamber view, the normal RV has a triangular or sickle shape. In the setting of PVD, the RV apical angle often “opens” and the RV and LV will often “share” the apex of the heart, taking on a more oblong shape (Fig. 8). Lopéz-Candeles showed that a relatively large or “open” RV apical angle was a common finding in the setting of chronic pulmonary hypertension, relating inversely to decreases in TAPSE and RV fractional area change.[40] The RA:LA ratio should also not exceed 1.0. Moreover, the direction of interatrial septal bowing can provide important information as to the relative pressure differences in the right and left atrium. Unlike mitral regurgitation, which occurs due to either intrinsic mitral valve (MV) disease (i.e., myxomatous mitral valve disease, rheumatic heart disease) or secondary regurgitation from LV dysfunction, the vast majority of cases of TR occur secondary to RV dysfunction and tricuspid annular dilatation. As a result, TR is a common accompanying feature of RV dysfunction, with greater degrees of TR typically signifying greater degrees of RV decompensation. Moreover, the rate of rise in TR velocity provides qualitative insight into RV systolic function, and forms the basis for estimating RV dP/dt by Doppler [41,42] (Fig. 9).

As the right heart progressively dilates, the nondistensible pericardium becomes an increasingly important determinant of ventricular diastolic function and diastolic ventricular interaction (pericardial constraint). Once the pericardial space has been fully occupied by a dilated right heart, further increases in RV size lead to diastolic septal bowing from right to left, with reciprocal reductions in LV (and LA) chamber size.[43] Systolic flattening of the septum is also common in PVD, and likely occurs due to a delay in the time to peak RV contraction, creating mechanical RV/ LV asynchrony[44] (Fig. 10). Magnetic resonance imaging studies have shown relatively strong correlations between the degree of RV systolic septal bowing and pulmonary vascular resistance.[45,46] Importantly, even mild systolic septal flattening is a distinctly abnormal finding, and occurring in relative isolation, is often one of the earliest signs of underling PVD and pulmonary hypertension. Eventually, septal bowing leads to impaired early diastolic filling of the left heart. Thus, a common Doppler Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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Figure 8: Apical four chamber view. Panel A demonstrates normal RV:LV size ratio (<1.0) and shape, with a preserved acute angle of the RV apex in a patient either without PH or with pulmonary venous hypertension. Panel B represents a patient with PAH or another form of PH with pulmonary vascular disease. Note the RV:LV ratio is increased (>1.0), the angle of the apex is less acute, and the RV is apex-sharing with the LV.

Figure 9: Continuous wave Doppler interrogation across the tricuspid valve. Panel A demonstrates a rapid rise in the peak velocity of TR envelope consistent with preserved RV function. Panel B demonstrates a slower rise to peak velocity consistent with significant right ventricular dysfunction.

feature in PVD with RV dysfunction is Doppler evidence of “diastolic dysfunction” (i.e., “E to A reversal” of the transmitral Doppler pattern). [47] However, Doppler evidence of diastolic dysfunction should not be considered synonymous with left atrial hypertension. Thus, it is important to develop a sense, noninvasively, for whether a patient’s Doppler evidence of diastolic dysfunction is the cause of the PH or instead, is a marker of impaired LV Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

filling related to RV dysfunction and septal bowing. This will be discussed in further detail below.

In the setting of PAH, a mild to moderate circumferential pericardial effusion is seen in up to half of patients, and is particularly common at the time of initial clinical presentation. [48] In general, a pericardial effusion typically indicates right heart decompensation, and 167

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Figure 10: Short axis image at the midventricular level. Note the difference in the degree of septal flattening between systole (A) and diastole (B). The predominant systolic septal bowing is typical for PAH and other pulmonary vascular disease states. Also note the mild-moderate, circumferential pericardial effusion (PE), a common accompanying feature of the decompensated right ventricle.

is likely conferred on the basis of longstanding right atrial hypertension and impaired myocardial lymphatic drainage.[49] The presence of a pericardial effusion has been one of the most consistent echocardiographic findings indicative of a poor prognosis in PAH. [7,48] Importantly, the temptation to pursue percutaneous or surgical pericardial drainage should be avoided unless there is especially compelling evidence of tamponade, as the effusion typically is the result (not the cause) of RV failure and right atrial hypertension. Hemnes et al. reported that attempted drainage of pericardial effusions in patients with PAH has been associated with very poor outcomes, with most deaths occurring within 12-24 hours of the procedure.[50] In our experience, pericardial effusions in PAH progressively decrease in size or resolve over weeks or months as the RV failure responds to diuresis and pulmonary vasodilator therapy. Thus, there are numerous ways to quantify right ventricular function, either directly or indirectly. Often, the limitations of the DE examination are so frequently cited that echocardiography laboratories, including at major academic medical centers, do not have a single quantitative measurement of RV function in their clinical echo protocol. This is unfortunate, as the inability to obtain an RV ejection fraction, for instance, should not be interpreted to mean that RV function cannot be assessed. It is important that clinical echo protocols include basic measurements of RV size, the relative proportion of the RV to the LV, and a direct measurement of RV systolic function. Whether the direct RV function assessment be RVFAC, TAPSE, RV TDI or another measurement is perhaps not as important as the laboratory making that 168

particular measurement consistently, and properly, such that the sonographers, echocardiographers, and clinicians can develop an understanding of ‘their’ measurement so that it may be optimally integrated into clinical practice.

DOPPLER HEMODYNAMIC ASSESSMENT Pulmonary vascular resistance

An elevated pulmonary vascular resistance (PVR) is the sine qua non of pulmonary vascular disease. Thus, a reliable, simple and noninvasive method of PVR assessment would be of great value. Abbas et al. showed that the ratio of trans-tricuspid flow velocity (surrogate of pressure) to the velocity-time interval obtained from the RV outflow tract (surrogate of flow) closely correlates to PVR in a population of patients with an average PVR of 2 mmHg/l/min.[51] This approach proved much less reliable in subjects with a PVR>8 mmHg/l/min.[52] This method is also, in actuality, an estimate of total pulmonary resistance, as there is no accounting for left atrial pressure. Thus, in a patient, or population of patients with significant left atrial hypertension, this formula would consistently lead to significant overestimations of the PVR and wrongly implicate pulmonary vascular disease as the cause of the PH in a patient with pulmonary venous hypertension. We will discuss a simpler approach to PVR estimation below.

Cardiac output

Cardiac output can be estimated by Doppler examination, employing the formula Q=A×V (Q=flow; A=cross sectional area; V=flow velocity. Typically, the LV outflow tract is used Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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as the site for Doppler interrogation, as LVOT dimensions and flow velocity are more easily obtained than in the RV outflow tract. The flow velocity envelope is integrated to obtain the velocity time integral (VTI). Heart rate is recorded. The cardiac output is then estimated using the following formula: CODoppler=[VTILVOT×(diameter of LVOT)2×(0.785)]×heart rate. Several studies have shown reasonable correlations between Doppler and invasively derived cardiac output.[53] In a cohort with moderate or severe PH, Doppler-estimated CO correlated reasonably well with invasive CO (r=0.74), however there were substantial discrepancies between values on an individual patient basis. Using a simpler approach, an RV outflow tract VTI<12 cm predicted a cardiac index <2.2 with a sensitivity and specificity of 86% and 71%, respectively. [29] Likewise, a TAPSE<1.8 cm or an Sa<10 cm/sec also are strong predictors of a low cardiac index.[29,36] Thus, even if precise CO estimation is not feasible, easily obtained Doppler and 2D echocardiographic measures can still provide useful information in identifying patients with a low cardiac index.

Integrated assessment of RV-PA interaction

Doppler interrogation in the RV outflow tract can provide important information in the patient with known or suspected pulmonary vascular disease, as this is a key anatomic and physiologic interface between the RV and pulmonary vasculature.

Pulsed wave Doppler interrogation in the RV outflow tract is performed just proximal to the pulmonic valve, with the goal being to obtain a flow velocity envelope (FVE) without pulmonic valve artifact. The AcT measured as the

time from baseline to peak velocity) is measured from this envelope, and most commonly is used to estimate mean pulmonary artery pressure, as mentioned above.[24] Aside from the AcT however, the shape of the FVE can be used to qualitatively differentiate varying levels of pulmonary hypertension. Prior work has shown that a rounded FVE has been associated with normal PA pressures, while patients with mild-moderate PH more often have a triangular, or dagger-shaped FVE (often with late-systolic notching), while those with severe PH typically manifest prominent midsystolic notching of the FVE (Fig. 11). However, these same authors pointed out that only 53% of patients with PH evidenced a notched FVE, suggesting that pressure is an associate, but not the actual physiologic cause of this notching pattern. The actual cause of Doppler notching in the RV FVE is early arrival of reflected arterial waves from the pulmonary vasculature, leading to “real-time” impedance to flow.[54] This was initially described in the setting of acute and chronic pulmonary emboli, relating to the introduction of a more proximal site of wave reflection owed to proximal clot burden.[55,56] However, Torbicki et al. showed that the time to midsystolic flow deceleration of the FVE did not differ between patients with chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic PAH (IPAH).[55] Thus, exaggerated wave reflection is likely present in other forms of PH (i.e., PAH) aside from thromboembolic disease, and that analyses of RVOT Doppler FVE may be applied more broadly to detect pulmonary vascular disease in a referral population of PH patients.

Figure 11: Pulsed wave Doppler signals from the RV outflow tract. Panel A demonstrates a non-notched flow velocity envelope. Panel B is more triangular with a late-systolic notching pattern. Panel C has a pronounced mid-systolic notching pattern. The difference in the shape of the Doppler patterns is largely determined by differences in pulmonary vascular resistance, not PA pressure. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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Recent work reported on the hemodynamic differences seen among a cohort of 79 patients (patients with acute and chronic pulmonary emboli excluded) with undifferentiated pulmonary hypertension, on the basis of differences in the shape of the Doppler FVE.[57] The normal PW Doppler profile in the RV outflow tract (RVOT) is smooth, parabolic, without “notching” of the Doppler envelope (Fig. 11, panel A). In contrast to early reports, this study showed that the absence of Doppler notching did not indicate a lack of PH. Instead, the lack of Doppler notching was strongly associated with PH arising from increased left atrial pressure in the absence of pulmonary vascular disease. In contrast, in the presence of an increased pulmonary artery stiffness and a high PVR, reflected waves will return to the RV during systole, impede RV ejection and cause “notching” of the Doppler profile (Fig. 11, panels B, C). A mid-systolic notch pattern is especially abnormal, and associated with an average PVR>8 Wood Units (WU), along with moderate to severe RV dysfunction. A notched Doppler pattern was present in 100% of incident cases of PAH, and predicted a PVR>3 WU with an odds ratio of 22:1. [57] These findings suggest that notching of the FVE is more indicative of pulmonary vascular disease (high PVR, low compliance) than pulmonary pressure, and helps explain why notching is present in some, but not all patients with PH. Thus, visual inspection of the RVOTDoppler profile represents a simple, rapid method of gleaning insight into the relative presence (‘notched’ pattern) or absence (‘no notch’ pattern) of pulmonary vascular disease. We have found this approach to be extremely useful and applicable in clinical practice. Potential future applications of FVE analysis include its use as a screening tool to predict present or future development of PAH in high-risk conditions such as scleroderma, and whether serial changes in notching coincide with clinical and hemodynamic changes in PVD patients on medical therapy.

ECHO-DOPPLER FINDINGS IN PULMONARY VASCULAR DISEASE PAH

The relatively non-muscular, compliant RV is put at a distinct physiologic disadvantage in PAH and other PVD states, yet these same characteristics allow the RV to act as a relatively reliable “transducer” of its increased vascular load. Therefore, the triad of decreased RV systolic function, increasing RV size, and septal bowing form the fundamental basis for the echocardiographic recognition of PAH, with or without demonstration of an increase in Doppler estimated PA systolic pressure. In 1973, Goodman et al. published one of the first studies describing the echocardiographic features of IPAH.[58] They noted that all patients had RV dilatation, and half 170

had an RV dimension greater than their LV dimension. In addition, patients commonly demonstrated abnormal, or paradoxical, septal motion, where the interventricular septum moved away from the center of the LV cavity in systole. This occurs when the curvature of the septum is convexed toward the LV at end-diastole, such that LV systole serves to ‘push’ the septum toward the RV. Aside from being a common echo feature in PAH, the relative loss of inward septal motion can account for a mild loss of LV systolic function in PAH, and thus low-normal or mildly reduced LV function can occur in PAH on this basis. [59] In a larger series, Bossone et al. showed that 96% of patients had a Doppler estimated pressure >60 mmHg at diagnosis, however, the overall correlation between Doppler and invasive pressure estimates was relatively low (r=0.31). The time to peak velocity (AcT) in the RV outflow tract was <100 ms in 94% of subjects. Ninety-eight percent of subjects had RV enlargement whereas three quarters of the patients had qualitatively reduced RV systolic function. Systolic flattening of the interventricular septum occurred in 90% of subjects. Moderate or severe tricuspid regurgitation occurred in 80% of subjects, whereas mild to moderate mitral regurgitation was present in only one patient. A small or moderate sized pericardial effusion was noted in about 16% of subjects. The average ratio of transmitral Doppler E wave velocity to A wave velocity (E/A ratio) was 0.93, with 70% of subjects demonstrating “E to A reversal,” typically denoted Grade I LV diastolic dysfunction. Importantly, all subjects in this study were shown to have normal left atrial pressure by right heart catheterization, underscoring the fact that Doppler evidence of ‘diastolic dysfunction’ is not necessarily synonymous with left atrial hypertension. In fact, the pattern of “E to A reversal,” also referred to as grade I diastolic dysfunction, typically equates to normal left atrial pressure, reflecting the necessary redistribution of LV filling into late diastole that must occur when LV relaxation is impaired in the context of a normal LV filling pressure.[60] In clinical practice, the presence of any or all of the triad of findings of RV dysfunction accompanied by grade I diastolic dysfunction, is a strong indicator of severe pulmonary hypertension in the context of a normal left atrial pressure and high pulmonary vascular resistance. Subsequent studies have reported on the clinical and prognostic significance of many of the typical echoDoppler findings in PAH. Earlier studies focused on more indirect measures of RV dysfunction, such as right heart dilatation, septal bowing, pericardial effusion and TR severity. Eysmann showed that the presence and severity of a pericardial effusion is a strong independent predictor of mortality in PAH. Similarly, a mitral E/A ratio <1.0 was a strong predictor of adverse outcome. [61] Raymond et al. also showed that the presence of a pericardial effusion, along with an increased right atrial Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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area index were predictive of mortality. [62] Eysmann et al. showed that a peak pulmonic flow velocity >60 cm/sec was predictive of a drop in PVR of >30% on acute vasodilator testing; none of the patients with a peak velocity <60 cm/sec were vasoreactive. [63] Likewise, decreased left ventricular and left atrial area, increasing RV:LV area ratio, and the degree of leftward septal bowing are also associated with an increased risk of systemic hypotension in response to calcium channel blocker therapy, likely reflecting the inability to sufficiently recruit RV stroke volume to overcome the drop in systemic vascular resistance.[64] Subsequent studies have focused on more direct assessment of RV systolic function. In a retrospective study by Tei et al., the mean RV MPI of patients with IPAH (0.83) was higher than in healthy controls (0.28), and patients with an RV MPI≥0.83 had <10% event free survival at five years, vs. >70% in those with an RV MPI<0.83.[38,65] A prospective study in patients with IPAH and PAH associated with connective tissue disease showed that a TAPSE<1.8 cm was associated with lower invasively derived stroke volume index, higher right atrial pressure, greater RV dilatation, right to left heart disproportion, septal bowing and a higher incidence of pericardial effusion. Two-year survival estimates were 88% and 50% for patients with a TAPSE≥1.8 cm and <1.8 cm, respectively.[29]

The typical changes in RV size, function, and septal position have been shown to improve in response to varying therapies. Following four months of therapy with bosentan in patients with PAH (84% IPAH, remainder PAH associated with CTD) serial DE examination showed an improved RV MPI, reduced RV end-systolic area and RV:LV diastolic area ratio, improved early diastolic LV filling, and decreased pericardial effusion scores.[66] The peak TR velocity did not fall significantly, suggesting either no significant change in PASP or a drop in PASP that was not detectable by Doppler method. Similarly, following three months of intravenous epoprostenol infusion, RV size decreased as did peak TR velocity and the noninvasive PVR estimate; the RV MPI did not change in response to epoprostenol infusion. [67] Preliminary data showed that 21 of 27 subjects with PAH increased their TAPSE>0.2 cm (mean+0.5 cm) after six months of PH specific therapy, and that these subjects exhibited improvements in six minute walk distance (median+115 meters), BNP (-210 pg/ml) and NYHA class (-1.0 functional class). There were no deaths or right heart failure admissions in those with a TAPSE was ≥2.0 cm at six month follow up on PH specific therapy vs. two deaths and four right heart failure hospitalizations in those with a TAPSE <2.0 cm on follow up.[68] Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Chronic pulmonary embolism

CTEPH is an uncommon complication of prior acute pulmonary emboli. [69,70] The major site of vascular impedance is often the proximal pulmonary vasculature, owed to the persistence of clot and vessel remodeling in the affected area. However, small vessel pulmonary arteriopathy is also known to occur in CTEPH, such that the degree of PVR elevation may be equal or greater to that seen in IPAH. [71] The end result is often that the overall burden of pulmonary vascular disease is comparable to that in PAH, and in some cases, worse due to the added hemodynamic load from the proximal obstruction. Thus, the typical triad of RV dysfunction, RV dilatation, and septal bowing is present in CTEPH and is largely indistinguishable from the various forms of PAH. Nevertheless, there are hemodynamic differences between CTEPH and PAH that can aid in differentiating the two conditions. Namely, in CTEPH, the presence of a discrete proximal obstruction leads to more exaggerated, earlier arrival of arterial reflected waves and thus a more pulsatile pulmonary vascular bed.[56] This increased pulsatility can be expressed as the fractional pulse pressure (FPP=PA pulse pressure/mean PA pressure); the typical FPP is 0.8 in PAH and ≥1.4 in CTEPH.[72,73] The FPP can also be estimated by Doppler, with a noninvasive FPP of 1.35 predicting CTEPH with a sensitivity of 95% and specificity of 100% over IPAH.[74] Serial DE exam following pulmonary endarterectomy (PEA) has shown increases in RV fractional area change as well as reductions in RV size, decreased septal bowing, and improved early diastolic LV filling.[75,76] An interesting study by Hardziyenka et al. showed that patients with early arrival of arterial reflected waves, as measured by a shorter time to notching of the pulmonary FVE, were the only CTEPH patients to benefit from PEA.[77] These findings prove that simple FVE analysis was able to predict clinical response to PEA and that a requisite degree of pulmonary vascular impedance and arterial wave reflection is needed in order for sufficient RV-PA recoupling to occur following surgical intervention.

Acute pulmonary embolism

Acute pulmonary embolism, and especially large, proximal emboli lead to a sudden increase in the pulmonary vascular impedance without a marked rise in the pulmonary artery pressure. This relates to the fact that the normal RV is typically incapable of generating a sufficient stroke volume to maintain a PA systolic pressure >60 mmHg (mean pressure of 40 mmHg) when suddenly uncoupled from a normal pulmonary vascular bed.[78,79] As a result, RV failure and cardiogenic shock may ensue despite a mean PA pressure between 20-40 mmHg.[80] Thus, it follows that the degree of RV dysfunction (not PA pressure) predicts the extent of 171

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perfusion defects by ventilation/perfusion scan.[81] In contrast, small subsegmental pulmonary emboli that are not associated with a marked rise in PA impedance will not lead to abnormal DE findings, highlighting the fact that the DE examination is insufficient to rule out an acute PE.[82] The relative degree of pulmonary hypertension helps establish the chronicity of the embolic event, as the average trans-tricuspid flow velocity in acute proximal pulmonary emboli (3.0 m/sec) is significantly lower than in patients with subacute PE (4.2 m/sec).[79] In contrast, patients with acute PE with a PASP>50 mmHg at the time of diagnosis are at increased risk of persistent pulmonary hypertension at one year follow up.[83] From a physiologic viewpoint, acute PE is an important and often dramatic clinical example underscoring the concept that pulmonary artery pressure is a poor measure of RV afterload. In fact, the relative disconnect between vascular impedance and PA pressure forms the basis for several relative “signature” DE findings in the setting of an acute pulmonary embolism. RV dilatation is almost universally present in the setting of a large PE, as the normally compliant RV will rapidly distend in response to the increased vascular load. However, unlike in PAH or other forms of chronic pulmonary vascular disease, RV hypertrophy will be conspicuously absent, and thus a simple qualitative clue for acute PE is RV dilatation and dysfunction in the relative absence of RV hypertrophy. Another common DE finding in acute PE is “McConnell’s sign,” which is visually appreciated as RV dysfunction along the RV base and mid segments, with a hinge point or “buckling” of the RV free wall near the RV apex.[84] This relative “sparing” of RV apical function most likely relates to tethering of the RV apex by a normal or hyperdynamic LV, via forces transmitted across the interventricular septum and interlaced muscle fibers shared by the RV and LV. Others have shown that the RVEF, RV TDI (Sa), and TAPSE are reduced in the setting of an acute PE.[85] A characteristic Doppler finding in acute PE is the “60/60 sign,” which refers to a markedly shortened AcT (<60 msec) in the FVE owed to the increased pulmonary artery impedence, combined with a PA systolic pressure <60 mmHg.[86] Another important finding to look for on the initial DE examination is right-sided heart thrombi or thrombi-intransit, which complicate approximately 4% of cases of acute pulmonary emboli.]87] Thrombi may be visualized within the right atrium, ventricle, and occasionally, are seen straddling the interatrial septum. Right heart thrombi are a very high-risk feature, typically associated with prior massive PE, severe RV dysfunction, and high in-hospital mortality.[87] In such cases, more aggressive strategies such as thrombolysis, catheter-based, or surgical embolectomy are typically warranted.[87,88] 172

Systemic to pulmonary venous shunts

A detailed overview of the various DE perturbations associated with the numerous forms of congenital systemic to pulmonary shunts (SPS) is beyond the scope of this review. Suffice to say that a variety of 2D and Doppler findings are associated with shunting at the venous, atrial, and ventricular levels. We will focus on the general principles of RV structure and function in this context as well as basic shunt assessment.

In the case of smaller shunts, or larger shunts at an earlier stage in the disease process, the RV is primarily subject to an increased volume load. Due to the relative compliance of the RV, volume loading is generally well tolerated which is likely why these lesions can go unnoticed for decades. In this circumstance, the primary DE findings are RV dilatation in the context of normal or hyperdynamic RV function. Owed to the increased RV preload in the face of normal RV afterload, a dilated and hyperdynamic RV is an important initial clue to the presence of a left to right shunt. On short axis, there is often bowing of the interventricular septum from right to left that is isolated to diastole. The degree of pulmonary hypertension varies, most often in direct relation to the size of the shunt and thus the amount of pulmonary blood flow. Herein lies another example of the relative disconnect between PA pressure and RV afterload, as the increased pressure is owed to, but not opposing, pulmonary blood flow. With time, excess pulmonary blood flow can lead to marked remodeling of the pulmonary vasculature, with the PVR reaching levels equal or greater to that seen in other forms of PAH. Under these conditions, the RV must accommodate the persistent volume load as well as a marked increased in RV afterload. However, unlike other forms of PAH, in the setting of a SPS, the rise in RV afterload occurs relatively slowly, often over decades. As a result, the structure and function of the RV is often markedly different in this context, particularly in the presence of Eisenmenger syndrome. Typically, the RV cavity is normal in size, maintains a relatively normal proportion relative to the LV, and exhibits marked concentric hypertrophy.[89] Right ventricular hypertrophy can often be appreciated by both thickening and excess RV trabeculations, along with a very conspicuous moderator band; these findings alone can often help distinguish PAH related to a SPS from other forms of PAH. RV dilatation and dysfunction in the setting of a chronic SPS is especially worrisome and often coincides with very late stage disease. An initial shunt assessment is often performed using rapid injection of agitated saline (“bubble study”), which opacifies the right heart chambers and allows for detection of both right to left shunts (early passage of bubbles Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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from right to left) or left to right (via a negative contrast jet created from the passage of blood into the opacified right heart chamber). Shunt quantification by Doppler is expressed in the same way as measured by cardiac catheterization, by the ratio of pulmonary to systemic blood flow. Doppler flow in the RV outflow tract (Qp) and LV outflow tract (Qs) are assessed to derive the Doppler Qp/Qs ratio. The RVOT diameter is typically about 0.5- 1.0 cm greater than the LVOT diameter; given that flow is equal to the product of cross sectional area and velocity, it follows that the integrated flow velocity signal (VTI) in the RVOT is typically less than the VTI in the LVOT. Thus, an initial clue to a sizeable left to right shunt is when the RVOT VTI is equal or greater than the LVOT VTI. Shunt localization by DE is performed by first assessing for 2D evidence of interatrial or interventricular septal defects. Further characterizations, including blood flow direction, blood flow velocity and estimated pressure gradients across shunts can be performed by color, pulsed wave and continuous wave Doppler examinations. Proper DE examination in the case of known or suspected congenital heart disease is best performed by a sonographer/ echocardiographer who are trained in the assessment of patients with congenital heart disease. Three-dimensional DE as well as cardiac magnetic resonance imaging can provide further characteristics of the location and defect size that assist in the treatment strategy of the SPS. Further SPS severity and shunt fraction quantification requires cardiac catheterization.

ECHO-DOPPLER FINDINGS IN PULMONARY VENOUS HYPERTENSION

By far the most common cause of pulmonary hypertension relates to passive elevation of the pulmonary artery pressure due to an increase in left atrial pressure. A variable degree of “reactive” pulmonary vascular remodeling may occur, typically relating to the severity and chronicity of the left atrial hypertension.[90,91] As a result, patients with pulmonary venous hypertension comprise a large percentage of patient referrals for pulmonary hypertension evaluation. Thus, an understanding of the noninvasive manifestations of pulmonary venous hypertension is critically important in the initial approach to patients with undifferentiated pulmonary hypertension. It follows that the noninvasive predictors of pulmonary venous hypertension include two-dimensional and Doppler findings that either reflect or predispose to left atrial hypertension, as well as more direct Doppler estimates of increased left atrial pressure.[92,93] Importantly, the LV ejection fraction is a very poor predictor of left atrial Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

hypertension, and thus a normal ejection fraction in no way, provides reassurance that the left atrial pressure is normal.

The two-dimensional echocardiographic examination can provide compelling initial evidence that either supports or refutes the presence of left atrial hypertension. One of the first clues to past or present left atrial hypertension is left atrial enlargement. This should certainly not be considered a physiologic measurement of left atrial pressure, however increasing LA size typically denotes chronically increased left atrial impedance and either the presence of, or predisposition for increased LA pressure. Left atrial enlargement is best appreciated in the parasternal long axis view, with a LA dimension at end-systole of 4.0 cm generally being the accepted cutoff. As an initial visual clue to LAE, one can simply look at the size of the LA relative to the aortic root, which is seen just anterior to the LA in this view; when the LA size exceeds aortic root size, this typically indicates LAE. Another important finding is the presence of left ventricular hypertrophy; LVH, even when mild, denotes chronic remodeling of the LV, typically the result of longstanding systemic hypertension. Even mild concentric LVH is a significant form of structural left heart disease, and is typically associated with increased LV chamber stiffness. Melenovsky et al. showed that left atrial size (expressed as left atrial volume), LV mass index, and the product of these two variables, were the strongest discriminants of non-systolic heart failure from hypertensive heart disease without a history of heart failure.[94] In the context of pulmonary venous hypertension, the interventricular septum will typically maintain a normal configuration on short axis imaging, convexed toward the right ventricle. Thus, the LV cavity will retain its round shape in both systole and diastole, with no evidence of septal flattening. In the apical four chamber view, the ratio of RV:LV dimension (or area) will typically remain <1.0, with the RV apex maintaining its sharp apical angle, with the LV forming the apex of the heart alone. Thus, the RV dysfunction ‘triad’ is conspicuously absent in most cases, consistent with a lack of pulmonary vascular disease.

The Doppler examination also provides important physiologic information with respect to valvular function, diastolic function, and left atrial pressure assessment. As a general statement, moderate or greater dysfunction of either the aortic or mitral valve is relatively uncommon when PVD is the primary source of the increased PA pressure. This is particularly true of the mitral valve. Of course, moderate or greater mitral stenosis is well known to cause severe pulmonary hypertension, largely on the basis of passive pulmonary venous congestion. However, moderate or greater mitral regurgitation is also 173

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distinctly uncommon in the setting of PAH, and therefore also provides compelling evidence for a pulmonary venous source of PH.[60] Importantly, MR severity can be underestimated by transthoracic Doppler imaging, especially when the MR jet is eccentric and off axis. Thus, complete Doppler interrogation using multiple different imaging planes is often required in order to appreciate the full extent of the MR. If there is clinical suspicion that the degree of MR is greater than reported by transthoracic DE examination, a TEE should be performed to obtain a more comprehensive structural and physiologic assessment of the MV.[95,96] Pulsed wave Doppler evidence of systolic pulmonary vein flow reversal also indicates severe MR, and represents the Doppler associate to large V waves in the left atrial pressure tracing.[96]

Lastly, Doppler interrogation of the mitral valve inflow provides a key component to the patient with known or suspected pulmonary hypertension. In normal sinus rhythm, left ventricular filling can be divided into an early, passive phase and a late, active phase. Pulsed wave Doppler interrogation across the mitral valve allows for quantification of these events, with the E wave and A wave Doppler envelopes corresponding to the early and late diastolic events, respectively. In normal individuals, in the absence of structural left heart disease, the E/A ratio is >1.0 with a transmitral E wave deceleration time (DT) between 160-240 msec, indicating that the bulk of LV filling occurs passively in early diastole as left atrial pressure exceeds diastolic ventricular pressure; atrial contraction serves to complete LV filling at enddiastole. The transmitral pattern can be altered in one of three ways, often expressed as Grades I, II, and III diastolic dysfunction.61 In Grade I diastolic dysfunction, the E/A ratio is <1.0 with a DT>240 msec, denoting a redistribution of left ventricular filling into late diastole due to impaired LV relaxation and typically, a normal left atrial pressure. Grade I diastolic dysfunction is a common feature seen in healthy persons over the age of 60, however may occur at any age in persons with structural left heart disease (i.e., LVH/hypertensive heart disease, impaired LV systolic function). As mentioned previously, an E/A ratio <1.0 is also a common finding in PAH, and is typically caused by RV enlargement, septal bowing and an abnormal diastolic ventricular interaction that impedes LV relaxation. Thus, the presence of Grade I diastolic dysfunction should not dissuade one from suspecting PAH or another PVD-related cause of pulmonary hypertension, particularly when accompanied by features of the RV dysfunction triad. In fact, this constellation of findings suggests the PH is occurring in the context of a normal left atrial pressure. Grade II diastolic dysfunction, referred to as the pseudonormal transmitral pattern, occurs when there is 174

structural left heart disease and/or age >60 years with an E/A ratio between 1-1.5 and a DT between 160-240 msec. This represents a more advanced stage of diastolic dysfunction, as left atrial hypertension is typically manifest. In grade III diastolic dysfunction, or restrictive transmitral filling, the E/A ratio typically exceeds 2.0 with a DT<160 msec; restrictive transmitral Doppler physiology is strongly suggestive of an increased LA pressure. (Fig. 12) Thus, Grade II and III diastolic dysfunction are strongly suggestive of an increased left atrial pressure at the time of DE examination is performed and are thus very uncommon findings in PAH. A PASP between 40 and 70 mmHg (mean PA pressure of ≈ 25-45 mmHg) in the presence of pseudonormal or restrictive transmitral flow is strongly suggestive of pulmonary venous hypertension as the dominant source of pulmonary hypertension. If this is coupled with normal septal position as well as normal RV size and shape, the diagnosis of pulmonary venous hypertension becomes almost certain.

Figure 12: Pulsed wave Doppler interrogation of the mitral valve at the level of the leaflet tips. Panel A demonstrates grade I diastolic dysfunction with “E-A reversal”. This finding is commonly seen in patients over the age of 65, or those with underlying left-sided heart disease. In addition, this pattern is commonly seen in PAH, highlighting how decreased RV function and increased RV size increase ventricular interdependence and impair early LV diastolic filling. Importantly, grade I diastolic dysfunction typically denotes normal resting left atrial pressure. Panel B demonstrates grade II diastolic dysfunction or a “pseudonormal” filling pattern (E>A). This is associated with moderate left atrial hypertension. Panel C demonstrates Grade III or restrictive mitral inflow (E>>A with a short deceleration time). This is seen in patients with markedly elevated left heart filling pressures. Pattern A is common in PAH; patterns B and C are rare in PAH and common in PVH. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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INTEGRATION OF THE DE EXAMINATION INTO THE INITIAL DIAGNOSTIC ASSESSMENT OF UN-DIFFERENTIATED PULMONARY HYPERTENSION From a clinician’s perspective, a useful initial diagnostic framework considers whether a patient’s pulmonary hypertension is from a pulmonary venous (“postcapillary”) or pulmonary arterial (“precapillary”) source. This approach is both rational and practical, given the prevalence of pulmonary venous hypertension, as well as the fact that the diagnostic and therapeutic considerations for these patients differ considerably. As outlined in the sections above, a variety of DE parameters have significant diagnostic and prognostic value in PH. It is customary that a transthoracic DE report will provide a list of normal and abnormal findings related to cardiac structure and function. Table 1 summarizes some of the salient 2-D and Doppler features that aid in differentiating the type of PH. However, what is often lacking is the needed degree of integration of these findings in order to assist the clinician in arriving at the correct overall diagnosis. For example, what information should prompt referral of a patient for invasive right heart catheterization?

With a more integrated approach to DE interpretation in mind, we recently devised a Doppler-echo scoring system to help discern PH pathophysiology. The initial data included 76 consecutive patients with undifferentiated PH. Components of the score included “left heart” and “right heart” parameters, with features of each receiving a score. The left heart parameters were LA enlargement, LVH, grade II or III diastolic dysfunction; yes=0 points, no=1 point. Right heart parameters included RV enlargement, TAPSE<2 cm, septal bowing (yes=1 point, no=0 points) and Doppler notching of the RVOTDoppler profile (yes=2 points, no=0 points). It is notable that a Doppler estimate of PA pressure was not part of the score. A high score (6- 8) would thus be compatible with a pulmonary vascular origin of PH whereas a low score (0-2) would suggest pulmonary venous hypertension. Patients with a score of 0-2 were older, with an elevated PCWP of 18 mm Hg, only mild to moderate PH (mean PA pressure 33 mm Hg) and a mean PVR of only 2.8 WU. By way of contrast, patients with a score of 6-8 had a normal PCWP (12 mm Hg), severe PH (mean PA pressure 50 mm Hg) and mean PVR of 10 WU. Notably, all patients with a score>6 had a PVR>4.5 WU, whereas only one patient with a score <3 had PAH.[97] Two examples of this integrated assessment are shown in Figures 13 and 14. All images in Figure 13 correspond Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

to patient 1 (pulmonary venous hypertension) and the images in Figure 14 to patient 2 (pulmonary arterial hypertension). In the DE examination of patient 1, the parasternal long axis view (Fig. 13, panel A) reveals LAE and left ventricular hypertrophy. The apical 4 chamber view (panel B) also reveals LAE and bowing of the interatrial septum to the right suggesting higher LA than RA pressure. The LVEF is normal. The transmitral Doppler pattern reveals Grade III diastolic dysfunction (panel C). The RV:LV ratio is <1.0 with a non-apex forming RV and a relatively normal TAPSE. The RVOTDoppler pattern is not notched (panel D). The echo score is 1 of 8. This is highly suggestive of PVH without pulmonary vascular disease. We would not likely refer this patient for invasive right Table 1: 2-D, Doppler, and M-Mode echocardiographic features of pulmonary venous hypertension and pulmonary arterial hypertension Pulmonary venous hypertension 2-D imaging Normal or dilated LV size LVH Variable LVEF Mitral annular calcification Dilated LA size RV:LV ratio <1 Sharp RV angle RV not apex forming Preserved septal shape (no flattening) No pericardial effusion Normal RV function, TAPSE≥2.0 cm Doppler imaging E>A, Type II or III (pseudonormal or restrictive diastolic filling pattern) MR grade≥2+, MR>TR Variable PASP (typically <70 mmHg) No systolic notching of FVE in RVOT AcT of FVE in RVOT>95 msec AV stenosis TDI with RV S’>10 cm/sec M-Mode imaging TAPSE≥2.0 cm

Pulmonary arterial hypertension* Normal or small LV size No LVH Normal LVEF No mitral annular calcification Normal LA size RV:LV ratio>1 Open/round RV angle Apex forming RV Septal flattening/D-shaped LV cavity Pericardial effusion Reduced RV function, TAPSE<2.0 cm Normal or E<A, Type I diastolic filling MR grade≤1+, TR>MR Variable PASP (typically ≥70 mmHg) Systolic notching of FVE in RVOT AcT of FVE in RVOT <70 msec No AV stenosis TDI with RV S’<10 cm/sec TAPSE<2.0 cm

*Pulmonary arterial causes to include pulmonary arterial hypertension (WHO Group I PH; IPAH), chronic thromboembolic PH and WHO group III pulmonary hypertension with a normal left atrial pressure and PVR>3 WU. LV: left ventricle; LVH: left ventricular hypertrophy; LVEF: Left ventricle ejection fraction; LA: left atrium; RV: right ventricle; TAPSE: tricuspid annular plane systolic excursion; E: early mitral diastolic inflow velocity; A: atrial, or late mitral diastolic inflow velocity; MR: Mitral regurgitation; TR: tricuspid regurgitation; PASP: Doppler estimated pulmonary artery systolic pressure; FVE: flow velocity envelope; RVOT: right ventricular outflow tract; AcT: acceleration time; AV: aortic valve; TDI: tissue Doppler imaging

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heart catheterization at this stage, as our suspicion for PAH or even for a high PVR is very low. Instead, we would manage the left heart condition and monitor the patientâ&#x20AC;&#x2122;s symptoms and PH closely.

The parasternal long axis view in patient 2 (Fig. 14, panel A) shows normal left ventricular wall thickness and left atrial size. Note the dilated coronary sinus, often indicative of high right atrial pressure (panel A, arrow). On the apical 4-chamber view (panel B), the RV:LV ratio is >1.0, with a rounded RV apical angle and an apex forming RV. The LVEF is normal. The transmitral flow pattern reveals grade I diastolic dysfunction (panel C). The TAPSE (not shown) is reduced (1.7 cm), consistent with moderate RV dysfunction. The RVOTDoppler pattern has a mid-systolic notching pattern (panel D), which has been shown to be 96% specific for a PVRâ&#x2030;Ľ5 WU.[98] The echo score here is 8 of 8, which is highly consistent with PH of pulmonary vascular origin. We would refer this patient for urgent right heart catheterization as well as complete the needed

Figure 13: Integrated 2-D and Doppler echocardiographic assessment of a patient with PVH. Note the left atrial enlargement (panel A and B) and the left to right atrial septal bowing (panel B, arrow). Panel C demonstrates a restrictive transmitral flow pattern. The pulsed wave Doppler of the RVOT reveals no notching in the FVE (panel D), consistent with a normal pulmonary vascular resistance.

Figure 14: Integrated 2-D and Doppler echocardiographic assessment of a patient with PAH. Note normal left atrial size with a dilated coronary sinus (panel A, arrow) and right to left atrial septal bowing (panel B). Panel C demonstrates a Grade I diastolic dysfunction pattern (panel C) and the pulsed wave Doppler profile in the RVOT reveals mid-systolic notching (panel D, arrows), consistent with a very high pulmonary vascular resistance. 176

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imaging and functional studies in order to rule out underlying lung disease or chronic thromboembolic PH.

EXERCISE ECHOCARDIOGRAPHY

Exercise DE is being used with increasing frequency in the assessment of patients with known or suspected PVD as well in the context of dyspnea of unclear etiology. In the former case, the presence or absence of exercise-induced pulmonary hypertension is thought to increase the diagnostic sensitivity of the DE examination for the early stages of pulmonary vascular disease; in the latter case, a rise in PA pressure is often thought to provide ‘proof’ that pulmonary hypertension as an important source of a patient’s dyspnea. Although conceptually attractive, exercise DE assessment and interpretation has multiple important limitations that need be addressed in order to best apply this modality in clinical practice. The first issue to address is whether there should be a rise in PA pressure with exercise. The time-honored teaching on this subject is that the PA pressure should not increase with exercise. However, studies do not support this and indicate that exercise-induced pulmonary hypertension is more common than once appreciated. In 1966, Damato reported on the hemodynamic responses to 24 normal healthy male volunteers who underwent upright treadmill exercise with a pulmonary artery catheter in place. The average peak oxygen consumption (VO2) was 30 ml O2/ kg/min (~8-9 METS), indicating normal, but not elite exercise performance. At peak exercise, 10 of the 24 normal subjects had a mean pulmonary artery pressure >30 mmHg, thus meeting the definition of exerciseinduced pulmonary hypertension; the increases in PA pressure correlated with increasing cardiac output and the pressure-flow relationship and total pulmonary resistance remained normal in all subjects.[99] In another cohort of more fit subjects, bicycle exercise up to 240 Watts led to an average increase in the mPAP of 37 mmHg.[100] Similarly, Bossone et al. showed that highly conditioned college athletes routinely increased their Doppler estimated PA systolic pressure to >50 mmHg at peak exercise whereas the healthy non-athletes typically did not exceed a PASP of 30 mmHg.[101] The degree of PASP elevation correlated best with changes in stroke volume, again indicating a normal pressure-flow relationship. T h e s e c o n d i m p o r t a n t l i m i t a t i o n o f exe rc i s e echocardiographic assessment of PA pressure is that changes in left atrial pressure are not accounted for during exercise DE. This is critical, given that exercise-induced pulmonary hypertension (in health and in disease) most commonly arises from the interaction between an increased cardiac output and a rise in the left atrial Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

pressure.[100,102] To the contrary, Laskey et al. showed that the PVR of patients with IPAH remained elevated during exercise, but unchanged from resting values.[103] Thus, exercise-induced pulmonary vasoconstriction is not typical, even in patients with established, severe pulmonary vascular disease.

The third limitation of exercise DE is the accuracy of Doppler PA pressure assessment. Also, age likely exerts an important influence on the relative change in PA pressure with exercise, owed to age-related increases in pulmonary vascular stiffness; thus, exercise-induced pulmonary hypertension, even at relatively low workloads, may be a part of the normal aging process, similar to the exaggerated increase in systemic arterial pressure with aging.[104] Lastly, it seems that the systemic blood pressure response to exercise should be factored into the interpretation of an exercise-induced rise in PA pressure. For example, a rise in PASP from 35 to 70 mmHg in the context of a rise in systemic systolic pressure from 120 to 210 mmHg indicates that the relative proportion of pulmonary to systemic blood pressure has remained quite similar from rest to exercise, thus questioning the clinical significance of the rise in PA pressure in this context.

Investigators have also used exercise echocardiography to help identify latent pulmonary vascular disease in highrisk groups such as scleroderma. Steen et al. showed that 24 of 54 scleroderma patients at high risk for PAH had an increase of 20 mmHg or more with exercise DE examination; 21 of the 24 underwent right heart catheterization. Of these subjects, 4 had resting PH and 17 showed mild exercise-induced PH by catheterization. The average PVR at the end of exercise was <3 WU.[105] Others have defined exercise-induced PAH to be present if the mPAP increased to >30 mmHg with a WP<20 mmHg and a PVR that need only be >1 WU.[106] Though defined differently, both studies confirmed some degree of exercise-induced PH in these subjects, however at such low PVR values, the physiologic and clinical significance of these findings are less clear. Interestingly, Reichenberger observed Doppler estimated increases in PASP with exercise in 16 of 33 patients with scleroderma (mean PASP 47 mmHg at a peak VO2 of 64% predicted), yet only 1 of the 16 subjects with exercise-induced PH developed manifest PAH over a 3 year follow up.[107] Taken together, one must exercise caution in how they interpret a rise in Doppler estimated PA pressure with exercise, as even when accurate a rise in PA pressure with exercise does not necessarily implicate the pulmonary vasculature as the source of pulmonary hypertension, that the PH is appropriate for PH specific therapies, nor whether the PH is the source of dyspnea in an individual patient. To this last point, patients with chronic obstructive 177

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pulmonary disease and pulmonary hypertension demonstrated the same aerobic exercise capacity as COPD patients without pulmonary hypertension; in both groups, exercise capacity was limited by exhaustion of the ventilatory reserve and did not correlate with pulmonary artery pressure.[108] Thus, the demonstration of a rise in PA pressure with exercise in many cases, amounts to an association, but not a diagnosis as to the source of dyspnea in an individual patient. For many of these reasons, the recently published expert consensus document from the American College of Cardiology/American Heart Association, recommends that, no treatment decisions be made on the basis of exercise echocardiography.[9]

An alternative approach to exercise DE may be to focus on the right ventricular functional response to exercise, especially considering that impaired RV functional reserve is the mechanism of exercise limitation in PAH and other forms of PVD.[109] This approach may provide a more direct and clinically relevant answer as to whether a patient has clinically significant latent pulmonary vascular disease or PH as their cause of dyspnea. If the RV function augments normally with exercise, the rise in PA pressure would likely be flow-mediated and of far less clinical significance. In contrast, a dilating and non-augmenting RV in response to exercise should indicate an impedance-mediated process of greater clinical significance. In normal subjects, TAPSE will increase from approximately 2.5 cm at rest to 2.83.0 cm at peak exercise. Preliminary evidence suggests that the RV functional response to exercise (change in TAPSE) is linked to clinical outcome. In a relatively small cohort of stable PAH patients, subjects either maintained a TAPSE similar to their resting TAPSE following graded supine ergometry, or had a fall in TAPSE with exercise. A fall in TAPSE with exercise was strongly associated with adverse clinical events within one year of follow up.[110] Importantly, a rise in the peak TR jet velocity following exercise was associated with better exercise-induced RV function and better clinical outcome. We suspect that more evidence will arise in the near future supporting the notion that the focus of exercise echocardiography should be placed primarily on the RV functional response to exercise.

SUMMARY

The echo-Doppler examination is a central part of the initial diagnosis and assessment of patients with pulmonary vascular disease and other forms of pulmonary hypertension. Often, the results of the initial DE examination are pivotal in the decision making process for which patients are referred for further hemodynamic assessment of their PH. As a result, it is important for the clinician to fully appreciate the echocardiographic features associated with underlying pulmonary vascular disease, as a missed 178

or delayed diagnosis can have devastating consequences. Overreliance on any single DE metric, and especially PA pressure estimation, detracts from the overall diagnostic potential of the DE examination. The right ventricle often bears witness to perturbations in the RV-PA interaction, with stereotypical changes in the size, shape and function of the RV often leading to the diagnosis of PVD even without a reliable noninvasive pressure assessment. Thus, clinical DE protocols should include basic measurements of RV size, the relative proportion of the RV to the LV, and a direct measurement of RV systolic function. This is especially important when considering that the morbidity and mortality in pulmonary vascular disease relates rests almost entirely on the ability of the right heart to adapt to its afterload. Attention should be directed toward the shape, or pattern of the flow velocity envelope leaving the RV outflow tract, as this provides important physiologic information about the pulmonary vasculature and its interaction with the ejecting right ventricle. Doppler evidence of diastolic dysfunction should be considered along a continuum that runs in parallel with rising left atrial pressure, and that right heart failure itself is an important cause of impaired LV relaxation. Integrating the relative ‘balance’ of right and left heart findings, along with proper Doppler interpretation often provides a wealth of clinical and pathophysiologic insight prior to invasive hemodynamic assessment. The end results are heightened awareness and improved identification of which patients should be referred for further invasive testing, as well the use of the DE information to compliment the findings from invasive testing.

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104. Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial pressure during rest and exercise in healthy subjects. A systematic review. Eur Respir J 2009;34:888-94. 105. Steen V, Chou M, Shanmugam V, Mathias M, Kuru T, Morrissey R. Exercise-induced pulmonary arterial hypertension in patients with systemic sclerosis. Chest 2008;134:146-51. 106. Tolle JJ, Waxman AB, Van Horn TL, Pappagianopoulos PP, Systrom DM. Exercise-induced pulmonary arterial hypertension. Circulation 2008;118:2183-9. 107. Reichenberger F, Voswinckel R, Schulz R, Mensch O, Ghofrani HA, Olschewski H, et al. Noninvasive detection of early pulmonary vascular dysfunction in scleroderma. Respir Med 2009;103:1713-8. 108. Pynnaert C, Lamotte M, Naeije R. Aerobic exercise capacity in COPD patients with and without pulmonary hypertension. Respir Med 2010;104:121-6. 109. Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Exercise pathophysiology in patients with primary pulmonary hypertension. Circulation 2001;104: 429-35. 110. Hacobian M, Cohen MC, Atherton D, Wirth JA. Right ventricular exercise echocardiographic predictors of worsened clinical status in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 2011;183:A4996. Source of Support: Nil, Conflict of Interest: None declared.

“Quick Response Code” link for full text articles The journal issue has a unique new feature for reaching to the journal’s website without typing a single letter. Each article on its first page has a “Quick Response Code”. Using any mobile or other hand-held device with camera and GPRS/other internet source, one can reach to the full text of that particular article on the journal’s website. Start a QR-code reading software (see list of free applications from http://tinyurl.com/ yzlh2tc) and point the camera to the QR-code printed in the journal. It will automatically take you to the HTML full text of that article. One can also use a desktop or laptop with web camera for similar functionality. See http://tinyurl.com/2bw7fn3 or http://tinyurl.com/3ysr3me for the free applications. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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Review Ar ti cl e

Lung transplantation for pulmonary hypertension M. Patricia George, Hunter C. Champion, and Joseph M. Pilewski Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

ABSTRACT Although medical therapies for pulmonary arterial hypertension have greatly improved, it remains a chronic and fatal disease. For patients who are refractory to medical therapy, lung transplantation is an important treatment option. This review discusses issues pertaining to indications for transplant, preparation for transplant and listing, operative issues, and outcomes for patients with pulmonary arterial hypertension. Key Words: surgical treatment, lung transplant, outcome, pulmonary arterial hypertension

INTRODUCTION Pulmonary arterial hypertension (PAH), initially described hemodynamically in 1951 by David Dresdale, was a disease that for decades had no effective treatment.[1] Prior to the transplant era, the chances for survival with pulmonary hypertension were grim, with median survival only 2.8 years.[2] However, two early discoveries changed the prognosis for patients with pulmonary arterial hypertension: lung transplantation and the discovery of epoprostenol. Heart-lung transplantation developed as a surgical means to treat pulmonary vascular disease, and the first heart-lung transplant, was performed at Stanford by Norman Shumway, John Wallwork, and Bruce Reitz in 1981.[3] Soon after the first successful heart-lung transplants, single and bilateral lung transplantation evolved.[4-6] Joel Cooper reported the first single lung transplant in a patient with pulmonary fibrosis in 1986, and soon the bilateral sequential lung transplant technique became favored.[4-6] With early surgical successes, the number of lung transplants registered per year worldwide continues to grow, surpassing 2700 transplants in 2009 (Fig. 1).[7] This early success in surgical treatment of PAH was soon followed by the major medical discovery of prostacyclin Address correspondence to:

M. Patricia George, MD Division of Pulmonary, Allergy, and Critical Care Medicine University of Pittsburgh, 628 NW MUH 3459 Fifth Avenue, Pittsburgh PA 15213 USA Phone: 412/692-2210 Fax: 412/692-2260 Email: georgemp2@upmc.edu 182

(epoprostenol)[8,9] A landmark randomized control trial demonstrated that intravenous epoprostenol produced improved symptoms, hemodynamics, and increased survival in patients with primary (idiopathic) PAH, thereby changing the course of this disease.[10,11] In a randomized controlled trial, epoprostenol was also associated with a 5-year survival of 55%.[12] Since this medical breakthrough, there have been many more discoveries, with the development of new prostacyclin analogs (treprostinil, iloprost) as well as development of other classes of medications. [13-16] These include endothelin receptor antagonists (bosentan, ambrisentan) [17,18] phosphodiesterase-5 (PDE5) inhibitors (sildenafil, tadalafil), [19] and newer agents currently under study (imatinib, riociguat).[20,21] These medications have been shown to improve hemodynamics, symptoms, exercise capacity, time to clinical worsening, and quality of life in patients with idiopathic PAH. A recent meta-analysis combined clinical trials of goal-oriented PAH therapy, and showed that active treatment was associated with an overall reduction in mortality of 43% (P=0.048).[22] The past 30 years have been notable for parallel developments in surgical and medical therapies for pulmonary hypertension (Fig. 2). Although successful Access this article online

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Website: www.pulmonarycirculation.org DOI: 10.4103/2045-8932.83455 How to cite this article: George MP, Champion HC, Pilewski JM. Lung transplantation for pulmonary hypertension. Pulm Circ 2011;1:182-91.

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developments in the medical treatment of patients with PAH has decreased the number of patients listed for lung transplantation, there remain patients who are refractory to, or progress despite multidrug therapy. For this population, lung transplantation often remains the only viable option for improving survival. This review article will address the indications for lung transplant in PAH, specific operative considerations unique to patients with PAH, and transplant outcomes in patients with PAH, both in terms of postoperative physiologic changes and survival.

Definitions and nomenclature in PAH

Number of Lung Transplants

PAH is defined by a mean pulmonary artery pressure greater than 25 mmHg at rest and a normal pulmonary capillary wedge pressure of 15 mmHg or less with a pulmonary vascular resistance greater than 3 Wood units.[23] As treatments have developed for PAH, so has our understanding and classification system. The initial classification scheme in 1973 involved only two categories: primary and secondary PAH.[1, 24] This was expanded into 5 major categories at the Second World Symposium 3000 2000 1000 0

86 988 990 992 994 996 998 000 002 004 006 008 2 2 2 2 2 1 1 1 1 1 1 Year

INDICATIONS: REFERRAL FOR LUNG TRANSPLANT IN PAH

Although we have made considerable progress in the medical management of PAH, not all patients respond equally well to medications. In addition, those who respond initially may suffer a sudden decline in clinical status. It is recommended that lung transplantation be utilized for patients who do not respond to optimal vasodilator therapy (Table 2). Sitbon and colleagues identified a high-risk subset of patients as those who 3 months following initiation of prostacyclin therapy remain in New York Heart Association functional class III or IV or do not achieve a 30% drop in pulmonary vascular resistance from baseline.[12] Other risk factors associated with poor outcomes include hyponatremia,

1 cl 951 as – sif D ic re at sd io al n e of m PA ak H es t he 19 fir W 81 st al – lw F he i or rs m od k th an ea yn d rt am Re -lu ic itz ng in tra a p ns at pla ie n 19 nt t b lu 86 w y ng – ith Sh J tra oe PA um ns l C H wa pl o y, an op 19 t e rp sig 90 er ni - E fo fic p rm an op st r tly os he t im en fir pr ol st ov is sin e s sh gl ur ow e vi n va in li R n C PA T H to 20 0 W 2 w HO – B or se fu ose ni nc n ng tio tan na im lc p la ro ss ve 20 ,a s an 06 nd ex d -S tim erc lo i w ld e t ise er en o ca s m af cl pa in ci ea il im ic ty n al , pu pro lm ve 20 on s e w 07 ar xe ith – y ar rcis ep Co te e op m ry ca ro bin pr pa ste at es ci su ty no ion re l i th m e r pr a ov py es of ex si er lde ci n se af ca il pa ci ty

Figure 1: Since the first lung transplant in 1986, the number of lung transplants continues to grow.[7]

on PAH in Evian, France in 1998. Categorization into groups based on putative similar pathophysiology helped investigators to conduct clinical trials, and led to the approval of 8 medicines for PAH.[24] In 2003 at the Third World Symposium on PAH in Venice, Italy, the terms primary and secondary PAH were eliminated, although some people still use these terms today.[25] Finally in 2008 the Fourth World Symposium of PAH at Dana Point, California, the nomenclature was further revised to better group similar diseases and account for mutations, and continues to be the nomenclature in use today (Table 1).[24] Lung transplantation has been performed commonly for patients in diagnostic groups 1,3, and 5. Patients with idiopathic pulmonary arterial hypertension (IPAH) comprise 3.3% of all transplant recipients and 5.4% of double lung transplant recipients.[7] This article will pertain mainly to patients with IPAH unless otherwise stated.

Ongoing: Trials in comination therapies Vasodilator therapy trials in APAH New agents: imatinib, riociguat Figure 2: Timeline of major medical and surgical developments in the treatment of pulmonary arterial hypertension. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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Table 1: Classification of pulmonary hypertension (PH), Dana Point, 2008 Group

Category of PH

Associated diseases

Pulmonary arterial hypertension (PAH)

2 3 4 5

PH owing to left heart disease PH owing to lung diseases or hypoxemia Chronic thromboembolic PH (CTEPH) PH with unclear multifactorial mechanisms

Idiopathic PAH Heritable Drug- and toxin-induced Associated with connective tissue disease, HIV, portal hypertension, schistosomiasis, chronic hemolytic anemia Systolic dysfunction, diastolic dysfunction, valvular disease Chronic obstructive pulmonary disease, interstitial lung disease Sarcoidosis, lymphangioleiomyomatosis

Table 2: Guidelines for referral for lung transplantation ISHLT guidelines for transplantation referral NYHA functional class III or IV, irrespective of ongoing therapy Rapidly progressive disease ISHLT guidelines for listing/transplantation Persistent NYHA class III or IV on maximal medical therapy Low (<350m) or declining six minute walk distance Failing therapy with intravenous epoprostenol, or equivalent Cardiac index of less than 2 liters/min/m2 Right atrial pressure exceeding 15 mmHg Additional risk factors for poor outcome in PAH Hyponatremia Hyperbilirubinemia Tricuspid annular plane systolic excursion (TAPSE) <1.8 cm Underlying connective tissue disease (Scleroderma) Chronic obstructive pulmonary disease Sarcoidosis Pulmonary fibrosis Syncope Combined emphysema, pulmonary fibrosis and PAH

hyperbilirubinemia, echocardiographic evidence of severe right ventricular dysfunction measured by tricuspid annular plane systolic excursion (TAPSE) less than 1.8 cm, and six minute walk distance less than 332 m.[26-29] Although much progress has been made in treatment of idiopathic pulmonary hypertension (IPAH), additional risk factors to consider in patients with PAH include history of underlying connective tissue disease (CTD) or other primary lung disease. In a study of patients in the REVEAL registry, patients with scleroderma had higher plasma brain natriuretic peptide levels, lower diffusing capacity for carbon monoxide, and significantly worse one-year survival than patients with IPAH (82% in patients with scleroderma vs 86% in all CTD-PAH vs 93% in IPAH).[30] Patients with pulmonary hypertension associated with underlying lung diseases such as chronic obstructive 184

pulmonary disease (COPD), pulmonary fibrosis, and sarcoidosis, also are at increased risk of mortality,[31-38] and those with combined emphysema, interstitial lung disease and pulmonary hypertension have a particularly high mortality risk, with only a 60% one-year survival.[39] Studies have shown variable effects of oral vasodilator therapy in the treatment of PAH associated with lung diseases, presumably due to worsening ventilation/ perfusion mismatch. [40-45] This has been somewhat overcome through the use of inhaled prostacyclins, which may have promise in COPD and interstitial lung diseases.[46,47] Nonetheless, responses to such medications in patients with underlying hypoxemia due to parenchymal lung disease are variable, and the potential for worsening persists. Hence in patients with primary parenchymal disease or CTD, the presence of PAH may indicate a need for expedited transplant evaluation.

Given the difficulty in predicting course of illness in patients with PAH, whether idiopathic or associated with pulmonary parenchymal disease (APAH), it is recommended that patients be referred early to a transplant center for evaluation. Early evaluation allows time for physicians and patients to explore any possible risk factors and devise strategies to overcome them (e.g., obesity and weight loss, deconditioning and pulmonary rehabilitation). There are also circumstances in which patients will not be considered viable candidates for lung transplantation. Contraindications include active cancer, substance abuse, noncompliance with medications, and lack of social support. The consensus statement on lung transplantation candidacy was last published 5 years ago,â&#x20AC;&#x2030;[48] and many would argue that, given our advancements in surgical and medical transplant care, previous contraindications may no longer apply. In addition, criteria for lung transplant candidacy varies significantly among centers, so early evaluation provides an opportunity for opinions at other more aggressive centers if patients are declined at one center. Acknowledging this evolution in practice, it is best to refer patients to the transplant center for preliminary evaluation. In addition, even when patients with PAH are initially too well to be listed for transplant, early evaluation allows for close follow up should the patientâ&#x20AC;&#x2122;s clinical Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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condition decline. Typically patients on the waiting list are seen every three to six months for a medical update and to update their LAS. This is especially important in pulmonary hypertension patients as any change in clinical status may place them at need for LAS appeal and expedited transplantation. Finally, if patients are followed at a tertiary referral center, they may benefit from opportunities to enroll in clinical trials for IPAH or APAH.

PREPARATION: EVALUATION, LISTING FOR TRANSPLANTATION, AND IMPACT OF THE LUNG ALLOCATION SCORE

Full lung transplant evaluation involves a detailed process to best determine the nature and trajectory of a potential candidate’s illness, as well as identify possible risk factors for potential modification. Depending on the center, much of the testing may be done locally, if patients and referring physicians prefer, however visit to the transplant center is usually a several day process. In addition to consultations with transplant pulmonology, transplant surgery, and social services, patients also undergo psychiatric screening and participate in a transplant orientation class. Patients also undergo full laboratory, electrocardiographic, radiologic testing, and cardiac catheterization. In addition, they also must be up to date on vaccines and age-appropriate cancer screening (Table 3).

In 2005, the method in which patients were prioritized for lung transplant underwent a major revision with the development of the lung allocation score (LAS). Prior to this, patients were prioritized on the waiting list by how much time they had accrued on the waiting list. This resulted in many deaths on the waiting list, and compelled physicians to list patients long before they were sick enough to justify the risks of lung transplant. In this era of long waitlist times, when patients’ with PAH deteriorated quickly, techniques such as balloon atrial septostomy were utilized by some physicians as a bridge to transplant.[49] To simplify the listing process, reduce time (and deaths) on the waiting list, and help assure that organs would go to those who were in most need, the LAS was developed.[50] The LAS is a scoring system developed from demographic and clinical characteristics, which takes into account waiting list urgency and the probability of post-transplant survival. The score is normalized to range between 0 and 100, and the sicker a patient is, the higher their score. Patients are placed on the waiting list according to blood type and size, with highest priority going to patients with the highest LAS. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

After development of the LAS, the likelihood of transplantation from the waiting list increased for all diagnoses. Deaths on the waiting list decreased for all diagnostic groups except IPAH, which remained unchanged. Under the LAS system, patients with IPAH were less likely to be transplanted than patients with IPF (hazard ratio [HR] 0.53; P<0.001) or CF (HR 0.49; P<0.001) and more likely to die on the waiting list than patients with COPD (HR 3.09; P<0.001) or CF (HR 1.83, P=0.025).[48, 51] Critics of the LAS system state that the factors accounted for in the equations are more heavily weighted towards pulmonary function tests, which do not correlate with disease severity in IPAH. In an analysis Table 3: Pre-transplant evaluation includes consultations and visits to evaluate the candidate’s pulmonary disease and risk factors for lung transplantation Consultations • Transplant pulmonologist – candidacy for transplant, risk factor assessment and modification, pretransplant management • Transplant surgeon – candidacy for transplant, risk factor assessment and modification • Social services – socioeconomic evaluation, consultation in fundraising if necessary • Psychiatry – mental health evaluation, addictions screening, medical adherence assessment Laboratory tests • Comprehensive metabolic panel, complete blood count, prothrombin and partial thromboplastin time, hypercoagulable screening • Serologic testing (e.g., human immunodeficiency virus, hepatitis, cytomegalovirus, herpes simplex virus) • Blood type and screen (x2), screening for antihuman leukocyte antigen panel reactive antibodies Radiographic tests • Chest radiograph • High resolution CT scan • Ventilation/perfusion scan • Barium swallow • Echocardiogram Cardiovascular tests • Electrocardiogram • Echocardiogram • 6 minute walk test • Cardiac catheterization Age-appropriate cancer screening • Colonoscopy within the last 5 years • Mammogram/PAP smear within the last year • Prostate cancer screening within the past year Education • Patients and family members attend class • Online and written materials also provided 185

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comparing mortality predicted by the LAS system to actual mortality in the REVEAL cohort containing 2967 patients with PAH, two additional variables were independently associated with increased mortality compared to the LAS in multivariable analysis: mean right atrial pressure greater than or equal to 14 mmHg and six minute walk distance less than or equal to 300 m.[52] Although modification of the LAS system is under discussion, the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplant Network (OPTN) Thoracic Organ Transplantation Committee has adopted criteria for appeal of an LAS in a patient with IPAH (Table 4). A patient with IPAH will be granted a LAS in the 90th percentile of all lung allocation scores when they satisfy all of the following criteria: the patient is deteriorating on optimal medical therapy, right atrial pressure is greater than 15 mmHg, and cardiac index is less than 1.8 L/min/m2.[53]

The impact of the LAS on patients with IPAH on the waiting list highlights the importance of close follow up while patients are on the waiting list, as they may meet criteria for LAS appeal either at time of listing of later in the course of their disease.

OPERATIVE ISSUES: SINGLE VERSUS DOUBLE LUNG TRANSPLANT

Most transplant centers now favor double lung transplantation over single lung transplantation (Table 5). Although lung transplantation began with heart-lung transplantation, with technical improvements in the 1990s, single lung transplantation became the procedure of choice for lung transplant when the left ventricular function was intact. Early studies showed that single lung transplantation is quite effective in lowering pulmonary artery pressures and improving right ventricular function. Early experience at the University of Pittsburgh explored outcomes in single versus double lung transplantation for IPAH. In a retrospective study comparing 37 double lung transplant recipients and 21 single lung transplant recipients transplanted between 1989-1996, one-month, one-year, and four-year survival was comparable between groups. As expected, time on cardiopulmonary bypass was significantly shorter in the single lung recipients. Mean pulmonary artery pressures were significantly lower in the double lung transplant recipients at 1 hour, 12 hours, and 24 hours post-transplant (P<0.02). While there was a slightly lower incidence of postoperative diffuse alveolar damage in the single lung recipients (43% versus 51% in double lung recipients), there was a trend toward slightly higher incidence of obliterative bronchiolitis among single lung transplant recipients (9/21, 42.9%) than double lung transplant recipients 186

(9/37, 24.3%, P=0.14).[54] In an earlier study, Bando and colleagues noted less improvement in pulmonary artery pressures and increased graft-related mortality in singlelung transplant recipients compared with double lung and heart-lung recipients.[55] In another study comparing single lung transplant recipients with and without pulmonary hypertension, Bando and colleagues found that preoperative pulmonary hypertension was associated with significantly lower one-year survival (53% versus 72%; P<0.05) and New York Heart Association functional class (P<0.05).[56]

At Johns Hopkins, Conte and colleagues reviewed the outcomes of all single and double lung transplants performed for IPAH or PAH associated with CTD or primary lung disease. In their review, patients with primary (idiopathic) PAH who received a double lung transplant had better survival than those who received a single lung transplant.[57] Among patients with CTDTable 4: Criteria for LAS appeal in lung transplant candidates with IPAH A patient will be granted a LAS in the 90th percentile if they satisfy all of the following criteria: 1. Patient deteriorating on optimal medical therapy 2. Right atrial pressure greater than 15 mmHg 3. Cardiac index less than 1.8 L/min/m2

Table 5: Comparison of single, double, and heart lung transplantation Single lung transplantation + Shortest time under anesthesia (may be advantageous in older patients or patients with comorbidities) + In cases of PGD, native lung may help sustain patient through early graft dysfunction + Allows a greater distribution of scarce resources (two patients can be transplanted from one donor) - Native lung, if colonized, may be a nidus of infection - Post-transplant monitoring with pulmonary function testing can be more difficult in patients with airway obstruction Double lung transplantation + Increased survival shown in several diagnostic groups (e.g., COPD, PAH) + Postoperative monitoring is often easier to interpret as data are not confounded by native lung function - Longer operative time may expose patients to increased operative risk Heart lung transplantation + May be the only option in patients with severe RV or LV dysfunction - Increased mortality - Extremely scarce resource and often long waiting times for transplant Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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associated PAH and APAH (secondary PAH), there was a trend towards improved survival in double lung transplant when the mean pulmonary artery pressure was greater than 40 mmHg.[57] Although single lung transplantation is feasible, [58-60] based on these findings and clinical experience, the majority of centers now favor double lung transplantation for PAH.

Improvement in surgical techniques with double lung transplantation as well as the ability of the right ventricle to recover postoperatively have rendered heart-lung transplantation much less common. In fact, most centers try to avoid heart-lung transplantation when possible, due to increased mortality as well as scarcity of organs. In the most recent analysis of the International Society of Heart Lung Transplantation (ISHLT) registry, median survival in heart-lung transplantation for IPAH was 3.8 years.[7] However, when a patient’s disease progresses to the point to right ventricular failure requiring inotropic support, they may require heart-lung transplantation rather than double lung alone. Right ventricular function, therefore, helps determine the window for lung transplantation in PAH.

OUTCOMES: PHYSIOLOGIC IMPROVEMENTS AND SURVIVAL POST LUNG TRANSPLANT

Immediate peri- and post-operative care in patients transplanted for PAH requires close monitoring and often may require temporary inotropic, vasopressor, and inhaled nitric oxide support. While patients no longer require their pulmonary hypertensive medications, they may require some support of the right ventricle as it recovers. In addition, patients should be monitored closely for the development of primary graft dysfunction in the first 72 hours. Given the complexities of peri-operative management in patients transplanted for PAH, it is recommended that they are managed at a higher volume center with experience in this disease.

The response of the right ventricle to lung transplantation is immediate and remarkable (Fig. 3). Patients are often admitted for surgery on combination vasodilator therapy, only to be completely off pulmonary hypertensive medications with dramatic improvement in pulmonary artery pressures. These improvements are evident in the operating room, as described in a prospective study of intraoperative TEE data: the mean pulmonary artery pressure in those with severe pulmonary hypertension decreased from 76±14 mmHg to 31±11 mmHg (P<0.05) immediately after lung transplantation.[61] In another study looking at hemodynamic data in seven single lung transplant recipients just beyond the immediate Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

postoperative period into the early postoperative period (mean 13 weeks post transplant), mean pulmonary artery pressures decreased from 64±18 mmHg to 18±5 mmHg (P=0.001), and pulmonary vascular resistance index decreased from 1924±663 dyne sec cm-9 to 233±73 dyne sec cm-9 (P=0.001).[60] In a retrospective review of 100 consecutive patients transplanted for idiopathic pulmonary hypertension or pulmonary hypertension secondary to congenital heart disease, reductions in mean pulmonary artery pressures (from 65.9±13.1 mmHg pre-transplant to 21.9±5.9 mmHg (P<0.001) and pulmonary vascular resistance (18.8±8.0 Woods Units pre-transplant to 2.1±0.9 Woods Units posttransplant, P<0.001) were seen at 24 hours and sustained at 1 year later, and improvement in right ventricular ejection fraction was notable at one year (26.8±12.6% pre-transplant to 56.6±8.8% at 1 year, P<0.001). [62] These results were seen in both single and double lung transplant recipients. Lung transplantation provides an opportunity for patients to extend their lives as well as improve quality of life. According to the most recent ISHLT registry data, overall median survival for all lung transplant recipients transplanted between January 1994 and June 2008 was 5.3 years, and among those who survive at least 1 year, median survival was 7.5 years.[7] When analyzed by eras in transplantation, overall median survival has significantly improved. Patients transplanted from 2000 through June 2007 have a median survival of 5.7 years, compared with 4.7 and 4.2 years in patients transplanted from 1998 to 1994, and 1995 to 1999, respectively.[7]

Patients with IPAH have a greater short-term risk after transplant, but also a better chance of long term survival. Patients with PAH have the lowest 3-month and 1-year survival rate (76% and 71.1%, respectively), when compared to patients with IPF (85%, 74.1%), CF (90%, 82.6%), and COPD (91%, 82.4%), see Table 6A).[7] In fact, in multivariable analysis, a diagnosis of IPAH was the greatest categorical risk factor for one-year mortality (relative risk [RR] 2.19, 95% confidence interval [95%CI] 1.63-2.95, P<0.0001).[7] However, when lung transplant recipients with IPAH live for at least one year, they have improved long-term survival compared to patients with other underlying lung diseases. Accounting for risk of early mortality by conditioning survival on living one year, patients with IPAH had a lower risk of 5-year mortality (RR 0.51, P=0.0032) and significantly improved longterm survival (median survival 9.3 years) compared with patients with COPD (6.6 years, P=0.01) and IPF (6.7 years, P<0.0001), Table 6B).[7] In lung transplant recipients who die within the first year, the most common causes of death are non-CMV infections 187

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Table 6A: Survival among lung transplant recipients based on diagnosis in patients transplanted between January 1990-June 2007[7] Year

IPAH N=1,065

COPD N=8,812

CF N=3,746

IPF N=4,695

1 3 5 7 10

71.1 60.3 51.7 44.5 32.4

82.4 65.3 50.8 38.5 22.9

82.6 67.5 57.4 50.0 39.6

74.1 58.5 45.9 35.4 22.3

Table 6B: Survival among lung transplant recipients based on diagnosis in patients transplanted between January 1990-June 2007, conditioned on survival to 1 year[7] Year

IPAH N=674

COPD N=6,649

CF N=2,779

IPF N=3,108

1 3 5 7 10

100 84.8 72.7 62.5 45.5

100 79.2 61.5 46.7 27.8

100 81.6 69.4 60.5 47.9

100 78.9 61.9 47.7 30.1

and graft failure.[7] Within the early post-operative period, primary graft dysfunction (PGD) is a significant concern in patients with IPAH (as well as in other patients with increased pulmonary arterial pressures in general), and is associated with increased risk of death.[63,64] PGD is defined as lung injury occurring within the first 72 hours post-transplant, and is considered grade 2-3 when the PaO2/FiO2 ratio is less than 300 and bilateral infiltrates are present on chest radiograph. [65] While the exact pathogenesis is unknown, pulmonary hypertension has been repeatedly associated with increased risk of PGD, and researchers hypothesize that increased shear stress associated with elevated pulmonary artery pressures during reperfusion may play a role.[64, 66-68] Several studies have identified a diagnosis of IPAH as a risk factor for developing PGD. Others have identified elevated pulmonary artery pressures as a risk factor for developing PGD in non-IPAH patients.[68,69] The difficulty with many of these studies, however, is that IPAH and pulmonary artery pressures cannot be completely isolated from other risk factors for PGD, namely use of cardiopulmonary bypass and blood products.

Figure 3: Double lung transplantation is an effective treatment for PAH. Chest radiographs (a) pre- and (b) post-double lung transplant demonstrate radiographic resolution of enlarged pulmonary arteries and right ventricular remodeling post transplant. Echocardiographic images (c) pre- and (d) post-transplant demonstrate resolution of right atrial enlargement and septal bowing seen in severe PAH. 188

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While the ISHLT data seem to indicate that the diagnosis of IPAH is a risk factor for one-year survival post transplant, it is quite possible that at high-volume centers that specialize in transplant for IPAH, survival is better than ISHLT data. A recent study showed that in general, high-volume transplant centers are associated overall improved five-year survival.[70] In a retrospective study of patients with PAH at the University of Pittsburgh, which has performed over 60 lung transplants per year over the past 7 years, one-year survival in cohort of 30 patients transplanted between 1994-2006 was 86%, compared to 66% in the comparable ISHLT cohort, and 58% in IPAH patients transplanted at the University of Pittsburgh from 1982 to 1993.[71] The authors attributed their improved outcomes to improvements in donor and recipient surgical techniques as well as improvements in postoperative medical management of transplant recipients[71] Similarly, a retrospective study of 220 patients transplanted between 1986 and 2008 at Marie-Lannelongue Hospital in Paris reported a 79% one-year survival among double lung transplant recipients in patients with IPAH. [72] These studies suggest potential benefit to performing transplants for PAH at experienced high-volume centers.

Most lung transplant recipients enjoy improved functional status post transplantation. In a single center survey comparing 54 lung transplant recipients to 44 transplant candidates, recipients reported higher levels of happiness with their life and health as well as improved functional status.[73] In a cross-sectional analysis of the functional status of lung transplant recipients in the ISHLT dataset, over 80% of survivors reported no limitations in activities, and less than 3% reported need for full assistance with activities.[7] In a study of US recipients using Karnofsky score for adult recipients, over 80% of survivors reported the ability to function at 80% their functional status or greater at years 2 and 3.[7] Although survival, functionality, and quality of life are enhanced post transplant, recipients are at increased risk of bronchiolitis obliterans syndrome (BOS) and other co-morbidities commonly seen with corticosteroids and chronic immunosuppression. The most common conditions include hypertension, chronic kidney disease, hyperlipidemia, and diabetes. According to ISHLT data, among 1-year survivors, 52.5% have hypertension, 26.3% have diabetes, 24.4% have kidney disease (1.7% on dialysis or requiring renal transplant), 24.2% have hyperlipidemia, and 9.6% have BOS. Among 5-year survivors, 84.4% have hypertension, 24.7% have kidney disease (3.3% on dialysis or requiring renal transplant), 56.5% have hyperlipidemia, 38% have diabetes, and 36.9% have BOS. [7] It is important for patients to realize that immunosuppression-related medical comorbidities of lung transplant are common, and that Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

lung transplantation, therefore, provides a treatment for their lung disease that requires life-long management. Patients are often told that lung transplant provides a treatment but not a cure, meaning that patients will exchange their chronic lung disease for another medical condition that requires active therapy for the rest of their lives. Nonetheless, when a patient is willing to accept this possibility, and provided there are no major complications, lung transplantation provides a means to significantly improve oneâ&#x20AC;&#x2122;s quality of life.

CONCLUSIONS

Despite significant medical advancements, PAH remains a chronic, terminal disease. For patients who are refractory to medical therapy, lung transplantation remains the only therapeutic option. It is important to refer patients early to a transplant center, as the center can follow patients through their pre-transplant course of disease and better decide when to list for transplantation. Communication between the referring physician and transplant team is key in co-managing patients prior to and after transplantation. Given the technical challenges, it may be beneficial for lung transplantation for PAH to be performed in an experienced center. In the majority of cases, lung transplantation provides patients the chance to improve their quality and duration of life.

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Source of Support: Nil, Conflict of Interest: None declared.

Author Help: Online submission of the manuscripts Articles can be submitted online from http://www.journalonweb.com. For online submission, the articles should be prepared in two files (first page file and article file). Images should be submitted separately. 1) First Page File: Prepare the title page, covering letter, acknowledgement etc. using a word processor program. All information related to your identity should be included here. Use text/rtf/doc/pdf files. Do not zip the files. 2) Article File: The main text of the article, beginning with the Abstract to References (including tables) should be in this file. Do not include any information (such as acknowledgement, your names in page headers etc.) in this file. Use text/rtf/doc/pdf files. Do not zip the files. Limit the file size to 1 MB. Do not incorporate images in the file. If file size is large, graphs can be submitted separately as images, without their being incorporated in the article file. This will reduce the size of the file. 3) Images: Submit good quality color images. Each image should be less than 2048 kb (2 MB) in size. The size of the image can be reduced by decreasing the actual height and width of the images (keep up to about 6 inches and up to about 1800 x 1200 pixels). JPEG is the most suitable file format. The image quality should be good enough to judge the scientific value of the image. For the purpose of printing, always retain a good quality, high resolution image. This high resolution image should be sent to the editorial office at the time of sending a revised article. 4) Legends: Legends for the figures/images should be included at the end of the article file. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

191

Review Ar ti cl e

Acute respiratory distress syndrome: A clinical review Michael Donahoe Department of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania USA

ABSTRACT The acute respiratory distress syndrome (ARDS) is a complex disorder of heterogeneous etiologies characterized by a consistent, recognizable pattern of lung injury. Extensive epidemiologic studies and clinical intervention trials have been conducted to address the high mortality of this disorder and have provided significant insight into the complexity of studying new therapies for this condition. The existing clinical investigations in ARDS will be highlighted in this review. The limitations to current definitions, patient selection, and outcome assessment will be considered. While significant attention has been focused on the parenchymal injury that characterizes this disorder and the clinical support of gas exchange function, relatively limited focus has been directed to hemodynamic and pulmonary vascular dysfunction equally prominent in the disease. The limited available clinical information in this area will also be reviewed. The current standards for cardiopulmonary management of the condition will be outlined. Current gaps in our understanding of the clinical condition will be highlighted with the expectation that continued progress will contribute to a decline in disease mortality. Key Words: hypoxia, hypoxic pulmonary vasoconstriction, clinical trial, gas exchange, ARDS, adult respiratory distress syndrome, acute lung injury, positive end expiratory pressure, acute cor pulmonale

INTRODUCTION The acute respiratory distress syndrome (ARDS) is a rapidly progressive form of acute respiratory failure characterized by severe hypoxemia and nonhydrostatic pulmonary edema. The syndrome represents a recognizable common pattern of acute alveolarcapillary injury in critically ill patients, yet a pathway triggered by a wide range of primary disease processes. The mechanisms by which diverse etiologies such as chest trauma, sepsis, and pancreatitis lead to a common clinical and pathologic syndrome remains unclear. Epidemiologic surveys confirm the impact of this clinical syndrome is significant at ~200,000 cases per year in the US alone, leading to significant patient morbidity and health care burden.[1] Grouping a diverse set of disparate illnesses into a common syndrome has allowed investigation of ARDS as a final common pathway. The syndrome has Address correspondence to:

Prof. Michael Donahoe Director, Medical Intensive Care Unit Division of Pulmonary, Allergy, and Critical Care Medicine University of Pittsburgh School of Medicine UPMC Montefiore Hospital â&#x20AC;&#x201C; NW628 3459 Firth Avenue, Pittsburgh PA 15213 USA Phone: 412/692-2214 Fax: 412/692-2260 Email: donahoem@upmc.edu 192

facilitated a broad range of clinical investigations into the epidemiology, basic biology, and clinical support measures for this syndrome. Yet, despite numerous randomized clinical trials aimed at regulating the lung inflammatory response, the only proven therapy to consistently reduce mortality is a protective ventilation strategy.[2] The risk of linking multiple diverse etiologies as a single common pathway is an enhanced focus on the syndrome and its clinical management, with a diminished view of the importance of the underlying cause. Specific treatments, when applied to a non-specific condition, might be expected to show variable effectiveness. This may explain the relative paucity of successful therapeutic interventions in ARDS to date (Table 1). In this review, we will explore the clinical features of ARDS including the evolution of the ARDS definition, the limitations to investigation as a common disease pathway, the current evidence to guide cardiopulmonary management in Access this article online

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How to cite this article: Donahoe M. Acute respiratory distress syndrome: A clinical review. Pulm Circ 2011;1:192-211.

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Table 1: Select clinical trials in ARDS Topic

Intervention

M

PaO2/ FiO2

–

PEEP[10,67,68]

–

–/+

Recruitment maneuvers (RM)[71-73]

–

High-frequency oscillation ventilation[12,104]

–

Partial liquid ventilation[105]

–

Fluid management[7]

–

–/+

Hemodynamic monitoring[8]

–

Prone positioning[11,80,106-109]

–

Extracorporeal gas exchange[53]

Inhaled Nitric Oxide[89,110,111]

–

Surfactant[112-115]

–

Corticosteroids (early)[116-119]

–

Ventilator management Tidal volume[2,64]

Non-ventilator management

Pharmacotherapy

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VFD Comments Mortality reduction with 6 ml/kg IBW vs. 12 ml/kg IBW Increased ventilator free days (VFD) and organ failure free days with 6 ml/ kg tidal volume Decreased oxygenation in first 72 hours with 6ml/kg tidal volume Decreased inflammatory biomarkers with 6ml/kg tidal volume No mortality or VFD difference with high vs. low PEEP using FiO2/PEEP titration tables Increased VFD in ARDS subgroup analysis with PEEP titration to Pplat Reduced requirement for rescue therapy with PEEP titration to Pplat No mortality or VFD difference using RM Transient improvements in oxygenation Initial improvement in oxygenation indices compared to conventional ventilation Higher mean airway pressures and pCO2 compared to conventional ventilation No mortality difference in underpowered trials No difference in mortality or ventilator free days Increase in oxygenation index with a conservative fluid management strategy Increase in ventilator free and ICU free days with a conservative fluid management strategy No increase in shock or renal complications with a conservative fluid management strategy No adverse or beneficial effect to use of pulmonary artery catheter in management of patients with ARDS No mortality benefit to use of prone positioning in ALI/ARDS patients Gas exchange improvement in the majority of patients Meta-analysis favors prone positioning in patients with more advanced ARDS with improvement in oxygenation and trend to mortality reduction suggesting role as “rescue” therapy Reduced mortality in ARDS patients referred to an ECMO center in comparison to usual care No mortality benefit Improved oxygenation indices No mortality benefit No significant benefit to oxygenation indices No benefit with 30mg/kg solumedrol q6hours Underpowered investigations suggest benefit at doses <1 mg/kg solumedrol per day. 193

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Table 1 continued Corticosteroids (late)[43,44]

–

Neuromuscular blocking agents[84] +

Azole therapy [120] Phosphodiesterase inhibitors [121] Inactivated recombinant factor VIIa [122] Aerosolized B-2 agonist therapy[123]

– – –

Conflicting mortality benefit with variable dosing schemes. Reduced mortality with administration of cisatracurium for 48 hours following presentation. No difference in rate of ICU acquired paresis. No mortality benefit. No mortality benefit. No mortality benefit.

–

No mortality benefit.

M –Mortality; í VFD: Ventilator-free days; ARDS: acute respiratory distress syndrome; ALI: acute lung injury

this disorder, and consider directions for future clinical investigation.

DEFINING A SYNDROME

Ashbaugh and colleagues established ARDS as a clinical entity in a case series reported in 1967.[3] They highlighted a respiratory distress syndrome in 12 patients manifested by the acute onset of tachypnea, hypoxemia, and loss of compliance after a variety of stimuli. The syndrome proved to be unresponsive to usual and ordinary methods of respiratory therapy. The clinical and pathological features resembled those seen in infants with respiratory distress and to conditions in congestive atelectasis and post perfusion lung injury. A theoretical relationship of this syndrome to alveolar surface-active agent was postulated. The ARDS syndrome was based upon five key clinical features: (1) the presence of a defined risk factor; (2) severe hypoxemia despite administration of supplemental oxygen; (3) bilateral pulmonary infiltrates; (4) reduced lung compliance; and (5) the absence of congestive heart failure.

In 1988, Murray and colleagues, attempted to expand the definition of ARDS to incorporate the risk factor, the relative acuteness of the disease process, and measures of severity.[4] The severity was graded using a Lung Injury Score (LIS), incorporating physiologic data representing oxygenation, positive end-expiratory pressure, compliance, and radiographic distribution. The LIS is often referenced in clinical trials of ARDS, but remains invalidated as a marker of mortality risk.[5]

In 1994, a joint American-European Consensus Conference (AECC) met to refine the definition of ARDS to standardize clinical research trials for the disease. The definition is summarized in Table 2.[6] The definition has subsequently been widely employed to define patient enrollment in a broad range of ARDS therapeutic trials.[2,7-12] Despite the apparent simplicity of this definition, a number of clinical limitations are recognized. 194

DIAGNOSTIC LIMITATIONS The pathology of ARDS is characterized by the evolution of interstitial and alveolar edema to advanced fibrosis. The characteristic lesion, termed diffuse alveolar damage, undergoes progression from an exudative, to proliferative, to a fibrotic phase. Pathologically, the lung evolves through these phases of injury and remodeling independent of the inciting cause, supporting the ARDS syndrome classification. Yet, studies of clinical–pathologic correlation have shown only modest agreement between the pathologic finding of diffuse alveolar damage and the AECC diagnostic criteria.[1316] More than half of patients referred for open lung biopsy in ARDS of unknown etiology, prove to have unanticipated diagnoses.[14,17,18] These published series of lung biopsy in acute lung injury (ALI)/ARDS criteria patients provide two important insights into the management of these patients. First, consideration can be given to open lung biopsy in ARDS patients, often performed at the bedside in reported series, as an important diagnostic tool when an exhaustive clinical workup including chest CT, bronchoalveolar lavage, and laboratory investigation fails to yield a specific inciting agent. Published series suggest that biopsy under these conditions can be safely performed and provides a significant diagnosis to alter therapy in 7080% of patients.[13-16] Biopsies have occurred a median of 1-2 weeks into ARDS therapy based upon the lack of an inciting agent and limited clinical improvement. However, a lack of randomization in these trials makes a definitive comparison to empiric therapy difficult to determine. Secondly, the variable clinical-pathologic correlation between the AECC clinical criteria for ALI/ARDS and lung pathology suggests that we might expect clinical trials using AECC inclusion criteria to have a broader range of pulmonary disease than expected. Do the AECC diagnostic criteria have additional limitations?

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Table 2: American European consensus definition of ARDS Criteria

Critique

Bilateral infiltrates on a frontal chest radiograph

Variability in plain film interpretation Poor correlation with CT distribution Significant fraction of clinical ARDS patients have elevated PCOP and normal cardiac output

Absence of left arterial hypertension pulmonary capillary occlusion pressure (PCOP) <18 if measured or no clinical signs to suggest CHF Severe hypoxemia: PaO2/FiO2 ratio <300 is consistent with ALI PaO2/FiO2 ratio <200 is ARDS

No standardization for PEEP Significance of ALI/ARDS distinction is controversial

ARDS: acute respiratory distress syndrome; ALI: acute lung injury

of positive end-expiratory pressure (PEEP). A patient with a PaO 2/FiO 2 ratio <200 on 15 cm H 2O PEEP is considered equivalent to a patient with a similar ratio on a PEEP of 5 cm H2O. Investigators have advocated that a standardized PEEP/FiO2 assessment is necessary to accurately classify ARDS severity to match prognostic outcome for study groups in clinical trials.[19,20] In one population of 170 patients that met AECC criteria for ARDS, a standardized assessment on PEEP>10 cm H20 and FiO2>0.5 demonstrated 99 patients (58.2%) continued to meet the AECC definition of ARDS, 55 patients (32%) were reclassified as acute lung injury (ALI), and 16 patients (9.4%) no longer met criteria for either (Fig. 1).[19] Most importantly, the reclassification was associated with a mortality rate of 45.5% in the reclassified ARDS group, 20% in the ALI group, and 6.3% in patients reclassified as acute respiratory failure without ALI. Failure to standardize the assessment of the PaO 2/FiO 2 in the diagnosis of ARDS could lead to a significantly imbalanced randomization in ARDS clinical trials with a bias that over or underestimates the expected outcome. A lack of standardization may also explain why the PaO2/FiO2 ratio has failed to consistently predict outcome in epidemiologic studies of patients with ARDS.[21] The ARDS Network, which has enrolled exclusively based upon AECC criteria, has retrospectively reviewed their study population and suggested FiO2, but not PEEP, could be used in addition to PaO2/FiO2 to select patient populations with high or low predicted mortality.[22] Yet, addition of this criteria did not appear to change conclusions regarding the effectiveness of their reported interventions.

The classic radiographic feature of ARDS also introduces some controversy. The AECC radiographic definition includes “bilateral infiltrates consistent with pulmonary edema on a frontal chest radiograph.” No attempt is made to grade the severity or distribution of the infiltrates. Comparative studies using blinded radiographic interpretation show only modest agreement between radiologists on studies that fulfill the AECC criteria. [23-25] Further, agreement between plain film chest radiographs and chest computed tomography (CT) with respect to infiltrate distribution in ARDS patients is poor. [26] Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Figure 1: Reclassification of patients meeting AECC ARDS criteria into acute respiratory distress syndrome (ARDS), acute lung injury (ALI), or acute respiratory failure (ARF) categories based upon response to four standard ventilator settings on Day 1. Mortality rate for individual groups is shown based upon the reclassification. P values refer to the differences in mortality rates. Reference 19 with permission.

Classification of ARDS by CT into diffuse and lobar infiltrative patterns appears to predict outcome, so accurate radiographic classification may be important in the analysis of comparative populations.[26]

The AECC criteria excludes hydrostatic edema with the requirement that left atrial hypertension is not present based upon either clinical assessment or by measurement of a left atrial pressure (LAP)<18 mm Hg. However, this variable may not be easy to assess non-invasively or even an important distinction clinically. In patients randomized to a fluid and catheter therapy trial using only the clinical exclusion of elevated LAP, a full 29% of the subjects subsequently were shown to have a pulmonary capillary occlusion pressure (PCOP)>18 mm Hg, 8% had a cardiac index <2.5 L/minute, and 3% had both when measured post randomization.[8] As the vast majority of the patients had normal cardiac function with an elevated PCOP, in a clinical condition consistent with ARDS, this appears to represent a normal variation of the syndrome 195

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classification. The prognostic significance of this variation remains undetermined.

In conclusion, the clinical-pathologic correlation between the AECC definition and the gold standard DAD pathology is only modest. Three of the critical components of the AECC definition of ARDS, specifically oxygenation (PaO2/ FiO2 ratio), the chest radiograph, and estimates of LAP may all be subject to significant interobserver variability. These factors must be considered in the design of ARDS clinical trials to avoid unintended randomization bias.

PREDICTIVE LIMITATIONS

Can we use a single variable to define the severity of ARDS? The AECC definition establishes a grading system for the severity of acute lung injury based solely upon the measurement of gas exchange indices. Acute lung injury is defined by a PaO2/FiO2<300 with ARDS defined by a PaO 2/FiO 2<200. The validity of this distinction remains controversial. While some series suggest the presence of ALI without ARDS (200<PaO2/FiO2<300) does not influence prognosis, other investigators note a clear distinction. [1,21,27,28] This inconsistency in the predictive value of PaO2/FiO2 may reflect the limitations of a single static measurement. The progression in gas exchange indices over time may provide a more accurate assessment.[29] Likewise, the clinical transition from ALI without ARDS to ARDS has also been identified as an important trend in gas exchange which adversely impacts prognosis.[1] The inciting cause is also an important variable in ARDS progression and prognosis. When specific etiologies of ARDS are compared, trauma-associated ALI has been consistently associated with a better prognosis in comparison to sepsis related ALI.[30-32] Patients with traumatic injuries demonstrated a lower odds ratio of death than patients with non-trauma related injury despite controlling for baseline demographic and clinical variables. Trauma patients have distinct biomarker profiles including reduced plasma markers traditionally associated with poor clinical outcomes in ALI including ICAM-1, SP-D, sTNFr-1, and vWF.[30] This pattern of biomarker distinction may signal a reduced magnitude of both epithelial and endothelial injury in the trauma patient. These data suggest an improved prognosis in trauma associated ALI can be attributed to the mechanism of lung injury rather than the characteristics of the population. Could the mechanism of lung injury distinguish the outcome in other ARDS populations? In a comparative ARDS animal model, the physiologic and pathologic characteristics of ARDS induced by a pulmonary 196

and extra pulmonary trigger have been compared.[33] Despite relatively similar levels of functional lung change compared to placebo treated animals, the epithelial insult (pulmonary) demonstrated greater inflammatory and ultrastructural change in the lung compared to an extrapulmonary injury. In human studies, lung compliance and the radiologic recruitment response to PEEP titration is reduced in ARDS secondary to a pulmonary cause (ARDSp) compared to an extrapulmonary (ARDSexp) insult.[34] The computed tomography (CT) appearance of these two ARDS conditions may also differ. ARDS of a pulmonary origin appears to be characterized by more frequent asymmetric lung consolidation and ground glass infiltrates in contrast to the more homogenous pattern of ARDSexp.[35] Comparison of outcome in pulmonary versus extrapulmonary triggers for ARDS patients has demonstrated conflicting results, but suggests a trend towards higher mortality in the ARDSp patient population when other prognostic variables are controlled.[5,29,36,37] If the inciting agent is an important prognostic variable, this must be considered in both clinical trial design and study analysis. As one example, the ARDSNet low tidal volume trial contained only 59 trauma patients in 432 total subjects randomized to the 6ml/kg treatment arm of this investigation.[2] Despite this small subgroup size, the therapeutic benefit of low tidal volume ventilation in ARDS appeared to be independent of the inciting agent.[32] Subgroup analysis is important to consider in the planning phase of ARDS trials, where possible, to determine the benefit of an ARDS intervention across different inciting agents.

In addition to influencing the prognosis, the inciting agent is also important in defining the risk of progression to ALI/ARDS. The most common risk factor for ARDS development is infection. Pulmonary infection has been associated with a higher risk of ARDS progression in comparison to non-pulmonary infections in “at risk” populations. [38] A more comprehensive, multi-center risk assessment, excluding patients with ALI/ARDS on presentation, has suggested the highest rate of ALI occurs after smoke inhalation (26%), shock (18%), aspiration (17%), aortic surgery (17%, and lung contusion (14%). The lowest rate of progression is seen with pancreatitis (3%).[39] The presence of gastroesophageal reflux appears to be a key clinical feature in patients that develop recurrent acute lung injury.[40] Understanding the risk factors for progression to ALI/ ARDS is especially important, considering only 6.8% of patients with a recognized risk factor on hospital admission progress to ALI and only 4% develop ARDS. [39] This gap between “at risk” patients and ALI/ARDS development makes ALI/ARDS prevention studies not feasible based Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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solely on investigation of patients “at risk.” The Lung Injury Predictor Score (LIPS) attempts to incorporate both specific known risk factors (i.e., pneumonia, sepsis, trauma) and recognized risk modifiers (i.e., alcohol, smoking, hypoalbuminemia) to better define patients at risk for ALI/ARDS.[41] The LIPS model discriminates patients with a small chance of developing ALI/ARDS (good specificity), while maintaining appropriate sensitivity as a screening tool. The model has now been validated in a larger multi-center cohort and appears to retain a similar level of calibration as the original derivation cohort.[39] Compared with at-risk patients that did not develop ALI, those who develop lung injury have an increased mortality (23 vs. 4%) and increased resource use as reflected in longer ICU (8 vs. 2 d) and hospital (15 vs. 6 d) stays.[39] When adjusted for severity of illness using APACHE II score, and predisposing conditions (LIPS), the development of ALI markedly increases the risk of inhospital death (odds ratio, 4.1; 95% CI, 2.9–5.7).

Other clinical features, in additional to the inciting agent, have been examined for their ability to predict outcome in the ARDS population. ARDS has a recognized time course from onset, through the pathophysiologic exudative, proliferative and fibrotic phases. Clinical observations suggest the timing of ARDS in relation to disease onset may be an important variable to consider. Classification of disease by onset in the clinical course as early (<48 hours) versus late (> 48 hours) appears to describe two different disease patterns and patient outcomes in a trauma population.[42] Patients with early post-traumatic ARDS appeared to have hemorrhagic shock with capillary leak as the most common etiologic agent, while a later onset was more frequently associated with infection/ pneumonia and progressive multiple organ failure. The timing in evolution of ARDS from an exudative to proliferative process may also influence the response to therapeutic interventions.[43,44] Race and ethnicity may be additional important clinical variables which influence outcome from ALI/ARDS. In a retrospective analysis, African-American and Hispanic patients had a significantly higher risk of death than white patients. [45] The increased mortality risk for African Americans was attributable to illness severity on presentation but could not be explained for the Hispanic population.

The AECC criteria provide a framework to define the ARDS patient population. Considered in isolation, the criteria do not address specific variables recognized to influence mortality risk in the population including the inciting agent, timing of the injury, and race and ethnicity factors. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Clinical studies in ARDS must consider these factors in the design and interpretation of clinical trials for this disorder.

ARDS OUTCOME AND PULMONARY VASCULAR DISEASE

While the AECC definition of ARDS focuses on the clinical manifestations of alveolar edema with radiographic and gas exchange criteria, ARDS is also a disease of the pulmonary circulation. Is the response of the pulmonary circulation an important variable in the clinical course of the patient with ARDS? Histologic studies in ARDS have demonstrated a pattern of diffuse pulmonary endothelial injury associated with both macro and microscopic thrombi formation. These early changes progress to fibrocellular intimal proliferation that can obliterate small vessels. Radiographic imaging confirms the vascular changes can be manifested as actual filling defects in the distal pulmonary vasculature.[46]

The vascular changes of ARDS could lead to a type of ventilation/perfusion (V/Q) mismatch contributing to an increase in physiologic dead space. In contrast to the variable results with oxygenation indices, an increase in pulmonary dead space fraction (Vd/Vt) has proven to be a powerful predictor of mortality in patients with ALI/ARDS.[47] For every 0.05 increase in the deadspace fraction, the odds of death in an ARDS study population increased by 45 percent (odds ratio, 1.45; 95 percent confidence interval, 1.15 to 1.83; P=0.002). The widespread acceptance of Vd/Vt as a prognostic tool for ARDS has been limited by the requirement for measuring mixed expired carbon dioxide. A modification of the Vd/ Vt equation using readily available clinical data has been described and this modified Vd/Vt remains predictive of ARDS outcome in a dose responsive manner.[48] The value of Vd/Vt as a predictive indictor requires further validation in larger populations. However, these findings do support the importance of vascular derangements as an important component of the ARDS phenotype and likely a significant predictor of outcome. Both pulmonary vascular hemodynamic variables and right ventricular dysfunction have been studied in the ARDS population as clinical markers of pulmonary vascular injury.[31,49] Pulmonary hypertension is recognized in a significant fraction of ARDS patients and the potential causes are quite diverse. These have been hypothesized to include altered vasomotor tone due to hypoxemia and/or hypercapnia, altered intrathoracic pressures in association with ventilator support, and in situ thrombosis. Without consideration of cause, early clinical studies suggested elevated pulmonary artery systolic pressure in ARDS 197

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patients was associated with an adverse prognosis.[31] These data have been further supported by a more recent analysis of hemodynamic data from the ARDSNet Fluids and Catheter Therapy Trial (FACTT).[50] The investigators assessed the transpulmonary gradient (TPG) (mean PA pressureâ&#x20AC;&#x201C;pulmonary capillary occlusion pressure [PCOP]) and the pulmonary vascular resistance index (PVRi) in a group of patients randomized to receive a pulmonary artery catheter to guide their ARDS management. Of note, all patients received a consistent protective ventilator strategy with target tidal volume ~ 6ml/kg ideal body weight and plateau pressures maintained <30 cm H20. The highest recorded daily value of TPG and PVRi was used for the analysis. In the population of 475 patients randomized to receive a pulmonary artery catheter for ARDS management, none of the baseline measures of cardiopulmonary dysfunction, including central venous pressure, PA systolic or diastolic pressure, pulmonary capillary occlusion pressure (PAOP), or cardiac index distinguished survivors from non-survivors. In the pulmonary artery catheter population, 73% demonstrated an elevated transpulmonary gradient (TPG>12). Patients with a TPG>12 mm Hg had a significantly greater mortality rate than patients with a TPG<12 mm Hg (30% vs. 19%; P=0.02). Patients with a persistently elevated TPG through day #7 of therapy had a significantly greater mortality than patients with an elevated TPG at day 0-1 which subsequently normalized. In multivariate analysis, pulmonary vascular dysfunction, as represented by an elevated TPG and PVRi remained an independent predictor of an adverse outcome in the ARDS population. These data further support an important predictive role for pulmonary vascular disease in ARDS outcome and a potential target for therapeutic intervention.

If pulmonary hypertension is an important clinical parameter in ARDS patients, then logically, right heart dysfunction will be frequent in the population. ARDS has been associated with acute right heart dysfunction assessed either by hemodynamic indices or by echocardiography.â&#x20AC;&#x2030;[5,49,51] An elevated right atrial:pulmonary capillary occlusion pressure ratio was a strong predictor of mortality in one series of patients meeting AECC criteria.[5] The value of this parameter as a predictive variable for mortality was not confirmed in the FACTT patient population, however.[50] Acute cor pulmonale (ACP), defined echocardiographically as RV dilatation with paradoxical septal motion, occurs in 22-25% of the ARDS population.[49] Although echocardiographic findings of ACP are associated with significant morbidity (increased length of stay (LOS)), the finding is not clearly predictive of an adverse outcome.[49,51] In the largest published echocardiography series of ARDS, patients receiving a consistent lung protective ventilation strategy (mean PEEP of 10 cm H20 and mean plateau pressure (Pplat) 198

of 23 cm H20), 22% of patients had evidence for acute cor pulmonale. Of this population, 19% demonstrated evidence of a moderate-to-large patent foramen ovale (PFO).[51] The incidence of right to left shunting increased to 34% in patients with echocardiograpic evidence of acute cor pulmonale. Although limited in scope, the available data suggest the presence of pulmonary vascular disease, especially with evidence for right heart dysfunction, holds important prognostic information for the ARDS patient outcome. The interaction of ventilator support variables, pulmonary artery pressures, and risk for right to left shunting, is a complex interaction to challenge the management of hypoxemia in this disorder. This interaction would be expected to influence the success of many of the treatment strategies for hypoxemia in ARDS including PEEP, prone ventilation, and vasodilator therapy.

DISEASE PREDICTION MODELS

Because the PaO2/FiO2 ratio has been inconsistently associated with defining prognosis in ARDS, clinical investigators have sought other markers to define severe ARDS for enrollment in clinical trials.[52,53]

Both traditional severity of illness models applied to ARDS (i.e., APACHE) and disease specific ARDS models have been considered to predict ARDS mortality from clinical data available early in the disease course.[54-56] The goals of a prediction model, if accurate, would be twofold. An accurate prediction model would provide an important resource to enhance surrogate discussion making regarding prognosis for the clinical management of ARDS. A well-calibrated model could also provide a tool to stratify cohorts of ARDS patients in clinical trials according to their mortality risk. Using the ARDSNet low tidal volume population, a simple model incorporating the parameters of age, serum bilirubin (mg/dL), net 24-hour urine volume (in-out [mL]), and hematocrit was devised to predict mortality in non-trauma ARDS patients with good calibration.[55] The model has been validated in a population of non-trauma patients from a second ARDSNet clinical trial (ALVEOLI). The main appeal of this model is the simplicity of the calculation rather than superiority to the more generalized ICU predictions models, such as APACHE III which also shows good prediction for the ARDS population. [29] The transportability of the ARDS specific model was subsequently examined in a non ARDSNet cohort of nontrauma patients.[56] The model showed an equal ability to discriminate between survivors and non-survivors with excellent calibration in high and low risk patients. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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However, for intermediate risk patients, the observed mortality was substantially higher than predicted by the model. The variability in calibration of disease specific models in different populations may reflect the unique characteristics of the development cohort. The more general populations, in contrast to the ARDSNet study populations, may have a different racial distribution, different clinical characteristics, and different severity of illness, all factors which might impact the calibration of a mortality prediction model.

In addition to clinical variables, numerous plasma biomarkers have been investigated in ARDS populations due to their hypothesized relationship to the disease pathogenesis. These biomarkers have included a broad array of mediators reflective of lung injury and repair mechanisms and provide insight to disease pathogenesis (Table 3). A major limitation of the current literature supporting these biomarkers is that the majority have been derived from a single ARDSNet population data set with little confirmation in more diverse populations. While statistically significant, the utility of these mediators individually or in combination to refine patient selection for clinical trials remains to be determined. A combination of clinical and biologic markers for risk prediction may provide a more accurate assessment of disease outcome in the population. In an ARDSNet population randomized to unique PEEP strategies, the addition of the biologic markers IL-8, SP-D, PAI-1 and TNFR1 to clinical predictive variables provided a stronger predictive calibration of patient mortality than clinical variables alone (AUC 0.850 vs. 0.815).[57] In ARDSNet populations from the tidal volume and PEEP trials, incorporation of five biomarkers (soluble intercellular

adhesion molecule-1, von Willebrand factor antigen, IL-8, SP-D, and sTNFr-1) significantly improved risk prediction when compared to the use of the Acute Physiology and Chronic Health Evaluation Score III alone.[58]

Imaging characteristics of the ARDS population have also been identified as important contributors to mortality prediction. Recognition of the limits of plain film radiographs has prompted the use of CT imaging in ARDS to provide a more refined description of the lung injury pattern and determination of lung recruitability.[26,59] The CT Scan ARDS Study Group has defined an ARDS severity score (ARDS-SS) based upon a combined assessment of physiologic and imaging characteristics.[26] ARDS mortality was higher in patients with diffuse attenuations (76%) in comparison to those with lobar and patchy attenuations (41 and 42%). The ARDS-SS appeared to discriminate patients with a high mortality rate >60% and may serve to identify patients for therapeutic trials of higher risk interventions. There is also a rapidly growing body of literature exploring genetic factors in patients who develop ARDS. Genomewide association screening studies of patients who either have ARDS or are at risk of developing ARDS have been summarized in a recent review.[60] These studies in ARDS are challenged by a heterogeneous phenotype, selection of the appropriate control population, inconsistent replication studies, insufficient population sampling, and complex interactions between the genetic risk and clinical variables. Additional variability can be seen in relation to race and population stratification. A more refined phenotype characterization will likely be needed to improve the success of genetic replication studies to confirm specific variants that contribute to prognosis.

Table 3: Biomarkers associated with ALI/ARDS prognosis Class

Mediator

Adhesion molecules Coagulation and fibrinolysis

Plasma soluble intracellular adhesion molecule-1[124] Plasma protein C levels[99] Plasminogen activator inhibitor-1[99] Plasma interleukin-6[64] Plasma interleukin-8[64] BAL interleukin-8[125] Plasma soluble tumor necrosis factor receptor I and II[126] Plasma interleukin-10[64] Plasma von Willebrand factor[127] Receptor for advanced glycation end products (RAGE)[128] Plasma surfactant protein D[129] Decoy receptor level 3[130] N-terminal probrain naturiuretic peptide (NT-pro BNP)[131]

Cytokine: Pro-inflammatory

Cytokine: Regulatory Endothelial cell activation Epithelial injury Misc. Right heart function

Prognostic role of greater value Mortality risk

VFD/ OFFDĂ

+ + + + + + + + + + + +

+ -

ĂVFD/OFFD: ventilator-free days/organ failure-free days; ARDS: acute respiratory distress syndrome; ALI: acute lung injury; adapted from Reference 132

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The development of models which incorporate additional descriptive parameters beyond the AECC criteria for ALI/ARDS are needed. By combining physiologic data with biomarkers, imaging characteristics, and genetic information investigators hope to create a more homogeneous disease model for targeted intervention. These models will require validation in large ALI/ARDS cohorts. A more homogeneous patient selection will allow investigation of both high and low risk interventions in a patient group specifically targeted based upon disease pathophysiology and course.

THERAPEUTIC STRATEGIES FOR RESPIRATORY MANAGEMENT Tidal volume

Correction of hypoxemia and hypercapnia are integral to ARDS management and the majority of patients with more advanced ALI and ARDS require mechanical ventilatory support. Over the past 30 years, accumulating basic science and clinical evidence has confirmed that mechanical ventilation can extend the inflammatory response of ARDS in response to cyclic tidal alveolar hyperinflation and recruiting/decrecruiting injury. [61] The cyclic overdistention produced by excessive transpulmonary pressure has been identified as one of the major determinants of ventilator induced lung injury (VILI).

A landmark paper published by Webb and Tierney in 1974 examined the response of normal lungs to incremental peak inflation pressures (PIP) of 14, 30, or 45 cmH2O without positive end-expiratory pressure (PEEP), as well as with PIP of 30 or 45 cmH2O with 10 cmH2O of PEEP.[62] The deadspace of the ventilatory circuit was adjusted to provide a consistent PaCO2 with all ventilation strategies. Ventilation at low inflation pressures (PIP 14 cmH2O) did not cause significant injury in comparison to ventilation with higher inflation pressures (30 or 45 cmH2O) which produced hypoxemia and perivascular edema. Ventilation at high inflation pressures (45 cmH2O) without PEEP produced severe lung injury and death within 35 min. The use of PEEP with the same inflation pressures conferred protection from the alveolar edema.

Dreyfuss et al. extended these observations by examining whether VILI resulted from a pressure mediated or lung volume (stretch) mediated injury. [63] Rats were subjected to incremental PIP but tidal volume could be restricted in one group using a thoracoabdominal binder to limit chest wall excursion. This study confirmed that high tidal volume ventilation, irrespective of airway pressure, produced severe lung injury characterized 200

by pulmonary edema, increased alveolar-capillary permeability, and structural abnormalities. In addition, PEEP once again was found to be “protective,” as the presence of PEEP prevented pulmonary epithelial damage and alveolar edema and significantly reduced interstitial edema and endothelial cell changes. As a result of these investigations, clinical researchers began to focus on the importance of “volutrauma” as an important clinical parameter to avoid in ARDS ventilator management.

Although numerous ventilatory strategies have been investigated, the ARDSNetwork low tidal volume (ARMA) trial comparing 6 ml/kg ideal body weight (IBW) tidal volume versus 12 ml/kg IBW tidal volume established a clinical relevance to the animal models of ventilator induced lung injury (VILI).[2] Each patient group also had their respective Pplat restrictions (<30 for 6ml/kg and <50 cm H20 for 12 ml/kg). The 6ml/ kg IBW tidal volume group showed a marked absolute survival benefit (31 vs. 40%, P=0.007). The low tidal volume strategy was also associated with a reduction in measured plasma biomarkers (tumor necrosis factor receptor (TNF 1r), interleukin-6, and interleukin-8), inflammatory mediators typically reflective of more severe lung injury.[64] This latter finding established a clinical biologic relevance between the lung protective ventilator strategy and the systemic inflammatory response of ARDS. The elevated blood inflammatory markers provide the link between the ventilator management strategy and progression of organ failure in ARDS. The enhanced inflammation associated with VILI, leading to the release of inflammatory mediators from the lung into the bloodstream, has been called biotrauma.[61]

The clinical data supporting the importance of tidal volume and Plat control in ARDS is supported by assessment of lung metabolic activity. By combining CT and PET imaging, investigators have determined that ARDS lung metabolic activity is increased in aerated regions in proportion to the tidal volume and Pplat.[65] Plat >26-27 cm H20 correlate with greater lung inflammation in these well ventilated regions consistent with an injury signal. These imaging data provide further support for a lung origin to changing systemic inflammatory mediators in response to tidal volume change.

Positive end-expiratory pressure

While the ARMA trial addressed the issue of tidal hyperinflation of the alveoli, it did not address the role of PEEP in regulating lung injury. Both groups in the ARMA trial were managed with identical protocolized changes in PEEP/FiO2 combinations, so the impact of PEEP on minimizing VILI could not be assessed. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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The evidence suggesting that large tidal volumes cause lung injury (volutrauma) is accompanied by evidence from animal models that recruitment/derecruitment cycling of atelectatic, edematous lung can also be harmful (atelectrauma).[66] As previously noted, evidence from animal models suggested that higher PEEP could prevent ventilator induced lung injury, independent of PEEP associated benefits to oxygenation.[63] The heterogeneous nature of ARDS, however, complicates the interaction of PEEP with the injured lung. In diseased regions, PEEP acts to stabilize lung volume and reduce the amount of lung volume undergoing tidal cycling opening and closing. In normal regions, PEEP leads to overdistention and exacerbates tidal hyperinflation. In contrast to functional metabolic imaging with tidal overdistention, the role of alveolar recruitment/derecruitment in enhancing lung metabolic activity and injury is less clear.[65]

ALI/ARDS investigators have extensively investigated the potential benefits of PEEP in patient management. A followup trial to ARMA, termed the Assessment of Low Tidal Volume and Elevated End-Expiratory Volume to Obviate Lung Injury (ALVEOLI) trial, randomized ALI patients to a high and low PEEP strategy. The randomization employed a consistent low tidal volume/Pplat strategy matched to two different PEEP /oxygenation tables for titration. The higher PEEP strategy was the intervention compared to the control, or lower PEEP/high FiO2 strategy of the ARMA trial.[10] The higher PEEP strategy did not show an improvement in outcome over the original ARMA PEEP management.

The Lung Open Ventilation Study (LOV), employed a level of PEEP, either higher or lower, based upon an oxygenation scale conceptually similar to the ALVEOLI trial.(67) The intervention group received a 40-sec breath hold at 40 cm H20 with PEEP set at 20 cm H20. The patients were then treated with FiO2/PEEP titration based upon a table. Despite the lack of a clear mortality benefit, this strategy did result in a significant improvement in secondary endpoints of reduced refractory hypoxemia, reduced death due to refractory hypoxemia, and reduced requirement for rescue therapy due to intractable hypoxemia, barotrauma, or acidosis. Rescue therapies included inhaled nitric oxide, prone ventilation, high-frequency oscillation, highfrequency jet ventilation, and extracorporeal membrane oxygenation. The Expiratory Pressure Study Group (EXPRESS) randomized an ALI population to achieve a high PEEP strategy based upon lung mechanics.[68] The randomization achieved a minimal distention strategy (low PEEP) and an increased recruitment strategy (high PEEP). In the minimal distention strategy, PEEP and inspiratory Pplat were kept as low as possible without falling below oxygenation Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

targets. External PEEP was set to maintain total PEEP (the sum of external and intrinsic PEEP) between 5 and 9 cm H2O. In the recruitment strategy, PEEP was adjusted based on airway pressure and was kept as high as possible without increasing the maximal inspiratory Pplat above 28 to 30 cm H2O. The recruitment strategy was titrated based on Pplat, regardless of its effect on oxygenation. Overall, this high PEEP recruitment strategy resulted in no effect on mortality in the randomized population. The recruitment strategy did result in better oxygenation, more ventilator free days, more organ failure free days, and a reduced requirement for rescue therapy.

Collectively, these three trials have studied 2,229 patients with a comparative hospital mortality of 33.9% in the high PEEP strategy and 36.3% in the lower PEEP strategy. A meta-analysis of the available clinical trials comparing PEEP levels in the setting of low tidal volume ventilation has concluded that a higher PEEP strategy is associated with improved survival in the subset of patients with ARDS.[69] In contrast, patients with ALI without ARDS may not benefit or may actually experience harm from higher PEEP levels. The higher PEEP strategy is associated with no evidence of serious adverse effects although a slight increase in pneumothorax was noted (absolute risk difference, 1.6%) A second meta-analysis of similar data has reached relatively similar conclusions although contradicts the mortality benefit.[70]

A supplement to high PEEP ventilator management has been the use of recruitment maneuvers. A recruitment maneuver periodically, but briefly, raises the transpulmonary pressure to higher levels than being used for tidal inflation. Theoretically, intermittent recruitment maneuvers could open collapsed alveoli, minimize the cycling stretch associated with recurrent airway opening, and improve respiratory system compliance. Three randomized trials have examined the use of recruitment maneuvers in ARDS patients.[71-73] As might be expected, transient recruitment maneuvers are associated with transient improvements in gas exchange but no apparent sustained benefit. The risks associated with recruitment maneuvers include both pulmonary risks, in relation to VILI, and hemodynamic risks secondary to compromised cardiac output. How should the three â&#x20AC;&#x153;negativeâ&#x20AC;? trials of high PEEP therapy be interpreted in the face of abundant animal studies favoring this strategy in the regulation of lung edema? Are the negative clinical trials limited by the heterogeneity of the PEEP response of the target ALI study population? Are oxygenation parameters inadequate to guide optimal lung recruitment and minimize VILI? These questions have prompted investigators to explore alternative strategies for PEEP titration. 201

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Radiographic studies using CT imaging, under conditions of increasing PEEP, have suggested the potential for alveolar recruitment is quite variable among patients with ARDS. [59,74] A poor correlation between radiographic recruitment of lung parenchyma and changes in gas exchange indices (PaO 2 /FiO 2 or PaCO 2 ) has been suggested.[59] A lobar or heterogeneous radiographic pattern is associated with overdistention of aerated lung regions during the application of PEEP, in contrast to a more diffuse pattern of lung injury.[74] These data suggest CT imaging may be a critically important tool to define recruitability of the ARDS lung and titrate PEEP to minimize risk. The use of quantitative CT in ARDS, despite its critical importance in defining ARDS pathophysiology, has not generally been accepted as a clinical tool. This may be related to perceived disadvantages for patient care including risk of patient transfer, radiation exposure, cost, and processing limitations. Alternative techniques, such as electrical impedance tomography (EIT) and lung ultrasound are, therefore, being explored as alternative tools to guide PEEP titration in the critically ill patient.[75]

In contrast to imaging strategies, the analysis of pressure:volume relationships has been proposed to titrate PEEP using a variety of methods. Both the lower inflection point of maximum curvature on the pressurevolume curve and the stress index have been employed with variable results.[76,77] The stress index, has been advocated as a measurement to more optimally set PEEP and avoid potential hyperinflation in patients with a more focal ARDS distribution (Fig. 2).[78] Unlike traditional static-pressure volume curves, the stress index is measured under conditions of constant flow, volume controlled ventilation. The stress index defines the slope of the airway opening pressure during a period of constant flow. A stress index>or<1 suggests a changing lung elastance during the inflation period. Values<1 suggest a continuous decrease in elastance during lung inflation and are consistent with hyperinflation. Values>1 suggest an increase in lung elastance consistent with tidal opening and closing of alveoli. In contrast to the ARMA PEEP/FiO2 titration tables in patients with more focal ARDS, the stress index led to consistent reduction in the prescribed PEEP level in order to avoid hyperinflation. Titration of PEEP to the stress index also led to reductions in plasma inflammatory mediators including interleukin-6, interleukin- 8, and soluble tumor necrosis factor receptor. These same biomarkers were reduced in association with low tidal volume ventilation in the ARMA trial.[64] The validity of the stress index technique as a more optimal measure for PEEP titration remains to be confirmed by other investigators. If validated, in combination with low tidal volume ventilation, PEEP titration based upon 202

mechanical indices could significantly further regulate biotrauma in VILI.

Airway pressure measurements reflect the elastance properties of both the lung and chest wall and higher airway pressure targets may be needed in patients with altered extrathoracic mechanics. Because ICU patients are characterized by widely variable abdominal and pleural pressures, ideally, ventilator settings could be optimized to achieve a targeted transpulmonary pressure (airway pressure-pleural pressure) to minimize alveolar overdistention and cyclic alveolar collapse.[79] Pleural pressure is traditionally estimated in humans by measurement of esophageal pressure using an esophageal balloon catheter. The use of transpulmonary pressure measurements to titrate PEEP demonstrated improved oxygenation and lung compliance during the initial 72 hours of monitoring in comparison to the 6ml/kg tidal volume and ARMA PEEP/FiO2 oxygenation table. In the transpulmonary pressure group, PEEP levels were set to achieve a transpulmonary pressure of 0 to 10 cm of water at end expiration, and tidal volume was limited to keep transpulmonary pressure <25 cm of water at end inspiration. The mortality was reduced in the group randomized to transpulmonary pressure monitoring but the investigation was underpowered for this question. The measurement of transpulmonary pressures is not standard in most ICUs. Further confirmation of this technique in larger patient samples is needed. At the current time, the strong animal data supporting the role of PEEP in limiting cycling opening/closing lung

Figure 2: The stress index is the coefficient b of a power equation (airway pressure = a · inspiratory time b+c), fitted on the airway opening pressure (Pao) segment (bold lines) corresponding to the period of constant-flow inflation (dotted lines), during constant-flow, volume-cycled mechanical ventilation. For stress index values of less than 1, the Pao curve presents a downward concavity, suggesting a continuous decrease in elastance during constant-flow inflation. For stress index values higher than 1, the curve presents an upward concavity suggesting a continuous increase in elastance. Finally, for a stress index value equal to 1, the curve is straight, suggesting the absence of tidal variations in elastance. Reference 78, with permission. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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injury (atelectrauma) has not been confirmed in clinical trials. Titration of PEEP based upon oxygenation indices alone does not reveal a therapeutic benefit to higher PEEP levels. This may reflect a poor correlation between oxygenation indices and alveolar stability. Radiographic and physiologic techniques have been described to better titrate PEEP for minimal VILI. These techniques require validation in large populations for both general acceptance and a demonstrated mortality effect. The elusive PEEP strategy for ARDS management may be dependent on measurement of “recruitment” rather than oxygenation as the characteristic that determines PEEP’s value (or detriment) in the management of the ARDS patients.

Prone positioning

The clinical investigations of prone positioning illustrate many of the challenges in patient selection and study design for ARDS clinical trials. Prone positioning has been recognized to improve oxygenation in animal models of ALI and in a significant fraction of patients with ALI/ARDS. The proposed mechanisms include an increase in endexpiratory lung volume, improved ventilation-perfusion matching, more uniform distribution of lung stress and strain with tidal cycling, and regional improvement in lung and chest wall mechanics. Regardless of mechanism, an improvement in oxygenation occurs in a majority of patients when this intervention is applied. The potential risks of this intervention are primarily pressure related injury and tube dislodgement with turning maneuvers.

Despite the improvements in oxygenation, early randomized clinical trials were unable to demonstrate a mortality benefit with this intervention. [11] The interpretation of these initial trials was limited by variable enrollment criteria (ALI/ARDS vs. ARDS alone), variable intervention duration (prone time), and lack of a consistent ventilation strategy (Pplat and tidal volume targets). These limitations were specifically addressed in the Prone-Supine II (PSII) investigation which randomized patients only meeting ARDS criteria (P/F ratio <200).[80] The patients were randomized according to the severity of the hypoxemia as moderate (P/F ratio of 100-200) and severe (P/F ratio <100). The randomization strategy was based upon prior RCT subgroup analysis that suggested more severely ill patients, and patients with improved CO2 exchange in response to prone positioning may benefit from this intervention.[11,81] Ventilation was standardized to a maximum tidal volume of 8 ml/kg and a Pplat of <30 cm H2O. PEEP and FiO2 settings were based upon oxygenation tables. Patients were ventilated in the prone position for a minimum of 20 hours per day. Despite controlling for many of the variables critiqued in prior RCT’s of prone ventilation, the investigators remained unable to find a mortality benefit in the study population or in the subgroup analysis. Yet, the PaO2/FIO2 ratio was Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

significantly higher in the prone group compared to the supine group, consistent with findings in earlier trials of prone ventilation. The beneficial effect of prone positioning on oxygenation was seen in both the moderate and severe hypoxemia study groups. Positive end expiratory pressure, tidal volume, and total minute ventilation were similar in the prone and supine groups. A significantly greater proportion of patients in the prone group, as compared with the supine group, experienced at least 1 complication (e.g., need for increased sedation, muscle paralysis, hemodynamic instability, device displacement). The investigation was admittedly underpowered to detect a mortality difference <15% in the population of very severe advanced hypoxemia. To overcome the issue of sample size for the most severe ARDS populations, meta-analysis has been employed to pool study results. These analyses have suggested that prone positioning can be beneficial when restricted to patients with very advanced disease (i.e., P/F ratio <100).[82,83] Collectively, the existing data suggest prone positioning is best considered a “rescue” regimen employed for patients with intractable hypoxemia.

Pharmacologic paralysis

Neuromuscular blocking agents (NMBS) are frequently used in the management of ARDS patients to facilitate patient-ventilator synchrony and improve poor oxygenation when traditional sedation is not adequate. Under these conditions, NMBA are frequently effective. Less clear is their role in the management of ARDS patients with less severe disease. Given the frequent association of NMBA with critical illness myopathy, understanding the risk/benefit profile of these medications in the treatment of ARDS patients is especially important. In a multi-center trial, patients with severe ARDS were defined as having a PaO2/FiO2 ratio of less than 150, a PEEP>5 cm of water, and a tidal volume of 6 to 8 ml per kilogram of predicted body weight.[84] Both groups continued to receive a lung protective ventilation strategy. These patients were then randomized to 48 hours treatment with cisatracurium compared to placebo. The primary outcome was the proportion of patients who died either before hospital discharge or within 90 days after study enrollment (i.e., the 90-day in-hospital mortality rate). The crude 90-day mortality was 31.6% (95% CI, 25.2 to 38.8) in the cisatracurium group and 40.7% (95% CI, 33.5 to 48.4) in the placebo group (P=0.08). No comparative increase in critical illness myopathy was seen in the cisatracurium population. How do we explain the beneficial effect of short-term pharmacologic paralysis in this clinical trial? As gas exchange indices were similar in both populations, this 203

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mechanism does not seem to explain the reported benefit. Theoretically, short-term paralysis may facilitate patientventilator synchrony in the setting of lung protective ventilation. Short-term paralysis would eliminate patient triggering, active expiratory muscle activity, and overventilation. In combination, these effects may serve to limit regional overdistention (volutrauma) and cyclic alveolar collapse (atelectrauma). Paralysis may also act to lower metabolism and overall ventilatory demand. The role of NMBS in the management of ARDS requires further exploration in additional clinical trials. Many questions remain in addition to the proposed mechanism of benefit. Whether the therapeutic benefit is drug (cisatracurium) or class specific remains undefined as does the optimal duration of therapy, and will require further studies.

High-frequency oscillatory ventilation

An alternative approach to the tidal cycling of conventional ventilation is the use of high-frequency oscillatory ventilation (HFOV). HFOV employs a relatively constant airway pressure, with CO 2 exchange accomplished through non-convective mechanisms produced by rapid pressure oscillations (300-900 breaths per minute) in the airway. This lung protective strategy of HFOV is theoretically achieved by alveolar recruitment with a relatively constant mean airway pressure and avoiding the low and high tidal swings in alveolar pressure associated with conventional ventilation. Animal models of ALI have suggested HFOV reduces the level of inflammatory mediators produced by the injured lung in comparison to conventional mechanical ventilation.[85] The risks of HFOV relate to barotrauma and hemodynamic compromise in association with the sustained elevation in mean airway pressure. A randomized trial confined to ARDS patients compared HFOV to conventional ventilation using a target tidal volume of <10 ml/kg in the conventional group.[12] This trial randomized 148 subjects with ARDS to the two ventilation strategies and confirmed an improvement in oxygenation indices with HFOV in the first 24 hours which was not sustained. No difference in mortality or ventilator free days could be confirmed in this relatively small sample size. A meta-analysis of published studies suggests HFOV applied early in ARDS patients (as opposed to rescue therapy) may be associated with a reduction in ARDS mortality and the need for alternative therapies, without any significant change in ventilator free days.[86] The average increase in PaO2/FiO2 ratio at 24-72 hours was 16-24% and the average increase in mean airway pressure was 22-33%. When the oxygenation index and PaCO2 were considered, however, HFOV demonstrated no advantage over conventional ventilation. No difference 204

in the risk of barotrauma, hemodynamic compromise, or endotracheal tube obstruction was evident. Again, these data suggest HFOV is best considered a rescue regimen for patients with intractable hypoxemia. Ongoing clinical trials hope to address more specifically the role of this therapy in patients with ARDS.

Extracorporeal membrane oxygenation

If a lung protective ventilatory strategy is critical to the support of ARDS patients, then extracorporeal life support should provide the most optimal methodology to achieve lung “rest.” The potential benefit of extracorporeal membrane oxygenation (ECMO) is offset by an incremental bleeding risk related to the need for anticoagulation, and an additional infection risk related to the need for intravascular catheters. Early clinical trials of ECMO employed primarily an arterial-venous strategy with larger bore catheters for patients with intractable hypoxemia.[87] More modern investigations have used a safer venovenous access approach and have appropriately compared ECMO, or a modification of ECMO called extracorporeal CO2 removal, with a lung protective ventilation strategy.

The Conventional Ventilation or ECMO for Severe Adult Respiratory Failure (CESAR) trial randomized 180 patients with ARDS and a Murray Lung Injury Score >3 or a pH<7.20 to either conventional therapy or transfer to an ECMO center for consideration of ECMO.[53] Patients were excluded from participation if they had been on high levels of inspired oxygen or high peak inspiratory pressure for longer than 7 days, had a contraindication to anticoagulation, or had a limited hope for recovery. The conventional therapy patients were assigned to a conventional ventilation strategy with target parameters (tidal volume 4-8 ml / kg and Pplat<30 cm H20) but received no standardized treatment protocol. The intervention group was transferred to an ECMO center for consideration of extracorporeal therapy. The ECMO center provided a comprehensive care program including lung protective ventilation, prone positioning, and nutrition support. Of the patients randomized to the ECMO arm, 63%, survived in comparison to 47% of those allocated to the conventional ventilation arm (relative risk 0·69; 95% CI 0·05–0·97, P=0·03). Of note, only 75% of the patients transferred for ECMO actually received the therapy, raising question as to whether the proposed intervention (ECMO) or better patient management in a highly specialized center was the most important intervention. Because of the extreme cost of the intervention, additional studies will be needed to define the role of extracorporeal support in the management of severe ARDS patients.

Inhaled vasodilators

The recognized pulmonary hypertension, right heart dysfunction, and severe hypoxemia which characterizes Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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ARDS has prompted investigators to consider treatment strategies to address both parameters. The most promising agents for treatment of hypoxemia and pulmonary hypertension have been inhaled vasodilators. Systemic administration of vasodilators including prostagladin based vasodilators and sildenafil have been unable to show a therapeutic effect in ARDS and are often associated with worsening of oxygenation indices.[88,89] These medications should be used only with extreme caution in patients with advanced hypoxemia.

In contrast, inhaled vasodilators reduce pulmonary arterial pressure and redistribute blood flow to well ventilated lung regions with little to no systemic side effects. The two most frequently investigated agents are inhaled nitric oxide and inhaled prostacyclin.

Inhaled nitric oxide (iNO) improves oxygenation and reduces pulmonary artery pressure without lowering systemic blood pressure in select patients with ARDS.[89] Inhaled NO may also modify the host activation of neutrophils and platelets in the setting of inflammation. The results of numerous clinical trials examining the effects of iNO in ARDS patients are summarized in a review and meta-analysis.[90] The analysis combines 12 trials which have enrolled 1237 patients. The combined analysis suggests iNO has a small beneficial effect on oxygenation (PaO2/FiO2 ratio and Oxygenation Index) but no significant population effect on pulmonary artery pressures. There was no measurable effect on mortality or ventilator free days in the pooled analysis. The analysis raises concern regarding safety suggesting an increased rate of renal dysfunction in the study population randomized to receive iNO. The existing studies are limited by a fixed dosing schedule for the iNO administration of variable duration. Because the iNO dose response appears to vary with time in ARDS patients, the fixed-dose intervention design may have revealed adverse effects associated with long term administration.[91] The inhaled prostacyclins, epoprostenol (prostaglandin I2 (PGI2) and alprostadil (PGE1) demonstrate similar vasodilator effects when compared to iNO including improved oxygenation and reduction in pulmonary hypertension. [92,93] However, these drugs lack the experience in randomized clinical trials characteristic of iNO. Based upon the published trials to date, the use of inhaled vasodilators must be considered a rescue therapy for patients with intractable hypoxemia and/or pulmonary hypertension where other interventions such as high PEEP titration, prone positioning, and HFOV have been unsuccessful. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

THERAPEUTIC STRATEGIES FOR HEMODYNAMIC MANAGEMENT In addition to problems with gas exchange, ARDS patients frequently have evidence for cardiovascular failure. Although a large number of clinical trials and epidemiologic studies have been devoted to identifying therapeutic strategies for respiratory failure, much less investigation has been devoted to understanding the hemodynamic changes that characterize the ARDS population. Population studies suggest that over 1/2 of ARDS patients have evidence for cardiovascular dysfunction on presentation.[27] Comparison between survivors and non-survivors of ARDS suggest indices of right ventricular function and pulmonary hypertension distinguish these patients on presentation.[5,31,50] However, few intervention trials currently exist to direct therapy in the ALI/ARDS population.

The issue of optimal hemodynamic monitoring has been debated in ARDS, primarily focused on the need for a pulmonary artery catheter (PAC) in disease management. An initial randomized trial of PAC use in patients with sepsis and ARDS showed that PAC exposure did not confer a 28-day survival benefit, differences in organ dysfunction, need for vasoactive medications, or duration of ventilator/ ICU/hospital days.[94] In this clinical trial, treatment decisions based upon the hemodynamic information were not determined by protocol but rather directed by the treating physician. . The Fluid and Catheter Treatment Trial (FACTT), as part of the ARDSNetwork, compared specific management protocols guided by either a PAC or central venous catheter.[8] This study showed no differences in clinical outcomes with respect to 60-day survival, ventilator-free days, renal function, need for hemodialysis, or vasopressor therapy. This trial incorporated device specific estimates of preload and fluid management. No differences in fluid management were noted with the use of the respective monitoring devices. Patients with ARDS secondary to non-pulmonary causes are underrepresented in the study population. As a result of the two previously mentioned trials, current clinical guidelines have moved away from advocating the use of the PAC in sepsis and/or ARDS management. ARDS fundamentally is characterized by increased capillary permeability. The permeability edema that characterizes ARDS is aggravated by any state which increases hydrostatic pressure. The inciting conditions of ARDS are typically associated with a systemic inflammatory response leading to a greater preload dependence of the ventricle for optimal function. Yet, elevations in pulmonary capillary occlusion pressure, 205

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Early and aggressive fluid resuscitation of patients with sepsis, the most common etiology of ARDS, has been shown to improve patient outcome and limit progression to organ failure.[95] Are the aggressive fluid resuscitation recommendations for sepsis treatment incompatible with the dry fluid strategy in ARDS? Actually, the findings are quite compatible if the timing of the intervention is considered. The ARDS Net conservative fluid strategy was initiated after the early period of resuscitation. The mean time from ICU admission to the first protocol instruction was 41.3±1.6 hours in the liberal-strategy group and 43.8±2.5 hours in the conservative-strategy group (P=0.42). The “dry” intervention strategy was implemented after the early aggressive resuscitation period had passed. These studies remind the clinician that ARDS is a dynamic disease process both clinically and pathologically so timing of the intervention is critically important in the design and analysis of clinical trials. In addition to fluid management, the interaction of cardiopulmonary interventions is important to consider in ARDS management. The presence of acute cor pulmonale (ACP) is related to the Pplat associated with mechanical ventilation in ARDS patients.[96] ACP was uncommon when the Pplat was <27 cm H20, whereas ACP was seen in a high fraction of patients (~35%) when PPlat was between 27 and 35 cm H2O. In the setting of an elevated Pplat, ACP has an additive effect on mortality. The interaction of pulmonary hypertension, right to left shunting, and specific ARDS therapies has also been examined. Increasing PEEP to levels above 10 cm H2O has been associated with a progressive decline in cardiac output, mean arterial pressure, and LV dimensions secondary to RV systolic overload.[97] The effect of PEEP on right ventricular function may be related to the effect of PEEP on the lung. Recruitment of atelectatic alveoli could improve regional oxygenation, decrease pulmonary vascular 206

FACTT Liberal ARMA 6 ml (1996-1999)

FACTT Conservative ALVEOLI all (1999-2002)

8000 6000 ml fluid

to achieve greater preload response, are classically associated with increasing lung water in the setting of injury to the alveolar:capillary membrane. This conflict in therapeutic goals was addressed when the NHLBI ARDSNetwork published their findings from a prospective, randomized controlled trial of fluid conservative versus fluid liberal management strategies in ARDS patients.[7] The fluid conservative intervention was associated with a net even fluid balance in the ARDS population during the first week of therapy (Fig. 3). This contrasted with the liberal treatment group and past ARDS experience, where net fluid balance approximates 1 liter per day of hospitalization. Despite the lack of a true mortality benefit, the fluid conservative strategy improved oxygenation and reduced the duration of time on mechanical ventilation. The incidence of nonpulmonary organ failure, especially renal failure and shock did not increase.

4000 2000 0 -2000

2 3 4 Days post randomization

Figure 3: Cumulative fluid balance over first 7 days post randomization in FACTT patients in the liberal fluid management (FACTT-liberal) and conservative fluid management (FACTT-conservative) strategies of the Fluids and Catheter Therapy Trial. The two study groups are compared to fluid balance data available from two additional ARDSNet ventilator trials (ARMA and ALVEOLI). In comparison to all three other trials, the FACTTconservative arm ended up with an overall even fluid balance over the 7-day interval. Reference 8 with permission.

resistance, and have no adverse effect on right ventricular function. Alternatively, augmentation of PEEP leading to overdistention of alveoli will increase pulmonary vascular resistance, creating a load on the right ventricle. The interaction of PEEP on the right ventricle may therefore be dependent on the balance of lung recruitment versus overdistention.[98]

Increasing the PEEP level induced PFO shunting in 9% of one study population without PFO shunting at baseline.[51] Reducing the PEEP level in patients with PFO shunting abolished the shunt in 13% of patients. The administration of inhaled nitric oxide abolished the shunt in 2 of 14 patients when this therapy was applied. The use of prone positioning did not abolish the PFO in any patients that received this intervention in contrast to prior investigations. In patients without a PFO, incremental PEEP titration was associated with improvements in the PaO2/FiO2 ratio. In contrast, for patients with a PFO, incremental PEEP titration was not associated with statistically significant change in the oxygenation indices (Fig. 4).[51] These data illustrate the complex interaction of assessing PEEP response by solely considering improvements in the PaO2/FiO2 ratio. PEEP can improve oxygenation in ARDS by stabilizing alveolar volume and decreasing intrapulmonary shunting. In isolation, this would lead to improvements in oxygenation. However, PEEP could successfully achieve alveolar recruitment without improving oxygenation. Changes in intrathoracic pressure associated with PEEP could alter cardiovascular performance by regulating systemic venous return and right ventricular afterload. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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in other gas exchange parameters including the PaO2/ FiO2 ratio and Lung Injury Score. The lack of therapeutic efficacy for activated protein C may reflect the complex nature of the vascular injury in ARDS analogous to similar single agent trials of anti-inflammatory therapeutics for this condition.

250

PaO2 / FiO2 ratio, mmHg

200

150

100

0 5

10 PEEP level, cmH2O

Figure 4: Ratio of PaO2/FIO2 during positive end-expiratory pressure (PEEP) titration in patients who had acute respiratory distress syndrome with echo findings of moderate-to-large shunting (shaded squares) or without shunting (white squares) across a patent foramen ovale. Reference 51 with permission.

If PEEP contributes to a decline in cardiac output, an associated fall in mixed venous oxygen saturation could offset any beneficial effect of PEEP on intrapulmonary shunting. Alternatively, even in the setting of a constant cardiac index, if PEEP raises right atrial pressure in the setting of a PFO, this could lead to greater right to left shunting and a worsening of intracardiac shunting while PEEP improves intrapulmonary shunting. The net effect could be no change or even a deterioration in gas exchange in the setting of successful alveolar recruitment. Very limited pharmacologic trials have been conducted specifically focused on the vascular manifestations of ARDS. The recognized fibrin deposition and small vessel thrombi within the lung circulation of patients with ALI, in addition to documented plasma protein C deficiency in these patients, prompted investigators to investigate a potential role for activated protein C in the treatment of this disorder.[99] Activated protein C (APC) is a novel therapy with anticoagulant and antiinflammatory properties approved for the treatment of patients with severe sepsis.[100] In a randomized clinical trial of ALI patients with an APACHE score <25, activated protein C demonstrated no benefit with regard to ventilator-free days (the study primary study endpoint), mortality, or lung injury score.[101] The trial was stopped after enrollment of 75 subjects by the DSMB for futility. Of interest in this investigation, activated protein C was associated with a reduction in the measured pulmonary deadspace fraction suggesting a physiologic signal despite the lack of change Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Currently available data highlights the interaction between ventilatory strategies in ARDS and right ventricular function. The majority of epidemiologic data has associated clinical markers of pulmonary hypertension and right ventricular dysfunction with an adverse outcome in patients with ARDS. A complex interaction between lung recruitment and cardiovascular function is recognized. Few intervention trials have studied the role of cardiovascular management strategies in the ARDS patient population. The intensivist must recognize the pulmonarycardiovascular interaction and assess both the physiologic benefits of ventilation strategies on gas exchange indices and the deleterious effect on right ventricular function and tissue oxygenation. This dynamic interaction applies to both PEEP and recognized rescue regimens including prone ventilation, HFOV, and inhaled vasodilators. The routine use of echocardiography allows informed clinical decisions in critically ill patients. The advance of portable imaging techniques should bring this information more readily to the patientâ&#x20AC;&#x2122;s bedside.

ARDS SURVIVORS

Despite the limited success of clinical intervention trials, the available clinical data suggests the prognosis from ALI/ARDS is improving. Analysis of mortality from the ARDSNetwork clinical trials, using a consistent disease definition, demonstrated a gradual decline from 35% mortality in 1996 to 26% in 2005.[102] This reduction persisted after adjustment for a low tidal volume ventilation strategy. As the mortality rate has shifted, attention has focused to the recovery process in ARDS. Despite the intensity of support needed to correct gas exchange deficits during the acute process, the respiratory system recovery appears to be relatively short-term and complete. However, the burden for long-term survivors of ARDS is focused on psychological and neuromuscular dysfunction. A carefully described ARDS cohort, tracked over 5 years, confirms near normal lung function recovery at both 1-year and 5-year intervals. [103] Despite this improvement, assessment of physical function in these survivors shows a plateau at year 2 with incomplete recovery to normal. Six minute walking distance remains reduced in comparison to normal individuals at 5-year follow-up. The majority of the surviving population was able to return to work at 1 year (78%) and 5 years (94%).â&#x20AC;&#x2030;[103] These data, and others, have provided a 207

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renewed focus on the non-ventilatory management of the ARDS patient to limit immobility and prevent neuromuscular function loss during the period of acute support.

SUMMARY

ARDS is a heterogeneous syndrome with common clinical and pathophysiologic components. Clinical investigations have sought to define the limitations of the current ALI/ ARDS classification system to refine prediction models for disease outcome and better design and conduct clinical trials of promising new therapies. The pessimist views a large collection of negative ARDS clinical trials as a sign of limited progress. The realist accepts the complex biology of the clinical disorder and ongoing progress in defining our techniques of treatment, monitoring, and recovery in this complex patient population.

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lung injury. Am J Respir Crit Care Med 2008;178:618-23. 102. Erickson SE, Martin GS, Davis JL, Matthay MA, Eisner MD. Recent trends in acute lung injury mortality: 1996-2005. Crit Care Med 2009;37:1574-9. 103. Herridge MS, Tansey CM, Matte A, Tomlinson G, Diaz-Granados N, Cooper A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011;364:1293-304. 104. Bollen CW, van Vught AJ, Sherry T, Beale RJ, Shah S, Findlay G, et al. Highfrequency oscillatory ventilation compared with conventional mechanical ventilation in adult respiratory distress syndrome: a randomized controlled trial. Crit Care 2005;9:R430-9. 105. Hirschl RB, Croce M, Gore D, Wiedemann H, Davis K, Zwischenberger J, et al. Prospective, randomized, controlled pilot study of partial liquid ventilation in adult acute respiratory distress syndrome. Am J Respir Crit Care Med 2002;165:781-7. 106. Guérin C, Gaillard S, Lemasson S, Ayzac L, Girard R, Beuret P, et al. Effects of systematic prone positioning in hypoxemic acute respiratory failure: A randomized controlled trial. JAMA 2004;292:2379-87. 107. Mancebo J, Fernández R, Blanch L, Rialp G, Gordo F, Ferrer M, et al. A multicenter trial of prolonged prone ventilation in severe acute respiratory distress syndrome. Am J Respir Crit Care Med 2006;173:1233-39. 108. Fernández R, Trenchs X, Klamburg J, Castedo J, Serrano JM, Besso G, et al. Prone positioning in acute respiratory distress syndrome: A multicenter randomized clinical trial. Intensive Care Med 2008;34:1487-91. 109. Voggenreiter G, Aufmkolk M, Stiletto RJ, Baacke MG, Waydhas C, Ose C, et al. Prone positioning improves oxygenation in post-traumatic lung injury-a prospective randomized trial. J Trauma 2005;59:333-43. 110. Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: Results of a European multicentre study. Intensive Care Med 1999;25:911-9. 111. Taylor RW, Zimmerman JL, Dellinger RP, Straube RC, Criner GJ, Davis K, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA 2004;291:1603-9. 112. Anzueto A, Baughman RP, Guntupalli KK, Weg JG, Wiedemann HP, Raventós AA, et al. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. N Engl J Med 1996;334:1417-21. 113. Spragg RG, Lewis JF, Wurst W, Hafner D, Baughman RP, Wewers MD, et al. Treatment of acute respiratory distress syndrome with recombinant surfactant protein C surfactant. Am J Respir Crit Care Med 2003;167: 1562-6. 114. Spragg RG, Lewis JF, Walmrath H, Johannigman J, Bellingan G, Laterre P, et al. Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome. N Engl J Med 2004;351:884-92. 115. Spragg RG, Taut FJ, Lewis JF, Schenk P, Ruppert C, Dean N, et al. Recombinant surfactant protein C-based surfactant for patients with severe direct lung injury. Am J Respir Crit Care Med 2011; 183:1055-61. 116. Bernard GR, Luce JM, Sprung CL, Rinaldo JE, Tate RM, Sibbald WJ, et al. High-dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med 1987;317:1565-70. 117. Luce JM, Montgomery AB, Marks JD, Turner J, Metz CA, Murray JF. Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Am Rev Respir Dis 1988;138:62-8. 118. Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, et al. Methylprednisolone infusion in early severe ARDS: Results of a randomized controlled trial. Chest 2007;131:954-63. 119. Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, et al. Hydrocortisone infusion for severe community-acquired pneumonia: A preliminary randomized study. Am J Respir Crit Care Med 2005;171:242-8. 120. Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: A randomized controlled trial. The ARDS Network. JAMA 2000;283:1995-2002. 121. Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome. Crit Care Med 2002;30:1-6. 122. Vincent JL, Artigas A, Petersen LC, Meyer C. A multicenter, randomized, double-blind, placebo-controlled, dose-escalation trial assessing safety and efficacy of active site inactivated recombinant factor VIIa in subjects with acute lung injury or acute respiratory distress syndrome. Crit Care Med 2009;37:1874-80. 123. Matthay MA, Brower RG, Carson S, Douglas IS, Eisner M, Hite D, et al. Randomized, placebo-controlled clinical trial of an aerosolized beta-2 agonist for treatment of acute lung injury. Am J Respir Crit Care Med 2011 May 11. [Epub ahead of print].

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124. Calfee CS, Eisner MD, Parsons PE, Thompson BT, Conner ER Jr, Matthay MA, et al. Soluble intercellular adhesion molecule-1 and clinical outcomes in patients with acute lung injury. Intensive Care Med 2008;35:248-57. 125. Lin WC, Lin CF, Chen CL, Chen CW, Lin YS. Prediction of outcome in patients with acute respiratory distress syndrome by bronchoalveolar lavage inflammatory mediators. Exp Biol Med (Maywood) 2010;235:57-65. 126. Parsons PE, Matthay MA, Ware LB, Eisner MD. Elevated plasma levels of soluble TNF receptors are associated with morbidity and mortality in patients with acute lung injury. Am J Physiol Lung Cell Mol Physiol 2005;288:L426-31. 127. Ware LB, Eisner MD, Thompson BT, Parsons PE, Matthay MA. Significance of von Willebrand factor in septic and nonseptic patients with acute lung injury. Am J Respir Crit Care Med 2004;170:766-72. 128. Calfee CS, Ware LB, Eisner MD, Parsons PE, Thompson BT, Wickersham N, et al. Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury. Thorax 2008;63:1083-9.

129. Eisner MD, Parsons P, Matthay MA, Ware L, Greene K. Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury. Thorax 2003;58:983-8. 130. Chen CY, Yang KY, Chen MY, Chen HY, Lin MT, Lee YC, et al. Decoy Receptor 3 levels in peripheral blood predict outcomes of acute respiratory distress syndrome. Am J Respir Crit Care Med 2009;180:751-60. 131. Bajwa EK, Januzzi JL, Gong MN, Thompson BT, Christiani DC. Prognostic value of plasma N-terminal probrain natriuretic peptide levels in the acute respiratory distress syndrome. Crit Care Med 2008;36:2322-7. 132. Spragg RG, Bernard GR, Checkley W, Curtis JR, Gajic O, Guyatt G, et al. Beyond Mortality: Future Clinical Research in Acute Lung Injury. Am J Respir Crit Care Med. 2010 May 15;181(10):1121.

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211

Review Ar ti cl e

Pulmonary vascular wall stiffness: An important contributor to the increased right ventricular afterload with pulmonary hypertension Zhijie Wang and Naomi C. Chesler Department of Biomedical Engineering, University of Wisconsin-Madison, Wisconsin, USA

ABSTRACT Pulmonary hypertension (PH) is associated with structural and mechanical changes in the pulmonary vascular bed that increase right ventricular (RV) afterload. These changes, characterized by narrowing and stiffening, occur in both proximal and distal pulmonary arteries (PAs). An important consequence of arterial narrowing is increased pulmonary vascular resistance (PVR). Arterial stiffening, which can occur in both the proximal and distal pulmonary arteries, is an important index of disease progression and is a significant contributor to increased RV afterload in PH. In particular, arterial narrowing and stiffening increase the RV afterload by increasing steady and oscillatory RV work, respectively. Here we review the current state of knowledge of the causes and consequences of pulmonary arterial stiffening in PH and its impact on RV function. We review direct and indirect techniques for measuring proximal and distal pulmonary arterial stiffness, measures of arterial stiffness including elastic modulus, incremental elastic modulus, stiffness coefficient b and others, the changes in cellular function and the extracellular matrix proteins that contribute to pulmonary arterial stiffening, the consequences of PA stiffening for RV function and the clinical implications of pulmonary vascular stiffening for PH progression. Future investigation of the relationship between PA stiffening and RV dysfunction may facilitate new therapies aimed at improving RV function and thus ultimately reducing mortality in PH. Key Words: biomechanics, impedance, vascular-ventricular coupling, right ventricular dysfunction, hypertrophy

INTRODUCTION Pulmonary hypertension (PH) is a complex disorder that manifests as abnormally high blood pressure in the vasculature of the lungs. Based on the causes of PH, the World Health Organization (WHO) has classified the disease into five categories including Group I, pulmonary arterial hypertension (PAH) resulting from increased pulmonary vascular resistance, Group II, PH associated with left heart disease, Group III, PH associated with lung diseases and/or hypoxemia, Group IV, PH due to chronic thrombotic and/or embolic disease, and Group V, other miscellaneous causes of PH.[1] The chronic structural and Address correspondence to:

Naomi C. Chesler, PhD Associate Professor of Biomedical Engineering University of Wisconsin at Madison 2146 ECB; 1550 Engineering Drive Madison WI 53706-1609 USA Phone: 608/265-8920 Fax: 608/265-9239 212

mechanical changes in the pulmonary vasculature that occur as a consequence of PH are referred to as pulmonary vascular remodeling. Structurally, these changes include smooth muscle cell (SMC) proliferation, changes in extracellular matrix (ECM) protein content, composition and cross-linking, and either dilation or constriction of vessels, depending on their location in the circulation. The mechanical consequences of these structural changes are increased resistance and decreased compliance. The increase in pulmonary vascular resistance (PVR) that occurs with pulmonary arterial hypertension (PAH) is well studied and characterized by narrowing of small arteries Access this article online

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Website: www.pulmonarycirculation.org DOI: 10.4103/2045-8932.83453 How to cite this article: Wang Z, Chesler NC. Pulmonary vascular wall stiffness: An important contributor to the increased right ventricular afterload with pulmonary hypertension. Pulm Circ 2011;1:212-23.

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Wang and Chesler: Pulmonary artery stiffening in PH

and arterioles. However, the decrease in compliance (i.e. increase in stiffness) is also important and affects the entire vasculature. Both narrowing and stiffening contribute to increased right ventricular (RV) afterload. RV afterload is a critical metric of PH progression because typically the cause of death in PH is right heart failure due to RV overload. Left untreated, the estimated median survival of PAH is 2.8 years. [2] Conventionally, mean pulmonary arterial pressure (mPAP) is used to diagnose and predict survival in PH. Because of the dominating influence of small artery narrowing on increases in mPAP, a traditional strategy for PH treatment has been to reduce or attempt to reverse this aspect of pulmonary vascular remodeling. However, it is becoming apparent that mPAP does not correlate with either the severity of symptoms or survival. More recently, parameters reflecting RV functional status, such as RV mass and size, mean right atrial pressure, ejection fraction and cardiac index, have been shown to be strong predictors of survival.[2,4-8] As a consequence, there is growing interest in therapies that act directly on the RV to restore function.[9] Importantly, RV function depends not only on the state of the heart muscle itself (oxygen supply and demand, metabolic status, etc.) but also the vascular bed to which it is coupled, which represents its afterload.

RV afterload results from a dynamic interplay between resistance, compliance and wave reflections. It can be measured by hydraulic load or hydraulic power, which is work per unit time generated by the heart to sustain forward blood flow.[10] The power provided by RV consists of two components: the steady power required to produce net forward flow and the oscillatory power required to produce zero-mean oscillations in flow.[11] Historically, the increase in RV afterload in PAH has been attributed to increased PVR, which only reflects the steady component of total RV power. However, over a third of the RV workload increase in PH is caused by large artery stiffening,[12] which mostly influences the oscillatory RV power. In clinical studies, an increase in PA stiffness was found to be an excellent predictor of mortality in patients with PAH,[13,14] which suggests an important role of PA stiffening in right heart failure. Thus, to obtain a comprehensive view of the contributions of the pulmonary vascular bed to RV function, one must consider the complete arterial tree and investigate both steady and oscillatory components of the RV power, which are determined by steady and oscillatory components of pulmonary hemodynamics. Pulmonary artery stiffness is an important determinant of the oscillatory component of pulmonary hemodynamics.

In this review, we will focus on the current state of knowledge of the impact of pulmonary arterial remodeling (narrowing and stiffening) on RV afterload during PH progression, with a particular focus on stiffening. To do so, Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

we review direct and indirect techniques for measuring proximal and distal pulmonary arterial stiffness, metrics of arterial stiffness including elastic modulus, incremental elastic modulus, stiffness coefficient b and others, the changes in cellular function and the extracellular matrix proteins that contribute to the pulmonary arterial stiffening, and the consequences of PA stiffening for RV function. We also discuss the coupling between RV and pulmonary circulation and interactions between the proximal and distal vascular beds. Finally, we recommend directions for future studies to better understand pulmonary vascular stiffening and its relationship to RV function, dysfunction and failure in PH.

MEASUREMENTS OF PULMONARY ARTERIAL STIFFENING Direct measurements

Direct measurement of pulmonary vascular stiffness can be performed in vivo and in vitro by quantifying arterial diameter as a function of pressure to generate pressurediameter relationships or PD curves. In large animals, large and small arteries can be tested;[15] in small animals, typically only large arteries are tested.[16-18] In vivo, usually either inner or outer diameter is measured as a function of pressure and wall thickness is either assumed[19] or ignored. In vitro, both inner and outer diameter can be measured as a function of pressure,[20] as well as factors that influence the mechanical behavior of the tissue.[20- 23] The most direct technique to measure stiffness is an isolated vessel mechanical test[15-18,24] in which the vessel inner and outer diameter are measured over a range of physiological and pathological pressures. This type of test allows fine control of the test conditions such that the effect of single parameter (e.g., SMC tone, collagen and/ or elastin content, drug treatment, etc.) on stiffness can be determined. Biaxial (in two directions) tests of arterial sections and uniaxial (in one direction) tests of tissue either in strips or rings can also be performed. [25, 26] Most biaxial and strip test methods do not allow the effects of smooth muscle cell (SMC) tone to be investigated but isolated vessel and ring tests do.[17,18,27-29] Indirect measures of proximal and distal arterial stiffness also exist, which we will review in the next section.

The most commonly used approach for assessing structural mechanical properties of arteries is PD curves. If wall thickness is measured optically or histologically, material properties can also be calculated. Because transmural pressure results in circumferential stretch of the arterial wall, most mechanical properties are characterized in the direction of circumference and sometimes derived from calculation of circumferential wall stress and strain. However, recent studies on systemic arteries have 213

Wang and Chesler: Pulmonary artery stiffening in PH

considered changes in longitudinal stretch with disease as well.[30-32] Calculated parameters either represent the whole vessel stiffness but dependent on geometry, such as pressure-strain modulus (Ep),[17,33- 35] stiffness constant β,[36,37] distensibility (D)[23,38-41] and compliance (C),[23,38,42-44] or describe the material properties of the wall independent of geometry, such as elastic modulus (E)[34,45] and incremental elastic modulus (Einc).[21,45,46] Sometimes the geometric-dependent mechanical properties are termed “extrinsic” since they depend on the amount of wall material whereas the geometry-independent material properties are termed “intrinsic” since they depend only on the constitutive materials themselves. For example, two arteries made of the exact same material but different wall thicknesses would have the same intrinsic properties but different extrinsic properties. A summary of commonly used arterial intrinsic and extrinsic mechanical and material properties are presented in Table 1. Consistently, pulmonary artery wall stiffness is found to increase during PH progression. [16-18,26,47,48] It is important to note that all of these parameters are linear approximations of non-linear relationships. That is, for sufficiently large changes in stress and strain (for E) or volume and pressure (for D), a single calculation (of E or D) will be a poor approximation of the true material or mechanical behavior. In a physiological pressure range, most of the above metrics are good approximations but when testing is performed over a larger range, curve fits

may be applied to individual sections. The best example is elastic modulus, E, which for most arteries is low in a low strain range due to loading of elastin and high in a high strain range due to collagen engagement. Thus, low and high strain moduli (Elow and Ehigh respectively) are often calculated separately.[17,26,47]

Besides these structural and material properties that can be measured from PD and sometimes pressure-length curves, other parameters that require less information and thus are more feasible for clinical measurements have been introduced to investigate PA stiffening during PH progression. One example is the relative area change (RAC).[14] RAC is calculated as the relative crosssection area change (ΔA/A) of the proximal PA from systole to diastole and it is reduced significantly in PH patients.[14] RAC shows a moderate inverse curvilinear relationship with mPAP and predicts mortality better than area distensibility. Interestingly, RAC does not require knowledge of the distending pressure, so it is neither a material nor structural property; instead it is a geometrical property.

It is well known that blood vessels are not purely elastic but in fact viscoelastic materials, which means the elastic deformation under dynamic loads exhibits time-dependent behavior. A consequence of arterial viscoelasticity is pressure energy loss. When a purely viscous material is deformed, all the energy is dissipated

Table 1: Summary of parameters commonly used to measure arterial elasticity Definition (unit) Pressure-strain modulus Ep (Pa) Elastic modulus E (Pa)

Formula Ep = E =

∆P R ∆R

σ ε

Incremental elastic modulus1 Einc (Pa)

Einc =

∆P 2(1 − ν 2 )Ri2Ro ∆Ro (Ro2 − Ri2 )

Incremental elastic modulus2 Einc (Pa)

Einc =

2PDo2 ∆P 2Di2Do + 2 2 ∆Do (Do − Di ) (Do2 − Di2 )

Stiffness constant β (dimensionless)

β =

ln(Ps / Pd ) (Rs / Rd − 1)

∆V V ⋅ ∆P

C =

∆V ∆P

Distensibility D (1/Pa) Compliance C (m3/Pa)

Notes R can also be replaced with diameter (D). Extrinsic mechanical property The slope of stress-strain (σ-ε) curve, assuming linear homogeneous, incompressible wall material. Thin-wall or thick-wall assumptions lead to different calculations of σ and ε. Intrinsic material property Ro and Ri are external and internal radii and can be replaced with corresponding diameters (D). Assuming locally linear, homogenous, incomepressible (if ν=0.5) wall material. Thick wall assumption. Intrinsic material property Modified Einc, assuming orthotropic cylindrical tube. Intrinsic material property Ps and Pd are systolic and diastolic pressures. Radius R can be replaced with diameter (D). Assume homogeneous, incompressible, isotropic material. Extrinsic mechanical property V (volume) can be replaced with A (area). Extrinsic mechanical property V (volume) can be replaced with A (area). Extrinsic mechanical property

P: pressure; R: radius; D: diameter; V: volume; A: area 214

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Wang and Chesler: Pulmonary artery stiffening in PH

and none is returned. When a purely elastic material is deformed, all the energy is returned, like a spring. A viscoelastic material is both viscous and elastic so some of the energy provided to the material during loading is dissipated during unloading and some is returned. Since most in vitro measurements do not perform dynamic loading-unloading tests such as occur in the intact animal or human due to physiological pulsatile pressure waveforms, mechanical properties obtained from in vivo or dynamic in vitro experiments are more realistic and physiological. For example, the compliance measured from static PD curves is less than that measured form the dynamic PD curves under the same pressures.[49] Although not well recognized, the characterization of arterial mechanical behavior including elasticity and viscosity may be of clinical importance in PH.

In systemic arteries, viscosity has been shown to change with aging, with atherosclerosis and systemic hypertension. [50-52] The effect of acute PH on arterial viscosity has been investigated by the group of Armentano. [53,54] Our group, to our knowledge, is the only one that has investigated changes in proximal PA viscoelasticity in chronic PH.[16,47,55] Traditionally, SMCs are considered to be the primary source of arterial viscosity[29,56] but our results suggest that SMCs may not be the only determinant. The damping capacity of large PAs increases after chronic hypoxia[16,47,55] and this increase correlates with the accumulation of collagen.[55] The clinical implications of increased PA viscosity during PH are unclear, but arterial viscosity likely increases circulatory energy loss[56] and affects wave reflections,[57] thus impairing dynamic interactions between heart and lung and increasing RV afterload.

Indirect measurements

Both proximal and distal pulmonary arterial stiffness can be measured indirectly from pulmonary pressure-flow relationships in vivo[58-63] or ex vivo in isolated whole lungs.[63-69] Advantages of the isolated, perfused and ventilated lung preparation are that pressure-flow relationships are not affected by anesthesia,[60] volume status [59] and level of sympathetic nervous system activation. [58] In addition, the effect of drugs on the pulmonary vasculature can be investigated independent of the effects of those drugs on the systemic vasculature. [70] However, in most isolated, ventilated, perfused lung preparations, only steady pressure-flow relationships are obtained, from which only distal arterial stiffness can be derived. Our group has used pulsatile flow waveforms to obtain pulsatile pressure-flow relationships, which allow estimates of proximal artery stiffness to be made, although these are still difficult to compare to in vivo measurements obtained with physiological flow waveforms.[68,70-72] The metrics of proximal and distal pulmonary arterial stiffness Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

that can be obtained by in vivo and ex vivo methods are reviewed below.

Steady pressure-flow relationships Increases in mPAP that occur with increases in flow whether in vivo (due to exercise or drugs) or ex vivo (due to imposed flow waveforms) can provide insight into distal arterial stiffness. If one imagines the distal pulmonary arterial bed to be a parallel network of rigid tubes, then any increase in flow will lead to a proportional increase in pressure. If more rigid tubes open as a result of increased flow (i.e., are recruited), then the increase in pressure will be less at high flows. If these rigid tubes increase in diameter with increased flow (i.e., by the mechanism of flow-induced vasodilation), then the increase in pressure at high flows will be less still. Finally, if the tubes are not in fact rigid but can distend, then the pressure-flow curve may plateau at high flow. A theoretical approach to measuring this distal arterial distensibility, assuming a fully recruited and dilated pulmonary vasculature, was first described by Linehan et al.[73]: 1

mPAP=

[(1+αPv )5 + 5αR0(Hct)CO] /5 -1 α

(1)

where Pv is pulmonary venous pressure, CO is cardiac output, R0 is the total pulmonary vascular resistance (mPAP/CO) at rest, Hct is the hematocrit, and α is the pulmonary arterial distensibility, which is assumed to be constant throughout the pulmonary vascular bed.

In vivo[7,74] and ex vivo[75] studies have demonstrated that PH decreases α. However, whether distal arterial stiffening impairs exercise capacity in PH by exacerbating flowinduced increases in mPAP remains unknown.

Pulsatile pressure-flow relationships From pulsatile pressure-flow relationships obtained either in vivo or ex vivo, indirect measurements of proximal arterial stiffness can be obtained. In addition, other characteristics of the pulmonary circulation can be determined such as PVR and wave reflections. Two approaches to analyze these pulsatile pressure-flow relationships are commonly used: a frequency domain method; and a time domain method. Impedance (Frequency domain analysis) The relationship between pulsatile blood pressure and flow can be quantified by the impedance.[76] Its calculation requires synchronized pulmonary arterial pressure and flow measurements, which are typically obtained with a right heart catheterization and either ultrasound[77,78] or a catheter-based flow sensor[79,80] in vivo or by direct recording of pressure and flow ex vivo. From these data, a comprehensive measurement of RV afterload is 215

Wang and Chesler: Pulmonary artery stiffening in PH

given by pulmonary arterial input impedance (PVZ). The calculation of PVZ requires a spectral analysis of the pulmonary arterial pressure waveform P and flow waveform Q and a mathematical elaboration (Fourier analysis) to derive a PVZ spectrum, which is expressed as the ratio of P to Q moduli and a phase angle (θ), both as a function of frequency[76]: PVZ (ω ) =

P(ω )

Q(ω )

(2)

q (ω ) = Φ(ω ) − f(ω ) (3) where ω is the frequency, Φ is the pressure phase and φ is the flow phase. This approach has been adopted in PH animal models using in vivo and ex vivo techniques and in patients.[19,68,78,81-83] Details of how to calculate impedance for the pulmonary circulation have been reviewed previously.[23,84,85]

The impedance spectra in systemic and pulmonary circulations share a similar, classic pattern of a high 0-Hz value (Z0) followed by a local minimum and oscillations at high frequencies (Fig. 1). Z 0 increases during PH progression and this parameter is equal to total PVR. Like PVR, Z0 is essentially as a measure of distal pulmonary resistance; it is the input impedance in the absence of flow oscillations. The average of the impedance modulus at higher harmonics is used as an estimation of characteristic impedance (Zc), which is the input impedance in the absence of wave reflection. Zc is determined principally by the ratio of stiffness of the proximal arteries to fluid inertia.[76,86] It is dependent on both the size and material properties of the proximal PAs. For example, an increase

Figure 1: Representative pulmonary vascular impedance (magnitude

Z and phase θ) spectra in a healthy mouse. 216

in proximal PA radius decreases Zc, whereas an increase in stiffness has the opposite effect. These relationships are described theoretically by: Zc =

rEh (4) 2p 2r 5

where E, h, and r are proximal PA elastic modulus, wall thickness and luminal radius, respectively, and r is the density of blood.[87,88] Zc is usually found to remain constant in subjects with PH,[68,76,89] which may be a combined result of increased proximal PA stiffness[16,17,26,47] and diameter. [14,16] This observation suggests that during PH, the RV and pulmonary vasculature adapt to maintain the mechanical load on the RV and conserve energy.[76,89] However, Zc has also been found to change (increase or decrease) with PH depending on the animal model used or different pathological mechanisms of PH.[61,62,81,82,88,90,91] A third parameter that can be derived from the impedance spectrum is pulse wave reflection (Г), [76,92] which is calculated by Γ=

Z0 − Zc (5) Z0 + Zc

The wave reflection increases significantly with PH,[68,93] which suggests a bigger impedance mismatch between the proximal and distal pulmonary vasculature and may have detrimental effects on the RV function as reported to occur in the systemic circulation.[10]

Overall, PVZ has the potential to be a better prognostic indicator than PVR alone because it captures both static and dynamic characteristics of the opposition to flow in the pulmonary circulation. PVR is typically a single-value measurement assuming a linear relationship between the pressure difference ΔP (ΔP = Pulmonary arterial pressure – left atrial pressure) and the flow (Q). When left atrial pressure is normal, total PVR can be measured by the ratio of mean pulmonary pressure and mean pulmonary flow (mPAP/Q). Both PVR and total PVR characterize the steady, time-averaged hemodynamics and represent only the static component of RV afterload. It is well known that progressive pulmonary artery remodeling during PH increases PVR. However, PVR is likely limited as a prognostic parameter because PVR alone is not sufficient to measure total RV afterload.[94] In fact, more and more evidence suggests that a global stiffness measurement[13,14,83] that includes both static and dynamic components is a better representative and potentially prognostic parameter for PH progression. Time domain analysis Although the rapid development of new technologies Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Wang and Chesler: Pulmonary artery stiffening in PH

and instrumentation may allow more widespread use of impedance analysis in the frequency domain, current clinical applications are limited because of the complexity of performing and interpreting the frequency domain analysis and results, respectively. Instead, the time domain analysis of the pulse pressure waveform is a useful surrogate for assessing Z0, Zc and other clinical indices of pulsatile pulmonary hemodynamics.[84,95,96] In the time domain analysis, Z0 is calculated as mean pressure divided by mean flow, which is the same as in the frequency domain, and Zc is calculated as Zc =

dP (6) dQ

where dP and dQ are pressure and flow increases taken prior to when flow reaches 95% of its maximal value during one cardiac cycle.[97,98] Because of the raid upstroke of the waveforms at this early ejection phase, the reflected waves do not have time to return to the proximal bed and thus the system is reasonably assumed to be free from wave reflections.[97] From Zc, the instantaneous pressure waveform is decomposed into forward (Pf) and backward (Pb) traveling waves using the linear wave separation method.[99] The global wave reflection index (RQ) is then calculated as the ratio of the amplitude of Pb to Pf. In contrast to the wave reflection (Î&#x201C;) that is most applicable for simple systems of one or two tubes[100] and thus characterizes mismatch between proximal and distal beds, RQ captures the wave reflections of the whole vascular bed.[101] Correlation between impedance measurements performed using frequency and time domain analyses requires further investigation. Our preliminary results have shown good agreement between the two methods.[102]

Pulse pressure (PP) is often measured in the time domain analysis of pulmonary hemodynamics and has been found to be a useful indicator of heart health.[103,104] PP is defined as the difference between systolic and diastolic pressure (Fig. 2) and is determined by the characteristics of ventricular ejection and proximal arterial stiffness. In both systemic and pulmonary circulations, PP is elevated when large arteries stiffen, even without changes in the distal vasculature.[105-108]

Another parameter derived from the pressure waveform is the augmentation index (AI, Fig. 2), defined as the ratio of the height from the inflection point (Pi) to peak systolic pressure (Î&#x201D;P), which is an estimate of the magnitude of the reflected pressure wave to the PP,[96] which may correlate with proximal PA stiffness. In normal subjects there is very little wave reflection, and PH increases wave Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Figure 2: An illustrative example of pressure waveform and the derivation of pulse pressure (PP) and augmentation index (AI). Pi is the inflection point, which may present either in the systolic or diastolic phase.

reflection.[79,89,93,96,109] AI can differentiate different types of PH, i.e., chronic pulmonary thromboembolism (CPTE) and primary pulmonary hypertension (PPH)[95,96] but it may be more sensitive to the proximal arteries than the whole vascular bed and can be confounded by other factors such as heart rate.[100,101] Finally, the relationship between AI and the severity of PH remains unknown.

A potentially more useful parameter is compliance, which conceptually is the inverse of stiffness. Compliance (C) is calculated as the ratio of stroke volume (SV) to PP.[110,111] Similar parameters measured in the systemic circulation have been shown to be related to conduit artery stiffening and correlated with mortality in patients with left ventricular dysfunction.[112] In PAH patients, compliance, which is sometimes called capacitance, has been shown to have prognostic value as well.[13,113] It is important to point out that unlike in the systemic circulation where arterial compliance is mainly localized to the aorta, arterial compliance in pulmonary circulation is distributed over the entire vascular bed.[111] An interesting relationship between compliance and resistance (PVR) has recently been observed in the pulmonary circulation: the product of PVR and C is constant.[23,91,111,114] In particular, Lankhaar et al. have shown that the product of PVR and C is a constant for patients with and without PH[91] and that treatment does not change this time constant [114] Importantly, these results explain why changes in PVR alone do not reflect the clinical outcomes of PH patients. PH leads to increased PVR and decreased C; but for a similar decrease of PVR due to therapy, the patients with higher starting PVR (more severe PH) will have a smaller increase in C than the patients with lower starting PVR (milder PH). Thus the former group of patients has improvement 217

Wang and Chesler: Pulmonary artery stiffening in PH

mainly in steady RV power requirements (due to a decrease in PVR) whereas the latter group of patients has improvement in both steady and oscillatory RV power requirements (due to comparable decrease in PVR and increase in C).

CELLULAR AND MOLECULAR CONTRIBUTORS TO PULMONARY ARTERIAL TIFFENING

The arterial remodeling that occurs in the progression of PH involves all three layers of the arterial wall. Histological evidence of remodeling consists of intimal fibrosis, increased medial thickness, accumulation of extracellular matrix proteins such as collagen, increased adventitial thickness, pulmonary arteriolar occlusion and plexiform lesions. The process is characterized by proliferative and obstructive changes that involve cell types such as endothelial, smooth muscle and fibroblast.[12,115] Detailed reviews on the cellular and molecular mechanisms of PA remodeling including genetic factors have been reported previously.[12,116] Stiffening of large PAs is linked with accumulation of collagen[16,47,48,117,118] and, in some studies, elastin.[16,26,47] However, if collagen and elastin concomitantly increase during PH, one cannot discern which is more responsible for arterial stiffening. A recent study suggests elastin remodeling contributes to PA stiffening in response to hypoxia-induced pulmonary hypertension (HPH) in neonatal calves,[26] but discrepant observations are also reported in other species in adults. For example, there was no change in elastin content in rodent large PAs after chronic hypoxia.[48,119] Our latest studies using a novel transgenic mouse model (Col1a1tml Jae) suggests changes in collagen rather than elastin track large PA stiffness during HPH progression and recovery.[17] Furthermore, we specifically examined the effects of collagen content vs. cross-linking in the passive, dynamic mechanical behavior of large PAs in chronic PH and found that collagen content is critical to large PA stiffening.[55]

Differential impacts of elastin and collagen metabolism on PH progression may exist and can be attributed to the age and type of PH developed. There is evidence suggesting that elastin may play a more important role in PH in newborns whereas collagen may have a larger impact in PH developed in adults. Studying the biomechanics of newborn calf extralobar arteries, Lammers et al.â&#x20AC;&#x2030;[26] showed a significant increase in low-strain elastic modulus with chronic hypoxia that was dependent on elastin. However, it is well known that newborn animals develop more severe pulmonary hypertension than adults with more dramatic vascular changes.[120-122] Since 218

the neonatal period is associated with significant elastin production in the pulmonary trunk even in normoxic conditions,[123] elastin synthesis may be particularly sensitive to modulation by hypoxia during this time of rapid growth. Another study using a set of transgenic and knockout mice with graded elastin insufficiency found that reduced elastin content in large PAs predisposed the mice to elevated RV pressures and RV hypertrophy.[124] With the genetic deficiency in elastin, peripheral PAs developed muscularization and proximal PAs exhibited increased overall stiffness, but the Einc remained constant over a wide range of pressure change (0-90 mmHg). However, the extent of pathological remodeling of heart and pulmonary vasculature was limited compared to those with similar pressure elevation induced by hypoxia, which suggests an adaptation occurred during the development from fetus to adult. Therefore, it is likely that different mechanisms (elastin vs. collagen) may dominate the development of PH, depending on the type of disease. The SMC tone changes significantly during PH development. This is especially prominent in the distal vasculature. It is well accepted that the acute phase of PH is manifested by vasoconstriction. In the chronic phase of PAH, remodeling occurs with endothelial layer thickening (and formation of plexiform lesions in severe PAH) and smooth muscle hypertrophy, which leads to reduced smooth muscle contractility. The proximal PAs seem to have limited changes in SMC tone,[17,18,125] but discrepant results are also reported.[27,28,126] The impact of SMC tone on proximal PA mechanical behavior in large animals or humans is an important area of future research.

CONSEQUENCES/CLINICAL RELEVANCE OF PULMONARY ARTERIAL STIFFENING

Right ventricular overload and heart failure

Right heart function is closely tied to survival in PH. For instance, RV function assessed via right atrial pressure and cardiac output is associated with mortality in addition to mPAP in patients with PAH.[2] Previously, much attention has been paid to the pulmonary circulation and basic mechanisms underlying pulmonary arterial dysfunction; however, little is known about the RV in health and diseased states. It is recognized now that effective treatment for PH should not only impact the pulmonary vasculature but also improve RV function.

Stiffening of the pulmonary vascular bed can increase RV workload, which may be caused by impaired conduit and buffering function of the proximal PAs and early wave reflections to the RV (Fig. 3). Under normal circumstances, the oscillatory RV power is about 25% of the total Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Wang and Chesler: Pulmonary artery stiffening in PH

(oscillatory + steady) RV power, which is higher than the proportion in the systemic circulation (~10%). [76,127] A recent study on the RV pulsatile hydraulic load in PAH patients has shown that while both oscillatory RV work and total RV work increase with PAH severity, the proportion remains constant (~23%).[111] The oscillatory RV work correlates with pulse pressure, which increases with proximal PA stiffening.[127,128] Therefore, PA stiffness increases oscillatory RV work; however, the direct impact on RV function remains undefined. The effects of distal PA stiffening (loss of distensibility α) on RV afterload are also unknown.

Figure 3: Hemodynamic interactions between the right ventricle and proximal and distal pulmonary arteries. PA: pulmonary artery. VVC: ventricular-vascular coupling.

Increased RV afterload leads to augmented myocardial oxygen demand and the RV adapts primarily by hypertrophy. Hypertrophy serves to decrease the ventricular wall stress and maintain cardiac output initially and thus could be a healthy response. However, during PH progression, severe hypertrophy reduces cardiac output and cardiac index, which are the hallmarks of right heart dysfunction and failure.[9] The indicators of the transition from healthy adaptive hypertrophy to pathological maladaptive remodeling remain unknown. To understand the molecular pathways that differentiate adaptive from maladaptive ventricular hypertrophy is an important area of current research.[129]

Ventricular vascular coupling (VVC) efficiency

To understand how pulmonary vascular remodeling affects ventricular output during PH progression, investigations into ventricular function alone or vascular function alone are not sufficient. Ideally, vascular function is efficiently matched to ventricular function, and vice versa. Ventricular pressure-volume (PV) loop analysis was first developed by Sagawa et al. [130] to describe the coupling efficiency between the left ventricle and systemic circulation, i.e., vascular-ventricular coupling (VVC). In this approach, the ventricular and arterial dynamic behaviors are quantified by ventricular endsystolic elastance (Ees, which represents contractility of the ventricle) and arterial effective elastance (Ea, which represents ventricular afterload), respectively, which are derived from the pressure-volume loops at different levels of preload (Fig. 4). The ratio of these two parameters (Ees/ Ea) yields a direct assessment of VVC efficiency. When the ventricle and vasculature are efficiently coupled, minimal energy is wasted in the pulse pressure and maximal energy is transmitted in the mean pressure. The optimal coupling efficiency (Ees/Ea) has been identified and is comparable for both sides of the heart. [131,132] Recently, there is increasing interest in PV loop analysis for PH because RV contractility is a more reliable way to differentiate the effect of therapies than mPAP.[84] In addition, the linkage between RV function and vascular function, which is characterized by coupling efficiency Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Figure 4: An illustrative example of vascular-ventricular coupling analysis from pressure-volume (PV) loops. Ventricular end-systolic elastance (Ees) and arterial effective elastance (Ea) are calculated from multiple loops by varying the preload.

(Ees/Ea), may reveal the mechanisms that differentiate physiological and pathological ventricular remodeling. During acute PH, the optimal ventricular-arterial coupling appears to be maintained regardless of species and the way in which PH is induced.[82] As effective afterload (Ea) increases, the ventricle increases contractility (Ees) such that optimal coupling (Ees/Ea) is maintained. However, such a balance may not exist in chronic PH due to both pulmonary vascular and right ventricular remodeling. Our recent study in mice demonstrated decreased pulmonary vascular–right ventricular coupling efficiency after chronic hypoxia.[132]

A potentially important consequence of PA wall stiffening may be impaired VVC efficiency via increased Ea. Optimal coupling between the RV and the pulmonary circulation in a healthy cardiopulmonary system is likely important to the adaptive response to acute stresses such as hypoxia or exercise. In conditions of impaired VVC, however, the RV may not be able to maintain cardiac output sufficiently to meet these challenges, leading to dysfunction and failure. 219

Wang and Chesler: Pulmonary artery stiffening in PH

Because very few studies have examined ventricularvascular coupling and pulmonary arterial stiffening concurrently, the linkage between changes in vascular and ventricular function is not established. For example, the arterial effective elastance (Ea) is thought to represent the RV afterload presented by the pulmonary vasculature. However, the influences of proximal arterial stiffness, distal arterial stiffness and distal arterial narrowing on Ea are not clear. Understanding the relationship between right heart function and pulmonary vascular remodeling will aid in discerning critical factors that are relevant to clinical outcomes of PH. Interactions between proximal and distal pulmonary arteries Finally, while there are different initiating mechanisms of PH (e.g., proximal occlusion and distal embolism), abnormalities in the upstream (proximal) and downstream (distal) PAs can affect each other via hemodynamics and result in a vicious cycle of remodeling (Fig. 3). In particular, large, conduit PA stiffening increases distal arterial cyclic strain damage,[133] which promotes SMC proliferation and narrowing. Increased flow pulsatility at distal arteries has been shown to induces inflammatory gene expression, leukocyte adhesion and cell proliferation in endothelial cells.[133] A similar mechanism has been demonstrated in the systemic circulation in which aortic stiffening causes damage to renal arterioles.[134,135] In turn, distal arterial narrowing increases mean pulmonary artery pressure, which dilates the proximal arteries, increasing circumferential stress and promoting SMC-mediated wall thickening,[12,136] which increase stiffness.[16-18,47]

SUMMARY AND FUTURE DIRECTIONS

It is vital to examine the structure-function relationship of pulmonary vascular system in the context of RV function, which predicts clinical outcomes and ultimately determines mortality in PH. Recently, pulmonary arterial stiffness has gained increasing recognition due to its clinical relevance to PH outcomes; however, studies that examine local properties such as stiffness typically do not quantify global cardiopulmonary function so the relationship between the two remains poorly defined. Studies that quantify impedance, as a more comprehensive metric of RV afterload, and vascular-ventricular coupling, to assess the efficiency of the whole cardiopulmonary system, are required to address this gap in our knowledge. Impedance provides insight into steady (distal) and pulsatile (proximal) components of the pulmonary hemodynamics; VVC measurements demonstrate the impact of pulmonary hemodynamics on RV function and vice versa. In addition, the role of arterial viscoelasticity in VVC efficiency remains to be determined. Furthermore, 220

at the cellular and molecular level, it would be useful to identify the cells and cellular signaling pathways that control PA stiffening and should be targets of treatment. Finally, a better understanding of the impact of pulmonary hemodynamics on RV function and vice versa may allow more accurate prognoses of RV failure. That is, the hemodynamic indicators of the transition from adaptive ventricular remodeling to maladaptive ventricular remodeling, the precursor of ventricular failure, may lead to better care and treatment for patients with PH.

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115. Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43 Suppl 12:13S-24. 116. Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 2008;118:2372-9. 117. Poiani GJ, Tozzi CA, Yohn SE, Pierce RA, Belsky SA, Berg RA, et al. Collagen and elastin metabolism in hypertensive pulmonary arteries of rats. Circ Res 1990;66:968-78. 118. Tozzi CA, Christiansen DL, Poiani GJ, Riley DJ. Excess collagen in hypertensive pulmonary arteries decreases vascular distensibility. Am J Respir Crit Care Med 1994;149:1317-26. 119. Merklinger SL, Wagner RA, Spiekerkoetter E, Hinek A, Knutsen RH, Kabir MG, et al. Increased fibulin-5 and elastin in S100A4/Mts1 mice with pulmonary hypertension. Circ Res 2005;97:596-604. 120. Peterson LH, Jensen RE, Parnell J. Mechanical properties of arteries in vivo. Circ Res 1960;8:622-39. 121. Tucker A, Migally N, Wright ML, Greenlees KJ. Pulmonary vascular changes in young and aging rats exposed to 5,486 m altitude. Respiration 1984;46:246-57. 122. Poiani GJ, Tozzi CA, Choe JK, Yohn SE, Riley DJ. An antifibrotic agent reduces blood pressure in established pulmonary hypertension in the rat. J Appl Physiol 1990;68:1542-7. 123. Leung DY, Glagov S, Mathews MB. Elastin and collagen accumulation in rabbit ascending aorta and pulmonary trunk during postnatal growth. Correlation of cellular synthetic response with medial tension. Circ Res 1977;41:316-23. 124. Shifren A, Durmowicz AG, Knutsen RH, Faury G, Mecham RP. Elastin insufficiency predisposes to elevated pulmonary circulatory pressures through changes in elastic artery structure. J Appl Physiol 2008;105:1610-9. 125. Madden JA, Vadula MS, Kurup VP. Effects of hypoxia and other vasoactive agents on pulmonary and cerebral artery smooth muscle cells. Am J Physiol 1992;263:L384-93. 126. Nagaoka T, Morio Y, Casanova N, Bauer N, Gebb S, McMurtry I, et al. Rho/Rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 2004;287:L665-72.

127. Saouti N, Westerhof N, Helderman F, Marcus JT, Boonstra A, Postmus PE, et al. Right ventricular oscillatory power is a constant fraction of total power irrespective of pulmonary artery pressure. Am J Respir Crit Care Med 2010;182:1315-20. 128. Mitchell GF. Pulse pressure, arterial compliance and cardiovascular morbidity and mortality. Curr Opin Nephrol Hypertens 1999;8:335-42. 129. Bernardo BC, Weeks KL, Pretorius L, McMullen JR. Molecular distinction between physiological and pathological cardiac hypertrophy: Experimental findings and therapeutic strategies. Pharmacol Ther 2010;128:191-227. 130. Sagawa K, Maughan L, Suga H, Sunagawa K. Cardiac Contraction and the Pressure-Volume Relationship: Oxford University Press; 1988. 131. Segers P, Georgakopoulos D, Afanasyeva M, Champion HC, Judge DP, Millar HD, et al. Conductance catheter-based assessment of arterial input impedance, arterial function, and ventricular-vascular interaction in mice. Am J Physiol Heart Circ Physiol 2005;288:H1157-64. 132. Tabima DM, Hacker TA, Chesler NC. Measuring right ventricular function in the normal and hypertensive mouse hearts using admittance-derived pressure-volume loops. Am J Physiol Heart Circ Physiol 2010;299: H2069-75. 133. Li M, Scott DE, Shandas R, Stenmark KR, Tan W. High pulsatility flow induces adhesion molecule and cytokine mRNA expression in distal pulmonary artery endothelial cells. Ann Biomed Eng 2009;37:1082-92. 134. O‘Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney: Cause and logic of therapy. Hypertension 2005;46:200-4. 135. O‘Rourke MF. Arterial aging: Pathophysiological principles. Vasc Med 2007;12:329-41. 136. Humphrey JD. Mechanisms of arterial remodeling in hypertension: Coupled roles of wall shear and intramural stress. Hypertension 2008;52:195-200. Source of Support: This work is in part supported by a grant from the National Institutes of Health (R01HL86939 to N.C.C) and a Postdoctoral Fellowship from the American Heart Association Midwest Affiliation (10POST2640148 to Z.W.), Conflict of Interest: None declared.

Staying in touch with the Journal 1) Table of Contents (TOC) email alert Receive an email alert containing the TOC when a new complete issue of the journal is made available online. To register for TOC alerts go to www.pulmonarycirculation.org/signup.asp. 2) RSS feeds Really Simple Syndication (RSS) helps you to get alerts on new publication right on your desktop without going to the journal’s website. You need a software (e.g. RSSReader, Feed Demon, FeedReader, My Yahoo!, NewsGator and NewzCrawler) to get advantage of this tool. RSS feeds can also be read through FireFox or Microsoft Outlook 2007. Once any of these small (and mostly free) software is installed, add www.pulmonarycirculation.org/rssfeed.asp as one of the feeds. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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Review Ar ti cl e

Computational models of the pulmonary circulation: Insights and the move towards clinically directed studies Merryn H. Tawhai1, Alys R. Clark1, and Kelly S. Burrowes2 1

Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand, 2 Oxford University Computing Laboratory, University of Oxford, Oxford, UK

ABSTRACT Biophysically-based computational models provide a tool for integrating and explaining experimental data, observations, and hypotheses. Computational models of the pulmonary circulation have evolved from minimal and efficient constructs that have been used to study individual mechanisms that contribute to lung perfusion, to sophisticated multi-scale and -physics structurebased models that predict integrated structure-function relationships within a heterogeneous organ. This review considers the utility of computational models in providing new insights into the function of the pulmonary circulation, and their application in clinically motivated studies. We review mathematical and computational models of the pulmonary circulation based on their application; we begin with models that seek to answer questions in basic science and physiology and progress to models that aim to have clinical application. In looking forward, we discuss the relative merits and clinical relevance of computational models: what important features are still lacking; and how these models may ultimately be applied to further increasing our understanding of the mechanisms occurring in disease of the pulmonary circulation. Key Words: physiome, finite element, heterogeneity

INTRODUCTION The pulmonary circulation is comprised of several scales of biological complexity: the genes, molecules, cells, and tissues that–as in any other organ system–work in concert to determine resultant function. The main function of the pulmonary circulation is to optimize the exposure of blood to alveolar air whilst maintaining a low enough resistance to accommodate passage of the full cardiac output. Malfunctions of structural components of the lung at any spatial scale can result in pulmonary vascular disease, to the detriment of gas exchange and right heart function. Vast amounts of data emerge from studies at each of these biological scales–particularly with the development of genetic and proteomic databases. The question then becomes, how can scientists integrate this data and knowledge across all of the biological scales to build on each new discovery and provide a collaborative advancement of knowledge that is greater than can be provided by Address correspondence to: Dr. Merryn H. Tawhai Auckland Bioengineering Institute University of Auckland Auckland, New Zealand Email: m.tawhai@auckland.ac.nz 224

studies at the individual scales? This integration of data and knowledge motivates the development of biophysically-based computational models in physiology. A mathematical model is a description of the behavior of a system using mathematical equations that describe physical processes, often in a simplified manner. (In the context of this review, the terms “mathematical model,” “computational model,” and “model” are synonymous and are used interchangeably throughout the text.) The use of such models in the biological realm is crucial to enable the integration and useful interpretation of data that results from experimental studies, and to provide an increased understanding of physiology. Computational models have been used to investigate problems across a wide range of disciplines. Computational Access this article online

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Website: www.pulmonarycirculation.org DOI: 10.4103/2045-8932.83452 How to cite this article: Tawhai MH, Clark AR, Burrowes KS. Computational models of the pulmonary circulation: Insights and the move towards clinically directed studies. Pulm Circ 2011;1:224-38.

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modeling is well established in, for example, engineering and weather prediction; but its application to biomedicine is more recent. The two major initiatives in this field are the International Union of Physiological Sciences Physiome Project (IUPS: see www. physiome.org.nz) and the European Virtual Physiological Human initiative (VPH: see www. vph.noe.eu). The IUPS Physiome Project aims to construct integrative biophysically-based models across the range of biological organization within and organism (genes, molecules, cells, tissue, whole organ), to provide an understanding of the structure-function relationships within a living entity.[1,2] The VPH initiative is Europe’s rendition of the Physiome Project and aims to develop predictive computational models of a living human body. [3] The ultimate drive of these initiatives is towards the clinical environment, to create personalized medicine aimed at increasing the efficiency of medical practice. The pulmonary vasculature in a typical human lung includes on the order of hundreds of thousands of arterial and venous vessels.[4-6] Gas exchange occurs across the thin walls of the alveolar capillaries, of which there are billions. The sheer number of vessels in this circuit–let alone the number of interactions at a cellular and sub-cellular level–means that numerous simplifying assumptions are required to enable construction of computational models. What is important to bear in mind is that a mathematical or computational model does not seek to represent each and every feature of an organ system. Such “mathematical microscopy” would do little to enhance understanding of function in the integrative system. A well designed model includes only the minimum information that is necessary to interpret a set of experimental data, or to test a specific hypothesis–for example, a modeling study of the distribution of humidity in the airways would not benefit from including the pulmonary circulation or the distal airways in the model, but it could be improved by coupling to distributed models of fluid transport through the ciliated epithelial cell.[7] Mathematical modeling of lung function has historically provided an important contribution to the understanding of pulmonary health and disease. The lung is a complex organ that works dynamically and reacts rapidly to changes in posture, environment and disease. Yet understanding of its different functions has been improved by using simplistic qualitative and quantitative models to explain inhaled gas transport,[8,9] respiratory gas transfer,[10] and pulmonary blood distribution,[11] amongst others. The continued increase in computational capability and the advancement of knowledge in related areas such as mathematics, computer science, image processing, biology and medicine has led, and is leading, to the development of ever more complex computational models in biomedicine. These advancements have made possible the creation of detailed anatomically-based models of the pulmonary airway and Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

vascular geometries.[12,13] This has enabled the solution of functional model equations within geometries that closely resemble the structure of a real lung, with the goal of understanding structure-function relationships, their spatial distribution, and inter-subject and inter-species variability. But how complex does a model need to be for it to provide useful information about physiology? The answer to this is dependent on the functional aspect of the pulmonary circulation that is being investigated. For example, do we want to investigate heterogeneity in lung function; or are we interested in whole lung measures? Are we modeling a diffuse or localized disease state? Are we interested in small- or large-scale function?

Models that use simple geometries and few equations are easier to understand intuitively than complex multiphysics and multi-scale models. The complex models also suffer from the perception that they have “too many free parameters” in comparison to the simple models. By and large, however, the situation is quite the reverse. The simple models rely on lumping together the detailed laws and principles that govern function in the lung, so these types of model often have to fit parameters that don’t have a specific physical meaning. An example is the Starling resistor model of the pulmonary circulation used by Mélot et al.[14] compared with their distensible vessel model, which is more strongly based on physical principles. In contrast, in the class of biophysicallybased models, each functional equation is a physical law with parameters that have a specific physical meaning. The model parameters are either well defined (e.g., viscosity of blood in the major arteries), estimated from experimental studies as invariable throughout the model (e.g., arterial wall elasticity), or poorly defined but still with a physical meaning that can be easily interpreted and quantified when experimental measurements become available. While a complex model may include explicit representation of each artery and vein in the pulmonary circulation, only a small set of equations with exactly the same parameters govern function within them; that is, the equations for flow, pressure, and vessel elasticity are identical at all levels of the trees. It is therefore exceedingly difficult to simply modify parameters in this type of model to better fit some functional outcome. The insights from a biophysically-based model often come from identifying how the model doesn’t fit some data–this can indicate the importance of otherwise neglected mechanisms in contributing to the integrated function of the lung. Structure-based modeling provides a non-invasive approach to investigation of function, particularly when intervention is not possible in clinical studies due to ill health. Predictive models are powerful tools for interpreting experimental measurements and forming new testable hypotheses. An example is the use of 225

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appropriate computational models in conjunction with imaging modalities, each method acting as a means to verify and guide the other. For example, functional imaging data can be compared with model predictions of flow in large arteries, thereby validating some of the function of the model. The model predictions can then be used to postulate the flow distribution in smaller vessels, which are not directly visible on clinical imaging, or to investigate conditions that are difficult to investigate using imaging alone, such as the differences in perfusion distribution in the upright posture compared with the more readily imaged prone and supine postures. A model may also be used to help interpret results from functional imaging studies, if the quantities being measured are uncertain. Computational models may also be used to obtain quick predictions of the functional consequences of certain changes in vascular geometry, for example the effect of pulmonary vasoconstriction, pulmonary embolism, or pulmonary hypertension, for individual subjects. To understand pulmonary disease and abnormal function first requires a thorough understanding of the mechanisms contributing to function in the “normal” healthy pulmonary circulation. Therefore, constructing physiologically realistic models of the normal pulmonary circulation has been a priority. These models must be validated–that is, compared with clinical or experimental data–before they can be used to investigate how perturbations to normal function manifest in disease. Validation remains the central challenge with this type of model, because the specific data that would provide a robust validation are often inaccessible to measurement. Studies of the pulmonary circulation generally aim to gain increased understanding of the mechanisms impacting on pulmonary vascular resistance (PVR), blood flow distribution, or the impact of alterations in pulmonary blood flow on gas exchange efficiency. Here we describe examples of models of the normal pulmonary circulation that have been used to investigate baseline function. We then discuss an example of model application in a clinically motivated problem: understanding the redistribution of blood flow and development of pulmonary hypertension in pulmonary embolism.

USING COMPUTATIONAL MODELS TO DEVELOP NEW INSIGHTS INTO THE BASIC FUNCTION OF THE PULMONARY CIRCULATION

Predicting pulmonary vascular resistance and pulmonary blood pressures

In the healthy adult lung the pulmonary vascular resistance (PVR) is low, allowing delivery of the entire cardiac output 226

with a relatively low right ventricular (RV) pressure (compared with left ventricular pressure). Total PVR can be calculated as the difference between mean pulmonary artery (PA) and mean left atrial (LA) pressure, divided by the cardiac output (where LA pressure is approximated by pulmonary wedge pressure). Because flow, pressure, and resistance are interrelated, elevation of PVR results in elevated RV pressure if the cardiac output is to be maintained. The lung has an in-built protective mechanism against elevation of PVR in the form of recruitment of capillaries and, to a smaller extent, distension of the elastic vessels comprising the circuit.[15] Under resting conditions a substantial portion of the capillary bed is un-recruited;[16] some or all of the de-recruited capillaries can open when cardiac output increases—and presumably under other conditions that elevate PA pressure—to increase the total cross-sectional area of capillary bed through which the blood traverses, and concomitantly decrease the PVR. The functional consequence is that during exercise in the healthy individual–when the cardiac output can increase six-fold–PA pressure increases only moderately.[17] When capillary recruitment is insufficient to prevent PVR rising above a critical level, this impacts on right heart function and capillary wall integrity, and potentially fluid filtration and edema formation will occur. Several modeling studies have investigated the relationship between vessel dimensions, vessel elasticity, and PVR. Most have taken a highly simplified approach to model geometry and fluid dynamics, which is sufficient for demonstrating the importance of vascular geometry and distensibility on pressure-flow relationships, and therefore on PVR. Perhaps the simplest approach to modeling blood flow in a complex vascular network is to represent the fluid flow as analogous to a current in an electrical circuit: if flow is steady then the analogue of a direct current (DC) circuit is used, and if flow is pulsatile the analogue of an alternating current (AC) circuit is used. Using the DC circuit as an example, Ohm’s Law states that the voltage drop (ΔV) across a circuit is equal to the current through the circuit (I) multiplied by the total resistance (R), so ΔV=IR. Similarly, in a steady fluid flow the pressure drop (ΔP) across a system of blood vessel ‘resistors’ is equal to the flow through the system (Q) multiplied by the total resistance (ΔP=QR). Most mathematical models of the pulmonary circulation use the electrical circuit analogy (e.g., references 18 through 22), but differ in two major features: (a) the structural representation of the blood vessels, which influences the estimation of the total resistance to blood flow; and (b) whether the model uses an AC or DC circuit analogy (so whether it includes or neglects the pulsatility of blood flow, respectively). The most simplified approach to representing the vascular structure and hence estimating the distribution of vascular Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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resistance is to assume that the pulmonary blood vessels are a symmetrically branching tree. Total resistance can then be calculated as the series and parallel summation of the individual vessels/resistors: because all blood vessels in a single generation of a symmetric tree are identical and act “in parallel,” their combined resistance is calculated as the individual resistance divided by the number of vessels in the generation; and the total resistance is simply the sum of the resistances of each generation. An advantage of the symmetric approximation is that because all pathways from the PA to the pulmonary veins are identical, the whole vasculature can in effect be treated as a single pathway. Dawson et al.[23] used this type of mathematical model of the pulmonary arterial tree to investigate the effect of vascular geometry and vessel mechanics on the mean pressure-flow relationship and longitudinal pressure profile. This study aimed to use the experimental data available at the time of the study to construct a range of possible hemodynamic outcomes. They found that hemodynamics were sensitive to both the elasticity of blood vessels (highlighting the possible role of disease in affecting elasticity) and the rate of change of vessel diameter from the main PA to distal blood vessels. While symmetric models are convenient and computationally inexpensive, they are very limited in the studies to which they can be applied. For example, any study in which the spatial distribution of a structural or functional property of the pulmonary circulation is important cannot use a symmetric tree model. Zhuang et al.[22] considered more complex branching structures that statistically matched (the same) morphometric cat lung data and–by assuming that blood flow was equally divided through vessels of the same Strahler order (and so simplifying the resistance calculations)–they studied the pressure-resistance-flow relationships within two different geometric structures. They found that both of their model structures provided similar predictions, and their predicted pressure-flow relationships and the blood pressure distribution through the models had some consistency with experimental data. The distribution of pressure drop in the models is illustrated in Figure 1(a). The most significant decrease in pressure occurred across the capillary bed. However, they concluded that some important physiological data was lacking in areas where their model did not match the experimental data. For example they could not match the data well when the airway or pleural pressure was altered from its baseline value. In short, they concluded that an interaction between experiment and modeling was required to fully describe the pulmonary circulation. A non-symmetric extra-alveolar tree structure was considered by Bshouty et al.[24,25] (Fig. 2), with each blood vessel’s resistance set independently. Their study differed from that of Zhuang et al. in its asymmetry within blood Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Figure 1: Blood pressure drop across four models with symmetric large vessels. [a] Zhuang et al.[22] Curves (1 and 2) show pressure drop across two models that statistically match the same morphometric data. Capillary beds join arteries and veins in parallel. [b] Clark et al.[29] Model A (red) joins large vessels similarly to Zhuang et al.; Model B (black) joins arteries and veins via a ladder model for combined series and parallel perfusion of capillary sheets. Figure sources: [a] redrawn from Zhuang et al.;[22] [b] from Clark et al.[29], used with permission.

Figure 2: The DC circuit representation of the pulmonary blood vessels reproduced from Bshouty et al. Each blood vessel is represented by a “resistor” with a unique resistance adding heterogeneity to the flow through each order of blood vessels. However, computational constraints prevented the construction of a model with more than four orders of arteries and veins. Redrawn from Figure 1 in Bshouty et al.,[25] used with permission.

vessel generations as well as including an upper bound for vessel distensibility with pressure. The model asymmetry complicates the calculation of resistance, so this study 227

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restricted the vessel tree to only 4 Strahler orders (compared with Zhuang’s 11-17). They investigated whether non-linearity in pressure-flow curves were a result of vessel distensibility or recruitment, and concluded that recruitment was likely the dominant factor. Each of these modeling studies assumed a steady blood flow (DC circuit analogue), which is considered a valid assumption in many models of the pulmonary circulation. [26] A class of pulsatile flow models also exists. The models are based on Zhuang’s geometrical approach and an AC circuit analogy to describe blood flow[18,19,21] in dogs, cats and humans. These models give additional temporal information compared with steady models. This additional information may be useful in some studies, for example in estimating the rate of change of shear stress at the endothelium due to the pulsatile blood flow. However, to date they have not been used widely outside the context of normal pulmonary function.

The models described above take a simplifying approach to both fluid dynamics (the movement of blood through the lungs) and geometry. Therefore, they have the distinct advantage that they can be solved quickly and easily to study normal function or disease which manifests in a reasonably uniform manner throughout the vasculature. An alternative to this simplifying approach is threedimensional computational fluid dynamics (3D CFD). This approach aims to solve the most accurate equations in the most anatomically correct model geometries possible. Unfortunately, the equations that govern fluid (blood) flow–the Navier-Stokes equations–are very difficult to solve, especially when the flow is turbulent. This means that application of 3D CFD to compute pulmonary blood flow requires substantial computing power, and model geometries are usually restricted to a small subsection of the vasculature. However, the accuracy of these models allows investigation into shear-stress distributions along vessel walls, and blood flow characteristics within a vessel itself. Tang et al.[27] used 3D CFD to model blood flow in the central pulmonary arteries and provided detailed predictions of wall shear stress and energy efficiency in these blood vessels at rest and in exercise. Their vessel structure was constructed from MRI images and so provided a very accurate geometrical description of the central blood vessels, compared with the simple cylinder (non-elastic) or tapered cylinder (elastic) representation of a blood vessel that is required in 1D models. They predicted a non-uniform blood flow distribution within these vessels and determined that there was a 10% reduction in energy efficiency between rest and exercise conditions, noting that this may have implications for the long term results of surgical procedures. In addition they predicted wall shear stress over the entire surface of these vessels–a finding that is interesting in the context of vasodilation, where shear 228

stress acts as a mechanical stimulus for the release of nitric oxide (NO). The major limitation of this field of modeling is that only a small subset of pulmonary blood vessels could be explicitly included, resulting in major assumptions concerning the behavior of the downstream blood vessels. In other studies by this group,[28] they have proposed a morphometry-based boundary condition to mimic the impedance of the downstream vasculature. Each sub-tree appending a 3D discretized artery has its parameters “tuned” such that the whole model has impedance that is appropriate for the intact pulmonary circulation. This is an important step in acknowledging the contribution of the downstream vasculature is determining the distribution of blood through the largest vessels, however this cannot account for the interaction between tissue mechanics, gravity, and blood flow, and how this changes with posture or increased cardiac output.

The models that have been introduced so far have neglected the intricacy of structure in the pulmonary microcirculation. Whether symmetric or asymmetric, the arteries and veins were assumed to be joined by a capillary bed that was perfused strictly in parallel. That is, a unit of capillary sheet that was supplied by a symmetrically branching set of arterioles. This neglects the morphometric structure of the pulmonary microvasculature, where small pre-capillary blood vessels arise from Strahler ordered arteries with order as high as 8;[6] small arterioles feed into the capillary plexus, as well as supplying daughter arterioles. Recognizing the importance of the anatomical geometry in determining the distribution of intra-acinar flow and resistance, Clark et al.[29] developed a microcirculatory model with a “ladderlike” structure. As shown schematically in Figure 3(a), each “rung” on the ladder represents the

Figure 3: Ladder model by Clark et al. In this ladder model of Clark et al.,[29] arterioles are in blue, venules in red, and capillary beds in purple. Arrows show direction of capillary blood flow. The schematic in Panel A illustrates the concept of the ladder model. This was the first computational model to include the serial and parallel capillary pathways. Panel B illustrates the ladder model implemented over a multi-branching asymmetric model of the human pulmonary acinus, from Clark et al.[32] Figure source: Reprinted from Clark et al.,[32] with permission from Elsevier; Panel A from Clark et al.,[29] used with permission. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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alveolar septae at a separate generation of a symmetrically branching tree. One set of “posts” on the ladder are the feeding arterioles, and the matching set of posts are the draining venules. The ladder model therefore includes combined series and parallel perfusion, where blood can either progress to the next generation of arterioles, or enter the capillary bed and pass to the venules without having to traverse the entire length of the intra-acinar arteriole tree. Coupling the symmetric ladder model to symmetric models for the arteries and veins confirmed earlier experimental observations of a stratified acinar blood flow from proximal to distal capillary beds.[30,31] The model also demonstrated that the hierarchical structure of blood vessels within the acinar unit pathways significantly decreases PVR when compared with capillary beds that connect only the most distal blood vessels. Figure 1(b) shows the pressure drop predicted through the symmetric large vessel and ladder model, compared with pressure drop in a model with symmetric arterioles supplying only a single distal capillary sheet. The number and size of the arterioles can be modified to give a similar prediction of pressure drop between the two models; however, the dimensions and effective numbers of these intra-acinar arterioles is unrealistic. Clark et al.[32] extended the model to an asymmetric acinar structure, showing heterogeneity in blood flow even at the level of the intra-acinar blood vessels.

The resistance of individual vessels depends on their size, which in turn depends on their hierarchy within the pulmonary circulation, and their location within the lung. And because of the hydrostatic pressure gradient, blood pressures vary considerably depending on the vascular pathway that blood traverses from the right to the left heart. Clark et al.[33] developed a subject-specific anatomically-based model for the entire pulmonary circulation that can be used to predict the distribution of vascular resistances and the pressure fluctuations along individual pathways. The model geometry is anatomically-based in that it captures the branching asymmetry of the extra-acinar pulmonary blood vessels and the spatial relationship between blood vessels and lung parenchymal tissue. It is subject-specific in that it describes the lung shape, the distribution of the largest blood vessels and the regional tissue density measured from multi-row detector computed tomography (MDCT) data in an individual. Additional modeling methodology was used to supplement the model from the level at which the imaging data had insufficient resolution. The model includes anatomically-based geometry of the lung surface and central blood vessels; computationallygenerated morphometrically-consistent models of the “accompanying” arterial and venous vessels (i.e., not including supernumerary vessels[34]) to the level of the acini;[13] a ladder model[29] attached to each of the ~32,000 Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

acini, consisting of 9 symmetric branches of intraacinar arteries and veins coupled in a serial and parallel arrangement through a ‘sheet’ flow representation of the pulmonary capillaries;[35] and a model of parenchymal tissue deformation,[36] to which the vascular networks are tethered. The anatomically-structured models for the pulmonary arteries and veins are illustrated in Fig. 4. Blood flow through the entire circuit of arteries, capillaries, and veins can be simulated after applying boundary conditions for pressure or flow at the level of the heart. Then by solving equations for Poiseuille resistance, conservation of mass, vessel elasticity, and a microcirculatory model–including gravity–predictions can be obtained for the regional distribution of blood flow, blood and transmural pressures, capillary recruitment, and vessel radius. Blood within the larger vessels is assumed to be Newtonian, however in the microcirculatory vessels the shear-thinning properties of blood are accounted for via an apparent viscosity parameter in the model equations.

Figure 5 shows the pressure variation through three pathways in the spatially-distributed model. The capillary pressure in each pathway is inversely proportional to the location of the tissue with respect to gravity: blood pressure upon entering the capillary bed is least in the non-dependent lung and greatest in the dependent lung. This can be explained by the larger hydrostatic pressure in the most dependent tissue. In contrast to the single pathway (symmetric) models where blood

Figure 4: Anatomically structured model of the human pulmonary circulation by Burrowes et al. The pulmonary arteries are colored red, and the pulmonary veins are colored blue. The geometry of the first 10-12 generations was manually segmented from MDCT imaging. The remainder of the vascular trees were generated using a volume-filling branching algorithm. Figure source: Burrowes et al.,[13] used with permission. 229

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Figure 5: Variation in pathway blood pressure from right to left heart in the full-circuit model. Vertical lines show the capillary bed, where the greatest pressure drop occurs. Results differ substantially from previous models (Fig. 1), which show continuous blood pressure drop. In contrast this illustrates the influence of the hydrostatic pressure gradient, with pathways to non-dependent (A) tissue having decreasing arterial blood pressures and increasing venous pressure, while pathways to the dependent tissue (C) having increasing arterial pressures and decreasing venous pressures.

pressure systematically decreases, the three pathways in Figure 5 illustrate a deviation from this, with increase in blood pressure in the arteries of the dependent pathway, and in the veins of the non-dependent pathway. This occurs again as a consequence of the hydrostatic pressure gradient, and is influenced by the orientation of the vessels as they traverse to the parenchymal tissue. Pathways that are oriented towards the non-dependent tissue experience pressure loss due to friction on the vessel walls (energy dissipation) plus decrease in the hydrostatic pressure; pathways that are oriented towards the dependent tissue experience the frictional pressure loss, but have added increase in hydrostatic pressure. The vessel sizes are determined by transmural pressure (the difference between blood pressure and external pleural pressure acting on the vessel); in regions where blood pressure is smallest, the magnitude of pleural pressure is greatest, and vice versa for locations where blood pressure is larger. Vessel size is therefore dependent on spatial location and the distance that the vessel sits along the flow pathway.

The spatial distribution of blood in the lung

Early experimental studies suggested that gravity was the primary determinant of blood flow distribution in the lung, due to the hydrostatic pressure gradient affecting the balance of forces at the capillary level and hence allowing or limiting flow.[11] The classic “zonal” description of blood flow distribution is therefore gravitationally dependent, with lung tissue in the non-dependent region (apices of the upright lung) receiving proportionately less of the cardiac output than tissue in the dependent region (base of the upright lung). The zonal model has persisted as the primary hypothesis for the distribution of pulmonary perfusion for over 30 years. More recent studies have highlighted irreversibility of the flow gradient with reversal of posture,[37] and large iso-gravitational heterogeneity of flow,[38] both of which are inconsistent 230

with a purely gravitational theory for flow distribution. These and other studies[37-41] have suggested that other factors play as much of–or even more of–a role in determining pulmonary blood flow distributions than the hydrostatic effects of gravity. For example, recent imaging studies have suggested that the influence of gravity on the regional distribution of blood flow in the lung is largely through the deformation of the parenchymal tissue[40-42] (the lung acting as a SlinkyTM), rather than via the balance of pressures at the microcirculatory level, as described by the classic zonal model. The anatomical geometry of the lung and vasculature have also been proposed to be important contributors.[38,43] The potential contribution of each mechanism has become a strongly debated issue. [44,45] What is clear is that reconciling data from different imaging or experimental studies is difficult–perhaps impossible–without a predictive, quantitative framework in which to test the different mechanisms that contribute to perfusion. Here we describe a fractal modeling approach that has been used to study an individual mechanism, and explain a recent physiologically-based computational model that seeks to reconcile data from different experimental studies, and to estimate the contribution of individual mechanisms when acting integratively in a single functioning lung.

An important feature of pulmonary blood flow distribution is the large degree of heterogeneity that is observed within isogravitational planes. This heterogeneity is accompanied by a spatial correlation in perfusion (high blood flow regions neighboring high blood flow regions and vice versa), which again occurs within isogravitational planes, suggesting a structural influence on pulmonary blood flow distribution. These observations have led to the construction of fractal models to describe pulmonary blood flow.[46] The fractal approach assumes that each vessel bifurcation (which includes a parent and two daughter branches) is a simple scaling of the previous bifurcation; that is, the fractal tree has self-similarity. The fractal branching models relate one aspect of structure to one aspect of function of the pulmonary vascular tree. The fractal model is sufficient for explaining how asymmetry in flow distribution at a bifurcation can result in perfusion heterogeneity at the tissue level. They also provide a mechanism to describe the spatially correlated distribution of flow and the gravity-independent heterogeneity of blood flow.[46-50] The interaction between theoretical fractal models and experimental validation has provided an insight into the importance of blood vessel structure to pulmonary blood flow distribution that was not attainable via experiment alone. However this is an examination of a single mechanism, without interaction with tissue mechanics or the constraint that is introduced by the microvasculature. A further limitation is the basis for the fractal models: the assumption of self-similarity Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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may hold on average, but there is marked variability in parent to child diameter ratios at all levels of the vascular tree, spatial variability in vessel dimension due to the regional differences in transmural pressure, and potentially major differences in structure and function between the accompanying (conventional) vessels and the supernumerary vessels[34] that would violate the assumption of self-similarity.

An alternative to the fractal approach to modeling blood flow is to construct anatomically-based models of the pulmonary vasculature and to solve equations describing blood flow within these geometries.[13,28] This type of model captures the structural aspects of the lung that lead to blood flow heterogeneity, and can accurately represent the hydrostatic effects of gravity and deformation of parenchymal tissue–ultimately allowing the relative contribution of each to perfusion distribution to be assessed. Anatomically-based models suffer from a high computational cost (unlike fractal models). However, advances in computational power have allowed rapid progression from models of blood flow in the arterial tree alone,[51] through coupling to a model of lung tissue deformation under gravity,[52] to a model that can describe the distribution of pulmonary blood flow though the full pulmonary circuit coupled to deformed tissue.[33] Using this modeling approach, one can investigate the effects of structure alone (heterogeneity and a reduction in blood flow through high resistance paths), hydrostatics (inducing a gravitational gradient in blood flow) and tissue deformation (increasing/decreasing gravitational gradients depending on lung size and posture).[33] This is achieved by ‘switching’ model components on and off–a task that can be achieved far more easily in a computational model than in a biological organism. The contribution of each of these factors–as revealed by a computational modeling study–is considered below. Clark et al.[33] developed an anatomically-based model of blood flow through the full pulmonary circuit of a single human subject coupled to a model of parenchymal tissue mechanics[36] to study the interdependence of structure, fluid transport, and mechanical behavior in perfusion of the lung. This complex multi-scale and multi-physics model is currently the only model in the literature that simultaneously includes all of the basic passive mechanisms that influence the distribution of blood flow in the lung. The model built upon previous structure-based models for perfusion[13,51-53] by coupling anatomically based pre-acinar geometries (representing the largest pulmonary arteries and veins) with the ladder model for perfusion in the pulmonary acinus,[29] as described in the previous section. Each artery, vein, or capillary is embedded within a model of the deforming parenchyma[36] such that the vessel-by-vessel transmural Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

pressure has an appropriate dependence on vessel blood pressure and the local elastic recoil pressure of the tissue (elastic recoil pressure is approximately equal and opposite to pleural pressure), and in the case of the capillaries the additional dependence on local air pressure. The coupling of models describing the microcirculation in an anatomically-based large vessel structure enables application of readily measurable pressure and/or flow boundary conditions at the heart rather than at the micro-circulatory level as previous anatomically-based models had been constrained to do. [13,51-53] Previous modeling studies of the relative influence of gravity and structure[13,52,54] considered perfusion of the arterial tree in isolation from the structure of the capillary bed or veins, instead using a linear increase in acinar blood pressure with decrease in gravitational height, hence each acinus within a single isogravitational plane was assumed to have the same blood pressure. The full-circuit model removes the necessity for this simplifying assumption, which allows more meaningful predictions of pulmonary perfusion gradients and heterogeneity than has previously been possible from this type of computational model. That is, by including the structure of each level of vessel in the circulatory tree, simulations of perfusion only require setting cardiac output and LA pressure, and selecting the orientation of the lung with respect to gravity. The “full-circuit” model is a comprehensive tool for studying the integrated function of the pulmonary circulation, and provides the only tool for teasing apart the individual contributions of the various passive mechanisms that are at play. Clark et al.[33] specifically addressed whether tissue deformation is the major contribution of gravity to the pulmonary perfusion gradient in the human lung, whether the hydrostatic pressure gradient makes a quantifiable contribution, and whether the balance of pressures at the micro-circulatory level remains a significant feature in the presence of other mechanisms of gravitational origin. The vascular trees are tethered to the parenchymal tissue, which is highly compliant and deforms readily in gravity due to its own weight. In the upright lung the gradient of deformation is in the cranial-caudal axis, with tissue near the base on average less expanded than tissue near the apices.[40,41] Note that the word “compression” is often misused in this context, with many authors and textbooks describing the lung tissue as “compressed” in the dependent region rather than “less expanded.” A material that is in compression has restoring forces that will act to return it to a more expanded state; in contrast the parenchyma in the dependent tissue is in tension, just to a lesser degree than the parenchyma in the non-dependent regions. Understanding this distinction is important when studying the mechanical deformation of the lung tissue. The study of Clark et al.[33] found that postural differences in perfusion gradients could be attributed largely to tissue 231

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deformation. Unlike previous findings in models of the ovine lung,[53] the orientation of the vascular structure with respect to gravity had little effect on perfusion gradients in the human lung. That is, the vascular structure did not contribute significantly to a persistence of the flow distribution pattern. Tissue deformation in the model supported experimental studies that describe the lung tissue as acting as a Slinky that deforms under gravity and hence changes the density of blood vessels and capillaries per unit volume,[40,41] but the model also added new insight into the individual contribution of each mechanism beyond the Slinky hypothesis. Each structural and gravitational feature of the pulmonary circulation was found to make a distinct contribution to the distribution of blood. Postural differences in perfusion gradients were explained by the combined effect of tissue deformation and extra-acinar blood vessel resistance to flow in the dependent tissue. The model also showed that gravitational perfusion gradients persisted when the effect of tissue deformation was eliminated, highlighting the importance of the hydrostatic effects of gravity acting directly on the weight of the blood (imagine a solid, non-deforming parenchyma with a vascular tree that contains blood). Heterogeneous large vessel resistance (due to geometric asymmetry of the vascular trees) was shown to cause variation in driving pressures across the microcirculation. This variation was amplified by the complex balance of pressures, distension, and flow at the micro-circulatory level. That is, the normal variation in resistance pathways of the vascular tree were found to result in isogravitational heterogeneity of flow and pressures at the entrance and exit of the microcirculation of each acinus. This heterogeneity was amplified by the zonal model, which considers the balance of arteriole, venule, and alveolar pressures, and the extent of local alveolar stretch. The influence of the vascular asymmetry combined with the zonal effect was enhancement of the isogravitational heterogeneity of tissue perfusion. The contribution of these mechanisms is summarized in the schematic in Fig. 6. An important outcome of the modeling study was the

Figure 6: Schematic of contributions to distribution of blood. Vascular asymmetry contributes to heterogeneity, and decrease in perfusion in the extremities; hydrostatic pressure gradient acts directly on blood to drive it preferentially downwards, and introduces a constraint at the capillary level; deformation of tissue establishes a gravitational gradient of vessels per unit tissue, enhancing the flow gradient; also contributes to reduction in flow in most dependent region; combined result is a gravitational gradient and isogravitational heterogeneity, each affected by multiple mechanisms. 232

ability to reconcile the experimental measurements that formed the basis of the zonal model with more recent studies using higher resolution (microsphere) techniques, and even more recent imaging studies that demonstrated the importance of tissue deformation. The model showed that each theory can co-exist within the same structure, and that each makes an important and distinct contribution to the distribution of blood flow. The model encapsulates each of the theories related to microcirculatory pressures, vascular geometry, and tissue deformation, and shows that these can be predicted on the basis of the physical behavior of the pulmonary circulation. This is only predicted however when structure and function are considered in parallel: a model with symmetric geometry (neglecting vascular asymmetry) or lacking a realistic spatial distribution of blood vessels (so neglecting the interaction with the deforming tissue) would only recognize the contribution of the hydrostatic pressure gradient.

Species differences in perfusion distribution

Experimental measurements of pulmonary perfusion are more easily obtained in animal studies than human. High resolution methods using microspheres are destructive, hence can only be used in animals, and MDCT imagingâ&#x20AC;&#x201C; which gives highest resolution for lung tissueâ&#x20AC;&#x201C;requires radiation exposure, so must be used minimally in humans. However humans have quite different vascular branching asymmetry to most other mammals, and this could influence the translation of outcomes from animal experiments to human physiology and pathophysiology. Species-specific branching and diameter asymmetry in the vascular trees of the lung has been well documented.â&#x20AC;&#x2030;[6,55] The quadruped pulmonary arteries and veins branch monopodially (a parent vessel gives rise to a major branch with relatively large diameter at a small branching angle to the parent, and a minor branch with relatively small diameter at a large branching angle). If the supernumerary arteries and veins are neglected, then the human pulmonary vascular trees are relatively more symmetric than in the quadruped lung. Various measurements of pulmonary perfusion gradients in animals and humans in different postures and at different lung volumes[38,40,41,47,56-60] have suggested differences between quadruped and human pulmonary perfusion gradients. [45] Burrowes et al.[53] used species-specific computational models of the pulmonary vasculature to study whether species differences in vascular asymmetry were sufficient to produce characteristic differences in pulmonary perfusion gradients in the human and ovine lung.

Species-specific models were derived from MDCT imaging, using the lung and lobe shapes as boundary conditions and the MDCT-segmented arteries as initial conditions for generating a volume-filling tree to Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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represent the pulmonary vasculature of each species.[53] The governing equations, method for numerical solution, and parameters in the two species models were the same. The only difference was in the branching pattern and branch diameters. This meant that any predicted difference in flow distribution was due to species-specific pulmonary arterial geometry. The regional distribution of perfusion in the ovine model was consistent with microsphere measurements in supine pig[47] and dog[61] lungs. The microsphere measurements showed the same characteristic distribution as the model, with flow lowest near the ventral and dorsal surfaces, and maximum at about 40% (dorso-ventral) height. Perfusion gradients in both species were smaller than those measured via imaging, which was likely due to neglecting tissue deformation in the model. Importantly, in both the model (after exclusion of decreasing flow in zone 4) and in experimental studies, animal perfusion gradients were generally larger than in human. The model predicted only a modest change in flow gradient with posture (supine to prone), similar to measurements from Glenny et al.,[47] suggesting that the arterial structure has a persistent effect on regional perfusion regardless of posture. When the ovine model was supine there was large flow resistance in the dorsal pathways that acted to reduce the flow in this region; the human dorsal pathways provided relatively less resistance than those to the ventral tissue, so there was a smaller reduction in flow.

A species comparison such as this is clearly only possible using a structure-based model that accounts for the species-specific morphometry of the vascular trees. Sheep and other quadrupeds with monopodially branching pulmonary vasculature are more frequently used as experimental animals in studies of lung function than primates, whose lung geometry is most similar to human. Sheep, pigs, and dogs are variously described as having lungs that are ‘similar to human’. While this may be true of lung size, and distribution and density of some cell and receptor types, it is not correct with respect to the tree geometries of the airways and blood vessels. The monopodial animal vasculature has markedly greater asymmetry of child vessel diameters than in the human lung, so greater potential for the vasculature to contribute to flow heterogeneity. The animal pulmonary vasculature also has long wide vessels that extend to the dorsaldiaphragmatic region. The modeling study demonstrated the consequence of these geometric differences on distribution of blood flow. Important species differences were highlighted that need to be accounted for when interpreting animal measurements in the context of human lung physiology. One caution is that the modeling study of Burrowes et al.[53] did not explicitly couple the arterial tree to the geometries of the capillary bed and venous tree, as in the later study of Clark et al.[33] Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Interesting future extensions to this work would be in considering smaller animals that are used as genetic models for disease, such as rats and mice. The same methodologies and governing equations apply, only now working with a smaller sized organ.

CLINICALLY DIRECTED MODELING STUDIES

Models describing pathophysiology in the pulmonary circulation are fewer in number than those describing normal physiology. However, they have been able to provide useful insights into disease and provide advances towards improving clinical practice. In 1999 Taylor et al. [62] proposed that surgical planning could be improved via predictive medicine. That is, that a simulation-based set of tools that could predict patient outcomes and test hypotheses would allow better surgical planning than diagnostic imaging and empirical data based on past treatments alone. The concept of predictive medicine is not restricted to the surgical arena; it can be–and should be–used in developing diagnostic procedures and treatment strategies for acute and chronic illnesses. Here we describe models that aim to advance understanding of the development of pulmonary hypertension (PH) in the presence of vascular obstruction.

Pulmonary embolism

Thromboembolic pulmonary embolism (PE) is a relatively common clinical condition that can result in acute or chronic elevation in PA pressure, thereby inducing secondary PH. Clinically, acute PE is poorly diagnosed and is responsible for many thousands of deaths each year.[63] If left untreated, chronic elevations in PA pressure may lead to RV hypertrophy (cor pulmonale) and ultimately to RV failure. PE is difficult to diagnose because of its range of symptoms and clinical features, and the response to acute PE is heterogeneous. The capability of stratifying risk amongst PE patients is therefore vital to enable optimal management.[64] PE is also often used to induce PH in animal models,[65] either by instilling inert beads, inflating a balloon catheter to obstruct an artery, or injecting autologous blood clots.

Arterial thromboembolic PE have been proposed to raise PA pressure by two mechanisms: first, by mechanical obstruction of the arterial tree, reducing the effective size of the vascular tree so elevating PVR; and, second, by release of vasoactive mediators (for example, serotonin and thromboxane A 2) from the blood clot, causing vasoconstriction and an increase in PVR.[66-68] There is some uncertainty as to the action of the second mechanism in the human pulmonary vasculature. It is clear clinically that while patients can tolerate occlusion of a major PA 233

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by a passive obstruction (such as a balloon catheter) or indeed removal of an entire lung, thromboembolic obstruction of a far smaller proportion of the vascular tree can result in RV failure via elevated PVR and PA pressure.[69,70] Many animal studies have demonstrated that PVR is far more sensitive to vascular occlusion by a thrombus than by a passive occlusion (e.g., references 65 through 67); others have demonstrated elevated levels of vasoactive mediators in the circulation in the presence of a blood clot in both animals and humans.[71-73] These studies have hence concluded that–more definitively, in animal lungs–vasoconstriction is an important mechanism for developing high PA pressure. The same amount of direct evidence for vasoconstriction in humans is not available, but the indirect evidence does suggest that ‘something other’ than mechanical obstruction must be contributing to the response to APE, and that this is likely to be vasoconstriction mediated by vascular interaction with the thrombus. Despite the prevalence of clinical PE and numerous animal experimental studies to understand its mechanisms, it is still not clear precisely how it affects gas exchange on a patient-specific basis, and how the degree of hypoxemia and elevation of RV pressure varies according to embolus distribution and severity. There is also some lack of certainty concerning the development of PH in human APE. The aim when developing computational models is to include only as much detail as is necessary to address the specific question of the study. Examples of this in the area of PE are the models of Mélot et al.,[14] who were the first to propose theoretical models for PE, and Roselli et al.,[74] who used a rudimentary model to investigate the effect of embolization on measurement of capillary pressure via venous occlusion. Mélot et al.[14] adopted a simplified Starling resistor model (based on Mitzner et al. [75]) that included 100 parallel resistors (each representing a pulmonary vessel), each with a randomly generated critical closing pressure, and a distensible vessel model based on Haworth et al.[76] and Zhuang et al.,[22] to investigate which model best described the relationship between PA pressure and flow in embolic PH in dogs. They found that the distensible vessel model was able to reproduce blood pressure-flow curves measured in dogs with embolic PH (induced using 500-μm glass beads). Their simulations provided reasonably accurate predictions of experimentally-derived PA pressure-flow and PA pressure-LA pressure curves pre- and postembolic occlusion. These early studies were designed to answer specific experimentally-led questions. At least part of the variable response to PE treatment is due to heterogeneity in embolus location. A structure-based model for PE is therefore essential to capture regionallyvarying changes in the distribution of perfusion postocclusion. 234

Burrowes et al. [77] presented a pilot study using the full-circuit model of Clark et al.[33] to investigate the extent to which RV dysfunction in PE can be attributed to mechanical obstruction of the vasculature, and whether the contribution of signaling from the embolus via vasoactive mediators can be estimated. Computed tomography pulmonary angiography (CTPA) from 10 patients acquired during routine clinical examination for PE was used to define the location of emboli in each subject. For each of the 10 subjects, the percentage of arterial occlusion in each artery from the main PA to the level of the segmental arteries was estimated from their CTPA, for use in post-occlusion simulations. Partial occlusions of individual arteries identified on the imaging were mapped onto the computational model, and their hemodynamic consequence was predicted by solving the functional flow model of Clark et al.[33] with application of boundary conditions for pressure and flow that assumed no increase in LA pressure or decrease in cardiac output. All but one subject demonstrated preferential redistribution of blood flow to non-dependent regions. This pattern of redistribution was because of increased potential for capillary recruitment in the non-dependent lung due to lower baseline capillary pressures and therefore lower recruitment at baseline.

In comparison to clinical data acquired in multiple patients with no prior cardiopulmonary disease and with variable levels of tissue obstruction,[70,78] the model showed far less increase in PA pressure with degree of tissue obstruction. All of the model results for mechanical obstruction in the absence of vasoconstriction predicted PA pressure at levels below the clinically defined hypertensive level (mean PA pressure >25 mmHg); this level of PA pressure was not reached until >65% of the vascular bed was occluded. This contrasts with the clinical data, in which PA pressure in most subjects with >30% of tissue occluded had reached this threshold.[70] The discrepancy between the model predictions and clinical reality cannot be explained by a simple mis-parameterization of the model: the model geometry is well founded in human pulmonary vascular morphometry,[13] is consistent with previous morphometric studies, [4,79] and was tailored to each patient for this study; the functional model is based largely on physical conservation laws, and where this isn’t the case the parameters in the functional equations come from experimental measurements. The modeling study therefore provided evidence that mechanical obstruction alone is insufficient to elevate PA pressure to hypertensive levels in the human lung, and this is because of the large reserve of unrecruited capillaries that open in the unobstructed tissue. Elevating PA pressure implies either increased cardiac output or increased PVR. Cardiac output is most likely to decrease in PE,[70] which leaves Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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increase in PVR as the only possibility for increasing PA pressure. There are two means by which PVR could be elevated in the model: through a decrease in the radius of the vessels, which under acute conditions is most likely due to vasoconstriction; and by obstruction with smaller emboli that are usually unresolved on the imaging.

As proxies for vasoconstriction and/or increased vascular tone, further simulations were performed with vascular constriction enforced by setting all vessel radii to 80% of their baseline value, and a reduction in vessel elasticity to 80% of baseline. Neither mechanism was sufficient by itself to increase PA pressure to hypertensive levels for any volume of occluded tissue. PA pressure increased twice as much (~14%) as a result of vascular constriction compared to the reduction in vessel elasticity (PA pressure increased by ~7%). This result provides indirect evidence that the release of vasoactive mediators from emboli plays an important role in whole organ response to PE.[66-68] Small sub-segmental emboli are not able to be assessed clinically (radiological examination of CTPA generally only identifies emboli down to the segmental level) and would be difficult, if not impossible, to assess experimentally. Inclusion of sub-segmental emboli in the full-circuit model (located one vessel downstream of a measured segmental partial occlusion) demonstrated that increases in PVR could be significant if subsegmental vessels are occluded in addition to partial occlusion of larger vessels (for example due to the break off of part of a large embolus). This provides a possible explanation for heterogeneity in PE outcome, particularly when taken in combination with vasoconstriction. This new prediction of the model requires clinical and experimental validation. The full-circuit model is a unique tool for this type of clinically relevant study. A model by itself cannot prove a hypothesis, but a model that is biophysically-based can disprove the physical possibility of certain hypotheses. In this case the model clearly demonstrated that it is physically impossible for a previously normal pulmonary circulation to develop high enough PVR to reach hypertensive levels of PA pressure via purely mechanical obstruction of <50% of the vascular bed. This is an example of the insight that a model can provide when it does not fit the experimental data.

Micro-emboli

Emboli can also develop within the micro-vasculature of the pulmonary circulation. Although this would rarely be diagnosed as a clinical condition, some cases of arterial PE show signs of small micro-emboli breaking off from larger clots, perhaps exacerbating symptoms. There is also Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

the rare occurrence of cor pulmonale as a result of tumor micro-emboli, in which clusters of tumor cells occlude small pulmonary arterioles. Cor pulmonale often develops more quickly with tumor emboli than blood clot emboli due to differences in interactions between the arterioles and the embolus.[80] Experimentally, the occlusion of multiple arterioles at the intra-acinar level has been shown to have a significant impact on pulmonary function, and–for an equivalent proportion of vascular bed occlusion–this impact is often greater than for emboli in the larger extraacinar vessels.[65,81] In contrast to emboli in the larger blood vessels, for small induced intra-acinar emboli (<170 µm in diameter) PH has been observed when less than 50% of the vascular bed is occluded.[81] Pulmonary microembolism using inert emboli is therefore a useful method for inducing hypertension and pulmonary edema in animal experiments.[65,82] To properly interpret results from these animal models, an understanding of the implications of micro-emboli is important. It has been suggested that the location of obstruction within the acinus (proximal or distal) may have a role in determining differences in response to intra- and extra-acinar emboli.[30] In addition, constriction or loss of elasticity in intra-acinar vessels may increase the severity of the response to embolization. [80,81] Finally, edema as a result of increased micro-vascular blood pressure, or mechanical injury to the vascular bed, may increase the severity of symptoms following embolus occlusion.[81] Clark et al. [32] used the ladder model described in a previous section [29] distributed over an asymmetric intra-acinar branching geometry,[83] as illustrated in Fig. 3b, to investigate blood flow redistribution and changes in vascular resistance following arterial occlusion at the microcirculatory level. An important application of this type of model is the ability to differentiate between the behaviors of different types of embolus. For example, PE can be induced in experimental animals using materials such as balloons,[84] glass beads,[82] or blood clots.[85] An embolus may occur in vivo due to a blood clot or a tumor. Each provides a mechanical obstruction to perfusion. However, although different types of embolus may ultimately have the same effect on pulmonary function, their interactions with surrounding blood vessels differ and these differences must be well understood to properly interpret experimental and clinical data.[81] The modeling study showed that with mechanical obstruction alone (without vasoconstriction), the size and location of emboli have an impact on the increase in PVR post-embolus occlusion, with larger or more proximally located emboli resulting in PH with a relatively small capillary bed occlusion. However, consistent with the studies of embolic obstruction in the larger arteries, the micro-circulatory model showed a rise in PVR, but 235

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not sufficient to increase PA pressure to PH levels until >50% of the capillary bed was occluded. This again was suggestive of other factors, such as vessel constriction or loss of elasticity, also contributing to observed hypertension. [65,81] Further simulations showed that proximally occluded vessels along with localized constriction has the potential to induce hypertension with <50% capillary occlusion. The model analysis further showed that it is possible for capillary blood pressures to be elevated to levels that may cause capillary damage at approximately the onset of PH, that in some cases red blood cell transit time across the capillary bed can be reduced to below that required for oxygen saturation in the non-occluded region, and that both a localized arteriole constriction or loss of compliance can have a significant effect on PVR post occlusion.

A structure-based model was necessary for study of micro-embolism in that the structure of acinar blood vessels leads to both heterogeneity and stratification in perfusion within the acinus, and this must be captured sufficiently for plausible predictions of intra-acinar occlusions with micro-emboli. The series and parallel arrangement of blood vessels within the acinus model, which is only captured in models of this type, allows for a redistribution of perfusion within the acinus itself following the introduction of micro-emboli. Because the model–like the real pulmonary acinus–has capacity for perfusion redistribution and recruitment of capillary blood volume, it allows for substantial portions of the acinus to be occluded before a significant rise in resistance occurs. If arterioles of a similar size to the embolus are occluded then the smaller the embolus, the less effect it has on PVR. But if the serial-parallel structure of the acinus is disrupted by occlusion of the proximal capillary beds, the effect of the loss of capillary surface area has a far greater effect on PVR. Proximally located smaller emboli have a more significant effect on PVR for the same percentage occlusion as larger emboli in the model due to a substantial shift in flow to the distal capillary beds which are at the end of the highest resistance vessel pathways.

The acinar micro-circulatory model that was used in this study is a more elaborate version of the original ladder model of Clark et al.[29] The difference between the models lies in their geometry. The ladder model is a sufficient representation of intra-acinar perfusion for coupling to structure-based models of the pulmonary circulation, where each of the ~32,000 acini and their circulation is modeled explicitly. The more geometrically accurate model was necessary for the study of intra-acinar flow redistribution. Accurate acinar geometry has also been shown necessary for modeling based studies of inert gas washing and mixing,[9] and the intra-acinar distribution of respiratory gas exchange.[86] 236

FUTURE DIRECTIONS Mathematical models of the pulmonary circulation have evolved from convenient tools with which to explain some experimental observations, to a new class of structure-based models that are giving a greater depth of understanding of blood flow in the lung and how it relates to the other physical processes with which it interacts. One obvious limitation of the current structure-based models described here is that they only include the passive features of the pulmonary circulation: the vascular geometries, blood flow, pressure, and tissue mechanics. That is, they do not include any of the vasoactive components that are likely to be important under non-baseline conditions. In terms of mathematics the models described above for PE are relatively simple–with complexity being introduced in the geometry. They suggest some, but not all, aspects of the pathophysiology. Looking forward, and in the context of the IUPS Physiome and VPH projects, a link between micro-scale behaviors and whole lung function is lacking. For example, a large part of the response to PE is likely to happen via cellular level signaling, which results in active alterations in vessel dimensions and so to PVR and perfusion distributions.

The pulmonary vasculature is a dynamic system that responds rapidly to vasoactive mediators. Blood vessel dilation occurs in response to shear stress mediating production of NO by the endothelium, and its signaling for smooth muscle relaxation. Conversely the vessels are stimulated to constrict by hypoxia and circulating vasoconstrictive mediators. The smooth muscle in the vessel walls appears to operate under a fine balance of vasoconstrictive and vasodilatative stimuli. The next generation of computational models will play a role in understanding how these stimuli translate into smooth muscle contraction, and whether there is positive feedback that leads to excessive increase in PVR, or negative feedback that ensures system stability. An example of how such a model would be composed has recently been presented by Politi et al.[87] for the airway tree. In this multi-scale model the balance of forces acting on a stimulated airway is considered over spatial scales from the intra-cellular calcium dynamics, to development of force via a crossbridge model, to a cross-section of a constricting airway that is embedded in a dynamically expanding and recoiling parenchyma. This study demonstrates the viability of creating a model that accounts for force development over such a wide range of scales. The additional complexity in the pulmonary vasculature is the sheer range of mediators to which the smooth muscle responds. And whereas smooth muscle activation in the airway tree is undesirable, in the pulmonary vasculature it seems to be a prevalent feature that is continually acting to–presumably–optimize the delivery of blood to the gas exchange tissue. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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A multi-scale modeling approach which links cellular mechanisms to arterial dilation and contraction and in turn to pulmonary function may be the only way to link small scale interactions with emergence of whole organ function.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the support provided by the Health Research Council of New Zealand and the Life Sciences Interface.

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Source of Support: This work was supported by the Health Research Council of New Zealand, and an EPSRC Fellowship at the Life Sciences Interface., Conflict of Interest: None declared.

Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Research A r t i cl e

Air travel can be safe and well tolerated in patients with clinically stable pulmonary hypertension Melanie Thamm, Robert Voswinckel, Henning Tiede, Friederike Lendeckel, Friedrich Grimminger, Werner Seeger, and Hossein A. Ghofrani Department of Internal Medicine, Medical Clinic II/V, University Hospital of Giessen and Marburg GmbH, Giessen, Germany

ABSTRACT Our aim was to determine what proportion of patients with pulmonary hypertension (PH) has undertaken air travel contrary to the general medical advice and to characterize these patients according to disease severity and medical treatment. In cooperation with Pulmonale Hypertonie e.V., the German patient organization, a questionnaire was distributed. In total, 430 of 720 questionnaires were returned completed. Of the 179 patients who travelled at least once by air, the distribution of New York Heart Association functional classes I/ II/ III/ IV was 2/ 77/ 74/ 8, respectively; 83 patients were receiving monotherapy; 58 patients were receiving a combination of two or more therapies; 57 patients were on long-term ambulatory oxygen treatment; and 29 patients used supplemental oxygen while travelling. Overall, 20 adverse events were reported, mostly of mild to moderate severity (i.e., peripheral edema, dyspnea), with need of medical intervention in only 7 cases. The 251 patients who did not travel by air were, on average, in more advanced stages of disease and/or clinically unstable. In conclusion, a majority of patients (159 out of 179) did not experience any complications during or directly after the flight even though no special precautions were taken. Thus we conclude that for patients with PH in a stable clinical condition, air travel can be safe and well tolerated. Key Words: air travel, high altitude, hypoxic pulmonary vasoconstriction, pulmonary hypertension, safety

INTRODUCTION Pulmonary hypertension (PH) is defined as a resting mean pulmonary arterial pressure ≥25 mmHg.[1] The subgroup of patients with pulmonary arterial hypertension (PAH) is defined by the additional criterion of a pulmonary capillary wedge pressure ≤15 mmHg. [1] PH may be associated with underlying diseases or may affect only the small pulmonary arterial vessels, which leads to vasoconstriction and vascular remodeling. Irrespective of its etiology, PH is a serious and often progressive disorder that results in right ventricular dysfunction and impairment of exercise tolerance, and may lead to right-heart failure and death. Advances in treatment that have occurred over the past two decades have led to substantial improvements in quality of life in patients with PAH.[2] These improvements encourage patients Address correspondence to: Dr. Melanie Thamm University Giessen Lung Center (UGLC), Paul-Meimberg-Str. 5; 35392 Giessen; Germany Phone: +49 641 99 42535 Fax: +49 641 99 42599 Email: Melanie.Thamm@innere.med.uni-giessen.de

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with PH to live as less restrictive as possible, which often involves air travel. More than 1 billion individuals worldwide travel on commercial aircraft each year, and there are a reported 0.31 in-flight deaths per million passengers carried. [3] Cardiovascular events represent the major cause of in-flight deaths. [4] Due to engineering and financial constraints, the ambient in-flight cabin pressure is maintained to the equivalent of a maximum altitude of 2438 m.[5,6] This reduction in cabin pressure is the equivalent of breathing 15% oxygen (compared with 21% oxygen at sea level).[7] In patients with PH, the hypobaric environment during air travel leads to a general hypoxic vasoconstriction in the lung, which exacerbates Access this article online

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Website: www.pulmonarycirculation.org DOI: 10.4103/2045-8932.83451 How to cite this article: Thamm M, Voswinckel R, Tiede H, Lendeckel F, Grimminger F, Seeger W, Ghofrani HA. Air travel can be safe and well tolerated in patients with clinically stable pulmonary hypertension. Pulm Circ 2011;1:239-43.

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pulmonary resistance and right ventricular load, and may lead to acute right-heart decompensation. Thus, in addition to typical flight-associated risks, such as deep vein thrombosis, lung embolism and alterations in fluid balance, individuals with cardiovascular disease also risk worsening of their underlying condition during air travel.

Hypoxic pulmonary vasoconstriction is a fundamental physiological mechanism that optimizes perfusionâ&#x20AC;&#x201C; ventilation matching in periods of regional hypoventilation of the lung. However, during global alveolar hypoxia, whether due to lung disease or environmental conditions such as high altitude, hypoxic pulmonary vasoconstriction results in increased pulmonary resistance and enhanced right-heart load.[8] Wide variations exist in individual responses to a hypobaric environment and the underlying mechanisms are not clearly understood. Thus, it is not known whether it is safe for patients with PH to travel by air and whether such travel is well tolerated. The aim of this retrospective survey was to evaluate the outcome and experiences of patients with PH who have travelled by air.

MATERIALS AND METHODS

We conducted an anonymized survey in cooperation with Pulmonale Hypertonie e.V. (PH e.V.), a German patient selfcare organization, concerning air travel in patients with PH, and the experiences of those who had undertaken air travel since their initial diagnosis.

Patient population

We contacted 720 patients with pulmonary hypertension who were members of PH e.V. and/or were routinely followed by the pulmonary hypertension department of the University Hospital of Giessen and Marburg (Giessen, Germany). The inclusion criteria were adult patients with a confirmed diagnosis of pulmonary arterial hypertension, which includes idiopathic PAH, familial PAH, chronic thromboembolic pulmonary hypertension, or PAH associated with congenital heart defects, collagen vascular diseases, or chronic lung diseases, on stable PHspecific therapy regimens, which means without changes in specific therapy at least for 3 months prior to air travel. Exclusion criteria were severe lung diseases without secondary PH, left ventricular diseases (i.e., dilated cardiomyopathy, ischemic cardiomyopathy, significant coronary heart disease or valvular diseases) and other chronic diseases affecting tolerance of air travel (for example, severe renal failure).

Study design

We sent the postal questionnaire to all patients with pulmonary hypertension who were members of PH e.V. and/or were routinely followed by the pulmonary 240

hypertension department of the University Hospital of Giessen and Marburg. A short explanatory section and a written consent form were distributed with the questionnaire. Response to the questionnaire was anonymous. If patients provided their contact details, these were documented separately. The questionnaire consisted of multiple-choice questions, free text and yes/ no questions.

Analysis

The returned questionnaires were checked for completeness and any incomplete or illegible ones were discarded. The number of respondents who had flown since initial diagnosis and their air travel experiences were recorded following descriptive analysis.

RESULTS

In total, 430 of 720 patients completed the anonymized questionnaire (response rate: 60%). All responders provided their written consent. Of the 430 respondents, 179 (42%) had undertaken one or more flights since the initial diagnosis of PH and 251 respondents (58%) had not flown since the diagnosis. In all, 159 (89%) patients who had travelled by air since their diagnosis of PH experienced no adverse events during or directly after flying, whereas 20 (11%) reported having had one or more adverse events during or directly after at least one of their flights. Patient characteristics, including disease etiology, functional class, therapy and supplemental oxygen status, are shown in Table 1 for non-flyers, flyers and flyers with adverse events.

The most common disease etiology was idiopathic PAH, which was reported in a similar proportion of non-flyers and flyers (30% vs. 35%). Most patients were in New York Heart Association (NYHA) functional class II or III (73% of non-flyers and 84% of flyers). However, more non-flyers than flyers were in NYHA functional class IV (11% vs. 4%). A similar proportion of non-flyers and flyers used PH-specific monotherapy (40% vs. 46%). However, the use of PH-specific combination therapy and supplemental oxygen was more common among non-flyers than flyers (53% vs. 32% and 59% vs. 32%, respectively), and fewer non-flyers than flyers were using only basic therapies such as diuretics and oral coagulation (7% vs. 15%). Of the flyers only four patients used supplemental oxygen during the flight at least, but seven patients stated that they normally have supplemental oxygen therapy. Among non-flyers, severely reduced exercise capability, the need for supplemental oxygen even at sea level, advice from their medical practitioners and fear of worsening of their disease, including to the extent of death, were described as the most important factors in deciding not to fly. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Thamm et al.: Air travel is safe for patients with PH

Of the 20 flyers who reported adverse events during or shortly after flying, 10 (50%) had flown at least three times since their diagnosis. 12 patients travelled by air more than three hours, 8 patients less than 3 hours. The most prevalent adverse events were dyspnea and peripheral edema, followed by exhaustion (Table 2). Most adverse events were of mild or moderate severity. Seven patients required medical intervention, one of whom needed to be referred to intensive care; the remaining six required diuretics (n=2), cardioversion for atrial fibrillation (n=1), psychological intervention for fear of flying (n=1), physical rest (n=1) and referral for further diagnostic work-up (n=1). Patient characteristics were similar for flyers overall, for flyers without adverse events and for those with adverse events. A similar proportion of all flyers and those with adverse events used supplemental oxygen during the flight (16% vs. 20%). However, 30% of patients with adverse events were using only basic therapy alone, compared with 15% of all flyers. But in total 73% of the flyers (130 of 179 patients) as well as 73% of the non-flyers (185 of 251 patients) had a basic therapy with Coumadin, so that there is no difference in the use of Coumadin, which might have affect the outcome. Only three patients of the “flyers” did not have any basic therapy, but the had at least a combination therapy of two or more specific drugs.

Our retrospective study of 430 patients with PH shows that air travel is common in this patient population, with almost half (42%) having undertaken one or more flights since the initial diagnosis of their disease. Furthermore, air travel was generally safe and well tolerated, with only a minority (11%) of patients who had travelled by air reporting that they had experienced adverse events during or shortly after their travels and only one of these patients requiring transfer to intensive care. Patients who did not travel by air were generally in poorer physical health than those who did fly. The proportion of patients who were in NYHA functional class IV was more than twice as high in the group of non-flyers than in the group of flyers. Similarly, the proportion of patients who required routine supplemental oxygen was almost twice as high in the non-flyer as in the flyer group. The proportion of flyers who were not on PH-specific therapy (30% vs. 15%) was twice as high in the group of flyers with adverse events as in those without adverse events.

DISCUSSION

Hypoxic pulmonary vasoconstriction contributes to ventilation–perfusion matching in the lung by diverting blood flow to oxygen-rich areas. However, during conditions of general hypoxia, such as those present at high altitude or during air travel, hypoxic pulmonary Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Table 1: Clinical characteristics of patients with pulmonary hypertension who were non-flyers, flyers and flyers with adverse events Non-flyers (n=251) Etiology, n (%)* Pulmonary arterial hypertension IPAH 75 (30) CHD 23 (9) CVD 9 (4) PH owing to 36 (14) lung disease CTEPH 43 (17) NYHA class, n (%)* I 1 (0.4) II 79 (31) III 106 (42) IV 27 (11) Supplemental oxygen, n (%) Yes 148 (59) Duration, 18–24 hours/day > 16 hours/day 117 (46) Therapy* Basic therapy 18 (7) only† PH-specific 100 (40) monotherapy, n (%)‡ PH-specific 133 (53) combination therapy§, n (%) Oxygen taken – during flight, n

All flyers (n=179)

63 22 7 18

(35) (12) (4) (10)

Flyers with adverse events (n=20)

10 (50) 2 (10) 2 (10) 3 (15)

36 (20)

3 (15)

2 (1 ) 77 (43) 76 (42) 8 (4)

0 (0) 7 (35) 10 (50) 1 (5)

57 (32) 8–12

7 (35) 8–12

19 (11)

3 (15)

26 (15)

6 (30)

83 (46)

6 (30)

58 (32)

8 (40)

29 (16)

4 (20)

CHD: congenital heart disease; CTEPH: chronic thromboembolic pulmonary hypertension; CVD: collagen vascular disease; IPAH: idiopathic pulmonary arterial hypertension; NYHA: New York Heart Association. *Numbers presented may not add up to total in some variables due to missing values. †Basic therapy includes diuretics and oral anticoagulation. ‡Monotherapy includes endothelin receptor antagonists, phosphodiesterase inhibitors, prostanoids or calcium channel blockers. §Defined as ≥two PH–specific drugs

Table 2: Adverse events in the group of 179 patients with pulmonary hypertension (PH) who were flyers Adverse event Dyspnea Peripheral edema Exhaustion Heart palpitations Chest pain Headache Worsening of general condition Fear of flying

Number of flyers with particular adverse event* (%) 6 6 3 2 2 2 2 1

(3.4) (3.4) (1.7) (1.1) (1.1) (1.1) (1.1) (0.6)

*In total, 20 flyers (11.2%) reported having had one or more adverse events during or directly after at least one of their flights.

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vasoconstriction may be disadvantageous because it leads to an increase in pulmonary vascular resistance and pulmonary arterial pressure, which may aggravate right-heart loading.[9] The consequences of acute hypoxia are increases in heart rate, myocardial contractility and cardiac output. In healthy individuals, the response to hypobaric hypoxia, such as occurs during air travel, is a mild tachycardia with increased myocardial oxygen demand. [10] In patients with significant impairment of myocardial function or of coronary flow reserve, symptoms or complications such as acute cardiac arrest, or atrial or ventricular fibrillation may occur. Increased sympathetic activity at altitudes of 1,500–3,000 m produces lower workload tolerances and a decreased work capacity that may cause worsening of an underlying disease. In addition, the general flight environment, which is characterized by inactivity, and includes an air humidity of 3–10% (compared with 70% at sea level in Europe) and increased perspiration of up to 90 ml/h (compared with 40 ml/h at sea level), increases the risk for other in-flight medical issues. A fluid ingestion of 100 ml/h is thus recommended to avoid deleterious circulatory effects such as thrombosis.[11] There are no data from controlled trials regarding air travel safety for patients with PH. Guidelines for PH by the American College of Cardiology Foundation and the American Heart Association recommend supplemental oxygen on commercial aircraft for patients with a pre-flight pulse oximetry saturation of less than 92%.[ 12] The European Society of Cardiology and European Respiratory Society guidelines for PH recommend in-flight supplemental oxygen for patients with PH in functional class III or IV and those with arterial blood oxygen pressure consistently below 8 kPa (60 mmHg).[13] A flow rate of 2 L/min is recommended to bring the inspired O2 pressure to the levels seen at sea level.[13] In the present study, a substantial proportion of flyers did not adhere to these guidelines: although 45% of flyers were in functional class III or IV, only 16% used supplemental oxygen in-flight. The focus on functional class III and IV patients in the European guidelines is interesting in light of the small difference in the rate of adverse events observed in the current study between functional class II (about 9%) and functional class III or IV (about 13%). For patients with chronic lung disease who are planning to travel by air, the European Respiratory Society advises a minimum vital capacity of 3 liters, a forced expiratory volume in 1 second (FEV1)>70% of reference, a minimum oxygen saturation of 85% and a minimum partial pressure of oxygen in arterial blood (paO2) of 70 mmHg, as well as a stable state of health.[14] The British Thoracic Society guidelines recommend a hypoxic challenge test similar to the high altitude simulation test (HAST) for adults 242

who have a resting oxygen saturation of 92–95% at sea level together with an additional risk factor, as the resting oxygen saturation on its own is not a good predictor of desaturation at high altitude.[10] The Air Emergency Task Force of the American Medical Association recommends that patients with emphysema, lung fibrosis and cystic fibrosis should use supplemental oxygen therapy during air travel, especially if paO2 is expected to be less than 55 mmHg without supplemental oxygen.[14] In Germany, there is no obligatory regulation concerning the pre-flight assessment of travellers with chronic diseases. In general, individuals are considered capable of flying if they can achieve a workload of 50 watt on a treadmill without discomfort or if they are able to walk the gangway of the aircraft on their own without experiencing dyspnea. General recommendations for air travellers with underlying chronic diseases include placing sufficient medication for the length of the travel in their carry-on luggage, adhering to dietary guidelines (such as avoiding high-sodium in-flight meals, alcohol and caffeinated beverages), carrying copies of their medical records (including their latest electrocardiogram, information on any implantable cardiac device and an updated medication list including any allergies), contacting the airline in advance if in-flight supplemental oxygen is required and wearing compression stockings for flights of more than 5000 km or longer than 8 hours.[15] Known contraindications for air travel for patients with cardiac disease include myocardial infarction or coronary artery bypass in the previous 2 weeks, unstable angina, poorly compensated heart failure, uncontrolled ventricular or supraventricular arrhythmias and NYHA functional class IV.[15] A requirement for pacemakers and defibrillators is no contraindication in itself, and there is no interference between modern implantable devices and aircraft systems. The US Federal Aviation Administration required in 2001 that larger aircrafts should carry at least one automatic external defibrillator and that at least one flight attendant should be trained in its use;[16] extrapolated data suggest that these precautions prevent up to 93 in-flight deaths from ventricular fibrillation worldwide each year.[15]

Our study suggests that air travel can be safe and well tolerated in patients with PH. In addition to the recommendations for air travel for patients with PH, evidence-based guidelines for other chronic diseases should also be adapted to some extent. If paO2 at rest is less than 75 mm Hg, a HAST should be performed. If a HAST is not available, patients with PH should undergo a cardiopulmonary exercise test (6-minute walk, spiroergometry according to their capacity). With additional right-heart echocardiography one can assess the response of the right heart to acute hypoxaemia by estimating systolic pulmonary pressure, especially an Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Thamm et al.: Air travel is safe for patients with PH

increase in pulmonary pressure, and parameters of right heart function (i.e., TAPSE, TEI, S´) during ventilation of hypoxic air.[8]

Despite the fact that this method is not validated by the time, it enables an assessment for possible reaction to acute pulmonary vasoconstriction and may help to decide if patient could be allowed to fly. It is recommended that patients with PH should only fly in a stable and compensated condition, and should use supplemental oxygen during the flight to minimize hypoxic vasoconstriction. However, this does not apply to patients with congenital heart diseases with severe right to left shunt, in whom supplemental oxygen has no additional effect.

A limitation of our retrospective, descriptive analysis is a potential selection bias. It is possible that patients who had positive experiences regarding their flight travels would have been more likely to return the questionnaire. In addition, patients who died during or shortly after their air travel would by necessity have been excluded from this analysis. Further limitation is, that the hemodynamic status of the patient at the time of the air travel is unknown, because of the survey based retrospective analysis character of this work, so that we cannot compare the outcome with the hemodynamic severity of the disease. The classification in WHO functional class groups was made by transferring self-assessment of the patients’ physical capacity at the time of the flight into the classification.

CONCLUSION

In conclusion, a surprisingly large proportion of patients with PH travel by air despite the additional risk, and air travel can be safe and well tolerated in these patients in WHO functional class II and III in a stable clinical condition. Compared with alternative methods of transport, air travel might be advantageous to some extent in patients with PH, as it has the potential of dramatically reducing the duration of travel. Those patients with relevant hypoxaemia at sea level should use supplemental oxygen during air travel. Patients who have an unstable physical condition, suffer from acute infections or recently changed their PH-specific medication should avoid travelling by air. This applies also for patients in WHO functional class IV. Hence, a physician evaluation is ultimately required prior to travel for every patient.

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ACKNOWLEDGMENTS The authors gratefully acknowledge the contributions of Pulmonale Hypertonie e.V. and of Dr. Anja Becher (Oxford PharmaGenesis).

REFERENCES 1.

Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54 Suppl 1:S55-66. 2. Barst RJ, Gibbs JS, Ghofrani HA, Hoeper MM, McLaughlin VV, Rubin LJ, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54 Suppl 1:S78-84. 3. Cummins RO, Chapman PJ, Chamberlain DA, Schubach JA, Litwin PE. In-flight deaths during commercial air travel: How big is the problem? JAMA 1988;259:1983-8. 4. DeJohn CA. The evaluation of in-flight medical care aboard selected U.S. air carriers. Washington D.C.: US Department of Transport, Federal Aviation Administration, Office of Aviation Medicine; 2000. 5. Mohr LC. Hypoxia during air travel in adults with pulmonary disease. Am J Med Sci 2008;335:71-9. 6. Luks AM, Swenson ER. Travel to high altitude with pre-existing lung disease. Eur Respir J 2007;29:770-92. 7. Martin SE, Bradley JM, Buick JB, Bradbury I, Elborn JS. Flight assessment in patients with respiratory disease: Hypoxic challenge testing vs. predictive equations. QJM 2007;100:361-7. 8. Ghofrani HA, Reichenberger F, Kohstall MG, Mrosek EH, Seeger T, Olschewski H, et al. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: A randomized, double-blind, placebo-controlled crossover trial. Ann Intern Med 2004;141:169-77. 9. Bartsch P, Gibbs JS. Effect of altitude on the heart and the lungs. Circulation 2007;116:2191-202. 10. British Thoracic Society Standards of Care Committee. Managing passengers with respiratory disease planning air travel: British Thoracic Society recommendations. Thorax 2002;57:289-304. 11. Ziegler T, Rendelmann S, Albrecht L, Gebauer C, Schoof B. Flugtauglichkeit für Urlaubsreisende. Brandenburgisches Ärzteblatt 2007;3:84-5. 12. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al. ACCF/AHA 2009 Expert consensus document on pulmonary hypertension. J Am Coll Cardiol 2009;53:1573–619. 13. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493-537. 14. Fischer R, Nowak D, Huber RM. [Fitness to fly of patients with lung disease]. Dtsch Med Wochenschr 2001;126:1115-7. 15. Possick SE, Barry M. Air travel and cardiovascular disease. J Travel Med 2004;11:243-8. 16. Caro JJ, Salas M, Ward A. Healing and relapse rates in gastroesophageal reflux disease treated with the newer proton-pump inhibitors lansoprazole, rabeprazole, and pantoprazole compared with omeprazole, ranitidine, and placebo: Evidence from randomized clinical trials. Clin Ther 2001;23:998-1017.

Source of Support: Dr. Anja Becher from Oxford PharmaGenesis provided medical writing support funded by Bayer Schering Pharma AG. Conflict of Interest: None declared.

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Research A r t i cl e

Log-transformation improves the prognostic value of serial NT-proBNP levels in apparently stable pulmonary arterial hypertension Elaine Soon1,2, Natalie J. Doughty¹, Carmen M. Treacy¹, Robert M. Ross¹, Mark Toshner1, Paul D. Upton1, Karen Sheares1, Nicholas W. Morrell2, and Joanna Pepke-Zaba1 1

Papworth Hospital NHS Trust, Papworth Everard, Cambridgeshire, UK; 2University of Cambridge, Cambridge, UK

ABSTRACT N-terminal pro B-type natriuretic peptide (NT-proBNP) is a product of cleavage of the cardiac prohormone pro B-type natriuretic peptide into its active form. It has proven to be a useful biomarker in left heart failure. However, studies examining the utility of serial measurements of NT-proBNP in pulmonary arterial hypertension (PAH) patients have shown mixed results. We compared three methods of predicting adverse clinical outcomes in PAH patients: the change in 6 minute walk distance (6MWD), the change in absolute levels of NT-proBNP and the change in log-transformed levels of NT-proBNP. All PAH patients presenting from MarchJune 2007 were screened. Patients who were clinically unstable, had abnormal renal function or hemoglobin levels or lacked a prior NT-proBNP were excluded. 63 patients were followed up for adverse clinical outcomes (defined as death, transplantation, hospitalisation for right heart failure, or need for increased therapy). Three methods were used to predict adverse events, i.e.: (a) comparing a 6MWD performed in March-June 2007 and a previous 6MWD. A decrease in 6MWD of ≥30m was used to predict clinical deterioration; (b) comparing a NT-proBNP value measured in March-June 2007 and a previous NT-proBNP. An increase in NT-proBNP of ≥250pg/ml was used to predict clinical deterioration (250pg/ml represented approximately 30% change from the baseline median value of NT-proBNP for this cohort); and (c) comparing the loge equivalents of two consecutive NT-proBNP values. We used the formula: loge(current NT-proBNP) - loge(previous NT-proBNP)=x. A value of x≥+0.26 was used to predict adverse events. This is equivalent to a 30% change from baseline, and hence is comparable to the chosen cut-off for absolute levels of NT-proBNP. A loge difference of ≥+0.26 identifies patients at risk of adverse events with a specificity of 98%, a sensitivity of 60%, a positive predictive value of 89%, and a negative predictive value of 90%. A drop in 6MWD of ≥30m has a specificity of 29%, a sensitivity of 73%, a positive predictive value of 24% and a negative predictive value of 24%. It seems possible to riskstratify apparently stable PAH patients by following the changes in their serial log-transformed NT-proBNP values. In this small pilot study, this method was better than relying on changes in the actual levels of NT-proBNP or changes in 6MWD. This needs to be validated prospectively in a larger cohort. Key Words: N-terminal pro B-type natriuretic peptide, 6-minute walk distance, biomarker

INTRODUCTION Pulmonary arterial hypertension (PAH) is the term used to describe a group of rare conditions characterized by increased pulmonary artery pressures which lead to progressive right ventricular failure and death. Assessment of hemodynamic indices and exercise tolerance as measured by the six minute walk distance Address correspondence to: Dr. Joanna Pepke-Zaba Papworth Hospital NHS Trust Papworth Everard, CB3 8RE, UK Tel: ++44 1480 364998 Fax: ++44 1480 364107 Email: Joanna.pepkezaba@papworth.nhs.uk 244

(6MWD) at baseline allows prediction of prognosis[1,2] to a certain extent. However, additional simple, accurate and non-invasive predictors of prognosis are still required. The need for this is accentuated by the fact that some treatments for PAH are inherently dangerous (e.g. heart-lung transplantation) and an accurate predictor of Access this article online

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Website: www.pulmonarycirculation.org DOI: 10.4103/2045-8932.83450 How to cite this article: Soon E, Doughty NJ, Treacy CM, Ross RM, Toshner M, Upton PD, Sheares K, Morrell NW, PepkeZaba J. Log-transformation improves the prognostic value of serial NT-proBNP levels in apparently stable pulmonary arterial hypertension. Pulm Circ 2011;1:244-9.

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Soon et al.: Log-transforming serial NT-proBNP in PAH

prognosis would be invaluable in establishing the optimal time to implement such measures. N-terminal pro B-type natriuretic peptide (NT-proBNP) is a product of cleavage of the cardiac prohormone pro B-type natriuretic peptide into its active form. It is a valuable prognostic biomarker in patients with left heart failure.[3,4] Indeed, treatment guided by serial monitoring of NT-proBNP has been suggested to be superior to treatment guided by a clinical disease severity score based on Framingham criteria.[5,6] As a result of such studies, NT-proBNP has been investigated as a biomarker in PAH. Baseline levels of NT-proBNP have been shown to correlate with hemodynamic indices, 6MWD and right ventricular dimensions.[7,8,9,10] Elevated baseline levels of NT-proBNP are also an independent predictor of mortality in patients with idiopathic PAH and PAH associated with scleroderma. [7,11,12] Despite this, studies examining the utility of serial measurements of NTproBNP in PAH patients have shown mixed results. A small study following 20 patients with PAH established that a reduction in levels of BNP of ≥50% from baseline following the introduction of epoprostenol was strongly indicative of event-free survival for the following year. [13] However a larger study in 94 PAH patients concluded that changes in serial NT-proBNP levels were not sensitive enough to detect clinical changes in World Health Organisation (WHO) heart failure class or 6MWD for the individual patient.[14]

Recently it has been shown that plasma concentrations of NT-proBNP follow a log-normal distribution in patients with chronic left heart failure. [15] This has led us to surmise that using the change in log-transformed NTproBNP might be a better prognostic method. We sought to compare this novel method with using the change in untransformed values of NT-proBNP, and the traditional method of using changes in 6MWD. 6MWD has been a traditional surrogate end-point for trials in PAH and a change of at least 30m has been accepted as clinically significant.[16,17,18,19]

MATERIALS AND METHODS Subjects

A cross-sectional study was performed. All patients with PAH admitted to Papworth Hospital from March to June 2007 were screened. The inclusion criteria were: (a) a diagnosis of pulmonary arterial hypertension (either idiopathic or associated with connective tissue disease, CTD or congenital heart disease, CHD) or chronic thromboembolic pulmonary hypertension (CTEPH); (b) a clinically stable condition at the time of review in March to June 2007. Stability was defined as a lack of Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

need for intervention, i.e. no change in types or doses of medication for PAH (including diuretics and excluding warfarin); and (c) an ability to perform a 6MWD not limited by any other condition other than their PAH.

The exclusion criteria were: (a) a diagnosis of pulmonary venous hypertension; (b) lack of a prior NT-proBNP level within the 6 months preceding their review; (c) a history of chronic renal problems and/or a creatinine of >150micromoll-1; and (d) an abnormal haemoglobin level, defined as ≤13.0 or ≥18.0 (men), or ≤11.5 or ≥16.0 (women). The latter were exclusion criteria since renal failure and anaemia have been shown to be related to increased NT-proBNP levels, independent of the severity of heart failure.[20,21]

Measurement of NT-proBNP

Peripheral venous blood was drawn at admission and stored in serum gel tubes. This was analysed using a sandwich immunoassay (Elecsys 1010) produced by Roche. The measuring range was 5-35,000pg/ml. The assay did not have any significant cross-reactions with atrial natriuretic peptide, B-type natriuretic peptide or N-terminal pro-atrial natriuretic peptide.

Study design

63 patients fulfilled the criteria for inclusion. Their NTproBNP levels from their admission in March-June 2007 and the NT-proBNP level measured within the previous 6 months were extracted by a single researcher. Two other researchers who were blinded to the NT-proBNP data examined the clinical course of these patients for fifteen months. Patients were classified as having an adverse event if any of the following occurred: (a) death, (b) transplantation, (c) need for additional targeted therapy for PAH, or (d) hospitalisation for right heart failure.

Three methods were used to predict the occurrence of clinical adverse events. The first involved the comparison of two consecutive 6MWD, i.e. the difference between a 6MWD performed in March-June 2007 and a 6MWD performed up to 6 months previously. A cut-off of 30m was used, i.e., a decrease in 6MWD of 30m or greater was used to predict the occurrence of clinical adverse events and an increase in 6MWD of 30m or greater was used to predict a stable clinical course. 30m was chosen as a cutoff point as many trials have demonstrated that a change of ≥30m or ≥10% from baseline is required in the 6MWD to be clinically significant.[16,17,18,19]

The second method involved the comparison of two consecutive NT-proBNP values, i.e. the difference between a NT-proBNP value measured in March-June 2007 and a NT-proBNP measured up to 6 months previously. An increase in NT-proBNP of ≥250pg/ml was used to predict 245

Soon et al.: Log-transforming serial NT-proBNP in PAH

the occurrence of adverse events and a drop of ≥250pg/ml was used to predict stability. These cut-offs were chosen as a change of 250pg/ml represents approximately 30% change from the baseline median value of NT-proBNP for this cohort.

The third method involved comparison of the two consecutive NT-proBNP values as above but transformed by taking their loge equivalents, i.e. values for NTproBNP were transformed to loge equivalents and the difference determined using the formula: loge(current NT-proBNP) - loge(previous NT-proBNP)=x. A cut-off value of 0.26 was used, i.e. a value of x≥+0.26 was used to predict the occurrence of adverse events and a value of x≤-0.26 was used to predict stability. The cut-off levels of +0.26 and -0.26 were chosen as they were equivalent to a 30% change from baseline, and hence comparable to the chosen cut-offs for absolute levels of NT-proBNP.

predictive value of 89%. A drop in 6MWD of ≥30m had a corresponding specificity of 29%, a sensitivity of 73%, a positive predictive value of 24% and a negative predictive value of 78%. Table 1: Baseline characteristics of the patients Characteristics

Values

Age, years Male: female Underlying diagnoses and number of patients, n=63

54.6 (16.1) 1: 1.52 Idiopathic PAH, n = 16 CTEPH, n = 32 PAH due to CTD, n = 7 PAH due to CHD, n = 8 48.2 (13.8) 2.3 (0.7) 10.1 (5.1) 358 (103) 858 (163-1963) PDE–5 inhibitor monotherapy, n = 20 ERA monotherapy, n = 18 Prostanoid monotherapy, n=5 Combination therapies, n = 20

Mean PA pressure, mmHg Cardiac index, lmin-1m-2 PVR, Wood units Baseline 6MWD, m Baseline NT-proBNP, pg/ml Targeted treatment for PAH

Statistical Analysis

Descriptive statistical analyses were carried out on the study population of 63 patients. Continuous variables are expressed as mean (SD) if normally distributed and as median (interquartile range) if not. The three methods were compared using receiver operating characteristic and Kaplan-Meier curves, and these were produced using Prism (version 5.0).

RESULTS

The 63 patients included in this study represented a mixture of idiopathic PAH, CTEPH and PAH associated with CTD and CHD. Their baseline characteristics are summarized in Table 1. Hemodynamic values were taken from the latest right heart catheter available. As a whole they had moderate-to-severe PAH with an average mean PA pressure of 48.2±13.8 mmHg and a cardiac index of 2.3±0.7 lmin-1m-2. 15 patients suffered an adverse event. Their characteristics as compared to the stable patients are shown in Table 2. As a whole the patients who deteriorated were younger but had a worse cardiac index (1.9±0.4 versus 2.4±0.7 lmin-1m-2, P<0.05). However, their other characteristics including mean PA pressures, WHO class and aetiologies of their PAH were not significantly different. There were also no significant differences in any of the 6MWD or the change in 6MWD. The best method at predicting the occurrence of adverse events was a change in loge NT-proBNP values of ≥+0.26. This had a specificity of 98%, a sensitivity of 60%, a positive predictive value of 90% and a negative 246

Values are expressed as mean (SD) if normally distributed or median (interquartile range) if not. Abbreviations: 6MWD: 6 minute walk distance; CHD: congenital heart disease; CTD: connective tissue disease; CTEPH: chronic thromboembolic pulmonary hypertension; ERA: endothelin receptor antagonist; NT-proBNP: N-terminal pro-B type natriuretic peptide; PA: pulmonary artery; PAH: pulmonary arterial hypertension; PDE-5: phosphodiesterase-5; PVR: pulmonary vascular resistance

Table 2: Comparison of the characteristics of stable and deteriorating patients Characteristics Age, years Male: female WHO class (I/II/III/IV) Aetiology of PAH

Mean PA pressure, mmHg Cardiac index, 1min-1m-2 PVR, Wood units Baseline 6MWD, m Baseline NT-proBNP, pg/ml

Stable patients (n=48)

Patients who deteriorated (n=15)

57.3 (15.1) 1: 1.1 1/27/20/0

46.3 (16.5)* 1: 6.5* 1/3/10/1

IPAN, n = 12 CTEPH, n = 26 CTD, n = 4 CHD, n = 6 47.0 (14.4)

IPAH, n = 4 CTEPH, n = 6 CTD, n = 3 CHD, n = 2 52.4 (11.1)

2.4 (0.7)

1.9 (0.4)*

9.4 (5.1) 370 (88) 429 (127-1525)

12.3 (4.3) 320 (136) 1510 (1089-2443)*

Values are expressed as mean (SD) if normally distributed or median (interquartile range) if not. Key: *p<0.05 Abbreviations: 6MWD: 6 minute walk distance; CHD: congenital heart disease; CTD: connective tissue disease; CTEPH: chronic thrombo-embolic pulmonary hypertension; IPAH: idiopathic pulmonary arterial hypertension; NT-proBNP: N-terminal pro-B type natriuretic peptide; PA: pulmonary artery; PAH: pulmonary arterial hypertension; PVR: pulmonary vascular resistance

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Conversely a change in loge NT-proBNP values of ≤ -0.26 was better than an increase in 6MWD of ≥30m at predicting a stable clinical course. The sensitivity for the loge NT-proBNP method was 93% (cf. 73% for 6MWD), specificity was 42% (cf. 29% for 6MWD), positive predictive value was 33% (also 33% for 6MWD) and the negative predictive value of 95% (cf. 78% for 6MWD). Receiver operating characteristic (ROC) curves were plotted for each of the three methods (Fig. 1A-1C). A ROC curve is a graphical plot of the sensitivity versus (1-specificity). A ROC curve representing a perfect prediction method would be a point in the upper left hand corner of the plot, representing 100% sensitivity and 100% specificity.[22] Conversely a ROC curve based on random chance would yield the ‘line of no-discrimination’, which is a diagonal line connecting the left bottom and top right corners. Therefore for a perfect prediction method the area under curve (AUC) would be 1.0 while a

prediction based on random chance would have an AUC of 0.5. P-values can also be calculated based on ROC curves to show whether a prediction method is significantly better than pure chance. The method using the change in loge NT-proBNP has an AUC of 0.82 (P=0.0002). Conversely the ROC based on the change in 6MWD has an AUC of 0.59 (P=0.31). Finally, Kaplan-Meier curves were constructed for each of these methods. The best method in discriminating between patients who deteriorated and those who did not was based on the change in log-transformed NTproBNP (Fig. 1D, P<0.001). Kaplan-Meiers based on the change in untransformed levels of NT-proBNP (Fig. 1E) did show significant discriminatory effects but this was not as significant as those based on the change in log-transformed NT-proBNP. The Kaplan-Meiers based on a decrease in 6MWD of ≥30m (Fig. 1F) failed to show significant discrimination.

Figure 1: Top section: ROC curves for predictions based on the change in log-transformed NT-proBNP (a), the change in untransformed levels of NT-proBNP (b), and changes in 6MWD (c). Middle section: sensitivities, specificities and AUC values for each method. Bottom section: Kaplan-Meier curves showing cumulative survival to event for each method i.e. change in log-transformed NT-proBNP (d), change in untransformed NT-proBNP (e), and change in 6MWD (f). Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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DISCUSSION This study was originally triggered by our observation that there are some PAH patients with a stable 6MWD but increasing NT-proBNP levels who then go on to suffer a significant adverse event within the following year. There is also no current guidance as to what constitutes a significant change in NT-proBNP levels for PAH patients. We accept that thinking in terms of a log change is not instinctive for clinicians. Therefore this concept is much more interpretable when one realises that a +0.26 difference in loge NT-proBNP is equivalent to a 30% change from baseline. This can be proven mathematically (Table 3). The main drawback of this study is that it is based on a small cohort which was reviewed retrospectively. However this study is meant to be a proof-of-concept model that demonstrates the applicability of this pragmatic approach to a wide population of PAH patients at different stages of their disease. Another drawback is that this method is not useful if the change in loge NT-proBNP lie between the chosen cut-off points. 28 out of 63 patients studied fell into this category. However this limitation also applies to other methods. When the 6MWD model was examined, 34 of the 63 patients had changes in their 6MWD between +30m and -30m. For this group, careful clinical monitoring with a low threshold for right heart catheterization remains the mainstay. Also, this study has necessarily excluded patients who were unable to perform a 6MWD as we were attempting to compare the use of 6MWD versus the use of NT-proBNP and loge NT-proBNP.

This study has also highlighted one of the aspects regarding 6MWD that is open to debate; namely that the change in 6MWD did not appear to track with clinical outcome. This has been suggested before by Sitbon,[23] who noted in their cohort of 178 IPAH patients that the increase from baseline of the 6MWD performed after three months of epoprostenol therapy did not correlate with survival. A meta-analysis of 16 trials involving 1962 PAH patients by Macchia[24] did not find a significant association between the placebo-corrected increase in 6MWD and estimated time to death. However a larger meta-analysis by Galiè[25] including 3199 PAH patients showed a significant reduction in overall mortality of 43%, associated with a significant average improvement in 6MWD of 35.6m. Therefore the relationship between changes in 6MWD and time to clinical worsening remains unclear. In our cohort, there are a few plausible explanations for this finding. Firstly, the 6MWD is easily affected by factors other than PAH, such as musculoskeletal problems and 248

Table 3: Proof that a change in log-transformed levels of 0.26 is equal to a 30% change from baseline levels of NT-proBNP Loge (current NT-proBNP) - loge (previous NT-proBNP)=0.26 Loge (current NT-proBNP/previous NT-proBNP)=0.26 Current NT-proBNP/previous NT-proBNP=e0.26=1.30 Current NT-proBNP=1.30* previous NT pro-BNP NT-proBNP: N-terminal pro-B type natriuretic peptide

psychological factors. In this study we have attempted to screen for such problems and to exclude patients in whom a 6MWD was felt to be unreliable. However a bias may still exist. Secondly, the patients in this study represented a mixture of aetiologies and treatments. This was done deliberately to capture a snapshot of the general population of patients with PAH that are seen in our centre and to prove that the novel method we proposed was generally applicable. Most of the validation of 6MWD as a prognostic tool has been done in selected and relatively homogeneous populations of different types of PAH. [18,19,26,27,28] The third explanation could be that this is a true finding, i.e. that the change in 6MWD is simply not very good at predicting clinical worsening. This is supported by preliminary findings from another study[29] which demonstrated that the AUC for using changes in 6MWD to predict clinical worsening was 0.56 (comparable with our value of 0.59).

Finally, one may speculate on the implications of this pilot study. It potentially provides a simple and pragmatic method to keep apparently stable patients under surveillance. It may prove useful in situations where a patient lives a significant distance away from their specialist centre. A positive test would then serve as a “red flag” that the patient needs to be reviewed urgently.

CONCLUSIONS

It seems possible to risk-stratify apparently stable PAH patients by following the changes in their serial logtransformed NT-proBNP values. The formula used was: loge (current NT-proBNP) - loge (previous NT-proBNP)=x.

A value of x≥+0.26; which is equivalent to a 30% increase from baseline, had a specificity of 98%, a sensitivity of 60%, a positive predictive value of 90% and a negative predictive value of 89% at predicting the occurrence of adverse events. In this small pilot study, this method was better than relying on changes in the actual levels of NTproBNP or changes in 6MWD. This needs to be validated prospectively in a larger cohort. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Soon et al.: Log-transforming serial NT-proBNP in PAH

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Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:40S-70. McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, et al. Prognosis of pulmonary arterial hypertension: ACCP evidencebased clinical practice guidelines. Chest 2004;126:78S-92. Gardner RS, Ozalp F, Murday AJ, Robbs SD, McDonagh TA. N-terminal pro-brain natriuretic peptide. A new gold standard in predicting mortality in patients with advanced heart failure. Eur Heart J 2003;24:1735-43. Bayes-Genis A, Pascual-Figal DA, Fabregat J, Domingo M, Planas F, Casas T, et al. Serial NT-proBNP monitoring and outcomes in outpatients with decompensation of heart failure. Int J Cardiol 2007;120:338-43. Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicolls MG, Richards AM. Treatment of heart failure guided by amino-terminal brain natriuretic peptide (N-BNP) concentrations. Lancet 2000;355:1126-30. Pascual-Figal DA, Domingo M, Casas T, Gich I, Ordonez-Llanos J, Martinez P, et al. Usefulness of clinical and NT-proBNP monitoring for prognostic guidance in destabilized heart failure outpatients. Eur Heart J 2008;29:1011-8. Fijalkowska A, Kurzyna M, Torbicki A, Szewczyk G, Florczyk M, Pruszczyk P, et al. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest 2006;129:1313-21. Blyth KG, Groenning BA, Mark PB, Martin TN, Foster JE, Steedman T, et al. NT-proBNP can be used to detect right ventricular systolic dysfunction in pulmonary hypertension. Eur Respir J 2007;29:737-44. Andreassen AK, Wergeland R, Simonsen S, Geiran O, Guevara C, Ueland T. N-terminal pro-B-type natriuretic peptide as an indicator of disease severity in a heterogeneous group of patients with chronic precapillary pulmonary hypertension. Am J Cardiol 2006;98:525-9. Leuchte HH, Holzapfel M, Baumgartner RA, Ding I, Neurohr C, Vogeser M, et al. Clinical significance of brain natriuretic peptide in primary pulmonary hypertension. J Am Coll Cardiol 2004;43:764-70. Nagaya N, Nishikimi T, Uematsu M, Satoh T, Kyotani S, Sakamaki F, et al. Plasma brain natriuretic peptide as a prognostic indicator in primary pulmonary hypertension. Circulation 2000;102:865-70. Williams MH, Handler CE, Akram R, Smith CJ, Das C, Smee J, et al. Role of N-terminal brain natriuretic peptide (N-TproBNP) in sclerodermaassociated pulmonary hypertension. Eur Heart J 2006;27:1485-94. Park MH, Scott RL, Uber PA, Ventura HO, Mehra MR. Usefulness of B-type natriuretic peptide as a predictor of treatment outcomes in pulmonary arterial hypertension. Congest Heart Fail 2008;10:221-5. Mackay LS, Hughes R, Peaston R, MacGowan G, Parry G, Fisher AJ, et al. Serial NT-probrain natriuretic peptide levels in patients with pulmonary arterial hypertension. J Heart Lung Transplant 2007;26:S248. Schou M, Gustafsson F, Kjaer A, Hildebrandt P. Long-term clinical variation of NT-proBNP in stable chronic heart failure patients. Eur Heart J 2007;28:177-82. Provencher S, Sitbon O, Humbert M, Cabrol S, Jais X, Simmoneau G. Longterm outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension. Eur Heart J 2006;27:589-95. Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2006;353:2148-57. Olschewski H, Simonneau G, Galiè N, Higgenbottam T, Naeije R, Rubin LJ, et al; Aerosolized Iloprost Randomized Study Group. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322-9.

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19.

Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension: The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;334:296-301. 20. Luchner A, Hengstenberg C, Lowel H, Riegger GA, Schunkert H, Holmer S. Effect of compensated renal dysfunction on approved heart failure markers: Direct comparison of brain natriuretic peptide (BNP) and N-terminal pro-BNP. Hypertension 2005;46:118-23. 21. Hogenhuis J, Voors AA, Jaarsma T, Hoes AW, Hillege HL, Kragten JA, et al. Anaemia and renal failure are independently associated with BNP and NT-proBNP levels in patients with heart failure. Eur J Heart Fail 2007;9:787-94. 22. Zweig MH, Campbell G. Receiver-operating characteristic (ROC) plots: A fundamental evaluation tool in clinical medicine. Clin Chem 1993;39: 561-77. 23. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve P, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension. J Am Coll Cardiol 2002;40:780-8. 24. Macchia A, Marchioli R, Marfisi RM, Scarano M, Levantesi G, Tavazzi L, et al. A meta-analysis of trials of pulmonary hypertension: A clinical condition looking for drugs and research methodology. Am Heart J 2007;153:1037-47. 25. Galiè N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomised controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394-403. 26. Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension: Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med 2000;161:487-92. 27. Paciocco G, Martinez FJ, Bossone E, Pielsticker E, Gillespie B, Rubenfire M. Oxygen desaturation on the six-minute walk test and mortality in untreated primary pulmonary hypertension. Eur Respir J 2001;17:647-52. 28. Badesch DB, Tapson VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: A randomized, controlled trial. Ann Intern Med 2000;132:425-34. 29. Carlin C, Blyth KG, McLure LE, Spooner R, Peacock AJ, Johnson MK. Serial NT-proBNP measurements predict early clinical worsening and mortality in pulmonary arterial and chronic thromboembolic pulmonary hypertension. Thorax 2008;63:A44.

Source of Support: This work was funded by an MRC (UK) Research Training Fellowship and the Sackler studentship (Elaine Soon), the British Heart Foundation and the NIHR Biomedical Research Centre (UK). Conflicts of Interest: Elaine Soon has received travel awards from GlaxoSmithKline and Encysive, an unrelated research award from Pfizer and the Sackler studentship. Natalie Doughty has received educational awards from Actelion, Pfizer, GlaxoSmithKline and Bayer and served on advisory panels for Actelion, Pfizer and GlaxoSmithKline. Carmen Treacy has received travel grants from Actelion. Robert MacKenzie-Ross has received travel grants from Pfizer and GlaxoSmithKline. Mark Toshner has received travel awards from Pfizer and GlaxoSmithKline. Paul Upton has received a research grant from Novartis and a travel grant from Actelion. Karen Sheares has received honoraria and travel grants from Actelion, United Therapeutics, Encysive and GlaxoSmithKline. Nicholas Morrell has received a research grant from Novartis. Joanna PepkeZaba has received honoraria from Actelion, Pfizer, GlaxoSmithKline and Bayer and research grants from Pfizer, Actelion, Schering and United Therapeutics, Conflict of Interest: None declared.

249

Research A r t i cl e

Vasoreactivity to inhaled nitric oxide with oxygen predicts long-term survival in pulmonary arterial hypertension Rajeev Malhotra1, Dean Hess2,3, Gregory D. Lewis1, Kenneth D. Bloch1,3, Aaron B. Waxman4, and Marc J. Semigran1 1 Department of Medicine, Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, 2Respiratory Care Services, Massachusetts General Hospital, Boston, 3Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, 4Pulmonary Critical Care Medicine and Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA

ABSTRACT Pulmonary vasodilator testing is currently used to guide management of patients with pulmonary arterial hypertension (PAH). However, the utility of the pulmonary vascular response to inhaled nitric oxide (NO) and oxygen in predicting survival has not been established. Eighty patients with WHO Group I PAH underwent vasodilator testing with inhaled NO (80 ppm with 90% O2 for 10 minutes) at the time of diagnosis. Changes in right atrial (RA) pressure, mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure, Fick cardiac output, and pulmonary vascular resistance (PVR) were tested for associations to long-term survival (median follow-up 2.4 years). Five-year survival was 56%. Baseline PVR (mean±SD 850±580 dyne-sec/cm5) and mPAP (49±14 mmHg) did not predict survival, whereas the change in either PVR or mPAP while breathing NO and O2 was predictive. Patients with a ≥30% reduction in PVR with inhaled NO and O2 had a 53% relative reduction in mortality (Cox hazard ratio 0.47, 95% confidence interval (CI) 0.23-0.99, P=0.047), and those with a ≥12% reduction in mPAP with inhaled NO and O2 had a 55% relative reduction in mortality (hazard ratio 0.45, 95% CI 0.22-0.96, P=0.038). The same vasoreactive thresholds predicted survival in the subset of patients who never were treated with calcium channel antagonists (n=66). Multivariate analysis showed that decreases in PVR and mPAP with inhaled NO and O2 were independent predictors of survival. Reduction in PVR or mPAP during short-term administration of inhaled NO and O2 predicts survival in PAH patients. Key Words: pulmonary arterial hypertension, vasodilator testing, nitric oxide, vasoreactivity

INTRODUCTION Pulmonary arterial hypertension (PAH) is a disease characterized by elevated pulmonary arterial pressures and progressive right ventricular dysfunction.[1,2] Right heart catheterization (RHC) with pulmonary vasodilator testing is recommended both to establish the diagnosis of PAH and to enable selection of appropriate medical therapy.[3,4] Vasodilators with a short duration of action, such as inhaled nitric oxide (NO), are preferred for vasodilator testing.[4] A decrease in mean pulmonary artery pressure (mPAP) by ≥10 mmHg to an absolute level Address correspondence to:

Dr. Marc J. Semigran Division of Cardiology, Massachusetts General Hospital GRB 800, 55 Fruit Street Boston MA 02114 USA Phone: 617-726-8862 Fax: 617-726-4105 Email: msemigran@ partners.org 250

of <40 mmHg without a decrease in cardiac output (CO) is defined as a positive pulmonary vasodilator response,[3-6] and responders are considered for long-term treatment with calcium channel antagonists (CCA).[7-9] Less than 15% of idiopathic PAH (IPAH) patients are deemed responders during testing, and even fewer exhibit longterm responsiveness to CCA.[8] It is unknown whether acute pulmonary vasodilator testing with inhaled NO and O2 can be used to predict Access this article online

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Website: www.pulmonarycirculation.org DOI: 10.4103/2045-8932.83449 How to cite this article: Malhotra R, Hess D, Lewis GD, Bloch KD, Waxman AB, Semigran MJ. Vasoreactivity to inhaled nitric oxide with oxygen predicts long-term survival in pulmonary arterial hypertension. Pulm Circ 2011;1:250-8.

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outcomes in PAH patients, particularly in those not treated with CCA. [4] In this study, we investigated the ability of pulmonary vasodilator testing with inhaled NO and O2 in PAH to add to previously described predictors of clinical outcomes. [10,11] We observed that the ability of inhaled NO and O2 to reduce PVR and mPAP each predict improved survival.

MATERIALS AND METHODS

Patient sample and data collection

All adult patients from the Massachusetts General Hospital Pulmonary Hypertension Center registry were included in this retrospective study if they (1) met criteria for PAH[2] defined as a mPAP >25 mmHg at rest and a PCWP ≤15 mmHg with a PVR greater than 240 dynes-sec/cm 5 and (2) if they underwent acute vasodilator testing with inhaled NO and O2 at the time of diagnosis and prior to the initiation of PAHspecific therapy during the years 2001-2008. Fifteen patients with PAH who underwent vasodilator testing were excluded from analysis because of concurrent PAH-specific treatment. Patients with IPAH, familial PAH, or PAH associated (APAH) with connective tissue disease, portal hypertension, congenital systemic pulmonary shunts, human immunodeficiency virus (HIV), anorexigen use, or genetic disorders such as Gaucher’s disease were included. Patients underwent evaluation for and were excluded from the study if diagnosed with a World Health Organization (WHO) non-Group I etiology for their pulmonary hypertension, including chronic thromboembolic pulmonary hypertension.[4] Baseline demographic and clinical data was collected including age, gender, ethnicity, presence of related comorbid conditions, WHO functional class, six-minute walk distance, diffusion capacity with carbon monoxide (DLCO), serum creatinine levels, and left ventricular ejection fraction (LVEF). Pharmacologic therapies for PAH were subsequently initiated at the discretion of the responsible physician. Fifty-five patients underwent vasodilator challenge from 2004-2008 and only patients that had a vasodilator response to inhaled NO and O2 by the current definition (≥10 mmHg decrease to less than 40 mmHg without a decrease in CO) were considered for CCA therapy.[5,12] Prior to this time, the decision to administer CCA therapy was made based on an earlier definition of a vasoreactive response: 20% reduction in both PVR and mPAP with inhaled NO and O2.[9] Patients who exhibited this response were placed on chronic CCA therapy only if they subsequently had a favorable response to acute administration of high doses of CCA. [7] Survival data was obtained both from hospital records and the Social Security Death Index (http://ssdi. rootsweb.ancestry.com/). A retrospective analysis of Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

factors predicting survival was performed. This protocol was approved by the Partners Institutional Review Committee (#2010P000308).

Acute pulmonary vasodilator testing

As part of standard practice, patients underwent placement of a pulmonary artery catheter with fluoroscopic guidance after obtaining informed consent. Baseline measurements obtained in patients while breathing room air included right atrial (RA) pressure, PAP, pulmonary capillary wedge pressure (PCWP), arterial oxygen saturation and partial pressure, mixed venous oxygen saturation and partial pressure, and hemoglobin concentration. An MRM-2 VO2 meter (Waters Associates, Rochester, Minn.) was used to obtain oxygen consumption. Measurements were repeated while patients were breathing 90% oxygen supplemented with 80 parts per million (ppm) NO for 10 minutes via facemask using an INOvent delivery system (Ikaria, Clinton, NJ). NO and NO2 concentrations and FiO2 were monitored continuously at the inlet of the facemask. The flow rate of NO gas mixed with O2 was adjusted to maintain NO2 concentrations below 2 ppm. Fick CO was calculated, using both the oxygen bound to hemoglobin as well as the dissolved oxygen in each blood sample. PVR was subsequently calculated as (mPAP–PCWP)/CO and was expressed in dynes-sec/cm5. In patients with congenital heart disease, pulmonary blood flow was utilized to calculate PVR. Cardiac index was calculated as the CO/(body surface area) and expressed in L/min/m2.

Statistical analyses

Statistical tests were performed using the STATA 8.0 software package (StataCorp LP, College Station, Tex.). Normality of data was assessed using the Shapiro-Wilk test. Continuous variables are expressed as mean±SD or median (interquartile range, IQR). Group baseline characteristics were compared using either the Student t test, Mann-Whitney U statistic, or Fisher’s exact test, as appropriate. Survival was determined starting from the day of acute pulmonary vasodilator challenge to the time of data collection. The Kaplan-Meier method was utilized to estimate the proportion of patients surviving at a given time point, and survival curves were compared using the log rank test. Age-adjusted and multivariate Cox proportional hazard ratio modeling was utilized to determine significant hemodynamic predictors of survival. Percent changes in PVR and mPAP induced by vasodilator challenge were analyzed both as continuous variables and dichotomous variables stratified by the median change. Correlation analysis was performed using a generalized linear model of regression. Forest plots for subgroup analysis were generated using GraphPad Prism 5.0 (GraphPad Software, La Jolla, Calif.). P-values were considered significant if ≤0.05. 251

Malhotra et al.: Inhaled NO and long-term survival in PAH

RESULTS

Table 1: Patient baseline characteristics PAH patients (n=80)

Surviving patients (n=49)

Nonsurviving patients (n=31)

Age at RHC (years)

55±17

50±17

62±14†

Gender - Female (%) Ethnicity (%) Caucasian Black Hispanic

57 (71)

38 (78)

19 (61)

65 (81) 6 (8) 5 (6)

38 5 3

27 1 2

Asian Native American Diagnosis (%) Idiopathic PAH Familial PAH Collagen vascular disease Portal hypertension (%) Congenital heart disease HIV-associated Anorexigen Gaucher’s disease Functional parameters WHO functional class I/II/III-IV Six-minute walk distance (m)* Hemodynamic parameters RA pressure (mmHg) PVR (dynes-sec/ cm5) Mean PAP (mmHg) Systolic PAP (mmHg) Diastolic PAP (mmHg) Cardiac index (L/min/m2) PCWP (mmHg) LVEF (%) DLCO (%) Hemoglobin (g/dL) MDRD Creatinine clearanceΔ

3 (4) 1 (1)

3 0

0 1

21 (26) 7 (9) 23 (29)

15 4 15

6 3 8

16 (20)

11†

7 (9)

3 (4) 2 (3) 1 (1)

3 1 1

0 1 0

4/22/54 (5/28/68) 350±160

3/16/30

1/6/24

370±160

280±160

10±6

9±5

12±6†

850±580

870±650

820±450

49±14 78±23

48±16 76±24

51±11 81±21

29±11

30±12

28±10

2.6±0.9

2.6±1.0

Baseline characteristics A total of 80 patients with PAH were evaluated with inhaled NO and O2 vasodilator testing at the time of diagnosis and had a median follow-up time of 2.4 years (IQR 1.0, 4.6). Baseline clinical characteristics and values of hemodynamic parameters are provided in Table 1. The PAH patients had a mean age of 55±17 years, a baseline mPAP of 49±14 mmHg, and a PVR of 850±580 dynes-sec/cm5. After vasodilator testing, patients were initiated on therapy for PAH including prostanoids (44%), phosphodiesterase 5 (PDE5) inhibitors (46%), endothelin receptor antagonists (ETA, 26%), CCA (18%), and warfarin (53%). Fourteen total patients were treated with CCA, 5 of whom met the current criteria for a vasoreactive response, 5 who met the criteria preceding 2004, and 4 patients who were started on CCA for other indications (3 with diltiazem for atrial fibrillation, 1 with amlodipine for systemic hypertension).

Pulmonary vasoreactivity to inhaled NO and O2 predicts survival

At 5 years, Kaplan-Meier survival for the overall population was 56%. Cox proportional hazard modeling identified age (hazard ratio (HR) 1.63 for every decade of age, 95% confidence interval (CI) 1.27-2.09, P<0.001), RA pressure >10 mmHg (HR 2.90, 95% CI 1.40-6.01, P=0.004), the presence of portopulmonary hypertension (Cox HR 2.89, 95% CI 1.37-6.12, P=0.005), renal dysfunction (Cox HR 1.21 for every 10 mL/min/1.73 m2 decrease in Modified Diet in Renal Disease (MDRD) creatinine clearance, 95% CI 1.06-1.39, P=0.005), and a reduced DLCO (Cox HR 1.34 for every 10% decrease, 95% CI 1.09-1.65, P=0.006) as univariate predictors of mortality. In addition, we identified that the percent decrease in PVR (ΔPVR) or mPAP (ΔmPAP) with inhaled NO and O2 from baseline predicted long-term survival in PAH patients both in univariate (Figs. 1 and 2) and age-adjusted multivariate analyses (Table 2). For every 10% reduction in baseline PVR with vasodilator, there was a reduction in ageadjusted mortality by a ratio of 0.82 (95% CI 0.69-0.98, P=0.025), while every 10% reduction in baseline mPAP with vasodilator reduced mortality by a factor of 0.60 (95% CI 0.43-0.83, P=0.002). Acute changes in PVR and mPAP in response to breathing inhaled NO and O2 were also able to predict survival after adjusting for multivariate predictors that included age, RA pressure, DLCO, and the presence of portopulmonary hypertension (Table 2). Baseline mPAP, PVR, and cardiac index were not predictors of survival. In univariate analysis, WHO Functional Class III and IV (versus Class I and II combined) exhibited a trend towards predicting mortality (Cox HR 2.05, 95% CI 0.88-4.79, P=0.096). The 7 patients (9%) demonstrating 252

10±4 10±3 10±4 68±8 69±9 68±12 61±21 67±20 51±21† 13.2±2.2 13.4±2.1 12.8±2.3 75 (57,99) 76 (61,102) 73 (52,93)

Values are presented as mean+SD, median (IQR), or n (%). *n=24. †P<0.05, comparing surviving patients to non-surviving patients with either the student t test, the Mann-Whitney U statistic, or Fisher’s exact test, as appropriate. Δ in ml/min/1.73 m2

vasodilator responsiveness defined by current guideline criteria (decrease in mPAP by at least 10 mmHg to <40 Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Malhotra et al.: Inhaled NO and long-term survival in PAH

Figure 1: Changes in PVR with inhaled NO and O2 predict survival in PAH. Kaplan-Meier survival curves for PAH patients stratified by vasoreactivity, defined by at least a 30% decrease in PVR with vasodilator challenge. The Log-rank test shows reduced mortality in vasoreactive patients (P=0.039).

Figure 2: Changes in mPAP with inhaled NO predict and O2 survival in PAH. Kaplan-Meier survival curves for PAH patients stratified by vasoreactivity, defined by at least a 12% decrease in mPAP with vasodilator challenge. The Log-rank test demonstrates reduced mortality in vasoreactive patients (P=0.049).

Table 2: Hemodynamic predictors of long-term survival Adjusted for age

Variable Baseline parameters Right atrial pressure >10 mmHg (n=30) versus≤10 mmHg (n=50) PVR (dynes-sec/cm5) mPAP (mmHg) Cardiac index (L/min/m2) Vasoreactivity parameters (continuous) ΔPVR in response to iNO (for every 10% decrease) ΔmPAP in response to iNO (for every 10% decrease) Vasoreactivity parameters (dichotomous) Vaso-responsive to iNO by guidelines[4] ΔPVR≥30% (vs.<30%) in response to iNO* ΔmPAP≥12% (vs.<12%) in response to iNO*

Adjusted for age and other multivariate predictors†

Cox HR (95% CI)

P-value

Cox HR (95% CI)

P-value

2.14 (1.03-4.44)

0.04

–

0.98 (0.93-1.05) 1.00 (0.98-1.03) 1.37 (0.90-2.10)

0.62 0.75 0.15

0.96 (0.87-1.06) 1.00 (0.96-1.04) 1.19 (0.67-2.13)

0.39 0.91 0.55

0.82 (0.69-0.98) 0.60 (0.43-0.83)

0.025 0.002

0.60 (0.44-0.80) 0.42 (0.25-0.71)

0.001 0.001

0.66 (0.16-2.80) 0.47 (0.23-0.99) 0.45 (0.22-0.96)

0.57 0.047 0.038

0.72 (0.14-3.73) 0.17 (0.06-0.54) 0.19 (0.06-0.57)

0.69 0.002 0.003

Variables are treated as either continuous or dichotomous, as indicated. iNO, inhaled nitric oxide and O2. ΔPVR, decrease in PVR. ΔmPAP, decrease in mPAP. *Grouped into upper versus lower median. †Adjusted for age, RA pressure, presence of portopulmonary hypertension, and DLCO

mmHg without a decrease in CO)[4] had a hazard ratio for mortality of 0.66 compared to the remaining 73 patients (95% CI 0.16-2.80).

The median reduction in PVR with inhaled NO and O2 was 30% (IQR 15%, 50%), while the median reduction in mPAP was 12% (IQR 4%, 21%). These medians were used to define vasoreactive and non-vasoreactive subgroups. Characteristics of the population stratified above and below the median for both ΔPVR and ΔmPAP are presented in Table 3. There were no differences in age, gender, WHO functional classification, six-minute walk distance, or baseline hemodynamic parameters between the vasoreactive and non-vasoreactive subgroups. When stratifying by PVR, inhaled NO and O2 reduced PVR by 50% (IQR 42%, 65%) in the vasoreactive subgroup and by 15% (IQR 6%, 20%) in the non-vasoreactive subgroup. When stratifying by mPAP, Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

inhaled NO and O2 decreased mPAP by 21% (IQR 15%, 25%) in the vasoreactive subgroup and by 4% (IQR -8%, +3%) in the non-vasoreactive subgroup. Kaplan-Meier survival analysis demonstrated a greater survival for those patients whose PVR decreased by at least 30% with inhaled NO and O2 (Fig. 1). Similarly, PAH patients in whom inhaled NO and O2 reduced mPAP by at least 12% exhibited greater survival (Fig. 2). Adjusted Cox proportional hazard modeling using changes in PVR and PAP as dichotomous variables stratified about the median was also performed (Table 2). A 30% decrease in PVR with breathing inhaled NO and O2 corresponded to a 53% reduction in age-adjusted mortality (HR 0.47, 95% CI 0.23-0.99, P=0.047) while a≥12% decrease in mPAP conferred a 55% reduction in mortality (HR 0.45, 95% CI 0.22-0.96, P=0.038). The hazard ratios remained significant after adjusting for age and other multivariate 253

Malhotra et al.: Inhaled NO and long-term survival in PAH

Table 3: Characteristics of patients stratified by pulmonary vasoreactivity to inhaled NO and O2 Stratified by ΔPVR

Age at RHC (years) Gender - Female (%) Diagnosis (%) IPAH or familial PAH Collagen vascular disease Portal hypertension Clinical data WHO functional class I/II/ III-IV Six-minute walk (m)† Baseline hemodynamic parameters PVR (dynes-sec/cm5) mPAP (mmHg) PCWP (mmHg) Cardiac index (L/min/m2) Response to inhaled NO and O2 ΔPVR (% reduction) ΔmPAP (% reduction)

Stratified by ΔmPAP

ΔPVR≥30% (n=41)

ΔPVR<30% (n=39)

ΔmPAP≥12% (n=40)

ΔmPAP<12% (n=40)

55±16 32 (78)

55±19 25 (64)

56±16 32 (80)

53±18 25 (63)

18 (44) 11 (27) 6 (15)

10 (26) 12 (31) 10 (26)

15 (38) 14 (35) 6 (15)

13 (33) 9 (23) 10 (25)

3/13/25 (7/32/61) 370±170

1/9/29 (3/23/74) 300±150

4/12/24 (10/30/60) 340±150

0/10/30 (0/25/75) 380±200

840±480 49±13 10±4 2.6±0.9

870±690 50±15 10±4 2.5±1.0

760±430 47±12 10±4 2.6±0.9

950±700 51±16 10±4 2.5±1.0

50 (42, 65) 21 (11, 25)

15 (6, 20)* 7 (0, 12)*

48 (29, 58) 21 (15, 25)

19 (13, 30)* 4 (-3, 8)*

Vasoreactivity was defined as a change greater than or equal to the median value. Variables are presented as mean+SD, median (IQR), or n (%). Comparisons between vasoreactive and non-vasoreactive groups of patients were made using the Student t test or Mann-Whitney U statistic, as appropriate, for continuous variables and Fisher’s exact test for categorical variables. The Kruskal-Wallis statistic was used to compare WHO functional classification. *P<0.05, comparing the above median and below median groups. †n=24 patients

predictors of survival: RA pressure, the presence of portopulmonary hypertension, and DLCO (Table 2). The age-adjusted Cox hazard ratio for the group of patients (n=30) that demonstrated vasoreactivity in both PVR (≥30% decrease) and mPAP (≥12% decrease) was 0.43 (95% CI 0.19-0.98, P=0.04), similar to the hazard ratio for each criterion alone.

The change in PVR while breathing NO and O2 correlated with changes in mPAP (correlation coefficient r=0.59, P<0.001) and changes in CO (r=0.58, P<0.001). The median change in CO with inhaled NO and O2 was 17% (IQR 6%, 39%). Changes in CO with vasodilator challenge did not predict survival and did not correlate with changes in mPAP. PCWP did not change significantly with vasodilator challenge (median change 0 mmHg, IQR 0,1 mmHg).

exhibited a vasoreactive PVR response and 25 patients had a mPAP response (48%). APAH patients with vasoreactivity by either PVR or mPAP criteria had lower mortality compared to non-vasoreactive patients (HR 0.26, P=0.01, Fig. 3A and HR 0.29, P=0.02, Fig. 3B, respectively). For the subgroup with collagen vascular disease associated PAH (n=23), 11 exhibited a PVR vasodilator response (48%) and 14 had a mPAP response (61%). PVR responsiveness was associated with a Cox HR of 0.11 (95% CI 0.01-0.97, P=0.047) and mPAP responsiveness with a HR of 0.24 (95% CI 0.05-1.23, P=0.09).

Prognostic value of vasoreactivity in patient subgroups

In the 52 patients (aged <65 years) deemed non-responsive by current guidelines,[4] a≥30% reduction in PVR with vasodilator challenge predicted improved survival (Cox HR 0.28, P=0.03, Fig. 3A). Similarly, a ≥12% reduction in mPAP during NO and O2 inhalation predicted a 77% reduction in mortality (Cox HR 0.23, P=0.02, Fig. 3B).

Having found that changes in PVR and mPAP while breathing NO and O2 predict long-term survival in PAH, we then sought to determine whether this ability to predict survival was sustained across multiple subpopulations. Vasoreactivity defined as a ≥30% decrease in PVR (Fig. 3A) or ≥12% decrease in mPAP (Fig. 3B) with vasodilator challenge showed similar trends in multiple subgroups for improved survival. In the subgroup of APAH (n=52), the median reductions in PVR and mPAP were 26% (IQR 12%, 49%) and 11% (4%, 21%). Of patients with APAH, 23 patients (44%)

Vasoreactivity in IPAH has been shown in prior studies to predict responsiveness to long-term CCA therapy,[8] but its importance in predicting survival in non-CCA

254

PAH-specific treatment is described in Table 4. The use of epoprostenol, ETAs, and PDE5 inhibitors were similar in responders and non-responders. CCAs were used more frequently in the vasoreactive group, although this difference did not achieve statistical significance. There was no association between the use of any particular therapeutic agent and improved survival (Table 4).

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Malhotra et al.: Inhaled NO and long-term survival in PAH

Figure 3: Changes in PVR and mPAP with inhaled NO and O2 predict survival across multiple subpopulations of PAH. Forest plots of age-adjusted Cox proportional hazard ratios are depicted on a logarithmic scale, with ratios less than 1 indicating a favorable prognosis with vasoreactivity to inhaled NO and O2. In (A), vasoreactivity is defined as a≥30% decrease in PVR with vasodilator compared to baseline. In (B), vasoreactivity is defined as a≥12% decrease in mPAP with vasodilator compared to baseline. * indicates vasodilator non-responsiveness by current guidelines.[3,4] † indicates PAH associated with collagen vascular disease (CVD), portal hypertension, congenital heart disease, HIV, anorexigen use, or Gaucher’s disease. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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treated patients has not been well established. [4] In the 66 patients who were never treated with CCA in our cohort, a≥30% reduction in PVR with vasodilator challenge predicted improved survival (Cox HR 0.42, P=0.04, Fig. 4A). Similarly, among the non-CCA patients, a≥12% reduction in mPAP during NO and O2 inhalation predicted a 58% reduction in mortality (Cox HR 0.46, P=0.05, Fig. 4B).

Safety

No adverse events or reactions to inhaled NO and O2 occurred during the acute vasodilator study.

DISCUSSION

This investigation demonstrates the prognostic utility of pulmonary vasoreactivity assessment with inhaled NO and O2 in patients with PAH. Specifically, we observed that vasodilator-induced reductions in PVR and mPAP predicted better long-term survival. Stratifying patients by the median change in PVR or mPAP while breathing NO and O2 identified high and lower risk PAH groups despite having similar baseline hemodynamic characteristics. Multivariate Cox regression analysis confirmed that the change in PVR or mPAP with inhaled NO and O2 is an independent predictor of mortality, even after adjusting for other known predictors

of outcome. Changes in cardiac output and PCWP with vasodilator challenge were not predictive of survival. Since PVR is a calculated variable derived from mPAP, PCWP, and cardiac output, it is the mPAP component that is critical in predicting survival in PAH. Although prior studies have utilized pulmonary vasodilator testing with inhaled NO to identify responders to CCA,[8,9,13-16] in this study we demonstrate that acute pulmonary vasoreactivity with NO and O2 predicts long-term survival even among those patients not treated with CCA. Univariate predictors of survival in our study population were age, RA pressure, the presence of portopulmonary hypertension, renal function, DLCO, and vasoreactivity. Unlike results from the NIH registry,[10,17] cardiac index was not a predictor of survival in our population. The mean cardiac index of 2.6±0.9 L/min/m2 in our population was greater than observed in the NIH registry and may not be a predictor of survival at the time of diagnosis in a group of PAH patients at an earlier stage in their disease. Moreover, the hemodynamic characteristics of our cohort were similar to those of the recently published REVEAL trial[18] in which cardiac index was also not found to be a predictor of survival in multivariate analysis. In 1985, Rich and colleagues first observed that an acute pulmonary vasodilator response in PAH with nifedipine and

Table 4: Subsequent treatment initiated in patients stratified by pulmonary vasoreactivity to inhaled NO and O2 Stratified by ΔPVR

Epoprostenol ET Antagonist PDE 5 Inhibitor CCA

ΔPVR≥30% (n=41)

ΔPVR<30% (n=39)

ΔmPAP≥12% (n=40)

ΔmPAP<12% (n=40)

16 (39%) 9 (22%) 19 (46%) 10 (24%)

19 (49%) 12 (31%) 18 (46%) 4 (10%)

18 (45%) 9 (23%) 22 (55%) 10 (25%)

17 (43%) 12 (30%) 15 (38%) 4 (10%)

Figure 4a: Acute pulmonary vasoreactivity with inhaled NO and O2 predicts survival in PAH patients not treated with calcium channel antagonists (CCA). Of the 66 PAH patients never treated with CCA, either a≥30% decrease in PVR (A) or a≥12% decrease in mPAP (B) with vasodilator at the time of diagnosis predicted improved Kaplan-Meier survival (P≤0.05 for both). 256

Stratified by ΔmPAP

Cox hazard ratio for mortality (95% CI) 1.18 0.80 0.92 0.45

(0.58-2.39) (0.34-1.86) (0.45-1.87) (0.14-1.48)

Figure 4b: Acute pulmonary vasoreactivity with inhaled NO and O2 predicts survival in PAH patients not treated with calcium channel antagonists (CCA). Of the 66 PAH patients never treated with CCA, either a≥30% decrease in PVR (A) or a≥12% decrease in mPAP (B) with vasodilator at the time of diagnosis predicted improved Kaplan-Meier survival (P≤0.05 for both). Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Malhotra et al.: Inhaled NO and long-term survival in PAH

hydralazine is predictive of survival.[19] Current guidelines recommend inhaled NO as the preferred short-acting agent for pulmonary vasoreactivity testing. [4] Intravenous (IV) adenosine is an alternative agent for vasodilator testing and, in a univariate model, the acute change in PVR with adenosine administration has been shown to predict survival in PAH patients subsequently treated with epoprostenol.[11] However, adverse effects such as palpitations and dyspnea are commonly experienced with the administration of adenosine. [6,20] Short-term infusion of prostacyclin has also been used in acute pulmonary vasodilator testing and, in a univariate analysis, a >50% decrease in total pulmonary resistance index predicted improved two-year survival.[21] However, only 10% of patients were observed to have this degree of response and patients that did not respond received no treatment. When compared to the acute effects of IV epoprostenol, inhaled NO was found to be a better predictor of longterm clinical outcome in PAH patients treated with oral vasodilators.[14] Although inhaled NO is the preferred agent in vasodilator testing to guide the use of CCA,[4] its role in predicting outcomes in the PAH population is not established. This study now demonstrates that the acute pulmonary vasodilator response to inhaled NO and O2 adds to the prognostic value of other variables such as age and RA pressure in predicting survival in PAH patients.

The definitions used in this investigation for a positive vasodilator response differ from those of current guidelines. The guideline-based criteria have been validated to identify the minority of PAH patients (1015%)[6] who respond to CCA therapy. The patients in our investigation meeting criteria for vasoreactivity by the current guidelines demonstrated a trend towards improved survival (HR 0.66, 95% CI 0.16-2.80). The thresholds for vasoreactivity utilized in this study–determined by population median values–effectively stratify the PAH population into high and lower risk mortality groups. Three-year survival for vasoreactive patients was 80% compared to only 48% in non-vasoreactive patients (Figs. 1 and 2). Survival in non-vasoreactive patients of our study (median survival 2.8 years) was the same as that reported in patients of the NIH registry,[10] despite the greater use of PAH-specific therapies in the present era. However, non-vasoreactive patients in the present study were older than those followed in the original NIH registry (55±19 vs. 36±15 years),[10,22] perhaps explaining the similarities in their survival despite the differences in their treatments. Current guidelines recommend pulmonary vasodilator testing only in patients with IPAH.[4] However, pulmonary vasoreactivity has been described and, in some cases, utilized to guide therapy in APAH.[23-25] In this investigation, we found that vasoreactivity with inhaled NO and O2 was Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

predictive of long-term survival in APAH patients (Fig. 3, A and B). Further study is warranted to determine if the broader applicability of vasodilator testing in PAH patients is indicated to guide chronic management. The utility of vasodilator testing has been well established to identify those PAH patients more likely to have a sustained benefit from CCA treatment.[4] This study suggests that there is prognostic value of vasodilator testing even in patients who are not candidates for CCA treatment.

Limitations

This study was performed in a retrospective manner and included a sample size of 80 patients; hence, the results, in particular the subgroup analyses, must be considered hypothesis generating and warrant further investigation prospectively. Patients were not randomized to PAHspecific therapies and, therefore, this may confound comparisons of survival between vasoreactive and non-vasoreactive groups. This study included patients with WHO Group I PAH, but the broader applicability of acute vasodilator testing in other forms of pulmonary hypertension has not been elucidated. Patient survival was not assessed prospectively in this study, but no patients were lost to follow-up. Moreover, we administered 80 ppm NO with 90% O2 for acute pulmonary vasodilator testing, as is our standard practice. Further study is needed to determine if our findings are applicable to the response of PAH patients breathing different concentrations of NO and oxygen. Methemoglobin levels were not assayed in this study, but have been assayed in prior studies utilizing the same protocol and found to be at safe levels (<1.5%).[26]

CONCLUSIONS

This investigation demonstrates that pulmonary vasodilator testing with inhaled NO and O2 can be used to identify subpopulations of PAH patients with high and lower risk of mortality. Further investigation is needed to determine if these high-risk PAH patients would benefit from a more aggressive therapeutic strategy.

ACKNOWLEDGMENTS

This work was performed at the Massachusetts General Hospital in Boston, Massachusetts.

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Sitbon O, Humbert M, Jagot JL, Taravella O, Fartoukh M, Parent F, et al. Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J 1998;12:265-70.

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McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: The impact of epoprostenol therapy. Circulation 2002;106:1477-82.

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Galie N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam T, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J 2004;25:2243-78.

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McLaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 1998;338:273-7.

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Morales-Blanhir J, Santos S, de Jover L, Sala E, Paré C, Roca J, et al. Clinical value of vasodilator test with inhaled nitric oxide for predicting long-term response to oral vasodilators in pulmonary hypertension. Respir Med 2004;98:225-34. Ricciardi MJ, Knight BP, Martinez FJ, Rubenfire M. Inhaled nitric oxide in primary pulmonary hypertension: A safe and effective agent for predicting response to nifedipine. J Am Coll Cardiol 1998;32:1068-73. Sitbon O, Brenot F, Denjean A, Bergeron A, Parent F, Azarian R, et al. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension. A dose-response study and comparison with prostacyclin.

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Source of Support: This work was supported by National Institutes of Health grants [Grants T32HL007208 (RM), K23HL091106 (GDL), and K24HL004021 (MJS)] from the National Heart, Lung, and Blood Institute. Conflicts of Interest: Dr. Bloch’s laboratory is supported in part by a sponsored research agreement between Massachusetts General Hospital and Ikaria. Dr. Bloch has obtained patents relating to the use of inhaled nitric oxide. These patents are assigned to Massachusetts General Hospital, which has licensed them to Ikaria (Clinton, NJ) and Linde Gas Therapeutics (Lidingo, Sweden). Dr. Waxman serves on the Scientific Advisory Boards of United Therapeutics Corporation and Pfizer Inc., and receives research funding from Gilead Sciences Inc., Medtronic Inc., Bayer Pharmaceuticals, and Actelion Pharmaceuticals Ltd. Drs. Malhotra, Hess, Lewis, and Semigran have no potential, Conflict of Interest: None declared.

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Research A r t i cl e

Hypoxic pulmonary hypertension in mice with constitutively active platelet-derived growth factor receptor-b Bhola K. Dahal1, Rainer Heuchel2,3, Soni Savai Pullamsetti1,4, Jochen Wilhelm1, Hossein A. Ghofrani1, Norbert Weissmann1, Werner Seeger1,4, Friedrich Grimminger1, and Ralph T. Schermuly1,4 3

1 University of Giessen Lung Centre (UGLC), Giessen, Germany, 2Ludwig Institute for Cancer Research, Uppsala, Sweden, CLINTEC, Karolinska University Hospital Huddinge, Stockholm, Sweden, 4Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany

ABSTRACT Platelet-derived growth factor (PDGF) has been implicated in the pathobiology of vascular remodeling. The multikinase inhibitor imatinib that targets PDGF receptor (PDGFR), c-kit and Abl kinases, shows therapeutic efficacy against experimental pulmonary hypertension (PH); however, the role of PDGFR-b in experimental PH has not been examined by genetic approach. We investigated the chronic hypoxia-induced PH in mice carrying an activating point mutation of PDGFR-b (D849N) and evaluated the therapeutic efficacy of imatinib. In addition, we studied pulmonary global gene expression and confirmed the expression of identified genes by immunohistochemistry. Chronically hypoxic D849N mice developed PH and strong pulmonary vascular remodeling that was improved by imatinib (100 mg/kg/day) as evident from the significantly reduced right ventricular systolic pressure, right ventricular hypertrophy and muscularization of peripheral pulmonary arteries. Global gene expression analysis revealed that stromal cell derived factor SDF)-1aď&#x20AC; was significantly upregulated, which was confirmed by immunohistochemistry. Moreover, an enhanced immunoreactivity for SDF-1a, PDGFR-b and CXCR4, the receptor for SDF-1a was localized to the a-smooth muscle cell (SMC) actin positive pulmonary vascular cells in hypoxic mice and patients with idiopathic pulmonary arterial hypertension (IPAH). In conclusion, our findings substantiate the major role of PDGFR activation in pulmonary vascular remodeling by a genetic approach. Immunohistochemistry findings suggest a role for SDF-1a/CXCR4 axis in pulmonary vascular remodeling and point to a potential interaction between the chemokine SDF-1 and the growth factor PDGF signaling. Future studies designed to elucidate an interaction between the chemokine SDF-1 and the PDGF system may uncover novel therapeutic targets. Key Words: hypoxia, remodeling, PDGFR, SDF-1a, imatinib

INTRODUCTION Pulmonary arterial hypertension (PAH) is a progressive and fatal disease for which no cure is yet available. Pulmonary vascular remodeling that involves abnormal vascular cell proliferation, survival and migration is the key feature of PAH pathology.[1,2] Moreover, PAH shares some mechanistic similarities with cancer. [3] Growth factors and inflammatory mediators have been implicated in the abnormal cellular events;[4] however, the precise molecular mechanisms is as yet incompletely understood. Address correspondence to:

Prof. Ralph Theo Schermuly Max-Planck-Institute for Heart and Lung Research Parkstrasse 1, 61231 Bad Nauheim, Germany Phone: ++ 49 6032 705380 Fax: ++ 49 6032 705385 Email: ralph.schermuly@mpi.bn.mpg.de Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Platelet-derived growth factor (PDGF) has been extensively studied over the past years. Upon ligand binding, the transmembrane PDGF receptor (PDGFR) monomers undergo hetero- and homodimerization, followed by increased intracellular tyrosine kinase (TK) activity and initiation of downstream signaling cascades that result in survival, proliferation and migration of cells.[5-8] Activation of the PDGFRs thus plays a crucial role during development, normal cellular homeostasis as well as pathophysiological Access this article online

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Website: www.pulmonarycirculation.org DOI: 10.4103/2045-8932.83448 How to cite this article: Dahal BK, Heuchel R, Pullamsetti SS, Wilhelm J, Ghofrani HA, Weissmann N, Seeger W, Grimminger F, Schermuly RT. Hypoxic pulmonary hypertension in mice with constitutively active platelet-derived growth factor receptor-Î˛. Pulm Circ 2011;1:259-68.

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conditions.[9] Perturbed TK activation including the PDGFR is implicated in many malignant and benign proliferative disorders.[3] Oncogenic PDGFR activation arising from gainof-function mutations in the activation loop of PDGFR-a has been found in gastrostromal intestinal tumors.[10] The altered regulation of PDGFR signaling has consistently been reported both in experimental and clinical PH.[11,12] In line with this, the multikinase inhibitor imatinib has been demonstrated to provide therapeutic benefit in experimental pulmonary vascular remodeling.[13] Yet, the pharmacological inhibition study does not rule out the role of the other imatinib targets such as c-kit and thus requires an investigation by genetic approach. In addition to the PDGF system, the chemokine SDF-1 signaling through its cognate receptor CXCR4 is involved in the growth and progression of cancers.[14-16] Interestingly, functional links between growth factors and chemokines are gradually emerging. The cross-talk between SDF-1/CXCR4 signaling and epidermal growth factor receptor (EGFR) has been described in cancer cells.[17] Recently, a coexpression of the SDF-1 with PDGFR has been demonstrated in human glioblastoma,[18] suggesting a possible cross-talk between SDF-1 and PDGF signaling. In the context that a growing number of studies implicate SDF-1 in vascular remodeling,[19-22] it is not unlikely that SDF-1 may colocalize with PDGFR in the pulmonary vasculature during structural remodeling. However, the chemokine SDF-1 has not been investigated along with the PDGFR in remodeled pulmonary vessels in experimental and clinical PH.

In the current study, we therefore employed transgenic mice with a point mutation in the activation loop of PDGFR-b (D849N) that confers ligand-independent receptor autophosphorylation resulting in increased cell motility and antiapoptotic signaling.[23] We assessed the development of PH and vascular remodeling in chronically hypoxic D849N mice and their response to imatinib therapy. We further investigated the chemokine SDF-1a, one of the differentially expressed genes under chronic hypoxia as revealed by global gene expression study. We analyzed the pulmonary expression/localization of SDF-1a, its receptor CXCR4 and PDGFR-b. In addition, we investigated their localization in lung tissues from patients with idiopathic pulmonary arterial hypertension (IPAH). Some of the results of this study have been previously reported in the form of an abstract.[24]

MATERIALS AND METHODS

Chronic hypoxic exposure and imatinib therapy of mice

Adult age- and sex-matched mice carrying an activating point mutation in PDGFRb (D849N) [23] and their 260

corresponding wild type (WT) control were used in the study. Pulmonary vascular remodeling was induced in mice by hypoxic exposure (10% O2) for 35 days as described.[13] After 21 days, both WT and D849N mice were randomized to receive either imatinib (100mg/ kg day) or placebo orally by gavage. Control mice were kept in identical chambers under normoxic condition (21% O2). All studies were approved by the local authority (Regierungspräsidium Giessen) and were performed according to the guidelines of the University of Giessen that comply with national and international regulations.

Hemodynamic and right ventricular hypertrophy At the end of therapy, hemodynamic and right ventricular hypertrophy (RVH) measurements were done as described. [25] Briefly, right ventricular systolic pressure (RVSP) was measured by a catheter inserted into the RV via the right jugular vein and systemic arterial pressure (SAP) was measured by catheterization of the carotid artery. The right ventricle (RV) was separated from the left ventricle plus septum (LV+S). The ratio of RV to LV plus septum [RV/ (LV+S)] as well as the ratio of RV to body weight (BW) [RV/ BW] was calculated as a measurement for RVH.

Histology and pulmonary vascular morphometry

Lung tissue preparation, sectioning, staining and vascular morphometry were done as described.[25] The degree of muscularization of peripheral pulmonary arteries was assessed by double-immunostaining the sections with an anti-a-smooth muscle actin antibody (dilution 1:900, clone 1A4, Sigma) and anti-human von Willebrand factor antibody (vWF, dilution 1:900, Dako). In each mouse, 80 to 100 intra-acinar arteries at a size between 20 and 70µm accompanying either alveolar ducts or alveoli were categorized as non-muscularized, partially muscularized or fully muscularized to assess the degree of muscularization.

Microarray experiments

RNA extraction and purification from murine lungs was performed as described.[26] RNA quality was assessed by capillary electrophoresis using the Bioanalyzer 2100 (Agilent Technologies, Calif.). Purified total RNA was amplified and Cy-labeled using the dual-color LIRAK kit (Agilent) following the kit instructions. Per reaction, 1µg of total RNA was used. The samples were labeled with either Cy3 or Cy5 to match a balanced dye-swap design. Cy3- and Cy5-labeled RNA were hybridized at 60°C overnight to 4x44K 60mer oligonucleotide spotted microarray slides (Mouse Whole Genome 4x44K; Agilent). Hybridization and subsequent washing and drying of the slides were performed following the Agilent hybridization protocol. The dried slides were scanned using the GenePix 4100A scanner (Axon Instruments, Downingtown, Penn.). Image analysis was performed with GenePix Pro 5.0 software, Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Dahal et al.: Mutant PDGFR- (D849N) and hypoxic PH

and calculated values for all spots were saved as GenePix results files. Stored data were evaluated using the R software and the Limma package from BioConductor. [27- 29] The spots were weighted for subsequent analyses according to the spot intensity, homogeneity, and saturation. The spot intensities were corrected for the local background using the method of Edwards[30] with an offset of 64 to stabilize the variance of low-intensity spots. The M/A data were LOESS normalized[31] before averaging. Genes were ranked for differential expression using a moderated t-statistic[32] Candidate lists were created by adjusting the false-discovery rate to 1% separately for each contrast.

precipitate was detected by immunoblotting using antiphosphotyrosine monoclonal antibody (sc-7020, Santa Cruz, Calif.).

Human lung tissues were obtained from donors and patients with IPAH undergoing lung transplantation. After explanation, lung tissues were formalin-fixed and paraffinembedded according to common tissue processing protocol. The study protocol for tissue donation was approved by the ethics committee of the University Hospital Giessen in accordance with national law and international guidelines. Written informed consent was obtained from each individual patient or the patient’s next kin.

PDGF-BB stimulation resulted in an increase in phosphorylation of PDGFR-b in WT and mutant mouse embryonic fibroblasts (MEFs). Imatinib largely abrogated the phosphorylation of PDGFR-b in both WT and mutant cells, demonstrating that imatinib was effective to inhibit both the WT and mutant receptor activation (Fig. 1). The inhibition of phosphorylation was not associated with decreased protein content as evident from the absence of alteration in the total PDGFR-b upon imatinib treatment.

Paraffin-embedded lung tissue sections (3 µm thickness) from chronic hypoxic mice and IPAH patients were immunostained for SDF-1a, CXCR4 and PDGFR-b. Following antigen retrieval the sections were pretreated with hydrogen peroxide (15%) to quench endogenous peroxidase activity. After the blocking steps with BSA (10%) for 1 hour and then with blocking serum (Impress kit, Vector Laboratories) for 20 minutes, the sections were incubated with primary antibodies at 4oC overnight. Rabbit anti-mouse SDF-1 (1:300, eBioscience), rabbit monoclonal anti-PDGFR-b (1:600, Y92, Abcam), rabbit polyclonal anti-CXCR4 (1:300, ab2074, Abcam) and rabbit polyclonal anti-SDF-1a (1:600, ab9797, Abcam) were used as primary antibodies. Development of the dye was carried out with peroxidase and substrate (NovaRed kit) according to manufacturer’s instructions (Vector laboratories). Finally, sections were counterstained with hematoxylin (Zymed laboratory) and coverslipped using mounting medium.

The presence of the gain-of-function mutation in PDGFR-b did not confer a significant increase in RVSP in the D849N mice (29.5±1.2 mmHg) as compared to that of WT (29.8±1.3 mmHg) mice under normoxic condition. However, chronic hypoxic exposure did result in a

Data analysis

Data were expressed as mean±SEM. The different groups were compared by one-way analysis of variance (ANOVA) and subsequent Newman-Keuls test. A value of P<0.05 was considered as statistically significant.

RESULTS

Patient characteristics

Mutant PDGFR-β (D849N) is sensitive to imatinib

Immunohistochemistry

Right ventricular systolic pressure (RVSP) of hypoxic mutant (D849N) mice

Mut (D849N)

PDGF-BB

Imatinib

–

pPDGF-β

PDGFR-β

Immunoprecipitation and immunoblotting

Cell culture, Immunoprecipitation (IP) and immunoblotting (IB) were performed as described. [23] Briefly, wild type and mutant mouse embryonic fibroblast cells were preincubated with or without imatinib (3μM) for 3 hours and stimulated with PDGF-BB (20ng/ ml, 10 min. 37°C). Rabbit polyclonal antibody that is isoform-specific for PDGFR-b (CTb)[33] was used for IP. Phosphorylated PDGFR-b in the Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Figure 1: Inhibition of mutant PDGFR-b (D849N) phosphorylation by imatinib. Wild type and mutant (D849N) murine embryonic fibroblasts (MEFs) were pre-incubated with or without imatinib (3μM) for 3 hours and stimulated with PDGF-BB (20ng/ml, 10 min.). Immunoprecipitation (IP)/ Western blot was performed to obtain relative amounts of PDGFR-b (lower panel) followed by membrane stripping and reblotting for phosphorylated PDGFR-b (upper bands). The phosphorylated- and total PDGFR-b are shown. WT-wild type; mut- mutant; pPDGFR-b- pan-phosphorylated PDGFR-b. 261

Dahal et al.: Mutant PDGFR- (D849N) and hypoxic PH

significantly higher RVSP in the D849N (38.9±1.8 mmHg) and WT mice (36.4±1.9 mmHg) compared to normoxic control, suggesting that the development of PH in hypoxic mutant and WT mice was comparable (Fig. 2). After PH was fully established, the treatment with imatinib for two weeks significantly reduced the RVSP in D849N and WT mice (33.6±0.7 and 32.4±0.4 mmHg, respectively) as compared to the placebo groups (Fig. 2). Both D849N and their WT control mice displayed similar systemic response to hypoxia and to the imatinib treatment as revealed by the comparable systemic arterial pressure (SAP) (Table 1).

Right ventricular hypertrophy (RVH) in hypoxic mutant (D849N) mice

The increased RVSP was accompanied by RVH as evidenced by a significantly higher RV/(LV+S) ratio (0.42 ±.01) in the hypoxic D849N mice as compared to normoxic control mice (0.27±0.02) (Fig. 3a). The RVH of the D849N mice was comparable to that of WT mice (RV/LV+S, 0.42±0.02) under chronic hypoxia. Corroborating the RVSP data, imatinib treatment significantly improved RVH as evident from reduced RV/(LV+S) in hypoxic D849N (0.33±0.01) and WT (0.32±0.01) mice compared to placebo group (Fig. 3a). We also analyzed RV/BW ratio and found that chronic hypoxic exposure led to an enhanced RV/BW in D849N and WT mice (0.37±0.02 and 0.34±0.03 mg/g, respectively), whereas imatinib significantly reduced the RV/BW (0.28±0.02 and 0.26±0.02 mg/g respectively) (Fig. 3b). 42

RVSP [mmHg]

36 34 32

Chronic hypoxia-induced pulmonary vascular remodeling in mutant (D849N) mice

We then investigated the effect of chronic hypoxia on vascular remodeling by assessing the degree of muscularization of peripheral pulmonary arteries. An increased muscularization was observed in the chronically hypoxic mice as reflected by an enhanced immunoreactivity for a-smooth muscle cell actin (Fig. 4a). Pulmonary vascular morphometry of hypoxic D849N and WT mice revealed a significant increase in partially (60.1±2.4% and 62.8±2.6%, respectively) and fully muscularized (16.8±2.1% and 10.6±1.6%, respectively) vessels and a decrease in non-muscularized vessels (23.1 ± 2.1% and 26.5±3.8%, respectively) as compared with normoxic control. Notably, D849N mice displayed a more severe degree of remodeling as evident from the higher percentage of fully muscularized vessels in comparison to WT mice (Fig. 4b). Consistent with the beneficial effects on RVSP and RVH, treatment of hypoxic D849N and WT mice with imatinib significantly decreased the proportions of partially (52.1±1.7% and 51.5±1.8%, respectively) and fully muscularized (7.4±0.6% and 8.5 ± 1.1%, respectively) vessels and increased the proportion of non-muscularized vessels (40.5±2.1% and 40±2.4%, respectively) (Fig. 4b).

Global gene expression study and localization of SDF-1α, CXCR4 and PDGFR-β in the lungs of mutant (D849N) mice

In order to investigate the genes and the biological pathways influenced by chronic hypoxia, global gene expression study of the lung homogenates was performed. Gene set enrichment analysis was employed to identify the differentially active pathways from the Kyoto Encyclopedia of Genes and Genomes database (KEGG). The analysis revealed that various biological pathways were differentially active in the D849N mice under hypoxia (Table 2). Majority of the identified pathways Table 1: Systemic arterial pressure, hematocrit and body weight of wild type and mutant (D849N) mice

Number SAP Hematocrit (n) (mmHg) (%)

28 26 WT

D849N

WT/ Imatinib

D849N

D849N/ Imatinib

Normoxia Hypoxia Figure 2: Right ventricular systolic pressure (RVSP) of hypoxic mutant (D849N) mice receiving imatinib. Wild type and D849N mice were exposed to hypoxia for 35 days or remained in normoxia throughout (normoxic control). Hypoxic mice (n=10) received imatinib orally by gavage from day 21 to day 35 at a dose of 100 mg· kg–1 BW. Hypoxic control animals (n=10) received placebo. RVSP (in mmHg) of different experimental groups are shown. Each bar represents mean±SEM. *P<0.05 vs. normoxic control; † P<0.05 vs. corresponding hypoxic control. 262

Normoxia WT D849N Hypoxia WT D849N Hypoxia + Imatinib WT D849N

BW (g)

10 10

88.7±5.0 79.8±6.0

37.3±0.0 38.3±1.0

27.6±1. 29.3±2.1

10 10

64.4±1.5 63.6±3.4

61.8±0.9 62.0±1.8

25.1±1.2 26.0±1.7

10 10

66.7±1. 76.1±4.1

61.8±0.0 60.0±1.0

24.1±0.0 25.3±1.3

Mean±SEM is given; SAP: systemic arterial pressure; BW: body weight; WT: wild type

Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Dahal et al.: Mutant PDGFR- (D849N) and hypoxic PH

0.50

0.45

RVIBW (mg/g)

0.40 RVI (LV+S)

0.40

0.35

0.30 0.25

0.25

0.20

D849N

WT/ D849N D849N/ Imatinib Imatinib

Normoxia

0.35

0.30

0.20

0.15

Hypoxia

D849N

WT/ D849N D849N/ Imatinib Imatinib

Normoxia

(a)

Hypoxia (b)

Figure 3: Right ventricular hypertrophy in hypoxic mutant (D849N) mice receiving imatinib. Wild type and D849N mice were exposed to hypoxia for 35 days or remained in normoxia throughout (normoxic control). Hypoxic mice (n=10) received imatinib orally by gavage from day 21 to day 35 at a dose of 100 mg· kg–1 BW. Hypoxic control animals received placebo (n=10). (a) RV/(LV+S) and (b) RV/BW (in mg/g) of different experimental groups are shown. Each bar represents mean±SEM. *P<0.05 vs. normoxic control; †P<0.05 vs. corresponding hypoxic control.

differentially influenced by chronic hypoxia were those involved in cellular processes and metabolism such as cell growth, division and immune response. Notably, the VEGF pathway was among the pathways with significantly altered activity (Table 2). Based on the gene expression data and the literature as outlined in the introduction, we further investigated the chemokine SDF-1a, one of the differentially regulated genes under hypoxia, by immunohistochemistry. Enhanced SDF-1a was detected predominantly in the smooth muscle cells (SMCs) in the hypoxic lungs as evident from the immunoreactivity for a-SMC actin (Fig. 5). Under normoxia, SDF-1a immunoreactivity was observed in peribronchial SMCs and to a lesser extent in airway epithelial cells. However, the immunoreactivity was intense in vascular SMCs under hypoxia (Fig. 5). Similarly, hypoxia resulted in enhanced expression of PDGFR-b which was predominantly localized in vascular SMCs. In addition, immunoreactivity was also found in peribronchial SMCs and airway epithelial cells. Staining for CXCR4, the receptor for SDF1a was present in the peribronchial SMCs and mildly also in mononuclear and airway epithelial cells. However, stronger immunoreactivity for CXCR4 was detected largely on vascular SMCs under hypoxia (Fig. 5). Overall, the data revealed an increased expression of SDF-1a, CXCR4 and PDGFR-b in hypoxic pulmonary vascular SMCs. However, we did not detect any remarkable qualitative difference in the immunohistochemistry findings between WT and D849N mice. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Table 2: KEGG biological pathways for differentially expressed genes in chronic hypoxic D849N mice ID

Name

3010 Ribosome 4650 Natural killer cell mediated cytotoxicity 4060 Cytokine-cytokine receptor interaction 4640 Hematopoietic cell lineage 4070 Phosphatidylinositol signaling system 5219 Bladder cancer 0562 Inositol phosphate metabolism 4662 C cell receptor signaling pathway 4670 Leukocyte transendothelial migration 4115 p53 signaling pathway 4610 Complement and coagulation cascades 5223 Non-small cell lung cancer 0230 Purine metabolism 5216 Thyroid cancer 0520 Nucleotide sugars metabolism 4370 VEGF signaling pathway

Genes P value

Adj. P

98 141

9,25E-08 0,0000 8,42E-08 0,0000

253

2,83E-05 0,0018

6,43E-05 0,0031

3,00E-04 0,0115

48 60

4,49E-04 0,0144 6,72E-04 0,0148

6,92E-04 0,0148

133

6,59E-04 0,0148

74 75

8,24E-04 0,0158 1,23E-03 0,0215

1,85E-03 0,0296

165 33 7

2,34E-03 0,0339 2,47E-03 0,0339 2,88E-03 0,0369

3,10E-03 0,0372

ID: KEGG pathway ID; Name: KEGG pathway ID; Genes: number of pathway genes; Adj. P - P values adjusted for multiple testing by Benjamini-Hochberg

263

Dahal et al.: Mutant PDGFR- (D849N) and hypoxic PH

Vascular muscularization [%] (20-70 mm)

60 50 40 *

# *

10 0

D849N

WT/ Imatinib

Normoxia

D849N

D849N/ Imatinib

Hypoxia (b)

Figure 4: Muscularization of pulmonary vessels in hypoxic mutant (D849N) mice receiving imatinib. Wild type and D849N mice were exposed to hypoxia for 35 days or remained in normoxia throughout (normoxic control). Hypoxic mice (n=10) received imatinib orally by gavage from day 21 to day 35 at a dose of 100 mg· kg–1 BW. Hypoxic control animals received placebo (n=10). Lung sections were immunostained for a-SMC actin (arrow) and vWF (arrow head) followed by pulmonary vascular morphometry. A total of 80 to 100 intra-acinar vessels were analyzed in each lung. (a) Representative photomicrographs are shown. (b) Proportions of non-muscularized (N), partially muscularized (P), or fully muscularized (M) pulmonary vessels, as percentage is given. Bar represents mean±SEM. #1.6 times higher than the fully muscularized vessels in hypoxic WT. *P<0.05 vs corresponding normoxic control; †P<0.05 vs corresponding hypoxic control. Scale bar=20 mm.

Localization of SDF-1α, CXCR4 and PDGFR-β in the lungs of IPAH patients

To investigate if the localization of SDF-1, CXCR4 and PDGFR-b in experimental PH mimics that of clinical PH, immunohistochemistry was performed on the lung tissues of patients with IPAH. In addition, we also stained for a-SMC actin to determine if the positive immunoreactivity was present in SMCs. Clearly, a robust vascular remodeling was present in the lungs from IPAH patients as evident from the thickened vascular wall comprising majority of a-SMC actin positive cells (Fig. 6). Immunoreactivity for SDF-1a, CXCR4 and PDGFR-b was observed mainly 264

in the a-SMC actin positive pulmonary vascular cells and it was considerably stronger in the lungs from IPAH patients compared to the donor lungs (Fig. 6). Overall, the data showed higher expression of SDF-1a, CXCR4 and PDGFR-b in SMCs of the remodeled pulmonary vessels in IPAH patients.

DISCUSSION

In the present study, we demonstrated: (1) that chronic hypoxic exposure resulted in strong PH and vascular remodeling in the mice with a gain-of-function mutation Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Dahal et al.: Mutant PDGFR- (D849N) and hypoxic PH

Figure 5: Localization of stromal cell derived factor (SDF)-1a, CXCR4and PDGFR-bin hypoxic murine lungs. The localization of SDF-1a, CXCR4 and PDGFR-b was performed by immunohistochemistry on lung tissues from normoxic and hypoxic mutant mice (n=6). The brown staining represents the positive immunoreactivity for the SDF-1a, CXCR4 and PDGFR-b as indicated (arrow) in the figure. Lung sections were also stained for a-SMC actin (purple staining, Arrow head). Representative photomicrographs of immunostained lung sections from mutant mice are shown. V- vessel, B- bronchiole, Scale=20 mm.

in PDGFR-b; (2) that imatinib exerted significant therapeutic benefit by reducing RVSP, RVH and pulmonary artery muscularization; and (3) that an enhanced immunoreactivity for SDF-1a, its receptor CXCR4 and PDGFR-b, was detected largely in pulmonary vascular SMCs in experimental as well as in clinical PH.

PDGF system is believed to play a key role in the pathogenesis of pulmonary vascular remodeling;[11-13] however, in vivo investigation by a genetic approach has been missing. Because knocking out PDGF and their receptors in mice is lethal at embryonic stages,[34] a gain-offunction strategy would serve as an alternative genetic tool. We therefore investigated mice carrying a gain-of-function mutation of PDGFR-b (D849N). [23] We found that chronic hypoxic exposure resulted in the development of PH and vascular remodeling in the D849N mice. The hypoxiainduced RVSP and RVH in D849N mice were comparable to the WT, whereas the pulmonary vascular remodeling was stronger as evident from the higher proportion of Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

fully muscularized vessels in the D849N mice. In general, the pulmonary vascular muscularization associated with chronic hypoxia is attributable to the PDGF-mediated proliferation and migration of vascular SMCs.[35-37] The ligand-independent receptor autophosphorylation and/or the increased sensitivity of the mutant PDGFR-b tyrosine kinase (TK) towards lower local concentration of PDGF[23] may have amplified the vascular SMC proliferation and/ or shifted the proliferation towards earlier time points, leading to an increased muscularization in the hypoxic D849N mice. The remodeling in D849N mice, nevertheless, did not turn out to be as severe as was anticipated. Our data may be explained by previous studies.[38,39] In a chronic liver injury model, the D849N mice showed an enhanced proliferative response in the initial stage of disease with only a weak influence on the chronic disease stage.[39] In line with this, a syngenic and orthotopic tumor model study revealed that the tumor growth was faster in the D849N mice during the early establishment phase, whereas the tumor growth rate was similar between WT 265

Dahal et al.: Mutant PDGFR- (D849N) and hypoxic PH

Figure 6: Localization of stromal cell derived factor (SDF)-1a, CXCR4ď&#x20AC; and PDGFR-b in lungs from IPAH patients. By immunohistochemistry, the localization of SDF-1a, CXCR4 and PDGFR-b was performed on serial sections of lung tissues from donors and patients with IPAH (n=4). The brown staining (arrow) represents the positive immunoreactive signal for the SDF-1a, CXCR4 and PDGFR-b. The lung tissues were also stained for a-SMC actin (purple color, arrow head). In addition, negative control staining was performed by using blocking solution instead of the primary antibody. Representative photomicrographs of immunostained and the negative control staining of the lung sections from donor and patients with IPAH are shown. V â&#x20AC;&#x201C; Vessel, Scale=20 mm.

and D849N mice during later phases.[38] The enhanced early tumor growth may be attributable to higher basal activation and to higher sensitivity of mutant PDGFR-b toward lower ligand concentrations.[23] However, in the current study, factors such as hypoxia and increased shear stress strongly induce the PDGF and PDGFR expression in vascular cells.[40,41] Thus, the availability of the ligand and the receptor may be attributed to yield a comparable PDGFR activation in hypoxic pulmonary vessels of WT and D849N mice. This notion is supported by the experimental evidence that the ligand-dimerized WT and D849N receptors elicit a comparable kinetics of TK autoactivation. [23] Moreover, study of a murine model of liver fibrosis has indicated that PDGFR signaling is not solely dependent on pure ligand activation,[38] and other factors such as reactive oxygen species can activate the receptor TK.[42]

Corroborating the previous finding,[13] we observed that imatinib significantly improved PH, RVH and pulmonary vascular remodeling in hypoxic WT and D849N mice. Moreover, we observed that imatinib inhibited the activation of mutant PDGFR-b (D849N) as effectively as that of WT receptor in vitro, suggesting that this could be the predominant mode of action involved in the therapeutic benefit. On the other hand, Gambaryan et al. report that imatinib prevents hypoxia-induced PH and vascular remodeling in mice by reducing the accumulation 266

of perivascular BM-derived c-kit+ progenitor cells.[43] However, the authors did not investigate the effects of imatinib after PH was established. We recently demonstrated that pharmacological inhibition of c-kit in a preventive approach ameliorated monocrotaline-induced PH, RVH and pulmonary vascular remodeling, but did not provide therapeutic benefit when we started the inhibition after the PH was established.[44] Taken together, it may be deduced that PDGFR signaling plays a major pathogenic role and imatinib provides therapeutic benefits by targeting PDGFR activation in experimental PH; whereas c-kit may be involved in the early development of experimental PH. We performed global gene expression studies and analyzed the data by pathway analysis database (KEGG). We found that various biological pathways were differentially active in D849N mice under hypoxia and as expected, the majority of the identified pathways were those involved in cellular processes and metabolism such as cell growth, division and immune response. Based on the gene expression data and the literature as outlined in the background, we investigated the chemokine SDF-1a, one of the differentially regulated genes under hypoxia. SDF-1a has been implicated in a range of pathological conditions including cancers and cardiovascular diseases. [45,46] The inflammatory and progenitor cell Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Dahal et al.: Mutant PDGFR- (D849N) and hypoxic PH

recruitments are described as the modes of SDF-1 function by activating its cognate receptor CXCR4. [22,47-49] However, the concordance as to the progenitor cell types recruited and their consequences in cardiovascular pathology is lacking. Some studies attribute a beneficial function to SDF-1a in therapeutic vascularization/angiogenesis by recruiting endothelial progenitor cells (EPC),[49] whereas others describe a detrimental role in neointima formation by recruiting smooth muscle progenitor cells (SPC),[22] suggesting that SDF-1a may have disease- or model specific functions. We found an enhanced immunoreactivity for SDF-1a and its receptor CXCR4 localized largely to the a-SMC actin positive cells in remodeled vessels. The higher SDF-1a/CXCR4 expression may be attributable to HIF-1 induction under hypoxic condition.[50,51] In line with the recent studies,[19,52] our data suggest a role for SDF-1 in the process of hypoxic pulmonary vascular remodeling. Moreover, SDF-1a expressed in neointimal SMCs has been proposed to play an essential role in local SPC recruitment,[22] suggesting a paracrine function for SDF1a. Subsequently, both autocrine and paracrine modes of actions have been proposed.[53] The involvement of SDF-1a in growth and progression of cancer implies that it may act both in autocrine and paracrine fashion in cancer cells. [14- 16] In the current study, the localization of SDF-1a and its receptor CXCR4 to vascular SMCs suggests that both autocrine and paracrine modes of action seem likely in the process of hypoxic pulmonary vascular remodeling. In addition, we detected a stronger immunoreactivity for SDF-1 and CXCR4 largely in a-SMC actin positive vascular cells in IPAH patients and our finding is line with a recent study. [54] Furthermore, we observed that PDGFR-b expression was enhanced in a-SMC actin positive pulmonary vascular cells in experimental and clinical PH, suggesting a coexpression of the chemokine SDF1a and PDGFR in remodeled vessels. Interestingly, the coexpression of SDF-1 and PDGFR has been observed in glioblastoma tissue and in addition, SDF-1 expression level in human glioma has been identified as a predictor of sensitivity to imatinib, [18] suggesting a functional link between SDF-1 and PDGFR signaling. Our findings hint towards a potential functional interaction between SDF-1a and PDGF signaling in the process of pulmonary vascular remodeling and thus may unravel a previously unrecognized similarity between cancer and PH. In conclusion, our findings substantiate the major role of PDGFR in pulmonary vascular remodeling by a genetic approach. The immunohistochemistry findings suggest a role for SDF-1a/CXCR4 axis in pulmonary vascular remodeling and point to a potential interaction between the chemokine SDF-1 and the growth factor PDGF signaling. Future studies designed to elucidate an interaction between the chemokine SDF-1 and the PDGF system may uncover novel therapeutic targets. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

ACKNOWLEDGMENTS We thank Ewa Bieniek for her technical assistance.

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Source of Support: German research foundation Deutsche Forschungsgemeinschaft (DFG). Conflict of Interest: None declared.

Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Research A r t i cl e

Activity of Ca2+-activated Cl- channels contributes to regulating receptor- and store-operated Ca2+ entry in human pulmonary artery smooth muscle cells Aya Yamamura, Hisao Yamamura, Amy Zeifman, and Jason X.-J. Yuan Department of Medicine, Section of Pulmonary, Critical Care, Sleep and Allergy, Institute for Personalized Respiratory Medicine, Center for Cardiovascular Research, and Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, USA

ABSTRACT Intracellular Ca2+ plays a fundamental role in regulating cell functions in pulmonary arterial smooth muscle cells (PASMCs). A rise in cytosolic Ca2+ concentration ([Ca2+]cyt) triggers pulmonary vasoconstriction and stimulates PASMC proliferation. [Ca2+]cyt is increased mainly by Ca2+ release from intracellular stores and Ca2+ influx through plasmalemmal Ca2+-permeable channels. Given the high concentration of intracellular Cl- in PASMCs, Ca2+-activated Cl- (ClCa) channels play an important role in regulating membrane potential and cell excitability of PASMCs. In this study, we examined whether activity of ClCa channels was involved in regulating [Ca2+]cyt in human PASMCs via regulating receptor- (ROCE) and store- (SOCE) operated Ca2+ entry. The data demonstrated that an angiotensin II (100 nM)-mediated increase in [Ca2+]cyt via ROCE was markedly attenuated by the ClCa channel inhibitors, niflumic acid (100 µM), flufenamic acid (100 µM), and 4,4’-diisothiocyanatostilbene-2,2’-disulfonic acid (100 µM). The inhibition of ClCa channels by niflumic acid and flufenamic acid significantly reduced both transient and plateau phases of SOCE that was induced by passive depletion of Ca2+ from the sarcoplasmic reticulum by 10 µM cyclopiazonic acid. In addition, ROCE and SOCE were abolished by SKF-96365 (50 µM) and 2-aminoethyl diphenylborinate (100 µM), and were slightly decreased in the presence of diltiazem (10 µM). The electrophysiological and immunocytochemical data indicate that ClCa currents were present and TMEM16A was functionally expressed in human PASMCs. The results from this study suggest that the function of ClCa channels, potentially formed by TMEM16A proteins, contributes to regulating [Ca2+]cyt by affecting ROCE and SOCE in human PASMCs. Key Words: angiotensin II, Ca2+ signaling, Ca2+-activated Cl- current, niflumic acid, TMEM16A

INTRODUCTION In pulmonary artery smooth muscle cells (PASMCs), cytosolic Ca2+ concentration ([Ca2+]cyt) is mainly regulated by a balance of Ca2+ release from intracellular stores and Ca2+ influx through plasmalemmal Ca2+-permeable channels, as well as Ca2+ sequestration into intracellular stores by the Ca2+-Mg2+ ATPase on the sarcoplasmic/ endoplasmic reticulum membrane (SERCA) and Ca2+ extrusion via the Ca2+-Mg2+ ATPase and Na+/Ca2+ exchanger Address correspondence to: Prof. Jason X.-J. Yuan Department of Medicine University of Illinois at Chicago COMRB Rm. 3131 (MC 719) 909 South Wolcott Avenue Chicago IL 60612 USA Phone: (312) 355-5911 Fax: (312) 996-1793 Email: jxyuan@uic.edu

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on the plasma membrane.[1,2] PASMCs functionally express various Ca2+-permeable channels including (a) voltagedependent Ca2+ channels (VDCCs) that are activated by membrane depolarization,[3] and (b) receptor-operated Ca2+ (ROC) channels that are stimulated and activated by vasoconstrictors, such as endothelin-1,[4] serotonin,[5] phenylephrine,[6] and histamine,[7] and by growth factors, including epidermal growth factor[8] and platelet-derived growth factor. [9] The activation of ROC channels by interaction between ligands and membrane receptors Access this article online

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Website: www.pulmonarycirculation.org DOI: 10.4103/2045-8932.83447 How to cite this article: Yamamura A, Yamamura H, Zeifman A, Yuan JX. Activity of Ca 2+ -activated Cl- channels contributes to regulating receptor- and store-operated Ca 2+ entry in human pulmonary artery smooth muscle cells. Pulm Circ 2011;1:269-79.

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results in receptor-operated Ca2+ entry (ROCE) that greatly contributes to increases in [Ca2+]cyt in PASMCs exposed to vasoconstrictors and growth factors.[1,10,11] PASMCs also possess (c) store-operated Ca2+ (SOC) channels that are opened by the depletion of Ca2+ from the sarcoplasmic reticulum (SR), which leads to capacitative Ca2+ entry, or store-operated Ca2+ entry (SOCE). SOCE is an important mechanism involved in maintaining a sustained elevation of [Ca2+]cyt and refilling Ca2+ into the depleted SR.[1,10-12] We showed previously that increased Ca2+ influx through SOC or SOCE contributes to stimulating PASMC proliferation; inhibition of SOCE significantly attenuated growth factormediated PASMC proliferation. These results suggest that SOCE plays a significant role in regulating proliferation in vascular smooth muscle cells.[9,13,14]

It has been well demonstrated that the activity of Ca activated Cl- (ClCa) channels play an important role in regulating contraction, migration, and apoptosis in many cell types. [15,16] In vascular smooth muscle cells, Cl Ca channels are activated by a rise in [Ca2+]cyt following agonistinduced Ca2+ release from the SR through inositol-1,4,5trisphosphate receptors (IP3Rs). In addition, the activation of ClCa channels is evoked by spontaneous Ca2+ release through ryanodine receptors in the SR and is responsible for eliciting spontaneous transient inward currents in several types of vascular smooth muscle cells. The intracellular Clconcentration in vascular smooth muscle cells (including PASMCs) is estimated to be 30 to 60 mM,[15-17] so the reversal potential for Cl- is supposed to be much less negative (ranging from -20 to -30 mV) than that for K+ (approximately -80 mV). Therefore, an increase in Cl- conductance in PASMCs under these conditions would generate inward currents (due to Cl- efflux) and cause membrane depolarization which subsequently induces Ca2+ influx by opening VDCCs and ultimately results in vasoconstriction. The molecular composition of ClCa channels in vascular smooth muscle cells (including PASMCs), however, is not fully identified. Recently, a transmembrane protein encoded by TMEM16A gene has been demonstrated to form ClCa channels in vascular smooth muscle cells.[18-20] 2+

In this study, we examined whether ClCa channel activity was involved in the regulation of [Ca 2+] cyt via ROCE and SOCE in human PASMCs using digital imaging fluorescence microscopy. We also examined the functional expression of ClCa channels (TMEM16A) in human PASMCs using electrophysiological and immunocytochemical approaches.

MATERIALS AND METHODS Cell culture

Human PASMCs (passage 5 to 10) from normal subjects 270

were purchased from Lonza (Walkersville, MD) Cells were cultured in Medium 199 (Invitrogen-GIBCO, Grand Island, NY) supplemented with 10% fetal bovine serum (Invitrogen-GIBCO), 100 U/ml penicillin plus 100 µg/ ml streptomycin (Invitrogen-GIBCO), 50 µg/ml D-valine (Sigma-Aldrich, St. Louis, MO), and 20 µg/ml endothelial cell growth supplement (BD Biosciences, Franklin Lakes, NJ) at 37°C. All cells were incubated in a humidified 5% CO2 atmosphere at 37°C. After reaching confluence, the cells were sub-cultured by trypsinization with 0.05% trypsinEDTA (Invitrogen-GIBCO), plated onto 25-mm cover slips (Fisher Scientific, Pittsburgh, PA). and incubated at 37°C for 1-3 days before electrophysiological and fluorescence microscopy experiments.

[Ca2+]cyt measurement

Human PASMCs cultured on 25-mm cover slips were placed in a recording chamber on the stage of an invert fluorescent microscope (Eclipse Ti-E; Nikon, Tokyo, Japan) equipped with an objective lens (S Plan Fluor 20×/0.45 ELWD; Nikon) and an EM-CCD camera (Evolve; Photometrics, Tucson, AZ). [Ca2+]cyt was monitored using a membranepermeable Ca2+-sensitive fluorescent indicator, fura-2 acetoxymethyl ester (fura-2/AM; Invitrogen-Molecular Probes, Eugene, OR) and imaged with NIS Elements 3.2 software (Nikon). Cells were loaded by incubation in HEPES-buffered solution containing 4 µM fura-2/AM for 60 min. at room temperature (25°C). The loaded cells were then washed with HEPES-buffered solution for 10 min. to remove excess extracellular indicator and allow sufficient time for intracellular esterase to cleave acetoxymethyl ester from fura-2. Cells were then excited at 340-nm and 380-nm wavelengths (D340×v2 and D380×v2 filters, respectively; Chroma Technology, Bellows Falls, VT) by a xenon arc lamp (Lambda LS; Sutter Instrument, Novato, CA) and an optical filter changer (Lambda 10-B; Sutter Instrument). Emission of Fura-2 was collected through a dichroic mirror (400DCLP; Chroma Technology) and a wide band emission filter (D510/80m; Chroma Technology). [Ca2+]cyt within a region of interest (5×5 µm) that was placed at the peripheral region of each cell was measured as the ratio of fluorescence intensities (F340/F380) every 2 sec. The HEPES-buffered solution had an ionic composition of 137 mM NaCl, 5.9 mM KCl, 2.2 mM CaCl2, 1.2 mM MgCl2, 14 mM glucose, and 10 mM HEPES. The pH was adjusted to 7.4 with 10 N NaOH. The external Ca2+-free solution was prepared by removing extracellular CaCl2 and adding 1 mM EGTA (to chelate the residual Ca2+ in the bath solution). The recording chamber was continuously perfused with HEPESbuffered solution at a flow rate of 2 ml/min. using a minipump (Model 3385; Control, Friendswood, TX). [Ca2+]cyt measurements were carried out at 32°C using an automatic temperature controller (TC-344B, Warner Instruments, Holliston, MA). Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Yamamura et al.: Functional role of ClCa channels in human PASMCs

Electrophysiological recording

The whole-cell Cl Ca current in a single PASMC was recorded using the patch-clamp technique with an Axopatch-1D amplifier (Molecular Devices-Axon, Foster City, CA), an analog-digital converter (Digidata 1200; Molecular Devices-Axon), and pCLAMP 8 software (Molecular Devices-Axon). The extracellular (bath) solution had an ionic composition of 137 mM NaCl, 10 mM tetraethylammonium (TEA) chloride, 5 mM 4-aminopyridine (4-AP), 2.2 mM CaCl2, 1.2 mM MgCl2, 14 mM glucose, and 10 mM HEPES. The pH was adjusted to 7.4 with 10 N NaOH. The low Cl- concentration solution was prepared by substituting 117 mM NaCl of the extracellular solution with the equal molar of sodium gluconate. The pipette (intracellular) solution contained 120 mM CsCl, 20 mM TEA chloride, 4.3 mM CaCl2, 2.8 mM MgCl2, 2 mM Na2ATP, 10 mM HEPES, and 5 mM EGTA. The pCa was fixed to 6.0, which was estimated by the Maxchelator program (http://www.stanford. edu/~cpatton/maxc.html). The pH was adjusted to 7.2 with 1 N CsOH. The recording chamber was continuously superfused with extracellular solution at a flow rate of 2 ml/min. using a perfusion system (VC-6; Warner Instrument, Hamden, CT). Electrophysiological recordings were carried out at room temperature (25°C).

Immunocytochemical staining

Cultured cells on 35-mm culture dishes with 14-mm glass bottom (MatTek, Ashland, MA) were fixed with 4% paraformaldehyde in Dulbecco’s phosphate buffered saline (DPBS; Invitrogen-GIBCO) for 10 min. at room temperature (25°C). Excessive paraformaldehyde was removed thoroughly with DPBS. The cells were then treated with DPBS containing 0.2% Triton X-100, 1% normal goat serum (Dako Denmark, Glostrup, Denmark), and TMEM16A antibody (pre-diluted, ab53213, Abcam, Cambridge, MA; or 1:100 dilution, ab53212, Abcam) for 12 hr. at 4°C. After washing repeatedly in DPBS, the cells were covered with DPBS containing 0.2% Triton X-100, 1% normal goat serum, and Alexa Fluor 488-labeled secondary antibody (1:100 dilution; Invitrogen-Molecular Probes) for 1 hr. at room temperature and then rinsed with DPBS. Then cells were mounted in VECTASHIELD hard-set mounting medium with 4’,6-diamidino-2phenylindole (DAPI, 1.5 µg/ml) (Vector Laboratories, Burlingame, CA) and placed on the stage of an invert fluorescent microscope (Eclipse Ti-E; Nikon) equipped with an objective lens (Plan Apo 60×/1.40 oil immersion; Nikon), a CCD camera (CoolSNAP ES2; Photometrics), and NIS Elements 3.2 software (Nikon). Immunocytochemical images were obtained using the specific filter sets for DAPI (Ex340-380/DM400/Em435-485; Chroma Technology) and Alexa Fluor 488 (Ex460-500/DM505/Em510-560; Chroma Technology). Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Drugs

Pharmacological reagents were obtained from SigmaAldrich. All hydrophobic compounds were dissolved in dimethyl sulfoxide (DMSO) at the concentration of 10 or 100 mM as a stock solution. It was confirmed that up to 0.1 % of DMSO did not affect these responses.

Statistical analysis

Pooled data are shown as the mean±SE. The statistical significance between two groups was determined by Student’s t-test. The statistical significance among groups was determined by Scheffé’s test after one-way analysis of variance. Significant difference is expressed in the figures as *P<0.05 or **P<0.01.

RESULTS

Inhibition of agonist-induced Ca2+ influx or ROCE by ClCa channel blockers in human PASMCs

The increase in [Ca2+]cyt evoked by agonist stimulation was imaged in human PASMCs loaded with 4 μM fura2/AM and quantitated in arbitrary units (au) by the change in F340/F380 ratio. Short-term application (2 min.) of 100 nM angiotensin II induced a transient increase in [Ca2+]cyt (by 0.49±0.01 au, n=150) (Figs. 1 and 2). The angiotensin II-induced [Ca2+]cyt increase was attenuated by 100 μM niflumic acid, a fenamate compound that is most frequently used as a blocker of ClCa channels (from 0.51±0.03 to 0.13±0.02 au, n=29, P<0.01) (Fig. 1a and d). The inhibitory effect of niflumic acid on the angiotensin II-mediated increase in [Ca2+]cyt was reversible upon washout (0.42±0.04 au, n=29). Pretreatment with 100 μM flufenamic acid, another fenamate compound that blocks ClCa channels, markedly reduced the angiotensin II-induced [Ca2+]cyt increase (from 0.51±0.02 to 0.13±0.03 au, n=33, P<0.01) (Fig. 1 b and e). A different type of Cl- channel blocker, 4,4’-diisothiocyanatostilbene-2,2’disulfonic acid (DIDS)–one of the stilbene derivatives that is structurally unrelated to fenamates–also caused a significant inhibition of the angiotensin II-induced [Ca2+]cyt increase (from 0.43±0.04 to 0.06±0.01 au, n=18, P<0.01) (Fig. 1c and f). These data indicated that the function of ClCa channels is involved in regulating ROCE in human PASMCs; inhibition of ClCa channels significantly and reversibly attenuates the agonist-mediated Ca2+ entry.

Effects of Ca2+ channel blockers on ROCE in human PASMCs

To elucidate the Ca2+ signal pathway for angiotensin II-induced ROCE, effects of the inhibitors for several different types of Ca 2+ channels were examined in human PASMCs. The angiotensin II-mediated increase in 271

Yamamura et al.: Functional role of ClCa channels in human PASMCs

Figure 1: Attenuation of ROCE by ClCa channel blockers in human PASMCs. Angiotensin II (AngII, 100 nM) was used to induce ROCE in human PASMCs. (a-c) Representative traces showing angiotensin II-induced [Ca2+]cyt increases in human PASMCs before, during, and after application of 100 μM niflumic acid (NFA; a), flufenamic acid (FFA; b), and DIDS (c). Blockage of ClCa channels reduces angiotensin II-induced [Ca2+]cyt elevation in human PASMCs. (d-f) Summarized data showing the reversible inhibitory effects of niflumic acid (d), flufenamic acid (e), and DIDS (f) on angiotensin II-induced [Ca2+]cyt rises in human PASMCs. Statistical significance (versus control) is indicated as **P<0.01.

[Ca2+]cyt was reduced by treatment with 50 μM SKF-96365, an inhibitor of non-selective cation channels (from 0.59±0.05 to 0.28±0.04 au, n=13, P<0.01) (Fig. 2 a and d). The application of 100 μM 2-aminoethoxydiphenylborate (2-APB), which blocks IP3Rs and also non-selective cation channels, abolished the angiotensin II-induced increase in [Ca2+]cyt (from 0.46±0.03 to 0.08±0.01 au, n=22, P<0.01) (Fig. 2 b and e). Blockage of VDCC with 10 μM diltiazem, however, had a trend to inhibit the angiotensin II-induced [Ca2+]cyt increase (from 0.45±0.02 to 0.36±0.03 au, n=35, P>0.05 by Scheffé’s test, but P<0.01 by Student’s t-test) (Fig. 2 c and f). These pharmacological data indicate that the angiotensin II-induced [Ca2+]cyt increase was mainly caused by Ca2+ release from the SR through IP3R followed by Ca2+ influx via non-selective cation channels in human PASMCs. Ca2+ influx through the diltiazem-sensitive L-type VDCCs slightly contributes to the angiotensin II-induced rise of [Ca2+]cyt in human PASMCs. 272

Inhibitory effect of ClCa channel blockers on SOCE in human PASMCs In the next set of experiments, we examined the effect of Cl Ca channel blockers on SOCE in human PASMCs (Fig. 3). SOCE was induced by passive depletion of Ca2+ from the SR with 10 μM cyclopiazonic acid (CPA), a blocker of SERCA. In the absence of extracellular Ca2+, application of CPA induced a transient increase in [Ca2+]cyt that was due predominantly to Ca2+ leakage from the SR to the cytosol. Restoration of extracellular Ca2+ after approximately 10 min. treatment with CPA caused another increase in [Ca2+]cyt that was apparently due to Ca2+ influx through store-operated cation (or Ca2+) channels or SOCE.

As shown in Figure 3, there were no significant differences in the resting [Ca2+]cyt (0.59±0.02 versus 0.62±0.02 au, n=55, P=0.25) and the amplitude of the increase in [Ca2+]cyt due to CPA-induced Ca2+ leakage from the SR to Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Yamamura et al.: Functional role of ClCa channels in human PASMCs

Figure 2: Effects of Ca2+ channel blockers on ROCE in human PASMCs. Angiotensin II (AngII, 100 nM) was used to induce ROCE in human PASMCs. (a-c) Representative traces showing angiotensin II-induced [Ca2+]cyt rises in human PASMCs before, during, and after application of 50 µM SKF-96365 (SKF, an inhibitor of nonselective cation channels; a), 100 µM 2-APB (which blocks IP3Rs and also non-selective cation channels; b), and 10 µM diltiazem (a VDCC blocker; c). (d-f) Summarized data showing effects of SKF-96365 (d), 2-APB (e), and diltiazem (f) on angiotensin II-induced [Ca2+]cyt increase in human PASMCs. Statistical significance (versus control) is indicated as **P<0.01.

the cytosol when cells were treated with 100 µM niflumic acid or vehicle (0.1% DMSO) (Fig. 3 a and b). The transient and plateau phases of CPA-induced increases in [Ca2+]cyt due to SOCE, as well as the amplitude and “rise-speed” of SOCE were all significantly decreased by 100 µM niflumic acid. The rise-speed of SOCE in the presence of niflumic acid (0.18±0.01 ratio/s, n=55) was significantly slower than that in the absence (0.36±0.04 ratio/s, P<0.01 (Fig. 3c). In addition, application of niflumic acid significantly reduced the amplitude of the transient (from 0.42±0.02 to 0.31±0.02 au, n=55; P<0.01) and plateau (from 0.15±0.01 to 0.10±0.01 au, n=55; P=0.02) phases of SOCE (Fig. 3a and d). Treatment of the cells with 100 µM flufenamic acid also significantly decreased the amplitude of the transient and plateau phases of CPA-induced SOCE in human PASMCs (n=34). These data clearly suggest that the activity of ClCa channels is involved in regulating SOCE in human PASMCs. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Effects of Ca2+ channel blockers on SOCE in human PASMCs

To functionally define the Ca2+ channels responsible for CPA-mediated SOCE, we examined the effects of different Ca 2+ channel blockers on SOCE in human PASMCs. The transient component of CPA-induced SOCE was significantly reduced by 50 µM SKF-96365 (0.21±0.01 au, n=51, versus vehicle control, 0.37±0.01 au, n=58; P<0.01) (Fig. 4 a, b and e) and 100 µM 2-APB (0.10±0.01 au, n=46, P<0.01) (Fig. 4 c and e). Application of 10 µM diltiazem slightly (but significantly) affected the transient component of SOCE (from 0.37±0.01 to 0.32±0.01 au, n=42, P<0.01), but had no effect on the plateau phase of SOCE (from 0.16±0.01 au, n=58, to 0.14±0.01 au, n=42, P=0.22) (Fig. 4 a, d and e). Similar to their effects on the transient phase of SOCE, 50 µM SKF-96365 (from 0.16±0.01, n=58, to 0.06±0.01 au, n=51; P<0.01) (Fig. 4a, b and e) or 100 µM 2-APB (to 0.05±0.01 au, n=46, P<0.01) 273

Yamamura et al.: Functional role of ClCa channels in human PASMCs

whole-cell patch-clamp configuration using a pipette (intracellular) solution containing 120 mM Cs +, 20 mM TEA (pCa=6.0) and a bath (extracellular) solution containing 10 mM TEA and 5 mM 4-AP. The mean cellcapacitance was 9.0±1.2 pF (n=14). Depolarizing pulses (500 ms) were applied from a holding potential of -60 mV to a series of test potentials ranging from -80 to +100 mV by 20-mV increments every 15 sec. Outward currents were elicited by depolarization from the holding potential to the positive potentials above 0 mV, and the averaged current density at +100 mV was 86±7 pA/ pF (n=14) (Fig. 5 a and b). The reversal potential of the whole-cell currents was -3.4±1.3 mV (n=14) (Fig. 5b), which is close to the theoretical (or calculated) equilibrium potential of Cl- (+0.1 mV). In addition, the reversal potential was shifted positively (to the right) by approximately 30 mV (positive shift by 36 mV in theory) by changing the extracellular Cl- concentration from 153.8 to 36.8 mM (data not shown). Importantly, we were able to detect inward “tail” currents when cells were repolarized to the holding potential (Fig. 5a), which is an important characteristic of ClCa currents. Furthermore, we analyzed the tail currents and the current-voltage relationship using the pulse protocol as follows: depolarizing pre-pulses were applied from a holding potential of -60 to +100 mV for 100 ms and subsequently test pulses were applied between -40 to +40 mV by 10-mV increments for 500 ms every 15 sec. (Fig. 5c). The current-voltage relationship revealed that the reversal potential of the tail currents (1.9±0.9 mV, n=4; Fig. 5d) was also very close to the theoretical (or calculated) equilibrium potential of Cl-. Figure 3: Attenuation of SOCE by ClCa channel blocker in human PASMCs. SOCE was induced by passive depletion of Ca2+ from the SR with 10 µM CPA in human PASMCs. (a) Typical trace of CPA-induced Ca2+ release and SOCE in the absence (vehicle, 0.1% DMSO) and presence of 100 µM niflumic acid (NFA) in a human PASMC. Blockage of ClCa channels caused a reduction of SOCE in human PASMCs. (b-d) Summarized data showing effects of niflumic acid on the resting [Ca2+]cyt (b), the rise speed of SOCE (c), the transient and plateau amplitudes of CPA-induced SOCE (d) in human PASMCs. Statistical significance versus vehicle control is indicated as *P<0.05 or **P<0.01.

(Fig. 4c and e) also significantly reduced the plateau phase of CPA-induced SOCE. These pharmacological data indicate that the Ca2+ signaling pathway for CPA-induced SOCE was mainly dependent on Ca2+ influx through non-selective cation channels in human PASMCs. The activity of VDCCs might be, in part, involved in the Ca2+ influx pathway in human PASMCs.

Whole-cell ClCa currents in human PASMCs

Electrophysiological and pharmacological properties of ClCa currents in human PASMCs were analyzed by 274

Application of 100 µM niflumic acid significantly attenuated both the outward ClCa current and the inward tail current in human PASMCs (Fig. 6). Niflumic acid decreased the outward currents elicited by depolarization from a holding potential of -60 to +60 mV (for 500 ms every 15 s) (from 37.4±5.3 to 16.5±1.2 pA/pF, n=3; P=0.046). The inward tail currents were also inhibited by the pretreatment with niflumic acid (-5.6±1.3 pA/pF, n=3, versus control of -22.2±4.7 pA/pF, P=0.040). These electrophysiological data indicate that ClCa channels sensitive to niflumic acid are functionally expressed in human PASMCs.

Expression of TMEM16A in human PASMCs

The molecular basis of ClCa channels in human PASMCs was identified by an immunocytochemical approach using two specific primary antibodies of TMEM16A (ab53213 and ab53212 from Abcam), a potential protein candidate for ClCa channels. Immunocytochemical experiments (Fig. 7) revealed that specific fluorescent signals of TMEM16A protein were localized in the cell membrane. Qualitatively, the same images were obtained from 3 Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Yamamura et al.: Functional role of ClCa channels in human PASMCs

Figure 4: Effects of Ca2+ channel blockers on SOCE in human PASMCs. SOCE was induced by passive depletion of Ca2+ from the SR with 10 µM CPA in human PASMCs. (a-d) Typical traces showing CPA-induced Ca2+ release and SOCE in the absence (vehicle, 0.1% DMSO; a) and presence of 50 µM SKF-96365 (SKF, a blocker for non-selective cation channels; b), 100 µM 2-APB (a blocker of IP3Rs and non-selective cation channels; c), and 10 µM diltiazem (an inhibitor of VDCCs; d) in human PASMCs. (e) Summarized data showing effects of Ca2+ channel blockers on the transient and plateau amplitudes of CPA-induced SOCE in human PASMCs. The number of cells examined is given in parentheses. Statistical significance versus vehicle control is indicated as **P<0.01.

separate sets of experiments. This result indicates that the activity of ClCa channels in human PASMCs is potentially due to channels formed by TMEM16A.

DISCUSSION

In vascular smooth muscle cells, ClCa channels are present for diverse physiological and pathological functions. In this study, we showed that the blockage of ClCa channels using pharmacological tools markedly attenuated both ROCE and SOCE in human PASMCs. Our electrophysiological and immunocytochemical data also indicated that the activity of ClCa channels functionally expressed in human PASMCs was due potentially to channels formed by TMEM16A proteins.

Intracellular free Ca2+ plays an important role in the regulation of contraction, proliferation, and migration of PASMCs. An increase in [Ca2+]cyt in PASMCs is a major trigger for pulmonary vasoconstriction and an important stimulus for PASMC proliferation that leads to pulmonary vascular remodeling under pathological conditions. Elevation of [Ca2+]cyt in PASMCs results from Ca2+ release from intracellular stores, such as the SR, and Ca2+ influx through plasmalemmal Ca 2+ channels, such as ROC channels, SOC channels, and VDCCs.[1,2] Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Angiotensin II is a vasoconstrictor that is commonly used for eliciting agonist-induced [Ca 2+] cyt rises in PASMCs and other vascular smooth muscle cells.[21,22] In this study, we used angiotensin II to induce ROCE because, at the concentration of 100 nM, it caused an increase in [Ca2+] cyt in a large number of human PASMCs (>70%). The angiotensin II-mediated increase in [Ca2+]cyt via ROCE was markedly reduced by two different types of ClCa channel inhibitors, fenamates (niflumic acid and flufenamic acid) and one of the stilbene derivatives (DIDS). Both niflumic acid and flufenamic acid are well known fenamates that are most frequently used as Cl Ca channel blockers in electrophysiological and pharmacological studies. However, these compounds have been reported to also act on other types of ion channels such as non-selective cation channels, [23] large-conductance Ca2+-activated K+ channels,[24] and transient receptor potential canonical subfamily (TRPC) channels.[25] Therefore, to confirm whether or not the inhibitory effects of niflumic acid and flufenamic acid on the angiotensin II-evoked increase in [Ca2+]cyt in human PASMCs were mediated by the blockage of ClCa channels, we analyzed the effects of another type of ClCa channel blocker, DIDS, a stilbene derivative that is structurally unrelated to fenamates, on the angiotensin II-induced [Ca2+]cyt increase. Similar to niflumic acid and flufenamic acid, DIDS also significantly suppressed the angiotensin II275

Yamamura et al.: Functional role of ClCa channels in human PASMCs

Figure 6: Inhibition of ClCa currents by niflumic acid in human PASMCs. Effect of niflumic acid on whole-cell ClCa currents was examined in human PASMCs. (a) Representative outward currents (black arrowhead), elicited by depolarization from a holding potential of -60 to +60 mV, and inward tail currents (gray arrowhead), induced by repolarization to -60 mV in the absence (black line) and presence (gray line) of 100 µM niflumic acid (NFA) in a human PASMC. (b) Summarized data showing the effect of niflumic acid on outward (black arrowhead in “a”) and tail (gray arrowhead in “a”) currents in human PASMCs. The number of cells examined is given in parentheses. Statistical significance versus control is indicated as *P<0.05.

Figure 5: Whole-cell ClCa currents in human PASMCs. ClCa currents were measured using a pipette solution containing 120 mM Cs+, 20 mM TEA and pCa 6.0, and a bath solution containing 10 mM TEA and 5 mM 4-AP in human PASMCs. (a) Representative outward currents (black arrowhead), elicited by depolarization from a holding potential of -60 mV to a series of test potentials (-80 to +100 mV) for 500 ms every 15 sec. and inward tail currents (gray arrowhead), induced by repolarization to -60 mV in a human PASMC. (b) I-V relationship at peak amplitude during depolarization (black arrowhead in “a”). The current reverses at about 0 mV, the theoretical equilibrium potential of Cl-. (c) Representative tail currents (gray arrowhead) at a series of test potentials (-40 to +40 mV) for 500 ms after depolarization from a holding potential of -60 to +100 mV for 100 ms every 15 sec. in a human PASMC. (d) I-V relationship of tail currents (gray arrowhead in “c”). The reversal potential is close to 0 mV.

induced [Ca2+]cyt increase, although it might have interfered with the fura-2 fluorescence due to its faint yellow colored solution at a concentration of 100 µM. These results, by using two different types of ClCa channel blockers, strongly suggest that the function of ClCa channels is involved in regulating ROCE in human PASMCs.

SOCE is essential for maintaining a high level of [Ca2+]cyt and for refilling intracellular Ca2+ stores (i.e., SR) in smooth muscle cells.[1,10-12] High levels of [Ca2+]cyt and sufficient levels of Ca2+ in the SR are required for proliferation of vascular smooth muscle cells.[1,10] SOCE is enhanced while SOC channels are upregulated during PASMC proliferation to increase Ca2+ influx and provide sufficient Ca 2+ for activation of the intracellular mechanisms responsible for cell proliferation and growth.[9,13,14] In 276

Figure 7: Expression of TMEM16A in human PASMCs. Immunocytochemical analysis of TMEM16A, a potential candidate for the ClCa channel subunit, was performed in human PASMCs using two specific primary antibodies (ab53213 and ab53212 from Abcam). Alexa Fluor 488 and DAPI were used as a secondary antibody and a nuclear marker, respectively. Specific signals of TMEM16A protein were detected on the plasma membranes of human PASMCs. Similar immunocytochemical images were obtained from 3 sets of independent experiments.

the present study, we demonstrated that the blockage of ClCa channels by niflumic acid and flufenamic acid reduced both the transient and plateau components of SOCE as well as the rise speed of SOCE in human PASMCs. These data indicate that the function of ClCa channels is also involved in regulating SOCE in human PASMCs (in addition to the effect on ROCE). Suppression of SOCE by blockage of ClCa channels is thought to cause reduced PASMC proliferation, which may be a novel strategy for Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Yamamura et al.: Functional role of ClCa channels in human PASMCs

preventing the abnormal proliferation under pathological conditions. TRPC channels have been demonstrated to be involved in agonist- or growth factor-mediated Ca2+ entry in PASMCs,[1,10,26] while functional coupling of stromal interaction molecule (STIM) proteins (STIM1 and STIM2) with TRPC and/or Orai channels have recently been suggested as a novel candidate for SOC channel subunits in PASMCs.[27-29] TRPC channel genes are thought to encode pore-forming subunits that compose ROC[30-32] and SOC[33-35] channels in many cell types of vascular smooth muscles including PASMCs.[9,13,14,36-38] Ca2+ entry via ROC and SOC channels is modulated by second messengers, phosphorylation of signal transduction proteins, and transcription factors.[2,10,39] The protein expression levels of TRPC, STIM and Orai are changed under pathological conditions such as in pulmonary arterial hypertension.[1,10,39] Smooth muscle cells contain a high concentration of Cl- in the intracellular space, which is considerably different from other cell types, such as neurons, cardiomyocytes, and skeletal muscle myocytes.[17] Therefore, increases in Clconductance across the plasma membrane (e.g., as a result of activation of ClCa channels when [Ca2+]cyt is increased) lead to Cl- efflux and inward currents, which consequently causes membrane depolarization, enhanced Ca2+ influx through VDCCs, increased [Ca 2+] cyt, and vasoconstriction.[15,16] In the present study, electrophysiological data indicated that ClCa channels were functionally expressed in human PASMCs and the Cl- currents through ClCa channels were sensitive to niflumic acid. The electrophysiological properties (e.g., the time-dependent outward current during membrane depolarization, the inward tail current during repolarization, the outward rectification, and the shift of reversal potential based on the change in extracellular Cl- concentration) and pharmacological properties (e.g., the dependency on intracellular Ca2+ concentration and the sensitivity to niflumic acid) of whole-cell ClCa currents obtained from human PASMCs were consistent with the same properties reported previously in PASMCs from rabbits[40] and rats.[41,42] The [Ca2+]cyt increase mediated by ROCE and SOCE also activates the ClCa channels, resulting in membrane depolarization followed by additional Ca2+ influx through VDCCs. Slight decreases in ROCE and SOCE by diltiazem, a VDCC blocker, suggested that VDCCs only partly contributed to the regulation of ROCE and SOCE, although the Ca2+ influx pathway was mainly due to non-selective Ca2+ channels sensitive to SKF-96365 and 2-APB in human PASMCs.

ClCa channels play important roles in diverse functions in vascular smooth muscle cells. In spite of its physiological and pathological significances, the molecular architecture of ClCa channels in vascular smooth muscle cells has not been clearly demonstrated. More recently, the TMEM16 Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

family, consisting of 10 genes in mammals, has been found as a novel candidate for ClCa channel subunits.[18-20,43] Heterologous expression of TMEM16A has been shown to generate Cl- currents sensitive to intracellular Ca2+ and with the degree of outward rectification, ion selectivity, and pharmacological profile[18-20] similar to the activity of native ClCa channels observed in many tissues containing interstitial cells of Cajal in gastrointestinal muscles,[44-46] airway epithelial cells,[47,48] as well as vascular smooth muscle cells.[42,49] The distribution pattern of TMEM16A in interstitial cells of Cajal in gastrointestinal muscles,[44-46,50] airway epithelial cells,[47,48] and vascular smooth muscle cells[49] implies the functional expression of ClCa conductance. In this study, TMEM16A protein was localized in the plasma membrane of human PASMCs, indicating that the activity of the ClCa channel in human PASMCs was, at least in part, due to channels formed by TMEM16A. It has been reported that the TMEM16A gene also has some splice variants[18,42,49,51] and TMEM16B, a closely related analogue, also can generate Cl- currents activated by Ca2+.[19, 52-54] It is unclear whether TMEM16B is another subunit that forms ClCa channels in human PASMCs. Pulmonary arterial hypertension is a fatal and progressive disease characterized pathologically by severe pulmonary vascular remodeling. A central aspect of pulmonary vascular remodeling is adventitial, medial, and intimal hypertrophy caused by excessive proliferation of fibroblasts and myofibroblasts in the adventitia, PASMCs in the media and endothelial cells in the intima. The concentric pulmonary vascular wall remodeling or thickened arterial and arteriole wall, narrows the intraarterial lumen, increases pulmonary vascular resistance and ultimately causes pulmonary hypertension. [2,39] Since SOC and ROC channels are upregulated in PASMC isolated from patients with idiopathic pulmonary arterial hypertension (IPAH) and from animals with hypoxiamediated pulmonary hypertension, Ca2+ entry through these upregulated cation channels may play an important pathogenic role in the initiation and progression of pulmonary vascular remodeling under the pathological conditions.â&#x20AC;&#x2030; [1,10,14,26,28,37] It remains unclear, however, whether the activity of ClCa channels is also involved in the sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling in patients with IPAH and animals with hypoxia-induced pulmonary hypertension. Based on the observations from this study, the attenuation of SOCE and ROCE by ClCa channel blockers (e.g., niflumic acid, flufenamic acid, and DIDS) may serve as a potential therapeutic approach for pulmonary vascular disease. Although it is suggested that Cl- channels are involved in SOCE and proliferation in PASMCs, [55,56] further experiments are necessary to elucidate the mechanism underlying the regulation of ROCE and SOCE by Cl Ca channels in human PASMCs. 277

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Source of Support: This work was supported, in part, by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (HL066012 and HL098053 to JX-JY), Conflict of Interest: None declared.

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Functional classification of pulmonary hypertension in children: Report from the PVRI pediatric taskforce, Panama 2011 Astrid E. Lammers1, Ian Adatia2, Maria Jesus del Cerro3, Gabriel Diaz4, Alexandra Heath Freudenthal 5, Franz Freudenthal5, S. Harikrishnan6, Dunbar Ivy7, Antonio A. Lopes8, J. Usha Raj9, Julio Sandoval9, Kurt Stenmark10, and Sheila G. Haworth11 Great Ormond Street Hospital for Children, London, UK, 2Stollery Children’s Hospital, University of Alberta, Edmonton, Canada, La Paz University Hospital, Madrid, Spain, 4National University, Bogota, Colombia, 5Kardiozentrum, La Paz, Bolivia, 6Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India, 7Denver Children’s Hospital, University of Colorado, USA, 8 Heart Institute, University of São Paulo, São Paulo, Brazil, 9University of Illinois at Chicago, Chicago, USA, 10University of Colorado, Denver, USA, 11Emeritus Professor, University College, London, UK 1

ABSTRACT The members of the Pediatric Task Force of the Pulmonary Vascular Research Institute (PVRI) were aware of the need to develop a functional classification of pulmonary hypertension in children. The proposed classification follows the same pattern and uses the same criteria as the Dana Point pulmonary hypertension specific classification for adults. Modifications were necessary for children, since age, physical growth and maturation influences the way in which the functional effects of a disease are expressed. It is essential to encapsulate a child’s clinical status, to make it possible to review progress with time as he/she grows up, as consistently and as objectively as possible. Particularly in younger children we sought to include objective indicators such as thriving, need for supplemental feeds and the record of school or nursery attendance. This helps monitor the clinical course of events and response to treatment over the years. It also facilitates the development of treatment algorithms for children. We present a consensus paper on a functional classification system for children with pulmonary hypertension, discussed at the Annual Meeting of the PVRI in Panama City, February 2011. Key Words: pulmonary hypertension, children, functional class

INTRODUCTION The members of the Pediatric Task Force of the Pulmonary Vascular Research Institute (PVRI) were very aware of the need to develop a functional classification system for children with pulmonary hypertension and discussed the problem at the Annual Meeting of the PVRI held in Panama City in February 2011. We now present the consensus document resulting from our deliberations. We expect that it will be modified and improved in the years to come.

BACKGROUND

Clinical classifications of functional status are created

Address correspondence to:

Dr. Astrid E Lammers Department of Paediatric Cardiology Great Ormond Street Hospital for Children Great Ormond Street London WC1N 3JH, UK Email: astridlammers@gmx.de 280

primarily so that physicians can apply a common language to describe the functional impact of the same underlying disease on individual patients. Classifications should facilitate communication between physicians, all those involved in caring for the patient and the funding agencies providing financial support. The design of clinical trials is heavily dependant on an accepted, standardized means of describing the efficacy or otherwise of the treatment being evaluated. Studying the natural history of a disease, both treated and untreated, is dependant on a universally accepted means of describing functional status. Most importantly, a good classification should encapsulate Access this article online

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Website: www.pulmonarycirculation.org DOI: 10.4103/2045-8932.83445 How to cite this article: Lammers AE, Adatia I, del Cerro MJ, Diaz G, Freudenthal AH, Freudenthal F, Harikrishnan S, Ivy D, Lopes AA, Raj JU, Sandoval J, Stenmark K, Haworth SG. Functional classification of pulmonary hypertension in children: Report from the PVRI pediatric taskforce, Panama 2011. Pulm Circ 2011;1:280-5.

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the clinical status of a patient and so make it possible to review the patientâ&#x20AC;&#x2122;s progress with time and their response to treatment.

Classifications of functional status are familiar to cardiologists caring for adult patients. The New York Heart Association (NYHA), the classification most widely used by adult cardiologists since 1964 describes the functional impact of heart failure and places patients with a similar degree of limitation and similar symptoms into one of four functional classes, Class IV being the most severely disabled (Table 1).[1] The Functional Classification of Pulmonary Hypertension in adults is based on the NYHA classification (Table 2) and was published in 1998 as a consensus document of the WHO Symposium held in Evian in that year.[2] Maintaining the best possible quality of life is crucial in any chronic disease. In adults, The Minnesota Living with Heart Failure (MLHF) questionnaire has been widely used in both hospital and primary care since it was designed in 1984, and has good reliability and validity.[3-5] This questionnaire can be useful in assessing patients with pulmonary hypertension,[6,7] as is the Short Form Health Survey 36 (SF-36).[8,9] The MLHF has been considered a significant predictor of outcome.â&#x20AC;&#x2030;[10] More recently, a disease specific questionnaire, the Cambridge Pulmonary Hypertension Outcome Review Utility Index (CAMPHOR) has been developed, primarily for cost-utility analysis but can also be useful in clinical studies.[11,12] There is no disease specific classification to assess Table 1: NYHA classification of functional status

functional status in children with pulmonary hypertension. Nor is there a generally accepted functional classification for children with heart disease. Measures of generic health status have been developed for children, principally the Children and Youth Version of the International Classification of Functioning, Disability and Health published in 2007. [13,14] This classification assesses body structure and function, level of activity and social participation. It was designed primarily to assess children with neuromotor disabilities. Disease specific functional classifications have been developed for use in children with other conditions such as cystic fibrosis, rheumatoid arthritis and juvenile idiopathic arthritis.[15-18] Quality of life is particularly difficult to assess in children. A Short Form Health Survey has been designed for children, SF-10[19] and can be used in children with pulmonary hypertension, but it is not disease specific. Nor does it help assess children less than 5 five years of age.

DESIGNING THE PROPOSED FUNCTIONAL CLASSIFICATION OF PULMONARY HYPERTENSION IN CHILDREN

The proposed Functional Classification of Pulmonary Hypertension in Children is based on the Evian pulmonary hypertension specific classification used in adults. It is not designed to assess quality of life and neither parent nor child makes a personal, direct contribution to the assessment. Particularly in children however, assessing

NYHA Class Symptoms I II III IV

Patients with heart disease but without limitation of physical activity Patients with heart disease resulting in slight limitation of physical activity Comfortable at rest Patients with heart disease resulting in marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, dyspnoea, palpitations, anginal pain Patients with heart disease resulting in inability to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort increases

Table 2: WHO classification of pulmonary hypertension in adults Class Symptoms I II III IV

Patients with pulmonary hypertension but without limitation of physical activity. Ordinary physical activity does not cause undue dyspnoea, fatigue chest pain or near syncope Patients with pulmonary hypertension resulting in slight limitation of physical activity. Comfortable at rest. Ordinary physical activity causes undue dyspnoea, fatigue, chest pain or near syncope Patients with pulmonary hypertension resulting in marked limitation of activity. Comfortable at rest. Less than ordinary activity causes dyspnoea or fatigue, chest pain or near syncope Patients with pulmonary hypertension resulting in inability to carry out any physical activity without symptoms. These patients manifest symptoms of right heart failure. Dyspnoea and/or fatigue may be present even at rest. Discomfort is increased by any physical activity undertaken. Syncope or near syncope can occur

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function and activity does inform the physician about the quality of life.

Designing a functional classification is particularly difficult in children because the age, physical growth and maturation achieved influences the way in which the functional effects of a disease are expressed. It is essential therefore to be able to encapsulate a child’s clinical status as he/she grows up in a consistent manner which makes it possible to monitor the clinical course of events over the years. In young children it is particularly challenging to distinguish whether any apparent deficiency in expectation can be attributed to the disease or is merely a normal variant in a developmental milestone. This is especially the case if pulmonary hypertension is

complicated by syndromic or chromosomal abnormalities that affect motor and sensory function. Since any parent is naturally loathe to acknowledge that their child is really ill, any clinical classification needs to be as objective as possible.

The proposed Functional Classification of Pulmonary Hypertension in Children follows the same pattern as the adult classification (Tables 3-7). There are four classes of disease severity, Class IV being the most severe. Class III has been subdivided into a) and b). We have tried to ensure that the classification will give a comprehensive summary of the child’s clinical condition, while keeping it practical and easy to use. We decided to define functional class in five different age groups (Table 3). Three of the groups

Table 3: Pediatric functional classification for children aged 0–0.5 years Class I II IIIa IIIb IV

Children with pulmonary hypertension Asymptomatic, growing and developing normally, no limitation of physical activity. Gains head control and increases body tone from 0 to 3 months, then rolls over and has no head lag. Sitting with support Slight limitation of physical activity, unduly dyspnoeic and fatigued. Falling behind physical developmental milestones. Comfortable at rest. Continues to grow along own centiles Marked limitation of physical activity, unduly fatigued. Regression of learned physical activities. Quiet and needs frequent naps. Comfortable at rest. Less than ordinary activity causes undue fatigue or syncope and/or presyncope. Growth compromised. Poor appetite. Requires excessive medical attention Growth severely compromised. Poor appetite. Supplemental feeding. Less than ordinary activity causes undue fatigue or syncope. Plus features of Class IIIa Unable to carry out any physical activity without undue dyspnoea, fatigue or syncope, not interacting with family. Syncope and/or right heart failure. Plus features of Class III

Table 4: Pediatric functional classification for children aged 0.5–1 years Class Children with pulmonary hypertension I II IIIa IIIb IV

Asymptomatic, growing along own centiles, no limitation of physical activity. Mobile, sitting, grasping, starting to stand, crawling, playing Slight limitation of physical activity, unduly dyspnoeic and fatigued when playing. Delayed physical development. Comfortable at rest. Continues to grow along own centiles Marked limitation of physical activity. Regression of learned physical activities. Stops crawling. Quiet and needs frequent naps. Hesitant and unadventurous. Comfortable at rest. Less than ordinary activity causes undue fatigue or syncope and/or presyncope. Growth compromised. Poor appetite. Requires excessive medical attention Growth severely compromised. Poor appetite. Supplemental feeding. Less than ordinary activity causes undue fatigue or syncope. Plus features of Class IIIa Unable to carry out any physical activity without undue dyspnoea, fatigue or syncope, not interacting with family. Syncope and/or right heart failure. Plus features of Class III

Table 5: Pediatric functional classification for children aged 1–2 years Class Children with pulmonary hypertension I II IIIa IIIb IV

282

Asymptomatic, growing along own centiles, no limitation of physical activity. Standing, starting to walk/walking, climbing Slight limitation of physical activity, unduly dyspnoeic and fatigued when playing. Delayed physical development. Comfortable at rest. Continues to grow along own centiles Marked limitation of physical activity. Regression of learned physical activities. Reluctant to play. Quiet and needs frequent naps. Hesitant and unadventurous. Comfortable at rest. Less than ordinary activity causes undue dyspnoea, fatigue, or syncope and/or presyncope. Growth compromised. Poor appetite Growth severely compromised. Poor appetite. Supplemental feeding. Less than ordinary activity causes undue fatigue or syncope. Plus features of Class IIIa Unable to carry out any physical activity without undue dyspnoea, fatigue or syncope, not interacting with family. Syncope and/or right heart failure. Plus features of Class III Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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deal with children less than two years of age when the most rapid physical development and maturation occurs. Between the ages of two and five years it becomes easier to communicate with the child, while by six years the child is able to describe what they are able to do and how they feel. Children become increasingly articulate with age unless neurodevelopmental problems complicate the assessment. The adult classification is appropriate for those aged 16 years and over. Obviously, the patient is placed in the functional class which best summarises their clinical status and not all the descriptors of a functional class need to be fulfilled in order to place the patient in a particular class. Bearing in mind that young children cannot tell one

how they feel, we sought to include objective indicators such as whether or not the child is thriving, the need for supplemental feeds and the record of school or nursery attendance. The threshold for supplemental feeding can vary with age and be influenced by comorbidities but the need for supplemental feeding is usually an indication of disease severity. Parents are often reluctant to acknowledge the extent to which their child’s schooling is compromised by illness, realising that absence from school reflects how sick their child really is. The days of school missed due to illness provides a measurable yardstick of illness severity. Therefore the classification includes guidelines suggesting an attendance of 75 or 50% or less to encourage them to give a realistic answer.

Table 6: Pediatric functional classification for children aged 2–5 years Class Children with pulmonary hypertension I

Asymptomatic, growing normally attending nursery/school regularly, no limitation of physical activity, playing sports with his/her classmates Slight limitation of physical activity, unduly dyspneoic and fatigued when playing with his/her classmates. Comfortable at rest. Continues to grow along own centiles. Nursery/school attendance 75% normal. No chest pain Marked limitation of physical activity Regression of learned physical activities. Not climbing stairs, reluctant to play with friends. Hesitant and unadventurous. Comfortable at rest. Less than ordinary activity (dressing) causes undue dyspnoea, fatigue, syncope and/or presyncope or chest pain. Nursery/schooling compromised<50% normal attendance Unable to attend nursery/school, but mobile at home. Wheelchair needed outside home. Growth compromised. Poor appetite. Supplemental feeding. Less than ordinary activity causes undue fatigue, syncope or chest pain. Plus features of Class IIIa) Unable to carry out any physical activity without undue dyspnoea, fatigue, syncope or chest pain, unable to attend school, wheelchair dependant, not interacting with friends. Syncope and/or right heart failure. Plus features of Class III

II IIIa

IIIb IV

Table 7: Pediatric functional classification for children aged 5–16 years Class I II IIIa IIIb IV

Children with pulmonary hypertension Asymptomatic, growing along own centiles, attending school regularly, no limitation of physical activity, playing sports with his/her classmates Slight limitation of physical activity, unduly dyspnoeic and fatigued when playing when playing with his/her classmates. Comfortable at rest. Continues to grow along own centiles. School attendance 75% normal. No chest pain Marked limitation of physical activity. No attempt at sports. Comfortable at rest. Less than ordinary activity causes undue dyspnoea, fatigue, syncope or chest pain. Schooling compromised, <50% normal attendance Unable to attend school, but mobile at home and interacting with friends. Wheelchair needed outside the home. Growth compromised. Poor appetite. Supplemental feeding. Less than ordinary activity (dressing) causes undue dyspnoea, fatigue, syncope and/or presyncope or chest pain. Plus features of Class IIIa) Unable to carry out any physical activity without undue dyspnoea, fatigue, syncope or chest pain, unable to attend school, wheelchair dependant, not interacting with friends. Syncope and/or right heart failure. Plus features of Class III

Table 8: What to expect of children in Functional Class I Age 0-0.5 years 0.5-1 year 1-2 years 2-5 years 6-15 years

Children with pulmonary hypertension, asymptomatic, growing and developing normally, no limitation of physical activity Gains head control and increases body tone from 0 to 3 months, then rolls over and has no head lag. Sitting with support Mobile, sitting, grasping, starting to stand, crawling, playing Standing, starting to walk/walking, climbing Attending nursery/school regularly, playing games with his/her peers Children attending school regularly, playing games with his/her peers

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DESCRIPTORS OF FUNCTIONAL CLASS Functional Class I This is defined, at all ages, as children with pulmonary hypertension who are asymptomatic, growing and developing normally and have no limitation of physical activity. Table 8 outlines the most important features seen in normal children in the five age groups used in this classification and which we expect to find in children categorised as functional Class I. The emphasis on motor development in the first two years of life gradually shifts to the childâ&#x20AC;&#x2122;s ability to interact with his/ her peers, participate in sporting activities and go to nursery and then school.

Functional Class II

At all ages children with pulmonary hypertension are categorised as Functional Class II when they have only a slight limitation of physical activity due to fatigue and or dyspnoea but are comfortable at rest. Dyspnoea can interrupt feeding in young children. At this stage of their disease most children do not experience syncope or presyncope but some children can do so while still having a good exercise tolerance. During the first six months of life they fall behind their developmental milestones but continue to grow along their own centiles. Infants and young children are readily fatigued and dyspnoeic when playing. Beyond two years of age, it is important to assess attendance at school or nursery, which should be at least 75% that of healthy children.

Functional Class IIIa

Functional Class IIIa is characterised by marked limitation of physical activity. In addition to failing to achieve their developmental milestones, children between the ages of six months and two years may show regression of newly learnt activities. Inactivity is noticeable, the child being quiet and taking frequent naps. Less than ordinary activity such as dressing is tiring and can cause dyspnoea. Children frequently experience syncope and /or presyncope. Older children can become withdrawn and less confident, choosing to spend time with their families rather than their friends. Growth is compromised and appetite is poor. Nursery/school attendance is less than 50% of normal. The parents frequently say that the child has required excessive medical attention.

Functional Class IIIb

In addition to the features characteristic of Class IIIa, children in Class IIIb often require supplemental feeding by nasogastric tube or gastrostomy. Older children can no longer go to school and although mobile at home they need a wheelchair when venturing out of doors. 284

Functional Class IV Children in Class IV are severely compromised and unable to carry out any physical activity without fatigue and /or dyspneoa. They are frequently syncopal, may complain of chest pain and often become quiet and withdrawn. Signs of right heart failure are frequently present, particularly in teenagers.

LIMITATIONS OF THE PROPOSED FUNCTIONAL CLASSIFICATION FOR CHILDREN

The growth and development of healthy children varies considerably and children with pulmonary hypertension will be subject to the same innate variability, increasing the difficulty facing the physician trying to assess the functional impact of disease. In addition, many children with pulmonary hypertension have multisystem disorders that may impact heavily on functional capacity independently of their pulmonary vascular disease. We have tried to ensure that the features characteristic of each functional class are objective but the opinion of the parents can influence judgement, particularly in a first child of young parents without extended family support who maybe uncertain about how their child differs from the normal. Some children are more stoical than others. Some physicians will recommend supplemental feeding more readily than others. Comorbidity further complicates assessment, primarily in children with neurodevelopmental handicap who may be syndromal. Despite all these and other caveats the Pediatric Task Force of the Pulmonary Vascular Research Institute believes that the proposed classification will facilitate the management of children with pulmonary hypertension.

CONCLUSIONS

The proposed Functional Classification of Pulmonary Hypertension in Children follows the same pattern and uses the same criteria as the adult classification, modified appropriately for children of all ages. The pediatric classification should therefore be understood readily by adult physicians during transition from pediatric to adult medical services, by all those caring for children with pulmonary hypertension and by those carrying out clinical research and designing clinical trials. It should facilitate the development of treatment algorithms for children, as has the adult classification in older patients with pulmonary hypertension.[20] This is a consensus document and we hope and expect that it will be improved upon with experience. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston ML, Brown and Co; 1994. p. 253-6. Rich S. Primary pulmonary hypertension: Executive summary from the World Symposium on Primary Pulmonary Hypertension. Evian FWHO, 1998. Gorkin L, Norvell NK, Rosen RC, Charles E, Shumaker SA, McIntyre KM, et al. Assessment of quality of life as observed from the baseline data of the Studies of Left Ventricular Dysfunction (SOLVD) trial quality-of-life substudy. Am J Cardiol 1993;71:1069-73. Heo S, Moser DK, Riegel B, Hall LA, Christman N. Testing the psychometric properties of the Minnesota Living with Heart Failure questionnaire. Nurs Res 2005;54:265-72. Naveiro-Rilo JC, Diez-Juarez DM, Romero Blanco A, Rebollo-Gutierrez F, Rodriguez-Martinez A, Rodriguez-Garcia MA. Validation of the Minnesota living with heart failure questionnaire in primary care. Rev Esp Cardiol 2010;63:1419-27. Chua R, Keogh AM, Byth K, O’Loughlin A. Comparison and validation of three measures of quality of life in patients with pulmonary hypertension. Intern Med J 2006;36:705-10. Zlupko M, Harhay MO, Gallop R, Shin J, Archer-Chicko C, Patel R, et al. Evaluation of disease-specific health-related quality of life in patients with pulmonary arterial hypertension. Respir Med 2008;102:1431-8. Brazier JE, Harper R, Jones NM, O’Cathain A, Thomas KJ, Usherwood T, et al. Validating the SF-36 health survey questionnaire: new outcome measure for primary care. BMJ 1992;305:160-4. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF 36). I. Conceptual framework and item selection. Med Care 1992;30:473-83. Cenedese E, Speich R, Dorschner L, Ulrich S, Maggiorini M, Jenni R, et al. Measurement of quality of life in pulmonary hypertension and its significance. Eur Respir J 2006;28:808-15.

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McKenna SP, Ratcliffe J, Meads DM, Brazier JE. Development and validation of a preference based measure derived from the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) for use in cost utility analyses. Health Qual Life Outcomes 2008;6:65. Meads DM, McKenna SP, Doughty N, Das C, Gin-Sing W, Langley J, et al. The responsiveness and validity of the CAMPHOR Utility Index. Eur Respir J 2008;32:1513-9. Lollar DJ, Simeonsson RJ. Diagnosis to function: classification for children and youths. J Dev Behav Pediatr 2005;26:323-30. Ogonowski J, Kronk R, Rice C, Feldman H. Inter-rater reliability in assigning ICF codes to children with disabilities. Disabil Rehabil 2004;26:353-61. Iglesias MJ, Cuttica RJ, Herrera Calvo M, Micelotta M, Pringe A, Brusco MI. Design and validation of a new scale to assess the functional ability in children with juvenile idiopathic arthritis (JIA). Clin Exp Rheumatol 2006;24:713-8. Hedin PJ, McKenna SP, Meads DM. The Rheumatoid Arthritis Quality of Life (RAQoL) for Sweden: adaptation and validation. Scand J Rheumatol 2006;35:117-23. Palmisani E, Solari N, Pistorio A, Ruperto N, Malattia C, Viola S, et al. Agreement between physicians and parents in rating functional ability of children with juvenile idiopathic arthritis. Pediatr Rheumatol Online J 2007;5:23. Cabrera ME, Lough MD, Doershuk CF, Salvator AE. An expanded scoring system including an index of nutritional status for patients with cystic fibrosis. Pediatr Pulmonol 1994;18:199-205. Turner-Bowker DM, Kosinski M, Zhao J, Saris-Baglama RN. SF-10 for Children™ A User‘s Guide. Lincoln (RI): QualityMetric Inc; 2003. Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009;34:1219-63.

Source of Support: Nil, Conflict of Interest: None declared.

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A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011 Maria Jesus del Cerro1, Steven Abman2, Gabriel Diaz3, Alexandra Heath Freudenthal 4, Franz Freudenthal4, S. Harikrishnan5, Sheila G. Haworth6, Dunbar Ivy2, Antonio A. Lopes7, J. Usha Raj8, Julio Sandoval9, Kurt Stenmark2, and Ian Adatia10 La Paz Children’s Hospital, Madrid, Spain, 2Children’s Hospital, University of Colorado School of Medicine, Aurora, Colorado, USA, 3 Universidad Nacional de Colombia, Bogotá, Colombia, 4Kardiozentrum, La Paz, Bolivia, 5Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India, 6University College, London, UK, 7Heart Institute, University of São Paulo, São Paulo, Brazil, 8University of Chicago at Illinois, Chicago, USA, 9National Institute of Cardiology, Mexico City, Mexico, 10Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta, Canada

ABSTRACT Current classifications of pulmonary hypertension have contributed a great deal to our understanding of pulmonary vascular disease, facilitated drug trials, and improved our understanding of congenital heart disease in adult survivors. However, these classifications are not applicable readily to pediatric disease. The classification system that we propose is based firmly in clinical practice. The specific aims of this new system are to improve diagnostic strategies, to promote appropriate clinical investigation, to improve our understanding of disease pathogenesis, physiology and epidemiology, and to guide the development of human disease models in laboratory and animal studies. It should be also an educational resource. We emphasize the concepts of perinatal maladaptation, maldevelopment and pulmonary hypoplasia as causative factors in pediatric pulmonary hypertension. We highlight the importance of genetic, chromosomal and multiple congenital malformation syndromes in the presentation of pediatric pulmonary hypertension. We divide pediatric pulmonary hypertensive vascular disease into 10 broad categories. Key Words: pulmonary hypertension, pulmonary hypertension in the newborn, pulmonary vascular disease, pediatric patient

INTRODUCTION The classification of pulmonary hypertension conceived at the 1998 WHO Symposium in Evian[1] and the subsequent revisions and refinements that resulted from symposia in Venice[2] and Dana Point[3] have contributed greatly to the understanding of pulmonary vascular disease, facilitated drug trials and improved our understanding of congenital heart disease in adult survivors. However, these classifications are not applicable readily to pediatric disease.[4-7] The response to the debate on the classification of pediatric pulmonary hypertension at the Pulmonary Vascular Research Institute (PVRI) meeting in Lisbon in 2010 suggested that there was a widespread, wellAddress correspondence to:

Prof. Ian Adatia 3A3.42 WMHC, Stollery Children’s Hospital 8440-112 St., Edmonton, T6G 2B7 AB Canada Email: iadatia@ualberta.ca 286

recognized need for the development of a classification system of pediatric pulmonary hypertensive vascular disease specifically for use in children. Also, it was recognized that physicians, who care for adult survivors of pediatric disease, might be able also to use such a classification in their assessments. As a result, the PVRI Pediatric Taskforce was initiated. This paper summarizes the work of the PVRI Pediatric Taskforce as presented at the 2011 annual meeting of the PVRI in Panama. Access this article online

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Website: www.pulmonarycirculation.org DOI: 10.4103/2045-8932.83456 How to cite this article: del Cerro MJ, Abman S, Diaz G, Freudenthal AH, Freudenthal F, Harikrishnan S, Haworth SG, Ivy D, Lopes AA, Raj JU, Sandoval J, Stenmark K, Adatia I. A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011. Pulm Circ 2011;1:286-98.

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DISCUSSION Difficulties in applying the Dana Point Classification to pediatrics

The areas of particular difficulty in applying the Dana Point Classification[3] in pediatrics are mentioned briefly here and expanded upon under specific headings later in the article. The fetal origins of pulmonary vascular disease are important not only in pediatric diseases, but also in adults as perinatal events are likely to play a key role in establishing the risk for pulmonary hypertension. The Dana Point Classification does not acknowledge the potential importance of developmental mechanisms. Pulmonary hypertensive vascular disease, even when presenting in adulthood, maybe related to fetal, perinatal and early childhood development. The perinatal origins of systemic hypertension and coronary artery disease in adults are now well recognized.[8] Neonatal pulmonary vascular disease received inconsistent attention at Evian, Venice and Dana Point. In particular the concepts of perinatal maladaptation, maldevelopment and pulmonary hypoplasia as causative factors in neonatal pulmonary hypertension were not listed. Furthermore as a tool in the real life clinical assessment of the young child, the Dana Point Classification often does not reflect the complex heterogeneity of factors that contribute to pediatric pulmonary vascular disease[6] (Fig. 1). For instance in pediatric practice, patients are commonly evaluated for pulmonary hypertension who may have been born prematurely, with chromosomal or genetic anomalies, congenital cardiac defects, as well as, sleep disordered breathing, chronic aspiration and secondary parenchymal pulmonary disease.

Aims of the PVRI Panama Classification

The classification system that we propose is based firmly in clinical practice. The specific aims of this new system are to improve diagnostic strategies, to promote appropriate clinical investigation and to improve our Chromosomal or Genetic Syndromes

Pathological insults on a growing lung

Developmental Abnormalities: Lung hypoplasia

Multifactorial Conditions Figure 1: Venn diagram illustrating the heterogeneity and multifactorial elements in pediatric pulmonary hypertensive vascular disease. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

understanding of disease pathogenesis, physiology and epidemiology and to guide the development of human disease models in laboratory and animal studies. It should be also an educational resource. This classification system unequivocally is not based on therapy of pulmonary hypertension or designed to be a therapeutic guide. The utility of an effective classification system lies in its ability to help us to make sense of our observations on each child, but be structured enough to permit unambiguous classification when possible but flexible enough to allow for the inclusion of as yet undiscovered ideas. Classifications are useful in medicine if they provide a framework for the diagnosis and management of a disease, and encourage epidemiological insight. A perfect classification, like the periodic table, would also have categories for as yet undiscovered disease or mechanisms of known disease complexes. We acknowledge the great value of the Dana Point Classification.[3] Indeed, there are elements that we have left untouched. We are cognizant that if our suggested classification system has any merit it is because–to paraphrase Sir Isaac Newton in 1676–only by “standing on the shoulders of giants” have we been able to see further. With this in mind, we propose a new classification of pediatric pulmonary hypertensive vascular disease.

Overall schema

We have used the term pediatric pulmonary hypertensive vascular disease in preference to pulmonary hypertension to exclude patients with pulmonary hypertension but without an elevated pulmonary vascular resistance (Table 1). This occurs in children with large systemic to pulmonary connections. These children do not require drug therapy for pulmonary hypertension but rather benefit from timely and accurate closure of the defect. We do, however, wish to include children who have undergone various stages of single ventricle treatment who may have a symptomatically elevated pulmonary vascular resistance but with a mean pulmonary artery pressure <25 mmHg. Thus we suggest that pediatric pulmonary hypertensive vascular disease be defined as a mean pulmonary artery pressure >25 mmHg and a pulmonary vascular resistance index >3.0 Wood units m2 for biventricular circulations. We suggest that pulmonary hypertensive vascular disease following a cavopulmonary anastomosis be defined as a pulmonary vascular resistance index >3.0 Wood units m 2 or a transpulmonary gradient >6 mmHg (mean pulmonary artery pressure minus mean left atrial pressure) even if the mean pulmonary artery pressure is <25 mmHg. We add the caveat that calculated pulmonary vascular resistance maybe increased, not only, by an increased transpulmonary gradient, but also, by decreased pulmonary blood flow. We acknowledge that 287

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pulmonary blood flow maybe difficult to estimate after a cavopulmonary anastomosis because of multiple sources of pulmonary blood flow.

The pulmonary artery occlusion, left atrial or systemic ventricular end diastolic pressures maybe increased or normal but these values are clearly important in considering the differential diagnosis.

We have divided pediatric pulmonary hypertensive vascular disease into 10 broad categories listed in order of frequency of presentation to the pediatric clinic (Table 1). There is no published all-inclusive epidemiological study or registry data on pediatric pulmonary hypertension. As far as we can tell the reports to date have excluded one or other of the categories in the classification system we present here. Therefore, when such data is available the order of the categories may need revision. We emphasize that we have attempted to provide a clinically useful classification (Table 2), which permits the categorization of patients with multifactorial causes of pulmonary hypertension especially when associated with a syndrome or chromosomal abnormality. To reflect the heterogeneity of pulmonary vascular disease in childhood we have included the possibility that a disease or condition may appear in different categories. This is particularly the case when a disease such as sickle cell, scimitar or antiphospholipid syndrome may cause different types of pulmonary hypertensive vascular disease.

may be influenced by the ongoing developmental and maturational signals. This may result in unique and different sequelae than those seen in adults exposed to a similar insult (Table 2). The lung-vascular unit is composed of alveolus, bronchiole, capillary, arteriole, venule and lymphatic channel and the development of each is dependent upon another.[9] Disease of one element in the lung-vascular unit may affect other components as for example in persistent pulmonary hypertension of the newborn, bronchopulmonary dysplasia[10] (Fig. 2) and alveolar capillary dysplasia with misalignment of the pulmonary veins.[11]

CATEGORY 1

Prenatal or developmental pulmonary vascular disease

Perhaps the most striking difference between the adult and childhood onset of pulmonary hypertensive vascular disease is that during fetal, neonatal and early postnatal life the pulmonary vasculature is exposed to pathological and/or environmental insults while it is still growing and maturing. This may result in maladaptation, maldevelopment or growth arrest. Natural attempts at recovery from insults

Figure 2: This figure illustrates the complexity of pulmonary hypertensive vascular disease in a two-year-old infant with bronchopulmonary dysplasia. (a) chest X ray, cardiomegaly and parenchymal lung infiltrates; (b) lung CT scan, showing lung extensive parenchymal damage with areas of atelectasis and emphysema; (c) CT angiogram, showing right ventricular and right atrial dilatation, and atrial septal defect; (d) CT angiogram showing left and right upper pulmonary vein stenosis; (e) reconstructed CT image showing persistent ductus arteriosus; and (fâ&#x20AC;&#x2030;) CT angiogram showing the severe stenosis of right upper pulmonary vein.

Table 1: The broad schema of 10 basic categories of Pediatric Pulmonary Hypertensive Vascular Disease

Category 1 2 3 4 5 6 7 8 9 10 288

Description Prenatal or developmental pulmonary hypertensive vascular disease Perinatal pulmonary vascular maladaptation Pediatric cardiovascular disease Bronchopulmonary dysplasia Isolated pediatric pulmonary hypertensive vascular disease (isolated pediatric PAH) Multifactorial pulmonary hypertensive vascular disease in congenital malformation syndromes Pediatric lung disease Pediatric thromboembolic disease Pediatric hypobaric hypoxic exposure Pediatric pulmonary vascular disease associated with other system disorders Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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Table 2: Detailed Classification of pediatric pulmonary hypertensive vascular disease 1. Prenatal or developmental pulmonary hypertensive vascular disease 1.1. Associated with maternal or placental abnormalities 1.1.1 Pre-eclampsia 1.1.2 Chorioamnionitis 1.1.3 Maternal drug ingestion (Nonsteroidal anti inflammatory drugs)[158-165] 1.2. Associated with fetal pulmonary vascular maldevelopment 1.2.1. Associated with Fetal Pulmonary Hypoplasia 1.2.1 a. Idiopathic pulmonary hypoplasia 1.2.1 b. Familial pulmonary hypoplasia 1.2.1.c. Congenital diaphragmatic hernia 1.2.1.d. Hepatopulmonary fusion 1.2.1.e. Scimitar syndrome 1.2.1.f. Associated with fetal pulmonary compression oligohydramnios omphalocele/gastroschisis cystic adenomatosis fetal tumours or masses 1.2.1.g. Associated with fetal skeletal malformations 1.2.2. Associated with Fetal Lung Growth Arrest/Maldevelopment 1.2.2.a. Acinar dysplasia 1.2.2.b. Congenital alveolar dysplasia 1.2.2.c. Alveolar capillary dysplasia with/out misalignment of pulmonary veins 1.2.2.d. Lymphangiectasia 1.2.2.e. Pulmonary artery abnormalities 1.2.2.f. Pulmonary venous abnormalities 1.3. Associated with fetal cardiac maldevelopment 1.3.1. Premature closure of foramen ovale or ductus arteriosus 1.3.1.a. Idiopathic 1.3.1.b. Drug induced 1.3.2. Congenital heart defects associated/causing pulmonary vascular disease in the fetus 1.3.2.a. Transposition of the great arteries (TGA) with intact ventricular septum 1.3.2.b. Hypoplastic left heart syndrome with intact atrial septum 1.3.2.c. Obstructed total anomalous pulmonary venous connection 1.3.2.d. Common pulmonary vein atresia 2. Perinatal pulmonary vascular maladaptation (persistent pulmonary hypertension of the neonate, PPHN) 2.1. Idiopathic PPHN 2.2. PPHN associated with or triggered by 2.2.1. Sepsis 2.2.2. Meconium Aspiration 2.2.3. Congenital heart disease 2.2.4. Congenital diaphragmatic hernia 2.2.5. Trisomy[13,18,21] 2.2.6. Drugs and Toxins Diazoxide 3. Pediatric heart disease 3.1 Systemic to pulmonary shunts 3.1.1. PAH associated with systemic to pulmonary shunt with increased PVRI, no R-L shunt 3.1.1.1. Operable 3.1.1.2. Inoperable 3.1.2 Classical Eisenmenger syndrome 3.1.2.1. Eisenmengerâ&#x20AC;&#x201C;Simple lesion (ASD, VSD, PDA) 3.1.2.2. Eisenmengerâ&#x20AC;&#x201C;Complex lesion (Truncus, TGA/VSD, single ventricle) 3.1.3. Small defect with elevated pulmonary arterial pressure/PVRI out of proportion to the size of the defect Coexistent with pulmonary hypoplasia Coexistent with inherited or idiopathic pulmonary hypertensive vascular disease 3.2 Post operative pulmonary arterial hypertension following 3.2.1. Closure of shunt with 3.2.1.1 persistent increase in PVRI>3 WU.m2 3.2.1.2 recurrent increase in PVRI>3 WU.m2 3.2.2. Arterial or atrial switch operation for TGA with intact ventricular septum 3.2.3. Repair of left heart obstruction

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Table 2 continued 3.2.4. Repair of tetralogy of Fallot 3.2.5. Repair of pulmonary atresia with VSD and MAPCA’s 3.2.6. Surgical aortopulmonary shunt 3.3. Pulmonary vascular disease following staged palliation for single ventricle physiology 3.3.1. A fter stage 1 (PA banding, modified Norwood, Hybrid procedure, aortopulmonary or ventricular pulmonary shunt, stenting PDA) 3.3.2. After SVC to PA anastomosis (Glenn) 3.3.3. After total cavopulmonary anastomosis (Fontan) 3.4. P ediatric pulmonary hypertensive vascular disease associated with congenital abnormalities of the pulmonary arteries/veins 3.4.1. PPHVD associated with congenital abnormalities of the pulmonary arteries 3.4.1.1. Origin of a pulmonary artery from the aorta 3.4.1.2. Unilateral isolation/ductal origin/“absence” of a pulmonary artery 3.4.2. PPHVD associated with congenital abnormalities of the pulmonary veins 3.4.2.1. Scimitar Complex 3.4.2.2. Pulmonary vein stenosis 3.4.2.3. Cantú syndrome[157] 3.5. Pulmonary venous hypertension 3.5.1. P ulmonary venous hypertension due to congenital left heart inflow or outflow disease: aortic stenosis, aortic incompetence, mitral stenosis, mitral regurgitation, supramitral ring, pulmonary vein obstruction, cor triatriatum, endocardial fibroelastosis, left ventricular hypoplasia/Shone’s complex, congenital cardiomyopathy, restrictive atrial septum in hypoplastic left heart syndrome 3.5.2. Pulmonary venous hypertension due to acquired left heart disease. Left sided Valvar Heart Disease (rheumatic/postendocarditis/rheumatoid arthritis) Restrictive /Dilated /Hypertrophic Cardiomyopathy Constrictive pericardial disease 4. Bronchopulmonary dysplasia 4.1 with pulmonary vascular hypoplasia 4.2 with pulmonary vein stenosis 4.3 with left ventricular diastolic dysfunction 4.4 with systemic to pulmonary shunts aortopulmonary collaterals atrial septal defect patent ductus arteriosus ventricular septal defect 4.5. with significant hypercarbia and /or hypoxia 5. I solated pediatric pulmonary hypertensive vascular disease (PPHVD) or isolated pulmonary arterial hypertension (PAH) 5.1. Idiopathic PPHVD/Idiopathic PAH 5.2. Inherited PPHVD/PAH 5.2.1. BMPR2 5.2.2. Alk 1, endoglin 5.2.3. Unidentified genetic cause 5.3. Drugs and Toxins 5.3.1. Definite association: Toxic oil 5.3.2. Likely association Amphetamine 5.3.4. Possible association Cocaine Methylphenidate Diazoxide Cyclosporin Phenylpropanolamine 5.4. Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis[156] 5.4.1 Idiopathic PVOD 5.4.2 Inherited PVOD 6. M ultifactorial pulmonary hypertensive vascular disease associated with multiple congenital malformations/syndromes 6.1. Syndromes with congenital heart disease 6.2. Syndromes without congenital heart disease Both 6.1 and 6.2 may include- VACTERL, CHARGE, Poland, Adams-Oliver Syndrome, Scimitar complex, Trisomy, Di George, Noonan, Von Recklinghausen disease, Dursun syndrome, Cantú syndrome 7. Pediatric lung disease 7.1. Cystic fibrosis

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Table 2 continued 7.2. 7.3. 7.4. 7.5. 7.6.

Interstitial lung diseases: surfactant protein deficiency etc. Sleep disordered breathing Chest wall and spinal deformities Restrictive lung diseases Chronic obstructive lung diseases

8. Pediatric thrombo-embolic disease causing pulmonary hypertensive vascular disease 8.1. Chronic thromboemboli from central venous catheters 8.2. Chronic thromboemboli from transvenous pacing wires 8.3. Ventriculoâ&#x20AC;&#x201C;atrial shunt for hydrocephalus 8.4. Sickle cell disease 8.5. Primary endocardial fibroelastosis 8.6. Anticardiolipin/antiphospholipid syndrome 8.7. Methylmalonic acidemia and homocystinuria 8.8. Due to malignancy: osteosarcoma, Wilms tumor 8.9. Post splenectomy 9. Hypobaric hypoxic exposure 9.1. High altitude pulmonary edema (HAPE) 9.2. Infantile subacute mountain sickness 9.3. Monge disease 9.4. Hypobaric hypoxic exposure associated with PPHN Congenital heart disease Isolated PPHVD or PAH 10. Pulmonary hypertensive vascular disease associated with other system disorders 10.1. Pediatric portal hypertension 10.1.1. C ongenital extrahepatic portocaval/portosystemic shunt (e.g., Abernethy Syndrome, left atrial isomerism, trisomy[21], portal vein atresia or thrombosis) 10.1.2. Liver cirrhosis 10.2. Pediatric hematological disease 10.2.1. Hemolytic anemias: beta-Thalassemia, sickle cell disease 10.2.2. Post splenectomy 10.3. Pediatric oncological disease 10.3.1. Pediatric pulmonary arterial hypertension associated with malignancy 10.3.2. Pulmonary veno-occlusive disease after bone marrow transplantation and chemotherapy[156] 10.4. Pediatric metabolic/endocrine disease 10.4.1.Gaucher disease 10.4.2. Glycogen storage disease [1,111] 10.4.3. Non ketotic hyperglycinemia 10.4.4. Mitochondrial depletion syndrome 10.4.5. Mucopolysaccharidosis 10.4.6. Hypothyroidism/Hyperthyroidism 10.5. Pediatric autoimmune or autoinflammatory disease 10.5.1. POEMS 10.5.2. Mixed connective tissue disease 10.5.3. Sclerodermaâ&#x20AC;&#x201C;limited and diffuse disease 10.5.4. Dermatomyositis 10.5.5. Systemic Lupus Erythematosis (SLE) 10.5.6. Antiphospholipid/anticardiolipin syndrome 10.5.7. Systemic-onset juvenile arthritis 10.5.8 Pulmonary veno-occlusive disease and SLE[156] 10.6. Pediatric infectious disease 10.6.1. Schistosomiasis 10.6.2. HIV infection 10.6.3. Pulmonary tuberculosis 10.7. Pediatric chronic renal failure 10.7.1 Pulmonary arterial hypertension predialysis and with hemodialysis or peritoneal dialysis 10.7.2 Pulmonary veno-occlusive disease after renal transplantation[156] Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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In utero, the fetal pulmonary circulation is characterized by high pulmonary artery pressure and markedly elevated pulmonary vascular resistance. In the first hours after birth, dramatic respiratory and circulatory events cause pulmonary vasodilation and favorable remodeling of the pulmonary vascular bed, which reduce pulmonary vascular resistance and lead to an increase in pulmonary blood flow. If successful transition of the pulmonary circulation occurs the pulmonary artery mean pressure decreases in the first three weeks of life to 10-20 mmHg, similar to adult levels.[12] In young children total pulmonary vascular resistance indexed is similar to adults. [13] Yet despite this physiological adaptation with reduction in pulmonary vascular resistance the ultra structural appearance of smooth muscle cells does not closely resemble that of the adult until about 2 years of age.[14] Fetal growth factors may influence postnatal pulmonary vascular form and function.[10] It is clear that pediatric pulmonary hypertension specialists manage increasing numbers of neonates and children whose pulmonary hypertension may have fetal origins. In particular the association of pre-eclampsia and bronchopulmonary dysplasia, [15] and disorders associated with lung hypoplasia and diseases associated with pulmonary vascular disease in utero. [11,16- 2 5] Pulmonary hypoplasia, the result of growth arrest, is an important concept in any classification system of neonatal pulmonary hypertensive disease. Pulmonary hypertensive vascular disease in children may occur against a background of varying degrees of pulmonary hypoplasia. This has been especially well documented particularly in congenital heart disease[9] congenital diaphragmatic hernia[26] and Down syndrome.[27,28] It is also relevant that alveolarisation and pulmonary vascular development may continue through the first 8 years of life.[9] The normal rate of vascular growth and changes in the cross sectional area of the pulmonary vascular bed at birth or during the first years of life is unknown. Notably lung hypoplasia may be found in around 10% of neonatal autopsies and in up to 50% of neonates with congenital anomalies.[28,29] It is possible that diverse post natal pulmonary vascular insults, even those resulting in adult onset disease, are more likely to result in pulmonary hypertension if the subject was born with a pulmonary vascular cross sectional area below the 3rd percentile. Thus the likelihood of developing pulmonary hypertension throughout life may be related to the initial surface area at birth, with the effects of each successive insult at least partly due to the balance between pulmonary vascular reserve and rate of pulmonary vascular attrition due to the pathological insult be it genetic, epigenetic or environmental. 292

CATEGORY 2 Perinatal pulmonary vascular maladaptation This category contains only the syndrome of persistent pulmonary hypertension of the newborn (PPHN) (Table 2). We recognize that there is considerable debate about the origins of PPHN and that it may reflect in utero pulmonary vascular disease.[30] Clinical observations that neonates with severe PPHN who die during the first days after birth already have pathologic signs of chronic pulmonary vascular disease suggest that intrauterine events may play an important role in this syndrome. [30- 32] Adverse intrauterine stimuli during late gestation, such as abnormal blood flow, changes in substrate or hormone delivery to the lung, chronic hypoxia, chronic systemic hypertension, inflammation or others, may potentially alter lung vascular function and structure, contributing to abnormalities of postnatal adaptation. [33,34] It seems likely that as the mechanisms of PPHN become understood better it will become necessary to reassess the classification. However, at present most would recognize PPHN as a disorder of transition from intra to extra uterine life.[35-43] Neonates born at high altitude frequently need more time to adapt to ex-utero life; some of them require supplementary oxygen for a few weeks. The pulmonary pressures remain increased above the normal age specific values for altitude, at this time. There is a delay in the pulmonary arterial remodeling after birth in those born at high altitude.[44] However, we have acknowledged the considerable, even fatal effect that birth at very high altitudes (≥ 2,500m) may impose in the early postnatal period. These newer observations [4,45] contrast with previous reports.[46] We suggest that PPHN is a disease of the first 30 days of life that usually presents at, or within a few days, after birth. However, we recognize that it would be prudent to accelerate and broaden the diagnostic evaluation of any neonate presenting with symptomatic pulmonary hypertension outside the first week of life as the etiology may not be PPHN.

CATEGORY 3

Pediatric cardiovascular disease Pediatric cardiovascular disease may be the most common disorder globally causing pulmonary vascular disease in children (Table 2).[47-49]

The list of cardiac abnormalities and diseases is more comprehensive in this section of the classification than in the Dana Point Classification but we have maintained the basic structure of the Dana point classification as it pertains to shunts.[5,7,50,51] We considered the essential Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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outcome of the diagnostic work up of a child with a shunt and elevated pulmonary vascular resistance index is to conclude whether or not the child should undergo cardiac repair or further evaluation. There is considerable interest in evaluating if a course of medical therapy will enable surgical repair in certain patients with borderline pulmonary vascular resistances. The interaction between congenital heart disease and genetic factors often makes it difficult to classify the cause of the pulmonary hypertensive vascular disease with certainty. For instance how should a child with an atrioventricular canal defect and BMPR 2 mutation be classified? [52] Or how should we classify a child with a minor cardiac shunt and a coexistent genetic or chromosomal anomaly? The classification allows for this eventuality and this area will become clarified in the future as we seek genetic links between congenital heart and pulmonary vascular disease. Persistent or late presenting pulmonary vascular disease after atrial or arterial switch for transposition of the great arteries with an intact septum is recognized with such increasing frequency that we have specified the condition in the classification. [53-55]

The classical Eisenmenger syndrome is well recognized as a multisystem disorder. However, the differentiation between complex and simple is clinically extremely important for both survival and functional level.[56] Some studies have suggested that children with Eisenmenger may have a more rapid clinical decline than adults.[57] There is growing concern that children with repaired congenital shunts and either persistent or recurrent pulmonary hypertension fare worse than patients with either Eisenmenger or idiopathic pulmonary hypertension.[47] It is likely that this subgroup will need further refinement in the future. The category entitled pulmonary venous hypertension includes in addition the cardiomyopathies, both acquired and congenital.[58,59]

Pulmonary vascular disease following staged surgery for single ventricle: The use of pulmonary hypertension specific agents in the treatment of children and adults following the Glenn or Fontan type surgery is widespread. Preliminary data from the Spanish registry suggests that 14% of children receiving sildenafil or bosentan have a single ventricle type lesion. The interaction of the pulmonary and systemic circulations when the kinetic energy for blood flow through both circulations is derived from a single ventricular mass (and without a dedicated subpulmonary ventricle) is complex and pulmonary vascular resistance plays an important Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

physiologic role.[60-62] Recent studies have suggested that exercise intolerance,[63,64] and even plastic bronchitis[65,66] and protein losing enteropathy[67] may be due in part to an increased pulmonary vascular resistance.[61,68] Hypobaric hypoxic exposure and congenital heart disease: We have included congenital heart disease at high altitude under Category 9 because high altitude may affect the incidence as well as the anatomy of the ductus arteriosus.[69] This pertains also to children with trisomy 21 born at high altitude. In addition, pulmonary vascular reactivity testing (including prolonged hyperoxia testing) and management criteria may differ from those used at sea level.[4,44,45,69-72]

CATEGORY 4

Bronchopulmonary dysplasia

Bronchopulmonary dysplasia (Table 2) remains the most common sequela after preterm birth, causing persistent cardiorespiratory problems throughout childhood and is growing as a significant problem in adulthood. [73,74] Twelve percent (12%) of births are premature and place the patient at risk of bronchopulmonary dysplasia or chronic lung disease of prematurity. Bronchopulmonary dysplasia is a complex disorder and much more than chronic parenchymal lung disease secondary to ventilation strategies. Bronchopulmonary dysplasia, although it has changed over the decades, is characterized by an arrest of vascular and alveolar lung growth,[75-78] which often has prenatal origins.[15] Thus a patient with bronchopulmonary dysplasia may have pulmonary hypertension due to decreased vascular growth compounded by intermittent or chronic hypoxia, hypercarbia due to lung and airway injury, a systemic to pulmonary shunt, diastolic cardiac dysfunction and pulmonary vein stenosis[79-83] (Fig. 2).

CATEGORY 5

Isolated pediatric pulmonary hypertensive vascular disease or isolated pediatric pulmonary arterial hypertension The category for isolated pulmonary hypertensive vascular disease or isolated pulmonary arterial hypertension (Table 2) resembles closely the Dana Point Classification. [84- 86] However, we suggest that the term “idiopathic” be reserved for those cases with truly “idiopathic” pulmonary hypertension i.e. unassociated with any other genetic, chromosomal etc. abnormality. In pediatrics the difficulties are encountered with a classification system if “idiopathic” pulmonary arterial hypertension is diagnosed together with a genetic defect or chromosomal syndrome.[6] 293

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Some drugs reported to cause pulmonary hypertension in children are different or (because they are used infrequently in pediatrics) less well validated from those described in adults.[87-92]

CATEGORY 6

Multifactorial causes of pulmonary hypertension associated with congenital malformation syndromes

on the task force with extensive clinical experience working at high altitude to be sufficiently different from other forms of pulmonary arterial hypertension to justify inclusion as a separate category. These differences include hypoxia in the absence of parenchymal lung disease, different genetic aspects, and different treatment strategies.[4,44-46,70,72,118-126]

CATEGORY 10

We are recognizing more frequently that children born with congenital malformations (Table 2) often suffer from pulmonary vascular disease due to a number of contributing factors. Examples include CHARGE, VACTERL, Down syndrome and Di George spectrum of disorders.â&#x20AC;&#x2030;[23,93-â&#x20AC;&#x2030;106] In addition, pulmonary vascular disease secondary to a shunt maybe more rapidly progressive in patients with genetic syndromes.[107]

Pediatric pulmonary hypertensive vascular disease associated with other system disorders

Pediatric lung disease

CONCLUSION

CATEGORY 7

The co-existence of certain lung diseases with pulmonary hypoplasia is recognized increasingly in children (Table 2). The classification of interstitial lung disease also suggests that lung hypoplasia and growth arrest are a common feature of a number of childhood interstitial lung diseases.[18] Pulmonary hypertension has a profound impact on the outcome of interstitial lung disease.[18] Genetic causes of lung disease are recognized and may have an impact on the prenatal pulmonary vasculature.[33,34,108,109]

CATEGORY 8

Pediatric thromboembolic disease

There is a lower incidence of pulmonary hypertension due to thromboembolic disease in children compared to adults. The associated or predisposing diseases associated with pulmonary thromboembolism in children are also in general different.[110-115] Although surgical options for chronic thromboembolic pulmonary hypertension have been explored less well in children, the success of surgical treatment of this disease in adults should encourage considering such an option in certain cases in the pediatric population (Table 2).[116,117]

CATEGORY 9

Pediatric hypobaric hypoxic exposure

Hypobaric hypoxic exposure or pulmonary hypertension due to high altitude (Table 2) was considered by those 294

Here we have listed disorders (Table 2), which may be complicated by or associated with pulmonary hypertension.[100,127,148-155] We draw attention to unique aspects of pediatric disease such as extrahepatic portal hypertension, which may occur secondary to portal vein thrombosis following umbilical line placement and be overlooked as liver function tests may be normal. We propose a comprehensive classification of pediatric pulmonary hypertension that includes pulmonary vascular hypertensive disorders occurring throughout early life from the neonate to adolescent. We emphasize the importance of prenatal and perinatal influences, including maldevelopment and lung hypoplasia, that may contribute to pulmonary vascular disease. We suggest that pediatric pulmonary hypertensive vascular disease be defined as a mean pulmonary artery pressure >25 mmHg and a pulmonary vascular resistance index >3.0 Wood units m2 for biventricular circulations. We suggest that following a cavopulmonary anastomosis pulmonary hypertensive vascular disease be defined as a pulmonary vascular resistance index >3.0 Wood units m2 or a transpulmonary gradient >6 mmHg even if the mean pulmonary artery pressure is <25 mmHg. We have classified pediatric pulmonary hypertensive vascular disease into 10 broad categories. The classification we propose is based firmly on clinical practice. The specific aims are to improve diagnostic strategies, promote clinical investigation and understanding of pathogenesis, physiology and epidemiology, and to guide the development of human disease models in laboratory and animal studies. We hope, at the least, that this classification system will serve as a catalyst for improvement and lead ultimately to better outcomes for our patients. If there are omissions or improvements to be made, we encourage interested readers to let us know through the PVRI website (http://pvri.info/ home). Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Snapshot

Drugs currently used for treatment of PAH Ankit Desai1 and Roberto Machado1 Class

Medication Mechanism Route Starting

Maintenance Half-life

Company Available

Standard

Digoxin

Inhibits Na+ pump

PO/IV

0.0625-0.25 mg daily

Increase q2 wks for desired effect

36-48 hrs

GSK

Globally

Diuretic

Multiple

Renal-based

PO/IV

Varies

Titrate as needed

Varies

Generic

Globally

Anti-coagulation

Warfarin

Vitamin K antagonist

Varies

Goal INR 2.0

40 hrs

Generic

Globally

Calcium channel blockers

Nifedipine XR

Block VDCC

30mg daily

Titrate to max dose as tolerated

7 hrs

Pfizer

Globally

Diltiazem XR

Block VDCC

PO/IV

120mg daily

Titrate to max dose as tolerated

5-10 hrs

Generic

Globally

Amlodipine

Block L-type VDCC

5mg daily

Titrate to max dose as tolerated

30-50 hrs

Generic

Globally

Nitric oxide

Increases cGMP

Inh

Acute test10-20ppm for 10 min

15-30 sec

INO Therapeutics

Globally

Adenosine

Via receptors A1, A2A, A2B, A3

Acute testing: 50 mg/kg/min

Titrate to symptoms or 350mcg/kg/min

<10 sec

Astellas Pharma US

Globally

Endothelin receptor antagonists (ERAs)

Bosentan

Block both ETA and ETB

62.5mg b.i.d

Increase to 125 mg, b.i.d. after 4 wks

5 hrs

Actelion

Globally

Ambrisentan

Block ETA only

5mg daily

Consider increase to 10 mg daily

9 hrs

Gilead

Globally

Sitaxsentan

Blocks ETA>>ETB

100mg daily

10 hrs

Pfizer

Sildenafil

PDE5 Inhibition

20mg 3 times daily

4 hrs

Pfizer

Globally

Tadalafil

PDE5 Inhibition

40mg daily

17.5 hrs

United Therapeutics

Globally

Beraprost

PGI2 analogue

20g, q.i.d.

Increase by 20g, q.i.d., as tolerated

35-40 min

United Therapeutics

Asia

Iloprost

PGI2 analogue

Inh

2.5mg 6-9 times daily

Increase to 5 mg 6-9 times daily

20-30 min

Actelion

Globally

Treprostinil

PGI2 analogue

Inh

6 mg, q.i.d.

Up to 18 mg, q.i.d.

4 hrs

Lung Rx, Inc

PGI2 analogue

1-2ng/ kg/min

13 min

Schering Healthcare

not in USA

Epoprostenol

PGI2 analogue

2ng/kg/min

Increase every 15 min until side effects occur

3-5 min

Actelion

Globally

Treprostinil

PGI2 analogue

1.25ng/kg/ min

Increase <1.25 ng/ kg/min q wk for 4 wks and after <2.5 ng/kg/ min q wk

4-5 hrs

United Therapeutics

Globally

Treprostinil

PGI2 analogue

1.25ng/kg/ min

Increase <1.25 ng/ kg/min q wk for 4 wks and after <2.5 ng/kg/ min q wk

4-5 hrs

United Therapeutics

Globally

PDE inhibitors

Prostacyclianalogues

Iloprost

Abbreviations: PAH: pulmonary arterial hypertension; PO: oral; IV: intravenous; Inh: inhalation; PDE: phosphodiesterase; VDCC: voltage-足dependent calcium channels; SC: subcutaneous; b.i.d.: twice a day; q.i.d.: four times a day.

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Website: www.pulmonarycirculation.org DOI: 10.4103/2045-8932.83457

University of Illinois at Chicago, Chicago, Illinois, USA How to cite this article: Desai A, Machado R. Drugs currently used for treatment of PAH. Pulm Circ 2011;1:299.

Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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Please write, or compose, your manuscript in a Word document that has the settings shown below for Text under “The Manuscript Preparation Process.” The Manuscript Preparation Process All submissions must be made online through our website (www. journalonweb.com/pc).

First-time authors will have to register at the website. (Registration is free but mandatory.)

Instructions for submission are also available at the Journal’s website (www. pulmonarycirculation.org). For “simpler” contributions (i.e., those having no figures or abstracts, such as a letter to the Editor or a guest editorial), you need to prepare only a Manuscript file (described below) to be submitted. For “full article” contributions, please prepare the required 3 separate files for submission at the same time. The 3 are: the MANUSCRIPT file (including all tables and all captions) the FIGURES file (all non-text components other than tables–graphs, photos, color images, illustrations, etc.) the LEGALITIES file.

Your MANUSCRIPT file (“the text file”) [1st of the 3 files to be submitted for an article-type contribution] • The acceptable format is Microsoft Word. • Maximum file size is 1 MB (.rtf or .doc). • Please do not zip the files, nor use a pdf, and kindly do not incorporate figures in this file. • Begin with a cover page (a.k.a. title page) showing: the total number of pages, total number of figures, and word counts for the text (excluding the References, tables and Abstract); type of contribution (original article, case report, review article, clinical trial, letter to editor, etc.); article title and running head (see below); names of all authors (with their highest academic degrees); name(s) of affiliations (department(s) and/or institution(s) to which the work should be credited); criteria for inclusion in the list of authors (please see Authorship Criteria, above.); and the name and contact information of the corresponding author. • Following your References section, please type the information that Journal staff will put in the little box (Sources of Support and Conflicts of Interest, if any). Your published article will end there, with that little box; however, here in your Manuscript File to be submitted, please follow that (the information to be boxed) with these two things, in this order: each actual table with its own title and its own caption; and then all figure captions. Title (of Article) Only the first word of your title is capitalized, with 3 exceptions: the word following a colon is capitalized; acronyms are all capital letters; and any word which is always capitalized is capitalized in the title (e.g., “Smith,” “United Kingdom,” etc.). • Table titles follow this same rule. By-line (the authors’ names–without the word “by”) • Spell out the first name and use an initial with a period for middle name: “John Q. Public” • 2 authors: use only the word “and”: “Abdul al-Nafis and Mary T. Smith” • 3 or more authors: use commas, and between the last 2 the word “and” preceded by a comma: “John Q. Public, Abdul al-Nafis, and Mary T. Smith”

Running Head The line that appears as a header for each page of an article after the first page, identifying the article with condensed versions of its authors and its titles, usually consisting of not more than 50 characters (including spaces). Example: Article Expression of mutant BMPR-II in pulmonary endothelial cells promotes apoptosis and a release of factors that stimulate proliferation of 300

pulmonary arterial smooth muscle cells Xudong Yang, Lu Long, Paul N. Reynolds, Nicholas W. Morrell Running Head Yang et al.: BMPR-II mutation and endothelial apoptosis •

Because “et” means “and,” it is not preceded by a comma in the running head.

Text (All Word Components from Abstract to Conclusions) • Language setting (Tools, Language): English (US). • Document size: US Letter (8.5 x 11). • Font type and size: Times New Roman (or equivalent serif font–not a sans-serif or “block letter” font like Helvetica or Arial), 11-pt. • Paragraphs: single-spaced; no paragraph indents; double-space between paragraphs. • Spacing: please do not use either the “Spacing Before” or “Spacing After” functions in the paragraph formatting options (both setting should read “0 pt.”). • Kerning: please do not kern your text (expand or condense words or lines). • Justification: left-justified text a.k.a. flush left a.k.a. quad left (do not justify margins). • Page numbers: use automatic page numbers in the footer. • When submitting your manuscript, please do not send the file with “Track Changes.”

Tables and Table Captions Tables should be self-explanatory and should not duplicate textual material. The tables along with their numbers should be cited at the relevant place in the text. • All tables for your article, and each one’s caption, should be placed (in the same Word document as the text) at the very end of the manuscript’s text, after the References. • Place each table on its own separate manuscript page. • Tables must be numbered consecutively in the order of their first citation in the text. • The table number should be Arabic, followed by a period and a brief title. • Type the table caption double-spaced. • For both the table title and the table caption, use the same size type as the text (11-pt.). • Explain in a footnote beneath the table’s caption all non-standard abbreviations that are used in each table. • Supply a brief column heading for each column in a table. • Do not use vertical lines between columns. Use horizontal lines above and below the column headings and at the bottom of the table only. Use extra space to delineate sections within the table. • Obtain permission for all borrowed, adapted, and modified tables and provide a credit line in the footnote. • Please remember that tables prepared with Excel are not accepted unless embedded within your text document. Figure Captions • Your figure captions must be carefully numbered to reflect the numbers you assigned to your figures (which are submitted separately from your manuscript–in your Figures file, described below). • For your figure captions, please type them in the order in which they are cited in your text, and so number them here: 1, 2, 3, etc. • When symbols, arrows, numbers, or letters are used to identify parts of a figure, identify and explain each one in the caption. • Explain any internal scale (magnification) and identify the method of staining in photomicrographs. • If your figure was inspired by a published figure of any kind, please end your caption with a parenthetical credit line: (Adapted from [source].) • If a figure has been published elsewhere, please submit written permission from the copyright owner to reproduce the material–in your Legalities file, described below.

References • References should be numbered consecutively in the order in which they are first mentioned in the text (not in alphabetic order, rather in Vancouver style). • Identify references in text, tables, and legends by Arabic numerals in superscript within brackets after the punctuation marks. • References cited only in tables or figures’ captions should be numbered in accordance with the sequence established by the first identification in the text of the particular table or figure. Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

Contributions to Pulmonary Circulation

• • •

List all authors for each reference; do not use “et al.” The format of references–examples of which may be seen in any previous issue of Pulmonary Circulation–is based on the formats used by the National Library of Medicine (NLM) in Index Medicus and The New England Journal of Medicine. Please verify all references against original sources, as the accuracy of reference data is the responsibility of the author.

Your FIGURES file

(all non-text components of your manuscript other than tables)

[2nd of the 3 files to be submitted for an article-type contribution]

During the submission process, you are asked to submit images in the following way: 1. Each figure is submitted separately, and captions are added directly into the website on an individual basis in jpg, gif, png format. 2. Then, please add all figures are into a .doc file in chronological order, and add as ‘Additional supporting material’. • • • • • • • • • • • • • • •

All figures must be submitted electronically. Acceptable formats are: jpg, gif, png. Maximum file size is 4 MB. Please do not zip the files. Submit high-quality figures, either color or black-and-white. Figures should be actual size. Figures should be numbered consecutively according to the order in which they are first cited in the text. Labels, numbers, and symbols should be clear and of uniform size. The lettering for figures should be large enough to be legible. Symbols, arrows, or letters used in photomicrographs should contrast with the background. Titles and detailed explanations belong in the captions for figures, not on the figures themselves (i.e., in your Manuscript file, not in this Figures file). Line art should not contain hair-thin lines (which are easily lost in reproductions). Line art must be saved at a resolution of at least 1200 dpi; photographs, CT scans, radiographs, etc, should be saved at a resolution of at least 300 dpi. Figures saved at 72 dpi are not acceptable. When graphs, scatter-grams or histograms are submitted, the numerical data on which they are based should also be supplied. The Journal reserves the right to crop, rotate, reduce, or enlarge photographs. If needed, videos can also be uploaded (mpg, mpeg, mp4, wmv; maximum file size 20 MB).

Your LEGALITIES file

[3rd of the 3 files to be submitted for an article-type contribution] • • • • •

A statement affirming that the manuscript has been read and approved by all the authors, that the requirements for authorship have been met, and that each author believes that the manuscript represents honest original work. Rights and permissions. (Please see Legal Requirements, below.) Ethical considerations. (Please see Legal Requirements, below.) Sources of support of each author. (Please see Legal Requirements, below.) Conflicts of interest of each author. (Please see Legal Requirements, below.)

The Submission Process

To submit your first manuscript to Pulmonary Circulation, simply follow these 10 easy steps. (For subsequent submissions, you already have your log-in name and password.) STEP 1: Make sure you have your file or your 4 files ready to send (for textonly contributions, your Manuscript file; for illustrated article-type contributions, your Manuscript file, your Figures file, and your Legalities file). STEP 2: Access www.journalonweb.com/pc STEP 3: Create a login name and set a password through a few simple steps. STEP 4: Log in as author using your login name and password. STEP 5: Enter the Article Type, Title, Key Words (3-5) and Abstract. (The Abstract, which should not exceed 2,000 characters, can be typed in or cut-and-pasted in the sot in the website.) Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

STEP 6: Upload the Manuscript file. Click ‘’Next.’’ STEP 7: If necessary, here you may add further files such as “Figures” and “Legalities”. Please ensure that figures are uploaded by selecting “Images” and “Additional supporting material.” The copyright form (which may also contain additional permission forms) must be uploaded as “Copyright form.” Upload your documents and additional material by browsing to locate the files in your computer. If you are submitting only a text file, skip this step by selecting “Next step> suggest reviewer.” STEP 8: Click “Next” to include suggested reviewers if you want, or to skip this step, click “Next.” STEP 9: Next page is the Preview page. Preview using links to all the files you have submitted. STEP 10: Click the “Submit the Manuscript” button at the end of the page. You will receive a notification in your email (please check your “junk” email folder if you don’t see the mail in a few minutes).

The Receiving Process

All manuscripts received are duly acknowledged as having been received and successfully opened.

Before being sent out for review of its contents, each manuscript is checked for its compliance with the Legal Requirements detailed below. Manuscripts that ignore those requirements are returned.

The Review Process

A received manuscript will be reviewed for possible publication with the understanding that it is being submitted solely to Pulmonary Circulation and has not been published anywhere, simultaneously submitted, or already accepted for publication elsewhere.

Pulmonary Circulation editors review all submitted manuscripts initially for suitability for formal peer review. Manuscripts with insufficient originality, ethical or legal problems, serious scientific or technical flaws, or lack of a significant message, are rejected before proceeding to formal peer-review. A manuscript deemed to be acceptable for review is then sent to reviewers (who many include ones named by the author in the Manuscript Preparation Process).

The Disposition Process

A reviewed manuscript is assigned to an editor who, based on the comments from the reviewers, makes a final decision on its disposition–rejection, acceptance, or acceptance with amendments.

The editor conveys to the author the comments and/or suggestions received from reviewers. The author may be requested to provide a point-by-point response to reviewers’ comments and to submit a revised version of the manuscript. This process is repeated until reviewers, editors, and authors are all satisfied with the manuscript.

The Editing Process

Manuscripts accepted for publication are copy-edited for grammar, punctuation, and other considerations. Page proofs are sent to the corresponding author.

The corresponding author is expected to return the corrected proofs within a specified time period. It may not be possible to incorporate corrections received after that period.

The Publishing and Printing Process

An article will be published online and will remain online for 2 weeks, after which it will go for printing.

The Tracking and Troubleshooting Process

Registered authors can keep track of their articles after logging into the website.

Instructions are also available at our website (www.pulmonarycirculation. org).

If you experience any problems during any of these various processes, please don’t hesitate to email the nearest of our editorial offices: the USA (gordonk [at] uic [dot] edu); India (drharikrishnan [at] hotmail [dot] com); and the UK (n.krol [at] imperial [dot] ac [dot] uk). 301

“We should be rightly proud of the great and extensive contributions made during the last century by physicians and investigators in the pulmonary circulation field and published in the prestigious journals mentioned above. However, journals specifically aiming at the pulmonary circulation and pulmonary vascular diseases are not available at present . . . Providing a high-quality venue for these investigators and clinicians to publish articles relevant to the pulmonary circulation is the major goal for this new journal, Pulmonary Circulation.” —Jason X.-J. Yuan, Nicholas W. Morrell, S. Harikrishnan, and Ghazwan Butrous

Why become a Pulmonary Circulation author? “Doctors who publish articles get asked to speak. My clients are invited to speak on a regular basis because of their articles.”

—R. Scott Lorenz, President of Westwind Communications, Plymouth, Michigan

“Doctors that publish a lot are a community of experts that share tips, techniques and new technologies long before they become available to the average doctor.”

—Robert K. Maloney MD, Los Angeles

“The pen is mightier than the sword.”

—Edward Bulwer-Lytton, English playwright (1839)

“Publishing your articles is a powerful tool reaching out to thousands of people who are looking for information.”

—Aniruddha Malpani MD, co-founder (with Anjali Malpani MD) of HELP (Health Education Library for People, the world’s largest free patient education library)

“The greater the number of publications you have, the greater the chance of securing a lectureship.”

—University of São Paulo, Brazil

“The greater the number of publications on a disease, the greater the chance of finding a treatment.”

—www. iptonline.com (Innovations in Pharmaceutical Treatment), UK

“Currently more than 250,000 patients with pulmonary hypertension are being treated in the Western world, while there are more than 35 million affected patients in poor countries with little or no therapy available. Pulmonary Circulation allows diverse knowledge of research, techniques and case studies to reach a wide readership of specialists in order to increase treatment and survival rates the world over.”

—www. PulmonaryCirculation.org

“Publish or perish.”

—Logan Wilson, The Academic Man (1942)

“The simplest metric is scholarly productivity or number of publications, and this metric has been found to be a good predictor of career trajectory.”

—DK Simonton, Creative Productivity (1997)

“For scientific societies, these metrics [number of publications] influence the selection of award recipients across the course of careers. For funding agencies, both public and private, assessments of science help identify areas of progress and vitality that may warrant additional resources. For legislative bodies and boards of directors, measures of science provide a means of documenting performance, ensuring accountability, and evaluating the return on their research investment.” —John T Cacioppo, President, Association for Psychological Science, The University of Chicago

PulmonaryCirculation.org: “Articles can be submitted electronically at www. Journalonweb.com/PC. If your article is submitted electronically, there is no need to send a hard copy.”

The first 6 letters of AUTHORITY are: AUTHOR. “The first peer-reviewed journal dedicated to pulmonary vascular disease . . . Pulmonary Circulation is the only journal devoted to the field of pulmonary circulation publishing original research articles, review articles, case reports and perspectives in pulmonary vascular disease and lung injury. The new journal stands at the forefront of the critical collaboration between basic scientists and clinicians in research on the pulmonary circulation system and clinical diagnosis and treatment of pulmonary vascular diseases.” 302

Pulmonary Circulation | April-June 2011 | Vol 1 | No 2

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Jason X.-J. Yuan, MD, PhD Nicholas W. Morrell, MD Harikrishnan S., MD

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Senior Editor Ghazwan Butrous, MD

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Executive Editor Harikrishnan S., MD

Editors Kurt R. Stenmark, MD Pulmonary C Kenneth D. Bloch, MD Stephen L. Archer, MD of pulmonary c Marlene Rabinovitch, MD review article þ The first peer-‐reviewed medical journal dedicated pulmonary vascular disease. Joe G.N.to Garcia, MD vascular disea þ Pulmonary Circulation is the only journal dStuart evoted Rich, to the fMD ield of pulmonary circulation publishing original forefront of the Martin R. Wilkins, research articles, review articles, case reports, snapshots, and pMD erspectives in pulmonary vascular disease clinicians in re Hossein A. Ghofrani, MD and lung injury. clinical diagnos Fike, MD between basic scientists and clinicians in þ The new journal stands at the forefront of Candice the critical D. collaboration Seeger, MDand treatment of pulmonary vascular research on the pulmonary circulation system Werner and clinical diagnosis Sheila G. Haworth, MD diseases. First d Patricia A. Thistlethwaite, MD, PhD þ Topics of research articles include clinical Chen trials, clinical research, drug development, basic science research, Wang, MD, PhD epidemiology and biomedical informatics, diagnostic and therapeutic guidelines. Antonio A. Lopes, MD

þ For more information: http://www.pulmonarycirculation.org/ Scientific Advisory þ NBoard o charge for processing your manuscript Clinical trials Robert F. Growver, MD, PhD þ No charge for color photographs Charles A. Hales, MD Clinical researc Editors-in-Chief þ No charge for publication Joseph Loscalzo, MD Jason X.-‐J. Yuan, MD PhD Drug developm Nicholas W. Morrell, MD John B. West, MD, PhD, þ IDSc mmediate publication on acceptance Harikrishnan S., MD Basic science r Magdi H. Yacoub, MD, DSc, FRS þ Open access

Senior Editor Ghazwan Butrous, MD PhD Executive Editor Harikrishnan S., MD Editors Kurt R. Stenmark, MD Kenneth D. Bloch, MD Stephen L. Archer, MD Marlene Rabinovitch, MD First Peer-Reviewed Journal Dedicated to Joe G.N. Vascular Garcia, Disease MD Pulmonary Stuart Rich, MD Martin R. Wilkins, MD Pulmonary Circulation is the only journal devoted to the field research articles of pulmonary circulationHossein publishing original A. Ghofrani, MD , review articles, case reports and perspectives in pulmonary Candice . Fike, Mstands D at the vascular disease and lung injury. TheDnew journal forefront of the critical collaboration basic and Werner between Seeger, Mscientists D clinicians in research on the pulmonary circulatory system and clinical diagnosis and treatment ofG pulmonary vascular Sheila . Haworth, Mdiseases D Patricia A. Thistlethwaite, MD PhD First dedicated journal on the pulmonary circulation Chen Wang, MD PhD Immediate publication on acceptance Antonio A. processing Lopes, Mmanuscript D No charge for No charge for color photographs Clinical trials No charge for publication Scientific Advisory Clinical research Open Board access Drug development Robert F. Grover, MD PhD Basic science research Charles A. Hales, MD Epidemiology and biomedical informatics Joseph Loscalzo, MD Diagnostic and therapeutic guidelines John B. West, MD PhD DSc Submit yourMagdi manuscript at: MD DSc FRS H. Yacoub, http://www.journalonweb.com/PC/

Pulmonary Circulation

Epidemiology a Diagnostic and

þ Submit your manuscript at: http://www.journalonweb.com/PC/

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Pulmona is an internatio The Pulmonary Vascular Research Institute (PVRI) is an international non-‐profit medical research organization dedicated to For information see: dedicated to increasing the awareness and more knowledge of pulmonary vascular diseases and facilitating advances in pulmonary v the treatment of affected people worldwide. http://www.pulmonarycirculation.org/ in the tr

Pulmonary Vascular Research Institute (PVRI) is an international, non-profit medical research organization dedicated to increasing the awareness and knowledge of pulmonary vascular diseases and facilitating advances in the treatment of affected people worldwide

CONTENTS Editorial Our journey continues

Jason X.-J. Yuan, Nicholas W. Morrell, S. Harikrishnan, Ghazwan Butrous

133

Guest Editorial

Classification of pediatric pulmonary hypertensive vascular disease: Does it need to be different from the adult classification? Robyn J. Barst

134

Review Articles

Overview of current therapeutic approaches for pulmonary hypertension Jason A. Stamm, Michael G. Risbano, and Michael A. Mathier

Diagnosis and assessment of pulmonary vascular disease by Doppler echocardiography Justin D. Roberts and Paul R. Forfia

Lung transplantation for pulmonary hypertension

M. Patricia George, Hunter C. Champion, and Joseph M. Pilewski

Acute respiratory distress syndrome: A clinical review Michael Donahoe

Pulmonary vascular wall stiffness: An important contributor to the increased right ventricular afterload with pulmonary hypertension Zhijie Wang and Naomi C. Chesler

Computational models of the pulmonary circulation: Insights and the move towards clinically directed studies Merryn H. Tawhai, Alys R. Clark, and Kelly S. Burrowes

138 160 182 192

212

224

Research Articles

Air travel can be safe and well tolerated in patients with clinically stable pulmonary hypertension

239

Log-transformation improves the prognostic value of serial NT-proBNP levels in apparently stable pulmonary arterial hypertension

244

Melanie Thamm, Robert Voswinckel, Henning Tiede, Friederike Lendeckel, Friedrich Grimminger, Werner Seeger, and Hossein A. Ghofrani

Elaine Soon, Natalie J. Doughty, Carmen M. Treacy, Robert M. Ross, Mark Toshner, Paul D. Upton, Karen Sheares, Nicholas W. Morrell, and Joanna Pepke-Zaba

Vasoreactivity to inhaled nitric oxide with oxygen predicts long-term survival in pulmonary arterial hypertension Rajeev Malhotra, Dean Hess, Gregory D. Lewis, Kenneth D. Bloch, Aaron B. Waxman, and Marc J. Semigran

250

Hypoxic pulmonary hypertension in mice with constitutively active platelet-derived growth factor receptor-b

259

Bhola K. Dahal, Rainer Heuchel, Soni Savai Pullamsetti, Jochen Wilhelm, Hossein A. Ghofrani, Norbert Weissmann, Werner Seeger, Friedrich Grimminger, and Ralph T. Schermuly

269

Guidelines and Consensus

Functional classification of pulmonary hypertension in children: Report from the PVRI pediatric taskforce, Panama 2011

280

A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011

286

Astrid E. Lammers, Ian Adatia, Maria Jesus del Cerro, Gabriel Diaz, Alexandra Heath Freudenthal, Franz Freudenthal, S. Harikrishnan, Dunbar Ivy, Antonio A. Lopes, J. Usha Raj, Julio Sandoval, Kurt Stenmark, and Sheila G. Haworth

Maria Jesus del Cerro, Steven Abman, Gabriel Diaz, Alexandra Heath Freudenthal, Franz Freudenthal, S. Harikrishnan, Sheila G. Haworth, Dunbar Ivy, Antonio A. Lopes, J. Usha Raj, Julio Sandoval, Kurt Stenmark, and Ian Adatia

Snapshot Drugs currently used for treatment of pulmonary arterial hypertension (PAH) Ankit Desai and Roberto Machado

299

Printed and published by Medknow Publications and Media Pvt. Ltd on behalf of Pulmonary Vascular Research Institute (PVRI), London, UK and printed at Dhote Offset Technokrafts Pvt. Ltd., Jogeshwari, Mumbai, and published at B5-12, Kanara Business Centre, Ghatkopar, Mumbai, India.