Pulmonary Arterial Hypertension : Focusing on a Future: Enhancing and Extending Life [1 ed.] 9781607506096, 9781607506010

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PULMONARY ARTERIAL HYPERTENSION

Pulmonary Arterial Hypertension : Focusing on a Future: Enhancing and Extending Life, edited by J. Antel, et al., IOS Press,

Solvay Pharmaceuticals Conferences Series Editors Werner Cautreels, Claus Steinborn and Lechoslaw Turski

Volume 10 Previously published in this series Vol. 9 Vol. 8 Vol. 7 Vol. 6 Vol. 5 Vol. 4 Vol. 3 Vol. 2

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Vol. 1

C.G. Kruse and H. Timmerman (Eds.), Towards Drugs of the Future – Key Issues in Lead Finding and Lead Optimization J.L. Junien and B. Staels (Eds.), Nuclear Receptors as Molecular Targets for Cardiometabolic and Central Nervous System Diseases B. Maisch and R. Oelze (Eds.), Cardiovascular Benefits of Omega-3 Polyunsaturated Fatty Acids B. Testa and L. Turski (Eds.), Virtual ADMET Assessment in Target Selection and Maturation C.G. Kruse, H.Y. Meltzer, C. Sennef and S.V. van de Witte (Eds.), Thinking About Cognition: Concepts, Targets and Therapeutics J. Antel, N. Finer, D. Heal and G. Krause (Eds.), Obesity and Metabolic Disorders G. Krause, J.R. Malagelada and U. Preuschoff (Eds.), Functional Disorders of the Gastrointestinal Tract J.G. Papp, M. Straub and D. Ziegler (Eds.), Atrial Fibrillation: New Therapeutic Concepts E. Ronken and G.J.M. van Scharrenburg (Eds.), Parkinson’s Disease

ISSN 1566-7685 (print) ISSN 1879-8306 (online)

Pulmonary Arterial Hypertension : Focusing on a Future: Enhancing and Extending Life, edited by J. Antel, et al., IOS Press,

Pulmonary Arterial Hypertension Focusing on a Future: Enhancing and Extending Life

Edited by

J. Antel Solvay Pharmaceuticals, Hannover, Germany

M.B. Hesselink † Solvay Pharmaceuticals, Hannover, Germany

and

R.T. Schermuly

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Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany University of Giessen Lung Center (UGLC), Giessen, Germany

Amsterdam • Berlin • Tokyo • Washington, DC

Pulmonary Arterial Hypertension : Focusing on a Future: Enhancing and Extending Life, edited by J. Antel, et al., IOS Press,

© 2010 The authors and IOS Press. All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without prior written permission from the publisher. ISBN 978-1-60750-601-0 (print) ISBN 978-1-60750-609-6 (online) Library of Congress Control Number: 2010933021 Publisher IOS Press BV Nieuwe Hemweg 6B 1013 BG Amsterdam Netherlands fax: +31 20 687 0019 e-mail: [email protected]

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LEGAL NOTICE The publisher is not responsible for the use which might be made of the following information. PRINTED IN THE NETHERLANDS

Pulmonary Arterial Hypertension : Focusing on a Future: Enhancing and Extending Life, edited by J. Antel, et al., IOS Press,

Pulmonary Arterial Hypertension J. Antel et al. (Eds.) IOS Press, 2010 © 2010 The authors and IOS Press. All rights reserved.

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Preface “The Solvay Pharmaceuticals Conferences: where industry meets academia in a search for novel therapies”

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Pulmonary Arterial Hypertension: New Insights Pulmonary arterial hypertension is diagnosed if the mean pulmonary artery pressure is greater than 25 mmHg at rest or at least 30 mmHg during exercise and is associated with enhanced pulmonary vascular resistance and with a mean pulmonary wedge pressure and left ventricular end diastolic pressure of less than 15 mmHg [1]. Persistent elevation of pulmonary artery pressure and vascular resistance leads to right ventricular failure and death [1]. The pathogenesis of pulmonary arterial hypertension involves several contributing processes: vasoconstriction, smooth muscle and endothelial cell proliferation, and thrombosis. Calcium channel blockers, anticoagulants, prostacyclin and its analogs, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors dominate therapy of pulmonary arterial hypertension today. However, this therapy does not improve long-term survival and the right heart dysfunction remains the main cause of death of pulmonary arterial hypertension sufferers, despite the implemented therapy. Disease modification and preventive strategies must be better addressed in order to achieve tangible therapeutic benefits for patients who are at risk for developing or already have pulmonary arterial hypertension. Therefore, the focus of therapy is shifting from treatment of the acutely sick towards disease modifying measures and health management. Such fundamental changes can only be achieved if interest of pharmaceutical industry is shifted towards research in this field. During the last decade progress in understanding of the role of endothelin receptors in vasoconstriction and proliferation was made, knowledge of mechanisms controlling circulation in the pulmonary artery has expanded, understanding of nitric oxide in the pathogenesis of pulmonary arterial hypertension has matured and new medicines such as bosentan, a dual endothelin A and B receptor antagonist [2], and sildenafil, a phosphodiesterase type 5 inhibitor, have been introduced [3]. The emerging therapies of pulmonary arterial hypertension involve 5-hydroxytryptamine transporter blockers, vasoactive intestinal peptide, statins, and voltage-gated potassium channel modulators [1]. The challenge is to ensure that new findings related to the pathogenesis of pulmonary arterial hypertension are adequately translated into therapies and are driving progress of drug finding by means of systems biology approaches combined with intelligent synthesis of molecules [4]. Increasing understanding of processes responsible for restriction of pulmonary circulation and vascular remodeling provides new basis for modification of

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the disease early in its course with the aim of improving quality of life of patients marked by significant prolongation of survival. The current volume contains contributions from the Tenth Solvay Pharmaceuticals Conference on Pulmonary Arterial Hypertension held in Riga (Latvia) December 11–12, 2008. It has been the aim of these conferences to bring together scientists from academia and from industry in order to stimulate exchange between them in a challenging setting. The focus of the recent conference was placed on the cardiopulmonary disorder “pulmonary artery hypertension”, characterized by multiple unknown aspects which obscure understanding of mechanisms involved in its pathogenesis, ways of its prevention and means limiting its progress, and on the aspects of drug finding and development. New diagnostic procedures and insights into therapy were highlighted including imaging, novel functional diagnostic approaches, disease monitoring, biomarkers and future therapeutics. W. Cautreels C. Steinborn L. Turski

References [1] [2] [3]

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[4]

A. Puri, M.D. McGoon, S.S. Kushwaha. Pulmonary arterial hypertension: current therapeutic strategies. Nat. Clin. Pract. Cardiovasc. Med. 4 (2007) 319–329. L.J. Rubin, D.B. Badesch, R.J. Barst et al. Bosentan therapy for pulmonary arterial hypertension. N. Engl. J. Med. 346 (2002) 896–903. S. Prasad, J. Wilkinson, M.A. Gatzoulis. Sildenafil in primary pulmonary hypertension. N. Engl. J. Med. 343 (2000) 1342. L. Turski. New business models required for today’s drug development. Conceptuur 44 (2005) 6–7.

As of February 2010, Solvay Pharmaceuticals is part of Abbott.

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List of Contributors Antel, J. Solvay Pharmaceuticals, Hannover, Germany Cautreels, W. Solvay Pharmaceuticals, Brussels, Belgium Dartevelle, P.G. Department of Thoracic & Vascular Surgery and Heart-Lung Transplantation, Marie Lannelongue Hospital, Paris-Sud University-133, Avenue de la Résistance, 92350 Le Plessis Robinson, France Fischer, Y. Solvay Pharmaceuticals GmbH, Hans-Boeckler-Allee 20, 30173 Hannover, Germany Ghofrani, H.A. Medical Clinic II/V, Department of Internal Medicine, University Hospital Giessen and Marburg GmbH, Klinikstrasse 36, 35392 Giessen, Germany

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Grimminger, F. Medical Clinic II/V, Department of Internal Medicine, University Hospital Giessen and Marburg GmbH, Klinikstrasse 36, 35392 Giessen, Germany Hassoun, P.M. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, School of Medicine, 1830 East Monument Street, Baltimore, MD 21287, USA Hesselink, M.B. † Solvay Pharmaceuticals, Hannover, Germany Janssen, W. Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany Kraemer, U. Department of pediatric surgery and intensive care, Erasmus Medical Center, Sophia Children’s Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands Olschewski, H. LKH/Medical University Graz, Auenbruggerplatz 20, A-8036 Graz, Austria

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Reichenberger, F. Medical Clinic II/V, Department of Internal Medicine, University Hospital Giessen and Marburg GmbH, Klinikstrasse 36, 35392 Giessen, Germany Reiss, I. Department of pediatric surgery and intensive care, Erasmus Medical Center, Sophia Children’s Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands Rottier, R. Department of pediatric surgery and intensive care, Erasmus Medical Center, Sophia Children’s Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands Schermuly, R.T. Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany Medical Clinic II/V, Department of Internal Medicine, University Hospital Giessen and Marburg GmbH, Klinikstrasse 36, 35392 Giessen, Germany Seeger, W. Medical Clinic II/V, Department of Internal Medicine, University Hospital Giessen and Marburg GmbH, Klinikstrasse 36, 35392 Giessen, Germany Sluiter, I. Department of pediatric surgery and intensive care, Erasmus Medical Center, Sophia Children’s Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands Steinborn, C. Solvay Pharmaceuticals, Hannover, Germany

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Tibboel, D. Department of pediatric surgery and intensive care, Erasmus Medical Center, Sophia Children’s Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands Turski, L. Solvay Pharmaceuticals, Weesp, The Netherlands Voswinckel, R. Medical Clinic II/V, Department of Internal Medicine, University Hospital Giessen and Marburg GmbH, Klinikstrasse 36, 35392 Giessen, Germany Weissmann, N. Medical Clinic II/V, Department of Internal Medicine, University Hospital Giessen and Marburg GmbH, Klinikstrasse 36, 35392 Giessen, Germany Wharton, J. Department of Experimental Medicine & Toxicology, Imperial College London, Hammersmith campus, London, W12 0NN, UK

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Wilkins, M.R. Department of Experimental Medicine & Toxicology, Imperial College London, Hammersmith campus, London, W12 0NN, UK

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Zhao, L. Department of Experimental Medicine & Toxicology, Imperial College London, Hammersmith campus, London, W12 0NN, UK

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Contents Preface W. Cautreels, C. Steinborn and L. Turski List of Contributors

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Conference Preface Jochen Antel, Mayke Hesselink † and Ralph Schermuly

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Surgical Treatment of Pulmonary Arterial Hypertension Philippe G. Dartevelle

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Pulmonary Arterial Hypertension Associated with Systemic Sclerosis: A Need for a More Focused Approach Paul M. Hassoun Established and New Therapies for Hypoxia and Non-Hypoxia-Related Pulmonary Hypertension Hossein A. Ghofrani, Robert Voswinckel, Frank Reichenberger, Norbert Weissmann, Ralph T. Schermuly, Werner Seeger and Friedrich Grimminger

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13

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Novel Anti-Proliferative Therapies in Pulmonary Hypertension Wiebke Janssen and Ralph Theo Schermuly

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What Animal Models Tell Us About Treatments for Pulmonary Hypertension Martin R. Wilkins, John Wharton and Lan Zhao

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Therapeutic Potential for Dual Inhibition of Endothelin Converting Enzyme and Neutral Endopeptidase in Pulmonary Arterial Hypertension Yvan Fischer

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Pulmonary Vascular Disease in the Newborn – From Pathophysiology to Therapeutic Strategies I. Sluiter, U. Kraemer, R. Rottier, D. Tibboel and I. Reiss

85

From Concept to Therapy – Alternative Route of Drug Application: Inhalation Horst Olschewski Author Index

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Conference Preface Solvay Pharmaceuticals Research Conferences have a history of following hard on the latest state-of-the-art of selected severe unmet medical needs with the objective of promoting scientific discourse, in-depth understanding and progress from various angles of a disease. Renowned experts who are at the forefront of scientific research were invited for the 2008 Solvay Pharmaceuticals Research Conference focusing on “Pulmonary Arterial Hypertension”, which took place at the Grand Palace Hotel in the midst of the beautiful historic district of Riga, Latvia. International experts contributing to Solvay Pharmaceuticals Research Conferences are typically well-known scientists working either on basic, preclinical, clinical, or epidemiological aspects of the selected diseases. This time we decided to go one step further and to invite an affected patient, namely Bruno Kopp who is suffering from idiopathic pulmonary arterial hypertension (IPAH) and in personam the chairman of the “Pulmonary Hypertension Association Europe”. He was of course the ideal person to address the patient’s needs for effective therapies, but also earlier diagnosis of this currently incurable disease.

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Pulmonary hypertension (PH) is a severe, potentially fatal disease that affects lung and heart. It is symptomatically characterized by shortness of breath, fatigue and fainting which is severely exacerbated through exertion due to an increase in blood pressure in the lung vasculature finally leading to a progressive worsening of hemodynamic function, right ventricular hypertrophy, right heart insufficiency and finally right heart failure (cor pulmonale). Besides of inherited forms, PH can finally result from a variety of underlying diseases, infections or injuries, such as collagen vascular diseases, chronic thrombotic or embolic diseases, HIV or other infections, drug- or toxin-related insults, left heart failure and COPD to name only a few. Pulmonary arterial hypertension (PAH) as a subgroup of PH is rare, progressive, currently incurable and terminally fatal. With a prevalence of about 15-50 patients per one million inhabitants, the disease is classified as an “orphan disease”. Subsequent to lung function examinations and exercise tolerance tests like the “six minute walk test”, final diagnosis of PAH requires right-sided heart catheterization. Clinically pulmonary hypertension is diagnosed when mean pulmonary artery pressure exceeds 25 mmHg (3300 Pa) at rest or 30 mmHg (4000 Pa) under exercise. The pathogenesis of PAH is not yet fully understood, however severe vasoconstriction and progressive tightening of blood vessels connected to and within the

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J. Antel et al. / Conference Preface

lungs through fibro-proliferative processes lead to plexiform lesions that are histopathological hallmarks of the disease. Without any treatment, the life expectancy of patients with PAH is about 3 years. Due to the advent of specialized clinical centers and the introduction of 3 classes of therapeutics, namely prostacyclin derivatives, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors, an improved quality of life and a slightly higher life expectancy have been achieved. These drugs target important pathways which are involved in the abnormal proliferation and contraction of the smooth muscle cells of the pulmonary arteries in PAH, leading finally to the observed symptomatic relieve. However PAH remains incurable as of now. One big issue besides the lack of a curative treatment is the late diagnosis frequently following months or even years of misdiagnosis. The conference opened with an introduction (Gerald Simonneau) into the various forms of PH and PAH, the recent history of classifications and re-classifications as well as an in-depth review of prevalences and incidences of the different subtypes of this disease. Lewis Rubin continued with a review of the available treatment strategies and highlighted the still existing medical need regarding a curative treatment. This overview of pharmacological treatment regimes was followed up by an indepth look into surgical strategies (Philippe Dartevelle), including lung and heart-lung transplantation strategies. While this results in a cure for some patients, it was also clear to the auditorium, that transplantation is only an option for selected patients.

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Paul Hassoun focused on PAH associated with systemic sclerosis, which unfortunately leads to an even severe prognosis. PAH in systemic sclerosis is unfortunately a common late-stage complication and the leading cause of death in these patients, whose response to current medical therapy has been disappointing. The first day closed with a deeply impressive talk of Bruno Kopp, who expressed the medical need from a patient’s perspective and illustrated his personal odyssey from a first misdiagnosis, the final diagnosis of inherited PAH and the up and downs when living with a severe disease. Everybody in the auditorium was touched by his strength, dedication and outstanding engagement in PAH patient organizations. Perfect, concise summaries and opening remarks by Marc Humbert and Ralph Schermuly were among the hallmarks of this conference. Ralph Schermuly also opened the second day’s session by particularizing the needs and drafting convincing plans for a future with potentially disease modifying treatments and concepts how to explore them clinically (see contribution of Ardeschir Ghofrani). Nazzereno Galiè followed this up by explaining challenges and solutions for a clinical development of PAH treatments within a changing regulatory environment. The gear was then switched to basic science, covering deep insights into the genetic predispositions and contributions (Richard Trembath), anti-proliferative treatment concepts (Ralph Schermuly) and the role of inflammation and inflammatory processes in PAH (Marc Humbert). The later two talks triggered therewith also an “out-of-the-box” thinking and

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discussions by looking for relations and opportunities deducible from oncological and antiinflammatory treatment approaches. The basic science session closed with two remarkable presentations. One about in vivo models (Martin Wilkins) and their translational value with regard to predicting efficacy and anticipating clinical relevance, and the other one about ECE/NEP inhibition in PAH (Yvan Fischer), a promising concept which was well-received by the scientific audience. The final session focused on the translation of concepts into clinical practice. Key challenges for early recognition, definite diagnosis and adequate therapeutic management, also with a view to subgroups were discussed by Nazzereno Galiè. A quite different topic on the first view, but with striking similarities, was presented by Dick Tibboel. He delivered an excellent talk about congenital diaphragmatic hernia (CDH), a severe birth defect characterized amongst others by a severe postnatal pulmonary hypertension. His talk should have triggered and intensified scientific projects for a deeper understanding of the pathogenesis of CDH and PAH with the consequence of developing treatment options for both rare diseases. Last but not least and important for success and patient’s compliance, concepts and consequences for efficient routes of drug administration were scheduled at the closure of the conference (see contribution of Horst Olschewski). We hope that this Solvay Pharmaceuticals Research Conference and its printed proceedings will further trigger research and development of more efficacious and hopefully curative therapies, pave ways for earlier diagnosis also through an increased visibility and awareness and finally meet the main objective of this conference with a view to the patient: Focusing on a future: enhancing and extending life with PAH.

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We acknowledge all contributors and participants of the conference who allowed for intense and fruitful scientific and social interactions. Last but not least we gratefully acknowledge the efforts of Mrs. Marjolein Mulder and Mrs. Stefanie Petrich for the excellent organization before, during, and after this great event. Jochen Antel Mayke Hesselink † Ralph Schermuly

__________________________

† Dr M.B. Hesselink unexpectedly passed away on June 23, 2009.

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Surgical Treatment of Pulmonary Arterial Hypertension Philippe G. Dartevelle Department of Thoracic & Vascular Surgery and Heart-Lung Transplantation, Marie Lannelongue Hospital, Paris-Sud University, 133 Avenue de la Résistance, 92350 Le Plessis Robinson, France Abstract. Pulmonary arterial hypertension is a severe disease that has been ignored for decades. However, there has been growing interest from respirologists, cardiologists, and thoracic surgeons due to development of new therapies that have improved the outcome and quality of life of patients suffering from pulmonary arterial hypertension. Surgery has a major place among new therapies and consists of either transplanting the lungs in end-stage pulmonary arterial hypertension after failure or escape from pharmacotherapy or curing postembolic pulmonary hypertension by pulmonary endarterectomy. Other procedures, such as endarterectomy of angiosarcomas or Potts anastomoses as a palliative treatment of pulmonary arterial hypertension in children, are less common.

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Keywords. Pulmonary arterial hypertension, pulmonary endarterectomy, pulmonary embolism, lung and heart-lung transplantation

Pulmonary arterial hypertension is a severe disease that has been ignored for a long time. Over the past twenty years, there has been increased interest from respirologists, cardiologists, and thoracic surgeons due to the development of new therapies that have improved the outcome and quality of PAH patients’ life. Among these new therapeutic options, surgery has a major place and consists of either transplanting the lungs in end-stage PAH after failure or escape from the medical treatment or curing by pulmonary endarterectomy postembolic pulmonary hypertension. Other procedures are less common such as endarterectomy of angiosarcomas, Potts anastomoses as a palliative treatment of PAH in children.

Lung Transplantation Lung transplantation (LT) is indicated in end-stage pulmonary vascular diseases not curable by any medical therapy or conservative procedure provided that general contra-indications for transplantation have been ruled out and that general conditions allow the candidate to be transplanted. Double lung transplantation and Heart-Lung transplantation are the usual procedures performed in PAH because of the frequent V/Q mismatch observed after single lung transplantation in this indication. Transplantation in pulmonary vascular diseases requires a higher organ donor quality than for lung Tx in other indications, the perioperative

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P.G. Dartevelle / Surgical Treatment of Pulmonary Arterial Hypertension

management is more difficult because these Tx are always performed under cardiopulmonary bypass and the heart function is often altered. Although the three types of LT are possible in PAH since each one reduces or normalizes the vascular resistances, each type of transplantation has its advantages and disadvantages in terms of allocation facilities, complications, length and difficulty of the postoperative course, airway complications and finally long-term results. Heart-Lung transplantation has the enormous advantage to be in fact a simple procedure performed through a median sternotomy and to transplant 1°) normal heart avoiding postoperative left heart dysfunction; 2°) airway blood supply from the coronary arteries preventing airway ischaemic complications, and; 3°) two lungs in one step. Single lung transplantation is the worst procedure in PAH although only one lung is needed and possibly from a living donor. Technically it is a simpler procedure which must be performed under cardiopulmonary bypass or ECMO, which consists of replacing one lung through a postero-lateral thoracotomy requiring three successive anastomoses, one on the main bronchus, one on the left atrium and the last on the pulmonary artery. In this unilateral transplantation, the postoperative course is usually difficult since this procedure in PAH is a model for major ventilation/perfusion mismatch at every postoperative event such as reperfusion edema, infection, rejection etc. Survival rate, maximum work load and quality of life are poorer than those observed after HLT or DLT. Double lung transplantation which is routinely performed sequentially without airway revascularization as a routine has the major advantage of preserving the native heart of the recipient and permitting the allocation of the donor’s heart to another recipient. This transplantation in this indication must always be performed under CPB or at least ECMO through a surgical approach which is a bilateral antero-lateral thoracotomy without sternal division at the opposite of what was initially described with the Clamshell incision which dramatically impairs the respiratory mechanics. This procedure consists of successively performing two single lung transplantations which totals six anastomoses. Two major complications related to the PAH impairing heart to be avoided by a cautious intraoperative management. Administration of inotropic agents may obstruct the right ventricle outlet of an over-hypertrophied muscle ventricle preventing ejection and an overflow ejected by the right ventricle into the low resistance vascular bed may be the cause of an haemodynamic pulmonary edema because the dysfunction of the left heart is no longer capable of dealing with a high cardiac output. Finally, the postoperative mortality in lung and Heart-Lung Tx is about 20% and the overall five year and 10-year survival rate are 50% and 34% respectively. There is an advantage for HLT compared to DLT in idiopathic PAH in Paris-Sud University series of 207 lung transplantations for PAH.

Pulmonary Endarterectomy in Chronic Thromboembolic PAH Chronic thromboembolic pulmonary arterial disease is the only cause of PAH totally curable by a surgical procedure which consists of restoring the pulmonary arterial tree by removing the endoluminal and fibrotic material resulting from pulmonary embolisms. Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by obstruction of large pulmonary arteries by acute and recurrent pulmonary emboli and organization of these blood clots. This disease, initially considered to be rare, is diagnosed more and more frequently, likely because of the availability of successful medical and surgical treatment. The development of centres specialized in the diagnosis and treatment of pulmonary hypertension and more consistent follow-up of patients presenting with acute

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pulmonary emboli also contribute to the ongoing increase in the number of patients diagnosed and treated for thromboembolic pulmonary hypertension. This surgical procedure is an endarterectomy of the entire vascular bed starting at the origin of each pulmonary artery and extending into all the segmental and subsegmental arteries up to 2 cm from the pleura. Since a major systemic vascularisation has developed to supply the obstructed territories, the pulmonary endarterectomy requires a circulatory arrest which permits the surgeon to perform this procedure without a major back-bleeding originating from the systemic circulation. As a circulatory arrest is always mandatory; the first step of the procedure after CPB institution is to cool the patient down to 20°C. Because clinically evident acute pulmonary embolism episodes are absent in approximately half of the patients with chronic thromboembolic pulmonary arterial hypertension (CTEPAH), the diagnosis can be difficult. Lung scinti-nuclear scan showing segmental unmatched perfusion defects is the best diagnostic tool to suspect chronic thromboembolic disease. Accessibility to endarterectomy can be assessed only in reference centres for PAH after expertise by pneumologists, radiologists and thoracic surgeons with a large experience in the surgical treatment of this disease. Pulmonary angiography and multislice angio CT scan confirm the diagnosis and determine the feasibility of endarterectomy according to the location of the disease, proximal versus distal. The lesions must start at the level of the pulmonary artery trunk or at the level of the lobar arteries in order to find a plan for the endarterectomy. When the haemodynamic gravity corresponds to the degree of obliteration, pulmonary endarterectomy can be performed with minimal perioperative mortality, providing definitive excellent functional results in almost all cases. Currently in expertise centres, the mortality rate of PEA is lower than 3% and more than 85% of the patients are definitively cured by surgery.

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Technique of Pulmonary Endarterectomy (PEA) Pulmonary endarterectomy is performed during circulatory arrest, removing obstructive material from each pulmonary artery and its lobar and segmental branches, in total 20 to 30 branches, and is the only way to reduce the pulmonary vascular resistance by at least 50%. The intraluminal material is at this stage composed of fibrous tissue inseparable from the intima, and therefore inaccessible to thrombectomy, or dilatation. Thus a true endarterectomy is required, starting at the level of right and left pulmonary arteries inside the pericardium and progressively extended distally into each of the branches of the pulmonary arterial tree. Patients suffering from this disease quickly develop a systemic hypervascular neovascularisation from bronchial and intercostal arteries through residual adhesions between the chest wall and the visceral pleura due to previous emboli. The development of a systemic to pulmonary artery circulation at the precapillary level results in significant back bleeding from the pulmonary artery at the time of endarterectomy. The only way to stop this bleeding, which continuously fills the pulmonary artery and obstructs the surgical field, is to arrest the systemic circulation under conditions of deep hypothermia between 18° and 20°C. In order to limit the time of circulatory arrest, the cardiopulmonary bypass is stopped only after identification of the correct plane for endarterectomy. After completion of endarterectomy on the first side, the extracorporeal circulation is resumed for about 15 minutes before the contralateral endarterectomy is performed. This sequential technique with intermediate reperfusion limits the cumulated period of circulatory arrest to less than 55 minutes.

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The operation is entirely performed through a median sternotomy and through the pericardium without having to open the pleura or to dissect the pulmonary artery outside the pericardium. This approach avoids the dissection of highly vascular tissue surrounding blood vessels and pleural adhesions. Pulmonary endarterectomy is truly an endovascular procedure that can benefit from video technology. The angioscope illuminates the lumen of the pulmonary artery, and the video-camera allows the distal arterial divisions to be better seen, displayed on screen for the surgeon and surgical assistants. Briefly, the operation is divided into five parts: 1) The first stage is to perform a median extrapleural sternotomy, a vertical pericardiotomy, to initiate cardiopulmonary bypass between the superior and inferior vena cava and the aorta. Profound cooling is immediately started and as the patient’s temperature is falling, the superior vena cava is completely dissected in order access to the right pulmonary artery. A vent is inserted through the right superior pulmonary vein into the left ventricle, decompression of the left heart is essential because of the significant venous return from the hypervascularized bronchial arteries through the pulmonary veins. Once the body temperature has reached 20°C, the ascending aorta is clamped and crystalloid cardioplegia is injected into the aortic root. A longitudinal arteriotomy is performed along the anterior aspect of the right pulmonary artery in the segment between the aorta and the superior vena cava. The endarterectomy is started by the identification of the correct plane in the media of the posterior surface of the pulmonary artery. This plane is developed circumferentially in the mediastinal artery and its branches and then in the intermediary arterial trunk and its branches. Cardiopulmonary bypass is then stopped to work in bloodless vessels and the endarterectomy plane is pursued into the lobar and segmental branches distally to the subsegmental branches of the basilar segments. 2) As the arteriotomy is closed, the patient is reperfused with cardiopulmonary bypass for approximately 15 minutes, the time necessary to close the arteriotomy with a back and forth running suture of 6-0 Prolene. Cardioplegia is repeated at this stage. 3) An arciform arteriotomy is made on the left pulmonary artery and the endarterectomy is performed according to the same principles as the right side. 4) The patient is reperfused during closure of the left arteriotomy, the cardiac chambers are deaired, the aorta is unclamped, and the patient is slowly rewarmed to 37°C. The postoperative course may be complicated by the risk of post-reperfusion pulmonary edema causing hypoxemia and occasionally requiring prolonged mechanical ventilation. Other complications include right heart failure secondary to persistently high pulmonary pressure, arteriotomy rupture during a spike of pulmonary hypertension, nosocomial pneumonia, haemoptysis - easily treated by embolization, or phrenic nerve palsy which can prolong dependence on mechanical ventilation. Rethrombosis of an endarterectomized area can rarely occur particularly in unilateral obstruction, and justifies anticoagulation as soon as possible after surgery. The patients often continue to improve haemodynamically and functionally for several months after the operation. The mortality rate of this surgery is approximately 2% in experienced centres since indications are better assessed using high quality imaging, surgery is better performed by experienced surgeons in this field used to performing this procedure and postoperative care are better administered. Among intra- and postoperative improvements must be mentioned the routine use of low cardiac output in order to avoid reperfusion pulmonary edema, the possible use of ECMO to treat a transitory haemodynamic instability and or bronchial artery embolization to control postoperative haemoptysis.

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Long-term outcome of patients undergoing PEA is excellent with a definitive normalization of haemodynamics in the majority of cases. In patients with incomplete immediate results the haemodynamics may deteriorate after several months or years even in the absence of new embolic event and a good observance of the anticoagulant treatment.

Endarterectomy for Angiosarcomas Among cases of obstructive PAH, approximately 3% are not related to a chronic thromboembolic disease but to the development of angiosarcomas from main pulmonary artery trunks. This primary malignancy of the pulmonary artery usually has its origin in the pulmonary artery trunk, surrounds the pulmonary valve and progressively extends toward branches of the pulmonary artery, most often bilaterally. The diagnosis is suggested by slowly progressive symptoms without acute episodes or previous thromboembolic disease, the presence of a large quantity of endoluminal material proximally particularly in the main pulmonary artery and the diagnosis is confirmed by positive TEP scan. The treatment of this type of malignant obstructive PAH lies on the same principles as a postembolic PAH because the tumour develops exceptionally outside of the arterial wall. Consequently a true pulmonary endarterectomy can be performed with a satisfactory tumor removal and a major postoperative haemodynamic improvement. These patients who may benefit from additional chemotherapy and lung metastasectomies have globally a poor prognosis considering the frequent tumor recurrence. Nevertheless approximately 20% of these patients have survived more than five years in the Paris-Sud series of 20 cases.

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Tumour Emboli into the Pulmonary Artery Renal cancer, thyroid cancer, testicular cancer and uterine cancer among others may release emboli to the pulmonary arteries which become obstructed either by embolization or by direct extension of the tumour through the vena cava and right heart chambers. Uterine leiomyomatosis deserves special mention; a benign tumour with vascular tropism that can lead to invasion of the inferior vena cava and obstruction the pulmonary arteries. Similarly, testicular tumours may continue to grow as a teratoma in the inferior vena cava and in the pulmonary arteries after response to chemotherapy and normalization of tumoral markers.

Hydatic Emboli Hydatic cysts of the liver can migrate spontaneously or during hepatic surgery into the inferior vena cava and the pulmonary arteries causing downstream thrombosis and obstruction of a large part of the pulmonary vascular bed. The diagnosis of this form of pulmonary hypertension is aided by the clinical context and positive serology. This type of PAH may also be treated by pulmonary endarterectomy when the distal bed is obliterated or resection of the intraluminal hydatic cyst when the distal bed is thrombus free.

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Potts Procedure This procedure consists of performing a direct anastomosis between the left pulmonary artery and the descending thoracic aorta without any prosthetic interposition. It permits a discharge of the pulmonary circulation into the low part of the body which consequently is less oxygen saturated than the upper body. The principle of this procedure lies on the fact that PAH in Eisenmenger syndrome are much better tolerated than idiopathic PAH and often have an unexpected long-term survival. This operation has to be performed through a left thoracotomy without cardiopulmonary bypass; it is associated with a 20% mortality rate and excellent long-term results in terms of function, quality of life and survival. Potts anastomoses might be a right alternative to transplantation in children with a suprasystemic PAH provided the preliminary results of some paediatric cardiac centres in the world are confirmed.

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Conclusion Lung and Heart-Lung transplantations are an ultimate treatment of PAH after failure or escape to the modern medical therapies. Postoperative mortality is around 20%, five year and 10-year survival rates are 50 and 34% respectively due to the complications of the immunosuppressive treatment and the frequent development of obliterans bronchiolitis syndrome. Potts procedure may offer a better prognosis than lung transplantation in suprasystemic PAH in children. Pulmonary endarterectomy is the curative treatment of chronic thromboembolic pulmonary hypertension and not just an alternative to lung transplantation; it is the treatment of choice whenever it is possible. It is a complex procedure requiring large experience in indication, surgery and postoperative care. The results depend on the experience of the surgical team as well as location of the obstruction and the severity of the disease; the mortality rate of the procedure is as low as 2% in reference centres. When performed at an early stage of the disease, before severe pulmonary arteritis occurs, the operative risk is minimal. Early surgery in patients with CTEPD even in the absence of PAH at rest should be actually indicated.

References [1] [2] [3] [4] [5] [6] [7]

K.R. McCurry, T.H. Shearon, L.B. Edwards et al. Lung transplantation in the United States, 19982007. Am. J. Transplant. 9 (2009) 942-958. J. Blanc, P. Vouhé, D. Bonnet. Potts shunt in patients with pulmonary hypertension. N. Engl. J. Med. 350 (2004) 623. P. Dartevelle, E. Fadel, A. Chapelier et al. [Surgical treatment of post-embolism pulmonary hypertension]. Rev. Pneumol. Clin. 60 (2004) 124-134. P. Dartevelle, E. Fadel, S. Mussot et al. [Surgical treatment of chronic thromboembolic pulmonary hypertension]. Presse Med. 34 (2005) 1475-1486. P. Dartevelle, E. Fadel, S. Mussot et al. Chronic thromboembolic pulmonary hypertension. Eur. Respir. J. 23 (2004) 637-648. W. Klepetko, E. Mayer, J. Sandoval et al. Interventional and surgical modalities of treatment for pulmonary arterial hypertension. J. Am. Coll. Cardiol. 43 (2004) 73S-80S. M.M. Madani and S.W. Jamieson. Technical advances of pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. Semin. Thorac. Cardiovasc. Surg. 18 (2006) 243-249.

Pulmonary Arterial Hypertension : Focusing on a Future: Enhancing and Extending Life, edited by J. Antel, et al., IOS Press,

P.G. Dartevelle / Surgical Treatment of Pulmonary Arterial Hypertension [8]

[9] [10] [11] [12]

N. Galiè, A. Torbicki, R. Barst 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. 25 (2004) 2243-2278. X. Jaïs, P. Dartevelle, F. Parent et al. [Postembolic pulmonary hypertension]. Rev. Mal. Respir. 24 (2007) 497-508. G.R. Manecke Jr., W.C. Wilson, W.R. Auger et al. Chronic thromboembolic pulmonary hypertension and pulmonary thromboendarterectomy. Semin. Cardiothorac. Vasc. Anesth. 9 (2005) 189-204. P.A. Thistlethwaite, A. Kemp, L. Du et al. Outcomes of pulmonary endarterectomy for treatment of extreme thromboembolic pulmonary hypertension. J. Thorac. Cardiovasc. Surg. 131 (2006) 307-313. S. Cabrol, R. Souza, X. Jaïs et al. Intravenous epoprostenol in inoperable chronic thromboembolic pulmonary hypertension. J. Heart Lung Transplant. 26 (2007) 357-362. Comment in: J. Heart Lung Transplant. 26 (2007) 1346-1347. J.F. Paul, A. Khallil, A. Sigal-Cinqualbre et al. Findings on submillimeter MDCT are predictive of operability in chronic thromboembolic pulmonary hypertension. AJR Am. J. Roentgenol. 188 (2007) 1059-1062.

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Pulmonary Arterial Hypertension Associated with Systemic Sclerosis: A Need for a More Focused Approach Paul M. Hassoun Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, School of Medicine, 1830 East Monument Street, Baltimore, MD 21287, USA Abstract. Pulmonary arterial hypertension (PAH), a common complication of systemic sclerosis, is one of the leading causes of mortality in patients with scleroderma. With a prevalence of scleroderma ranging from ~70 to 240 patients/million, and a conservative estimate that about 10% of these patients develop PAH, scleroderma-related PAH (SSc-PAH) is a very frequent etiology of PAH (WHO Group I) throughout the world. However, trials indicate that SSc-PAH patients have a significantly poorer response to therapy compared to other forms of PAH such as idiopathic PAH. This perhaps relates to limited understanding of the pathogenesis of SSc-PAH, lack of adequate specific outcome measures (that factor in components of the cardiovascular response in these patients) and limited knowledge on the phenotypic and genotypic characteristics that underlie development of PAH and disease progression. This review discusses specific features of SSc-PAH and the potential reasons for poor outcomes, currently available and FDA-approved therapy for this syndrome, as well as needed future developments required to alter the overall poor prognosis in this disorder.

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Keywords. Pulmonary arterial hypertension, scleroderma, therapy, survival

I.

Introduction

Pulmonary hypertension, defined as a mean pulmonary arterial pressure greater than 25 mmHg, with pulmonary capillary wedge pressure equal or less than 15 mmHg and pulmonary vascular resistance greater than 3 Wood Units is a cause of significant morbidity and mortality [1-3]. PAH (WHO Group I) includes a heterogeneous group of clinical entities, such as idiopathic PAH and pulmonary hypertension associated with connective tissue diseases (e.g. systemic sclerosis), with characteristic pathological changes [4]. The present review focuses on scleroderma-related PAH (SSc-PAH).

II.

Systemic Sclerosis

Systemic sclerosis (SSc). SSc is a heterogeneous disorder characterized by dysfunction of the endothelium, dysregulation of fibroblasts resulting in excessive production of collagen, and abnormalities of the immune system [5]. These processes lead to progressive fibrosis of the skin and internal organs resulting in organ failure and death. Although the etiology of

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SSc is unknown, genetic and environmental factors are thought to contribute to host susceptibility [6]. SSc, whether presenting in the limited or diffuse form, is a systemic disease with the potential for multiple organ system involvement including the gastrointestinal, cardiac, renal, and pulmonary systems [7]. Pulmonary manifestations include PAH, interstitial fibrosis, and increased susceptibility to lung neoplasms. Estimates of incidence and prevalence of systemic sclerosis have varied widely by the period of observation, disease definition, and population studied [8]. There is also marked geographic variation in the occurrence of the disease, supporting a role for environmental factors in disease pathogenesis. Prevalence of SSc ranges from 30-70 cases per million in Europe and Japan [9-11] to ~240 cases per million in the United States [12]. Incidence varies similarly by geographic area, with the highest rates found in the US (~19 persons per million per year) [8].

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Prevalence of Scleroderma-Associated PAH (SSc-PAH). Estimates of the prevalence of PAH in patients with SSc have varied widely based on the definition of pulmonary hypertension and the method of obtaining the measurements (i.e. echocardiography or cardiac catheterization). Using strict hemodynamic criteria obtained by right heart catheterization, the prevalence of pulmonary hypertension is between 8 and 12% [13,14]. In all patients with SSc, PAH significantly worsens survival and is, after interstitial lung disease, the leading cause of mortality in these patients [12,15,16]. With a conservative estimate of PAH prevalence of 10% among patients with SSc in the United States, the prevalence of SSc-PAH may be as high as 24 individuals per million, which indicates that SSc-PAH might be much more common than other forms of PAH in the WHO group I, including IPAH [2]. Thus, with a one-year survival rates for SSc-PAH patients ranging from 50-87% [13,15,17-19] (considerably lower than the 88% one-year survival for IPAH patients [20]), the current onus for the PAH community is to develop improved therapies for these particular patients. Genetics and SSc-PAH. While some progress has been made in understanding the genetics of IPAH with the discovery of specific mutations in the bone morphogenesis protein receptor (BMPR2) [21,22], little is known about genetic and/or phenotypic characteristics that might predict the development of PAH and/or explain the generally poor outcomes observed in SSc-PAH. An increasing number of candidate genes have been reported to be associated with SSc in different populations. Examples include a variant in the promoter of monocyte chemotactic protein-1 (MCP-1) [23]; variants in CD19 (-499G>T and a GT repeat polymorphism in the 3'-UTR region) [24]; a variant in the promoter of the IL-1 alpha gene (IL1A -889T) [25,26]; and a 3-SNP haplotype in IL-10 [27]. Thus, there is compelling data supporting a genetic basis for SSc although little progress has been made regarding genetic involvement in SSc-PAH [28]. Of note, BMPR2 mutations have not been identified in two small cohorts of SSc-PAH patients [28,29]. Therefore, genes relevant to the pathogenesis of SSc-PAH, and perhaps related to poor outcome, need to be urgently identified; their definition will likely require robust, wellcharacterized patient populations to provide adequate power for analysis. Lack of Adequate Outcome Measures in SSc-PAH. Since 2000, over 1,000 patients have been entered in multicenter placebo-controlled trials of PAH therapy. These trials have used simple outcome measures to assess efficacy of treatment, i.e. essentially the non-encouraged 6 minute walk test (6MWT) and resting hemodynamics [30,31]. The 6MWT is a simple and non-invasive submaximal exercise test that correlates with cardiopulmonary performance [32] and has a strong independent association with mortality [20,32-34]. The changes in outcome measures in these trials were small but significant (e.g.

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mean increases in the walking distance ranging between 17-70 meters and decreases in mean PA pressures of only a few mm of Hg [31,33]) but correlated, for some studies, with improved survival [33] and functional status [31,33]. This suggested that response to therapy was only partly related to resting hemodynamic measurements. However, a metaanalysis conducted by Macchia et al on data from 16 randomized and fairly homogenous (in their inclusion of patients from WHO group I with similar functional class) clinical trials of PAH therapy revealed that changes in 6MWT were not predictive of survival [35] and, therefore, raises concern about the use of 6MWT as a valid endpoint [36]. With the advent of more effective therapy, novel and more reliable outcome measures are needed to detect significant and predictive functional changes when comparing effects of different drugs or combination therapy to standard PAH therapy. Recognizing the limitations of the currently-employed outcome measures, investigators have called for improved outcome measures which would ideally be reproducible and more specific to heart or lung function, and predictive of survival [37, 38]. Whether obtained invasively or non-invasively, current cardiopulmonary hemodynamic parameters provide global assessments of function. They do not allow dissection or consideration of the components of the cardiovascular response, in particular RV function, proximal and distal vascular remodeling, and the interaction between the pulmonary vasculature (PV) and the RV, which may be particularly important in patients with SSc-PAH. Indeed patients with SSc (even in the absence of PAH) tend to have depressed RV function [39,40] and left ventricular systolic as well as diastolic dysfunction [41] Like IPAH patients, SSc-PAH patients have severe RV dysfunction at time of presentation but have more severely depressed RV contractility compared to IPAH patients [42]. In addition, SSc-PAH patients tend to have more commonly LV diastolic dysfunction and a high prevalence of pericardial effusion (34% compared to 13% for IPAH) [19]. In both groups, pericardial effusion portends a particularly poor prognosis [19]. SSc-PAH patients also tend to have more severe hormonal and metabolic dysfunction such as high levels of N-terminal brain natriuretic peptide (NT-proBNP) [43] and hyponatremia [44]. Both NT-proBNP and hyponatremia have been shown, at baseline and with serial changes (for NT-proBNP [43]), to correlate with survival in PAH [43, 44]. Finally, it is noteworthy that awareness of the negative impact of PAH on survival in scleroderma remains somewhat underappreciated, perhaps explaining delay in diagnosis and referral to specialized centers for treatment of PAH.

III. Therapy for Scleroderma-Related PAH Aside from alleviating symptoms, therapy aims at improving functional activity and quality of life, and prolonging survival, all of which have been partially achieved with currently available therapies, but mostly in patients with IPAH [45]. Indeed, it has become clearer in the past few years that certain subgroups of patients with PAH, particularly patients with SSc-PAH have a strikingly divergent response to therapy and overall worse outcome compared to patients with idiopathic PAH (IPAH) in spite of seemingly milder hemodynamic alterations [17-19]. While the reasons for these clinical differences remain unclear, there may be fundamental structural changes involving the pulmonary vasculature and the RV in patients SSc-PAH [19,42] as already discussed above, resulting in marked RV-pulmonary vascular dysfunction in this entity and poorer outcome. Evidence of chronically impaired endothelial function [46-48], affecting vascular tone and remodeling, has been the basis for current therapy of PAH. Vasodilator therapy using high-dose calcium channel blockers is an effective long-term therapy [49], but only for a minority of patients (e.g. less than 7% [50] of IPAH patients) who demonstrate acute

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vasodilation (e.g. to NO or adenosine) during hemodynamic testing, and an even smaller number of patients with SSc-PAH. Indeed, the vast majority of SSc-PAH patients fail to show a vasodilator response to acute testing [51]. Therefore, high-dose calcium channel therapy is usually not indicated for patients with SSc-PAH although most patients often receive these drugs at low dosage, typically for Raynaud’s syndrome.

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a) Anti-inflammatory Drugs. It has been increasingly recognized that inflammation may play a significant role in various types of pulmonary hypertension [52], including IPAH and PAH associated with connective tissue diseases and human immunodeficiency virus infection. Interestingly, occasional patients with severe PAH associated with some forms of connective tissue disease (such as systemic lupus erythematosus, primary Sjögren syndrome, and mixed connective tissue diseases) have had dramatic improvement of their pulmonary vascular disease with corticosteroids and/or immunosuppressive therapy [53], emphasizing the relevance of inflammation in these subsets of patients. However, this type of dramatic response is generally not observed in patients with SSc-PAH whose disease is usually quite refractory to immunosuppressive drugs [53]. b) Prostaglandins. Prostacyclin (e.g. epoprostenol) has potent pulmonary vasodilator but also anti-platelet aggregating and anti-proliferative properties [54], and has proven effective in improving the exercise capacity, cardiopulmonary hemodynamics, NYHA functional class, symptoms, as well as survival in patients with PAH when given by continuous infusion [33,55,56]. Although there have been no randomized trials using this agent to assess long-term effect on survival, analysis of cohorts of patients on continuous intravenous epoprostenol compared with historical control groups (a questionable comparison for many reasons) demonstrated clear benefits in survival in patients with NYHA classes III and IV [20,34]. Treprostinil, a prostacyclin analogue suitable for continuous subcutaneous administration, has been shown to have modest effects on symptoms and hemodynamics in PAH [57]. In a small study of 16 patients (among whom 6 had connective tissue disease related PAH), recently FDA-approved intravenous treprostinil was shown to improve hemodynamics 6MWD, FC, and hemodynamics after 12 weeks of therapy [58]. Although the safety profile of this drug is similar to IV epoprostenol, required maintenance doses are usually twice as high compared to epoprostenol. However, for patients with SSc-PAH, the lack of requirement of ice packing and less frequent mixing of the drug offer significant advantages considering these patients’ sensitivity to cold exposure. In summary, both epoprostenol and treprostinil are FDA-approved for PAH, but are cumbersome therapies requiring continuous parenteral administration with potential numerous adverse and severe side-effects (e.g. infection and possibility of pump failure [59]), which make these drugs less than ideal. In SSc-PAH, continuous intravenous epoprostenol improves exercise capacity and hemodynamics [60], compared to conventional therapy, however there has been no demonstrable effect on survival. In addition, several reports of pulmonary edema in SScPAH patients treated with prostaglandin derivatives, both in acute and chronic settings, have raised the suspicion of increased prevalence of veno-occlusive disease in these patients [61-63], and concern about usefulness of these drugs for this entity. In addition, considering the frequent digital problems and disabilities that these patients often experience, this form of therapy can be quite challenging and may increase the already heavy burden of disease in these patients. Nevertheless, intravenous prostaglandin therapy remains a valuable therapeutic option for patients with SSc-PAH with NYHA class IV and in class III patients who demonstrate no improvement on oral therapy.

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c) Endothelin Receptor Antagonists. Randomized, placebo-controlled trials of 1216 weeks duration demonstrated a beneficial effect of bosentan therapy on functional class, 6 minute walk distance, time to clinical worsening and hemodynamics in PAH [31,64]. In these studies, roughly one fifth of the population consisted of SSc-PAH patients while a large majority had a diagnosis of IPAH. A subgroup analysis, performed by Rubin et al, reported a non-significant trend towards a positive treatment effect on 6 minute walk distance among the SSc-PAH patients treated with bosentan compared to placebo [31]. At most, bosentan therapy prevented deterioration in these patients. This less than optimal effect of therapy in patients with SSc-PAH is unclear but may be related to the severity of PAH at time of presentation, as well as other factors such as, hypothetically, more severe RV and pulmonary vascular dysfunction, as compared to patients with other forms of PAH (e.g. IPAH). Our experience suggests that long-term outcome of first-line bosentan monotherapy is inferior in SSc-PAH compared to IPAH patients, with no change in functional class and worse survival in the former group [65]. In an effort to target the vasoconstrictive effects of endothelin while preserving its vasodilatory action, selective endothelin-A receptor antagonists have been developed. Sitaxsentan, which is only approved in Europe for treatment of PAH, improved exercise capacity (change in peak VO2 at week 12, which was the main endpoint of the study) [66]. Elevation in liver enzymes were noted in 10% of patients at the higher dose tested (300 mgs orally once daily). Patients with PAH associated with CTD represented 24% of the study group. A post-hoc analysis of 42 patients (33 patients who received the drug and 9 patients who received placebo) with CTD-PAH demonstrated improved exercise capacity, quality of life and hemodynamics with sitaxsentan although elevated liver enzymes were reported in 2 patients [67]. A large placebo-controlled, randomized trial of ambrisentan, the only currently FDA-approved selective endothelin receptor antagonist improved 6MWT in PAH patients improved 6MWT at week 12 of treatment, however, the effect was larger in patients with IPAH compared to patients with PAH-associated CTD [68]. Ambrisentan is generally well tolerated although peripheral edema (in up to 20% of patients [68]) and congestive heart failure have been reported. d) Phosphodiesterase Inhibitors. Sildenafil, a phosphodiesterase type V inhibitor that reduces the catabolism of cGMP, thereby enhancing the cellular effects mediated by nitric oxide, has become a widely used and highly efficacious therapy for PAH. A recent clinical trial showed that sildenafil therapy led to an improvement in the 6MWD in patients with IPAH and PAH related to connective tissue diseases or repaired congenital heart disease (patients were predominantly functional class II or III) at all three doses tested (20, 40, and 80 mg, given three times a day). Since there were no significant differences in clinical effects and time to clinical worsening at week 12 between the doses, the FDA recommended a dose of 20 mgs three times a day. In a post-hoc subgroup analysis of 84 patients with PAH related to connective tissue disease (forty-five percent of whom had SSc-PAH), data from the SUPER study suggest that sildenafil at a dose of 20 mgs improved exercise capacity (6MWD), hemodynamic measures and functional class after 12 weeks of therapy [69]. However, for reasons that remain unclear (but in part related to the limitations of that study such as post-hoc subgroup analysis), there was no effect for the dose of 80 mgs three times a day on hemodynamics in this subgroup of patients with CTDrelated PAH. For this reason and because of the potential of increased side-effects (such as bleeding from arterio-venous malformations) at high doses, we have opted at our center for sildenafil dosage of 20 mgs three times a day for our SSc-PAH patients as standard therapy. Higher doses are occasionally attempted in case of limited response. At this time, because of its favorable safety profile, oral sildenafil is our drug of choice for first-line oral therapy for SSc-PAH patients with FC II or III. The impact of long-term sildenafil therapy on

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survival in patients with SSc-PAH remains to be determined. The results of a large, randomized study of tadalafil, a once-daily phosphodiesterase inhibitor, have been recently reported [70]. The treatment effect upon 6MWD, time to clinical worsening, and quality of life was significant in subjects who received 40 mg daily. Statistically significant improvements in 6MWD were noted in the PAH-CTD group although the proportion of patients with SSc was not reported. Over half of the patients were on therapy with bosentan, which may have impacted the magnitude of response to additional therapy with tadalafil. Thus, tadalafil may be a useful alternative to sildenafil in the treatment of PAH-SSc given its safety profile and once daily dosage.

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e) Tyrosine Kinase Inhibitors. The finding that there is pathologically aberrant proliferation of endothelial and smooth muscle cells in PAH [71], as well as increased expression of secreted growth factors such as VEGF and bFGF, has led some investigators to liken this condition to a neoplastic process reminiscent of advanced solid tumors [72]. As a result, anti-neoplastic drugs have been tested in experimental models [73,74] and some occasional patients in case reports [75-77]. Two strategies are currently tested for treatment of PAH: disruption of PDGF signaling and disruption of the VEGF signaling pathway with drugs like imatinib (Gleevec®/Glivec®) and sorafenib (Nexavar®). Whether these new anti-neoplastic drugs with anti-tyrosine kinase activity will have a role in SSc-PAH (where there is evidence for both dysregulated proliferation and increased expression of growth factors such as VEGF [78]) remains to be determined. f) Combined Therapy. It is now common practice in various pulmonary hypertension centers to add drugs when patients fail to improve on monotherapy. Several multicenter trials are now exploring the efficacy of various combinations of two oral drugs or one oral and one inhaled drug. The recently published results of the PACES trial demonstrate that adding sildenafil (at a dose of 80 mgs three times a day) to intravenous epoprostenol improves exercise capacity, hemodynamic measurements, time to clinical worsening, and quality of life [79]. About 21% of these patients had CTD, including 11% with SSc-PAH. Although no specific subgroup analysis is provided, improvement was apparently mainly in patients with IPAH and limited to patients who had relatively better exercise function at baseline. We have recently reported our experience of adding sildenafil to patients with IPAH or SSc-PAH after they failed initial monotherapy with bosentan [80]. While the combination improved the 6MWD and FC in IPAH patients, the outcome in patients with SSc-PAH was less favorable, but may have halted clinical deterioration. In addition, there were more side-effects reported in the SSc-PAH compared to the IPAH patients, including hepatotoxicity that developed after addition of sildenafil to bosentan monotherapy [80]. Sildenafil and bosentan are substrates of the CYP3A4 cytochrome, and combination therapy leads to significant increases in bosentan serum levels, and significant decreases in sildenafil concentration (since bosentan induces CYP3A4) [81]. The clinical significance of these findings is unclear at this time. g) Anticoagulation. The rationale for the use of anticoagulation in severe PAH is based on pathologic evidence of pulmonary thromboembolic arterial disease and thrombosis in situ in patients with IPAH [82], and clinical studies (a retrospective analysis in [83] and a small, non-randomized prospective study [49]) demonstrating a significant beneficial effect of anticoagulation on survival in IPAH. Based essentially on the findings of these studies, anticoagulation is routinely recommended in the treatment of IPAH patients. The role of anticoagulation in other forms of PAH, in particular in SSc-PAH or other forms of connective tissue diseases is less clear. Theoretically, there is potential for increased bleeding in patients with connective tissue disorders, particularly with SSc where

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19

gastrointestinal telangiectasias may be common. Our experience with anticoagulation in over 100 patients with SSc-PAH suggests that less than 50% of these patients remain on long-term anticoagulation therapy. The reason for discontinuing anticoagulation is often related to occult bleeding in the gastrointestinal tract from a source which, in our experience, is often difficult to diagnose. h) Lung Transplantation. Lung transplantation (LT) is typically offered as a last resort to patients with PAH who fail medical therapy. Although CTD is not an absolute contra-indication to lung transplantation, patients with CTD often have associated morbidity and organ dysfunction other than the lung that place them at a specifically high risk for LT. For these reasons, patients with SSc-PAH are often denied the LT option. However, if properly screened and approved for LT, patients with SSc experience similar rates of survival 2 years after the procedure compared with patients who receive LT for pulmonary fibrosis or IPAH [84].

IV.

Survival of Patients with CTD and PAH

While there has been a recent significant increase in the number of drugs targeting specific pathways in PAH [45], survival of patients with SSc-PAH on modern therapy remains unacceptably low despite recent claims of improvement trends in patients with SSc-PAH compared to similar historical controls [85]. The reason for a discrepancy in survival between IPAH and SSc-PAH patients remains poorly understood and may involve complex pathogenic alterations affecting not only the proximal and distal pulmonary vessels but also the heart (such as inflammatory myocarditis). Thus, a better understanding of the underlying pathophysiology of pulmonary vascular and cardiac remodeling, as well as RVpulmonary vascular coupling in this disease, is needed for better targeted therapy. Whether specific anti-inflammatory agents or drugs targeting tyrosine kinase activity hold any promise of enhanced response is unclear at this time but needs to be further explored.

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V.

Conclusion

SSc-PAH is a common cause of pulmonary hypertension but has significantly worse outcome compared to other diseases, such as IPAH, within group I of the WHO classification. In addition, modern therapy for PAH appears to be of limited value in SScPAH. Similarly, currently available markers of disease severity or response to therapy in SSc-PAH are either limited or lacking. Therefore, there is an urgent need to identify potential genetic causes and novel physiologic and imaging biomarkers that will allow a better understanding of the underlying pathogenesis and serve as reliable tools to monitor therapy in this devastating syndrome.

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Pulmonary Arterial Hypertension J. Antel et al. (Eds.) IOS Press, 2010 © 2010 The authors and IOS Press. All rights reserved. doi:10.3233/978-1-60750-609-6-25

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Established and New Therapies for Hypoxia and Non-Hypoxia-Related Pulmonary Hypertension Hossein A. Ghofrani, Robert Voswinckel, Frank Reichenberger, Norbert Weissmann, Ralph T. Schermuly, Werner Seeger, and Friedrich Grimminger Medical Clinic II/V, Department of Internal Medicine, University Hospital Giessen and Marburg GmbH, Klinikstrasse 36, 35392 Giessen, Germany

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Abstract. Pulmonary hypertension can occur as an isolated disease affecting the lung vessels only, in association with underlying hypoxic lung disorders or due to chronic thromboembolic disease. Regardless of the underlying disease, chronic cor pulmonale is associated with progressive clinical deterioration and a poor prognosis in most cases. The aim of specific therapies for pulmonary hypertension is to reduce pulmonary vascular resistance and thereby improve right ventricular function. Currently three classes of drugs (prostanoids, endothelin receptor antagonists, phosphodiesterase 5 inhibitors) are approved for the treatment of pulmonary arterial hypertension (PAH) in a defined patient population (group I according to the recent WHO classification). However, these medications may also lower pulmonary vascular resistance in patients with associated lung diseases (e.g. chronic obstructive pulmonary disease or lung fibrosis) and significant pulmonary hypertension, for whom these drugs are not yet approved. As non-selective vasodilators may induce gas-exchange disturbances, which preclude their long-term use in these patients, such substances should be avoided in the hypoxemic patient. In this article we provide an update of the current understanding of hypoxia- and non-hypoxia-related pulmonary hypertension, addressing both the pathophysiological understanding of different disease aetiologies as well as the therapeutic options currently available. Keywords. Pulmonary hypertension, hypoxia, chronic obstructive pulmonary disease, interstitial lung disease, PDE5 inhibitors, endothelin antagonists, plateletderived growth factor, prostacyclin

Hypoxia-Related Pulmonary Hypertension The recent WHO classification regards pulmonary hypertension associated with hypoxia or chronic diseases of the respiratory system as separate entity, including chronic obstructive pulmonary disease (COPD), interstitial lung diseases, sleep-disordered breathing, as well as chronic exposure to high altitude and some rare neonatal diseases [1]. While hypoxia has major impact on pulmonary circulation, other factors such as hypercapnia or polycythemia seem to play a minor role for the development of pulmonary hypertension [2,3]. Adaptation of perfusion to ventilation is one of the most important features of pulmonary physiology. The key regulator of this phenomenon is hypoxic pulmonary vasoconstriction, originally described by Von Euler and Liljestrand [4], which ensures an optimized gas-exchange [5,6]. Von Euler and Liljestrand described for the first time pulmonary vasoconstriction as a response to hypoxic breathing in cats. This physiological response is operative in most

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mammals and assures that pulmonary blood flow is directed preferentially to wellventilated areas of the lung, at rest as well as during exercise. As changes in the distribution of blood flow to different areas of the lung must occur rapidly (e.g. when changing from prone to supine position, or when stressing the pulmonary circulation upon exercise) adjustments of vessel diameter in the respective regions of the lung must be regulated immediately [5,7,8]. A key molecule for this fast response, which links alveolar ventilation (and thus the degree of regional oxygenation) to local lung perfusion is nitric oxide [5]: it has been conclusively shown that the fall in lung NO-production precedes the rise in pulmonary pressure upon induction of acute experimental hypoxic pulmonary vasoconstriction, as well as that lung NO-production is closely related to the degree of alveolar ventilation [9]. Thus, while regional acute hypoxic pulmonary vasoconstriction is crucially required to assure optimized adaptation of the perfusion to ventilation, chronic general hypoxia is one of the most frequent inducers of chronic pulmonary hypertension. Furthermore, structural changes in pulmonary arteries are described in early chronic obstructive pulmonary disease (COPD), emphysema and interstitial lung diseases [10].

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Pulmonary Hypertension Associated with Interstitial Lung Disease Patients with pulmonary arterial hypertension associated with collagen vascular diseases (CVD, e.g. scleroderma) are classified as PAH based on the actual WHO classification. Many of these patients have a minor to moderate degree of interstitial lung disease. Despite the proven clinical efficacy of specific PAH treatment in CVD-associated PAH, this has not yet been shown in other PH-associated forms of interstitial lung disease. Interstitial lung diseases lead to dyspnea of the patient due to a combination of restrictive changes of the parenchyma and gas-exchange deterioration. Relevant pulmonary hypertension may develop and significantly contribute to dyspnea at rest or under exercise. The molecular and cellular mechanisms that trigger and expedite the development of pulmonary hypertension in interstitial lung diseases are not well understood. Although historical observations suggested a correlation of vital capacity and DLCO with severity of pulmonary hypertension in IPF patients [11], recent data do no longer support a direct correlation of lung function tests to the existence of pulmonary hypertension [12,13], which implicates the necessity of focused diagnostic procedures (echocardiography, right heart catheter) to rule out pulmonary hypertension in patients with interstitial lung disease. Elevated levels of brain natriuretic peptide may be a useful plasma marker to detect patients with pulmonary hypertension in this collective [13]. Pulmonary hypertension has an impact on mortality in idiopathic pulmonary fibrosis [14,15] and interstitial lung disease associated with scleroderma [16]. Therefore, manifest pulmonary hypertension in patients with ILD warrants treatment in order to improve exercise capacity, dyspnea and survival. Due to the pre-existing gas-exchange problems of these patients, the ideal drug to treat pulmonary hypertension should introduce an intrapulmonary selective vasodilatation, i.e. vasodilatation selectively in well-ventilated areas of the lung in order to maintain optimal gas-exchange. In patients with idiopathic pulmonary fibrosis, inhaled nitric oxide - the prototype of an intrapulmonary selective vasodilator - and sildenafil were shown to act as intrapulmonary selective vasodilators, whereas intravenous prostacyclin leads to increase in shunt flow fraction and increased hypoxemia [17]. Inhaled iloprost showed comparable pulmonary and intrapulmonary selective vasodilatation [18]. Comparable data does not yet exist for the endothelin receptor antagonist bosentan. As bosentan is supposed to lack acute vasodilatory capacity, long-term clinical experience with bosentan does not suggest a negative impact on gas-exchange. Controlled trials addressing the use of these drugs in pulmonary hypertension associated with interstitial lung disease are still missing. In cases where severity of pulmonary hypertension appears to be inappropriate to the extension of

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ILD, specific treatments for PAH may be used in the attempt to improve symptoms. However, due to lack of controlled clinical trials, specific treatment can currently not generally be recommended. Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease (COPD) Pulmonary hypertension has been found in about one third of COPD patients, however exercise induced pulmonary hypertension may affect up to 91% of all patients [19,20]. Interestingly, early structural changes in the pulmonary vasculature have even been described in smokers, irrespective of the presence of changes in the airways [21]. Occurrence of severe PH is less frequently reported in COPD and might develop in acute exacerbation of the underlying respiratory disease; on the other hand, in late stages of COPD chronic right heart failure, the classical so-called cor pulmonale is a common finding in most of the patients. About 5-20% of patients with chronic obstructive respiratory diseases are estimated to develop severe PH without any other major contributing factor [22,23]. Interestingly, many COPD patients with severe pulmonary hypertension have a rather moderate degree of airway obstruction, more pronounced hypoxemia and less hypercapnia. This leads to the assumption that these patients may represent a distinct subgroup of COPD-associated pulmonary hypertension associated with significantly impaired survival [24]. The importance of the issue is displayed by the fact, that COPD is worldwide one of the most frequent diseases with a considerable increase in incidence over the next decade [25]. Although long-term oxygen therapy (LTOT) improves survival in patients with COPD, prognosis of patients with COPD and a mean pulmonary artery pressure >25 mmHg is still poor despite this measure [26]. Due to possible comorbidities in this patient population, additional cardiovascular disorders such as left heart disease or thromboembolic pulmonary hypertension should be considered.

Non-Hypoxia-Related Pulmonary Hypertension

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Pulmonary Arterial Hypertension (PAH) The recent WHO conference on pulmonary hypertension (PH) has defined five main classes of chronic pulmonary hypertension [1], based on clinical and therapeutic similarities between the rather heterogeneous groups of underlying diseases. Group I of this classification, the so-called pulmonary arterial hypertension (PAH), is composed by pulmonary vascular diseases with predominantly precapillary vascular remodelling, and includes idiopathic and familiar PAH (formerly known as primary pulmonary hypertension), pulmonary hypertension associated with collagen vascular diseases (e.g. lupus erythematosus, scleroderma, CREST syndrome, Sjögren syndrome), PH associated with congenital heart disease (left-to-right shunt, Eisenmenger syndrome), PH associated with primary liver disease, PH associated with HIV infection or drugs and toxins (e.g. anorexigens). Diseases that comprise significant histopathological involvement of the capillary or postcapillary vasculature like pulmonary capillary haemagiomatosis and pulmonary veno-occlusive disease (PVOD) are also classified as PAH. Additionally rare storage diseases (Gaucher’s disease, type-1 glycogen storage), haemoglobinopathies, splenectomy or myeloproliferative disorders may lead to pulmonary hypertension and are classified as PAH. In the paediatric field, persistent pulmonary hypertension of the newborn comprises histopathological and clinical similarities to the adult disease and therefore belongs to the same group.

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The idiopathic and/or familial pulmonary arterial hypertension (IPAH/FPAH) is the best known PAH subgroup, although the incidence is rather low with about 3-5 cases per million and year. In absence of any underlying disease the diagnosis of IPAH is made. The same applies to FPAH with the difference that other family members have also been affected by the disease. Significant efforts have been made in the past to understand the pathogenesis of this fatal disease. The linkage of mutations in the gene of the bone morphogenetic protein receptor 2 (BMPR2) to the disease in 50% of the families as well as in about 25% of the sporadic patients with IPAH was a breakthrough [27,28]. Most of these mutations are point mutations (with more than 50% located in the kinase regions of the receptor), but larger mutations leading to lack of one or several exons of the BMPR2 gene have also been described [29,30]. It is supposed that all mutations lead to malfunction of BMPR2, which signals through a highly conserved signalling pathway via SMAD proteins and via alternative pathways. How loss of BMPR2 signalling leads to vascular remodelling exclusively in the lung is still not well understood. BMPR2 mutation has also been described for a patient suffering from PVOD, suggesting a close pathogenetic link of IPAH and PVOD [31]. BMPR2 belongs to the superfamily of transforming growth factor receptors. Mutations of two other receptors out of this superfamily (Alk-1, endoglin) also lead to vascular malformation and disease, the hereditary haemorrhagic teleangiectasia (HHT) [32,33]. Interestingly, Alk-1 mutations may also be associated with pulmonary hypertension and the general features of dominant autosomal inheritance, disease penetrance in heterozygous patients (homozygous mutations are lethal) and high variability of phenotype even with the same genotype are shared by IPAH and HHT. The lack of BMPR2 mutations in a significant number of IPAH and FPAH patients as well as the variations in onset, progress and severity of disease are currently not understood but implicate the existence of additional genetic mutations and contributing factors. A severe form of PH can be induced by the human immunodeficiency virus infection. It has been hypothesized that viral products themselves are a driving force of the disease [34]. Histopathological similarities between the highly vascularised Kaposi sarcoma, which was linked to the angiogenic HIV tat-protein and the Kaposi sarcoma associated herpes virus (HHV-8], and the pathognomonic plexiform lesions in IPAH exist [35]. The importance of infection of pulmonary vessels with HHV-8 in IPAH patients is under discussion [36]. Many other factors contribute to the pathogenesis of PH in patients and animal models. Established mediators of pulmonary vascular remodelling are e.g. endothelin-1 (ET-1), thromboxane, platelet-derived growth factor (PDGF), transforming growth factorbeta (TGF-β), epidermal growth factor (EGF), serotonin, inflammatory cytokines, hypoxia, increased shear stress and vessel wall tension. Putative regulators of vascular “antiremodelling” are prostacyclin, nitric oxide and vascular endothelial growth factor. Several of the above mentioned players are actually targeted by current therapies of PAH, as it will be described below in more detail. Chronic Thromboembolic Pulmonary Hypertension The interest in the medical treatment of patients with chronic thromboembolic pulmonary hypertension (CTEPH, group IV of the WHO classification of pulmonary hypertension) is growing. Only a minority of these patients is eligible for therapy with surgical desobliteration by pulmonary endarterectomy (PEA). Nevertheless, the determination of eligibility for PEA is mandatory in every patient presenting with thromboembolic disease as this is the only causal therapy at hand. The risk and benefits of PEA have to be balanced for each patient and the decision should be made by expert centres for pulmonary hypertension in close collaboration with specialized cardiothoracic surgeons [37-39]. A

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prerequisite for this approach is the location of the vascular obstruction in the proximal (down to subsegmental) pulmonary arteries [40]. Once a substantial percentage of the pulmonary vasculature is occluded by thromboembolic material, secondary - putatively shear stress-related - mechanisms of vascular remodelling may be triggered in the nonoccluded vascular bed, which result in a progressive increase in total lung vascular resistance independent of additional events of embolic occlusion of vessel lumen [41,42,43]. Finally, in patients having undergone surgical desobliteration without satisfactory resolution of pulmonary hypertension (PH), medical treatment of PH may represent the only therapeutic option. Experimental studies clearly suggest that systemic or inhaled vasodilators may reduce pulmonary vascular resistance in pulmonary embolism models, however, these investigations were restricted to the early postembolic period [44,45]. Several clinical trials suggest that specific treatments for PAH may exert beneficial effects in patients with CTEPH [46-49].

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Treatments of Pulmonary Hypertension The European Society of Cardiology (ESC) as well as the American College of Chest Physicians (ACCP) generated clinical guidelines on the diagnosis and treatment of pulmonary arterial hypertension [50,51]. Current treatments of pulmonary hypertension address mainly three aspects of the disease: 1) pulmonary vasoconstriction, 2) vascular obstruction by recurrent embolism or local thrombosis, and 3) vascular remodelling. The latter aspect of pulmonary arterial hypertension is the most difficult feature to treat. Based on the previous considerations, the use of vasodilators, some of which may also have some anti-proliferative effect, and anticoagulants has been established for many forms of chronic pulmonary hypertension. The first preclinical and clinical data indicated the efficacy of purely anti-proliferative substances for the treatment of severe pulmonary hypertension (see section on Possible Future Therapies). Although available specific drugs for the treatment of pulmonary hypertension are currently only approved for the treatment of patients suffering from PAH (group I according to the recent WHO classification), patients with hypoxia-related pulmonary hypertension or chronic thromboembolic pulmonary hypertension may also benefit from these treatments. Eligible vasodilator therapies for the treatment of hypoxia-related pulmonary hypertension are those that can reduce pulmonary vascular resistance without worsening gas-exchange through the induction of ventilation/perfusion mismatch. The same may be of relevance for patients with chronic thromboembolic pulmonary hypertension in which gas-exchange disturbances may accompany the rise in pulmonary vascular resistance. In the following we will mainly focus on the currently approved therapies for the treatment of pulmonary arterial hypertension and only briefly summarize which of these specific therapies have shown efficacy in patients with associated forms of pulmonary hypertension in early clinical studies. Basic Therapy Some basic rules should be followed before treating patients with specific therapies for PAH. An active lifestyle is important for the psychological well-being of the patient as well as to prevent physical de-conditioning. Patients should be advised to perform according to their individual capabilities but to strictly avoid events that lead to significant shortness of breath. Episodes of dizziness, light-headedness, near-fainting or syncopes should be considered as alarming signs of severe right ventricular insufficiency and require consequent restriction of physical activity to a level that prevents these symptoms. Female patients of childbearing potential should be advised to use safe contraceptive measures as

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pregnancy may often induce rapid disease progression that may not be stabilized with current therapies. In cases of chronic hypoxemia (PaO2