PULMONARY HYPERTENSION – FROM BENCH RESEARCH TO CLINICAL CHALLENGES Edited by Roxana Sulica and Ioana Preston Pulmonary Hypertension – From Bench Research to Clinical Challenges Edited by Roxana Sulica and Ioana Preston Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2011 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. 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Used under license from Shutterstock.com First published November, 2011 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechweb.org Pulmonary Hypertension – From Bench Research to Clinical Challenges, Edited by Roxana Sulica and Ioana Preston p. cm. ISBN 978-953-307-835-9 free online editions of InTech Books and Journals can be found at www.intechopen.com Contents Preface IX Part 1 Pulmonary Vascular Function and Dysfunction 1 Chapter 1 Pulmonary Hypertension: Endothelial Cell Function 3 Rajamma Mathew Chapter 2 Integrin-Mediated Endothelial Cell Adhesion and Activation of c-Src, EGFR and ErbB2 are Required for Endothelial-Mesenchymal Transition 25 Enrique Arciniegas, Luz Marina Carrillo, Héctor Rojas and José Cardier Chapter 3 Interplay Between Serotonin Transporter Signaling and Voltage-Gated Potassium Channel (Kv) 1.5 Expression 49 Christophe Guignabert Chapter 4 Deregulation of BMP Signaling in the Pathogenesis of Pulmonary Hypertension 67 Miriam de Boeck and Peter ten Dijke Chapter 5 3 and 6 CYP450 Eicosanoid Derivatives: Key Lipid Mediators in the Regulation of Pulmonary Hypertension 83 Caroline Morin, Samuel Fortin, Christelle Guibert and Éric Rousseau Part 2 Hypoxia and Its Effects on Pulmonary Vasculature and Heart 109 Chapter 6 Hypoxic Pulmonary Arterial Hypertension in the Chicken Model 111 Aureliano Hernández and Martha de Sandino VI Contents Chapter 7 Inadequate Myocardial Oxygen Supply/Demand in Experimental Pulmonary Hypertension 151 B. J. van Beek-Harmsen, H. M. Feenstra and W. J. van der Laarse Part 3 Clinical Evaluation and Diagnostic Approaches for Pulmonary Hypertension 167 Chapter 8 Assessment of Structural and Functional Pulmonary Vascular Disease in Patients with PAH 169 Juan Grignola, Enric Domingo, Rio Aguilar-Torres and Antonio Roman Chapter 9 Dyspnea in Pulmonary Arterial Hypertension 191 Dimitar Sajkov, Karen Latimer and Nikolai Petrovsky Chapter 10 Echocardiography in Pulmonary Hypertension 209 Chin-Chang Cheng and Chien-Wei Hsu Part 4 Several Clinical Forms of Pulmonary Hypertension 219 Chapter 11 Pulmonary Hypertension in Systemic Sclerosis 221 Muhammad Ishaq Ghauri, Jibran Sualeh Muhammad and Kamran Hameed Chapter 12 Clinical Syndromes and Associations with Persistent Pulmonary Hypertension of the Newborn 231 Jae H. Kim and Anup Katheria Chapter 13 Sarcoidosis Associated Pulmonary Hypertension 253 Veronica Palmero, Phillip Factor and Roxana Sulica Chapter 14 Pulmonary Hypertension in Patients with Chronic Kidney Disease 263 Alessandro Domenici, Remo Luciani, Francesco Principe, Francesco Paneni, Giuseppino Massimo Ciavarella and Luciano De Biase Part 5 Special Considerations in Evaluation and Management of Pulmonary Hypertension 273 Chapter 15 Perioperative Management of Pulmonary Hypertension 275 Philip L. Kalarickal, Sabrina T. Bent, Michael J. Yarborough, Kavitha A. Mathew and Charles Fox Contents VII Chapter 16 Pregnancy and Pulmonary Arterial Hypertension 289 Jean M. Elwing and Ralph J. Panos Chapter 17 Pulmonary Hypertension in the Critically Ill 305 Michelle S. Chew, Anders Åneman, John F. Fraser and Anthony S. McLean Preface The lung has a unique vascular structure and function; it has low pressure, low resistance circulation with a highly compliant system which accommodates the same amount of flow as the systemic circulation. In addition, pulmonary and systemic vasculatures have divergent responses to various stimuli. For example, pulmonary arteries constrict in the setting of hypoxia, while systemic circulation dilates. This is due to distinctive developmental characteristics, anatomic and histological structure, as well as physiological properties. These properties stem from a particular array of molecular and cellular mediators which favor vasodilation and maintenance of thin- walled and pliable pulmonary resistance vessels. Pulmonary hypertension is characterized by a mediator imbalance with a predominance of vasoconstriction and cell proliferation involving all layers of the vessel. The end result is an increase in pulmonary vascular resistance, increased workload of the right ventricle, and right ventricular hypertrophy to maintain an adequate flow. Subsequently, right ventricular dilatation ensues the signs and symptoms of right heart failure occurence. Therefore, while the origin of the anatomical disturbance is at the level of the pulmonary arteries resistance, the end result is right heart failure. While there are still gaps in understanding pulmonary vasculature, tremendous progress has been made in understanding its functionality, its adaptation to hypoxia, the effects of increased pulmonary vascular resistance on the right ventricular function, and the molecular pathways affected in this process. As a result, there are currently seven therapies for pulmonary arterial hypertension and the field is rapidly moving forward, with several novel molecular targets under development. Therefore, a textbook addressing developmental, cellular and clinical findings about pulmonary vascular disorders is relevant and much needed. The textbook “Pulmonary Hypertension - From Bench Research to Clinical Challenges” addresses the following topics: structure and function of the normal pulmonary vasculature; disregulated cellular pathways seen in experimental and human pulmonary hypertension; clinical aspects of pulmonary hypertension in general; presentation of several specific forms of pulmonary hypertension, and management of pulmonary hypertension in special circumstances. Therefore, the X Preface textbook should be of interest to basic and clinical researchers with particular interest in pulmonary vascular diseases; clinicians and trainees (clinical and research fellows, residents and students). This book is unique in that it combines pulmonary and cardiac physiology and pathophysiology with clinical aspects of the disease. The first two sections which comprise seven chapters include the basic knowledge and the recent discoveries related to structure and cellular function of the pulmonary vasculature. The chapters also describe disregulated pathways known to be affected in pulmonary hypertension. A special section deals with the effects of hypoxia on the pulmonary vasculature and the myocardium. The remaining three sections of the book comprise ten chapters and introduce the methods of evaluating pulmonary hypertension to the reader. The chapters present several forms of pulmonary hypertension which are particularly challenging in clinical practice (such as pulmonary arterial hypertension associated with systemic sclerosis), and lastly, they address special considerations regarding management of pulmonary hypertension in certain clinical scenarios such as pulmonary hypertension in the critically ill. The textbook is written by international scientists and physicians with expertise in pulmonary vascular diseases. Many of them are active in preclinical, translational and clinical research involving the pulmonary vasculature, as well as in treating patients with various forms and severities of pulmonary hypertension. We hope that the textbook will enhance the scientists' knowledge about the complexities of the pulmonary vasculature, stimulate trainees to dedicate part of their future clinical work to understanding and treating patients with pulmonary hypertension, and that it will increase the clinicians' awareness to the importance of correct and early diagnosis and adequate treatment. Dr. Roxana Sulica, Director of the Beth Israel Pulmonary Hypertension Program, Assistant Professor of Medicine, Albert Einstein College of Medicine, USA Ioana R. Preston, MD Assistant Professor of Medicine Tufts University School of Medicine Co-Director, Pulmonary Hypertension Center Pulmonary, Critical Care and Sleep Division Tufts Medical Center, Boston, MA, USA [...]... cascade is activated to stop the blood loss by forming a clot (Shovlin 2010) TF, a member of cytokine superfamily that functions as high affinity receptor 10 Pulmonary Hypertension – From Bench Research to Clinical Challenges and a cofactor for plasma factors VII/VIIa, the initiator of blood coagulation TF is not expressed in EC, but it is rapidly induced by infection and inflammatory cytokines (TNFα, IL-1β)... and 4 Pulmonary Hypertension – From Bench Research to Clinical Challenges associated with congenital heart defects, connective tissue diseases, portal hypertension, infection, chronic hemolytic anemia, and persistent pulmonary hypertension of the newborn Recently, pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis have been added to this group as a subcategory Gr II: PH due to left... inositol triphosphate receptor (IP3R), heterodimeric GTP binding protein, Ca2+ 6 Pulmonary Hypertension – From Bench Research to Clinical Challenges ATPase and several transient receptor potential channels localize in caveolae, and interact with caveolin-1 Production of vasodilators such as nitric oxide (NO), prostacyclin (PGI2) and endothelium-derived hyperpolarizing factor [EDHF] within caveolae... attractive strategy to pursue for the treatment of PH 7 References Achcar RO, Demura Y, Rai PR, Taraseviciene-Stewart L, Kasper M et al Loss of caveolin and heme oxygenase expression in severe pulmonary hypertension Chest 2006; 129:696705 18 Pulmonary Hypertension – From Bench Research to Clinical Challenges Angiolillo DJ, Ueno M, Goto S Basic principles of platelet biology and clinical implications... both vWF and Ang2 are stored in Weibel Palade bodies and during stress/activation, these bodies deliver their cargo at the endothelial cell surface 14 Pulmonary Hypertension – From Bench Research to Clinical Challenges Caveolin-1 is essential for normal functioning of SMC Under normal circumstances, caveolin-1 inhibits receptor and non-receptor tyrosine kinases by sequestering them to caveolae and prevents... 74:936-943 20 Pulmonary Hypertension – From Bench Research to Clinical Challenges Kawamura C, Kizaki M, Yamato K, Uchida H, Fukuchi Y et al Bone Morphogenic protein-2 induces apoptosis in human myeloma cells with modulation of STAT3 Blood 2000; 96:2005-2011 Kawut SM, Horn EM, Berekashvili KK, Widitz AC, Rosezweig EB et al von Willebrand factor independently predicts long-term survival in patients with pulmonary. .. caveolae of endothelial cells Hypertension 2009; 53:189-195 Raoul W, Wagner-Ballon O, Saber G, Hulin A, Marcos E et al Effects of bone marrowderived cells on monocrotaline- and hypoxia-induced pulmonary hypertension in mice Respir Res 2007, 8:8 22 Pulmonary Hypertension – From Bench Research to Clinical Challenges Rath G, Dessy C, Feron O Caveolae, caveolin and control of vascular tone: nitric oxide (NO)... indicates that caveolin-1 has lost its inhibitory function (Huang 2008, Mathew 2011b, Murata 2002) Thus, this complex formation renders both eNOS and 16 Pulmonary Hypertension – From Bench Research to Clinical Challenges caveolin-1 dysfunctional Statins therapy has shown to protect eNOS function in hypoxiainduced PH The major effect of statins is reported to be the uncoupling of eNOS/caveolin-1 complex,... clear that EC orchestrates a complex metabolic machinery involving a number of signaling molecules to maintain vascular health These multiple 12 Pulmonary Hypertension – From Bench Research to Clinical Challenges signaling pathways cross talk at different levels to preserve normal function and cell survival Dysregulation of one signaling pathway has a profound effect on the other pathways, resulting in... reduces the expression of VE-cadherin and β-catenin In caveolin-1 deficient EC, increased activity of eNOS accompanied by reactive oxygen species (ROS) generation leads to nitration; the 8 Pulmonary Hypertension – From Bench Research to Clinical Challenges consequent inactivation of p190RhoGAP-A results in RhoA activation and increased permeability Inhibition of RhoA or eNOS reduces hyper-permeability in . PULMONARY HYPERTENSION – FROM BENCH RESEARCH TO CLINICAL CHALLENGES Edited by Roxana Sulica and Ioana Preston Pulmonary Hypertension – From Bench Research to Clinical. secondary to drug toxicity and Pulmonary Hypertension – From Bench Research to Clinical Challenges 4 associated with congenital heart defects, connective tissue diseases, portal hypertension, . heterodimeric GTP binding protein, Ca 2+ Pulmonary Hypertension – From Bench Research to Clinical Challenges 6 ATPase and several transient receptor potential channels localize in caveolae,