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Pulmonary Hypertension: The Present and Future Norbert F. Voelkel, MD Department of Internal Medicine Pulmonary and Critical Care Medicine Division Victoria Johnson Center for Pulmonary Obstructive Disease Research Vrrginia Commonwealth University Riclunond,Vrrginia 2011 PEOPLE'S MEDICAL PUBLISHING HOUSE-USA SHELTON, CONNECTICUT Pl:iopk'1 Medical PubJilllllDa B'oale-USA 2 EmezpEiao DIM, Sui:le 509 Shdltln. er OOl8'f Thi:~ Fu: 203-40'l-OllS4 E-mail: [email protected] PM PH-USA 0 2011 PMPH-USA, Lid. All d,gtD ~Without Hmllillg the d,gtD 1llllkr copyrlght reacn'ed tlloYe, DO part al 11111 pullllcallon may be rqirocb:ed. l1llred ill crr hmodaced ildo a Idlicml syl1elll. or traD.mliUed, in mt folm or by my_, (e1ecCnmic. merbamr..J. ~ ~ « olhmwile), willloai 1bD piior wrillm pcmziaiOll. alt be pd.Iii.Ila:. s 111213 14/PMl'llJ9 8 7 6 43 2 l JSBN-13: 97S-1-6079S-037-0 JSBN-10: 1..(iC)79S-037-S Plildcd. ill Cbilla by Plqllt;'1 Medical Pll.bll.lh:lng Howie F.dilar: ]-Malloy;~ Nowgai; am.~: Mary Mc:K'ooa. LlbrarJ of COllplll CetpJOjln1.m..PabJkatlon DaJa (Cll'TKJ Sala ud Dllltrlbatlcm Co1llldo U1llllld Dlfdom. ~ Mkl4k &rt Afrtco Brw.il Ml:Gmw-IBll R.rer-BdacMlon McG:ra.w Bill Bdilcal!Oll. SapaPcdldD' Thanedd Ca.m-:Oao S'hnppenhmgrn Bold BeaizAIYel, Fmeip 1l'ado Dqllr1mom 300WakcSl Mlidcahcad R. SmlNIO Aha dot Suilol, 102 I 7di. lloor Whilby, Ommio LIN 9B6 Babhlrc, SL6 2QL Bmo'illn Novo Caada Ellg1md SllO Plolo 00"71-090 'Ill!: 1-800-S6S-S7S8 Thi: 44-0-1628-50'1500 Bmzil Fu: 1-800-461·5885 Fax: 44-0-1628-&SS~ 'M: SS-16-3512-"39 www.mcgrawhill.ca www.mcgmv-hlll.co.ak www.mpapedlclolllcmeddcom.br &m,,.RJpa ~ 'IMlla1td, Pldl/pptllu, lltdonula. 1C.nB.dSia P, Baho.lnl&alhac.tnl# Ji. JWVfm\ Sri Lada, M.alapia Iolm SCIOU • <:ompmy ~ 1bt:ific .Rilft. Kmw 4819/Xl P.llh1ad sn. 24 Mi:Gmw-IBD. l!dllcalioo. lilae:nallcmal PabHJhr.r'• Aaency Amai Road, Dlreya Gllllj, New Delhi-110002 P.O.Bm.878 60 Tull BlliD.LiDk llldla Kimbenm, PA 19442 ~&ms Tel: 91-11-232668fil/67 USA Thl:~1S80 Fax: 91-11-23266818 Fu: 6S.Q62.3354 Thi: 610-827-1640 Bmdl:cblpuhll<tmW:am www..nqraw-hl!Lcam.aa Fu: 610-827-1671 JWpla'1 ~ af C'iiola AM.l'lmllo; Nnt Z1a1M4 .Alrptia New G11i11t4 Peopl&'• Medk:ll~Hau& l'fXl'I Ff/411mfa. So'-hkwll, Cool bkr1tdl lnlmlalioaal' 1ndo Dclpllmicm:t Ulllled PQbll.sbm StrviOC$ Umllcd Woodalane Ply Umited No. 19, Pin Jill 'Ylllln N1111 Li 1-32-S~ Ullit 7/S VUD Place Cluloyq Dlltlict Shimlgllw>ku, 'lbtJo 14<MXXY.2 Wmrinood NSW 2Url BeijiD,g l<Xml Jap1111 Alu1l'ah P.R.Oiina Thi: 03-5479-7251 Thi: 61-2-9970-S Ill 'nil: 8610-67653342 Fu: 03-5479-7307 Fu: 61-2-9970-Slm Fa:x: 861().67691034 l!mlll: [email protected] www.~.c:om.• www.~ Nodce: The lllllhora an.cl pu11Habt.r have made C'l'Cly effort lo C11N1e that tbe p!llit.nt ccc ftCOmmezid.ed h::u:lJI. illcludini dlOicc of dt1IP llld drQa clocaps, ls ill acccrd with CbD KCqltCld sbmdll:d and practio& at thD limo of pibHartkn Hanwl; liDoe web llld ftlg\llldiml. comtlmlly dllmge dDW:l1 ~th& relldclr is 1llpd lo chec:k !be procb:t .iufumlaiiou m. im:luded iD th& pac:bgo of old! drug. which illc:ludea nioommm.W ~ ~ lll!ld oonin!pdieufon&. Thh it p111icW.ady implllllnt with 1:ltW or~ ll9ed dtup. ArI.'f ~ ~ pticulady one llmllvillg mecllcati.oa, illYot.a iDba:ezlt !bkt hat mllltb o welgbed a11 a cao-by-c:ue buh a,piDst tho~ llltlciplllecl Th& nmer ii c:amkmd dt.at Ille plllpOIO af thiJ bOCJk is IO im-.l lld eaJiPtm; th& illfomllliOll c:ollllliDed hm:lin ii notilllmded -. mid lho'idd not bo ~ 11, a lllbllilule forilldlridlial ~ llld ~ Dedicated to the memory of John (Jack) T. Reeves and Jane Morse, pioneers of pulmonary hypertension research The vital spirit hath its origin from the left ventricle of the heart, but its perfection chiefly from the lungs ... It is generated by the air, which we inspire, mixt in the lung with the elaborated subtil blood, which the right ventricle communicates to the left. Now this communication is not made through the septum of the heart, as 'tis commonly believed; but the subtil blood is driven by a wonderful contriv ance, from the right ventricle of the heart, through a long duct, into the lungs, by which it is prepared and made bright; then it passeth from the vena arteriosa into the vena venosa ... Lastly the whole mixture is brought into the left ventricle of the heart by diastole. Micheal Servetus, A.K.A. Rev6s Christianisimi Restitutio, 1553* *An Impartial History ofM icheal Servetus: Burnt Alive at Geneva for Heresie. London: Aaron Ward, 1724. Contents Contributors vii Acknowledgments xi Introduction xiii I. The Wide Spectrum of Pulmonary Vascular Diseases: "The Sick Lung Circulation" Norbert F. Voelkel 2. Mechanisms of Lung Vascular Remodeling II Norbert F. Voelkel 3. Ion Channels and Transporters In Pulmonary Arterial Hypertension 19 Thenappan Thenappan, Lin Piao, Jalees Rehman, and Stephen L. Archer 4. Reconclllng Matrix Remodeling and Vasoconstrlctlon In Pulmonary Hypertension 51 Peter Lloyd Jones 5. The Immune Response In Pulmonary Hypertension 67 Yon K. Sung and Mark R. Nicolls 6. The Pathoblology of the Complex Vascular Lesions In Severe Pulmonary Hypertension-Angiogenesis and Cancer 87 Norbert F. Voelkel and Carlyne D. Cool 7. Pulmonary Veno-Occlusive Disease 105 David Montani, Dermot S. O'Callaghan, and Marc Humbert B. Left Heart-Related Pulmonary Venous Hypertension 119 Julio Sandoval, Arturo Carrillo, Felipe Mass6, Virgilia Soto, Rodolfo Barragan, Tomas Pulido, Valentin Herrera, Efren Santos, and Norbert Voelkel 9. Pulmonary Hypertension and Interstitial Lung Disease 141 Laszlo Farkas and Martin R.J. Kolb 10. Animal Models of Pulmonary Hypertension 161 Norbert F. Voelkel 11. Right Heart Failure In Pulmonary Hypertension 177 Herman J. Bogaard, Ramesh Natarajan, Jose Gomez-Arroyo, Antonio Abbate, and Norbert F. Voelkel 12. Genetics of Severe Pulmonary Hypertension 197 Rajiv D. Machado, Richard C. Trembath, and Nicholas W. Morrell 13. Pulmonary Hypertension In Children 211 Christian Apitz and Dietmar Schranz v vi • Contents 14. Endocrine Aspects of Pulmonary Hypertension 239 Lori B. Sweeney and Laveena Chhatwani 15. The Role of Exercise in the Prognosis, Diagnosis and Management of Pulmonary Arterial Hypertension 251 Daniel C. Grinnan, Ross Arena, and Herman J. Bogaard 16. Treatment Strategies for Severe PAH: The Present and Future 269 Dermot S. O'Ca1laghan, Marc Humbert, and Gerald Simonneau 17. Inhaled Drugs for the Treatment of Pulmonary Hypertension: Challenges and Benefits 281 Peter R Byron and Masahiro Sakagami 18. Biomarkers, Registries, and Outcomes JO I R. Paul Fairman 19. On the Pathobiology and Treatment of Cancer and Pulmonary Arterial Hypertension 317 Roland Mertelsmann and Ralph Wiisch Epilogue 341 Index 345 Contributors Antonio Abbate, MD, PhD Pulmonary and Critical Care Medicine Division Victoria Johnson Center for Pulmonary Assistant Professor Obstructive Disease Research Department of Internal Medicine Virginia Commonwealth University Division of Cardiology Richmond, Virginia Victoria Johnson Center for Pulmonary Obstructive Disease Research Peter R. Byron, PhD Virginia Commonwealth University Richmond, Virginia E. Claiborne Robins Professor and Chairman Christian Apitz, MD Department of Pharmaceutics Virginia Commonwealth University Clinical Research Fellow Richmond, Virginia Division of Pediatric Cardiology University Children's Hospital Arturo Carrillo, MD Giessen, Germany Fellow, Cardiology Stephen L. Archer, MD, FAHA The National Institute of Cardiology Mexico City, Mexico Professor of Medicine Head, Cardiology Department of Medicine Laveena Chhatwanl, MD Section of Cardiology Fellow, Department of Internal Medicine The University of Chicago Pulmonary and Critical Care Medicine Chicago, Illinois Division Virginia Commonwealth University Ross Arena, PhD Richmond, Virginia Assistant Professor Department of Physical Therapy Carlyne D. Cool, MD Virginia Commonwealth University Associate Professor Richmond, Virginia Department of Pathology University of Colorado Rodolfo Barragan, MD Aurora, Colorado Deputy Director, Cardiothoracic Surgery Division R. Paul Fairman, MD The National Institute of Cardiology Professor Mexico City, Mexico Department of Internal Medicine Herman J. Bogaard, MD, PhD Pulmonary and Critical Care Medicine Division Assistant Professor Virginia Commonwealth University Department of Internal Medicine Richmond, Virginia vii viii • Contributors Laszlo Farkas, MD, PhD Department of Pathology and Laboratory Medicine Post-doctoral Researcher Institute for Medicine and Engineering Department of Medicine University of Pennsylvania Division of Respirology Philadelphia, Pennsylvania Firestone Institute for Respiratory Health McMaster University Martin R.J. Kolb, MD, PhD Hamilton. Ontario, Canada Research Director Jose Gomez-Arroyo, MD Firestone Institute for Respiratory Health Associate Professor Post-doctoral Researcher Department of Medicine and Pathology Department of Internal Medicine Molecular Medicine Pulmonary and Critical Care Medicine McMaster University Division Hamilton. Ontario, Canada Victoria Johnson Center for Pulmonary Obstructive Disease Research Virginia Commonwealth University Rajiv D. Machado, PhD Richmond, Virginia Department of Medical and Molecular Genetics Division of Genetics and Molecular Medicine Daniel C. Grinnan, MD King's College School of Medicine Assistant Professor Guy's Hospital Department of Internal Medicine London. United Kingdom Pulmonary and Critical Care Medicine Division Virginia Commonwealth University Felipe Masso, MD, PhD Richmond, Virginia Head of Molecular Biology Department Valentin Herrera, MD The National Institute of Cardiology Mexico City, Mexico Head of Cardiothoracic Surgery Department The National Institute of Cardiology Roland Mertelsmann, MD Mexico City, Mexico Professor of Medicine Marc Humbert, MD, PhD IMBS Director Department of Medicine I Professor of Medicine Oncology, Hematology, and Stem Cell Centre National de Ref6rence de !'Hypertension Transplantation Pulmonaire Sevm Freiburg University Medical Center Service de Pneumologie et R6animation Freiburg, Germany Respiratoire H6pital Antoine B6clhe Clamart, France David Montanl, MD, PhD Praticien Attache Peter Lloyd Jones, PhD Centre National de R6f6rence de !'Hypertension Associate Professor of Pathology and Pulmonaire Sevm Laboratory Medicine Service de Pneumologie et ~tion Lecturer in Architecture Respiratoire Director, Penn-CMREF Center for Pulmonary Hap.ital Antoine-B6clhe Hypertension Assistance Publique-H6pitaux de Paris Co-Director, Sabin+Jones LabStudio C1amart, France Contributors • ix Nicholas W. Morrell, MD, PhD Jalees Rehman, MD Professor of Cardiopulmonary Medicine Assistant Professor Department of Medicine Department of Medicine University of Cambridge School of Section of Cardiology Clinical Medicine The University of Chicago Division of Respiratory Medicine Chicago, Illinois Addenbrooke's and Papworth Hospitals Cambridge, United Kingdom Masahiro Sakagami, PhD Ramesh Natarajan, PhD Assistant Professor Department of Pharmaceutics Associate Professor Virginia Commonwealth University Department of Internal Medicine Richmond, Virginia Pulmonary and Critical Care Medicine Division Victoria Johnson Center for Pulmonary Julio Sandoval, MD, FACC Obstructive Disease Research Virginia Commonwealth University Professor, Cardiopulmonary Medicine Richmond, Virginia The National Institute of Cardiology Mexico City, Mexico Mark R. Nicolls, MD Efren Santos, MD, MS Associate Professor Chief, Department of Medicine Assistant Professor Pulmonary and Critical Care Medicine Division Cardiopulmonary Department VA Palo Alto Health Care System The National Institute of Cardiology Stanford University Mexico City, Mexico Stanford, California Dietmar Schranz, MD Dermot S. O'Callaghan, MD Professor of Pediatrics Centre National de Reference de !'Hypertension Department of Pediatric Cardiology Pu1monaire s~ Head, Pediatric Heart Centre Service de Pneumologie et Reanimation Justus-Liebig-University of Giessen Respiratoire Giessen, Germany HOpital Antoine Beclere, C1amart Gerald Simonneau, MD Lin Piao, PhD Professor Research Associate Centre National de Reference de !'Hypertension Section of Cardiology Pulmonaire s~ Department of Medicine Service de Pneumologie et Reanimation The University of Chicago Respiratoire Chicago, Illinois HOpital Antoine Bklm Clamart, France Tomas Pulido, MD Virgilia Soto, MD Associate Professor Head of Clinical Cardiology Pathology Department The National Institute of Cardiology The National Institute of Cardiology Mexico City, Mexico Mexico City, Mexico x • Contributors Yon K. Sung King's College School of Medicine Guy's Hospital Instructor. Deparbnent of Medicine London. United Kingdom Pulmonary and Critical Care Medicine Division Norbert F. Voelkel, MD Stanford University Stanford, California Professor of Medicine and Pathology E. Raymond Fenton Chair of Pulmonary Lori B. Sweeney, MD Research Department of Internal Medicine Acting Chief, Endocrinology and Metabolism Pulmonary and Critical Care Medicine Division Eisenhower Army Medical Center Victoria Johnson Center for Pulmonary Fort Gordon, Georgia Obstructive Disease Research Virginia Commonwealth University Thenappan Thenappan, MD Richmond. Virginia Fellow. Department of Medicine Ralph Wisch, MD Section of Cardiology The University of Chicago Professor of Medicine Chicago. Illinois IMBS Co-Director Department of Medicine I Richard C. Trembath, PhD Oncology, Hematology. and Stem Cell Transplantation Professor. Department of Medical and Freiburg University Medical Center Molecular Genetics Frei.burg, Germany