Pulmonary Arterial Hypertension
2004; Lippincott Williams & Wilkins; Volume: 109; Issue: 24 Linguagem: Inglês
10.1161/01.cir.0000132476.87231.6f
ISSN1524-4539
AutoresJohn H. Newman, Barry L. Fanburg, Stephen L. Archer, David B. Badesch, Robyn J. Barst, Joe G. N. Garcia, Peter N. Kao, James A. Knowles, James E. Loyd, Michael D. McGoon, Jane H. Morse, William C. Nichols, Marlene Rabinovitch, David M. Rodman, Troy Stevens, Rubin M. Tuder, Norbert F. Voelkel, Dorothy B. Gail,
Tópico(s)Vascular Anomalies and Treatments
ResumoHomeCirculationVol. 109, No. 24Pulmonary Arterial Hypertension Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBPulmonary Arterial HypertensionFuture Directions: Report of a National Heart, Lung and Blood Institute/Office of Rare Diseases Workshop* John H. Newman, Barry L. Fanburg, Stephen L. Archer, David B. Badesch, Robyn J. Barst, Joe G.N. Garcia, Peter N. Kao, James A. Knowles, James E. Loyd, Michael D. McGoon, Jane H. Morse, William C. Nichols, Marlene Rabinovitch, David M. Rodman, Troy Stevens, Rubin M. Tuder, Norbert F. Voelkel and Dorothy B. Gail John H. NewmanJohn H. Newman From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). , Barry L. FanburgBarry L. Fanburg From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). , Stephen L. ArcherStephen L. Archer From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). , David B. BadeschDavid B. Badesch From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). , Robyn J. BarstRobyn J. Barst From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). , Joe G.N. GarciaJoe G.N. Garcia From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). , Peter N. KaoPeter N. Kao From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). , James A. KnowlesJames A. Knowles From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). , James E. LoydJames E. Loyd From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). , Michael D. McGoonMichael D. McGoon From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). , Jane H. MorseJane H. Morse From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). , William C. NicholsWilliam C. Nichols From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). , Marlene RabinovitchMarlene Rabinovitch From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). , David M. RodmanDavid M. Rodman From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). , Troy StevensTroy Stevens From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). , Rubin M. TuderRubin M. Tuder From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). , Norbert F. VoelkelNorbert F. Voelkel From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). and Dorothy B. GailDorothy B. Gail From the Departments of Medicine, Nashville VA Medical Center (GRECC), and Vanderbilt University, Nashville, Tenn (J.H.N., J.E.L.); Department of Medicine, New England Medical Center, Boston, Mass (B.L.F.); Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (S.L.A.); Department of Medicine, University of Colorado Health Science Center, Denver, Colo (D.B.B., D.M.R., N.F.V.); Pulmonary Hypertension Center (R.J.B.) and Department of Medicine (J.A.K., J.M.), Columbia University and College of Physicians and Surgeons, New York, NY; Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md (J.G.N.G., R.M.T.); Departments of Medicine/Pulmonary and Critical Care and Pediatrics, Stanford University Medical Center, Stanford, Calif ( P.N.K., M.R.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (W.C.N.); Department of Pharmacology, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile (T.S.); and Division of Lung Diseases, NHLBI, Bethesda, Md (D.B.G.). Originally published22 Jun 2004https://doi.org/10.1161/01.CIR.0000132476.87231.6FCirculation. 2004;109:2947–2952Pulmonary arterial hypertension (PAH) is characterized by vascular obstruction and the variable presence of vasoconstriction, leading to increased pulmonary vascular resistance and right-sided heart failure. PAH can present in an idiopathic form, usually called primary pulmonary hypertension (PPH), and PAH is also associated with the scleroderma spectrum of diseases, HIV infection, portal hypertension with or without cirrhosis, and anorectic drug ingestion. Idiopathic PAH occurs in women more often than men (>2:1), has a mean age at diagnosis of 36 years, and is usually fatal within 3 years if untreated. Modern treatment has markedly improved physical function and has extended survival, and the 5-year mortality rate is ≈50%. We still do not understand what initiates the disease or what allows it to progress. New studies of the pathogenetic basis of PAH will lead to targeted therapies for PAH. The National Heart, Lung and Blood Institute (NHLBI) and the Office of Rare Diseases (ORD), National Institutes of Health, convened a workshop to bring together investigators with various interests in vascular biology and pulmonary hypertension to identify new research directions. Discussion included genetics of PAH, receptor function, mediators, ion channels, extracellular matrix, signaling, and potential clinical approaches.Background and QuestionsMolecular genetic studies have demonstrated mutations in a receptor in the transforming growth factor (TGF-β) superfamily, called bone morphogenetic protein receptor 2 (BMPR2), in most cases of familial pulmonary hypertension.1,2 Less common mutations associated with PAH occur in Alk1, a TGF receptor that also causes hereditary hemorrhagic telangectasia.3 Because only ≈10% to 20% of persons with a BMPR2 mutation develop PAH, it is likely that other genes, genetic polymorphisms, and environmental factors are necessary to initiate the pathological sequence that leads to disease.4 Most cases of PAH are not associated with known inherited genetic mutations.5 Thus, external stimuli coupled with as-yet-undefined genetic susceptibility to disease are likely responsible for most cases of PAH. The abnormal transduction of signals related to BMPR2 and Alk/endoglin is unknown and needs aggressive investigation. This will involve understanding of extracellular stimuli, receptor and membrane channel responses, and activation of a variety of intracellular molecules such as SMAD proteins, mitogen-activated protein (MAP) kinases, and nuclear transcription factors.6Several basic questions are unanswered. First, is there a common final pathway that is activated in response to a variety of disease-producing stimuli, or are there multiple independent pathways? Second, what cell or cells initiate the process in the vascular bed? Third, how does a mutated BMPR2 or Alk1 fail to suppress cellular abnormalities? Fourth, why are women at higher risk for disease? Finally, are affected vessels subject to an autonomous process, or does the disease require ongoing stimuli and therefore have the potential to be reversed? Multimodality therapy needs to be considered for clinical study, especially with endothelin A receptor antagonists and phosphodiesterase 5 inhibitors. Drugs known to protect the systemic vascular bed, such as the HMG Co-A reductase inhibitors, are candidates for treatment trials. Other drugs, such as elastase inhibitors, that have efficacy in experimental disease in animals need to be explored.7PathogenesisThe Figure depicts the biological milieu from which abnormal pulmonary vascular responses might lead to PPH. The figure is necessarily simplified and serves only as a guide for discussion of pathogenesis. Discussion of potential therapies will interdigitate with mechanisms of disease. Download figureDownload PowerPointSome cellular processes implicated in the pathogenesis of PPH. Extracellular mediators and cells (platelets) are highlighted in yellow, cell surface receptors and ion channels in purple, intracellular signaling in blue, and nuclear responses in green. See text for detailed descriptions of pathogenic mechanisms and interactions among the many pathways that span the extracellular, membrane, cytosolic, and nuclear domains. VEGF indicates vascular endothelial growth factor; its receptor is KDR. Intracellular transduction of this pathway is poorly understood. Endothelin is vasoactive and a mitogen, acting through Ca2+ channels and ERK/Jun kinases. TIE is the angiopoietin receptor, a system found to be upregulated in pulmonary vascular disease.56 Alk1 and BMPR1-2 are receptors of the TGF-β superfamily, and BMP indicates bone morphogenetic protein. Alk1 mutations cause hereditary hemorrhagic telangiectasia and some cases of PPH. Epidermal growth factor (EGF), tumor necrosis factor (TNF)-α, angiotensin II (ANGII), and platelet-derived growth factor (PDGF) are all proliferative stimuli that act through tyrosine kinase receptors and are partially transduced by intracellular oxidant species. In the intracellular domain, SMADs are regulatory proteins that activate nuclear transcription factors and interact with MAP kinases. AML1 is a nuclear transcription factor of potential importance. Elastase, downstream of AML1, has been implicated in vascular disease in experimental animals. Viral proteins are found in vascular lesions in the lungs of patients with PAH, raising the possibility that they participate in its pathogenesis.57BMPR2 and Alk/Endoglin MutationsMultiple loss-of-function mutations have been described in BMPR2 and ALK1.1,2,3,5 Activation of the TGF-β-BMPR2 axis leads to suppression of proliferation and activation of apoptosis; conversely, these loss-of-function mutations exaggerate the susceptibility of vascular cells to proliferate.8 Somatic mutations in endothelial cells microdissected from plexogenic lesions are found within the human MutS Homolog 2 gene that lead to reduced protein expression of TGF-β and thus suppression of apoptosis.9 Furthermore, pulmonary artery smooth muscle cells (PASMCs) from BMPR-knockout mice have abnormally enhanced proliferation rates in response to growth factors in vitro.10 The extensive diversity and tissue specificity of the SMAD system and the heteromultimeric formation of different TGF/BMP receptor subtypes may explain the localization of the disease to the small pulmonary arteries.K+ Channels, Vascular Tone, and ProliferationVasoconstriction is a feature in some cases of pulmonary hypertension, and mechanisms relevant to PPH might exist in the pulmonary response to hypoxia. Hypoxia inhibits ≥1 voltage-gated potassium channels (Kv) in the PASMCs, opening voltage-gated calcium channels, raising cytosolic Ca2+, and initiating constriction.11Kv1.5 or Kv2.1 channels are downregulated in the PASMCs in humans with PAH12 and in rats with chronic hypoxia-induced pulmonary hypertension.13 Furthermore, DNA microarray studies have shown downregulation of Kv channel genes in lungs of patients with PAH. In contrast, the genes for inward rectifier potassium channels (Kir) are upregulated in PAH.14 Whether these Kv channel abnorm
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