Idiopathic Pulmonary Arterial Hypertension

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Jun 13, 2012 - Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) and activin receptor-like kinase 1, both members of the transforming ...

Bone Morphogenetic Protein Receptor 2 Mutations in Adults and Children With Idiopathic Pulmonary Arterial Hypertension : Kari E. Roberts, Robyn J. Barst, Jude J. McElroy, Allison Widlitz, Kiran Chada, James A. Knowles and Jane H. Morse Chest 2005;128;618S DOI 10.1378/chest.128.6_suppl.618S The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/128/6_suppl/618S.1.full.html

Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright2005by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692

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Bone Morphogenetic Protein Receptor 2 Mutations in Adults and Children With Idiopathic Pulmonary Arterial Hypertension Association With Thyroid Disease* Kari E. Roberts, MD; Robyn J. Barst, MD, FCCP; Jude J. McElroy, AB; Allison Widlitz, PA; Kiran Chada, PhD; James A. Knowles, MD, PhD; and Jane H. Morse, MD

(CHEST 2005; 128:618S) Abbreviations: BMPR2 ⫽ bone morphogenetic protein receptor type 2; IPAH ⫽ idiopathic pulmonary arterial hypertension

in the bone morphogenetic protein receptor M utations type 2 (BMPR2) and activin receptor-like kinase 1,

both members of the transforming growth factor-␤ family, have been reported in pulmonary arterial hypertension. The primary aim of the study was to determine the frequency of BMPR2 mutations in 75 children and 66 adults with idiopathic pulmonary arterial hypertension (IPAH). Our secondary aim was to ascertain whether clinical parameters such as thyroid disease and antinuclear antibodies defined the mutation-positive patients. Clinical evaluation consisted of right heart catheterization, evaluation of thyroid function, and serologic determinations of ANAs and specific autoantibodies related to connective tissue diseases. Exonic BMPR2 mutations were determined by nucleic acid sequencing. Five novel exonic BMPR2 mutations were found in 4 of 66 adults (6%) and in 1 of 75 children (1%) with IPAH. The four adults had two frameshift mutations (exons 9 and 12) and two nonsense mutations (exons 2 and 9), whereas the child had an exon 9 missense mutation. Remarkably, all five BMPR2 mutation-positive patients had thyroid disease (100%; but two cases are still being reviewed), but it was present in only 24% of the adults and 5% of the children without mutations. Three of the adults and the child had thyroiditis, and one had adult follicular hyperplasia. A high titer of antimicrosomal antibodies was present in the child and an adult with thyroiditis. All of the BMPR2 mutation-positive adults were antinuclear antibody⫹ but lacked autoantibodies characteristic of a specific connective tissue disease. BMPR2 mutations were found in a minority of adults and *From the Departments of Medicine (Drs. Roberts and Morse), Pediatrics (Dr. Barst and Ms. Widlitz), and Psychiatry (Mr. McElroy and Dr. Knowles), Columbia University College of Physicians and Surgeons, New York, NY; and the Department of Biochemistry (Dr. Chada), Robert Wood Johnson Medical School, Piscataway, NJ. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to James A. Knowles, MD, PhD, New York State Psychiatric Institute, Unit 28, Room 5916, 1051 Riverside Dr, New York, NY 10032; e-mail: [email protected] 618S

in even fewer children with IPAH. Remaining to be investigated are whether the children have a different disease from adults, the confirmation of the association between the presence of thyroid disease and mutations in BMPR2, and if valid, the reason for this interesting association.

Acute Cardiopulmonary Hemodynamic Effects of Brain Natriuretic Peptide in Patients With Pulmonary Arterial Hypertension* James R. Klinger, FCCP; Jeanne Houtchens; Sejal Thaker; Nicholas S. Hill, FCCP; and Harrison Farber, FCCP

(CHEST 2005; 128:618S– 619S) Abbreviations: BNP ⫽ brain natriuretic peptide; iNO ⫽ inhaled nitric oxide; mPAP ⫽ mean pulmonary artery pressure; PAH ⫽ pulmonary arterial hypertension

natriuretic peptide (BNP) has been shown to B rain reverse hypoxic pulmonary vasoconstriction and to

blunt the development of hypoxic pulmonary hypertension in animal models, but its acute cardiopulmonary effects on adult patients with established pulmonary arterial hypertension (PAH) has not been well-studied. We compared the acute pulmonary vasodilator effect of BNP to that of inhaled nitric oxide (iNO) [5, 10, 20 ppm] and/or IV epoprostenol (4 to 12 ng/kg/min) in 13 adult patients with PAH. Each patient received two BNP infusions (a 2 ␮g/kg bolus followed by a 3-h infusion at 0.01 ␮g/kg/min) separated by a washout period of at least 6 h. One BNP infusion was preceded by a 100-mg oral dose (50-mg if the age of the patient was ⬎ 65 years) of the phosphodiesterase inhibitor sildenafil. BNP changes from baseline hemodynamic measurements are shown in Table 1. The mean pulmonary artery pressure (mPAP) was lower with the combination of sildenafil plus BNP than with sildenafil alone (44.6 ⫾ 3.8 vs 40.6 ⫾ 3.9 mm Hg, respectively; p ⫽ 0.027). A ⬎ 20% decrease in peripheral vascular resistance (PVR), was seen in 3 of 8 patients who had received iNO, in 10 of 13 patients who had received epoprostenol, in 3 of 13 patients who had received BNP, in 3 of 11 who had received sildenafil, and in 5 of 12 patients who had received sildenafil plus BNP. BNP infusion was stopped in one patient because of transient hypotension. In the group that received sildenafil plus BNP, mPAP was significantly lower than baseline for up to *From the Division of Pulmonary Medicine, Rhode Island Hospital, Providence RI; and the Division of Pulmonary Medicine, New England Medical Center, Boston, MA; and Boston University Medical Center, Boston, MA. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: James R. Klinger, MD, FCCP, Rhode Island Hospital, SWP Rm 422B, Pulmonary and Critical Care Medicine, 593 Eddy St, Providence, RI 02903; e-mail: [email protected] brown.edu

47th Annual Thomas L. Petty Lung Conference: Cellular and Molecular Pathobiology of Pulmonary Hypertension

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Bone Morphogenetic Protein Receptor 2 Mutations in Adults and Children With Idiopathic Pulmonary Arterial Hypertension : Kari E. Roberts, Robyn J. Barst, Jude J. McElroy, Allison Widlitz, Kiran Chada, James A. Knowles and Jane H. Morse Chest 2005;128; 618S DOI 10.1378/chest.128.6_suppl.618S This information is current as of June 13, 2012 Updated Information & Services Updated Information and services can be found at: http://chestjournal.chestpubs.org/content/128/6_suppl/618S.1.full.html Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.chestpubs.org/site/misc/reprints.xhtml Reprints Information about ordering reprints can be found online: http://www.chestpubs.org/site/misc/reprints.xhtml Citation Alerts Receive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link to the right of the online article. Images in PowerPoint format Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint slide format. See any online figure for directions.

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