Vol 110, No 17, October 26, 2004
`ISSN 0009-7322
`hittp://circ.ahajournals.org
`
`American Heart
`Associations
`
`Learn and Live..
`
`EDITORIALS
`2552 Anti-oxLDL Antibodies: Pathogenic or
`Protective?
`Selahide Mya=)|
`Cellular Basis for Therapeutic COTitre
`beCOluay oeiiiigs
`(o}ey(=)
`
`Pry
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`Page 1
`
`ORIGINAL ARTICLES
`2562 Diagnosis of Sleep-Related Breathing
`Disorders
`:
`Scharf et al
`Tachycardia-Related Channel on Voltage
`Map
`Arenalet al
`SETSanNaITeI)iTS
`Stewart et al
`RVElectrograms Localize LV Tachycardia
`Patel et al
`HSP60 Antibodies and Atrial Fibrillation
`Mandalet al
`ATP ys Shock for Rapid Ventricular
`Tachycardia
`Wathen etal
`Clinical Inhibition of PAR1 by Aprotinin
`Day et al
`Poor Relationships in Fontan
`Ohuchi et al
`PulmonaryArtery Impedance and Power
`Weinberg et al
`CHARMLow-LVEFTrials PVA
`Young et al
`Fetal Tachycardia: Effects of Hyperglycemia
`Schmidt et al
`STAT6 and Heart Failure
`Hikoso et al
`:
`Coronary Artery Stenosis in CT
`Hoffmannet al
`LYM and AGTRI and AGTR2 Variants
`Kuznetsovaet al
`
`Tc.Regulation by Phosphatases in AF
`Christ et al
`Bone MarrowStemCells Differentiate Into
`Myocytes
`Xu et al
`
`eNOS Modulates Cardiac Autonomic
`BESTIS
`Massion etal
`Integrin Profile of Smooth Muscle
`Progenitors
`Deb etal
`Triglycerides and Cardiovascular Diseases
`Asia Pacific Cohort Studies
`Collaboration
`ApoB Versus Non-HDL Cholesterol in MetS
`Sattar et al
`Sirolimus Reduces Acute Rejection and
`Transplant Vasculopathy
`Keoghet al
`COX-2 Regulation of Hypoxia-Induced
`Thrombosis
`:
`Pidgeonetal
`B,-Mediated Dilation of CoronaryArterioles
`Hein et al
`CRP Regulation of Neutrophil-Platelet
`Adhesion
`Khreiss et al
`
`AHASCIENTIFIC STATEMENTS
`2721
`Practice Standards for ECG NYCSTeoweae Tn
`15CSSNYT)
`Drew et al
`Kawasaki Disease Diagnosis, Treatment,
`Management
`Newburgeretal
`
`2747
`
`:
`~
`‘Electronic Pages:
`e Image: Primary Cardiac Lymphoma Presenting
`| With Stroke
`:
`¢ Book Review: Cardiac Electrophysiology:From
`Cell to Bedside, Fourth Edition.
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`Liquidia's Exhibit 1093
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`Liquidia's Exhibit 1093
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`JOURNAL OF THE AMERICAN HEA (P) GU 66 — E(2)
`
`Abstracts
`
`jneyeel
`
`THLULL
`sessions
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`KOU LITO
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`Page 2
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`Sessions: November 7—10
`Exhibits: November 7—9
`New Orleans, Louisiana
`scientificsessions.org
`
`Named and Invited Lectures 2004
`
`2004 Russell Ross Memorial LeeTRSeeMetraTleas SC)nmeIYI George LymanDuff Memorial Lecture * 2004 Sol Sherry
`Distinguished Lecture in Thrombosis * 2004 Thomas W. Smith Memorial Lecture * 2004 George E. Brown Memorial Lecture
`* 2004 Dickinson W. Richards Memorial Lecture * 2004 Katharine A. Lembright Award+ 2004 William W. L. Glenn Lecture
`* 2004 William J. Rashkind Memorial Lecture « 2004 T. Duckett Jones Memorial Lecture * 2004 Charles T. Dotter Memorial
`Lecture * 2004 LaennecSociety Lecture * 2004 Ancel Keys Lecture * 2004 Lewis K. Dahl Memorial Lecture * 2004 Robert
`I, Leyy EndowedLecture in Lipid Metabolism
`
`New and Young Investigator Award/Prize Abstract Finalists
`Lewis N. and Arnold M. Katz Basic Science Research Prize for Young Investigators * Melyin L. Marcus YoungiIny estigator
`Awardsin Cardiovascular Science * Cournand and Comroe Young Inyestigators Prizes in CardiopulmonaryandCritical
`Care * Outstanding Research Awardin Pediatric Cardiology * Melyin Judkins Young Iny estigator Award in Catdioyascular
`Radiology * Vivian Thomas Young Investigator Award * Martha N. Hill New Inyestigator Awards * Elizabeth Barrett-
`Connor Research Awardin Epidemiology and Preyentionfor Investigators in Training * Samuel A. Levine Young Clinical
`Investigator Awards * Laennec Society Young Clinician Award » NPAM New Inyestigator Award
`
`Abstracts From the Scientific Sessions 2004
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`SCIENCE TECHNOLOGY
`Supplement to
`Circulation Volume 110 Number17 October26, 2004
`-
`AND INNOVATION
`1
`‘
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`19
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`NOV
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`2004
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`THE BRITISH LIBRARY
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`Abstracts From Scientific Sessions 2004
`Morial Convention Center
`New Orleans, Louisiana
`November 7-10, 2004
`
`|
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`Ui
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`organeeCeoeemOCTET
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`Named and Invited Lectures
`- 2004 Russell Ross Memorial Lectureship in Vascular Biology
`Garebes FilteGerel, MD | acoso 468 5i10~1mr +n nansueRntOs 4hammsmuewsapimianime?ueaesecessc.. I-A
`| 2004 George Lyman Duff Memorial Lecture
`[Beni IN. GEE MAD os suas ain nemosmean eg are s4S SAR aneansavewsequar gna tine wemecuvenseosesauca
`;
`I-A
`- 2004 Sol Sherry Distinguished Lecture in Thrombosis
`DOSED: WOgMEE POD nas nnn nnn 1GGhsrA@hane sueennwrgsouseniaiansensuuemepeyeeae cguaecs... I-A
`| 2004 Thomas W.Smith Memorial Lecture
`| Donald M. Bers, PRDec e vec vvtttttte treet tee tree II-B
`| 2004 George E. Brown Memorial Lecture
`| David A. Kass, MD, FAHA ooo ccc teteteeebbbeceeebeeeeeeeeeeee U-B
`2004 Dickinson W. Richards Memorial Lecture
`Kenneth Weir, MD, FAHA
`
`PRR ROTTS EN SEH N ER Cee eee ERE WHEE EEN eee uewswaew eae 4s EREE acces II-C
`2004 Katharine A. Lembright Award
`Diane M. Becker, RN, MPH, ScD, FAHA o.oo.e ce cce ecco ceccceeeece I-C
`2004 William W. L. Glenn Lecture
`| Beietloy eee MD ss: meme mee apfimsuusnustvin+onsmeretmpampans@s vaens coceneseeaceeessc
`=
`| 2004 William J. Rashkind Memorial Lecture
`| Betsy Dresser, PAD eek eee e eee cceeeeeeveeceseeaueesteeceresieceeeenereecccc oe IlI-D
`| 2004 T. Duckett Jones Memorial Lecture
`aee IlI-D
`2004 Charles T. Dotter Memorial Lecture
`[PONE Wether, BD oo oc snsis on nun eamsmerunemraai@nsarsomnemeggipwanvaditilesncseeecocesecocecee. T-D
`2004 Laennec Society Lecture
`Namette K. Wenger, MD, FAHA occ cee ovbeveeee ee L-E
`2004 Ancel Keys Lecture
`Panwin R. Labarthe, MD, MPH, PAD. ve vee cveeveeeeeeeeecce T-E
`Note: Abstract numbers are arrangedto coincide with abstracttitles in theAmerican HeartAssociation’s Scientific Sessions 2002 Program.
`Subject and authorindexes are keyed to abstract numbers. Authors ofall Named and Invited Lectures and New and YoungInvestigator
`Award/Prize Abstracts are presentedin the expanded Table of Contents within this Abstracts issue. Indexesare located at the backofthis issue.
`All other supplements to this volume ofCirculation will be indexed in the last Decemberissue,
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`IH-C
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` CIRCULATION(ISSN 0009-7322)is published weekly except combinedthefirst two weeks in January andthe last two weeks in December by Lippincott Williams & Wilkins at 16522
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`2004 Lewis K. Dahl Memorial Lecture
`Rhian M. Touyz MD, PhD... 0.6ee EERE EER EE Ener e renters ees W-F
`2004 Robert J. Levy Endowed Lecture in Lipid Metabolism
`Ronald M. Krauss, MD, FAHA 1.0... ccc ccc cee eee ene nee e tenet e teense ernst eer r esas Til-F
`New and Young Investigator Award/Prize Abstract Finalists
`Lewis N. and Arnold M. Katz Basic Science Research Prize for Young Investigators
`Karl-Ludwig Laugwitz, Alessandra Moretti, Jason Lam, Peter Gruber, Yinhong Chen, Sarah Woodard, Lizhu
`Lin, Chen-Leng Cai, Michael Reth, Sylvia Evans, Kenneth R. Chien ......... 0.0 c eee teen enter eee ene Il-G
`Patrick Most, Mirko Voelkers, Sven T. Pleger, Erhe Gao, Melanie Boerries, Andrew Remppis, Hugo A. Katus,
`Wolter F Roe coq occ eis he ih 4x8 0a Cp Eae Foes PSS so OR He tin aha Mi aR A CARRS RTE SS OR GIS BENE See T OS IIL-G
`Sathyamangla V. Naga Prasad, Aruni Jayatilleke, Howard A. Rockman .......00seeeee vere eee een en eens W-H
`Da-Zhi Wang, Dongsun Cao, Zhigao Wang, Shijie Li, Eric N, Olson ...,...... Se ee SS ee ee oe es 2 0-H
`Min Xie, Sam C. Wang, Dou Zhang, Arun J.C. Prahash, Hidemasa Oh, Motoaki Sano, Xiaozhen Wang, Jennifer
`S. Pocius, George E. Taffet, Lloyd H. Michael, Tse-Hua Tan, Mark L. Entman, MichaelD. Schneider ......... TI-H
`Melvin L. Marcus Young Investigator Awards in Cardiovascular Science
`Roselle Abraham, Peter Lim, Charles A. Henrikson, Roland Emokpae, Ronald Li, Leslie Tung, Eduardo Marbén .... YH-I
`Garvan C. Kane, Atta Behfar, D. Fearghas O’Cochlain, Roy B. Dyer, Xiao-Ke Liu, Denice M. Hodgson,
`Santiago Reyes, Takashi Miki, Susumu Seino, Andre Terzic ... 1... 6.0 seen ener enn nee nents DIT
`Ryoji Koshida, Petra Rocic, Shuichi Saito, William M. Chilian ... 00.01. cece ect erent ener tees W-I
`Gangjian Qin, MasaakiIi, Andrea Wecker, Evelyn Bord, Hong Ma, David A. Goukassian, Yung-sup Yoon, Raj
`Kishore, Yan Zhu, Douglas W. Losordo 0... . ccc cee ent ee eee eee ene ee eens I-J
`Yao Liang Tang, Yi Tang, Keping Qian, Y. Clare Zhang, Leping Shen, M. Jan Phillips) 02.4506. cee sented Ii-J
`Subodh Verma, Chao-Hung Wang, William Stanford, Shu-Hong Li, Richard D. Weisel ........0. 0.0 eee venes I-J
`Cournand and Comroe Young Investigators Prizes in Cardiopulmonary and Critical Care
`Kimberly A. Boddicker, Yi Zhang, Loyd R. Davies, Richard E. Kerber ....... 0.0 ec eeeveeeee ete ees ne ee ees UI-K
`Sebastien Bonnet, M. Evangelos D. Michelakis, Sean McMurtry, Gwyneth Harry, Sandra Bonnet, Alois Haromy,
`Stephen L. Archer 0.0... cece eee nee e enn e tenes Aad bum binges Sa ht Se ews Se Se Sd as T-K
`Pietro Caironi, Fumito Ichinose, Rong Liu, Rosemary C. Jones, Kenneth D. Bloch, Warren M. Zapol ......... Ti-L
`Junyan Gu, Deyanira Prastein, Charles White, Jeffrey Manchio, Richard N. Pierson, Bartley P. Griffith, Paul
`Gurbel, Udaya Tandry, Robert Poston .. 0... cece cc cee eee enna teen eee eeeneeerenntes TO-L
`Christopher J. Mingone, Sachin A. Gupte, NoorjahanAli, Richard A. Oeckler, Susan. C. Olson, Michael S. Wolin .... TH-L
`Outstanding Research Award in Pediatric Cardiology
`Brian Feingold, Seda Selamet, Sang C. Park, Beth F. Printz, C. Becket Mahnke, Shing Lee, Charles S.
`Kleinman, Donna M. Timchak, William H. Neches, Welton M. Gersony ...... 0. cece cece eee eens T-M
`Marco Stramba-Badiale, Karine Goulene, Giuliano Bosi, Roberta Bini, Silvia G. Priori, Raffaella Bloise, Lia
`Crotti, Patrizia Salice, Viasta Fesslova, Savina Mannarino, Giuseppe Latini, Roberto Giorgetti, Peter J. Schwartz ........ T-M
`Wayne Tworetzky, Audrey C. Marshall, Laura B. Myers, Lisa J. Bergersen, Russell T. Jennings, Carol B.
`Benson, Louise E. Wilkins-Haug, James E. Lock .... 1.2 c cee nee nee n ene nen ee T-N .,
`Melvin Judkins Young Investigator Award in Cardiovascular Radiology
`Fabao Gao, Bensheng Qiu, Sourav Kar, Xiangcan Zhan, Lawrence V. Hofmann, Xiaoming Yang ...........:. Il-N
`C. Javidan-Nejad, D.C. Lesniak, G.S. Chrysant, J. Zheng, R.J. Gropler, T.K. Pilgram, P.K. Woodard ......... -O
`Saman Nazarian, David A. Bluemke, Albert C. Lardo, Menekhem M. Zviman, Katherine C. Wu, Stanley Watkins,
`Clerio Azevedo, Timm L. Dickfeld, Glenn R. Meininger, Ronald D. Berger, Hugh Calkins, Joao A. Lima, Henry
`R. Halperin ooo een enn EEE EEE E EE EORTC EEE EEE EE EEE EE OES -O
`MonvadiB. Srichai, Chelif Junor, L. Leonardo Rodriguez, Arthur E, Stillman, Richard A. Grimm, Michael L.
`Lieber, Joan A. Weaver, Nicholas G. Smedira, Richard D, White (1.0... ccc cece eee eee eee eee Iil-O
`Vivian Thomas Young Investigator Award
`Sydney L. Gaynor, Hersh S. Maniar, Jeffrey B. Bloch, Paul Steendijk, Marc ReMOOn Foot sl ete ea a Ill-P
`Faraz Kerendi, Michael E. Halkos, Hajime Kin, Joel S. Corvera, Daniel J. Brat, Mary B. Wagner, Jakob
`Vinten-Johansen, Zhi-Qing Zhao, Joseph M. Forbess, Kirk R. Kanter, Paul M. Kirshbom ...........+.-+++++ Iil-P
`Paul V. Kochupura, Evren U. Azeloglu, Damon J. Kelly, Sergey V. Doronin, Stephen F. Badylak, Irvin B.
`Krukenkamp, Ira S. Cohen, Glenn R. Gaudette .... 0... ce eee cee eee e eens SS gta": Il-P
`Stephen Kolakowski Jr, Mark F. Berry, Todd Grand, OmarFisher, M. Astrid Moise, Jeffrey Cohen, Vivian Hsu,
`Y. Joseph WOO. sis big vc ig coe bane es 5 Rue OES RUE ES ESTE GEES ee od eRe Cae eee eee ee eee ee ean II-Q
`Frank Langer, Filiberto Rodriguez, Saskia Ortiz, Allen Cheng, Mary K. Zasio, David Liang, George T.
`Daughters, Neil B. Ingels, D. Craig Miller
`.........0..0 ees ee eee ce ieln nese. 555 OR Ea SS m-Q
`Pierre Voisine, Jian Li, Cesario Bianchi, Tanveer A. Khan, Marc Ruel, Shu-Hua Xu, Jun Feng, Audrey
`Rosinberg, Tamer Malik, Yasunari Nakai, Frank W. Sellke ............- dee RAT aa casey ome ners ae IlI-R
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`MarthaN. Hill New Investigator Awards
`... 00... occ ccc cece cee nenes I-R
`Wen-Wen Li, Anita L. Stewart, Nancy Stotts, Erika S. Froelicher
`Philip Moons, Kristien Van Deyk, Kristel Marquet, Els Raes, Leentje De Bleser, Sabina De Geest, Werner Budts .... T1II-R
`
`Lorraine §. Evangelista, Kathleen Dracup, Lynn Doering, Debra K. Moser, Jon Kobashigawa ............... HI-S
`Elizabeth Barrett-Connor Research Award in Epidemiology and Prevention for Investigators iin Training
`Matthew Allison, Michael Criqui, Elena Ho, Julie Denenberg ..........0. 00000 ccc ccc ec cee cece In-T
`Khawaja Afzal Ammar, Steven J. Jacobsen, Richard J. Rodeheffer .... 0.0.0.0. occ ccc cece eee I0-T
`ApoorS. Gami, Daniel E. Howard, Eric J. Olson, Virend K. Somers...00... I-T
`Frederick A. Masoudi, Charles Baillie, Yongfei Wang, Edward P. Havranek, JoAnne Micale Foody, John F.
`Steiner, Harlan M.Krumhole oc o5 ce ccas nc gesk og tse bs Rime WAST RET E Ts dS BAER TEN OTTERS RAT ERI AS I-U
`Nona Sotoodehnia, David Siscovick, Matteo Vatta, Bruce Psaty, Russell Tracy, Jeffrey Towbin, Rozenn Lemaitre,
`Thomas Rea, Peter Durda, Joel Chang, Thomas Lumley, Lewis Kuller, Greg Burke, Susan Heckbert .......... I-U
`Tianying Wu, Susan E. Hankinson, Walter C. Willett, Edward Giovannucci ... 0.0... cee IiI-V
`
`Samuel A. Levine Young Clinical Investigator Awards
`Michaela Scheuermann-Freestone, Damian Tyler, George K. Radda, Stefan Neubauer, Kieran Clarke ......... T-w
`Michelle M. Kittleson, Shui Q. Ye, RafaelA. Irizarry, John V. Conte, Giovanni Parmigiani, Leslie W. Miller,
`Yingjie Chen, Jennifer L. Hall, Joe G.N. Garcia, Joshua M. Hare oo. ccc ccc ccc ete tee teerees Il-w
`Hidenobu Koga, Seigo Sugiyama, Kiyotaka Kugiyama, Keisuke Watanabe, Hironobu Fukushima, Tomoko
`Tanaka, Tomohiro Sakamoto, Michihiro Yoshimura, Hideaki Jinnouchi, Hisao Ogawa ..... 00... ccc cece eee I-W
`
`Francesca Nesta, Maire Leyne, Charles Simpson, Daisy Dai, Jane E. Marshall, Chaim Yosefy, Judy Hung, Susan
`
`A. Slaugenhaupt, Robert A. Levine .. 0. icc ccc ccc ccc ee eee eet teen ene bebe beeen W-x
`Khim Leng Tong, Sanjiv Kaul, Xin-Qun Wang, Diana Rinkevich, Saul Kalvaitis, Todd Belcik, Wolfgang Lepper,
`William A. Foster, Kevin Wet ois siccsciusnicencan wee em su im ee se meee eae ae od He ewe Saw bese meet ees Dew e W-X |
`
`Laennec Society Young Clinician Award
`Marcus Y. Chen, William A, Baker, Bryan R. Haugen, Robert A. Quaife 2...c ee eens ii-Y
`Andrew C. Lee, Elyse Foster, Yerem Yeghiazarians
`.. 0.0.00.ee cence eee e eae m-y
`Molly Ware, Eric Awtry, Michael Klein, Thomas Ryan 0.0.00 cc cece ence c seen ee eee I-Y
`
`NPAMNewInvestigator Award
`M. Robinson, M. Scheuermann-Freestone, P. Leeson, K. Clarke, S. Neubauer, F. Wiesmann ............0.04. WI-Z
`
`
`
`AbstractsFromtheScientificSessions2004 ........................... W-1
`AuthorIndex .... 0.2.0... cect eee eee ene es UI-837
`SubjectIndex
`..... de pkg eT
`Cake go ‘
`oo eae bases t pees:
`I1I-893
`Abstracts From the Resuscitation Science Symposium ................. THI-1095
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`American Heart Association Embargo Policy for Scientific Sessions Abstracts
`
`Abstracts, lectures, and otherpresentations included in the Scientific Sessions 2004 Supplementpublished in the
`Oct. 26 issue of Circulation: Journal of the American Heart Association are embargoedforrelease at the time of
`presentation at the American Heart Association’s Scientific Sessions 2004 (Nov. 7-10) and information may not
`be released before then. Presentation times are listed in the Scientific Sessions 2004 Final Program.
`
`b
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`7 M
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`7 S
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`Basic Science
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`
`
`IIl-295
`Abstracts From Scientific Sessions 2004
`of membranous RhoA and phosphorylated ERM in brainstem were greater both in angiotensin
`
`SSCohypoina:” bral=bealnhypothe
`
`Il-treated rats and SHR than in WKY. Valsartan reduced the expression levels of membranous
`
`hearth»—iarmus isms stom siom cortex * hear
`
`
`
`
`RhoA in angiotensin ll-treated rats and SHR. In addition, Y-27632 or valsartan reduced the
`plasma
`iT)
`1p
`Tha
`TNF-a
`LS
`L-1p
`BW
`lung/BW
`expression levels of phosphorylated ERM in both groups. Subcutaneous infusion of phenyl-
`
`
`
`
`Dlsmall- oma Om—POM=emg1-6 bring omg Rate Ratio
`
`
`ephrine increased SBP to the samelevel of angiotensin Il infusion in WKY, However,it did not
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`alter the expression levels of membranous RhoA and
`ERM. Conclusions: These
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`results suggest that 1) the pressor response induced by central infusion of angiotensin II is
`substantially mediated by activation of Rho/Rho-kinase pathway in brainstem via AT1
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`Endothelial Nitric Oxide and Hypertension in AutonomicFailure
`Alfredo Gamboa, Cyndya Shibao, Andre Diedrich, Bonnie K Black, Ginnie Farley, Satish R
`, David Robertson, Italo Biaggioni; Vanderbilt Univ, Nashville, TN ,
`More than helf of patients with autonomicfailure (AF) have severe supine hypertension despite
`low or unresponsive norepinephrine levels and often undetectable plasma renin activity. Supine
`hypertension is related to increased vascular resistance but the Mechanism is not known. To
`test the hypothesis that nitric oxide deficiency contributes to supine hypertension we blocked
`endogenous nitric oxide synthase with L-NMMA in 5 AF patients and 7 normal controls (supine
`SBP 17326 and 107+5 mmHg, respectively). Systolic blood pressure (SBP) was normalized
`to 110 mmHg in AF with graded head-up tilt, and baroreflexes were eliminated with
`trimethaphan in normal controls to mimic autonomic failure. The pressor response to graded
`doses of L-NMMA was shifted to the left in AF (Figure); The dose
`to increase SBP
`by 30 mmHg was 3,4-fold lower in AF compared to controls (13624 and 4654103 j.g//min
`respectively, p<0.02). In conclusion, contrary to our original hypothesis, our results suggest an
`increased tonic release of nitric oxide in AF, Thus, NO deficiency does not contribute to supine
`hypertension in autonomic failure. On the contrary, this enhanced tonic NO may contribute to
`orthostatic hypotension in these patients.
`
`50
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`L-NMMA dose (p:/k/min)
`
`Pulmonary Arterial Hypertension: New
`Therapies
`Subspecialty: Integrative Biology
`.
`Wednesday
`Ernest N Morial Convention Center, Hall 12
`Abstracts 1414-1418
`
`:
`Inhaled Treprostinil Sodium (TRE) For the Treatment of Pulmonary
`Hypertension
`
`1414
`
`Robert Voswinckel, Beate Enke, Andre Kreckel, Frank Reichenberger, Stefanie Krick,
`Henning Gall, Tobias Gessler, Thomas Schmehl, Markus G Kohstall, FriedrichGrimminger,
`Hossein A Ghofrani, Werner Seeger, Horst Olschewski; Univ Hosp Giessen, Glessen,
`Germany
`
`Objective: To evaluate the effects of inhaled TRE on pulmonary hemodynamics and gas
`exchange in severe pulmonary hypertension (PH) and to assess safety, tolerability and clinical
`efficacy in patients with severe PH, Background: TRE is a stable Prostacyclin analogue that has
`been approved for treatment of pulmonary arterial hypertension as a continuous subcutaneous
`infusion.
`lloprost, another prostacyclin analogue, has been shown to be efficacious in a
`randomised controlled study as repetitive inhalation. Methods:
`In an open-label study a
`preservative free solution of inhaled TRE was applied to 17 patients with severe pulmonary
`hypertension during Swan-Ganz catheter investigation. Patients received a TRE inhalation by
`use of the pulsed OptiNeb® ultrasound nebulizer (3 single breaths, TRE solution 600 pg/ml).
`Hemodynamics were observed for 2 hours, Two Patients with Idiopathic PAH received
`Compassionate treatment with 4 inhalations of TRE per day after the acute test. Results:
`Patients (male/female= 4/13) suffered from iPAH (n=5), PAH other (1=8) and CTEPH (n=4);
`PVR 948 = 112 dyn*s*cm’®, PAP 48.3 + 2.7 mmHg, PAWP 8.9 + 0.5 mmHg, CVP 10.8 + 1.6
`mmHg, CO 3.8 + 0.3 Vmin, Sv02 61.8 * 1.8 %, TRE inhalation resulted in a sustained, highly
`pulmonary selective vasodilatation over 120 minutes. Maximum PVR decrease was -31.2 + 4.5
`% after 30 min. PVR and SVR at 120 minutes after inhalation were 89.2 = 4.2% and 101.0 +
`4.0 % of the baseline values, respectively. The AUC for the observation period (120min) was
`-22.9 + 3.8 % for PVR and -4,9 + 3.2% for SVA. The Compassionate use patients have been
`treated for more than 3 months. In both patients NYHA class improved (from IV to lil and from
`Ii to I), and six minute walk increased (from 0 m (bedridden) to 143 m, and from 310 m to
`486 m, respectively), No side effects have been observed by the patients during long-term
`treatment. Conclusion: Inhaled TRE shows Strong pulmonary selective vasodilatory efficacy
`with a long duration of effect following single acute dosing,Tolerability is excellent even at high
`drug concentrations and short inhalation times (3 breaths). Long-term treatmenteffects are
`very promising. The current results warrant controlled studies investigating this approach in a
`larger series of patients. Supported by Lung
`:
`
`Rho-kinase in Pulmonary Hypertension
`
`1415
`
`i |
`
`}
`
`1413
`Oral Administration of a Mineralocorticoid Receptor Antagonist Reduces
`Brain, Heart, and Blood-borne Proinflammatory Cytokines in Heart Failure
`Yu-Ming Kang, Carver College of Med, Univ of lowa, lowaCity, IA; Ralph F Johnson, Univ of
`lowa, lowa City, |A; Zhi-Hua Zhang, Carver College of Med, Univ of lowa, lowa City, IA;
`Robert M Weiss, Carver College of Med, Univ of lowa and VA Med Ctr, lowa City, 1A; Alan K
`'
`Johnson, Univ of lowa, lowa City, lA; Robert B Felder; Carver College of Med, Univ of lowa
`| and VA Med Ctr, lowa City, 1A
`Introduction: Brain and blood-borne cytokines may contribute to neurohumoral excitation in
`i heart failure (HF). We previously reported that blockade of mineralocorticoid feceptors (MR) in
`Ken Ishikura, Norikazu Yamada, Akihiro Tsuji, Satoshi Ota, Mashio Nakamura, Masaaki Ito,
`the central nervous system with spironolactone (SL) reduces circulating tumor necrosis factor
`Naoki Isaka, Takeshi Nakano; Mie Univ Sch of Med, Tsu, Japan
`| (TNF)-c in HF rats. Theeffect of SL on proinflammatory cytokines (PIC) in the brain and on
`' other importantcirculating PIC - interleukin (IL)-18 and IL-6 - was notdetermined. Hypothesis:
`Objectives: Pulmonary hypertension (PH) Is a poor prognostic disease with limited treatment.
`| Chronic treatment with oral SL will reduce brain and blood-borne PIC in rats with HF following
`Rho-kinase is involved in the pathophysiology of several diseases underlying smooth muscle
`| MI. Methods and Results: Rats underwent Coronary artery ligation to induce Ml (48.2+2.0%
`hypercontraction, But the role of is unknown. The purpose of this preliminary report was to
`' of left ventricle, with ejection fraction of 35.5+4.1% by echocardiography), or sham surgery
`indicate the efficacy of fasudil, a Rho-kinase inhibitor in patients with pulmonary hypertension
`|
`(SHAM). Six weeks later,
`immunohistochemistry of the paraventricular nucleus (PVN) of
`using interventional hemodynamic assessment. Methods: Fasudil was intravenously injected in
`hypothalamus,a region critical to cardiovascular regulation, revealed more PVN neurons (Mlvs
`10 patients (9 female, mean + SD,46 + 15years, NYHA Il n=2,lil n=7, W n=1) with primary
`| SHAM, ““P<0.01) positive for TNF-a (59.5+3.3** vs 10.8£0.9) anid IL-18 (70.7+3.9" vs
`(n=5) and secondary (n=5) PH who were not received any vasodilator. Fasudil was
`| 1381.2) in Ml (n=6) than in SHAM (n=6) rats. Double staining
`that these
`administrated 30mg with 1mg/min, Hemodynamic data were measured using Swan-Ganz
`Neurons were distributed among PVN neurons expressing Fra-like immunoreactivity, indicating
`catheter until 60 minutes after starting administration of fasudil. Hemodynamic and arterial
`Chronic neuronal activation. Mi rats (n=6) treated with SL (1 Mmg/kg/day orally for 6 weeks) had
`| fewer(MI+SL\vS Ml, #P<0.01) Fra-likepositive PVN neurons (85.545.4#vs 183.8+5.0), and
`blood gas data of baseline and the lowest total pulmonary resistance (IPR)
`time were
`Compared. Results: The lowest TPR time was within 30 to 60 minutes after administration,
`fewer PVN neurons positive for TNF-cc (22.4-+1.8%# vs 32.4%1,7%) and IL-18 (19.11.3%#
`Administration of fasudil significantly decreased TPR from 13.6 + 6.8U to 10.3 + 4.9 U(-23.2
`i VS 38.4£2.1%).Levels of TNFear, IL-1and IL-6 in brain and heart tissues and in plasma were
`= 9,2 %, p < 0.001) and mean pul
`arterial pressure (mPAP) from 43.6 + 14.5 mmHg
`i also lower in Mi rats treated with SL (see table). Conclusion: in rats with ischemia-induced
`to 38.8 = 13.9 mmHg (-11.6 + 10.4%, p< 0.02). Cardiac index (Cl) was significantly
`heart failure, orally administered SL has a global inhibitory influence on the eppearance of
`increased from 2.39 + 0.66 L/min/m?to 2.74 + 0.73 Umin/m? (+16.5 + 15.1 %, p < 0.01).
`cytokines in brain, heart and plasma. The beneficial
`influence of MR
`Although TPR was equally decreased in bath primary and secondary PH, the changes in the
`antagonism in patients with HF may result at least in part from blocking aldosterone-induced
`parameters that prescribed TPR, namely Cl and mPAP, were different between the two groups
`Cytokine synthesis. (Table: *P<0.05 MI+SL vs MI+VEH)
`Subjects. Increased Cl was a major factor into reducing TPR in primary PH, while reduced mPAP
`
`
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`Liquidia's Exhibit 1093
`Page 6
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`Liquidia's Exhibit 1093
`Page 6
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