Vol 110, No 17, October 26, 2004
`‘ISSN 0009-7322
`http:llcirc.ahajournals.org
`
`SUPPLEMENT T0
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`Alnerlcan Heart
`- Association»)
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`Learn and Live...
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`1 t .
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`JOURNAL OF THE AMERICAN HEART ASSOCIATION
`
`Abstracts
`
`from
`
`scientific
`seSS|onS
`
`Sessions: November 7—1 0
`Exhibits: November 743
`New Orleans, Louisiana
`
`scientificsessions.org
`
`g basic science
`1-
`-
`1
`-
`C ll'llca SCICUC€
`
`314%
`
`pop UifltiOl] science
`
`Named and Invited Lectures 2004
`
`2004 Russell Ross Memorial Lectureship in Vascular Biolog) - 2004 George Lillian Duff Memorial Lecture 0 2004 Sol Sherry
`Distinguished Lecture in Thrombosis - 2004 Thomas \t. Smith Memorial Lecture - 2004 George Ii. Bron-n Memorial Lecture
`- 2004 Dickinson W. Richards Memorial Lecture ' 200-! Katharine A. Lemhrighl Auard ' 2004 William \\ . L. Glenn Lecture
`- 2004 William J. Rashkind Memorial Lecture - 2004 'l'. [)uckett Jones Memorial Lecture - 2004 Charles T. Hotter Klenmrial
`Lecture - 2004 Lacnncc Society Lecture - 2004 Alice] Keys Lecture - 2004 Lewis K. Dahl Memorial Lecture - 2004 Rohert
`l. Len Endowed Lecture in Lipid Metabolism
`
`
`
`New and Young Investigator Award/Prize Abstract Finalists
`t
`'I
`Lewis N. and Arnold M. Kata Basic Science Research l’rile for Young Investigators - :\lcl\in L. Marcus Toime lmcs’li
`Awards in ('ardimascular Science - (fournand and ('onlroc Young Investigators [’rircs in (‘ardiopuImonar) and Critical
`Care - Outstanding Research Award in Pediatric ('ardiolog) - \lt‘lt‘ill Judkim Young liiicstigator \mn'd in ('arthniaxcular
`Radiolog) ' Vivian Thomas Young Investigator Award - Martha 54. Hill Ne“ linestigator .\uards - ‘lilizalielh Barri-lb
`(‘onnor Research Anard in Epidemiolog) and l’rcicntion for Intestigators in 'l‘rainine - Seunuel
`it. Lennie \ oone ( limcal
`lnwstigutor Awards - Laennec Society Young (‘Iinician Award - \'l'.\\l Ne“ lnu‘stigalor \“nrtl
`
`Abstracts From the Scientific Sessions 2004
`__—____———
`
`Liquidia's Exhibit 1008
`Page 1
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`Liquidia's Exhibit 1008
`Page 1
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`

`

`Circulation
`
`JOURNAL OF THE AMERICAN HEART ASSOCIATION
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`Liquidia's Exhibit 1008
`Page 2
`
`Liquidia's Exhibit 1008
`Page 2
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`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`2:: Science
`
`
`branous FlhoA and phosphorylated ERM in brainstem were greater both in angiotensln
`rats and SHR than to WKY. Valsartan reduced the expression levels of membranous
`
`. m angiotensin tI-treated rats and SHR.
`in addition, Y-27632 or vaisartan reduced the
`ion levels of phosphorylated ERM in both groups. Subcutaneous intrusion of phenyl-
`
`it increased SBP to the same level of angiotensin II infusion in WKV. However, it did not
`.
`
`the expression levels of membranous RhoA and phosphorylated ERM. Conclusions: These
`its suggest that 1) the pressor response induced by central infusion of angiotensin Ii
`is
`w.
`tlaily mediated by activation or Rho/Rho-kinase pathway in brainstem via ATt
`
`rs, 2) this pathway may also be involved in hypertensive mechanism in SHFI.
`
`1412
`
`"2' .
`
`. elial Nitric Oxide and Hypertension in Autonomic Failure
`
`..o Gamboa, Cyndya Shibao. Andre Diedrich. Bonnie it Black, Ginnie Farley, Satish Fl
`David Robertson, Italo Biaggioni; Vanderbilt Univ. Nashville, TN
`
`
`: than half of patients with autonomic failure (AF) have severe supine hypertension despite
`4,)
`.
`or unresponsive noreplnephrine levels and often undetectable plasma renin activity. Supine
`I:
`i-nsion is related to increased vascular resistance but the mechanism Is not known. To
`
`
`the hypothesis that nitric aside deficiency contributes to supine hypertension we blocked
`menous nitric oxide synthase with LINMMA in 5 AF patients and 7 normal controls (supine
`
`, ., 17316 and 107:5 mmHg. respectively). Systolic blood pressure (SBP) was normalized
`:l. 110 mmHg in AF with graded head-up tilt. and baroretiexes were eliminated with
`
`" u aphan in normal controls to mimic autonomic failure. The pressor response to graded
`.
`t of L-NMMA was shifted to the left in AF (Figure): The dose necessary to increase SBP
`
`i. 30 mml-lg was 34—fold lower in AF compared to controls (136:24 and 465:103 ug/klmin
`-. I tively, p<0,02). In conclusion, contrary to our original hypothesis, our results suggest an
`.:s -ased tonic release of nitric oxide in AF. Thus. N0 deficiency does not contribute to supine
`wnensioh in autonomic iailure. 0n the contrary, this enhanced tonic NO may contribute to
`gmostatlc hypotension in these patients.
`
`50
`
`
`
`33
`
`as
`
`250
`160
`LnNMMA dose (plklmln)
`
`500
`
`1413
`.
`Dial Administration of a Mineralocorticoid Receptor Antagonist Reduces
`Brain, Heart, and Blood-borne Proinflammatory Bytokines in Heart Failure
`
`IA; Ralph F Johnson. Univ of
`iii-Ming Kang, Carver College of Med. Univ of Iowa. Iowa City.
`lime. Iowa City,
`IA; Zni-Hua Zhang. Carver College of Med. Univ of Iowa, Iowa City.
`IA;
`Ptben M Weiss, Carver College of Med. Univ oi Iowa and VA Med Ctr. Iowa City,
`IA; Atan K
`Althnson. Univ of Iowa,
`iowa City.
`IA; Robert 0 Folder: Carver College 0! Med, Univ of lowa
`hid VA Med Ctr, Iowa City,
`IA
`
`.,'I I-uctlon: Brain and blood-borne cytokines may contribute to neurohumorai excitation in
`illitrt failure (HF), We previously reported that blockade of rnrneralocorticoid receptors (MR) in
`its central nervous system with spironolactone (SL) reduces circulating tumor necrosis factor
`“NH-a in HF rats. The effect of SL on proinflammatory cytokines (PIC) in the brain and on
`“let important circulating PtC - interleukin (IL)-1 it and lL-6 — was not determined. Hypothesis:
`,
`tonic treatment with oral SL will reduce brain and blood-borne PIC in rats with HF following
`,',
`. Methods and Results: Flats undenrrent coronary artery ligation to induce Ml (48.2:2.0%
`._left ventricle, with ejection fraction of 35.5:4.1% by echocardiography). or sham surgery
`
`M). Six weeks later,
`immunohistochemistiy of the paraventricular nucleus (Pi/N) of
`pothaiamus. a region critical to cardiovascuiar regulation, revealed more PVN neurons (MI vs
`
`-M, "P<0.01) positive for TNF-a (595:3.3" vs 10.8:0.9) and IL»1.6 (i0.7:3,9“ vs
`-'.8:1.2) in MI (n=6) than in SHAM (n:6) rats. Double staining demonstrated that these
`[I drops were distributed among PVN neurons expressing Fra2like lmmunoreactivity, indicating
`y
`Inic nouronal activation MI rats (n:6) treated with SL (1 mg/kg/day orally for 6 weeks) had
`i" or (MI+SL vs Ml, #P<0.01) Fra-like positive PVN neurons (B5.5:5.4# vs 103.8150). and
`i.- er PVN neurons positive for TNF-at (22.411.8“r’uit vs 32.4:1.7%) and lL-1B (19.1 11.3%#
`r. 38.4: 2.1 V»). Levers of TNF-rr. IL-1 ,0 and lL-S in brain and heart tissues and In plasma were
`2‘..
`lower in MI rats treated with SL (see table). Conclusion: In rats with ischemiaainouoed
`‘r-I‘t failure, orally administered SL has a global inhibitory influence on the appearance of
`Ilnflarnmatory cytokines in brain. heart and plasma. The beneficial
`influence of MR
`Iiagonism in patients with HF may result at least in part from blocking aldosterone‘induced
`.L okine synthesis. (Table: ‘P<0.05 MI+SL vs Ml-rVEH)
`
`Abstracts From Scientific Sessions 2004
`Ill—295
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`
`Pulmonary Arterial Hypertension: New
`Therapies
`Subspecialty: Integrative Biology
`Wednesday
`Ernest N Mortal Convention Center, Hall 12
`Abstracts 1414—1418
`
`1414
`
`Inhaled Treprostinil Sodium (THE) For the Treatment of Pulmonary
`Hypertension
`Robert Voswinckel. Beats Enke, Andre Kreckei, Frank Heichenberger, Stefanie Krick,
`Henning Gall, Tobias Gessier. Thomas Schmehl, Markus G Kuhstall, Friedrich Grimminger.
`Hossein A Ghofranl, Werner Seeger, Horst Olschewski; Univ Hosp Giessen, Giessen,
`Germany
`
`Objective: To evaluate the effects of inhaled THE on pulmonary hemodynamics and gas
`exchange in severe pulmonary hypenension (PH) and to assess safety. tolerabiiity 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 openulabel study a
`preservative free solution of inhaled TRE was applied to 17 patients with severe pulmonary
`hypertension during Swanuiianz catheter investigation. Patients received a TRE inhalation by
`use of the pulsed 0pttNeb® uttrasound nebulizer (3 single breaths. TRE solution 600 rig/ml).
`Hemodynamics were observed for 2 hours. Two patients with Idiopathic PAH received
`compassionate treatment with 4 inhalations of THE per day after the acute test. Results:
`Patients (malelfemale= 4/13) suffered from iF‘AH (n=5), PAH other (n =8) and CTEPH (n=4);
`PVH 948 1 112 dyn’s‘cm's. PAP 48.3 1 2.7 mml-lg, PAWP 8.9 i 0.5 mmHg,CVP10.s : 1.6
`mmHg, 00 3.8 1 0.3 lrmin. Sv02 61.0 1 1.8 %. TRE inhalation resulted in a sustained, highly
`pulmonary selective vasodilatation over 120 minutes. Maximum PVFI decrease was -31.2 t 4.5
`“In after 30 min. PVFI and SVR at 120 minutes after Inhalation were 89.2 1 4.2 “A and 101.0 1
`4.0 “It oi the baseline values, respectively, The A00 for the observation period (120min) was
`22.9 : 3.8 “In for PVR and ~49 : 3.2% for SVR. The compassionate use patients have been
`treated for more than 3 months. In both patients NYHA class improved (lrorn Iv to Ill and from
`III to II), and six minute walk increased (from 0 rn (bedridden) to 143 m, and from 310 m to
`486 m, respectively). No side effects have been observed by the patients during tong-term
`treatment. Conclusion: Inhaled THE shows strong pulmonary selective vasodilatory efficacy
`with a long duration of eflect following single acute dosing, Tolerabillty is exceIIent even at high
`drug concentrations and short inhalation times (3 breaths). Long-term treatment sheets are
`very promising. The current results warrant controlled studios investigating this approach In a
`larger series of patients. Supported by Lung FIX
`
`1415
`
`Rho-kinase in Pulmonary Hypertension
`
`Ken Ishikura. Norikazu Yamada, Akihiro Tsujl. Satoshi Dta, Mashio Nakamura, Masaaki Ito.
`Naoki Isaka. Takeshi Nakano; Mie Univ Sch ot Med. Tsu, Japan
`
`Objectives: Pulmonary hypertension (PHI is a poor prognostic disease with limited treatment.
`FIIIo-kinase is involved in the pathophysiology of several diseases underlying smooth muscle
`hypercuntraction. But the role of is unknown. The purpose of this preliminary report was to
`indicate the efficacy of fasudil, a Flho-kinase inhibitor in patients wrth pulmonary hyporiieicldn
`using interventional hemodynsmic assessment. Methods: Fasudll was intravenously intermedia-
`10 patients (9 female, mean 1 SD, 45 1 15 years. Nri-IA II n=2, lll n=T. N n=1) with primary.
`(n25) and secondary (n25) PH wan fire not fiww‘grewgeasumredm Fasul‘ll,7
`l m-
`administrated am with 1mglmln.
`em ynarn c
`_
`_
`1
`.7
`
`
`catheter until no mginines after startind administration of nation. Wham E18531
`blood gas data of baseline and the lowest total pulmonary resetaoos (TPR) time triers
`compared. Results: The lowest TPR time was within 30 to 60 minutes alter administration.
`Administration or fasudll significantly decreased TPR from 13.6 t 6.8 U to’10.3 t 4.0 U (-232
`t 9.2 %. p < 0.001) and mean pulmonary arterial pressure (mPAP) from-13.0 : 14.5 mint-lg
`to 38.8 t 13.9 mmHg (-11.0 i 10.4 91.. p < 0.02). Cardiac index (Cl) was significanity
`increased from 2.39 t 0.66 Liminlm’to 2.74 i 0.73 Umlnlmz (+105 3 15.1 91., p < 0.01).
`Although TPR was equally decreased In both primary and secondary PH, die changes in the
`parameters that prescribed TPR. namely Cl and mPAF, were different between the two groups
`subjects. increased cl was a major factor into reducing TPR in primary PH, while reduced mPAP
`
`
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`Liquidia's Exhibit 1008
`Page 3
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