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Circulatioiri Volume 90 Number 2 August 1994

Cardiovascular NewsRepresentative William H. Natcher Dies After 41 Years in CongressClaudia Lous, MBA; Scott Ballin, JD ...................................................................... 647

New HorizonsClaude Lenfant, MD ........................................................................ 648

Brief CommunicationsIndirect Angiogenic Cytokines Upregulate VEGF and bFGF Gene Expression in VascularSmooth Muscle Cells, Whereas Hypoxia Upregulates VEGF Expression OnlyEdi Brogi, MD; Tiangen Wu, MD; Atsushi Namiki, MD; Jeffrey M. Isner, MD ...... ............................. 649

Clinical Investigation and Reports

Molecular and Cellular ResponsesCa2+-Transporting ATPase, Phospholamban, and Calsequestrin Levels in Nonfailing andFailing Human MyocardiumMatthew A. Movsesian, MD; Mohsen Karimi, BS; Karen Green, BS; Larry R. Jones, MD, PhD .... ............... 653

Effects of L-Arginine on Impaired Acetylcholine-induced and lschemic Vasodilation of theForearm in Patients With Heart FailureYoshitaka Hirooka, MD; Tsutomu /maizumi, MD; Tatsuya Tagawa, MD; Masanari Shiramoto, MD;Toyonari Endo, MD; Shin-ichi Ando, MD; Akira Takeshita, MD ......... ........................................ 658Plasma Level and Gene Polymorphism of Angiotensin-Converting Enzyme in Relation toMyocardial InfarctionF. Cambien; 0. Costerousse; L. Tiret; 0. Poirier; L. Lecerf; M.F. Gonzales; A. Evans; D. Arieiler;J.P. Cambou; G. Luc; R. Rakotovao; P. Ducimetiere; F. Soubrier; F. Alhenc-Gelas ..... ........................ 669

Induction of Acidic Fibroblast Growth Factor and Full-Length Platelet-Derived GrowthFactor Expression in Human Cardiac Allografts: Analysis by PCR, In Situ Hybridization,and ImmunohistochemistryXiao-Ming Zhao, MD; Tiong-Keat Yeoh, MD; William H. Frist, MD; Diane L. Porterfield, BS;Geraldine G. Miller, MD ........................................................................ 677

Correlation Between Cellular Rejection of Cardiac Allografts and Quantitative ChangesAmong T-Cell Subsets Identified by Vf3 Epitope ExpressionJohn F. Cariquist, PhD; M. Elizabeth Hammond, MD; Robert L. Yowell, MD, PhD; Cherilyn Holland, RN;Sandy Swanson, RN, BSN; Jeffrey L. Anderson, MD ............. ........................................... 686

Increased Secretion of Tumor Necrosis Factor-et and Interferon-y by MononuclearLeukocytes in Patients With lschemic Heart Disease: Relevance in SuperoxideAnion GenerationK Vaddi, DVM, PhD; F.A. Nicolini, MD; P. Mehta, MD; J.L. Mehta, MD, PhD ...... ............................ 694

lschemic Preconditioning During Coronary Angioplasty Is Prevented by Glibenclamide,a Selective ATP-Sensitive K+ Channel BlockerFabrizio Tomai, MD; Filippo Crea, MD; Achille Gaspardone, MD, MPhil; Francesco Versaci, MD;Ruggero De Paulis, MD; Alfonso Penta de Peppo, MD; Luigi Chiariello, MD; Pier A. Gioffre, MD .... ............... 700

Parallel Analysis of Tissue-Type Plasminogen Activator and Type 1 PlasminogenActivator Inhibitor in Plasma and Endothelial Cells Derived From Patients With ChronicPulmonary ThromboemboliIrene M. Lang, MD; James J. Marsh, PhD; Mitchell A. Olman, MD; Kenneth M. Moser, MD;Raymond R. Schleef, PhD ........................................................................ 706

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Spatiotemporal Relation Between Gap Junctions and Fascia Adherens Junctions DuringPostnatal Development of Human Ventricular MyocardiumNicholas S. Peters, MD, MRCP; Nicholas J. Severs, PhD; Stephen M. Rothery, BSc;Christopher Lincoln, FRCS; Magdi H. Yacoub, FRCS; Colin R. Green, PhD ................................... 713

Coronary Heart Disease/Myocardial Infarction/Peripheral Vascular DiseaseDouble-Blind Efficacy and Safety Study of a Novel Anti-lschemic Agent, Ranolazine,Versus Placebo in Patients With Chronic Stable Angina PectorisUdho Thadani, MBBS, MRCP, FRCP(C); Michael Ezekowitz, MD, PhD; Linda Fenney, MD;Yu-Kun Chiang, PhD; for the Ranolazine Study Group ...................................................... 726

Histological Alterations in Chronically Hypoperfused Myocardium: Correlation WithPET FindingsAlex Maes, MD; Willem Flameng, MD, PhD; Johan Nuyts, PhD; Marcel Borgers, MD, PhD;Bharati Shivalkar, MD; Jannie Ausma, MSc; Guy Bormans, PhD; Christiaan Schiepers, MD, PhD;Michel De Roo, MD, PhD; Luc Mortelmans, MD, PhD ...................................................... 735

Effects of Thrombolytic Therapy Administered 6 to 24 Hours After Myocardial Infarctionon the Signal-Averaged ECG: Results of a Multicenter Randomized TrialJonathan S. Steinberg, MD; Judith S. Hochman, MD; Christopher D. Morgan, MD; Paul Dorian, MD;C. David Naylor, MD, DPhil; Pierre Theroux, MD; Eric J. Topol, MD; Paul W. Armstrong, MD;the LATE Ancillary Study Investigators ................ .................................................... 746

Limitation of Infarct Size and Preservation of Left Ventricular Function After PrimaryCoronary Angloplasty Compared With Intravenous Streptokinase in AcuteMyocardial InfarctionMenko Jan de Boer, MD; Harry Suryapranata, MD; Jan C.A. Hoomtje, MD; Stoffer Reiffers, PhD;Ay Lee Liem, MD; Kor Miedema, PhD; Wim Th. Hermens, PhD; Marcel J.B.M. van den Brand, MD;Felix ZijIstra, MD ....................................................................................... 753

Effects of Treatment on Outcome in Mildly Symptomatic Patients With lschemia DuringDaily Life: The Atenolol Silent lechemia Study (ASIST)Carl J. Pepine, MD; Peter F. Cohn, MD; Prakash C. Deedwania, MBBS; Robert S. Gibson, MD;Eileen Handberg, RN, MSN; James A. Hill, MD; Elinor Miller, MD; Ronald G. Marks, PhD;Udho Thadani, MD; for the ASIST Study Group ............................................................ 762

Associations of the HDL2 and HDL3 Cholesterol Subfractions With the Development oflschemic Heart Disease in British Men: The Caerphilly and Speedwell Collaborative HeartDisease StudiesPeter M. Sweetnam, MSc; Colin H. Bolton, PhD; John W.G. Yamell, MD, MFCM;David Bainton, MB, MRCP; lan A. Baker, MB, MRCP; Peter C. Elwood, MD, FRCP;Norman E. Miller, MD, DSc, MRCP .................... ................................................... 769

Macrophage Infiltration in Acute Coronary Syndromes: Implications for Plaque RupturePedro R. Moreno, MD; Erling Falk, MD; Igor F. Palacios, MD; John B. Newell, BA;Valentin Fuster, MD, PhD; John T. Fallon, MD, PhD ........................................................ 775

Association Between QT Interval and Coronary Heart Disease in Middle-aged and ElderlyMen: The Zutphen StudyJacqueline M. Dekker, MSc; Evert G. Schouten, PhD, MD; Peter Klootwijk, MD; Jan Pool, PhD, MD;Daan Kromhout, PhD, MPH . ............................................................................ 779

Acute Vascular Effects of Estrogen in Postmenopausal WomenDavid M. Gilligan, MD; Diane M. Badar, RN; Julio A. Panza, MD; Arshed A. Quyyumi, MD;Richard 0. Cannon Ill, MD .............................................................................. 786

Use of Aortic Counterpulsation to Improve Sustained Coronary Artery Patency DuringAcute Myocardial Infarction: Results of a Randomized TrialE. Magnus Ohman, MD; Barry S. George, MD; Christopher J. White, MD; Morton J. Kem, MD;Paul A. Gurbel, MD; Robert J. Freedman, MD; Conor Lundergan, MD; Joseph R. Hartmann, MD;J. David Talley, MD; Martin J. Frey, MD; George Taylor, MD; Jeffrey D. Leimberger, PhD; Paul M. Owens, RN;Kerry L. Lee, PhD; Richard S. Stack, MD; Robert M. Calff, MD for the Randomized IABP Study Group ..... ......... 792

Independent Impact of Thrombolytic Therapy and Vessel Patency on Left VentricularDilation After Myocardial Infarction: Serial Echocardiographic Follow-upAleksandar D. Popovi6, MD, PhD; Aleksandar N. Neskovic, MD; RadeBabi_ , MD;Velibor Obradovic, MD, PhD; Ljubica Bozinovic, MD, PhD; Jelena Marinkovic, PhD; Jar-Chi Lee, MS;Ming Tan, PhD; James D. Thomas, MD, FACC .................. .......................................... 800

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Early Detection of Abnormal Coronary Flow Reserve in Asymptomatic Men at High Riskfor Coronary Artery Disease Using Positron Emission TomographyFirat Dayanikli, MD; David Grambow, MD; Otto Muzik, PhD; Lori Mosca, MD; Melyvn Rubenfire, MD;Markus Schwaiger, MD ................................................................................. 808Intensive Vascular Training in Stage lib of Peripheral Arterial Occlusive Disease:The Additive Effects of Intravenous Prostaglandin E1 or Intravenous PentoxifyllineDuring TrainingP. Scheffler, MD; D. de la Hamette, MD; J. Gross, MD; H. Mueller, MD; H. Schieffer, MD. 818

Congestive Heart Failure/Valvular Heart DiseasePlasma Arteriovenous cGMP Difference as a Useful Indicator of Nitrate Tolerance inPatients With Heart FailureTakayoshi Tsutamoto, MD; Masahiko Kinoshita, MD; Yasunori Ohbayashi, MD; Atsuyuki Wada, MD;Yukiharu Maeda, MD; Takako Adachi, MD . 823Echocardlographic Prediction of Survival After Surgical Correction of OrganicMitral RegurgitationMaurice Enriquez-Sarano, MD; A. Jamil Tajik, MD; Hartzell V. Schaff, MD; Thomas A. Orszulak, MD;Kent R. Bailey, PhD; Robert L. Frye, MD . 830

Scopolamine Improves Autonomic Balance in Advanced Congestive Heart FailureMaria Teresa La Rovere, MD; Andrea Mortara, MD; Paolo Pantaleo, MD; Roberto Maestri, BE;Franco Cobelli, MD; Luigi Tavazi, MD .......... 838

Characterization of the Early Lesion of 'Degenerative' Valvular Aortic Stenosis:Histological and Immunohistochemical StudiesCatherine M. Otto, MD; Johanna Kuusisto, MD; Dennis D. Reichenbach, MD; Allen M. Gown, MD;Kevin D. O'Brien, MD . 844

Three-Dimensional Left Ventricular Deformation in Hypertrophic CardiomyopathyAlistair A. Young, PhD; Christopher M. Kramer, MD; Victor A. Ferrari, MD; Leon Axel, PhD, MD;Nathaniel Reichek, MD . 854

Electrophysiology/Arrhythmias/PacingImplantation by Electrophysiologists of 100 Consecutive Cardioverter Defibrillators WithNonthoracotomy Lead SystemsS. Adam Strickberger, MD; John D. Hummel, MD; Emile Daoud, MD; Mark Niebauer, MD;Brian D. Williamson, MD; K Ching Man, DO; Laura Horwood, RN; Alice Schmittou, RN;Steven J. Kalbfleisch, MD; Jonathan J. Langberg, MD; Fred Morady, MD . 868

Mechanism of 'Inappropriate' Sinus Tachycardia: Role of Sympathovagal BalanceCarlos A. Morillo, MD; George J. Klein, MD; Ranjan K Thakur, MD; Huagui Li, MD, PhD;Marco Zardini, MD; Raymond Yee, MD . 873

Reduced Heart Rate Variability and Mortality Risk in an Elderly Cohort: The FraminghamHeart StudyHisako Tsuji, MD; Ferdinand J. Venditti, Jr, MD; Emily S. Manders, BS; Jane C. Evans, MPH;Martin G. Larson, ScD; Charles L. Feldman, ScD; Daniel Levy, MD .......................................... 878

Anatomic, Electrical, and Mechanical Factors Affecting Bipolar Endocardial Electrograms:Impact on Catheter Ablation of Manifest Left Free-Wall Accessory PathwaysRiccardo Cappato, MD; Michael Schluter, PhD; Lluis Mont, MD; Karl-Heinz Kuck, MD . 884

Angioplasty/Atherectomy/Stents (Cardiac and Peripheral)Coronary Vasoconstriction After Percutaneous Transiuminal Coronary Angioplasty IsAttenuated by Antiadrenergic AgentsLuisa Gregorini, MD; Jean Fajadet, MD; Gabriel Robert, MD; Bernard Cassagneau, MD;Monique Bernis, MD; Jean Marco, MD . 895

Low Molecular Weight Heparin in Prevention of Restenosis After Angioplasty: Results ofEnoxaparin Restenosis (ERA) TrialDavid P. Faxon, MD; Theodore E. Spiro, MD; Steven Minor, MD; Giles Cote, MD; John Douglas, MD;Ronald Gottlieb, MD; Robert Califf, MD; K Dorosti, MD; Eric Topol, MD; John B. Gordon, MD;Magness Ohmen, MD; and the ERA Investigators .......................................................... 908

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Magnetic Resonance Imaging of the lliofemoral Arteries After Balloon DilationAngioplasty of Aortic Arch Obstructions in ChildrenPatricia E. Burrows, MD; Lee N. Benson, MD; Paul Babyn, MD; Cathy MacDonald, MD ........................ 915

Cardiopulmonary BypassRandomized Study of Aprotinin and DDAVP to Reduce Postoperative Bleeding AfterCardiopulmonary Bypass SurgeryEduardo Rocha, MD; Francisco Hidalgo, MD; Rafael Llorens, MD; Jose M. Melero, MD;Jos6 L. Arroyo, MD; Jose A. Paramo, MD ..921......................... ........... ... ........... ...... 921

Congenital Heart Disease/HypertensionSex-Specific Determinants of Increased Left Ventricular Mass in the Tecumseh BloodPressure StudyRoy Marcus, MD; Lisa Krause, MS; Alan B. Weder, MD; Agnes Dominguez-Mejia, MD;Nicholas J. Schork, MA; Stevo Julius, MD, ScD . 928

Quantification of Collateral Blood Flow in Coarctation of the Aorta by Velocity EncodedCine Magnetic Resonance ImagingJohann C. Steffens, MD; Michael W. Bourne, MD; Hajime Sakuma, MD; Margaret O'Sullivan, RN;Charles B. Higgins, MD ................................................................................. 937

Basic Science Reports

Cellular, Molecular, Biological, and Immunological ResearchTranscatheter Delivery of c-myc Antisense Oligomers Reduces Neointimal Formation in aPorcine Model of Coronary Artery Balloon InjuryYi Shi, MD; Ali Fard, MD; Anthony Galeo, MD; Howard G. Hutchinson, MD; Pawan Vermani, MD;George R. Dodge, PhD; David J. Hall, PhD; Farida Shaheen, PhD; Andrew Zalewski, MD . 944

Mononuclear Cells From Dogs With Acute Lung Allograft Rejection Cause Contraction ofPulmonary ArteriesAlexander R.J. Cale, MB, FRCS; Fabio Ricagna, MD; Lars Wiklund, MD;Christopher G.A. McGregor, MB, FRCS; Virginia M. Miller, PhD .......... 952

Myofibrillar Ca2+ Sensitization Predominantly Enhances Function and MechanicalEfficiency of Stunned MyocardiumLoe Kie Soei, MD; Loes M.A. Sassen, MD; Dong Sheng Fan, MD; Tineke van Veen, MD; Rob Krams, MD;Pieter D. Verdouw, PhD ................................................................................. 959

Ischemia/Vasoconstriction/InfarctionPhysical Conditioning Decreases Norepinephrine-lnduced Vasoconstriction in Rabbits:Possible Roles of Norepinephrine-Evoked Endothelium-Derived Relaxing FactorHsiun-ing Chen, PhD; Hsing-Tan Li, MS; Chien-Chih Chen, BS . 970

Unexpected Interaction Between ,-Adrenergic Blockade and Heart Rate Variability Beforeand After Myocardial Infarction: A Longitudinal Study in Dogs at High and Low Risk forSudden DeathPhilip B. Adamson, MD, MSc; Ming H. Huang, MD; Emilio Vanoli, MD; Robert D. Foreman, PhD;Peter J. Schwartz, MD; Stephen S. Hull, Jr, PhD . 976

Determinants of Coronary Artery Reactivity in Premenopausal Female CynomolgusMonkeys With Diet-induced AtherosclerosisJ. Koudy Williams, DVM; Carol A. Shively, PhD; Thomas B. Clarkson, DVM . 983

Effect of an Eccentric Severe Stenosis on Fibrin(ogen) Deposition on Severely DamagedVessel Wall in Arterial Thrombosis: Relative Contribution of Fibrin(ogen) and PlateletsAlessandra Mailhac, MD; Juan Jose Badimon, PhD; John T. Fallon, MD, PhD;Antonio Fernandez-Ortiz, MD, PhD; Beat Meyer, MD; James H. Chesebro, MD;Valentin Fuster, MD, PhD; Lina Badimon, PhD . 988

Angioplasty/Atherectomy/StentsNeutrophil Implications in Platelet Deposition and Vasoconstriction After Deep ArterialInjury by Angioplasty in PigsYahye Merhi, PhD; Lucie L-Lacoste, MSc; Jules Y. T. Lam, MD .............................................. 997

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Localized Arterial Wall Drug Delivery From a Polymer-Coated Removable Metallic Stent:Kinetics, Distribution, and Bloactivity of ForskolinThomas L. Lambert, MD; Vishva Dev, MD; Eldad Rechavia, MD; James S. Forrester, MD;Frank Litvack, MD; Neal L. Eigier, MD .................................................................. 1003

Arrhythmias/Electrophysiology/PacingEffects of Heptanol, Class Ic, and Class Ill Drugs on Reentrant Ventricular Tachycardia:Importance of the Excitable Gap for the Inducibility of Double-Wave ReentryLucas Boersma, MD; Josep Brugada, MD; Hoshiar Abdollah, MD; Charles Kirchhof, MD;Maurits Allessie, MD . ..................................................................... 1012

Exercise Rehabilitationa-Adrenoceptor Stimulation With Exogenous Norepinephrine or Release of EndogenousCatecholamines Mimics lschemic PreconditioningZehyani Bankwala, MD; Sharon L. Hale, BS; Robert A. Kloner, MD, PhD .......... .......................... 1023

Current PerspectivesHolding Smokers Accountable for Heart Disease CostsWayne H. Kaesemeyer, MD . .................................................................... 1029

Pathogenesis of Acute Myocardial Infarction: Novel Regulatory Systems of BioactiveSubstances in the Vessel WallChuichi Kawai, MD ......................... ............................................ 1033

Three-dimensional Reconstruction of Intracoronary Ultrasound Images: Rationale,Approaches, Problems, and DirectionsJos R.T.C. Roelandt, MD, PhD; Carlo di Mario, MD, PhD; Natesa G. Pandian, MD; Li Wenguang, MSc;David Keane, MB, MRCPI; Comelis J. Slager, PhD; Pim J. de Feyter, MD, PhD; Patrick W. Serruys, MD, PhD ...... 1044

Coronary Artery Disease Regression: Convincing Evidence for the Benefit of AggressiveLipoprotein ManagementH. Robert Superko, MD; Ronald M. Krauss, MD ........................... .............................. 1056

Clinicopathological ConferenceA 67-Year-Old Man With Increasingly Frequent AnginaWilliam L. Winters, Jr, MD . ..................................................................... 1070

Images in Cardiovascular MedicineArteriovenous FistulaRichard W. Lowry, MD; Mark J. Hausknecht, MD ....................... ................................. 1077

Special ReportHeart Rate Variability as a Prognostic Tool in Cardiology: A Contribution to the ProblemFrom a Theoretical Point of ViewMaximilian Moser, PhD; Michael Lehofer, MD, PhD; Andrea Sedminek, MD; Manfred Lux, BA;Hans-Georg Zapotoczky, MD; Thomas Kenner, MD; Abraham Noordergraaf, PhD ........ ................... 1078

Clinical Cardiology FrontiersPredicting and Preventing Sudden Death From Cardiac CausesJames K Gilman, MD; Sohail Jalal, MD; Gerald V. Naccarelli, MD ........... .............................. 1083

Key References

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Key References on Heart FailureBeverly H. Lorell, MD; Lynne Stevenson, MD . ........................................................... 1093


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EditorialsDownsizing Cardiology: Getting the Process StartedLynn 0. Langdon, MS; Melvin D. Cheitlin, MD ................... ... 1101

Changes in the Topology of Gap Junctions as an Adaptive Structural Responseof the MyocardiumMadison S. Spach, MD ............................... ... 1103

CorrespondenceAspirin Versus Heparin in the Acute Phase of Unstable AnginaAlain Moise, MD, MSc; Michel Roos, MD, PhD ..... Reply.. Pierre Theroux, MD ............. 1107

Oufflow Tract Obstruction and Failed Mitral RepairSerban Mihaileanu, MD..... Reply.. Kamthorn S. Lee, MD; Harry M. Lever, MD;William J. Stewart, MD ...............1107

Time Course of Endothelial Dysfunction in Diabetes MellitusThomas C. Wascher, MD; Wolfgang F. Graier, PhD; Babak Bahadori, MD; Hermann Toplak, MD

.Reply.. Michael T. Johnstone, MD; Shelly J. Creager, BSN; Kathleen M. Scales, BS;Jorge A. Cusco, MD; Byron K. Lee, BA; Mark A. Creager, MD ............................................. 1109

The Patent Infarct-Related Artery After Myocardial InfarctionKenneth McDonald, MD..... Reply... Atsushi Hirayama, MD; Kazuhisa Kodama, MD;Hideo Kusuoka, MD .................. 1110

An Alternative Pathophysiological Mechanism for Unstable AnginaPaolo Golino, MD, PhD..... Reply.. Moshe Flugelman, MD; Stephen E. Epstein, MD ................... 1112

Interposed Abdominal Compression-CPR: Which Patients Are Benefited? Why?Mario A. Inchiosa, Jr, PhD; Elizabeth A.M. Frost, MD..... Reply..... Jeffrey B. Sack, MD;Michael B. Kesselbrenner, MD ...................................... 1113

Instructions to Authors ..................... .................................................... A16Annotated Table of Contents ...................... A24Abstract File Cards ..................... A47

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(irculatioir Volume 90 Number 2 August 1994

Annotated Table of ContentsCardiovascular NewsRepresentative William H. Natcher Dies After 41 Years in CongressClaudia Lous, MBA; Scott Ballin, JD . .......... 647

New HorizonsClaude Lenfant, MD ... .......... ......................................................... .......... 648

Brief CommunicationsIndirect Angiogenic Cytokines Upregulate VEGF and bFGF Gene Expression in VascularSmooth Muscle Cells, Whereas Hypoxia Upregulates VEGF Expression OnlyEdi Brogi, MD; Tiangen Wu, MD; Atsushi Namiki, MD; Jeffrey M. Isner, MD .649

We investigated whether low oxygen tension or or TGF-,31 (0.1 to -10 ng/mL). Hypoxia was acytokines known to promote neovascularization in potent stimulus for VEGF gene expression but hadvivo could modulate the expression of either vas- no apparent effect on bFGF steady-state mRNAcular endothelial growth factor (VEGF) or basic levels. Certain indirect angiogenic cytokines, suchfibroblast growth factor (bFGF) in human vascular as PDGF-BB or TGF-p1, may thus act via induc-smooth muscle cells (SMCs). Northern analysis tion of bFGF and VEGF gene expression in cellsdetected low basal levels of VEGF and bFGF resident near endothelial cells in vivo. HypoxiamRNA in extracts of unstimulated SMCs. How- constitutes a potent stimulus for VEGF gene ex-ever, both VEGF and bFGF transcripts increased pression but does not regulate bFGF under theafter administration of PDGF-BB (10 or 20 ng/mL) same experimental conditions.

Clinical Investigation and ReportsMolecular and Cellular ResponsesCa2+-Transporting ATPase, Phospholamban, and Calsequestrin Levels in Nonfailing andFailing Human MyocardiumMatthew A. Movsesian, MD; Mohsen Karimi, BS; Karen Green, BS; Larry R. Jones, MD, PhD ................. 653

Ca 2+-transporting ATPase, phospholamban, andcalsequestrin were quantified immunochemically intotal protein extracts of nonfailing left ventricularmyocardium from the hearts of unmatched organdonors with normal left ventricular contractility(n =6) and failing left ventricular myocardium fromthe excised hearts of transplant recipients withclass IV heart failure resulting from idiopathic

dilated cardiomyopathy (n=6). Ca 2'-transportingATPase, phospholamban, and calsequestrin pro-tein levels were identical in the two groups. Theseresults indicate that down-regulation of the Ca2'-transporting ATPase and phospholamban is notpart of the cellular pathophysiology of dilatedcardiomyopathy in humans.

Effects of L-Arginine on Impaired Acetylcholine-induced and lschemic Vasodilation of theForearm in Patients With Heart FailureYoshitaka Hirooka, MD; Tsutomu Imaizumi, MD; Tatsuya Tagawa, MD; Masanari Shiramoto, MD;Toyonari Endo, MD; Shin-ichi Ando, MD; Akira Takeshita, MD ................................................. 658

In patients with heart failure (HF) and controlsubjects (C), we determined vasodilator responsesof the forearm to intra-arterial infusions of acetyl-choline (ACh) and sodium nitroprusside (SNP) atgraded doses and those after 10 minutes of arterialocclusion before and after L-arginine. Vasodilatorresponses to ACh and after arterial occlusion wereattenuated in HF, whereas responses to SNP were

comparable between the two groups. L-Arginineaugmented the maximal vasodilation induced byACh and during reactive hyperemia only in HF.L-Arginine had no effects on the responses to SNPin C or HF. Impaired ischemic vasodilator capacityin HF may be due in part to a defect in the releaseof nitric oxide from the endothelium.

Plasma Level and Gene Polymorphism of Angiotensin-Converting Enzyme in Relation toMyocardial InfarctionF. Cambien; 0. Costerousse; L. Tiret; 0. Poirier; L. Lecerf; M.F. Gonzales; A. Evans; D. Arveiler;J.P. Cambou; G. Luc; R. Rakotovao; P. Ducimetiere; F. Soubrier; F. Alhenc-Gelas ............................. 669

The angiotensin-converting enzyme (ACE) playsan important role in the production of angiotensin

II and the degradation of bradykinin, two peptidesinvolved in cardiovascular homeostasy. Presence of

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a polymorphism in the ACE gene (ACE Ss) hasbeen postulated from segregation analysis ofplasma ACE in families. This putative polymor-phism, which strongly affects the plasma and cellu-lar levels of ACE, probably by modulating ACEgene transcription, has not yet been identified atthe molecular level; however, an insertion/deletionpolymorphism is present in the 16th intron of theACE gene (ACE I/D) and appears to be a verygood marker for ACE Ss. The biological role ofACE suggests that the ACE gene polymorphismcould affect the predisposition to myocardial in-farction (MI). We have recently shown, in a largecase-control study (ECTIM), that the marker alleleD of the ACE gene, which is associated with higherlevels of ACE in plasma and cells, was morefrequent in male patients with MI than in controlsubjects, especially in patients considered at lowrisk. ACE activity has now been measured fromfrozen aliquots of plasma in a large subsample ofthe ECTIM study (n= 1086). Plasma ACE level didnot differ between patients and control subjects inthe older age group (255 years) but was higher in

patients than in control subjects in the younger agegroup (<55 years); P<.005 after adjustment onACE I/D and other risk factors. In patients, plasmaACE levels decreased with age (R= -.225,P< 10`4), but in control subjects no such trend wasobserved. In the low-risk group (ApoB <1.25 mg/dL, body mass index <26 kg/m2, and not treatedwith hypolipidemic drugs), plasma ACE level wasincreased in patients when compared with controlsubjects among homozygotes and heterozygotes forthe ACE I allele (P<.015). Analysis of the distri-bution of plasma ACE by using commingling analy-sis conditional on the marker genotype ACE I/Denabled us to infer the frequencies and effects ofthe postulated ACE Ss genotypes. The resultssuggest that the higher plasma ACE levels inpatients than in control subjects in the younger agegroup were due to a difference in frequency of thepostulated S allele (.47 versus .36). These resultsextend our previous findings and indicate thatplasma ACE level may be a risk factor for MI,independent of the ACE I/D polymorphism.

Induction of Acidic Fibroblast Growth Factor and Full-Length Platelet-Derived GrowthFactor Expression in Human Cardiac Allografts: Analysis by PCR, In Situ Hybridization,and ImmunohistochemistryXiao-Ming Zhao, MD; Tiong-Keat Yeoh, MD; William H. Frist, MD; Diane L. Porterfield, BS;Geraldine G. Miller, MD ........................... .......................................... 677

Expression of acidic fibroblast growth factor(aFGF) and platelet-derived growth factor A chain(PDGF-A) was examined in biopsies of cardiacallografts and normal hearts. Reverse transcrip-tase/polymerase chain reaction, in situ hybridiza-tion, and immunohistochemistry were used to de-tect mRNA and protein. aFGF mRNA was

expressed in 80% of allograft biopsies but was notdetected in normal hearts. mRNA for the longform of PDGF-A chain was present in 70% ofallograft biopsies but none of the normal hearts.Myocytes and vascular walls were the predominantsources of aFGF in transplanted human hearts.

Correlation Between Cellular Rejection of Cardiac Allografts and Quantitative ChangesAmong T-Cell Subsets Identified by Vj3 Epitope ExpressionJohn F. Cariquist, PhD; M. Elizabeth Hammond, MD; Robert L. Yowell, MD, PhD; Cherilyn Holland, RN;Sandy Swanson, RN, BSN; Jeffrey L. Anderson, MD. ........................................................ 686

A panel of antibodies to T-cell receptor subfamilieswas used to quantitate T-cell subsets (by flowcytometry) at weekly intervals for cardiac trans-plant recipients. A normal range of variability wasestablished by serial determinations for healthycontrols. For patients, 57 of 240 tests (24%) felloutside of this range (P<.004, x 2). The occurrence

of abnormal subset alterations correlated with theoccurrence of biopsies positive for cellular rejection(P<.001) but not vascular rejection or the initiationof high-dose prednisone therapy (P=NS). T-cellsubset measurement may predict cellular rejectionand provide insights into the physiology of graftrejection.

Increased Secretion of Tumor Necrosis Factor-a and Interferon-y by MononuclearLeukocytes in Patients With lschemic Heart Disease: Relevance in SuperoxideAnion GenerationK. Vaddi, DVM, PhD; F.A. Nicolini, MD; P. Mehta, MD; J.L. Mehta, MD, PhD ......... ......................... 694

Secretion of tumor necrosis factor-a (TNF-a) andinterferon-y (IFN-y) by isolated mononuclear leu-kocytes (incubated with concanavalin A for 48hours) from patients with stable angina pectorisand others with unstable angina pectoris was mea-sured by ELISA. Secretion of both TNF-a andIFN-y was higher (P<.02) in coronary artery dis-ease (CAD) patients than in the control subjects.

Basal neutrophil superoxide radical generation wasalso maximally increased in CAD patients. Therewas no relationship between the extent of CADand cytokine secretion. Increased cytokine secre-tion in CAD may play a role in endothelial injury,cellular deposition, and activation and progressionof atherosclerosis.

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lschemic Preconditioning During Coronary Angioplasty Is Prevented by Glibenclamide,a Selective ATP-Sensitive K' Channel BlockerFabrizio Tomai, MD; Filippo Crea, MD; Achille Gaspardone, MD, MPhil; Francesco Versaci, MD;Ruggero De Paulis, MD; Alfonso Penta de Peppo, MD; Luigi Chiariello, MD; Pier A. Gioffre, MD ................... 700

Brief episodes of ischemia render the heart moreresistant to subsequent ischemia. The aim of thisstudy was to establish whether glibenclamide, aselective KATP channel blocker, abolishes the isch-emic preconditioning observed in humans duringcoronary angioplasty following repeated ballooninflations. In glibenclamide-treated patients, themean ST-segment shift during the second ballooninflation was similar and the severity of cardiac

pain was greater than those during the first infla-tion. Conversely, in placebo-treated patients boththe mean ST-segment shift during the second in-flation and the severity of cardiac pain were signif-icantly less. In conclusion, in humans ischemicpreconditioning during brief repeated coronaryocclusions is completely abolished by pretreatmentwith glibenclamide, thus suggesting that it is mainlymediated by KATP channels.

Parallel Analysis of Tissue-Type Plasminogen Activator and Type 1 PlasminogenActivator Inhibitor in Plasma and Endothelial Cells Derived From Patients With ChronicPulmonary ThromboemboliIrene M. Lang, MD; James J. Marsh, PhD; Mitchell A. Olman, MD; Kenneth M. Moser, MD;Raymond R. Schleef, PhD . .............................................................................. 706

To understand whether an abnormality exists in thevascular fibrinolytic system of patients with chronicnonresolving pulmonary thromboemboli, endothe-lial cells were isolated from a series of patients, andthe levels of two key regulators of the fibrinolyticsystem (ie, tissue-type plasminogen activator andtype 1 plasminogen activator inhibitor) in the con-

ditioned media were analyzed under either basal orthrombin-stimulated conditions. The data indicatethat this patient population does not display aninherent defect in the ability of pulmonary arteryendothelial cells to produce and secrete these twofibrinolytic proteins.

Spatiotemporal Relation Between Gap Junctions and Fascia Adherens Junctions DuringPostnatal Development of Human Ventricular MyocardiumNicholas S. Peters, MD, MRCP; Nicholas J. Severs, PhD; Stephen M. Rothery, BSc;Christopher Lincoln, FRCS; Magdi H. Yacoub, FRCS; Colin R. Green, PhD ................................... 713

The growing postnatal human heart maintains elec-tromechanical function while undergoing substan-tial changes of cellular topology. Age-relatedchanges in the distribution of the intercellularjunctions that maintain myocardial electromechan-ical integrity were investigated in ventricular myo-cardium from 23 pediatric patients by immunolo-calization of gap junctions (connexin43) and fasciaeadherentes (N-cadherin). Neonatal ventricular

myocardium has a punctate distribution of bothjunction types over the entire surface of the myo-cytes. Progressively greater association between thejunction types occurs as they redistribute to thepositions of mature intercalated disks by 6 years ofage, and these alterations may govern age-relatedchanges in myocardial conduction and adaptabilityto altered hemodynamics.

Coronary Heart Disease/Myocardial Infarction/Peripheral Vascular DiseaseDouble-Blind Efficacy and Safety Study of a Novel Anti-lschemic Agent, Ranolazine,Versus Placebo in Patients With Chronic Stable Angina PectorisUdho Thadani, MBBS, MRCP, FRCP(C); Michael Ezekowitz, MD, PhD; Linda Fenney, MD;Yu-Kun Chiang, PhD; for the Ranolazine Study Group ...................................................... 726

Ranolazine modulates the metabolism of ischemicmyocardial cells and improves the efficiency ofoxygen use. This study was conducted to evaluatethe antianginal and anti-ischemic effects and safetyof different doses of ranolazine administered tidcompared with placebo in 319 patients with stable

angina pectoris. Assessments included laboratoryevaluations, Holter monitoring, 12-lead ECGs, andexercise treadmill tests. Therapy with ranolazine30, 60, and 120 mg t.i.d. was not superior toplacebo.

Histological Alterations in Chronically Hypoperfused Myocardium: Correlation WithPET FindingsAlex Maes, MD; Willem Flameng, MD, PhD; Johan Nuyts, PhD; Marcel Borgers, MD, PhD;Bharati Shivalkar, MD; Jannie Ausma, MSc; Guy Bormans, PhD; Christiaan Schiepers, MD, PhD;Michel De Roo, MD, PhD; Luc Mortelmans, MD, PhD ............ .......................................... 735

Positron emission tomography (PET) findings offlow and metabolism were correlated with histolog-ical findings in patients with coronary artery dis-

ease. Thirty-three patients underwent NH3/FDGflow/metabolic imaging with PET 1 or 2 days beforecoronary artery bypass grafting. During surgery,

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biopsies were taken from the left ventricular ante-rior wall. An association was found between PETmeasurements of flow and metabolism and theextent of myocardial fibrosis in the biopsies. Cells

with reduced contractile material and increasedglycogen content were present mainly in hypocon-tractile areas perfused by the stenosed artery.

Effects of Thrombolytic Therapy Administered 6 to 24 Hours After Myocardial Infarctionon the Signal-Averaged ECG: Results of a Multicenter Randomized TrialJonathan S. Steinberg, MD; Judith S. Hochman, MD; Christopher D. Morgan, MD; Paul Dorian, MD;C. David Naylor, MD, DPhil; Pierre Theroux, MD; Eric J. Topol, MD; Paul W. Armstrong, MD;the LATE Ancillary Study Investigators .................................................................... 746

Thrombolytic therapy reduces mortality after acutemyocardial infarction, even when treatment is ini-tiated relatively late after onset of symptoms. Themechanism underlying this survival benefit is in-completely understood. In a prospectively designedancillary study of a randomized, placebo-controlledtrial of late thrombolytic therapy (LATE), thesignal-averaged (SA) ECG was recorded beforehospital discharge in an effort to assess the effect ofthrombolytic therapy on arrhythmia substrate.Three hundred ten patients were enrolled at 23participating sites; 160 patients received placebo,and 150 patients received recombinant tissue-typeplasminogen activator (rTPA) therapy 6 to 24hours after onset of symptoms. Compared with

placebo, rTPA tended to reduce the frequency ofSAECG abnormality (filtered QRS duration >120milliseconds) by 37% (95% CI, -64%, +6%;P=.087) and the filtered QRS duration (105.7±13.8versus 108.8±14.6 milliseconds, P=.05). In the pre-specified subgroup of 185 patients with ST elevationon the qualifying ECG, rTPA resulted in a 52%reduction (95% CI, 4% to 77%, P=.011) of SAECGabnormality and a shorter filtered QRS duration(105.7±10.9 versus 110.7±15.9 milliseconds, P=.01).No benefit was seen in patients without ST elevationon ECG. Late thrombolytic therapy produced a morestable electrical substrate, which probably representsan important mechanism of mortality benefit.

Limitation of Infarct Size and Preservation of Left Ventricular Function After PrimaryCoronary Angioplasty Compared With Intravenous Streptokinase in AcuteMyocardial InfarctionMenko Jan de Boer, MD; Harry Suryapranata, MD; Jan C.A. Hoomtje, MD; Stoffer Reiffers, PhD;Ay Lee Liem, MD; Kor Miedema, PhD; Wim Th. Hermens, PhD; Marcel J.B.M. van den Brand, MD;Felix Zijlstra, MD ....................................................................................... 753

The purpose of the study was to compare primarycoronary angioplasty and intravenous streptokinasetreatment with regard to infarct size measured withserial enzyme release and left ventricular ejectionfraction measured with a radionuclide technique in301 patients with acute myocardial infarction. Earlyeffective blood flow through the infarct-related cor-onary vessel could be accomplished within 2 hoursafter hospital admission in 92% of all patients

assigned to angioplasty therapy. Estimated infarctsize was 23% smaller in patients assigned to primarycoronary angioplasty (P=.012), and global left ven-tricular ejection fraction (50% versus 45%) wassignificantly better in the angioplasty-assigned pa-tients (P<.001). These effects were more pro-nounced in patients presenting within 2 hours aftersymptom onset or with anterior wall infarction.

Effects of Treatment on Outcome in Mildly Symptomatic Patients With lschemia DuringDaily Life: The Atenolol Silent lschemia Study (ASIST)Carl J. Pepine, MD; Peter F. Cohn, MD; Prakash C. Deedwania, MBBS; Robert S. Gibson, MD;Eileen Handberg, RN, MSN; James A. Hill, MD; Elinor Miller, MD; Ronald G. Marks, PhD;Udho Thadani, MD; for the ASIST Study Group ................. ............................................ 762

A multicenter, randomized, double-blind, placebo-controlled study of 306 outpatients with daily lifesilent ischemia due to coronary artery disease wasconducted. They had mild or no angina and wererandomized to receive either atenolol or placebo.After 4 weeks of treatment, the number and dura-

tion of ischemic episodes decreased in the atenololgroup as event-free survival at 1 year improvedcompared with the placebo group. The most pow-erful univariate and multivariate correlate of event-free survival was absence of ischemia at 4 weeks.

Associations of the HDL2 and HDL3 Cholesterol Subfractions With the Development oflschemic Heart Disease in British Men: The Caerphilly and Speedwell Collaborative HeartDisease StudiesPeter M. Sweetnam, MSc; Colin H. Bolton, PhD; John W.G. Yarnell, MD, MFCM;David Bainton, MB, MRCP; Ian A. Baker, MB, MRCP; Peter C. Elwood, MD, FRCP;Norman E. Miller, MD, DSc, MRCP ................................................................... 769

The Caerphilly and Speedwell studies are based ona total of 4860 men. By first follow-up, 251 IHD

events had occurred. Fasting lipids, including HDLsubfractions, were measured in both cohorts, using a

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different laboratory for each. Univariately, bothHDL2 and HDL3 cholesterol were inversely associ-ated with risk of IHD, but no linear combination ofthe two subfractions was a better predictor of IHD

than total HDL cholesterol alone. However, the trueassociations of the major HDL subfractions withIHD may not become clear until problems with themeasurement of the subfractions are resolved.

Macrophage Infiltration in Acute Coronary Syndromes: Implications for Plaque RupturePedro R. Moreno, MD; Erling Falk, MD; Igor F. Palacios, MD; John B. Newell, BA;Valentin Fuster, MD, PhD; John T. Fallon, MD, PhD ........................................................ 775

Immunostaining with anti-human macrophagemonoclonal antibody was performed to quantifythe macrophage content of atherectomy specimensfrom 26 patients with stable angina, unstable an-gina, and non-Q-wave myocardial infarction. Thepercentage of macrophage-rich area (mean±SEM)was larger in unstable angina (13.3±5.6%) and

non-Q-wave myocardial infarction (14.1+4.6%)than in stable angina (3.14±1%) (P=.018). Thisstudy concludes that macrophage-rich areas aremore frequently found in patients with acute coro-nary syndromes, suggesting that macrophages mayplay a significant role in coronary plaque ulcerationand rupture.

Association Between QT Interval and Coronary Heart Disease in Middle-aged and ElderlyMen: The Zutphen StudyJacqueline M. Dekker, MSc; Evert G. Schouten, PhD, MD; Peter Klootwijk, MD; Jan Pool, PhD, MD;Daan Kromhout, PhD, MPH . ............................................................................ 779

Heart-rate-adjusted QT-interval (QTc) is prognos-tic of sudden death in myocardial infarction pa-tients. We investigated the predictive value of QTcfor coronary heart disease in a longitudinal study ofmiddle-aged and elderly men. Middle-aged menwith QTc 420 msec`12 or more had 4.3 (95% confi-

dence interval [CI], 1.3 to 13.8) times higher coro-nary heart disease mortality rates than men withQTc less than 385 msec`.2. In elderly men this was3.3 (95% CI, 1.0 to 11.6). Because QTc is easilydetermined, it may provide a valuable contributionto risk stratification.

Acute Vascular Effects of Estrogen in Postmenopausal WomenDavid M. Gilligan, MD; Diane M. Badar, RN; Julio A. Panza, MD; Arshed A. Quyyumi, MD;Richard 0. Cannon Ill, MD ................................................................. 786

Although hormone replacement therapy has beenassociated with reduction of cardiovascular eventsin postmenopausal women, the mechanisms thatmediate this apparent benefit are unclear. Becauseimprovement in vasomotor function may representone of the beneficial effects of estrogen administra-tion, we investigated the acute effects of physiolog-ical levels of estrogen on the vascular responses ofestrogen-deficient postmenopausal women. Thestudy included 40 postmenopausal women 60±8years old (mean±SD), 20 of whom had one ormore conditions associated with vascular dysfunc-tion (hypertension, hypercholesterolemia, diabetes,or coronary artery disease). The forearm vascularresponses to the endothelium-dependent vasodila-tor acetylcholine were studied before and duringinfusion of 17,B-estradiol into the ipsilateral bra-chial artery. In 31 subjects, the effect of estradiolon the responses to the endothelium-independentvasodilator sodium nitroprusside was also studied.Women with risk factors for vascular dysfunctionhad significantly reduced vasodilator responses toacetylcholine (P=.01) and to sodium nitroprusside

(P<.001) compared with healthy subjects. Intra-arterial infusion of 17/8-estradiol increased theforearm venous estradiol concentration from16±10 to 318±188 pg/mL, levels typical of repro-ductive-age women at midcycle, but caused novasodilation. However, estradiol potentiated theforearm vasodilation induced by acetylcholine by18±30% (P<.001) in women with risk factors forvascular dysfunction and by 14±23% (P=.03) inhealthy women. Estradiol also potentiated the fore-arm vasodilation induced by sodium nitroprussidein women with risk factors for vascular dysfunctionby 14±21% (P<.001) but not in healthy women.Physiological levels of 17,8-estradiol selectively po-tentiate endothelium-dependent vasodilation inhealthy postmenopausal women and potentiateboth endothelium-dependent and endothelium-in-dependent vasodilation in postmenopausal womenwith risk factors for atherosclerosis and evidence ofimpaired vascular function. These vascular effectsmay be partly responsible for the long-term benefitof estrogen therapy on cardiovascular events inpostmenopausal women.

Use of Aortic Counterpulsation to Improve Sustained Coronary Artery Patency DuringAcute Myocardial Infarction: Results of a Randomized TrialE. Magnus Ohman, MD; Barry S. George, MD; Christopher J. White, MD; Morton J. Kern, MD;Paul A. Gurbel, MD; Robert J. Freedman, MD; Conor Lundergan, MD; Joseph R. Hartmann, MD;J. David Talley, MD; Martin J. Frey, MD; George Taylor, MD; Jeffrey D. Leimberger, PhD; Paul M. Owens, RN;Kerry L. Lee, PhD; Richard S. Stack, MD; Robert M. Califf, MD for the Randomized IABP Study Group ........... ... 792

A total of 182 patients who had patency restoredduring acute cardiac catheterization within the first24 hours of onset of myocardial infarction were

randomly assigned to aortic counterpulsation for 48hours (96 patients) or standard care (86 patients).The number of units of blood transfused and the

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rates of severe bleeding complications and vascularrepair or thrombectomy were similar in bothgroups. Patients randomized to aortic counterpul-sation had significantly less reocclusion of the in-farct-related artery and a significantly lower inci-dence of a composite clinical end point (death,

stroke, reinfarction, emergency angioplasty or by-pass surgery, recurrent ischemia) during follow-up.Careful use of prophylactic aortic counterpulsationcan improve overall clinical outcome in patientsundergoing cardiac catheterization during myocar-dial infarction.

Independent Impact of Thrombolytic Therapy and Vessel Patency on Left VentricularDilation After Myocardial Infarction: Serial Echocardiographic Follow-upAleksandar D. Popovic, MD, PhD; Aleksandar N. Neskovic, MD; Rade Babic, MD;Velibor Obradovi6, MD, PhD; Ljubica Bozinovi6, MD, PhD; Jelena Marinkovi6, PhD; Jar-Chi Lee, MS;Ming Tan, PhD; James D. Thomas, MD, FACC ............................................................ 800

To investigate the independent impact of thrombo-lytic therapy and patency of the infarct-relatedartery on early ventricular dilation after myocardialinfarction, we studied 131 patients with serial quan-titative echocardiography, 81 of whom receivedthrombolytic therapy. Left ventricular end-systolicand end-diastolic volumes and ejection fractionwere measured on days 1, 2, 3, 7, 21, and 42 afterthe infarction. Both thrombolytic therapy and ves-sel patency were independently and additively as-

sociated with significantly smaller ventricular vol-umes, with thrombolysis yielding significantlysmaller end-systolic volumes as early as day 1. Theimpact of thrombolysis was most striking early aftermyocardial infarction, whereas vessel patency wasthe primary determinant of subsequent ventriculardilation. Thus, thrombolysis and vessel patency, inan additive and complementary manner, preventinfarct expansion and subsequent left ventricularremodeling.

Early Detection of Abnormal Coronary Flow Reserve in Asymptomatic Men at High Riskfor Coronary Artery Disease Using Positron Emission TomographyFirat Dayanikli, MD; David Grambow, MD; Otto Muzik, PhD; Lori Mosca, MD; Melyvn Rubenfire, MD;Markus Schwaiger, MD .......................................................

To compare coronary flow reserve as a measure ofvascular integrity in asymptomatic middle-agedmen with family history of coronary artery diseaseand high-risk lipid profile with men without riskfactors for coronary artery disease, we measuredabsolute myocardial blood flow at rest and inconjunction with intravenous adenosine using N-13ammonia dynamic positron emission tomographyscanning. The mean global absolute myocardialblood flow at rest was not significantly differentamong groups (group 1 [low-risk men], 76± 18;

group 2 [high-risk men] 66±8; P=NS; in mL/100 gper minute). However, blood flow after adenosineinfusion was higher for group 2 (group 1, 217+56;group 2, 264±39; P<.001), which resulted in alarger coronary flow reserve for group 2 (group 1,2.93±0.86; group 2, 4.27+0.52; P<.001). Thus,noninvasive quantification of absolute myocardialblood flow may allow early assessment of alter-ations of vascular reactivity to adenosine in relationto coronary disease risk in asymptomatic men.

Intensive Vascular Training in Stage lib of Peripheral Arterial Occlusive Disease:The Additive Effects of Intravenous Prostaglandin E1 or Intravenous PentoxifyllineDuring TrainingP. Scheffler, MD; D. de la Hamette, MD; J. Gross, MD; H. Mueller, MD; H. Schieffer, MD .............

Forty-four patients with peripheral arterial occlu-sive disease lIb were randomly assigned to 4 weeksof treatment either of intensive vascular trainingalone (n=15) or in combination with either IVpentoxifylline (n= 15) or prostaglandin El (n= 14).After therapy the increases in symptom-free walk-ing distance in the exercise-only group (119%) andthe pentoxifylline group (105%) were similar. In

contrast, prostaglandin El plus exercise achieved aremarkable improvement of 604%. After 1 year, inthe exercise-only and pentoxifylline groups themaintained increase in walking distance was only30%. In the prostaglandin El group, maintainedimprovement was 149%, and most patients werestill in stage lla.

Congestive Heart Failure/Valvular Heart DiseasePlasma Arteriovenous cGMP Difference as a Useful Indicator of Nitrate Tolerance inPatients With Heart FailureTakayoshi Tsutamoto, MD; Masahiko Kinoshita, MD; Yasunori Ohbayashi, MD; Atsuyuki Wada, MD;Yukiharu Maeda, MD; Takako Adachi, MD ........... ..................................................... 823

The present study was performed to evaluate theeffects of nitroglycerin (GTN) on plasma arterio-venous cGMP production and to compare its he-modynamic effects in patients with congestive heartfailure (CHF). We also estimated the potential

clinical value of plasma arteriovenous cGMP pro-duction as an indicator of nitrate tolerance. Plasmaarterial and venous cGMP levels, atrial natriureticpeptide level, and hemodynamic parameters weremeasured before and after GTN infusion in 14

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patients with CHF. Although the plasma levels ofarterial cGMP and atrial natriuretic peptide de-creased immediately after GTN, the plasma level ofvenous cGMP did not change. GTN infusioncaused a dose-dependent increase in plasma arte-riovenous cGMP production, and there was a pos-itive correlation between the decrease of pulmo-nary capillary wedge pressure and the increase of

plasma arteriovenous cGMP production immedi-ately after GTN. Hemodynamic tolerance was ob-served after both 12 and 24 hours, when plasmaarteriovenous GMP production was also attenu-ated. These findings indicate that the plasma arte-riovenous cGMP difference is a clinical indicator ofvasodilatory action of GTN and a useful indicatorof nitrate tolerance in patients with CHF.

Echocardiographic Prediction of Survival After Surgical Correction of OrganicMitral RegurgitationMaurice Enriquez-Sarano, MD; A. Jamil Tajik, MD; Hartzell V. Schaff, MD; Thomas A. Orszulak, MD;Kent R. Bailey, PhD; Robert L. Frye, MD ................. ................................................. 830

The preoperative predictors of survival were ana-lyzed in 409 patients with pure, organic mitralregurgitation operated on between 1980 and 1989and with preoperative echocardiograms. Survival at10 years was 58% (88% of expected). Operativemortality was 6.6% but declined to 3.7% between1985 and 1989. Age (P=.0003), operative year(P=.003), and functional class (P=.016) but not leftventricular function predicted operative mortality.

With multivariate analysis, the most powerful pre-dictor of late survival was echocardiographic ejec-tion fraction (P=.0004). At 10 years, survival was72±4%, 53±9%, and 32±12% for patients withejection fraction >60%, 50% to 60%, and <50%,respectively. These results suggest that early oper-ation should be considered in patients with severemitral regurgitation before occurrence of left ven-tricular dysfunction.

Scopolamine Improves Autonomic Balance in Advanced Congestive Heart FailureMaria Teresa La Rovere, MD; Andrea Mortara, MD; Paolo Pantaleo, MD; Roberto Maestri, BE;Franco Cobelli, MD; Luigi Tavazzi, MD ................................................................ 838

The possibility of manipulating neurohumoral ac-tivation associated with congestive heart failure byinterfering with the parasympathetic limb of neuralcontrol was assessed in 21 patients with advancedhemodynamic decompensation. Autonomic controlof the heart was evaluated by means of heart ratevariability at baseline, at 24 hours after transder-mal scopolamine administration (one patch), andat 48 hours after scopolamine withdrawal. Scopol-amine induced significant increases (all P<.05) inmean RR interval and in time-domain and spectral

parameters of heart rate variability (SD by 45%,root mean of square successive difference by 54%,high-frequency power by 65%), which returned tobaseline after scopolamine withdrawal. Individualanalysis showed that in the 7 patients in whomscopolamine did not increase mean RR interval,heart rate variability also did not change. Weconclude that low-dose scopolamine is effective inincreasing cardiac parasympathetic activity in con-gestive heart failure.

Characterization of the Early Lesion of 'Degenerative' Valvular Aortic Stenosis:Histological and Immunohistochemical StudiesCatherine M. Otto, MD; Johanna Kuusisto, MD; Dennis D. Reichenbach, MD; Allen M. Gown, MD;Kevin D. O'Brien, MD ............................................................. 844

Histological and immunohistochemical studieswere performed on aortic valve leaflets from 27individuals (6 healthy individuals, 15 with mildmacroscopic leaflet thickening, and 6 individualswith clinical aortic stenosis). Focal areas of suben-dothelial thickening on the aortic side of the leafletwere characterized by displacement of a subendo-thelial elastic lamina; accumulation of lipid, pro-

tein, and microscopic mineralization; and accumu-lation of numerous macrophages, occasionalT-lymphocytes, iand rare a-actin-positive cells. Weconclude that the early lesion of "degenerative"aortic stenosis is an active inflammatory processwith some similarities and some dissimilarities withatherosclerosis.

Three-Dimensional Left Ventricular Deformation in Hypertrophic CardiomyopathyAlistair A. Young, PhD; Christopher M. Kramer, MD; Victor A. Ferrari, MD; Leon Axel, PhD, MD;Nathaniel Reichek, MD ............... ................................................ 854

Three-dimensional (3D) systolic motion and defor-mation were assessed in vivo in 7 patients withhypertrophic cardiomyopathy (HCM) and 12 nor-mal volunteers by use of magnetic resonance tag-ging. Radial motion (toward the long axis) de-creased slightly in patients with HCM, whereaslongitudinal displacement (parallel to the long axis)of the base toward the apex was markedly reduced(P<.001). Circumferential and longitudinal short-

ening were both reduced in the septum (P<.01 atall levels). The principal strain associated with 3Dmaximal contraction was slightly depressed in mostregions but significantly in the basal septum andanterior walls (P<.05). In contrast, LV torsion(twist of the apex about the long axis relative to thebase) was greater in HCM patients than controlsubjects (P<.01).

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Electrophysiology/Arrhythmias/PacingImplantation by Electrophysiologists of 100 Consecutive Cardioverter Defibrillators WithNonthoracotomy Lead SystemsS. Adam Strickberger, MD; John D. Hummel, MD; Emile Daoud, MD; Mark Niebauer, MD;Brian D. Williamson, MD; K. Ching Man, DO; Laura Horwood, RN; Alice Schmittou, RN;Steven J. Kalbfleisch, MD; Jonathan J. Langberg, MD; Fred Morady, MD ..................................... 868

An implantable defibrillator (ICD) with a nontho-racotomy lead system is usually implanted by anelectrophysiologist and a surgeon. This study's pur-pose was to prospectively evaluate the safety andefficacy of ICD implantation with a nonthoracot-omy lead system by electrophysiologists in 100consecutive patients. The nonthoracotomy lead sys-tem with an ICD was successfully implanted in 96

patients (96%). The average procedure durationwas 161±57 minutes, with no procedure-relateddeaths. Acute complications occurred in 10 pa-tients and were most commonly anesthesia-related.In conclusion, a high success rate can be expectedwhen electrophysiologists implant an ICD with anonthoracotomy lead system.

Mechanism of 'Inappropriate' Sinus Tachycardia: Role of Sympathovagal BalanceCarlos A. Morillo, MD; George J. Klein, MD; Ranjan K Thakur, MD; Huagui Li, MD, PhD;Marco Zardini, MD; Raymond Yee, MD ..........................................................

"Inappropriate" sinus tachycardia (IST) is an un-common atrial tachycardia characterized by inap-propriate tachycardia and exaggerated accelerationof heart rate with "normal" P wave. The mecha-nism leading to IST is incompletely understood. Todetermine the role of autonomic balance in thegenesis of IST, 6 female patients aged 23 to 38years with IST and 10 age- and sex-matched controlsubjects underwent standardized autonomic func-tion evaluation. Sympathovagal balance to the sinusnode assessed by calculating the low frequency/

......873high frequency ratio using power spectral analysiswas similar in control subjects and IST patients.Cardiovagal reflex was markedly depressed in allpatients. f-Adrenergic hypersensitivity to isopro-terenol as well as high intrinsic heart rate werenoted in all cases. These findings suggest that themechanism leading to IST is related to a primarysinus node abnormality characterized by a highintrinsic heart rate, depressed efferent cardiovagalreflex, and 83-adrenergic hypersensitivity.

Reduced Heart Rate Variability and Mortality Risk in an Elderly Cohort: The FraminghamHeart StudyHisako Tsuji, MD; Ferdinand J. Venditti, Jr, MD; Emily S. Manders, BS; Jane C. Evans, MPH;Martin G. Larson, ScD; Charles L. Feldman, ScD; Daniel Levy, MD .......................................... 878

To evaluate the prognostic implications of reducedheart rate variability in an elderly, community-based population, the first 2 hours of ambulatoryECG recordings obtained on 736 original subjectsof the Framingham Heart Study were reprocessed(mean age, 72 years). Five frequency domain andthree time domain measures were obtained. Dur-ing 4-year follow-up, 74 subjects died. Proportionalhazards regression analysis was used to evaluateassociations of heart rate variability measures with

all-cause mortality adjusting for relevant risk fac-tors. In separate analyses, four frequency domainvariables (all P<.01) and the standard deviation oftotal normal RR intervals (P<.01) were signifi-cantly associated with all-cause mortality. When allheart rate variability measures were assessed in astepwise analysis that included other risk factors,low-frequency power (0.04 to 0.15 Hz) was the onlyheart rate variability measure selected.

Anatomic, Electrical, and Mechanical Factors Affecting Bipolar Endocardial Electrograms:Impact on Catheter Ablation of Manifest Left Free-Wall Accessory PathwaysRiccardo Cappato, MD; Michael Schluter, PhD; Lluis Mont, MD; Karl-Heinz Kuck, MD ........................

To assess the influences of a varying anatomy ofaccessory pathway (AP) and atrioventriculargroove, of different ablative approaches, and of RFpulses preceding the final pulse, local bipolar en-docardial electrograms were retrospectively ana-lyzed in a uniform cohort of 62 consecutive patientswith a single manifest AP located on the left freewall; the AP had been ablated by a uniform ap-

proach with a single catheter advanced retro-gradely toward the mitral annulus. The study showsthat the effect of anatomic variations of the AP andthe atrioventricular groove is reflected in the bipo-lar endocardial electrogram and needs to be con-sidered in the approach to ablation. Also, electro-gram criteria are introduced for successful ablationat both the ventricular and the atrial AP insertion.

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Angioplasty/Atherectomy/Stents (Cardiac and Peripheral)Coronary Vasoconstriction After Percutaneous Transluminal Coronary Angioplasty IsAttenuated by Antiadrenergic AgentsLuisa Gregorini, MD; Jean Fajadet, MD; Gabriel Robert, MD; Bernard Cassagneau, MD;Monique Bemis, MD; Jean Marco, MD ..................... .............................................. 895

Vasoconstriction occurs after percutaneous translu-minal coronary angioplasty (PTCA) along the dilatedvessel. The vasomotor changes, initiated by the me-chanical stretch of the stenotic region, are thought tobe due to various mechanisms but whether the sym-pathetic nervous system plays a role in this phenom-enon remains unknown. Quantitative angiography(ARTREK) was performed in 45 patients undergo-ing an epicardial vessel PTCA for a stenosis of76±1% (1) in basal conditions, (2) after PTCA, and(3) 30 minutes after PTCA (vasoconstriction). In 14control patients, the same measurements were ob-tained up to 60 minutes after PTCA. Coronarydiameters were measured along the PTCA vessel atthe narrowest stenosis level and at a level peripheralto stenosis. In 36 patients two diameters were alsomeasured at a proximal segment and at a distalsegment along a nonmanipulated vessel. Thirty min-utes after PTCA the dilated segment underwent a-31±2% (mean±SEM, ANOVA, P<.05) reductionin diameter when compared with PTCA values, andthe segment peripheral to stenosis showed a reduc-tion of - 17±2% (P<.05). In all patients a significantvasoconstriction also was observed along the controlvessel (proximal segment, -14+3%; P<.05 versusbasal; and distal segment, - 17±2%). At the time ofmaximal vasoconstriction (30 minutes after PTCA),the patients (treatment groups) received (1) 18 ,ug/kgIC phentolamine (Phe, n=7), (2) 14 ,ug/kg IC yohim-bine (YO, n=7), (3) 16 ,g/kg IC propranolol (Pro)followed by 18 p£g/kg IC phentolamine (Pro+Phe,n=7), and (4) 0.2 mg/kg IC bretylium (Bre, n=10).In 14 patients (control groups) an intracoronaryinjection of warm saline was given. After drug injec-tions, angiograms were repeated at 5-minute inter-

vals for 20 minutes and ended after a 300-,ug intra-coronary trinitroglycerin injection. At stenosis level,Phe and Bre counteracted vasoconstriction, inducinga dilatation of +19±3% and +22±6%, respectively,while Pro+Phe caused a dilatation of + 16±9%above the PTCA values (P<.05 versus PTCA). YOonly partially reversed vasoconstriction (from-33±4% to -12±4%, P=NS versus PTCA). Atperipheral-to-stenosis level, vasoconstriction wasabolished by Phe (+26±7%, P<.05 versus basal),while it was still present after Pro+Phe (-23±2%)and Bre (-18±4%). In addition, Phe and Bre dilatedthe control vessel at the proximal segment (+ 17±6%and +8±4%, respectively, P<.05 versus basal), whileYO and Pro+Phe only counteracted vasoconstriction(from -15±3% to +7.6±1% and from -16±3% to+4±5%, respectively, P=NS versus basal). At thedistal segment only Phe produced a vasodilatation of+23 ± 1%; YO counteracted constriction (from-16±2% to +9±6%, P<.05 versus basal), whereasafter Pro+Phe and Bre, the vasoconstriction per-sisted. The mechanical stretch and ischemia causedby balloon inflation induced vasoconstriction medi-ated by a-adrenergic receptors (mainly a,), overcom-ing a (3-mediated dilatation. The use of differentantiadrenergic drugs showed that Phe counteractspost-PTCA vasoconstriction, and the simultaneoususe of a- and ,3-receptor blocking agents (Pro+Pheand Bre) reveals the presence of a peripheral, pre-dominant 13-mediated dilatation. The presence ofvasoconstriction also along the control vessels notbranching from the stretched ramus provides evi-dence for the existence of neural sympathetic vaso-constrictor reflexes.

Low Molecular Weight Heparin in Prevention of Restenosis After Angioplasty: Results ofEnoxaparin Restenosis (ERA) TrialDavid P. Faxon, MD; Theodore E. Spiro, MD; Steven Minor, MD; Gilles Cot6, MD; John Douglas, MD;Ronald Gottlieb, MD; Robert Califf, MD; K Dorosti, MD; Eric Topol, MD; John B. Gordon, MD;Magness Ohmen, MD; and the ERA Investigators .......................................................... 908

Heparin, an anticoagulant, possesses antiproliferativeeffects and has been shown to reduce neointimalproliferation and restenosis following vascular injuryin experimental studies. The primary aim of thisdouble-blind multicenter study was to determine if 40mg Enoxaparin, a low molecular weight heparin,administered subcutaneously once daily for 1 monthafter successful angioplasty would reduce the inci-dence of restenosis. Four hundred fifty-eight patientswere randomized at nine clinical centers (231 toplacebo and 227 to Enoxaparin). The primary endpoint was angiographic or clinical restenosis. Angio-graphic restenosis was defined as a loss of 50% of theinitial gain as measured by quantitative coronaryangiography (QCA) at a core laboratory. In theabsence of QCA, clinical evidence of restenosis wasdefined as death, myocardial infarction, repeat revas-

cularization, or worsening angina. Using the inten-tion-to-treat analysis for all patients, restenosis oc-curred in 51% of the placebo group and 52% of theEnoxaparin group (relative risk, 1.07, P=.625). Like-wise, no difference in restenosis was evident when thechange in minimal lumen diameter or other angio-graphic definitions of restenosis were used. Ad-verse clinical events were infrequent and did notdiffer between the groups with the exception ofminor bleeding complications, which were morecommon in the Enoxaparin group. Enoxaparin (40mg/d SC for 1 month) following successful angio-plasty did not reduce the incidence of angiographicrestenosis or the occurrence of clinical events over6 months. The treatment was well tolerated, al-though in-hospital minor bleeding was more com-mon with active treatment.

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Magnetic Resonance Imaging of the lliofemoral Arteries After Balloon DilationAngioplasty of Aortic Arch Obstructions in ChildrenPatricia E. Burrows, MD; Lee N. Benson, MD; Paul Babyn, MD; Cathy MacDonald, MD ..........

To determine the incidence of obstructive lesionsin the iliofemoral arteries after balloon dilationangioplasty (BDA) for aortic arch obstruction inchildren, 63 children, including 36 patients who hadundergone transfemoral BDA, were evaluated withgradient imaging of the pelvic vessels. The iliofem-oral arteries were normal in all 15 children withoutprior catheterization but were mildly narrow in 7

.... 915and severely stenotic or occluded in 14 children(39%) after BDA, including 6 of 9 patients treatedfor acute femoral artery thrombosis. Eight patientswith severe obstructive changes had no history offemoral artery thrombosis. Analysis of technicalfactors indicated the number of catheter exchangesto be a significant contributing factor.

Cardiopulmonary BypassRandomized Study of Aprotinin and DDAVP to Reduce Postoperative Bleeding AfterCardiopulmonary Bypass SurgeryEduardo Rocha, MD; Francisco Hidalgo, MD; Rafael Llorens, MD; Jose M. Melero, MD;Jose L. Arroyo, MD; Jose A. Paramo, MD .........................................................

We tested the efficacy and safety of aprotininversus desmopressin acetate (DDAVP) in patientsundergoing cardiopulmonary bypass. Patients wererandomly assigned to aprotinin, one dose ofDDAVP, two doses of DDAVP, or no treatment.Patients treated with aprotinin had a significantreduction in the postoperative blood loss (P<.01)as well as in the amount of blood used (P<.01)

compared with all other groups. No significanteffect of the two DDAVP regimens on postopera-tive blood loss was observed. A significant reduc-tion of FbDP levels was observed only in theaprotinin group (P<.001). Aprotinin offers a betteralternative than DDAVP in the prevention ofbleeding in these patients.

Congenital Heart Disease/HypertensionSex-Specific Determinants of Increased Left Ventricular Mass in the Tecumseh BloodPressure StudyRoy Marcus, MD; Lisa Krause, MS; Alan B. Weder, MD; Agnes Dominguez-Meiia, MD;Nicholas J. Schork, MA; Stevo Julius, MD, ScD ........................................................ 928

Left ventricular mass was determined by echocar-diography in 851 normotensive men and women 18to 42 years old participating in the Tecumseh BloodPressure Study and was indexed to body surfacearea. Using sex-specific criteria, we classified sub-jects with a left ventricular mass index of >9Othpercentile as having left ventricular hypertrophy. In

men, left ventricular hypertrophy was associatedwith enhanced sympathetic nervous system reactiv-ity and with markers of insulin resistance. Inwomen, left ventricular hypertrophy was associatedwith increased adiposity. Thus, in the absence ofhypertension, factors promoting increased left ven-tricular mass index differ in men and women.

Quantification of Collateral Blood Flow in Coarctation of the Aorta by Velocity EncodedCine Magnetic Resonance ImagingJohann C. Steffens, MD; Michael W. Bourne, MD; Hajime Sakuma, MD; Margaret O'Sullivan, RN;Charles B. Higgins, MD .............................

Knowledge about the volume of collateral flowprovides insight into the severity of coarctation ofthe aorta and may be critical in planning theoperative approach. There is currently no methodfor the quantification of collateral flow in coarcta-tion of the aorta. In this study, we applied velocityencoded cine magnetic resonance imaging (VENC-MR) to establish the flow pattern and volume ofcollateral flow in the descending thoracic aorta innormal subjects and patients with coarctation, in-troducing a new possibility to quantify the severityof the coarctation by determining the amount ofcollateral flow. VENC-MR was used to measureflow in the proximal and distal descending thoracicaorta in 10 normal subjects. In 23 patients withcoarctation, flow was measured near the coarcta-tion site and above the diaphragm. Patients weredivided into a group with moderate to severecoarctation and a group with mild coarctation on

............ ...................... 937the basis of clinical gradient between upper andlower extremities and the estimation of the gradi-ent across the coarctation by Doppler echocardiog-raphy. The gradient across the coarctation and thedegree of anatomic narrowing were also assessedby MR imaging. In normal volunteers, VENC-MRshowed a 7±6% decrease in total flow, from prox-imal to distal aorta. The interobserver reproduc-ibility was 3.9% to 4.9% (mean, 4.4%). In patientswith moderate to severe coarctation, VENC-MRdemonstrated an 83±50% increase in total flowfrom proximal to distal aorta, yielding a significantchange compared with normal subjects (P<.01).Patients with mild coarctation showed a normalflow pattern and no significant change in total flow.There was a significant relation between theamount of flow increase in the distal aorta and thereduction in luminal diameter at the coarctationsite (r=.94) as well as the clinical gradient (r=.84).

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This study shows the normal flow pattern in the measure collateral flow in coarctation and serves asdescending thoracic aorta and its reversal in coarc- a unique method for providing this important mea-tation due to collateral flow. Thus, VENC-MR can surement of the severity of coarctation of the aorta.

Basic Science Reports

Cellular, Molecular, Biological, and Immunological ResearchTranscatheter Delivery of c-myc Antisense Oligomers Reduces Neointimal Formation in aPorcine Model of Coronary Artery Balloon InjuryYi Shi, MD; Ali Fard, MD; Anthony Galeo, MD; Howard G. Hutchinson, MD; Pawan Vermani, MD;George R. Dodge, PhD; David J. Hall, PhD; Farida Shaheen, PhD; Andrew Zalewski, MD .944

Vascular smooth muscle cell proliferation and theaccumulation of extracellular matrix play an impor-tant role in the development of vascular restenosis.This study presents the evidence that antisenseoligodeoxynucleotides targeting the c-myc proto-oncogene independently inhibited vascular smoothmuscle cell proliferation and type I collagen syn-thesis. Using transcatheter delivery of oligodeoxy-nucleotides, we determined the feasibility of such

approach to sustain their concentration at the siteof balloon injury in the coronary vasculature. Fi-nally, c-myc antisense significantly reduced neoin-timal formation in a porcine model of coronarydenudation. These findings underscore the impor-tance of the c-myc proto-oncogene in vascularremodeling and suggest a therapeutic potential ofantisense oligodeoxynucleotides in the preventionof coronary restenosis.

Mononuclear Cells From Dogs With Acute Lung Allograft Rejection Cause Contraction ofPulmonary ArteriesAlexander R.J. Cale, MB, FRCS; Fabio Ricagna, MD; Lars Wiklund, MD;Christopher G.A. McGregor, MB, FRCS; Virginia M. Miller, PhD ............................................. 952

Mononuclear cells isolated from peripheral bloodof dogs with rejecting lung allografts cause cell-dependent contractions of pulmonary arteries.These contractions are mediated in part by inter-

action of the cells with the vascular endotheliumand involve either cell- or endothelium-derivedsuper oxide, nitric oxide, and endothelin-1.

Myofibrillar Ca2+ Sensitization Predominantly Enhances Function and MechanicalEfficiency of Stunned MyocardiumLoe Kie Soei, MD; Loes M.A. Sassen, MD; Dong Sheng Fan, MD; Tineke van Veen, MD; Rob Krams, MD;Pieter D. Verdouw, PhD . ....................................................................... 959

Myocardial stunning is characterized not only by adecreased regional postischemic function but alsoby a relatively high oxygen consumption (ie, de-creased mechanical efficiency). Several lines ofevidence suggest that the underlying mechanismmay involve a decreased sensitivity of the myofibrilsto calcium, but in vivo evidence is lacking. Wetherefore evaluated this hypothesis in vivo usingEMD 60263, a calcium-sensitizing agent, which isdevoid of any phosphodiesterase-inhibiting proper-ties. We first established the effect of two consec-utive doses of EMD 60263 (0.75 and 1.5 mg/kg IV,n=7), administered at 15-minute intervals, on seg-ment length shortening (SLS), external work index(EW; the area inside the left ventricular pressure-segment length loop), myocardial oxygen consump-tion (MVo2), and mechanical efficiency (EW/MVo2) in anesthetized pigs with normalmyocardium. After the highest dose of EMD60263, SLS in the distribution area of the leftanterior descending coronary artery (LADCA) in-creased from 13±+1% at baseline to 17±+1%(P<.05). However, EW, MVo2, and EW/MVo2were not significantly affected (123+10%, 98+9%,and 85-+±13% of baseline, respectively). In 14 otheranesthetized pigs, myocardial stunning was inducedby two sequences of 10 minutes of LADCA occlu-sion and 30 minutes of myocardial reperfusion.

After induction of stunning, the two doses of EMD60263 (n=7) or saline (3 and 6 mL, n=7) wereinfused. In the distribution area of the LADCA,the stunning protocol caused decreases in SLSfrom 16±1% to 8±1% (P<.05) and in EW to49±5% of baseline (P<.05), whereas MVo2 wasonly minimally affected (P>.05). Consequently,mechanical efficiency decreased to 59±8% of base-line (P<.05). Saline infusion did not affect any ofthese regional myocardial variables, but after ad-ministration of EMD 60263 SLS recovered dose-dependently to 15±2% after the highest dose ofthe drug. EW and mechanical efficiency also recov-ered dose-dependently to 89±4% (P<.05 versusstunning) and to 88±7% (NS versus baseline) ofbaseline, respectively. In the not-stunned segment,SLS increased from 15±2% (at baseline) to18±2% (after the highest dose), and EW per beatwas not changed significantly. An adrenergic modeof action of EMD 60263 was excluded by blockingthe a- and /3-adrenergic receptors with phentol-amine and propranolol, respectively, 15 minutesbefore administration of EMD 60263 (ie, 15 min-utes into the second reperfusion period) in fiveadditional experiments. In these experiments theEMD 60263-induced increases in SLS and EWwere not attenuated. Because EMD 60263 de-creased heart rate from 106±4 to 76±3 beats per

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minute (P<.05) in the animals with stunned myo-cardium, we performed five experiments with thespecific negative chronotropic compound zatebra-dine (UL-FS 49, 0.1 to 0.5 mg/kg) to rule outbradycardia as a factor contributing to the effects ofEMD 60263. These zatebradine doses loweredheart rate from 116±5 to 55±1 beats per minute

(P<.05) but had no effect on SLS of stunned andnot-stunned myocardium. Calcium sensitization af-fects function and mechanical efficiency of stunnedmyocardium more profoundly than of not-stunnedmyocardium, lending support to the hypothesis thatCa2' desensitization of the myofibrils is involved inmyocardial stunning.

Ischemia/Vasoconstriction/InfarctionPhysical Conditioning Decreases Norepinephrine-Induced Vasoconstriction in Rabbits:Possible Roles of Norepinephrine-Evoked Endothelium-Derived Relaxing FactorHsiun-ing Chen, PhD; Hsing-Tan Li, MS; Chien-Chih Chen, BS .............................................. 970

Physical activity can reduce sympathetic tone andmay be beneficial to human health. Whether thevascular responses to norepinephrine (NE), an ad-renergic vasoconstrictor, could be altered by chronicexercise was unclear. We therefore conducted thisstudy to investigate the effects of endurance exercisetraining on NE-induced vasoconstrictive response inhealthy rabbits. Possible mechanisms were also stud-ied. Twenty-four male New Zealand White rabbitswere used for this study. They were divided into twogroups: control and training. The training group wastrained on a treadmill with running speed of 0.88km/h at a 00 grade for 10 to 60 minutes per day, for 5days a week for a total of 8 weeks. At the end of theexperiments, thoracic aortae (3 mm long) were iso-lated. The vascular tension was measured with a forcetransducer. The dose-response relation of NE-in-duced vasoconstriction was determined and com-pared for control (n=5) and trained (n=6) groups.To verify the possible involvement of endothelium-derived relaxing factor (EDRF) in the alteration ofNE-induced vasoconstriction after exercise training,we compared the vascular responses to NE in endo-thelium-intact, Nw-nitro-L-arginine (L-NNA, 10`4

mol/L)-pretreated, or denuded vessel segments (n=4for each experiment of each group). EDRF release inthe presence or absence of NE was also evaluated bythe increased tension induced by hemoglobin (10`mol/L), an EDRF scavenger (n=6 for the controlgroup and n=8 for the trained group). In addition,vascular responses to some specific adrenergic ago-nists (ie, phenylephrine, an al-agonist, and clonidine,an a2-agonist) were also studied to see if a specificadrenergic receptor was involved (n=4 for each ex-periment of each group). Our results indicated that(1) [NE]ED5v of the thoracic aorta was elevated byexercise training; (2) in the presence of NE, EDRFrelease from the thoracic aorta, assessed by additionof hemoglobin or L-NNA, was higher in the trainedgroup than in the control group; (3) both phenyleph-rine (10`8 mol/L) and clonidine (10-6 mol/L) couldevoke vasorelaxation that would be inhibited byL-NNA; and (4) in addition to causing vasoconstric-tion, NE could stimulate EDRF release, possibly viaal- and a2-receptors of endothelial cells. Our datasuggest that exercise training may decrease NE-induced vasoconstrictive response and may increaseNE-stimulated EDRF release.

Unexpected Interaction Between 3-Adrenergic Blockade and Heart Rate Variability Beforeand After Myocardial Infarction: A Longitudinal Study in Dogs at High and Low Risk forSudden DeathPhilip B. Adamson, MD, MSc; Ming H. Huang, MD; Emilio Vanoli, MD; Robert D. Foreman, PhD;Peter J. Schwartz, MD; Stephen S. Hull, Jr, PhD ........................................................... 976

Heart rate variability was measured before andperiodically after myocardial infarction to deter-mine differences in recovery characteristics be-tween dogs at high and low risk for lethal arrhyth-mias. Additionally, each variability measurementwas made before and after /3-blockade. Heart ratevariability did not recover in high-risk subjects

within 30 days of the infarction but recovered topreinfarction levels by 10 days in the low-risksubjects. P-Blockade increased heart rate variabil-ity before myocardial infarction in low-risk but notin high-risk animals. This increase was not presentafter myocardial infarction.

Determinants of Coronary Artery Reactivity in Premenopausal Female CynomolgusMonkeys With Diet-induced AtherosclerosisJ. Koudy Williams, DVM; Carol A. Shively, PhD; Thomas B. Clarkson, DVM ...........................

Determinants of coronary artery reactivity wereassessed in premenopausal female monkeys withdiet-induced coronary artery atherosclerosis.Quantitative angiography revealed that the coro-nary arteries from socially subordinate monkeysconstricted and those of dominant monkeys dilatedin response to acetylcholine. Social status andplasma estradiol concentrations measured shortlybefore angiography were closely associated withcoronary artery reactivity to acetylcholine. Neither

..... 983social status nor endogenous estrogen productionhad effects on responses of coronary arteries tonitroglycerin and serotonin. Plasma lipids, plaqueextent, and blood pressure were not associated withcoronary artery reactivity. It is concluded thatendogenous estrogen production and social statusare important determinants of acetylcholine-mediated dilation among premenopausal femalemonkeys.

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Effect of an Eccentric Severe Stenosis on Fibrin(ogen) Deposition on Severely DamagedVessel Wall in Arterial Thrombosis: Relative Contribution of Fibrin(ogen) and PlateletsAlessandra Mailhac, MD; Juan Jose Badimon, PhD; John T. Fallon, MD, PhD;Antonio Fernandez-Ortiz, MD, PhD; Beat Meyer, MD; James H. Chesebro, MD;Valentin Fuster, MD, PhD; Lina Badimon, PhD . ............................................................ 988

Fibrin(ogen) deposition on an eccentrically ste-notic, severely damaged vessel wall and its relationto platelet deposition was investigated. Both fibrin-(ogen) and platelet deposition were maximal at thelevel of the stenosis (P<.02), although the formerdemonstrated a significantly lesser increase fromthe prestenotic to the stenotic area, as well as a

lesser decrease from the latter to the poststenoticregion (P<.05). The relative contribution of fibrin-(ogen) and platelets in thrombus formationchanged over time, with fibrin(ogen) being pre-dominant in the thrombus layers adjacent to aseverely injured vessel wall regardless of the localshear rate levels.

Angioplasty/Atherectomy/StentsNeutrophil Implications in Platelet Deposition and Vasoconstriction After Deep ArterialInjury by Angioplasty in PigsYahye Merhi, PhD; Lucie L-Lacoste, MSc; Jules Y.T. Lam, MD .............. ................................ 997

The implication of neutrophils in thrombogenesisand vascular tone regulation was investigated afterdeep carotid arterial injury in vivo by using aneutropenic pig model. Induction of neutropeniadid not affect platelet aggregation to ADP or `tCrplatelet deposition to injured and uninjured arte-rial segments, but it reduced significantly the an-giographic arterial vasoconstrictive response at thesite of endothelial injury in vivo. Aspirin treatment

in combination with neutropenia significantly de-creased platelet aggregation and deposition andfurther reduced the arterial vasoconstrictive re-sponse. These results demonstrate an importantrole for neutrophils in the vasoconstrictive re-sponse after arterial injury, when platelet countand function were unaltered. The acute arterialresponse to injury may be influenced by platelets,neutrophils, and their cooperative interactions.

Localized Arterial Wall Drug Delivery From a Polymer-Coated Removable Metallic Stent:Kinetics, Distribution, and Bloactivity of ForskolinThomas L. Lambert, MD; Vishva Dev, MD; Eldad Rechavia, MD; James S. Forrester, MD;Frank Litvack, MD; Neal L. EigIer, MD .................. ................................................ 1003

We studied the kinetics, distribution, and bioactiv-ity of local arterial wall delivery of forskolin from apolyurethane-coated stent in a rabbit carotidmodel. The quantity of forskolin bound to the stentdecreased exponentially with a half-life of 5.8hours. Blood concentrations peaked at 140±39pg/LL at 4 hours. The adjacent arterial mediacontained 60±39 ng/mg, which was 380- and 460-fold greater than the contralateral carotid mediaand the systemic blood, respectively. Media forsko-lin concentrations declined over time proportional

to the mass of drug remaining on the stent with atissue half-life of 5.0 hours. Forskolin release wasassociated with a sustained 92% increase in carotidflow and a 60% decrease in local arterial resistance.Forskolin prolonged the time to flow variation andocclusion by more than 12-fold compared with baremetal stents and 5-fold compared with polyure-thane-coated stents. A polymer-coated metallicstent can deliver biologically active forskolin to thelocal arterial wall in high concentrations relative tothe blood or other tissues.

Arrhythmias/Electrophysiology/PacingEffects of Heptanol, Class Ic, and Class Ill Drugs on Reentrant Ventricular Tachycardia:Importance of the Excitable Gap for the Inducibility of Double-Wave ReentryLucas Boersma, MD; Josep Brugada, MD; Hoshiar Abdollah, MD; Charles Kirchhof, MD;Maurits Allessie, MD .......... 1012

In 11 Langendorff-perfused rabbit hearts, rings ofanisotropic left ventricular myocardium were cre-ated by a cryoprocedure. Rapid pacing inducedreentrant ventricular tachycardia (VT) around thering. During control, entrainment at high ratescould terminate VT in all hearts. In 4 hearts with alarge excitable gap, rapid pacing could also accel-erate VT by induction of double-wave reentry. Inthe 7 hearts that could not be accelerated, Org7797

(experimental class Ic) and heptanol (electricaluncoupler) prolonged the cycle length of VT andincreased the ratio between the excitable gap andthe refractory period. Double-wave reentry wasnow inducible in all hearts. D-Sotalol (class III)decreased the ratio between the excitable gap andthe refractory period, which either rendered dou-ble-wave reentry nonsustained or prevented accel-eration of VT.

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Exercise Rehabilitationa-Adrenoceptor Stimulation With Exogenous Norepinephrine or Release of EndogenousCatecholamines Mimics lschemic PreconditioningZehyani Bankwala, MD; Sharon L. Hale, BS; Robert A. Kloner, MD, PhD .................................... 1023

To test the hypothesis that transient adrenergic stim-ulation can mimic preconditioning, we randomizedrabbits to receive norepinephrine versus saline ortyramine versus saline 10 minutes before 30 minutesof coronary occlusion, followed by reperfusion. Wefound that exposing the myocardium to ischemicpreconditioning or to catecholamines caused a signif-icant reduction in area of necrosis divided by the area

at risk when compared with controls. When thea-adrenergic effects of norepinephrine were blockedby prazosin treatment, no beneficial reduction ininfarct size was observed. We conclude that eitherexogenous norepinephrine or endogenous release ofnorepinephrine and/or other catecholamines bytyramine can mimic the effects of ischemic precondi-tioning in a rabbit model.

Current PerspectivesHolding Smokers Accountable for Heart Disease Costs

Wayne H. Kaesemeyer, MD ........................................................................... 1029This article discusses escalating health care costs interms of their principal component, cardiovasculardiseases. The role of cigarette smoking is high-lighted throughout. A Smoker's Accountability

Trust is proposed for the prevention of nonfatalmyocardial infarction. It is demonstrated that thisapproach can contain costs by controlling the rootcauses of their acceleration.

Pathogenesis of Acute Myocardial Infarction: Novel Regulatory Systems of BioactiveSubstances in the Vessel WallChuichi Kawai, MD ................................................................................... 1033

Three-dimensional Reconstruction of Intracoronary Ultrasound Images: Rationale,Approaches, Problems, and DirectionsJos R.T.C. Roelandt, MD, PhD; Carlo di Mario, MD, PhD; Natesa G. Pandian, MD; Li Wenguang, MSc;David Keane, MB, MRCPI; Cornelis J. Slager, PhD; Pim J. de Feyter, MD, PhD; Patrick W. Serruys, MD, PhD .. 1044

Intracoronary ultrasonography provides detailedtomographic imaging of the arterial wall, but thecomplex morphology of an atherosclerotic plaquemakes three-dimensional visualization necessaryfor correct analysis. Advances in computer technol-ogy have now made three-dimensional reconstruc-tion an almost on-line reality, which explains itsrecent rapid introduction to the catheterization

laboratory for both guidance and assessment of theresults of catheter-based interventions. How everexciting the prospects may be, three-dimensionalreconstructions at present remain partially artifi-cial. This article is a critical review of the possibil-ities and limitations, with potential solutions forrefinement of this exciting development.

Coronary Artery Disease Regression: Convincing Evidence for the Benefit of AggressiveLipoprotein ManagementH. Robert Superko, MD; Ronald M. Krauss, MD

Ten randomized trials in a total of 2095 subjects thatused coronary arteriography as an end-point mea-

surement tool have consistently reported reductionin the percentage of patients arteriographically de-fined as progressing (mean, 23.6%) and an increasein the percent regressing (mean, 20.0%) comparedwith control groups. Intervention was directed atplasma lipoprotein change, which averaged 28%

greater reduction in LDL cholesterol, 11% greatertriglyceride reduction, and 11% greater HDL cho-lesterol increase compared with control groups.These trials present convincing evidence that lipo-protein manipulation can result in improved arterio-graphic measurements and fewer cardiovascularevents in a cost-effective manner.

Clinicopathological ConferenceA 67-Year-Old Man With Increasingly Frequent AnginaWilliam L. Winters, Jr, MD ................................................................. 1070

Images in Cardiovascular MedicineArteriovenous FistulaRichard W. Lowry, MD; Mark J. Hausknecht, MD .. . 1077

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Special ReportHeart Rate Variability as a Prognostic Tool in Cardiology: A Contribution to the ProblemFrom a Theoretical Point of ViewMaximilian Moser, PhD; Michael Lehofer, MD, PhD; Andrea Sedminek, MD; Manfred Lux, BA;Hans-Georg Zapotoczky, MD; Thomas Kenner, MD; Abraham Noordergraaf, PhD ........................... 1078

Heart rate variability (HRV) contains informationfrom different parts of the autonomous nervoussystem (ANS). It has been shown recently that theprognostic value ofHRV seems remarkable. In thisstudy, two simple methods to calculate HRV (stan-dard deviation [SD] and respiratory sinus arrhyth-mia [RSA]) are compared with respect to their

Clinical Cardiology Frontiers

sensitivity to autonomic influences. From the re-sults, a conclusion is drawn that RSA should be themore suitable parameter for prognosis of outcomeof cardiac infarction. The combined use of RSAand SD could provide a semiquantitative descrip-tion of both branches of the ANS.

Predicting and Preventing Sudden Death From Cardiac CausesJames K Gilman, MD; Sohail Jalal, MD; Gerald V. Naccarelli, MD ............. 1083

Sudden cardiac death usually occurs secondary to aventricular tachyarrhythmia. Even under ideal cir-cumstances only 20% of patients who have anout-of-hospital cardiac arrest survive to hospitaldischarge. Therefore, aggressive treatment andscreening of high-risk patients are mandatory toimprove survival rates. Risk stratification of high-risk patients, such as the post-myocardial infarction(MI) population, has been of limited value. Be-tween 70% and 85% of "high-risk" post-MI pa-tients, as defined by these screening tests, will nothave a sustained ventricular tachyarrhythmia overseveral years of follow-up. The use of a-blockersand possibly amiodarone may have some benefit inreducing mortality in high-risk patients after an

MI. Several ongoing trials are studying the use ofserial drug testing, amiodarone, and implantablecardioverter-defibrillators in reducing the inci-dence of sudden cardiac death in patients withpotentially lethal ventricular arrhythmias. Al-though implantable cardioverter-defibrillators ap-pear to be superior to antiarrhythmic drugs inreducing sudden cardiac death, total mortality maynot be altered. In sustained ventricular tachyar-rhythmias, sotalol and amiodarone appear to besuperior to other drugs in preventing arrhythmiarecurrence. Ongoing trials, such as the Antiar-rhythmic Drug versus Implantable Device (AVID)trial may define the best strategy in these high-riskpatients.

Key ReferencesKey References on Heart FailureBeverly H. Lorell, MD; Lynne Stevenson, MD ............... ............................................. 1093

EditorialsDownsizing Cardiology: Getting the Process StartedLynn 0. Langdon, MS; Melvin D. Cheitlin, MD ........................................................... 1101

Changes in the Topology of Gap Junctions as an Adaptive Structural Responseof the MyocardiumMadison S. Spach, MD . .............................................................................. 1103

CorrespondenceAspirin Versus Heparin in the Acute Phase of Unstable AnginaAlain Moise, MD, MSc; Michel Roos, MD, PhD..... Reply.. Pierre Theroux, MD 1107

Outflow Tract Obstruction and Failed Mitral RepairSerban Mihaileanu, MD..... Reply... Kamthorn S. Lee, MD; Harry M. Lever, MD;William J. Stewart, MD ................................... 1107

Time Course of Endothelial Dysfunction in Diabetes MellitusThomas C. Wascher, MD; Wolfgang F. Graier, PhD; Babak Bahadori, MD; Hermann Toplak, MD

Reply. Michael T. Johnstone, MD; Shelly J. Creager, BSN; Kathleen M. Scales, BS;Jorge A. Cusco, MD; Byron K. Lee, BA; Mark A. Creager, MD .............................................

The Patent Infarct-Related Artery After Myocardial InfarctionKenneth McDonald, MD..... Reply.. Atsushi Hirayama, MD; Kazuhisa Kodama, MD;Hideo Kusuoka, MD ..................................................................................

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An Alternative Pathophysiological Mechanism for Unstable AnginaPaolo Golino, MD, PhD ..... Reply.. Moshe Flugelman, MD; Stephen E. Epstein, MD ................... 1112

Interposed Abdominal Compression-CPR: Which Patients Are Benefited? Why?Mario A. Inchiosa, Jr, PhD: Elizabeth A.M. Frost, MD ..... Reply... Jeffrey B. Sack, MD;Michael B. Kesselbrenner, MD ...... .. 1113

Instructions to Authors .......................................................Al

Annotated Table of Contents .................................. A24Abstract File Cards .A.4.. ...................7...................... A47

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