The American Journal of Cardiology - lib.ajaums.ac.irlib.ajaums.ac.ir/booklist/297258.pdf · Pim van der Harst, Folkert W. Asselbergs, Hans L. Hillege, Stephan J.L. Bakker, Adriaan

CONTENTS THE AMERICAN JOURNAL OF CARDIOLOGY�

VOL. 100, NO. 10 NOVEMBER 15, 2007

Coronary Artery Disease

Prevalence of Low High-Density LipoproteinCholesterol in Patients With Documented CoronaryHeart Disease or Risk Equivalent and ControlledLow-Density Lipoprotein Cholesterol ................1499Alawi A. Alsheikh-Ali, Jen-Liang Lin, Paul Abourjaily,Dineli Ahearn, Jeffrey T. Kuvin, and Richard H. Karas

Comparison of Two- Versus Three-DimensionalMyocardial Contrast Echocardiography forAssessing Subendocardial Perfusion AbnormalityAfter Percutaneous Coronary Intervention in PatientsWith Acute Myocardial Infarction ...................1502Katsuomi Iwakura, Hiroshi Ito, Atsushi Okamura,Toshiya Kurotobi, Yasushi Koyama, Motoo Date,Koichi Inoue, Hiroyuki Nagai, Michio Imai, Yo Arita,Yuko Toyoshima, Makito Ozawa, and Kenshi Fujii

Usefulness of Atherogenic Dyslipidemia forPredicting Cardiovascular Risk in Patients WithAngiographically Defined Coronary ArteryDisease ........................................................1511Marcello Arca, Anna Montali, Sofia Valiante,Filomena Campagna, Giovanni Pigna, Vincenzo Paoletti,Roberto Antonini, Francesco Barillà, Gaetano Tanzilli,Annarita Vestri, and Carlo Gaudio

Effect of Losartan in Treatment of Exercise-InducedMyocardial Ischemia .....................................1517Giancarlo Longobardi, Graziamaria Corbi,Francesco Cacciatore, Pasquale Abete, Giuseppe Furgi,Dino Franco Vitale, Franco Rengo, and Nicola Ferrara

Impact of 64-Slice Cardiac Computed TomographicAngiography on Clinical Decision-Making inEmergency Department Patients With Chest Pain ofPossible Myocardial Ischemic Origin ...............1522Ronen Rubinshtein, David A. Halon, Tamar Gaspar,Ronen Jaffe, Jacob Goldstein, Basheer Karkabi,Moshe Y. Flugelman, Asia Kogan, Reuma Shapira,Nathan Peled, and Basil S. Lewis

Prognostic Value of Coronary Flow Reserve inMedically Treated Patients With Left AnteriorDescending Coronary Disease With Stenosis 51% to75% in Diameter ...........................................1527Fausto Rigo, Rosa Sicari, Sonia Gherardi,Ana Djordjevic-Dikic, Lauro Cortigiani, andEugenio Picano

Comparison of Diagnostic Accuracy of 64-SliceComputed Tomography Coronary Angiography inWomen Versus Men With Angina Pectoris ......1532W. Bob Meijboom, Annick C. Weustink,Francesca Pugliese, Carlos A.G. van Mieghem,Nico R. Mollet, Niels van Pelt, Filippo Cademartiri,Koen Nieman, Eleni Vourvouri, Eveline Regar,Gabriel P. Krestin, and Pim J. de Feyter

Clinical and Angiographic Correlates of Short- andLong-Term Mortality in Patients UndergoingCoronary Artery Bypass Grafting ...................1538Rajendra H. Mehta, Emily Honeycutt, Linda K. Shaw,Carmelo A. Milano, Peter K. Smith, Robert A. Harrington,and Michael H. Sketch, Jr.

Preventive Cardiology

Progression of Coronary Artery Calcium in Type 1Diabetes Mellitus ...........................................1543Tina Costacou, Daniel Edmundowicz, Catherine Prince,Baqiyyah Conway, and Trevor J. Orchard

Effect of Withdrawal of Pravastatin Therapy on C-Reactive Protein and Low-Density LipoproteinCholesterol ...................................................1548Pim van der Harst, Folkert W. Asselbergs,Hans L. Hillege, Stephan J.L. Bakker, Adriaan A. Voors,Dirk J. van Veldhuisen, and Wiek H. van Gilst, for thePREVEND-IT Investigators

Arrhythmias and ConductionDisturbances

Comparison of C-Reactive Protein Levels in PatientsWho Do and Do Not Develop Atrial FibrillationDuring Electrophysiologic Study .....................1552Bahar Pirat, Ilyas Atar, Cagatay Ertan, Huseyin Bozbas,Oyku Gulmez, Haldun Muderrisoglu, and Bulent Ozin

Acute Effects of His Bundle Pacing Versus LeftVentricular and Right Ventricular Pacing on LeftVentricular Function ......................................1556Luigi Padeletti, Randy Lieberman, Jan Schreuder,Antonio Michelucci, Andrea Collella, Paolo Pieragnoli,Giuseppe Ricciardi, William Eastman, Sergio Valsecchi,and Douglas A. Hettrick

A4 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 100 NOVEMBER 15, 2007

Heart Failure

Usefulness of High-Speed Rotational CoronaryVenous Angiography During CardiacResynchronization Therapy ............................1561Dan Blendea, Moussa Mansour, Ravi V. Shah,Jeffrey Chung, Veena Nandigam, E. Kevin Heist,Theofanie Mela, Vivek Y. Reddy, Robert Manzke,Craig A. McPherson, Jeremy N. Ruskin, andJagmeet P. Singh

Role of Multislice Computed Tomography forPreprocedural Evaluation Before Revision of aChronically Implanted Transvenous Left VentricularLead ............................................................1566Angelo Auricchio, Antonio Sorgente, Jagmeet P. Singh,Francesco Faletra, Cristina Conca,Giovanni B. Pedrazzini, Elena Pasotti, Francesco Siclari,and Tiziano Moccetti

Prognostic Usefulness of Anemia and N-TerminalPro-Brain Natriuretic Peptide in Outpatients WithSystolic Heart Failure .....................................1571Morten Schou, Finn Gustafsson, Caroline N. Kistorp,Pernille Corell, Andreas Kjaer, and Per R. Hildebrandt

Valvular Heart Disease

Quantitative Assessment of Severity of MitralRegurgitation by Serial Echocardiography in aMulticenter Clinical Trial of Percutaneous MitralValve Repair .................................................1577Elyse Foster, Hal S. Wasserman, William Gray,Shunichi Homma, Marco R. Di Tullio,Leonardo Rodriguez, William J. Stewart, Patrick Whitlow,Peter Block, Randy Martin, John Merlino,Howard C. Herrmann, Susan E. Wiegers,Frank E. Silvestry, Andrew Hamilton, Alan Zunamon,Kimberly Kraybill, Ivor L. Gerber, Sarah G. Weeks,Yan Zhang, and Ted Feldman

Valve Structure and Survival in QuinquagenariansHaving Aortic Valve Replacement for Aortic Stenosis(�Aortic Regurgitation) With Versus WithoutCoronary Artery Bypass Grafting at a Single USMedical Center (1993 to 2005) ......................1584William Clifford Roberts, Jong Mi Ko, Giovanni Filardo,Albert Carl Henry, Robert Frederick Hebeler, Jr,Edson Hoi-Kam Cheung, Gregory John Matter, andBaron Lloyd Hamman

CardiomyopathyDepression, Anxiety, and Quality of Life in PatientsWith Obstructive Hypertrophic CardiomyopathyThree Months After Alcohol Septal Ablation ....1592Eva R. Serber, Samuel F. Sears, Christopher D. Nielsen,William H. Spencer III, and Karen M. Smith

MiscellaneousPrevalence of an Increased Ascending andDescending Thoracic Aorta Diameter Diagnosed byMultislice Cardiac Computed Tomography in MenVersus Women and in Persons Aged 23 to 50Years, 51 to 65 Years, 66 to 80 Years, and 81 to88 Years ......................................................1598Sarah Kaplan, Wilbert S. Aronow, Hoang Lai,Albert J. DeLuca, Melvin B. Weiss, Hajir Dilmanian,David Spielvogel, Steven L. Lansman, andRobert N. Belkin

Responsiveness to Dobutamine Stimulation inPatients With Left Ventricular Apical BallooningSyndrome .....................................................1600Satomi Fujiwara, Yasuchika Takeishi, Shogen Isoyama,Go Aono, Kaname Takizawa, Hidehiko Honda,Tatsushi Otomo, Mikio Mitsuoka, Yuko Itoh,Masayoshi Terashima, Isao Kubota, andTaiichiro Meguro

Readers’ CommentsThe Corrected Values for Duration and Frequency ofAngina at Baseline in the Clinical OutcomesUtilizing Revascularization and Aggressive DrugEvaluation Trial ............................................1604

Correction ....................................................1604

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CONTENTS A5

EDITOR IN CHIEF

William C. Roberts, MDBaylor Heart & Vascular InstituteBaylor University Medical CenterWadley Tower No. 4573600 Gaston AvenueDallas, Texas 75246(214)826-8252Fax: (214)826-2855

ASSOCIATE EDITORS

Paul A. GrayburnClyde W. YancyASSISTANT EDITORSVincent E. FriedewaldRobert C. KowalJeffrey M. SchusslerCarlos E. Velasco

EDITORIAL BOARDCARDIOVASCULARMEDICINEIn AdultsAntonio AbbateJ. Dawn AbbottGeorge S. AbelaJonathan AbramsJoseph S. AlpertMartin A. AlpertEzra A. AmsterdamJeffrey L. AndersonRichard W. AsingerPablo AvanzasGary John BaladyThomas M. BashoreEric BatesJeroen J. BaxGeorge A. BellerWilliam E. BodenMonty M. BodenheimerRobert O. BonowJeffrey S. BorerHarisios BoudoulasMartial G. BourassaEugene BraunwaldJeffrey A. BrinkerDavid L. BrownAlfred E. BuxtonMichael E. CainRichard O. Cannon IIIBernard R. ChaitmanKanu ChatterjeeJohn S. ChildRobert J. CodyLawrence S. CohenMarc CohenC. Richard ContiMichael H. CrawfordGregory J. DehmerEfthymios N. DeliargyrisJames A. de LemosAnthony N. DeMariaPablo DenesGeorge A. DiamondJohn P. DiMarcoMichael J. DomanskiGerald DorrosUri ElkayamKenneth A. EllenbogenMyrvin H. EllestadStephen G. EllisToby R. EngelAndrew E. Epstein

N. A. Mark Estes, IIIMichael EzekowitzRodney H. FalkJohn A. FarmerDavid P. FaxonTed FeldmanJack FerlinzJerome L. FlegGerald F. FletcherJames S. ForresterJoseph A. FranciosaGary S. FrancisW. Bruce FyeWilliam H. GaaschWilliam GanzJulius M. GardinBernard J. GershMihai GheorghiadeRaymond GibbonsD. Luke GlancyStephen P. GlasserMichael R. GoldSamuel Z. GoldhaberRobert E. GoldsteinSidney GoldsteinSteven A. GoldsteinJ. Anthony GomesAntonio M. Gotto, Jr.K. Lance GouldDonald C. HarrisonRichard H. HelfantPhilip D. HenryL. David HillisDavid R. Holmes, Jr.Mun K. HongYuling HongWilliam G. HundleyAmi S. IskandrianAllan S. JaffeJoel S. KarlinerJohn A. KastorSanjiv KaulKenneth M. KentRichard E. KerberDean J. KereiakesMorton J. KernSpencer B. King IIIRobert E. KleigerGeorge J. KleinLloyd W. KleinPaul KligfieldRobert A. KlonerJohn B. KostisCharles Landau

Richard L. LangeCarl J. LavieCarl V. LeierJoseph Lindsay, Jr.Gregory Y.H. LipJoseph LoscalzoG.B. John ManciniFrancis E. MarchlinskiFrank I. MarcusBarry J. MaronRandolph P. MartinAttilo MaseriDean T. MasonCharles MaynardMichael D. McGoonDarren K. McGuireRaymond G. McKayJawahar L. MehtaRichard S. MeltzerFranz H. MesserliEric L. MichelsonRichard V. MilaniAlan B. MillerWayne L. MillerGary S. MintzFred MoradyArthur J. MossJames E. MullerRobert J. MyerburgGerald B. NaccarelliNavin C. NandaChristopher O’ConnorRobert A. O’RourkeErik Magnus OhmanAntonio PacificoRichard L. PageSebastian T. PalmeriEugene R. PassamaniAlan S. PearlmanCarl J. PepineJoseph K. PerloffBertram PittDon PoldermansPhilip J. PodridArshed A. QuyyumiCharles E. RackleyC. Venkata RamNathaniel ReichekRobert RobertsWilliam J. RogersMaurice E. SaranoMelvin M. ScheinmanDavid J. SchneiderJohn S. Schroeder

Pravin M. ShahPrediman K. ShahJamshid ShiraniRobert J. SiegelMarc A. SilverMark E. SilvermanRoss J. Simpson, Jr.Steven N. SinghSidney C. Smith, Jr.Burton E. SobelJohn C. SombergDavid H. SpodickLynne W. StevensonJohn R. StrattonJonathan M. TobisEric J. TopolTeresa S. M. TsangByron F. VandenbergHector O. VenturaGeorge W. VetrovecRobert A. VogelRon WaksmanDavid D. WatersNanette K. WengerRobert WilenskyJames T. WillersonBarry L. ZaretDouglas P. ZipesIn Infants and ChildrenHugh D. AllenBruce S. AlpertStanley J. GoldbergWarren G. GuntherothHoward P. GutgesellJohn D. KuglerJames E. LockJohn W. MooreLowell W. PerryDavid J. SahnRichard M. SchiekenCARDIOVASCULAR SURGERYEugene H. BlackstoneLawrence I. BonchekLawrence H. CohnJohn A. ElefteriadesThomas L. SprayRELATED SPECIALISTSL. Maximilian BujaMichael EmmettBarry A. FranklinCharles B. HigginsJeffrey E. SaffitzRenu Virmani

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Prevalence of Low High-Density Lipoprotein Cholesterol in Patients WithDocumented Coronary Heart Disease or Risk Equivalent and

Controlled Low-Density Lipoprotein CholesterolAlawi A. Alsheikh-Ali, MDa, Jen-Liang Lin, MDb, Paul Abourjaily, PharmDb, Dineli Ahearn, MDb,

Jeffrey T. Kuvin, MDa, and Richard H. Karas, MD, PhDa,*

Current guidelines identify low-density lipoprotein (LDL) cholesterol as the primary target forcardiovascular prevention but also recognize low high-density lipoprotein (HDL) cholesterol asan important secondary target. This study was conducted to determine the prevalence of lowHDL cholesterol in a contemporary ambulatory high-risk population across various LDLcholesterol levels, including patients taking statins. Screening of 44,052 electronic medicalrecords from a primary care practice identified 1,512 high-risk patients with documentedcoronary heart disease (CHD) or CHD risk equivalents. Low HDL cholesterol (<40 mg/dl inmen, <50 mg/dl in women) was present in 66% of the 1,512 patients. Low HDL cholesterol wasprevalent across all LDL cholesterol levels but most prevalent in patients with LDL cholesterol<70 mg/dl (79% vs 66% in those with LDL cholesterol 71 to 100 mg/dl and 64% in patients withLDL cholesterol >100 mg/dl, p <0.01). Low HDL cholesterol was equally and highly prevalent inpatients taking statins (67%) and those not taking statins (64%) (p � NS). HDL cholesterol andLDL cholesterol levels correlated poorly (R2 � 0.01), and this was unaffected by gender or statintreatment. In conclusion, in high-risk patients with CHD or CHD risk equivalents, low HDLcholesterol levels remain prevalent despite statin treatment and the achievement of aggressive LDL
cholesterol goals. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:1499–1501)
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n part on the basis of the recent update to the Nationalholesterol Education Program Adult Treatment Panel III,

n which low-density lipoprotein (LDL) cholesterol lower-ng targets were made more aggressive, there is currentlyn intense focus on aggressive interventions to lower LDLholesterol.1 Given that the medical therapy used to achievehese targets may also increase high-density lipoproteinHDL) cholesterol, the prevalence of low HDL cholesteroln a contemporary population including statin-treated pa-ients with low LDL cholesterol levels is unknown. This isn important and clinically relevant issue because it identi-es the proportion of patients who have already achieved

heir LDL cholesterol goals but are still in need of additionalherapy to increase their HDL cholesterol levels. This isarticularly relevant given the relatively high rate of car-iovascular events observed in patients despite aggressivetatin treatment and the ongoing Atherothrombosis Inter-ention in Metabolic Syndrome With Low HDL/High Tri-lycerides and Impact on Global Health Outcomes (AIM-IGH) study, which is exploring the benefits of increasing

ow HDL cholesterol levels in addition to statin therapy inatients with established cardiovascular disease.2 Hence, inhe present analysis, we sought to determine the prevalencef low HDL cholesterol in a contemporary ambulatory high-isk population across various levels of LDL cholesterol ando determine whether this is affected by statin therapy.

aDivision of Cardiology and Molecular Cardiology Research Institutend bDivision of General Internal Medicine, Department of Medicine,ufts-New England Medical Center and Tufts University School of Med-

cine, Boston, Massachusetts. Manuscript received April 19, 2007; revisedanuscript received and accepted June 14, 2007.

*Corresponding author: Tel: 617-636-8776; fax: 617-636-1444.
CE-mail address: [email protected] (R.H. Karas).
002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2007.06.058

ethods and Results

e used electronic medical records from a large primaryare practice affiliated with an academic tertiary care hos-ital, with 27 primary care physicians, 7 nurse practitioners,nd �55,000 outpatient visits per year. Through a comput-rized search, we screened 44,502 medical records to iden-ify high-risk patients, defined as having documented coro-ary heart disease (CHD) or CHD risk equivalents. Patientsere noted as having CHD if they had 1 of the following:HD by coronary angiography, history of myocardial in-

arction, myocardial ischemia on perfusion imaging, angina,r coronary artery bypass graft surgery. Patients were noteds having CHD risk equivalents if they had 1 of the follow-ng: diabetes mellitus, peripheral vascular disease, abdom-nal aortic aneurysm, or carotid artery disease complicatedy a stroke or a transient ischemic attack.

Only patients with a complete lipid profiles in the 12onths preceding the analysis were included. In patientsith multiple lipid profiles during that period, the most

ecent profile was used. For the purposes of this analysis,nd based on current national guidelines, low HDL choles-erol was defined as �40 mg/dl in men and �50 mg/dl inomen.1,3 The use of lipid-altering medications was noted.he primary analysis focused on determining the prevalencef low HDL cholesterol across LDL cholesterol levels andy statin use. Accordingly, we compared the prevalence ofow HDL cholesterol across the following categories ofDL cholesterol levels: LDL cholesterol �70, 71 to 100,nd �100 mg/dl, as well as by statin use. Additionally,nivariate linear regression was used to assess the relationetween LDL cholesterol and HDL cholesterol in the entireohort, as well as separately by statin use and gender.
omparison across the groups was made using the chi-
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quare test, and statistical significance was set at a 2-sidedvalue �0.05. The computerized medical record search andresent analysis were approved by the institutional reviewoard at Tufts-New England Medical Center.

Our search identified 1,512 high-risk patients, of whom35 had documented CHD and 877 had CHD risk equiva-ents. Most patients (66%) had low HDL cholesterol. Asisted in Table 1, compared with patients with optimal HDLholesterol values, those with low HDL cholesterol wereounger, more likely to be women, and more likely to haveiabetes mellitus or hypertension. Low HDL cholesterolas prevalent across all levels of LDL cholesterol, butost prevalent in patients with LDL cholesterol �70 mg/dl

79% vs 66% in those with LDL cholesterol 71 to 100g/dl and 64% in patients with LDL cholesterol �100g/dl, p �0.01; Figure 1). The prevalence of low HDL

igure 1. Prevalence of low HDL cholesterol (HDL-C) levels across LDLholesterol (LDL-C) levels.

able 1haracteristics of patients with optimal high-density lipoprotein cholester

ariable All Patients(n � 1,512)

ge (yrs) 63 � 12en 54%iagnosisCoronary artery disease 42%Coronary artery bypass grafting 8%Diabetes mellitus 71%Hypertension 71%Peripheral vascular disease§ 6%otal cholesterol (mg/dl) 177 � 40DL cholesterol (mg/dl) 108 � 34DL cholesterol (mg/dl) 42 � 13riglycerides (mg/dl) 138 � 87tatin use 65%uration of statin therapy (mo) 19 � 12iacin use 4.2%uration of niacin therapy (mo) 15 � 10ibrate use 4%uration of fibrate therapy (mo) 21 � 14

Continuous variables are presented as mean � SD.* p �0.05 for optimal HDL cholesterol versus low HDL cholesterol.† Defined as �40 mg/dl in men and �50 mg/dl in women.‡ Defined as �40 mg/dl in men and �50 mg/dl in women.§ Peripheral vascular disease also included abdominal aortic aneurysm (

r transient ischemic attack (documented in 1% of patients).

holesterol across all levels of LDL cholesterol was true in w

en and women (Figure 2). As expected, statin use wasore common in patients with lower LDL cholesterol levels

69% in patients with LDL cholesterol �70 mg/dl and 75%n patients with LDL cholesterol 71 to 100 mg/dl) comparedith patients with higher LDL cholesterol levels (57% inatients with LDL cholesterol �100 mg/dl) (p �0.01). Theigh prevalence of low HDL cholesterol was seen in pa-ients taking statins (67%) as well as those not taking statins64%) (p � NS). There was a poor correlation betweenDL cholesterol and LDL cholesterol levels (R2 � 0.01;igure 3), demonstrating that �1% of the variability inDL cholesterol could be explained by variability in LDL

holesterol. This poor correlation between the 2 markersas apparent in both genders and whether or not patients

igure 2. Prevalence of low HDL cholesterol (HDL-C) levels across LDLholesterol (LDL-C) levels in men and women.

ared with those with low high-density lipoprotein cholesterol

Optimal HDL Cholesterol†

(n � 513)Low HDL Cholesterol‡

(n � 999)

64 � 12 62 � 12*60% 52%*

42% 42%7% 8%

66% 74%*68% 73%*6% 6%

174 � 39 178 � 41110 � 32 106 � 34

54 � 12 35 � 7*138 � 87 138 � 87

63% 66%19 � 11 19 � 12

4.9% 3.5%17 � 10 14 � 9

5% 4%20 � 13 21 � 11

ented in 1% of patients) and carotid artery disease complicated by stroke

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1501Coronary Artery Disease/HDL-C in Patients With Controlled LDL-C

When low HDL cholesterol was defined as �40 mg/dl inoth genders (as opposed to �40 mg/dl in men and �50 mg/dln women), 51% of patients had low HDL cholesterol. LowDL cholesterol was equally prevalent in statin users andonusers (51% in each group) and was prevalent across allDL cholesterol levels but most prevalent in patients withDL cholesterol �70 mg/dl (64% vs 51% in those with LDLholesterol 71 to 100 mg/dl and 48% in patients with LDLholesterol �100 mg/dl, p �0.01).

The use of niacin or fibrates was rare (�5%) and was notifferent in patients with low HDL cholesterol compared withhose with optimal HDL cholesterol levels. In niacin users, allatients were taking the extended-release formulation of niacint a mean dose of 907 mg/day, with 41% of patients taking �1/day of extended-release niacin. The proportion of patientsith optimal HDL cholesterol was similar in niacin users andonusers (40% vs 34%, p � NS). Likewise, the proportion ofatients with optimal HDL cholesterol was similar in fibratesers and nonusers (35% vs 34%, p � NS).

iscussion

n the present analysis of a large contemporary high-riskopulation, we make 3 observations. First, despite statinreatment and with aggressively controlled LDL cholesterol,ost of these high-risk patients had low HDL cholesterol

evels. Second, there was essentially no relation betweenDL cholesterol and LDL cholesterol, highlighting the in-ependent nature of these 2 lipid targets. Third, present-daytrategies to increase HDL cholesterol are underused.

The present findings are consistent with previous obser-ations of prevalent low HDL cholesterol in high-risk pa-ients.4,5 However, these previous observations predate theidespread use of statins and the adoption of aggressiveDL cholesterol goals. The present analysis expands on

hese earlier studies by demonstrating a similar pattern ofrevalence of low HDL cholesterol and undertreatmentven in high-risk patients, including those with CHD riskquivalents but no documented CHD, as well as patients

igure 3. Relation between HDL cholesterol (HDL-C) and LDL cholesterolLDL-C) levels in high-risk patients with CHD or CHD risk equivalents.

aking statins and those with aggressively controlled LDL

holesterol levels. It is well appreciated that despite theirajor impact on cardiovascular prevention, the relative risk

eduction with statin monotherapy is typically in the rangef 25% to 35%, indicating that most cardiac events continueo occur.6 Interestingly, the notion that a significant numberf major adverse cardiac events are not prevented withtatins alone appears to hold true even with aggressive LDLholesterol lowering.6,7 Given the observed prevalence ofow HDL cholesterol in statin-treated patients and thoseith well-controlled LDL cholesterol in this analysis, it is

onceivable that the gap in cardiovascular prevention withtatin monotherapy could be bridged with strategies to in-rease HDL cholesterol. Furthermore, the lack of a mean-ngful relation between HDL cholesterol and LDL choles-erol in our population is consistent with the epidemiologicbservation that the prognostic significance of HDL choles-erol on cardiovascular outcomes is independent of totalholesterol or LDL cholesterol levels.8

Several limitations to the present analysis are worth noting.he findings represent the practice and patient characteristicsf a single center and may not reflect national trends. More-ver, because we included only patients who had completeipid panels measured, it is likely that the prevalence of lowDL cholesterol reported here is an underestimate, becauseatients who do not have lipid panels measured are more likelyo remain untreated. Furthermore, the analysis is limited byack of data on other variables that may affect HDL cholesterolevels, such as body mass index, obesity, and tobacco use.inally, our reliance on a single lipid profile does not factor inubsequent treatment decisions by providers.

. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunning-hake DB, Pasternak RC, Smith SC Jr, Stone NJ. Implications of recentclinical trials for the National Cholesterol Education Program AdultTreatment Panel III guidelines. Circulation 2004;110:227–239.

. ClinicalTrials.gov. Niacin Plus Statin to Prevent Vascular Events. Available at:http://clinicaltrials-nccs.nlm.nih.gov/ct/show/NCT00120289?order�1.Accessed June 13, 2007.

. Mosca L, Banka CL, Benjamin EJ, Berra K, Bushnell C, Dolor RJ,Ganiats TG, Gomes AS, Gornik HL, Gracia C, et al. Evidence-basedguidelines for cardiovascular disease prevention in women: 2007 up-date. Circulation 2007;115:1481–1501.

. Genest J Jr, McNamara JR, Ordovas JM, Jenner JL, Silberman SR, Ander-son KM, Wilson PW, Salem DN, Schaefer EJ. Lipoprotein cholesterol,apolipoprotein A-I and B and lipoprotein (a) abnormalities in men withpremature coronary artery disease. J Am Coll Cardiol 1992;19:792–802.

. Mosca L, Merz NB, Blumenthal RS, Cziraky MJ, Fabunmi RP, SarawateC, Watson KE, Willey VJ, Stanek EJ. Opportunity for intervention toachieve American Heart Association guidelines for optimal lipid levels inhigh-risk women in a managed care setting. Circulation 2005;111:488–493.

. Alsheikh-Ali AA, Kuvin JT, Karas RH. High-density lipoprotein cho-lesterol in the cardiovascular equation: does the “good” still count?Atherosclerosis 2005;180:217–223.

. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, BelderR, Joyal SV, Hill KA, Pfeffer MA, Skene AM. Intenive versus moderatelipid lowering with statins after acute coronary syndromes. N EnglJ Med 2004;350:1495–1504.

. Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, KnokeJD, Jacobs DR Jr, Bangdiwala S, Tyroler HA. High-density lipoproteincholesterol and cardiovascular disease. Four prospective American
studies. Circulation 1989;79:8–15.
http://clinicaltrials-nccs.nlm.nih.gov/ct/show/NCT00120289?order=1

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Comparison of Two- Versus Three-Dimensional MyocardialContrast Echocardiography for Assessing Subendocardial PerfusionAbnormality After Percutaneous Coronary Intervention in Patients

With Acute Myocardial Infarction

Katsuomi Iwakura, MD*, Hiroshi Ito, MD, Atsushi Okamura, MD, Toshiya Kurotobi, MD,Yasushi Koyama, MD, Motoo Date, MD, Koichi Inoue, MD, Hiroyuki Nagai, MD,

Michio Imai, MD, Yo Arita, MD, Yuko Toyoshima, MD, Makito Ozawa, MD, and Kenshi Fujii, MD

Myocardial contrast echocardiography (MCE) visualizes myocardial perfusion abnormal-ities after acute myocardial infarction. However, the limited view of 2-dimensional echo-cardiography reduces its ability to estimate perfusion abnormalities, especially in thesubendocardial region. Three-dimensional echocardiography provides images of the leftventricular endocardium directly. This study was conducted to evaluate the ability of3-dimensional MCE to assess abnormalities of subendocardial perfusion. Intracoronary 2-and 3-dimensional MCE was performed after primary percutaneous coronary interventionin 47 patients with acute myocardial infarction. Myocardial perfusion within the risk areawas evaluated as good, poor, or no reflow on 2-dimensional MCE or as good, poor, or nomyocardial opacification in endocardium on 3-dimensional MCE. The 2 methods showeddifferent distributions of perfusion patterns: good, poor, and no reflow on 2-dimensionalMCE in 31 (66%), 9 (19%), and 7 (15%) patients and good, poor, and no myocardialopacification in endocardium on 3-dimensional MCE in 17 (36%), 16 (34%), and 14 (20%)patients, respectively. Although only 19 patients (61%) with good reflow on 2-dimensionalMCE showed myocardial perfusion grade 3 on angiography, 16 of 17 patients (94%) withgood myocardial opacification in endocardium on 3-dimensional MCE showed myocardialperfusion grade 3. Although there were no significant differences in peak creatine kinaseamong the 3 subsets classified by 2-dimensional MCE, peak creatine kinase showedsignificant differences not only among the 3 groups but also among the subsets classified by3-dimensional MCE. Classification by 3-dimensional MCE also predicted regional wallmotion after 4.6 � 2.7 months, with significant differences between each pair of groups,whereas there was significant overlap of these values between the group with poor reflowand other 2 groups by 2-dimensional MCE. In conclusion, 3-dimensional MCE is a feasibleway to assess subendocardial perfusion and predicts infarct size and functional recoverymore precisely than 2-dimensional MCE. © 2007 Elsevier Inc. All rights reserved. (Am J
Cardiol 2007;100:1502–1510)
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eal-time 3-dimensional echocardiography visualizes thentire left ventricle. It provides superior assessment of ab-ormalities in regional wall motion compared with 2-di-ensional echocardiography.1,2 It also visualizes endocar-

ial surface structure within a beating heart.3 The aims ofhis study were to test the ability of intracoronary 3-dimen-ional myocardial contrast echocardiography (MCE) in as-essing subendocardial myocardial perfusion after primaryercutaneous coronary intervention in patients with acuteyocardial infarction (AMIs) and to compare its perfusion

atterns with those obtained using 2-dimensional MCE. We

Division of Cardiology, Sakurabashi Watanabe Hospital, Osaka, Japan.anuscript received March 24, 2007; revised manuscript received and

ccepted June 17, 2007.*Corresponding author: Tel: 81-6-6341-8651; fax: 81-6-6341-0785.

cE-mail address: [email protected] (K. Iwakura).


lso compared the ability of these 2 modalities to predictunctional recovery.

ethodsStudy population: From October 2004 to December

005, 68 consecutive patients with ST-elevation AMIs un-erwent primary percutaneous coronary intervention in oc-luded coronary arteries �24 hours after symptom onsetnd subsequently underwent intracoronary 2- and 3-dimen-ional myocardial contrast echocardiographic studies. Theiagnosis of ST-elevation AMI was based on chest pain for30 minutes, ST-segment elevation of �2 mm in �2 con-

iguous electrocardiographic leads, and an increase of �3imes in serum creatine kinase (CK) levels. Seven patientsere excluded because of poor echocardiographic images,

ncluding 2 patients for whom 2-dimensional MCE wasdequate but 3-dimensional MCE was suboptimal for visu-lization of the subendocardial surface, even after image
ropping. Also, 14 patients who did not undergo follow-up
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1503Coronary Artery Disease/Three-Dimensional MCE in AMI

eft ventriculographic studies were excluded. Therefore, thenal study population consisted of 47 patients. The studyrotocol was approved by the hospital’s ethics committee.nformed consent was obtained from each patient beforeardiac catheterization.

Study protocol: After admission, 12-lead electrocardio-rams were recorded, and echocardiography was performedith a SONOS 7500 (Philips Medical Systems, Andover,assachusetts). We spent �10 minutes recording the echo-

ardiograms. After the administration of aspirin (243 mg)nd intravenous heparin (100 U/kg), we performed coronaryngiography using the right femoral approach. Then weerformed primary percutaneous coronary intervention toeduce the residual diameter stenosis by 50%. After thenterventional procedure, we assessed the myocardial per-usion grade on coronary angiography such that the super-mposition of noninfarcted territories was minimal.4 Weepeatedly recorded 12-lead electrocardiograms during andfter each interventional procedure to determine the pres-nce or absence of additional ST-segment elevation.5

Approximately 15 minutes after the last interventionalrocedure, we performed 2-dimensional MCE with theONOS 7500 using an S4 transducer, as previously re-orted.5,6 In brief, we injected 2 ml of sonicated ioxaglateHexabrix-320; Tanabe Corporation, Osaka, Japan) contain-ng microbubbles (mean size 12 �m) into the right coronaryrtery in patients with inferior wall infarctions and the leftoronary artery in those with anterior or posterior wallnfarctions. We recorded 2-dimensional echocardiogramsrom the apical 2- and 4-chamber views. Then we per-ormed real-time 3-dimensional MCE using the Live 3Dystem. We observed 3-dimensional images from the apical- or 4-chamber view with an X4 matrix array transducerPhilips Medical Systems) in second harmonic mode. Careas taken to clearly observe the endocardial surface by

djusting time-gain compensation and lateral gain controlhen possible. Then we again injected microbubbles into

he culprit coronary artery and recorded a myocardial con-rast echocardiographic image for 20 heart beats. All myo-ardial contrast echocardiographic images were digitallytored on CD-ROMs for further analysis.

We performed left ventriculography in 42 patients (89%)nd measured left ventricular end-diastolic and end-systolicolume indexes (in milliliters per square meter) along withjection fraction using the biapical Simpson’s rule.egional wall motion (SD/chord) within the culprit artery

erritory was analyzed using the centerline method. Fol-ow-up coronary angiography and ventriculography wereerformed in all patients 4.6 � 2.7 months later.

Analysis of echocardiographic data: An experiencedchocardiographer blinded to clinical, angiographic, and-dimensional myocardial contrast echocardiographic datanalyzed 2-dimensional myocardial contrast echocardio-raphic images to determine myocardial perfusion withinhe risk area. The risk area was defined as myocardialegments showing dyskinesia, akinesia, or severe hypoki-esia on the initial echocardiogram. To assess the risk area
nd myocardial perfusion, we used the apical long-axis view e
r apical 4-chamber view for patients with anterior andosterior wall infarctions, whereas the apical 2-chamberiew was used for patients with inferior wall infarctions. Wepplied the echocardiographic view that showed the greatestxtent of abnormality of wall motion. We divided the leftentricular wall into myocardial segments on the basis ofhe 16-segment model endorsed by the American Societyf Echocardiography7 and scored myocardial opacifica-ion in each segment as 1 (homogenous opacification),.5 (patchy opacification or opacification only in epicar-ium), or 0 (no opacification).8 The average contrastcore was calculated by dividing the sum of contrast scoresn segments within the risk area by the number of these seg-ents. Myocardial perfusion in each patient was graded as

ood (average score � 1), poor (0.5 � score � 1.0), and noscore � 0.5) reflow.

A sonographer blinded to clinical, angiographic, and-dimensional myocardial contrast echocardiographic datassessed the subendocardial contrast opacification of end-ystolic 3-dimensional myocardial contrast echocardio-raphic images. To assess the risk area and myocardialerfusion, we used the echocardiographic windows to in-lude the whole risk area within 3-dimensional echocardio-raphic images when possible. We observed myocardialpacification from the left ventricular cavity side. “Shade”ode was activated to reduce the interference of opacifica-

ion from the epicardial layers. If the endocardial surfaceas not clearly visible from the original view of the 3-di-ensional image, the image was cropped through the plane

et along the endocardium to obtain a clear image of thendocardial surface (Figure 1). Risk area was defined as ayocardial zone showing no contraction of endocardial

urface. We cropped the image carefully so that thebtained image included the whole risk area. We dividedhe entire left ventricle into myocardial segments corre-ponding to the 16-segment model on 2-dimensional

igure 1. Cropping of 3-dimensional myocardial contrast echocardio-raphic image. Left, the upper figure shows the side view of the pyramidal-dimensional image. When the endocardial surface was not clearly ob-erved from surface of the original 3-dimensional image, the image wasropped through a plane set along the endocardium (the “cropping” plane).ight, a 3-dimensional myocardial contrast echocardiographic imageropped to show the endocardial surface.

chocardiograms9 and scored endocardial opacification

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ithin each segment as 1 (enhancement as good as thatithin a nearby normal segment), 0.5 (enhancement was

igure 2. Two- and 3-dimensional myocardial contrast echocardiograms ofmage obtained for a patient with an inferior wall infarction, showingchocardiogram before the injection of microbubbles, cropped to reveal then the endocardial surface within the risk area (between the arrows) as go

igure 3. Two- and 3-dimensional myocardial contrast echocardiogram ofmage obtained for a patient with a posterior wall infarction, showingchocardiogram before the injection of microbubbles. (C) Three-dimensioisk area (between the arrows), whereas good contrast enhancement was o

bserved but not as strong as that within the normal area), a

r 0 (no clear enhancement). We calculated the averagendocardial contrast score in the segments within the risk

nt with AMI. (A) A 2-dimensional myocardial contrast echocardiographiceflow within the risk area (between the arrows). (B) A 3-dimensionalardial surface. (C) Three-dimensional MCE showed contrast enhancementn the nearby normal myocardium (good MOE).

nt with AMI. (A) A 2-dimensional myocardial contrast echocardiographiceflow within the risk area (between the arrows). (B) A 3-dimensionalE showed no contrast enhancement on the endocardial surface within thed in the nearby normal myocardium (no MOE).

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Table 1Clinical parameters in the study patients

2-dimensional MCE 3-dimensional MCE

Good Reflow Poor Reflow No Reflow p Value Good MOE Poor MOE No MOE p Value

No. of patients 31 9 7 17 16 14Age (yrs) 62 � 11 60 � 10 55 � 11 0.30 63 � 12 63 � 9 55 � 10 0.08Men/women 24/7 9/0 5/2 0.25 15/2 13/3 10/4 0.50Peak creatine kinase (IU/L) 1,977 (892–4,205) 3,906 (802–5,094) 5,553 (2,059–8,175) 0.06 931 (338–1,888) 2,257 (1,282–4,230) 6,082 (3,447–7,265) �0.0001Peak CK-MB (IU/L) 118 (67–323) 291 (87–414) 317 (224–537) 0.12 90 (24–119) 239 (87–326) 383 � 144 �0.0001Risk factors

Diabetes mellitus 12 (39%) 4 (44%) 3 (43%) 0.94 6 (35%) 7 (44%) 6 (43%) 0.86Hypertension 19 (61%) 5 (56%) 5 (71%) 0.81 10 (59%) 11 (69%) 8 (57%) 0.77Hyperlipidemia 16 (52%) 6 (67%) 2 (29%) 0.32 12 (71%) 5 (31%) 7 (50%) 0.08Smoking 22 (71%) 8 (89%) 6 (86%) 0.44 12 (71%) 12 (75%) 12 (86%) 0.60Onset to reperfusion time (h) 8.3 (3.2–19.4) 7.0 (2.9–18.9) 3.5 (2.7–7.6) 0.52 4.9 (3.3–17.1) 9.3 (3.9–15.9) 3.9 (2.6–8.5) 0.46Stent implantation 29 (93%) 9 (100%) 5 (71%) 0.10 16 (94%) 15 (94%) 12 (86%) 0.65Thrombectomy 21 (68%) 7 (78%) 6 (86%) 0.58 12 (71%) 11 (69%) 11 (79%) 0.82Anterior wall infarction 17 (55%) 6 (67%) 5 (71%) 0.64 11 (65%) 7 (44%) 10 (71%) 0.26Multivessel disease 8 (26%) 3 (33%) 1 (14%) 0.68 4 (24%) 5 (31%) 3 (21%) 0.80Additional ST elevation 11 (36%) 1 (11%) 5 (71%) 0.04 2 (12%) 7 (44%) 8 (57%) 0.02

Medication after infarctionAngiotensin-converting enzyme inhibitor/

angiotensin receptor blocker28 (90%) 9 (100%) 7 (100%) 0.44 16 (94%) 14 (88%) 14 (100%) 0.37

� blocker 13 (42%) 6 (67%) 4 (57%) 0.38 6 (35%) 8 (50%) 9 (64%) 0.27

Peak CK-MB and onset to reperfusion time are expressed as median and IQR (25th to 75th percentile). Other values are expressed as mean � SD or as numbers and percentages of patients. The p valuesfor the differences among the 3 subsets were determined using analysis of variance.

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as graded as good (average score � 1), poor (0.5 �core � 1.0), or no (score �0.5) MOE.

Statistical analysis: All continuous variables were com-ared using 1-way analysis of variance and are expressed asean � SD, except peak CK, CK-MB, and elapsed time to

eperfusion, which were compared using the Kruskal-Wallisest, because of nonparametric distribution, and are ex-ressed as medians and interquartile ranges (IQRs; 25th and5th percentiles). The significance of differences was cal-ulated using Tukey’s honestly significantly different testor factor analysis. Categorical variables were comparedsing Fisher’s exact test. Changes in regional wall motionetween initial and follow-up ventriculography among theroups were analyzed using multivariate analysis of vari-nce. Differences were considered significant at p �0.05 (2ided). JMP version 5.0.1 (SAS Institute Inc., Cary, Northarolina) was used for statistical analysis.

esultsPatient characteristics: The mean age of the study pa-

ients was 61 � 11 years (range 40 to 81), and 38 patients81%) were men. The culprit artery was the left anteriorescending coronary artery in 28 patients, the left circum-ex coronary artery in 6 patients, and the right coronaryrtery in 13 patients. Multivessel disease was observed in 12atients. The median of the elapsed time from symptomnset to coronary reperfusion was 7.2 hours (IQR 2.9 to6.1). The median values of peak CK and CK-MB levelere 2,228 IU/L (IQR 931 to 5,094) and 208 IU/L (IQR 84

o 364), respectively. Twenty-four patients (51%) had hy-ercholesterolemia, which was considered present if it wasreviously diagnosed or total cholesterol on admission was220 mg/dl.10 Nineteen patients (40%) had diabetes mel-

itus, 29 patients (62%) had hypertension, and 36 patients77%) were current smokers. Two patients had histories ofMIs in areas other than the present infarct territory. Stentsere implanted in the culprit lesions in 43 patients (92%),

nd thrombectomy was performed before angioplasty ortenting in 34 patients (72%). Thrombolysis In Myocardialnfarction (TIMI) flow grade 3 was obtained in 40 patients85%). Angiotensin-converting enzyme inhibitors or angio-ensin receptor blockers were administered in 44 patients94%) after infarction and � blockers in 23 patients (49%).

Assessment of endocardial perfusion with 3-dimen-ional MCE: Figure 2 shows 2- and 3-dimensional myo-ardial contrast echocardiographic images of a patient withn inferior wall infarction. After coronary reperfusion, 2-di-ensional MCE showed good reflow within the risk area.hree-dimensional MCE showed distinct contrast enhance-ent within the risk area, and we judged this patient as

aving good MOE. The peak CK and CK-MB levels of thisatient were 1,977 and 118 IU/L, respectively. Figure 3hows myocardial contrast echocardiographic images of aatient with a posterior wall infarction. Two-dimensionalCE showed good reflow within the risk area. Three-

imensional MCE showed almost no endocardial contrastnhancement within the risk area (no MOE). The peak CKnd CK-MB levels of this patient were high, 4,758 and 414
U/L, respectively. g
Two-dimensional MCE showed good reflow in 31 of 47tudy patients (66%), poor reflow in 9 patients (19%) and noeflow in 7 patients (15%). The characteristics of the pa-ients in each group are listed in Table 1. The incidence ofnterior wall infarction was greater in the groups with nond poor reflow than in the group with good reflow (p �.01). Additional ST elevation after reperfusion was morerequently observed in the group with no reflow (p � 0.04).here were significant differences in the incidence of mul-

ivessel disease (p � 0.02) and collateral grade (p � 0.03)mong the 3 subsets (Table 1). TIMI flow grade 3 wasbtained in 28 of the patients with good reflow (90%),hereas in 7 of those with poor reflow (78%) and in 5 of

hose with no reflow (71%), no significant difference wasbserved (p � 0.38).

The distribution of 3-dimensional myocardial contrastchocardiographic perfusion categories was different fromhat for 2-dimensional MCE. Good MOE was observed in7 patients (36%), poor MOE in 16 patients (34%) and noOE in 14 patients (30%). TIMI flow grade 3 was obtained

n all patients with good MOE but in only 12 of those withoor MOE (75%) and 11 of those with no MOE (79%) (p �.03). Among the 31 patients with good reflow on 2-dimen-ional MCE, only 14 patients (45%) showed good MOE,nd 4 (13%) showed no MOE. All 7 patients with no reflowhowed no MOE (Table 2). The incidence of additional STlevation was lowest in the patients with good MOE (p �.02). The group with poor MOE had the longest elapsedime to reperfusion (p � 0.04; Table 1).

Among the 31 patients with good reflow, only 19 (61%)howed TIMI myocardial perfusion grade 3 after coronaryntervention, and 6 showed perfusion grade 0 or 1 on cor-nary angiography after the intervention. In contrast, 16 of7 patients (94%) with good MOE showed myocardialerfusion grade 3 (Table 2).

Prediction of infarct size with 2- and 3-dimensionalCE: There were no significant differences in peak CK

nd CK-MB levels among the 3 groups classified with-dimensional MCE (Table 1). In contrast, the group witho MOE on 3-dimensional MCE had the significantly high-st peak CK value, followed by the groups with poor MOEnd good MOE (Table 1). The differences in peak CK wereignificant not only among the 3 groups (p �0.0001) butlso in each pair of 3 groups classified by 3-dimensionalCE (Figure 4). CK-MB also showed significant differ-

nces among the 3 groups (p �0.0001). The patients with

able 2valuation of myocardial perfusion with 2- and 3-dimensionalyocardial contrast echocardiography

-dimensionalCE

3-dimensional MCE

Good MOE Poor MOE No MOE Total

ood reflow 14 13 3 31oor reflow 3 3 3 9o reflow 0 0 7 7otal 17 16 14 47

Data are expressed as numbers of patients.

ood MOE had significantly lower CK-MB than those

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ith poor MOE (p � 0.01) or no MOE (p �0.0001)Figure 4). These results indicate that myocardial perfu-ion grade defined by 3-dimensional MCE reflected dif-erences in infarct size more distinctively than that de-ned by 2-dimensional MCE.

Prediction of left ventricular functional and morpho-ogic outcomes with 2- and 3-dimensional MCE: At base-ine, there was no significant difference in regional wallotion among the 3 groups defined by 2-dimensional MCE

Table 3). The group with good MOE had the best regionalall motion among the 3 groups defined by 3-dimensionalCE at baseline (Table 3). Approximately 4.6 � 2.7

igure 4. Peak CK and CK-MB levels among the groups classified on thelthough there was a significant difference in peak CK between the patienith poor reflow showed no significant differences in peak CK compared

ignificant in each pair among the groups with no, poor, and good MOE onmong the 3 subsets on the basis of 2-dimensional MCE. (D) There was ao MOE and between the subsets with good MOE and poor MOE.

able 3arameters on left ventriculography on admission and 2- and 3-dimension

2-dimensional MCE

Good Reflow Poor Reflow No Re

o. of patients 27 6 9egional wall motion(SD/chord)

�2.59 � 0.88 �2.92 � 0.74 �3.10 �

eft ventricular end-diastolicvolume index (ml/m2)

59.3 � 15.1 63.0 � 7.0 73.9 �

eft ventricular end-systolicvolume index (ml/m2)

30.4 � 10.5 34.7 � 9.2 48.2 �

jection fraction (%) 48.8 � 9.0 47.9 � 10.3 38.0 �

Data are expressed as mean � SD. The p values for the differences am* p �0.05; † p �0.001 versus good reflow or good MOE.

onths later, regional wall motion in the group with no 0

eflow (�2.84 � 0.83) was lower than that of the groupith good reflow (�1.37 � 1.11) (p � 0.004). However,

egional wall motion was not statistically different betweenhe group with poor reflow (�1.73 � 0.71) and the groupsith good or no reflow (Figure 5). In contrast, there were

ignificant differences in regional wall motion in each pairf the 3 groups defined by 3-dimensional MCE (Figure 5).mong the 42 patients in whom initial ventriculographyas performed, the improvement of regional wall motion

rom baseline to follow-up was highest in the group withood MOE, followed by the groups with poor and no MOE1.59 � 0.98 vs 1.19 � 0.71 vs 0.31 � 0.84, respectively, p �

f 2- or 3-dimensional myocardial contrast echocardiographic images. (A)ing no reflow on 2-dimensional MCE and those with good reflow, those

e subsets with good and no reflow. (B) The differences in peak CK werensional MCE. (C) No significant difference was observed in peak CK-MBcant difference in peak CK-MB between the subsets with good MOE and

cardial contrast echocardiography

3-dimensional MCE

p Value Good MOE Poor MOE No MOE p Value

16 13 130.31 �2.28 � 0.91 �3.03 � 0.67* �2.99 � 0.71 0.02

0.31 57.4 � 13.6 56.6 � 13.2 73.7 � 30.1 0.06

0.06 27.5 � 8.7 30.8 � 7.4 44.7 � 25.6* 0.02

0.05 53.9 � 9.4 44.8 � 6.1* 41.0 � 9.1† 0.0006

3 subsets were determined using analysis of variance.

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igure 5. Regional wall motion in the chronic stage among the groups clasmages. (A) On follow-up left ventriculography, patients showing no reflohose with good reflow, although the subsets with poor reflow showed no siifferences in regional wall motion in each pair among the groups with n

igure 6. Left ventricular volume indexes and ejection fractions in theyocardial contrast echocardiographic images. (A) On follow-up left ventr

r end-systolic volume indexes among the groups with no, poor, and good reCE had larger end-diastolic volume indexes than those with good MO

C) Although the subset with good reflow had better ejection fractions than tn the ejection fraction compared with the other 2 subsets. (D) Those withhose with poor or good MOE.

han that assessed with 2-dimensional MCE. f

There were no differences in end-diastolic and in end-ystolic volume indexes among the 3 groups defined by-dimensional MCE at baseline and follow-up (Table 3).he group with no reflow had significantly lower ejection

n the basis of 2- or 3-dimensional myocardial contrast echocardiographicdimensional MCE showed significantly poorer regional wall motion thant differences compared with the 2 other subsets. (B) There were significant, and good MOE on 3-dimensional MCE.

stage among the groups classified on the basis of 2- or 3-dimensionalaphy, there were no significant differences in left ventricular end-diastolic

2-dimensional MCE. (B) The patients showing no MOE on 3-dimensionallarger end-systolic volume indexes than those with good or poor MOE.et with no reflow subset, the subset with poor reflow showed no differencesE on 3-dimensional MCE had significantly poorer ejection fractions than

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t follow-up, the group with good reflow had higher ejec-ion fractions than the group with no reflow, but the ejectionractions of those in the group with poor reflow showedignificant overlap with those of the other 2 subsets (Figure). At baseline, end-diastolic volume indexes were compa-able among the 3 groups defined by 3-dimensional MCE.he group with good MOE had smaller end-systolic volume

ndexes than the group with no MOE and better ejectionractions than the other 2 groups on initial ventriculographyTable 3). At follow-up, the group with no MOE had aarger end-diastolic volume index than the group with good

OE and larger end-systolic volume indexes and poorerjection fractions than the other groups (Figure 6).

iscussion

e successfully visualized subendocardial perfusion afterrimary coronary intervention with intracoronary 3-dimen-ional MCE in patients with AMIs. Myocardial perfusionatterns assessed with 2-dimensional MCE are not neces-arily coincident with those assessed with 3-dimensionalCE; among 31 patients who were judged as having good

eflow with 2-dimensional MCE, only 17 patients (55%)ad good MOE. Classification based on 3-dimensionalCE predicts infarction size and functional outcomes more

recisely than that based on 2-dimensional MCE.Two-dimensional myocardial contrast echocardiographic

tudies have demonstrated that the no-reflow phenomenons associated with the absence of functional recovery inatients with AMIs.6,11,12 However, the presence of micro-ascular integrity does not always go along with functionalecovery in the chronic stage,13 and thus 2-dimensional

CE might overestimate the possibility of functional re-overy.11 The lower frequency of good MOE comparedith that of good reflow (36% vs 66%) might explain theiscordance between microvascular integrity assessed with-dimensional MCE and functional recovery. TIMI perfu-ion grade 3 is reported to be achieved in �30% of patientsith AMIs after primary coronary intervention,4,14 whereas

bout 70% of patients obtain good reflow on 2-dimensionalCE.6,13,15 The present study indicated that 3-dimensionalCE reflects myocardial perfusion grade far better than

-dimensional MCE.The sonicated contrast medium used in the present study

ontains microbubbles of various sizes.6 Large bubblesork as ultrasound scatters rather than reflects to produce

alse signals in the neighboring myocardium. This interfer-nce might make it difficult for 2-dimensional MCE toiscriminate between the contrast intensities of endocar-ium and epicardium.16 Myocardial perfusion in selectedchocardiographic planes of 2-dimensional MCE does notlways reflect that of the entire risk area. If the echocardio-raphic plane does not transect the center of the infarctone, 2-dimensional MCE would show perfusion at thearginal zone, where even hyperemic blood flow would be

resent. The high contrast intensity around the no-MOErea in the 3-dimensional myocardial contrast echocardio-raphic image in Figure 3 would show such hyperemic flown the marginal area.

We used intracoronary injection of microbubbles rather
han intravenous injection. Policy in Japan prohibits the use
f Levovist (Schering AG, Berlin, Germany), the only ul-rasonic contrast agent for intravenous MCE available in ourountry, in patients with AMIs. The intravenous injection ofontrast agent would lead to the filling of left ventricle withicrobubbles, which would inhibit the direct observation of

he endocardium. Still, intracoronary injection limits thelinical usability of 3-dimensional MCE, and further studyn the possibility of using intravenous 3-dimensional MCEs required.

The present 3-dimensional MCE technique has severalimitations. An appropriate “cropping” of the images isequired for the proper assessment of MOE. The contrastignal from the midlayers might somehow contribute toubendocardial opacification because of the limited spatialesolution of 3-dimensional echocardiography and of ablooming” artifact.17 The spatial resolution of 3-dimen-ional images is still inferior to that of 2-dimensional im-ges. In addition, a broader echocardiographic window isequired for 3-dimensional MCE than for 2-dimensional

CE. These disadvantages of 3-dimensional MCE led tohe exclusion of 2 patients from the present study because ofuboptimal 3-dimensional images, and such exclusion mighteaken the superiority of 3-dimensional MCE in the present

tudy. We evaluated perfusion patterns and MOE only visu-lly. Quantitative measures using replenishment curves are aset available only for 2-dimensional MCE.18 Advances inechnology are expected to resolve these limitations.

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2. Collins M, Hsieh A, Ohazama CJ, Ota T, Stetten G, Donovan CL,Kisslo J, Ryan T. Assessment of regional wall motion abnormalitieswith real-time 3-dimensional echocardiography. J Am Soc Echocar-diogr 1999;12:7–14.

3. Inoue K, Ito H, Iwakura K, Kawano S, Okamura A, Kurotobi T, DateM, Otsu K, Hori M, Fujii K. Usefulness of high-resolution real-timethree-dimensional echocardiography to visualize the left ventricularendocardial surface in myocardial infarction. Am J Cardiol 2006;97:1578–1581.

4. Gibson CM, Cannon CP, Murphy SA, Ryan KA, Mesley R, Marble SJ,McCabe CH, Van De Werf F, Braunwald E. Relationship of TIMImyocardial perfusion grade to mortality after administration of throm-bolytic drugs. Circulation 2000;101:125–130.

5. Iwakura K, Ito H, Kawano S, Shintani Y, Yamamoto K, Kato A,Ikushima M, Tanaka K, Kitakaze M, Hori M, et al. Predictive factorsfor development of the no-reflow phenomenon in patients with reper-fused anterior wall acute myocardial infarction. J Am Coll Cardiol2001;38:472–477.

6. Ito H, Tomooka T, Sakai N, Yu H, Higashino Y, Fujii K, MasuyamaT, Kitabatake A, Minamino T. Lack of myocardial perfusion imme-diately after successful thrombolysis. A predictor of poor recovery ofleft ventricular function in anterior myocardial infarction. Circulation1992;85:1699–1705.

7. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, LaskeyWK, Pennell DJ, Rumberger JA, Ryan T, Verani MS. Standardizedmyocardial segmentation and nomenclature for tomographic imagingof the heart: a statement for healthcare professionals from the CardiacImaging Committee of the Council on Clinical Cardiology of theAmerican Heart Association. Circulation 2002;105:539–542.

8. Ragosta M, Camarano G, Kaul S, Powers ER, Sarembock IJ, GimpleLW. Microvascular integrity indicates myocellular viability in patientswith recent myocardial infarction. New insights using myocardialcontrast echocardiography. Circulation 1994;89:2562–2569.

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to quantify global left ventricular mechanical dyssynchrony. Circula-tion 2005;112:992–1000.

0. Iwakura K, Ito H, Kawano S, Okamura A, Kurotobi T, Date M, InoueK, Fujii K. Chronic pre-treatment of statins is associated with thereduction of the no-reflow phenomenon in the patients with reperfusedacute myocardial infarction. Eur Heart J 2006;27:534–539.

1. Bolognese L, Antoniucci D, Rovai D, Buonamici P, Cerisano G,Santoro GM, Marini C, L’Abbate A, Fazzini PF. Myocardial contrastechocardiography versus dobutamine echocardiography for predictingfunctional recovery after acute myocardial infarction treated with pri-mary coronary angioplasty. J Am Coll Cardiol 1996;28:1677–1683.

2. Iwakura K, Ito H, Nishikawa N, Sugimoto K, Shintani Y, YamamotoK, Higashino Y, Masuyama T, Hori M, Fujii K. Use of echocardiog-raphy for predicting myocardial viability in patients with reperfusedanterior wall myocardial infarction. Am J Cardiol 2000;85:744–748.

3. Galiuto L, Iliceto S. Myocardial contrast echocardiography in theevaluation of viable myocardium after acute myocardial infarction.Am J Cardiol 1998;81(suppl):29G–32G.

4. Costantini CO, Stone GW, Mehran R, Aymong E, Grines CL, CoxDA, Stuckey T, Turco M, Gersh BJ, Tcheng JE, et al. Frequency,correlates, and clinical implications of myocardial perfusion after
primary angioplasty and stenting, with and without glycoprotein IIb/
IIIa inhibition, in acute myocardial infarction. J Am Coll Cardiol2004;44:305–312.

5. Porter TR, Li S, Oster R, Deligonul U. The clinical implications of noreflow demonstrated with intravenous perfluorocarbon containing mi-crobubbles following restoration of Thrombolysis In Myocardial In-farction (TIMI) 3 flow in patients with acute myocardial infarction.Am J Cardiol 1998;82:1173–1177.

6. Kaul S, Jayaweera AR, Glasheen WP, Villanueva FS, GutgesellHP, Spotnitz WD. Myocardial contrast echocardiography and thetransmural distribution of flow: a critical appraisal during myocar-dial ischemia not associated with infarction. J Am Coll Cardiol1992;20:1005–1016.

7. Heinle SK, Noblin J, Goree-Best P, Mello A, Ravad G, Mull S,Mammen P, Grayburn PA. Assessment of myocardial perfusion byharmonic power Doppler imaging at rest and during adenosine stress:comparison with (99m)Tc-sestamibi SPECT imaging. Circulation2000;102:55–60.

8. Wei K, Jayaweera AR, Firoozan S, Linka A, Skyba DM, Kaul S.Quantification of myocardial blood flow with ultrasound-induced de-struction of microbubbles administered as a constant venous infusion.
Circulation 1998;97:473–483.

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Usefulness of Atherogenic Dyslipidemia for PredictingCardiovascular Risk in Patients With Angiographically Defined

Coronary Artery Disease

Marcello Arca, MDa,*, Anna Montali, BSca, Sofia Valiante, MDa, Filomena Campagna, PhDa,Giovanni Pigna, MDa, Vincenzo Paoletti, MDa, Roberto Antonini, PhDa, Francesco Barillà, MDb,

Gaetano Tanzilli, MDb, Annarita Vestri, PhDc, and Carlo Gaudio, MDb

The identification of factors contributing to residual cardiovascular risk is important toimprove the management of patients with established coronary artery disease (CAD). Thisstudy was conducted to assess the predictive value of atherogenic dyslipidemia (defined ashigh triglycerides and low high-density lipoprotein [HDL] cholesterol) for long-term out-comes in patients with CAD. In 284 patients (238 men, 46 women; mean age at baseline59.2 � 8.9 years) with coronary stenosis (>50% in >1 vessel), the presence of atherogenicdyslipidemia was prospectively associated with the incidence of major adverse cardiovas-cular events (MACEs) during a median follow-up of 7.8 years. MACEs were defined ascardiovascular death, nonfatal myocardial infarction, nonfatal stroke, the recurrence ofangina, and revascularization procedures. MACEs were observed in 111 (39.1%) patientswith CAD. MACEs occurred more frequently in patients with atherogenic dyslipidemia(50.9%) than in those with isolated low HDL cholesterol or high triglycerides (33.0%) orwith normal HDL cholesterol and triglyceride concentrations (29.2%) (p <0.01 for trend).Kaplan-Meier survival analysis showed a decrease in event-free survival in patients withcompared with those without atherogenic dyslipidemia (log-rank p � 0.006). Patients withatherogenic dyslipidemia presented with increased plasma concentrations of remnants,denser low-density lipoprotein, more atherogenic HDL particles, and insulin-resistantstatus. After adjustment for potential confounding variables, the magnitude of increasedrisk associated with atherogenic dyslipidemia was 1.58 (95% confidence interval 1.12 to2.21, p � 0.008). In conclusion, these data provide evidence that atherogenic dyslipidemiais an independent predictor of cardiovascular risk in patients with CAD, even stronger thanisolated high triglycerides or low HDL cholesterol. © 2007 Elsevier Inc. All rights re-
served. (Am J Cardiol 2007;100:1511–1516)
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any patients with established coronary artery diseaseCAD) manifest elevated serum triglycerides associatedith low high-density lipoprotein (HDL) cholesterol levels,condition usually defined as atherogenic dyslipidemia.1ore detailed analyses frequently reveal other lipoprotein

bnormalities in these patients, such as increased remnantipoproteins, elevated apolipoprotein (apo) B, and the pres-nce of small low-density lipoprotein (LDL) particles, all ofhich have been implicated as being independently proathero-enic.2–4 Moreover, atherogenic dyslipidemia has been indi-ated as the central component of the metabolic syndrome.n fact, most patients aged �35 years with atherogenicyslipidemia met the Adult Treatment Panel III definition

Departments of aClinical and Medical Therapy, Unit of Medical Ther-py, bthe Heart and Great Vessels Attilio Reale, and cExperimental Med-cine and Pathology, I° Medical School, La Sapienza University of Rome,ome, Italy. Manuscript received April 21, 2007; revised manuscript

eceived and accepted June 13, 2007.Dr. Arca was supported by Grant 8.1.1.3.3.3.1 Progetto Finalizzato

rom the Ministry of Health and by Grant CTB 00.00176.ST74 from theational Research Council, Rome, Italy.

wE-mail address: [email protected] (M. Arca).

or the metabolic syndrome,5 and atherogenic dyslipide-ia, whether familial or sporadic, often precedes the full

linical manifestation of this syndrome.6 Therefore, theultiplex array of metabolic abnormalities of atherogenic

yslipidemia may well support its role into residual riskn patients with CAD. The purpose of this investigationas to determine the impact of dyslipidemia involvingigh triglycerides and low HDL cholesterol on cardio-ascular outcomes in a cohort of patients with angio-raphically documented CAD.

ethods

he present study included 530 consecutive patients withngiographic evidence of coronary atherosclerosis (�1 ste-oses �50% in �1 epicardial vessel). They underwentoronary angiography from December 1993 to August 1997or myocardial infarctions (n � 220) or angina pectoris (n �10). The angiographic diagnoses were based on standardriteria.7 All angiograms were independently evaluated by 2eaders, who did not know that the patients were to bencluded in the study. None of the patients was enrolleduring the acute phase of the ischemic syndrome. Those
ith concurrent histories of thyroid, liver, or renal disease
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nd those already taking lipid-lowering medications were ex-luded. After angiographic evaluation, 383 patients (72.3%)eceived revascularization procedures (256 with coronary by-ass and 127 with percutaneous coronary intervention) and47 (27.7%) medical therapy alone.

Patients’ medical histories, known CAD risk factors, andurrent medications were recorded using a structured ques-

able 1omparison of baseline characteristics of 530 patients with coronaryrtery disease with and without follow-up data

haracteristic Patients WithFollow-up(n � 284)

Patients WithoutFollow-up(n � 246)

pValue

ge (yrs) 59.2 � 8.9 60.2 � 10.1 0.24en 238 (83.8%) 197 (80.0%) 0.31omen 46 (16.2%) 49 (20.0%)enopause 44 (95.6%) 47 (95.9%) 0.30ody mass index (kg/m2) 26.6 � 3.6 26.7 � 4.0 0.80ypertension 140 (49.3%) 109 (44.3%) 0.26ypercholesterolemia 97 (34.1%) 78 (31.7%) 0.52moker 135 (47.5%) 130 (52.8%) 0.26iabetes mellitus 52 (18.3%) 46 (18.7%) 0.91asting blood glucose (mg/dl) 91.4 � 29.8 93.3 � 32.1 0.55lasma insulin (�UI/L)‡ 13.1 � 7.5 14.2 � 8.4 0.25OMA‡ 3.13 � 2.98 3.48 � 2.96 0.26istory of myocardial

infarction*125 (66.1%) 95 (64.6%) 0.82

o. of narrowed coronaryarteries

1 or 2 180 (63.5%) 168 (68.3%) 0.27�3 104 (36.5%) 78 (31.7%)edications

Angiotensin-convertingenzyme inhibitors

130 (46.0%) 128 (52.0%) 0.16

Calcium channel blockers 157 (55.2%) 119 (48.6%)� blockers 75 (26.6%) 58 (23.6%)

nterventionRevascularization

procedures†216 (76%) 167 (68%) 0.046

ipid status (mg/dl)Total cholesterol 216.0 � 46.2 212.2 � 46.6 0.34HDL cholesterol 41.8 � 11.6 41.1 � 11.9 0.52Triglycerides‡ 186.6 � 126.2 187.4 � 107.0 0.76LDL cholesterol 137.9 � 40.2 134.9 � 41.9 0.41Apo B 117.4 � 25.9 117.7 � 35.7 0.93Non-HDL cholesterol 174.2 � 46.0 171.1 � 46.2 0.43iomarkers (mg/dl)Fibrinogen 318.2 � 57.7 317.0 � 64.4 0.83Uric acid 6.1 � 4.7 6.0 � 1.6 0.70Creatinine 1.1 � 0.7 1.1 � 0.8 0.99

The definitions of hypertension and diabetes mellitus are reported in theext. Hypercholesterolemia was defined as a history of hypercholesterol-mia and/or total cholesterol �240 mg/dl. The frequency of menopauseas calculated across the sample of women.* Documented histories of myocardial infarction were available in 336

ubjects (189 with and 147 without follow-up information); stenotic ves-els were defined as those with �50% stenosis.

† Revascularization procedures included 153 and 103 coronary bypassrocedures and 63 and 64 percutaneous coronary interventions in patientsith and without follow-up, respectively.‡ Statistical comparisons were performed using log-transformed data.HOMA � homeostasis model assessment.

ionnaire. The diagnosis of type 2 diabetes mellitus was t

ased on history of treatment with hypoglycemic agentsnd/or fasting blood glucose �126 mg/dl8 and that of hy-ertension on the presence of elevated systolic (�140 mmg) and/or diastolic (�90 mm Hg) blood pressure and/or

he current use of antihypertensive drugs.9 Data collectionncluded height and weight (to determine body mass index,ssessed as weight in kilograms divided by the square ofeight in meters) and systolic and diastolic blood pressures.asting blood samples for laboratory measurements werelso obtained early in the morning after overnight fasting.

The study protocol was approved by the institutionalthics committee, and written informed consent was ob-ained from each participant.

Follow-up for the occurrence of untoward cardiovascularvents was obtained by annual telephone interviews withatients or family members. Interviews were carried out bytrained research cardiologist using a structured question-

aire. In a few instances, the questionnaire was sent by mail.hen possible, obtained information was verified through

atients’ physicians or hospital records. Of the originalohort, 200 patients (37%) were lost to follow-up, 38 (7.0%)ere not willing to participate, and 8 (1.5%) provided in-

omplete information. Reliable follow-up data were ob-ained for 284 patients (53.6%), and these patients are re-erred to here as the study population.

The primary clinical outcome was the composite ofajor adverse coronary events (MACEs), defined as car-

iovascular death, nonfatal myocardial infarction, nonfa-

able 2eaths and cardiovascular events during follow-up in the cohort of 284atients with coronary artery disease

vent n (%)

otal cardiovascular events 111 (39.1%)ardiovascular deaths 30 (10.0%)onfatal myocardial infarction 33 (11.6%)ngina pectoris 53 (18.7%)evascularization procedure† 43 (15.1%)onfatal stroke 13 (4.6%)oncardiovascular deaths 19 (6.7%)eoplasm 10 (3.5%)ther* 9 (3.2%)

* Renal insufficiency and respiratory disease.† Revascularization included 21 coronary bypass procedures and 22

ercutaneous coronary interventions.

able 3istribution of major adverse cardiovascular events according to theresence of atherogenic dyslipidemia or dyslipidemia involving isolatedigh triglycerides or low high-density lipoprotein cholesterol

roups MACEs UnadjustedOdds Ratio

95% CI pValue

atients with atherogenicdyslipidemia (n � 114)

58 (50.9%) 2.31 1.23–4.32 0.009

orderline patients (n � 97) 32 (33.0%) 1.22 0.63–2.24 0.557atients without atherogenic

dyslipidemia (n � 73)21 (29.2%) 1

Definitions of patients with and without atherogenic dyslipidemia asell as borderline patients are reported in the text.

al stroke, stable or unstable angina, and revasculariza-

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1513Coronary Artery Disease/Atherogenic Dyslipidemia and Cardiovascular Outcomes

ion procedures. The median length of follow-up was 7.8ears (range 1 to 9.8), with total cohort follow-up of,307.5 patient-years.

Cholesterol and triglyceride concentrations in whole plasmand lipoprotein fractions were measured with a TechniconA-1000 Autoanalyzer (Technion, Milan, Italy) using stan-ard enzymatic methods. HDL cholesterol was determinedfter the precipitation of apo B–containing lipoproteins withextran sulfate, and LDL cholesterol was estimated usingriedewald’s formula.10 In samples with triglycerides �400g/dl, LDL cholesterol was estimated after the isolation of

ery low-density lipoproteins, as described previously.11

lasma levels of apo B were measured using an immunotur-idimetric method (Kone Instruments, Espoo, Finland)12; thosef apo A-I and apo A-II as well as those of HDL particlesontaining only apo A-I or HDL particles containing apo A-Ind apo A-II were determined as previously reported.13 Veryow-density lipoprotein and intermediate-density lipoproteind �1.019 g/ml) and LDL (d � 1.019 to 1.063 g/ml) werebtained using sequential ultracentrifugation, as described pre-iously.14 In isolated lipoprotein fractions, apo B levels wereeasured using a previously reported procedure.14

Plasma glucose was measured using a glucose oxidaseethod adapted for the Technicon RA-1000 Autoanalyzer.ibrinogen and uric acid concentrations were determinedsing standard methods. Plasma insulin concentrations wereetermined by radioimmunoassay (Biodata Insulin Kit; Bio-ata, Milan, Italy). The interassay coefficient of variationas 7.5%. Insulin resistance was estimated by homeostasisodel assessment using the following formula: fasting

lood glucose (mmol/L) � insulin (�UI/L)/22.5.15

Categorical variables were compared using chi-square orisher’s exact tests. Differences between continuous vari-bles were evaluated using Student’s t test or the Mann-hitney U test, depending on the shape of the distribution

urves. Patients were divided into 3 subgroups on the basisf their triglyceride and HDL cholesterol levels at the timef enrollment. Subjects with atherogenic dyslipidemia wereefined as those with triglycerides �150 mg/dl and HDL

igure 1. Kaplan-Meier curves showing the cumulative incidence of Myslipidemia. Patients with dyslipidemia involving isolated high triglyceridn the group without atherogenic dyslipidemia.

holesterol �40 mg/dl (for men) or �50 mg/dl (for women) a

ccording to the Adult Treatment Panel III criteria.16 Sub-ects without atherogenic dyslipidemia were defined ashose with triglycerides �150 mg/dl and HDL cholesterol

40 mg/dl (for men) or �50 mg/dl (for women). Subjectsith isolated high triglycerides (�150 mg/dl) or low HDL

holesterol (�40 mg/dl for men, �50 mg/dl for women)ere classified as borderline. The cumulative event plots

ccording to dyslipidemia involving high triglycerides andow HDL cholesterol were estimated using the Kaplan-

eier method and compared using the log-rank test. Allurvival analyses were conducted for the primary end pointf MACEs. Data from patients who died from causes notelated to cardiovascular disease were censored at the timef death. Hazard ratios for future cardiovascular eventsssociated with atherogenic dyslipidemia were estimatedsing Cox regression models, where possibly confoundingariables were included.

The p values are 2-sided; a p value �0.05 was consid-red statistically significant. All computations were carriedut using SPSS version 13.0 (SPSS, Inc., Chicago, Illinois).

esults

t baseline, study patients’ mean age was 59.2 � 8.9 years,nd there a large preponderance of men. They were over-eight and, overall, presented the expected distribution of

lassic coronary risk factors (Table 1). Two thirds hadistories of myocardial infarctions, and 36% showed �3tenotic coronary vessels on angiographic examination.ompared with patients for whom follow-up data were notvailable, no significant differences in the distribution ofajor coronary risk factors or in the severity of CAD were

bserved (Table 1). Only the prevalence of revasculariza-ion procedures tended to be higher in patients with than inhose without follow-up data.

During follow-up, 30 patients (10%) died from cardio-ascular disease, 33 (11.6%) had nonfatal myocardial in-arctions, and 13 (4.6%) had nonfatal strokes; 53 patients18.7%) complained of new episodes of stable or unstable

during follow-up according to the presence or absence of atherogenicw HDL cholesterol (defined as the borderline group; see text) are included

ACEses or lo

ngina, and 43 (15.1%) underwent revascularization proce-

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ures (Table 2). This resulted in a total number of newACEs of 111 (39.1%). Nineteen noncardiovascular deaths

6.7%) were also reported in the study population, most dueo cancer. During follow-up, 80 patients (31.6%) initiatedipid-lowering medications, mostly statins (90%).

The comparison of the baseline characteristics of patientsith and without MACEs did not reveal significant differ-

nces (all p �0.2), with the exception of lower HDL cho-

able 4aseline distribution of coronary risk factors and other biochemicalharacteristics in patients with coronary artery disease with and withouttherogenic dyslipidemia

ariable Atherogenic Dyslipidemia p Value

Yes(n � 114)

No†

(n � 170)

ge (yrs) 58.1 � 7.7 59.9 � 9.7 0.10en 94 (82%) 144 (85%) 0.62omen 20 (17%) 26 (15%)enopause 20 (100%) 24 (92%) 0.50ody mass index (kg/m2) 27.0 � 2.9 26.3 � 4.0 0.17ypertension 57 (50%) 83 (49%) 0.90ypercholesterolemia 39 (34%) 58 (34%) 1.00moker 63 (55%) 72 (42%) 0.039iabetes mellitus 24 (21%) 28 (16%) 0.35asting blood glucose (mg/dl) 97.1 � 37.7 87.2 � 21.7 0.018lasma insulin (�UI/L)‡ 13.7 � 8.3 12.8 � 6.9 0.25OMA‡ 3.57 � 4.07 2.82 � 1.77 0.044istory of myocardial

infarction*53 (72%) 72 (63%) 0.21

o. of narrowed coronaryarteries

1 or 2 59 (52%) 85 (50%) 0.859�3 37 (32%) 58 (34%)edications

Angiotensi-convertingenzyme inhibitors

55 (48%) 78 (46%)

Calcium channel blockers 21 (18%) 30 (18%) 0.59� blockers 47 (41%) 78 (45%)InterventionRevascularization

procedures72 (63%) 100 (59%) 0.169

ipid status (mg/dl)Total cholesterol 221.7 � 49.1 212.1 � 43.9 0.09HDL cholesterol 33.8 � 6.3 47.1 � 11.2 0.001Triglycerides‡ 252.7 � 162.9 142.3 � 63.2 0.0001LDL cholesterol 139.2 � 42.9 137.1 � 38.4 0.67Apo B 126.9 � 26.7 110.7 � 23.1 0.0001Non-HDL cholesterol 187.9 � 49.1 165.0 � 41.4 0.0001iomarkers (mg/dl)Fibrinogen 318.4 � 58.5 318.0 � 57.4 0.96Uric acid 6.1 � 1.5 6.2 � 6.0 0.83Creatinine 1.1 � 1.0 1.1 � 0.3 0.32

Definitions of hypertension, diabetes mellitus, and hypercholesterolemias in Table 1.

* Documented histories of myocardial infarction were available in 74atients with and 115 patients without atherogenic dyslipidemia.

† The group without atherogenic dyslipidemia includes subjects withormal triglyceride and HDL cholesterol levels as well as borderlineubjects, as defined in the text.

‡ Statistical comparisons were performed on log-transformed data.Abbreviation as in Table 1.

esterol (39.8 � 11.4 vs 43.0 � 11.5 mg/dl, p � 0.021) and (

igher triglyceride (199.0 � 134.8 vs 178.6 � 120.1 mg/dl,� 0.053) levels in those with MACEs. Also, the reported

se of statins during follow-up was not different betweenroups (32% in patients with and 29% in those withoutACEs; data not shown).MACEs occurred more frequently in patients with than

n those without atherogenic dyslipidemia, with a significantwofold increase in the unadjusted risk (Table 3). Also, theorderline group showed a slightly higher incidence ofACEs compared with patients with normal triglyceride

nd HDL cholesterol levels, but the difference was nottatistically significant. Figure 1 shows the Kaplan-Meiervent-free survival curves for patients with and withouttherogenic dyslipidemia. In this analysis, borderline pa-ients were pooled with those with normal triglyceride andDL cholesterol levels. At the 5-year follow-up time point,

he event-free survival rates were 90% and 95% in patientsith and without atherogenic dyslipidemia, respectively. In

he 2 groups, rapid decreases in event-free survival werebserved after 6 years (91.2% vs 86%, respectively), withverall incidences of MACEs of 48.2% and 31.2% in pa-ients with and without atherogenic dyslipidemia, respec-ively. The estimated median interval time for a new event was.3 years (95% confidence interval [CI] 9.0 to 9.6) and 9.5ears (95% CI 9.4 to 9.6) in patients with and without athero-enic dyslipidemia, respectively (log-rank p � 0.006).

Patients with atherogenic dyslipidemia showed, by def-nition, markedly reduced HDL cholesterol and increasedriglyceride levels (Table 4), but also, non-HDL cholesterol

able 5lasma lipoprotein composition and apolipoprotein levels in patientsith coronary artery disease with and without atherogenic dyslipidemia

ariable Atherogenic Dyslipidemia p Value

Yes(n � 73)

No(n � 104)

LDL� IDLCholesterol (mg/dl) 41.1 � 18.6 24.7 � 14.2 0.0001Triglycerides (mg/dl) 170.9 � 119.5 86.6 � 59.2 0.0001Protein (mg/dl) 33.6 � 9.8 23.5 � 9.9 0.0001Apo B (mg/dl) 16.6 � 7.2 10.6 � 5.5 0.0001Apo B/cholesterol (%) 48.9 � 11.8 44.7 � 11.6 0.02Cholesterol/apo B ratio 2.55 � 0.66 3.87 � 14.78 0.449�1.09 g/ml infranatantCholesterol (mg/dl) 183.7 � 41.8 190.6 � 33.7 0.227Triglycerides (mg/dl) 83.4 � 54.7 61.9 � 23.0 0.0001DL (d � 1.019–1.063 g/ml)Cholesterol (mg/dl) 149.0 � 40.7 144.8 � 31.2 0.435Apo B (mg/dl) 110.5 � 25.0 100.1 � 20.7 0.0001Cholesterol/apo B ratio 1.35 � 0.16 1.45 � 0.16 0.0001po A-I (mg/dl)* 111.7 � 20.6 124.0 � 23.7 0.036po A-II (mg/dl)* 32.8 � 7.7 37.0 � 11.0 0.097articles containing apo A-I

(mg/dl)*45.7 � 13.1 50.0 � 11.3 0.17

articles containing apo A-Iand apo A-II (mg/dl)*

65.6 � 16.6 73.6 � 20.3 0.10

* Data were available for 25 patients with and 41 patients withouttherogenic dyslipidemia.

IDL � intermediate density lipoprotein; VLDL � very low densityipoprotein.

p �0.001) and apo B (p �0.001) were significantly in-

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1515Coronary Artery Disease/Atherogenic Dyslipidemia and Cardiovascular Outcomes

reased in these patients compared with those withouttherogenic dyslipidemia. Conversely, plasma levels of totalnd LDL cholesterol were not different. The abnormalitiesn lipoprotein composition associated with atherogenic dys-ipidemia were evaluated by comparing subgroups of pa-ients with (n � 73) and without (n � 104) high triglycer-des and low HDL cholesterol (Table 5). Patients withtherogenic dyslipidemia showed increased concentrationsf cholesterol, triglycerides, and apo B in the lipoproteinraction with density �1.019 g/ml; also, the cholesterol/apo

ratio and the percentage of apo B to cholesterol in thisraction were higher, suggesting the accumulation of rem-ant particles. These patients also presented with increasedoncentrations of apo B and higher cholesterol/apo B ratiosn the lipoprotein fraction with density of 1.019 to 1.063/ml, indicating a preponderance of protein-rich, denserarticles in the LDL fraction. Plasma apo A-I (p � 0.036)ut not apo A-II (p � 0.09) was significantly lower inatients with than in those without atherogenic dyslipide-ia. A tendency toward reduced concentrations of HDL

articles containing only apo AI and HDL particles contain-ng apo A-I and apo A-II was observed in the latter patients,ut the difference did not reach statistical significance, per-aps because of the small numbers.

In addition, patients with atherogenic dyslipidemia showedt baseline significantly higher levels of fasting blood glucoseut not of plasma insulin (Table 4). However, when insulinensitivity was evaluated by homeostasis model assessment,hese patients had significantly increased values of this param-ter, suggesting the presence of an insulin-resistant state.mong the other considered risk factors, only smoking was

ound to be significantly more frequent in patients with athero-enic dyslipidemia.

To assess the independent strength of atherogenic dys-ipidemia for cardiovascular risk, 2 Cox regression modelsere developed. Age- and gender-adjusted relative risk

howed a 1.73-fold (95% CI 1.18 to 2.53, p � 0.005)ncreased risk for MACEs in patients with atherogenic dys-ipidemia. This association remained significant (relativeisk 1.58, 95% confidence interval 1.12 to 2.21, p � 0.008)ven after the inclusion in the Cox model of those athero-enic variables (smoking, apo B, non-HDL cholesterol,asting blood glucose, and homeostasis model assessmentnsulin resistance) that were found to be significantly dif-erent between patients with and without atherogenic dys-ipidemia.

iscussion

he results of this prospective study demonstrate thattherogenic dyslipidemia is a strong and independent pre-ictor of cardiovascular risk outcomes in patients with an-iographically documented CAD. Patients with this lipidisorder had significantly lower event-free survival rateshan those with normal triglyceride and HDL cholesteroltatus. After adjustment for possible confounding variables,e estimated that the magnitude of increased cardiovascular

isk associated with atherogenic dyslipidemia was about.6-fold. More interestingly, this increased risk was signif-cantly higher than that yielded by dyslipidemia involving
solated low HDL cholesterol or high triglycerides. e
Previously published studies have evaluated the predictiveole of individual components of atherogenic dyslipidemia inopulations with cardiovascular disease, with inconsistent re-ults. For example, in the Veterans Affairs High-Density Li-oprotein Cholesterol Intervention Trial (VA-HIT) study,17 anntervention study that enrolled men with histories of CAD andow HDL cholesterol, HDL cholesterol but not triglyceridesas a significant predictor of cardiovascular events in theultivariate analysis. In the Baltimore Coronary Observa-

ional Long-Term Study (COLTS),18 a retrospective cohorttudy with 18-year follow-up, multivariate analysis foundhat triglyceride levels of 100 to 199 mg/dl predicted neworonary events independently of HDL cholesterol levelsnd diabetes in men and women with CAD. Moreover, inatients enrolled in the Bypass Angioplasty Revasculariza-ion Investigation (BARI) study, neither HDL cholesterolor LDL cholesterol predicted outcomes during follow-up.n contrast, serum triglycerides were predictive of nonfatalyocardial infarction but not angina pectoris. Only non-DL cholesterol was a strong and independent predictor ofonfatal myocardial infarction and angina pectoris whendded to the multivariate models.19

It has been suggested that such inconsistency is related tohe strong metabolic links between triglycerides and HDLholesterol that may confound their predictive role in thetatistical models. Alternatively, we suggest that the clinicalefinition of atherogenic dyslipidemia may better character-ze a cluster of proatherogenic alterations in the same pa-ients. We confirmed this in our cohort, in which patientsith this dyslipidemia presented a wide range of abnormal-

ties, such as increased plasma concentrations of remnants,enser LDL, more atherogenic HDL particles (as suggestedy the reduction of those containing apo AI and apo AII),nd insulin-resistant status. Apparently, body mass indexas not associated with atherogenic dyslipidemia, but we

annot infer about visceral adiposity because, unfortunately,aist circumference was not measured in our study patients.lso, the prevalence of hypertension did not differ betweenatients with and without atherogenic dyslipidemia, butrevious analyses have illustrated a weaker association be-ween blood pressure and atherogenic dyslipidemia.5

In interpreting these results, a number of limitations muste considered. In general, the present study shares the lim-tations of nonrandomized observational studies (i.e., unsus-ected selection biases and confounding) but has the advan-age of being prospective in design, with large patient-yearollow-up. In addition, a relatively large number of newvents were registered, thus making statistical estimationsore robust. Follow-up data were available only in a subset

f the original cohort, but the comparison of baseline char-cteristics of patients with and without follow-up did noteveal differences, indicating a “random effect” in the se-ection of patients included in the follow-up analysis. Ourtudy may have lacked adequate statistical power to assesshe true predictive value of isolated low HDL cholesterol origh triglycerides compared with atherogenic dyslipidemia,hich was available in a larger number of patients. Never-

heless, considering the length of the follow-up, a sizablexposure time can be estimated for patients with isolatedow HDL cholesterol (1,264 patient-years) or high triglyc-
rides (1,247 patient-years). Moreover, it is possible that the

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se of statins, which have a larger effect on LDL cholesterolhan on high triglycerides and low HDL cholesterol,20 mightave blunted the association of cardiovascular risk withDL cholesterol and inflated that with atherogenic dyslipi-emia. However, it must be noted that only approximately0% of patients reported beginning statins during follow-up.his low prevalence, which is very similar to that reported for

he same years in Italy in patients with CAD,21 is unlikely toave created spurious associations between atherogenicyslipidemia and cardiovascular outcomes. Finally, in ourtudy, several factors influencing the prognosis in patientsith CAD (e.g., the left ventricular ejection fraction) wereot measured, thus leaving open the possibility that thendependent predictive power of atherogenic dyslipidemian these patients could be smaller.

In conclusion, our findings, demonstrating that atherogenicyslipidemia has a significant impact on residual cardiovascu-ar risk, strongly indicate that this condition represents a usefulriterion to identify patients with CAD with poorer prognoseso target for more specific therapeutic interventions.

cknowledgment: We wish to thank Dr. Bruno Mazza-ella and Renzo Cantini for technical support with labo-atory measurements. We also thank the cardiologists andamily doctors for their dedication in following up pa-ients with CAD.

1. Grundy SM. Atherogenic dyslipidemia: lipoprotein abnormalities andimplications for therapy. Am J Cardiol 1995;75(suppl):45B–52B.

2. Twickler TB, Dallinga-Thie GM, Cohn JS, Chapman MJ. Elevatedremnant-like particle cholesterol concentration: a characteristic featureof the atherogenic lipoprotein phenotype. Circulation 2004;109:1918–1925.

3. Packard CJ, Saito Y. Non-HDL cholesterol as a measure of athero-sclerotic risk. J Atheroscler Thromb 2004;11:6–14.

4. Grundy SM. A constellation of complications: the metabolic syn-drome. Clin Cornerstone 2005;7:36–45.

5. Wyszynski DF, Dawn M, Waterworth DM, Philip J, Barter PJ, CohenJ, Kesäniemi YA, Mahley RW, McPherson R, Waeber G, et al.Relation between atherogenic dyslipidemia and the Adult TreatmentProgram-III definition of metabolic syndrome (Genetic Epidemiologyof Metabolic Syndrome Project). Am J Cardiol 2005;95:194–198.

6. Vinik AI. The metabolic basis of atherogenic dyslipidemia. Clin Cor-nerstone 2005;7:27–35.

7. Austen WG, Edwards JE, Frye RL, Gensini GG, Gott VL, GriffithLS, McGoon DC, Murphy ML, Roe BB. A reporting system onpatients evaluated for coronary artery disease: report of the Ad Hoc
Committee for Grading of Coronary Artery Disease, Council on
Cardiovascular Surgery, American Heart Association. Circulation1975;51(suppl):5– 40.

8. Guidelines Committee. 2003 European Society of Hypertension—European Society of Cardiology guidelines for the management ofarterial hypertension. J Hypertens 2003;21:1011–1059.

9. Expert Committee on the Diagnosis and Classification of DiabetesMellitus. Report of the Expert Committee on the diagnosis and Clas-sification of Diabetes Mellitus. Diabetes Care 2000;1(suppl):S4–S19.

0. Friedewald WT, Levy RJ, Fredrickson DS. Estimation of the concen-tration of low-density-lipoprotein cholesterol in plasma without use ofthe preparative ultracentrifuge. Clin Chem 1972;18:499–502.

1. Lipid and lipoprotein analysis. In: Manual of Laboratory Operations.Publication NIH F5-628. Washington, District of Columbia: LipidResearch Clinics Program; 1984.

2. Campagna F, Montali A, Baroni MG, Antonini TM, Ricci G, AntoniniR, Verna R, Arca M. Common variants in the lipoprotein lipase gene,but not those in the insulin receptor substrate-1, the �3-adrenergicreceptor and the intestinal fatty acid binding protein-2 gene influencethe lipid phenotypic expression in familial combined hyperlipidemia.Metabolism 2002;51:1298–1305.

3. Montali A, Vega GL, Grundy SM. Concentration of apolipoproteinAI–containing particles in patients with hypoalphalipoproteinemia.Arterioscler Thromb 1994;14:511–517.

4. Arca M, Vega GL, Grundy SM. Hypercholesterolemia in postmeno-pausal women: metabolic defects and response to low-dose lovastatin.JAMA 1994;271:453–459.

5. Matthews DR, Hasker JP, Rudenski AS, Naylor BA, Treacher DF,Turner RC. Homeostasis model assessment insulin resistance andbeta-cell function from fasting plasma glucose and insulin concentra-tion in man. Diabetologia 1985;28:412–419.

6. National Cholesterol Education Program (NCEP) Expert Panel onDetection, Evaluation, and Treatment of High Blood Cholesterol inAdults (Adult Treatment III). Third report of the National CholesterolEducation Program (NCEP) Expert Panel on Detection, Evaluation,and Treatment of High Blood Cholesterol in Adults (Adult TreatmentPanel III) final report. Circulation 2002;106:3143–3421.

7. Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC,Schaefer EJ, McNamara JR, Kashyap ML, Hershman JM, Wexler LF,Rubins HB. Relation of gemfibrozil treatment and lipid levels withmajor coronary events. VA-HIT: a randomized controlled trial. JAMA2001;285:1585–1591.

8. Miller M, Seidler A, Moalemi A, Pearson TA. Normal triglyceridelevels and coronary artery disease events: the Baltimore CoronaryObservational Long-Term Study. J Am Coll Cardiol 1998;31:1252–1257.

9. Bittner V, Hardison R, Kelsey FS, Weiner BH, Jacobs AK, Sopko G.Non–high-density lipoprotein cholesterol levels predict five-year outcomein the Bypass Angioplasty Revascularization Investigation (BARI). Cir-culation 2002;106:2537–2542.

0. Stein EA, Lane M, Laskarzewski P. Comparison of statins in hypertri-glyceridemia. Am J Cardiol 1998;81(suppl):66B–69B.

1. Vanuzzo D, Pilotto L, Ambrosio GB, Pyorala K, Lehto S, De BacquerD, De Backer G, Wood D; EUROASPIRE Study Group. Potential forcholesterol lowering in secondary prevention of coronary heart diseasein Europe: findings from EUROASPIRE [European Action on Sec-ondary Prevention Through Intervention to Reduce Events] study.
Atherosclerosis 2000;153:505–517.

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Effect of Losartan in Treatment of Exercise-InducedMyocardial Ischemia

Giancarlo Longobardi, MDa,*, Graziamaria Corbi, MD, PhDa,b, Francesco Cacciatore, MDa,Pasquale Abete, MDc, Giuseppe Furgi, MDa, Dino Franco Vitale, MDa, Franco Rengo, MDa,c,

and Nicola Ferrara, MDa,b

Because no controlled clinical studies are available about the possible role of angiotensin IIreceptor blockers in preventing effort myocardial ischemia, we evaluated the effect ofangiotensin II receptor blocker/losartan in preventing exercise-induced myocardial isch-emia in patients with coronary artery disease. Twenty-four sedentary patients with chronicstable ischemia were prospectively randomized to 28 days (double blind) of losartan 100 mgor losartan placebo in 2 divided doses. In each patient the treatment was crossed over to thealternative regimen (28 days, double blind) after a 1-week placebo period (single blind). Atthe end of each phase a new exercise stress test was performed. At baseline, systolic bloodpressure was significantly decreased after losartan 100 mg compared with losartan placebo.At submaximal exercise, systolic blood pressure and rate–pressure product were lower afterlosartan 100 mg administration compared with losartan placebo, and these findings re-mained significant at 1-mm ST depression and at peak exercise. Losartan 100 mg admin-istration versus losartan placebo significantly delayed the time to 1-mm ST-depressiononset and decreased ST-segment depression at peak exercise and time to recovery ofST-segment depression. Losartan 100 mg administration compared with losartan placebowas able to significantly increase exercise duration and maximal workload during exercisestress testing. In conclusion, in our study, losartan decreased electrocardiographic param-eters of myocardial ischemia in patients with coronary artery disease, suggesting a possiblerole of this drug in treatment of patients with effort myocardial ischemia. © 2007 Elsevier
Inc. All rights reserved. (Am J Cardiol 2007;100:1517–1521)
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o the best of our knowledge, no controlled clinical studiesre available on the possible role of angiotensin II receptorlockers in preventing effort myocardial ischemia. There-ore, we evaluated the effect of losartan in preventing ex-rcise-induced myocardial ischemia in patients with coro-ary artery disease (CAD).

ethodsPatient groups: We prospectively studied 24 sedentary

atients (17 men and 7 women; mean 59 � 2 years of age,ange 55 to 63) with chronic stable angina and symptomuration of 6 to 48 months. All had reproducible positivexercise test results for myocardial ischemia, with horizon-al downsloping ST segment �1 mm and �1 critical ste-osis (internal diameter decrease �70%) in the proximal/3 of 1 major epicardial coronary artery. All subjects wereormotensive, in sinus rhythm, and without evidence of leftentricular hypertrophy or conduction defects, which couldnterfere with the interpretation of ST-segment changes.

aCardiology Division, Fondazione “Salvatore Maugeri,” IRCCS, Sci-ntific Institute of Telese Terme, Telese Terme, bDepartment of Healthciences, School of Medicine, University of Molise, Molise, and cDepart-ent of Clinical Medicine, Cardiovascular and Immunological Sciences,

Federico II” University of Naples, Naples, Italy. Manuscript receivedpril 28, 2007; revised manuscript received and accepted June 14, 2007.

bE-mail address: [email protected] (G. Longobardi).

here was no evidence of previous myocardial infarction,eart failure, cardiomyopathy, or valvular disease. No pa-ient was taking digitalis. Nitrate preparations and calciumntry blockers were withdrawn 4 days before the study and-adrenergic blocking agents 2 weeks before. The institu-

ional ethics committee approved the study protocol and allatients gave informed consent.

Exercise test: Computer-assisted bicycle exercise testsere performed between 09:00 A.M. and 12:00 P.M. in a ther-ostatically controlled room. A standard 12-lead electrocar-

iogram and arterial blood pressure were recorded in the stand-ng position at baseline, at 1-minute intervals during exercise,t peak exercise, at each minute up to 10 minutes after exer-ise, at 1.0-mm ST-segment depression, at onset of angina, andhen clinically indicated. All electrocardiographic leads were

ontinuously monitored before, during, and after exercise, andp-to-date QRS complexes were continuously displayed oncreen. The level of the ST-segment, 80 ms after J point, wasalculated after signal averaging using a computer-assistedystem (Marquette Case 15 Treadmill, Marquette Electronics,ilwaukee, Wisconsin) in all 12 leads. Calculated values were

rinted out, in addition to heart rate, against time in trendormat with a measurement of ST-segment level with an ac-uracy of 0.1 mm. Myocardial ischemia was diagnosed whenhorizontal or downsloping ST-segment depression of 1 mm

t 80 ms from J point was observed in �1 lead. Electrocar-iographic strips of all tests were evaluated independently in
linded fashion by 2 cardiologists; in case of disagreement, a
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hird observer reviewed the tracings and the majority judgmentas binding. The test was interrupted at the occurrence of anyf the following criteria: ST-segment depression �2 mm,aximal age-related heart rate, severe chest pain, physical

xhaustion, or other harmful conditions such as hypotension,evere arrhythmia, or dyspnea. At the beginning of each exer-ise test patients were instructed to promptly report the onset ofnginal pain. The following parameters were measured: heartate and blood pressure at rest; time (seconds) to onset of.0-mm ST-segment depression; heart rate, blood pressure, andate–blood pressure product (heart rate multiplied by systoliclood pressure) at each minute of exercise and at onset of.0-mm ST-segment depression; maximal ST-segment depres-ion; METs of oxygen consumption at onset of 1-mm ST-egment depression and at peak exercise; exercise durationseconds); and time to recovery of ST-segment depressionseconds).

Study design: A double-blinded, randomized, crossovertudy technique was used (Figure 1). All patients began ther-py with a 1-week placebo run-in period (single blind). Afterhis regimen a baseline exercise stress test was performed.ubjects were randomized to 28 days (double blind) of losartan00 mg in 2 divided doses or to 28 days of losartan placebo individed doses. Losartan and placebo tablets were identical in

ppearance. For each patient, treatment was crossed over to thelternative regimen (28 days in double blind) after a 1-weeklacebo period (single blind). At the end of each phase a newxercise stress test was performed. During the study patientsere requested to report as accurately as possible any side

ffect with the number, time to onset, duration, and triggeringircumstances of anginal attacks. In case of angina attack,atients received sublingual nitroglycerin.

Coronary arteriography: Coronary arteriography wasonducted by Judkins technique the morning after anvernight fast. Intramuscular diazepam (10 mg) was ad-inistered 30 minutes before the study. Selective coro-

ary arteriography was performed in standard projection

Figure 1. Study design

nd analyzed to quantify severity of stenosis. For each 1

oronary artery the frame showing the most significantercent narrowing in any projection over the length ofhat artery was selected and enlarged 10 times. Diameterf stenosis and that of the most nearly “normal” proximalr distal segments were measured with a digital calliper.he ratio of the 2 measurements was taken as the percentarrowing of that artery. For each vessel, the projectionelected for this evaluation was agreed to by 3 experi-nced angiographers. Significant CAD was defined as70% decrease in luminal diameter of �1 major coro-

ary artery.

Statistical analysis: Student’s t test for paired data wassed to compare hemodynamic and electrocardiographicarameters during exercise tests. Data are expressed asean � SD unless otherwise indicated. Statistical signifi-

ance was defined by a p value �0.05. Analysis based onhe Hills-Armitage method did not find period or order ofandomization effects.

esults

emodynamic data are presented in Table 1. At baseline,ystolic blood pressure was significantly decreased after losar-an 100 mg compared with losartan placebo (p �0.05). Atubmaximal exercise (960 kg), systolic blood pressure andate–pressure product were lower after losartan 100 mg admin-stration (p �0.005) compared with losartan placebo. At 1-mmT depression, systolic blood pressure and rate-pressure prod-ct significantly decreased after losartan 100 mg administra-ion compared with losartan placebo (p �0.001 and �0.02,espectively). At peak exercise, systolic blood pressure andate-pressure product were significantly decreased after losar-an 100 mg administration compared with losartan placebo (p

0.001 and �0.005, respectively).Losartan 100 mg administration versus losartan placebo

ignificantly delayed time to 1-mm ST-depression onset479 � 106 vs 475 � 84 seconds, p �0.01) and decreasedT-segment depression at peak exercise (1.3 � 0.5 versus

� electrocardiogram.

.0 � 0.4 mm, p �0.05) and time to recovery of ST-

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1519Coronary Artery Disease/Losartan and Myocardial Ischemia

egment depression (120 � 63.6 vs 177 � 89 seconds,�0.01; Figure 2).Losartan 100 mg administration compared with losartan

lacebo was able to significantly increase exercise duration603 � 66 vs 565 � 80 seconds, p �0.001) and maximalorkload (4,208 � 76 vs 3,742 � 87 kg, p �0.001) during

xercise stress testing (Figure 3).

iscussion

ur results showed that losartan 100 mg is able to decreaseransient exercise-induced myocardial ischemia by decreasingime to onset of 1-mm ST segment depression, ST-segmentepression at peak exercise, and time to recovery of ST-egment depression and increasing exercise duration and max-mal workload. The mechanism of action, similar to that ofitrates, is probably related to a combination of peripheral andoronary circulations throughout vasodilation in conductiverteries, with a relative decrease in afterload, and vasodilatorffects on epicardial and resistance vessels in the coronaryirculation.

Angiotensin plays a key role in regulating arterialascular function by decreasing nitric oxide productionnd increasing reactive oxygen species as superoxide.or these reasons it causes a decrease in coronary vaso-ilator capacity, proliferation of smooth muscle cells, andncrease of platelet aggregation1,2 and, because it is in-olved in lipoprotein metabolism, can represent a causef atherogenesis.3,4

Pharmacologic agents able to antagonize these unde-irable actions are angiotensin-converting enzyme (ACE)nhibitors and angiotensin II receptor blockers. It is wellnown that these substances are useful in treatment ofypertension and in decreasing adverse outcomes in pa-ients with high risk of CAD, myocardial infarction, or

able 1emodynamic data during exercise stress testing at basal condition, at

ime to one-millimeter ST-depression onset, and at peak exercise afterour weeks of losartan placebo and losartan 100 mg administration

ariable LosartanPlacebo(n � 12)

Losartan100 mg

(n � 12)

pValue

aselineHeart rate (beats/min) 70 � 12 72 � 11 NSSystolic blood pressure (mm Hg) 132 � 7 126 � 9 �0.05Rate–pressure product (U �10�2)

91 � 12 89 � 17 NS

ubmaximal workload (960 kg)Heart rate (beats/min) 91 � 9 92 � 11 NSSystolic blood pressure (mm Hg) 168 � 19 150 � 14 �0.005Rate-pressure product (U � 10�2) 152 � 19 139 � 27 �0.005t 1-mm ST depressionHeart rate (beats/min) 123 � 12 129 � 15 NSSystolic blood pressure (mm Hg) 213 � 16 197 � 12 �0.001Rate-pressure product (U � 10�2) 263 � 32 237 � 42 �0.02eakHeart rate (beats/min) 127 � 13 132 � 13 NSSystolic blood pressure (mm Hg) 218 � 9 203 � 10 �0.001Rate-pressure product (U � 10�2) 279 � 24 252 � 38 �0.005

eft ventricular dysfunction.5–15 However, use of these i

rugs in treatment of transient myocardial ischemia istill debated. In this regard, a previous study demon-trated that captopril and enalapril were not effective inecreasing exercise and dipyridamole-induced myocar-ial ischemia in patients with CAD16 and recently, in theuinapril Anti-Ischemia and Symptoms of Angina Re-uction (QUASAR) trial, Pepine et al17 concluded thathort-term ACE inhibition in patients with coronary dis-ase and without hypertension, left ventricular dysfunc-ion, or acute myocardial infarction is not associated withignificant effects in transient ischemia. In contrast,udhir et al18 demonstrated in mongrel dogs that selec-

ive angiotensin II (AT1)-receptor blockade determined aasodilator effect on epicardial and resistance coronaryessels and that this effect was about 2 times that of ACEnhibition. This significant difference should be due to aigher degree of epicardial coronary vasodilation inducedy losartan compared with enalaprilat. The investigators

igure 2. Losartan 100 mg administration versus losartan placebo signifi-antly delayed time to 1-mm ST-depression onset (p �0.01) and decreasedT-segment depression at peak exercise (p �0.05) and time to recovery ofT-segment depression (p �0.01).

ndicated 3 possible causes of this phenomenon: (1) the

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xistence of non-ACE biochemical pathways for convert-ng angiotensin I into angiotensin II; (2) an insufficientosage of enalaprilat (this hypothesis seems to contrastith the significant effects of ACE inhibition on resis-

ance coronary vessels); and (3) a lower concentration ofCE in conductance vessels.18 In addition, blockade of

he AT1 receptors provokes a reflex increase of angio-ensin II and could determine an additional vascular ef-ect by stimulation of the AT2 receptor.19

On the basis of these observations, we believed it wasmportant to define the role of AT1 receptors and theirntagonists in physiologic and pathologic human coronaryirculation and, to better clarify this point, we conducted aouble-blinded, crossover, placebo-controlled trial on a se-ected study group of patients with stable myocardial isch-mia and provided a 28-day drug treatment.

In an elegant review, Thadani20 reported that in pa-ients with CAD a severe coronary narrowing is likelyssociated with nonobstructive plaques potentially re-ponsible for significant adverse outcomes. For theseeasons correct treatment of patients with chronic CADust aim to prevent clinical adverse events (myocardial

nfarction, unstable angina, death). However, treatmentf effort transient myocardial ischemia still plays anmportant role in the management of these patients.20 Inhis regard recently published data have demonstratedhat interventional and surgical managements are effec-ive in removing angina but less able to decrease mortal-

igure 3. Losartan 100 mg administration compared with losartan placeboas able to significantly increase (A) maximal workload (p �0.001) and

B) exercise duration (p �0.001) during exercise stress testing. Values areeans � SDs (bars).

ty or incidence of myocardial infarction compared with

edical therapy. The Second Randomized Interventionreatment of Angina (RITA-2) trial demonstrated thatatients considered eligible for percutaneous translumi-al coronary angioplasty and medical therapy could beafely managed with pharmacologic treatment if symp-oms are well controlled. Percutaneous transluminal cor-nary angioplasty did not influence the risk of death oryocardial infarction. The choice of medical or interventional

reatment should depend on severe co-morbidity or responsive-ess to medical therapy and on symptoms not well controlled byedical therapy.21 Ours is the first observation that losartan is able

o decrease effort myocardial ischemia, suggesting another reason,n addition to decreasing adverse outcomes in patients with CAD,o use this drug.

1. Behrendt D, Ganz P. Endothelial function. From vascular biology toclinical applications. Am J Cardiol 2002;90(suppl):40L–48L.

2. Navalkar S, Parthasarathy S, Santanam N, Khan BV. Irbesartan, anangiotensin type 1 receptor inhibitor, regulates markers of inflamma-tion in patients with premature atherosclerosis. J Am Coll Cardiol2001;37:440–444.

3. Singh BM, Mehta JL. Interactions between the renin-angiotensin sys-tem and dyslipidemia: relevance in the therapy of hypertension andcoronary heart disease. Arch Intern Med 2003;163:1296–12304.

4. Khan BV, Navalkar S, Khan QA, Rahman ST, Parthasarathy S. Irbe-sartan, an angiotensin type 1 receptor inhibitor, regulates the vascularoxidative state in patients with coronary artery disease. J Am CollCardiol 2001;38:1662–1667.

5. The SOLVD Investigators. Effect of enalapril on survival in patientswith reduced left ventricular ejection fractions and congestive heartfailure. N Engl J Med 1991;325:293–302.

6. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, CuddyTE, Davis BR, Geltman EM, Goldman S, Flaker GC, et al. Effect ofcaptopril on mortality and morbidity in patients with left ventriculardysfunction after myocardial infarction. Results of the survival andventricular enlargement trial. The SAVE Investigators. N Engl J Med1992;327:669–677.

7. The SOLVD Investigators. Effect of enalapril on mortality and thedevelopment of heart failure in asymptomatic patients with reducedleft ventricular ejection fractions. N Engl J Med 1992;327:685–691.

8. Yusuf S, Pepine CJ, Garces C, Pouleur H, Salem D, Kostis J, BenedictC, Rousseau M, Bourassa M, Pitt B. Effect of enalapril on myocardialinfarction and unstable angina in patients with low ejection fractions.Lancet 1992;340:1173–1178.

9. Yusuf S, Kostis JB, Pitt B. ACE inhibitors for myocardial infarctionand unstable angina. Lancet 1993;341:829.

0. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.Effect of ramipril on mortality and morbidity of survivors of acutemyocardial infarction with clinical evidence of heart failure. Lancet1993;342:821–828.

1. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effectsof an angiotensin-converting–enzyme inhibitor, ramipril, on cardio-vascular events in high-risk patients. The Heart Outcomes PreventionEvaluation Study Investigators. N Engl J Med 2000;342:145–153.

2. The PROGRESS Collaborative Group. Randomised trial of a perin-dopril-based blood-pressure–lowering regimen among 6,105 individ-uals with previous stroke or transient ischemic attack. Lancet 2001;358:1033–1041.

3. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Mich-elson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S, for theCHARM Investigators and Committees. Effects of candesartan onmortality and morbidity in patients with chronic heart failure: theCHARM-Overall programme. Lancet 2003;362:759–766.

4. Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ,Konstam MA, Riegger G, Klinger GH, Neaton J, Sharma D, ThiyagarajanB. Effect of losartan compared with captopril on mortality in patients withsymptomatic heart failure: randomised trial the Losartan Heart FailureSurvival Study ELITE II. Lancet 2000;355:1582–1587.

5. Cohn JN, Tognoni G. Valsartan Heart Failure Trial Investigators. A
randomized trial of the angiotensin receptor blocker valsartan inchronic heart failure. N Engl J Med 2001;345:1667–1675.

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1521Coronary Artery Disease/Losartan and Myocardial Ischemia

6. Longobardi G, Ferrara N, Leosco D, Nicolino A, Acanfora D, Furgi G,Guerra N, Papa A, Abete P, Rengo F. Failure of protective effect ofcaptopril and enalapril on exercise and dipyridamole-induced myocar-dial ischemia. Am J Cardiol 1995;76:255–258.

7. Pepine CJ, Rouleau JL, Annis K, Ducharme A, Ma P, Lenis J, DaviesR, Thadani U, Chaitman B, Haber HE, et al, for the QUASAR StudyGroup. Effects of angiotensin-converting enzyme inhibition on tran-sient ischemia: the Quinapril Anti-Ischemia and Symptoms of AnginaReduction (QUASAR) trial. J Am Coll Cardiol 2003;42:2049–2059.

8. Sudhir K, MacGregor JS, Gupta M, Barbant SD, Redberg R, Yock PG,Chatterjee K. Effect of selective angiotensin II receptor antagonism
and angiotensin converting enzyme inhibition on the coronary vascu-
lature in vivo. Intravascular two-dimensional and Doppler ultrasoundstudies. Circulation 1993;87:931–938.

9. Horiuchi M, Akischita M, Dzau VJ. Recent progress in angiotensin IItype 2 receptor research in the cardiovascular system. Hypertension1999;33:613–621.

0. Thadani U. Current medical management of chronic stable angina.J Cardiovasc Pharmacol Ther 2004;9(suppl):S11–S29.

1. Henderson RA, Pocock SJ, Clayton TC, Knight R, Fox KA, Julian DG,Chamberlain DA, for the Second Randomized Intervention Treatmentof Angina (RITA-2) Trial Participants. Seven-year outcome in theRITA-2 trial: coronary angioplasty versus medical therapy. J Am Coll
Cardiol 2003;42:1161–1170.

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Impact of 64-Slice Cardiac Computed Tomographic Angiographyon Clinical Decision-Making in Emergency Department Patients

With Chest Pain of Possible Myocardial Ischemic Origin

Ronen Rubinshtein, MDa, David A. Halon, MBChBa, Tamar Gaspar, MDb, Ronen Jaffe, MDa,Jacob Goldstein, MDa, Basheer Karkabi, MDa, Moshe Y. Flugelman, MDa, Asia Kogan, MDc,

Reuma Shapira, MDc, Nathan Peled, MDb, and Basil S. Lewis, MDa,*

To examine the impact of contrast enhanced multidetector computed tomography (MDCT)on clinical decision-making in patients who present to the emergency department (ED)with chest pain of possible ischemic origin, we studied 58 consecutive patients (age 56 � 10years, 36% female) with chest pain, intermediate risk, and no ischemic electrocardiographicchanges or increased biomarker measurements. After standard ED patient assessmentincluding cardiology consultation, a diagnosis of acute coronary syndrome was made in 41patients (71%), hospitalization was recommended in 47 (81%), and 32 (55%) were sched-uled for an early invasive strategy. Patients underwent 64-slice contrast agent–enhancedMDCT with image reconstruction in multiple formats using retrospective electrocardio-graphic gating, which revealed normal (no or trivial atheroma) coronary vasculature in 15patients, nonobstructive atheroma in 20 patients, and obstructive coronary disease (>1luminal narrowing of >50%) in 23 patients. After MDCT, the diagnosis of acute coronarysyndrome was revised in 18 of 41 patients (44%; 16 normal MDCT/widely patent stents, 2alternative diagnoses), planned hospitalization canceled in 21 of 47 patients (45%; 13normal MDCT/patent stent, 8 minor branch vessel disease), and planned early invasivestrategy altered in 25 of 58 patients (43%; unnecessary in 20 of 32, advisable in 5 of 26others). Effect of MDCT on clinical decisions was greater in the 36 patients without knownpreceding coronary disease. In 32 patients discharged from the ED (11 after initial triage, 21patients after MDCT), there were no major adverse cardiac events (e.g., death, myocardialinfarction, unplanned revascularization) during a 12-month follow-up period. In conclusion,contrast agent–enhanced 64-slice cardiac MDCT was a valuable diagnostic tool in the EDtriage of patients with chest pain of possible ischemic origin and decreased the need forhospitalization by almost half in this patient cohort. © 2007 Elsevier Inc. All rights reserved.
(Am J Cardiol 2007;100:1522–1526)
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ontrast agent–enhanced multidetector computed tomogra-hy (MDCT), which provides high-quality noninvasive im-ges of the heart, great vessels, and coronary vasculature,as recently been shown to be useful and reliable in themergency department (ED) triage of patients with chestain of possible ischemic origin1–3 and specifically in theiagnosis of an acute coronary syndrome (ACS).3 Current-eneration 64-slice scanners require minimal patient coop-ration (i.e., short breath-hold), have improved image qual-ty (i.e., better spatial and temporal resolution), and highiagnostic accuracy.4–8 MDCT can visualize coronarylaque and thrombus,9 and is also gaining a role in thevaluation of coronary stents10,11 and bypass grafts.12,13 Inhis study, we examined the impact of 64-slice MDCT

aDepartments of Cardiovascular Medicine, bRadiology, and cEmer-ency Medicine, Lady Davis Carmel Medical Center and the Ruth andruce Rappaport School of Medicine, Technion–Israel Institute of Tech-ology, Haifa, Israel. Manuscript received May 6, 2007; revised manu-cript received and accepted June 17, 2007.

*Corresponding author: Tel: 972-4-825-0288; fax: 972-4-834-3755.
pE-mail address: [email protected] (B.S. Lewis).

canning on clinical decision-making and patient disposi-ion in patients presenting to the ED with possible ischemichest pain.

ethods

he study was performed during a 3-month period in whichonsecutive patients presenting to the ED with a nondiag-ostic chest pain syndrome were considered for study in-lusion, depending only on availability of study personnel.he standard ED protocol in the medical center triagesatients into 3 groups on the basis of clinical presentation,istory, electrocardiogram, and biomarkers (i.e., serum tro-onin): very low probability or exclusion of ACS (i.e.,llows discharge from the ED), intermediate probability ofCS (i.e., generally requires hospitalization for further as-

essment), and ACS with high-risk features (i.e., requiresospitalization in a monitored unit and early invasive an-iography). Intermediate-group patients may undergo exer-ise stress testing and/or myocardial perfusion scintigraphyt the discretion of the ED physician, particularly those whoave normal baseline electrocardiographic findings. The
resent study population has been described in detail3 and
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1523Coronary Artery Disease/Impact of 64-Slice MDCT on ED Decisions

ssentially included patients in the intermediate group, asatients with clear-cut noncardiac symptoms at first triageere discharged, whereas patients with high-risk features or

lear evidence of an ACS were hospitalized and treatedirectly. We also excluded patients in whom MDCT wasontraindicated by current criteria: this included patientsith symptomatic congestive heart failure14 and patientsith contraindication to intravenous contrast agents (i.e.,

ontrast agent allergy or increased serum creatinine level�1.3 mg/dl for men, �0.9 mg/dl for women] or rapidrregular heart rate [atrial fibrillation or frequent ventricularrrhythmia]). The study cohort represented 20% of patientsresenting to the emergency room with acute chest painyndromes during the study period (there were another 24%t high risk, 36% at low risk, and 20% at intermediate riskho had study exclusion criteria).Patient triage and preliminary decision-making was per-

ormed according to standard ED protocol. A presumptiveiagnosis or exclusion of ACS was recorded according toonsensus of 2 cardiologists, who also recorded their rec-mmendation regarding need for hospitalization and needor an early invasive strategy. Those recommendations wereased on the patient history, risk factors, and clinical pre-entation, as patients with electrocardiographic changes typ-cal of ischemia or increased biomarker measurements werexcluded from this study.

After MDCT scanning, the findings were used by the car-iologist group to reconsider the clinical diagnosis and patientisposition. The diagnosis of ACS was altered if the MDCTcan was normal or showed nonobstructive or minor coronaryarrowing only, or if, in patients with previous invasive an-iography, there were no new obstructive lesions. A decisiono hospitalize was changed if, in the opinion of the 2 cardiol-gists, the MDCT findings effectively excluded any reasonableossibility of ACS. If the MDCT scan revealed unexpectedignificant obstructive coronary artery disease (CAD), the pre-ious decision to discharge was reconsidered and the patientas hospitalized for further evaluation. The recommendation

or early invasive strategy, based and recorded initially accord-ng to American College of Cardiology/American Heart As-ociation guidelines, was also revised after availability ofDCT findings.MDCT scans (Brilliance 64; Philips Medical Systems,

leveland, Ohio) were performed with retrospective electro-ardiographic gating. Beta blockers (oral metoprolol 50 to 100g or intravenous metoprolol 2.5 to 10 mg) or calcium antag-

nists (verapamil 80 mg in 1 asthmatic patient) were used toecrease heart rate: average rate during MDCT was 65 � 9eats/min (range 47 to 91). Dedicated software allowed cor-ection for R-wave irregularity after data acquisition.15–17 Aontrast medium–enhanced scan was performed with a bolusf 82 � 19 ml (range 40 to 150) contrast medium (Ultravist70 mg I/ml; Schering, Berlin, Germany) injected into anntecubital vein at a flow rate of 5 to 6 ml/s, followed by a0-ml saline solution chaser bolus. The larger volumes ofontrast agent were required in patients with longer scanength/time, as dose was calculated as follows: (Calculatedcan time [seconds] �5) � flow rate (milliliters per second).

Ten percent was added to total dose in patients weighing80 kg and 20% for patients with body weight �100 kg.
en percent of total dose was reduced in patients with body p
eight �70 kg. A larger volume of contrast agent was usedn patients after coronary artery bypass grafting or if thelinical presentation indicated the need for scanning ofulmonary vessels to exclude pulmonary embolism (5 pa-ients) or the aorta to exclude dissection (5 patients; bothdditional scans were performed in 3 patients for the so-alled triple rule out).18 Scanning was performed at 120 kV,ffective tube current 600 to 1,000 mAs (higher mAs inbese patients), slice collimation 64 � 0.625 mm acquisi-ion, 0.4-second gantry rotation time, and pitch 0.2. Overallcan time (and breath-hold) was dependent on the additionalnformation needed beyond native coronary arteries (i.e.,ypass grafts, pulmonary arteries, aortic dissection scans)nd was usually �15 seconds. Total time for the MDCTxamination was typically 10 to 15 minutes. Mean effectiveadiation dose was calculated to be 13.5 � 4.8 mSv (range.8 to 26.1, depending on total information needed and heartate). All patients gave written informed consent accordingo a protocol approved by the institutional review board.

MDCT scans were analyzed jointly by a cardiologist (RRr DAH) and radiologist (TG) who were aware of clinicalndings suggesting an intermediate risk for ACS. Coronaryrterial findings were reported in 3 categories: normal, non-bstructive atheromatous plaque, or obstructive (�1 lumi-al narrowing �50%). Proximal, middle, and distal segmentsf native arteries and bypass grafts were reported individually,ased on the American Heart Association reference model andovering all available coronary segments. Differences in inter-retation were resolved by consensus or third investigator ifecessary. Postprocessing and data analysis took longer thanhe MDCT examination. An MDCT report reached the EDithin 60 to 90 minutes in most cases.Statistical analysis was performed using Statistix 8 soft-

are (Analytical Software, Tallahassee, Florida). Patientanagement changes were analyzed using the McNemar

ymmetry test for statistical significance. A p value �0.05as considered significant.

esults

he study sample included 58 patients (age 56 � 10 years;6% women; Table 1). More than one third (22, 38%) had

able 1atient characteristics (n � 58)

haracteristic Value

ean age � SD (yrs) 56 � 10nown CAD 22 (38%)Previous percutaneous coronary intervention 15Previous bypass surgery 4Previous surgery and percutaneous intervention 2Previous coronary angiography (no revascularization) 1istory of myocardial infarction 14 (24%)iabetes mellitus 12 (21%)ystemic hypertension 33 (57%)yperlipidemia 32 (55%)urrent smoker 22 (38%)verage TIMI risk score (range) 1.3 (0–3)

TIMI � Thrombolysis In Myocardial Infarction.

reviously diagnosed CAD, in keeping with the usual patient

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opulation presenting to the ED. Thrombolysis In Myocardialnfarction risk score was low (mean 1.3, range 0 to 3), asxpected in patients with low to intermediate risk of ACS.

MDCT scans of diagnostic quality were obtained in allatients. Image quality was poor in �5% of coronary seg-ents and these were typically nonproximal. The MDCT

can findings were normal (no or trivial atheroma) in 15atients, showed nonobstructive atheroma (�50% stenoses)n 20, and showed obstructive coronary disease (�50%uminal narrowing involving major coronary vessel/branch)n 23, including patients with previous angiographicallyroven obstructions.

A provisional clinical diagnosis of ACS was made in 41atients (71%) before MDCT (Figure 1), 19 with a historyf coronary disease and 22 without. Among the 17 patients

Without known CAD (N=36)

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igure 1. Impact of MDCT findings on diagnosis of ACS (A), decision toC). Impact of MDCT findings on clinical decision-making was greater in

ith symptoms diagnosed to be noncardiac in origin on d

nitial ED assessment, 3 (17%) had known coronary diseasend 2 (12%) had previous percutaneous coronary interven-ions. After MDCT, the diagnosis of ACS was altered in 10f 22 patients (45%) without known coronary disease (p �.002) and 8 of 19 patients (42%) with known coronaryisease (p � 0.005). These 18 patients had normal coronaryessels (n � 11), widely patent stents (n � 5), or a clearoncoronary cause of chest pain (n � 2, 1 aortic dissectionistal to composite ascending aortic graft and 1 pancreaticumor and normal coronary arteries). In 1 other patient,

DCT showed a left subclavian artery stenosis proximal tofunctional left internal mammary artery bypass graft; thisatient was included as having ACS in the present analysis.n none of the patients considered to have noncardiac symp-oms on primary triage did the MDCT findings lead to a

With known CAD (N=22)

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1525Coronary Artery Disease/Impact of 64-Slice MDCT on ED Decisions

Hospitalization was initially planned for 47 patients81%; 19 with known CAD and 28 without). After MDCT,ospitalization was considered unnecessary in 14 of 28atients (50%) without a history of CAD (p � 0.0002) andn 7 of 19 patients (37%) with a history of CAD (p � 0.008;igure 1), the reasons being normal MDCT findings oridely patent stents in 13 (28%) and minor branch stenosisr distal vessel disease in 8 (17%). In 9 of those patients,DCT showed CAD that was unchanged from previous

nvasive angiographic findings and a decision was made noto hospitalize the patient.

On the basis of initial ED triage, an early interventionaltrategy was planned for 32 patients (55%; 78% of thosecheduled for hospitalization). After MDCT, this strategyas considered unnecessary in 20 of 32 patients (62%; 2

lternative diagnosis, 7 small or distal/minor vessel diseasen MDCT, 11 normal MDCT or widely patent stents). In 5f 15 other patients initially scheduled for hospitalizationut not necessarily an early invasive strategy, MDCThowed severe significant coronary stenoses (Figure 2) withnew recommendation of early angiography. Overall, the

umber of patients scheduled for an early interventionaltrategy was lower by 53% (p � 0.004) in patients withoutnown previous CAD and by 38% (p � NS) in those withnown previous CAD. For the group as a whole, angiogra-hy was canceled or delayed in 20 of 32 patients anddvanced in 5 of 26 patients (chi-square 14.74, p � 0.0001).

Invasive angiography was performed during hospitaliza-ion in 17 of 26 patients (65%). Obstructive CAD (�50%tenosis) was confirmed in 16 patients, there was 1 false-ositive finding of MDCT (overestimation of a mid-rightoronary artery stenosis). In the 32 patients discharged fromhe ED (11 after initial triage, 21 patients after MDCT),here were no major adverse cardiac events (e.g., death,yocardial infarction, unplanned revascularization) during

he 12-month follow-up period. Three patients returned tohe ED and 1 of these was hospitalized temporarily withecurrent chest pain with no biomarkers or electrocardio-

igure 2. Contrast agent–enhanced MDCT shows 3-vessel disease (arrowsan with diabetes mellitus and chest pain who had normal electrocardiog

raphic changes.

iscussion

n this group of patients presenting to the ED with chestain of uncertain origin, contrast agent–enhanced 64-sliceDCT scanning led to a revision of the initial ED diagnosis

f ACS in 44% of cases, obviated hospitalization in 45%,nd led to a change in the planned management strategy in3% of the patient cohort. The changes in decision-makingfter MDCT were less in patients with known CAD, pre-umably reflecting the effect of a higher pretest probabilityn physician thinking. Follow-up data showed that the ra-ionale of MDCT-based ED triage appeared to be wellounded and triage was reliable in defining patients with aow event rate.

The study demonstrates the usefulness of MDCT in clinicalecision-making, based on the assumption that contrast agent–nhanced MDCT has high diagnostic accuracy. Some patientsho have ACS do not have large-vessel disease and the syn-rome of ACS can be explained by disease in the medium tomall coronary vessels, which may not be defined appropri-tely by MDCT. Larger multicenter studies are needed toetter define the true accuracy and incremental benefitchieved, and these will probably be undertaken with currentlymerging newer technologies (possibly dual-source or 256-lice equipment). Although we obtained excellent imagingesults in the present study, in older patients with more exten-ive calcification, multiple stents, and bypass grafts, interpre-ation of MDCT images may still be problematic, and thoseatients may benefit from a wider physiologic assessment ornvasive coronary angiography. Last, we did not assess theotential for cost savings in this pilot study because patientumbers were small and economic analyses are institution- andealth care system–dependent.

1. Hoffmann U, Nagurney JT, Moselewski F, Pena A, Ferencik M, ChaeCU, Cury RC, Butler J, Abbara S, Brown DF, Manini A, et al.Coronary multidetector computed tomography in the assessment ofpatients with acute chest pain. Circulation 2006;114:2251–2260.

ing severe �75% proximal left anterior descending lesion in a 49-year-oldfindings on exercise treadmill testing during initial ED evaluation.

) includ

2. Goldstein JA, Gallagher MJ, O’Neill WW, Ross MA, O’Neil BJ, RaffGL. A randomized controlled trial of multi-slice coronary computed

1

1

1

1

1

1

1

1

1


tomography for evaluation of acute chest pain. J Am Coll Cardiol2007;49:863–871.

3. Rubinshtein R, Halon DA, Gaspar T, Jaffe R, Karkabi B, FlugelmanMY, Kogan A, Shapira R, Peled N, Lewis BS. Usefulness of 64-slicecardiac computed tomographic angiography for diagnosing acute cor-onary syndromes and predicting clinical outcome in emergency de-partment patients with chest pain of uncertain origin. Circulation2007;115:1762–1768.

4. Nikolaou K, Flohr T, Knez A, Rist C, Wintersperger B, Johnson T,Reiser MF, Becker CR. Advances in cardiac CT imaging: 64-slicescanner. Int J Cardiovasc Imaging 2004;20:535–540.

5. Achenbach S, Daniel WG. Computed tomography of the coronaryarteries: more than meets the (angiographic) eye. J Am Coll Cardiol2005;46:155–157.

6. Raff GL, Gallagher MJ, O’Neill WW, Goldstein JA. Diagnostic ac-curacy of noninvasive coronary angiography using 64-slice spiralcomputed tomography. J Am Coll Cardiol 2005;46:552–557.

7. Mollet NR, Cademartiri F, van Mieghem CA, Runza G, McFadden EP,Baks T, Serruys PW, Krestin GP, de Feyter PJ. High-resolution spiralcomputed tomography coronary angiography in patients referred fordiagnostic conventional coronary angiography. Circulation 2005;112:2318–2323.

8. Pugliese F, Mollet NR, Runza G, van Mieghem C, Meijboom WB,Malagutti P, Baks T, Krestin GP, deFeyter PJ, Cademartiri F. Diag-nostic accuracy of non-invasive 64-slice CT coronary angiography inpatients with stable angina pectoris. Eur Radiol 2006;16:575–582.

9. Halon DA, Rubinshtein R, Shiran A, Lewis BS. Resolution of anintra-coronary filling defect in the proximal left anterior descendingcoronary artery demonstrated by 64-slice multi-detector computed
tomography. Catheter Cardiovasc Interv 2006;67:246–249.
0. Gaspar T, Halon DA, Lewis BS, Adawi S, Schliamser JE, RubinshteinR, Flugelman MY, Peled N. Diagnosis of coronary in-stent restenosiswith multi-detector row computed tomography. J Am Coll Cardiol2005;46:1573–1579.

1. Jones CM, Athanasiou T, Dunne N, Kirby J, Aziz O, Haq A, Rao C,Constantinides V, Purkayastha S, Darzi A. Multi-detector computedtomography in coronary artery bypass graft assessment: a meta-anal-ysis. Ann Thorac Surg 2007;83:341–348.

2. Sheth T, Dodd J, Hoffmann U, Abbara S, Finn A, Gold HK, Brady TJ,Cury RC. Coronary stent assessability by 64 slice multi–detectorcomputed tomography. Catheter Cardiovasc Interv 2007;69:933–938.

3. Lewis BS, Halon DA. Integrating multidetector computed tomographyinto clinical practice: computed tomography scanning shows its metal.J Am Coll Cardiol 2007;49:960–962.

4. Lee TH, Goldman L. Evaluation of the patient with acute chest pain.N Engl J Med 2000;342:1187–1195.

5. Heuscher DJ, Chandra S. Multi-phase cardiac imager. United Statespatent #6510337, January 21, 2003.

6. Manzke R, Grass M, Nielsen T, Shechter G, Hawkes D. Adaptivetemporal resolution optimization in helical cardiac cone beam CTreconstruction. Med Phys 2003;30:3072–3080.

7. Vembar M, Garcia MJ, Heuscher DJ, Haberl R, Matthews D, BohmeGE, Greenberg NL. A dynamic approach to identifying desired phys-iological phases for cardiac imaging using multislice spiral CT. MedPhys 2003;30:1683–1693.

8. Raptopoulos V. Cardiac CT for evaluating chest pain in the emergencydepartment. In: Lewis BS, Ongen Z, Flugelman MY, Halon DA, eds.Progress in Coronary Artery Disease. Bologna, Italy: Medimond,
2005:179–185.

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Prognostic Value of Coronary Flow Reserve in Medically TreatedPatients With Left Anterior Descending Coronary Disease

With Stenosis 51% to 75% in Diameter

Fausto Rigo, MDa, Rosa Sicari, MD, PhDd,*, Sonia Gherardi, MDb,Ana Djordjevic-Dikic, MD, PhDe, Lauro Cortigiani, MDc, and Eugenio Picano, MD, PhDd

According to American College of Cardiology/American Heart Association/Society forCardiovascular Angiography and Interventions 2005 guidelines on percutaneous interven-tion, intracoronary physiologic measurement in the assessment of effects of intermediatecoronary stenoses in patients with anginal symptoms is a class IIa indication. This studyassessed the additional prognostic value of Doppler echocardiographically derived coro-nary flow reserve (CFR) in patients with single-vessel disease and intermediate stenosisseverity. We enrolled 86 patients (44 men; 66 � 10 years of age) with angiographicallyassessed single-vessel coronary artery disease of the left anterior descending coronaryartery (LAD) with quantitatively assessed diameter stenosis severity 50% to 75%. Allpatients underwent dipyridamole (up to 0.84 mg/kg over 6 minutes) stress echocardiogra-phy with wall motion analysis by 2-dimensional echocardiography and CFR evaluation ofthe affected artery by Doppler. All patients were followed up for a median of 14 months(first quartile 10, third quartile 18) after diagnostic coronary angiography (without percu-taneous intervention for a clinically driven decision). Mean diameter stenosis of the LADwas 58 � 10%. Mean CFR of the LAD was 2.09 � 0.5. Regional wall motion abnormalityat peak stress was present in 17 patients. During follow-up, 24 events occurred: 6 nonfatalST-elevation myocardial infarctions and 18 non–ST-elevation myocardial infarctions.Thirty-month spontaneous event-free survival was higher in patients with normal CFR andlower in patients with decreased CFR (86% vs 30%, p � 0.0001). At Cox analysis, a CFR<2 (hazard ratio 24.2, 95% confidence interval 3.2 to 179.7, p � 0.002) was the onlyindependent prognostic predictor of outcome. In conclusion, in medically treated patientswith single-vessel disease of intermediate severity, decreased CFR is associated with aworse outcome. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:
1527–1531)
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his study assessed the prognostic impact of dual imagingf left ventricular function and coronary flow reserveCFR)1–7 during dipyridamole stress echocardiography inatients with single-vessel disease of the left anterior de-cending coronary artery (LAD) and stenosis severity 50%o 75% diameter decrease.

ethods

rom the Echo Persantine International Cooperative (EPIC)tudy data bank, we selected 86 patients (44 men; 66 � 10ears of age) prospectively enrolled from 5 centers (Mestre,esena, Lucca, Belgrade, and Pisa). All patients met the

ollowing inclusion criteria: (1) stable chest pain syndrome;

aCardiology Division, Umberto Io Hospital, Mestre-Venice; bCardiol-gy Division, Cesena Hospital, Cesena; cCardiology Division, Campo diarte Hospital, Lucca; and dCNR, Institute of Clinical Physiology, Pisa,

taly; and eInstitute for Cardiovascular Disease, Clinical Center of Serbia,elgrade, Yugoslavia. Manuscript received April 26, 2007; revised manu-

cript received and accepted June 17, 2007.*Corresponding author: Tel: 0039-050-315-2397; fax: 0039-050-315-

216.
eE-mail address: [email protected] (R. Sicari).

2) eligibility for dipyridamole stress echocardiography bytandard wall motion criteria; (3) coronary angiographyerformed systematically after stress echocardiographywithin 1 week) and showing single-vessel disease with auantitatively assessed diameter decrease of 50% to 75% inhe LAD; and (4) enrollment in a follow-up program. Ex-lusion criteria were (1) technically poor acoustic windowrecluding satisfactory imaging of the left ventricle (for-dimensional echocardiography) or the LAD (for CFRssessment); (2) single-vessel disease of the left circumflexr right coronary artery; (3) valvular heart disease; and (4)nwillingness to give informed consent.

According to individual needs and physicians’ choices,0 patients were evaluated after antianginal drugs had beeniscontinued, and 46 patients were evaluated during antian-inal treatment (nitrates and/or calcium antagonists and/or �lockers).

The study was approved by the institutional reviewoard. All patients gave their written informed consenthen they underwent stress echocardiography. When pa-

ients signed the written informed consent, they also autho-ized physicians to use their clinical data. Stress echocar-iographic data were collected and analyzed by stress
chocardiographers not involved in patient care. Coronary
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ngiography was performed within 1 week of stress echo-ardiography, and results were available to the interven-ional cardiologist at the time of catheterization but werenlikely to have affected decision making. All patients wereollowed up for a median of 14 months (first quartile 10,hird quartile 18) with a minimum predefined follow-upime of 3 months.

Two-dimensional echocardiography and 12-lead electro-ardiographic monitoring were performed in combinationith high-dose dipyridamole (up to 0.84 mg over 6 minutes)

ccording to well-established protocols.8,9 During the pro-edure, blood pressure and electrocardiogram were re-orded each minute. CFR was performed during standardtress echocardiographic examination by semi-simultaneousmaging of wall motion and LAD flow (Figure 1).1 CFR wasssessed using a broad-band high-frequency (5 to 12 MHz)ransthoracic transducer (S12) or 3.5 to 7.0 MHz with secondarmonic capability (S8). Coronary flow in the mid-distal por-ion of the LAD was searched in the low parasternal long-axisross section under the guidance of color Doppler flow map-ing.1 CFR was considered normal when it was �2.10 Qual-ty control of stress echocardiographic performance andeading in enrolled centers was previously described inepth.11 Briefly, the reader from each recruiting center methe predefined criteria for stress echocardiographic reading.t that point, the center could start recruiting patients, and

eading of the stress echocardiogram from the recruitingenter was directly entered in the data bank.

Coronary angiography in multiple views was performedccording to standard Judkins or Sones technique. At leastviews (including 2 orthogonal views) were acquired for

he left coronary artery and �2 orthogonal views for theight coronary artery. Additional appropriate projectionsere obtained in case of superimposition of side branches or

oreshortening of the segment of interest. A vessel wasonsidered to have significant obstruction if its diameter

0

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igure 1. Protocol of dipyridamole stress echocardiography. 2D echo � 2-dlectrocardiogram; PW � pulsewave.

as narrowed by 50% compared with the prestenotic seg- v

ent. All stenotic segments were evaluated by an automateddge detection system providing percent stenosis diameter.

Follow-up data were obtained from �1 of 4 sources:eview of a patient’s hospital record, personal communica-ion with a patient’s physician and review of a patient’shart, a telephone interview with a patient conducted byrained personnel, and/or a staff physician visiting patientst regular intervals in the outpatient clinic. According totudy protocol) follow-up information was obtained every 3onths. By inclusion criteria, follow-up data were obtained

n all patients. Events were defined as death, nonfatal acuteoronary syndromes (ST-elevation myocardial infarction oron–ST-elevation myocardial infarction), and clinicallyriven coronary revascularization (surgery or angioplasty).T-elevation myocardial infarction was defined by typicalymptoms, ST elevation on electrocardiogram, and cardiacnzyme changes. Non–ST-elevation myocardial infarctionas an acute coronary syndrome causing typical chest pain,

ardiac enzyme increase, and/or electrocardiographic mod-fications consistent with acute ischemia12 requiring hospi-alization. Follow-up data were analyzed for prediction ofeath, ST-elevation myocardial infarction, and non–ST-el-vation myocardial infarction.

Therefore, the outcome event was spontaneously oc-urring events (death and nonfatal myocardial infarction)or spontaneous event-free survival. Only the most severeutcome was considered an end point when follow-upas censored at the time of revascularization procedures.hen �1 of these events occurred, the patient was cen-

ored at the time of the most severe event. Statisticalnalyses included descriptive statistics (frequency andercentage of categorical variables and mean � SD ofontinuous variables), Kaplan-Meier survival curves, andox proportional hazards models. The following covari-tes were analyzed: age, gender, smoking, typical chestain, hypertension, diabetes, hypercholesterolemia, pre-

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1529Coronary Artery Disease/Coronary Flow Reserve and Intermediate Stenosis Severity

est and at peak stress, � wall motion score index (vari-tion of wall motion score between rest and stress),lectrocardiographic modifications during dipyridamoletress, presence of angina during dipyridamole stress,resence of medical therapy at time of testing, CFR, andresence of angiographically assessed coronary arteryisease. Differences between survival curves were com-ared with log-rank test. All analyses were performedsing SPSS (SPSS, Inc., Chicago, Illinois), and p values0.05 were considered statistically significant.

esults

he main clinical and echocardiographic data are presentedn Table 1. Mean CFR of the LAD was 2.09 � 0.5. Atndividual patient analysis, 39 patients had normal CFR�2.0, mean 2.4 � 0.4) and 47 had abnormal CFR (mean.76 � 0.2).

CFR>2 (86%)

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igure 2. Kaplan-Meier survival curves (considering spontaneous cardiacvents as an end point) in patients stratified according to normal (�2) orbnormal (�2) CFR on Doppler echocardiogram during high-dose dipy-idamole stress echocardiography. The best survival is observed in patientsith normal CFR.

able 1indings at rest and stress in the study population (n � 86)

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ge (yrs) 66 � 10en/women 44/42

moker 25ypertension 72iabetes mellitus 16ypercholesterolemia 55ngina pectoris on effort 24revious myocardial infarction 20all motion score index at rest 1.09 � 0.2all motion score index at peak stress 1.13 � 0.2

est positivity for wall motion criteria 17atients with CFR �2 39est performed on antianginal therapy 46�-blocking agents 35Calcium antagonists 24Long-acting nitrates 15AD on coronary angiogram (percent diameter

stenosis)86 (56 � 10)

During a median follow-up of 14 months (first quartile a

0, third quartile 18), a total of 24 events (28%; 6 nonfatalT-elevation myocardial infarctions and 18 non–ST-eleva-

ion myocardial infarctions) occurred. No cardiac deathccurred during follow-up. Twenty-three of 47 patients withn abnormal CFR developed events versus 6 of 17 with aositive test result by wall motion criteria (51% vs 35%, p0.05).The 3-year infarction-free survival showed a signifi-

antly better outcome for those patients with normal CFRFigure 2), whereas a worse outcome was observed in pa-ients with impaired CFR. Univariate predictors of sponta-eous events are presented in Table 2. At Cox analysis, aFR �2 (hazard ratio 24.0, 95% confidence interval 3.2 to79.7, p � 0 .002) was the only independent prognosticredictor of outcome.

iscussion

n medically treated patients with single-vessel LAD steno-is severity of 50% to 75% diameter narrowing, CFR pro-ides independent information for prognostic stratification,nd a decreased CFR is associated with a worse outcome.FR is more often decreased in this set of patients com-ared with test positivity by wall motion criteria, thus iden-ifying a subgroup at higher risk of developing spontaneousvents. Nonetheless, no cardiac death occurred during fol-ow-up, indicating a low-risk group overall.

Several studies have evaluated invasive pressure-derivedractional flow reserve in patients with intermediate coro-ary stenosis severity to identify those at higher risk ofeveloping events if left untreated.13–17 In a recent study,17

large cohort of 407 consecutive patients treated accordingo the results of fractional flow reserve was reported: 2/3 ofatients with intermediate lesions were left unrevascular-zed, with a favorable and comparable outcome comparedith a revascularized group when fractional flow reserveas �0.80. These results agree with the DEFER study,here there was no significant difference in late outcomeetween revascularized and nonrevascularized patients withfractional flow reserve �0.75.15 Similar results were ob-

ained in a small series of 15 patients16 or in retrospective

able 2nivariate predictors of spontaneous events

RR (95% CI) p Value

ge 0.9 (0.9–1.0) 0.91en 0.5 (0.2–1.2) 0.14iabetes 0.8 (0.3–2.4) 0.74ypercholesterolemia (LDL �100 mg/dl) 0.7 (0.3–1.6) 0.45moking habit 0.6 (0.2–1.7) 0.38ypertension 1.1 (0.3–3.2) 0.85revious myocardial infarction 1.0 (0.4–2.4) 0.95ngina on effort 0.8 (0.3–2.4) 0.83all motion score index at rest 0.7 (0.15–3.7) 0.73all motion score index at peak stress 0.96 (0.18–4.5) 0.93

est positivity for wall motion criteria 1.4 (0.5–3.5) 0.4edical therapy at time of testing 1.4 (0.6–3.2) 0.4FR �2 24.2 (3.2–179.7) 0.002

CI � confidence interval; LDL � low-density lipoprotein; RR � rela-ive risk.

nalyses.14 In the present study, we employed a noninvasive

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oppler technique during conventional vasodilator stresschocardiography for assessment of CFR. This approachas several advantages, including the possibility to obtainow and function information in the same sitting and easyccess, low cost, and radiation-free nature of the ultrasoundechnique.18 Echocardiographically assessed CFR has alsoeen extensively validated in its prognostic correlates.19–22

rom a pathophysiologic viewpoint, when comparing theesults with fractional flow reserve, one should recognize,owever, that fractional flow reserve is a specific index forpicardial stenosis, whereas CFR addresses conduit andicrovascular circulations.Noninvasive prognostic assessment of single-vessel dis-

ase is an unresolved issue to date.6 Stress echocardiogra-hy based on conventional wall motion analysis is certainlyffective in risk stratification of single-vessel disease,6 and

significantly higher 4-year infarction-free survival rateas found in invasively treated patients with a positive test

esult, but not in those with a negative stress test result,ased on regional wall motion analysis.6 However, the sen-itivity of the 2-dimensional echocardiographic technique isow in patients with single-vessel disease of intermediateeverity, especially in patients on medical therapy. This isnown in the literature for all types of stress and is con-rmed in the present study,23–25 even with the “fast” oraccelerated” infusion protocol granting optimal sensitivityor vasodilator stress echocardiography.9 The practice oferforming coronary revascularization on the basis of cor-nary anatomic findings only, without preprocedural non-nvasive stress testing, is a frequent therapeutic option,nflating risks and costs of patient care.26 A strategy ofelecting for revascularization only patients with a de-reased CFR and/or inducible wall motion abnormalitiesould certainly improve the cost-benefit practice comparedith indiscriminate “carpet bombing” with dilatation for all

tenoses independent of the underlying clinical picture andhysiologic substrate. The American Heart Association/merican College of Cardiology/Society for Cardiovascularngiography and Interventions on percutaneous coronary

nterventions guidelines and the American Heart Associa-ion scientific statement from the committee on diagnosticnd interventional cardiac catheterization have indicatedhat, in the presence of an intermediate lesions, when frac-ional flow reserve is �0.75 or CFR is �2.0, the stenosis isonsidered hemodynamically significant and percutaneousoronary intervention can be supported. If fractional floweserve is �0.80 or CFR �2.5, the clinical benefit of per-utaneous coronary interventions can be questioned.27,28

1. Rigo F, Richieri M, Pasanisi E, Cutaia V, Zanella C, Della ValentinaP, Di Pede F, Raviele A, Picano E. Usefulness of coronary flow reserveover regional wall motion when added to dual-imaging dipyridamoleechocardiography. Am J Cardiol 2003;91:269–273.

2. Nohtomi Y, Takeuchi M, Nagasawa K, Arimura K, Miyata K, KuwataK, Yamawaki T, Kondo S, Yamada A, Okamatsu S. Simultaneousassessment of wall motion and coronary flow velocity in the leftanterior descending coronary artery during dipyridamole stress echo-cardiography. J Am Soc Echocardiogr 2003;16:457–463.

3. Lowenstein J, Tiano C, Marquez G, Presti C, Quiroz C. Simultaneousanalysis of wall motion and coronary flow reserve of the left anteriordescending coronary artery by transthoracic Doppler echocardiogra-
phy during dipyridamole stress echocardiography. J Am Soc Echocar-diogr 2003;16:607–613.
4. Chirillo F, Bruni A, De Leo A, Olivari Z, Franceschini-Grisolia E,Totis O, Stritoni P. Usefulness of dipyridamole stress echocardiogra-phy for predicting graft patency after coronary artery bypass grafting.Am J Cardiol 2004;93:24–30.

5. Ascione L, De Michele M, Accadia M, Granata G, Sacra C, D’AndreaA, Guarini P, Tuccillo B. Incremental diagnostic value of ultrasono-graphic assessment of coronary flow reserve with high-dose dipyrid-amole in patients with acute coronary syndrome. Int J Cardiol 2006;106:313–318.

6. Cortigiani L, Picano E, Landi P, Previtali M, Pirelli S, Bellotti P, BigiR, Magaia O, Galati A, Nannini E. Value of pharmacologic stressechocardiography in risk stratification of patients with single-vesseldisease: a report from the Echo-Persantine and Echo-DobutamineInternational Cooperative Studies. J Am Coll Cardiol 1998;32:69–74.

7. Rigo F, Cortigiani L, Pasanisi E, Richieri M, Cutaia V, Celestre M,Raviele A, Picano E. The additional prognostic value of coronary flowreserve on left anterior descending artery in patients with negativestress echo by wall motion criteria. A transthoracic vasodilator stressecho study. Am Heart J 2005;149:684–689.

8. Armstrong WF, Pellikka PA, Ryan T, Crouse L, Zoghbi WA. Stressechocardiography: recommendations for performance and interpreta-tion of stress echocardiography. Stress Echocardiography Task Forceof the Nomenclature and Standards Committee of the American So-ciety of Echocardiography. J Am Soc Echocardiogr 1998;11:97–104.

9. Dal Porto R, Faletra F, Picano E, Pirelli S, Moreo A, Varga A. Safety,feasibility, and diagnostic accuracy of accelerated high-dose dipyrid-amole stress echocardiography. Am J Cardiol 2001;87:520–524.

0. Rigo F. Coronary flow reserve in stress-echo lab. From pathophysio-logic toy to diagnostic tool. Cardiovasc Ultrasound 2005;3:8–19.

1. Picano E, Lattanzi F, Orlandini A, Marini C, L’Abbate A. Stressechocardiography and the human factor: the importance of beingexpert. J Am Coll Cardiol 1991;17:666–669.

2. Gibler WB, Cannon CP, Blomkalns AL, Char DM, Drew BJ, Hol-lander JE, Jaffe AS, Jesse RL, Newby LK, Ohman EM, et al, for theAmerican Heart Association Council on Clinical Cardiology (Subcom-mittee on Acute Cardiac Care); Council on Cardiovascular Nursing,and Quality of Care and Outcomes Research Interdisciplinary WorkingGroup; Society of Chest Pain Centers. Practical implementation of theguidelines for unstable angina/non–ST-segment elevation myocardialinfarction in the emergency department: a scientific statement from theAmerican Heart Association Council on Clinical Cardiology (Subcom-mittee on Acute Cardiac Care), Council on Cardiovascular Nursing,and Quality of Care and Outcomes Research Interdisciplinary WorkingGroup, in collaboration with the Society of Chest Pain Centers. Cir-culation 2005;111:2699–2710.

3. Kern MJ, Donohue TJ, Aguirre FV, Bach RG, Caracciolo EA, Wol-ford T, Mechem CJ, Flynn MS, Chaitman B. Clinical outcome ofdeferring angioplasty in patients with normal translesional pressure-flow velocity measurements. J Am Coll Cardiol 1995;25:178–187.

4. Bech GJ, De Bruyne B, Bonnier HJ, Bartunek J, Wijns W, Peels K,Heyndrickx GR, Koolen JJ, Pijls NH. Long-term follow-up afterdeferral of percutaneous transluminal coronary angioplasty of inter-mediate stenosis on the basis of coronary pressure measurement. J AmColl Cardiol 1998;31:841–847.

5. Bech GJ, De Bruyne B, Pijls NH, de Muinck ED, Hoorntje JC,Escaned J, Stella PR, Boersma E, Bartunek J, Koolen JJ, Wijns W.Fractional flow reserve to determine the appropriateness of angioplastyin moderate coronary stenosis: a randomized trial. Circulation 2001;103:2928–2934.

6. Chamuleau SA, Tio RA, de Cock CC, de Muinck ED, Pijls NH, vanEck-Smit BL, Koch KT, Meuwissen M, Dijkgraaf MG, de Jong A, etal. Usefulness of fractional flow reserve for risk stratification of pa-tients with multivessel coronary artery disease and an intermediatestenosis. Am J Cardiol 2002;89:377–380.

7. Legalery P, Schiele F, Seronde MF, Meneveau N, Wei H, Didier K,Blonde MC, Caulfield F, Bassand JP. One-year outcome of patientssubmitted to routine fractional flow reserve assessment to determinethe need for angioplasty. Eur Heart J 2005;26:2623–2629.

8. Picano E. Sustainability of medical imaging. Education and debate.BMJ 2004;328:578–580.

9. Rigo F, Varga Z, Di Pede F, Grassi G, Turiano G, Zuin G, Coli U,Raviele A, Picano E. Early assessment of coronary flow reserve by
transthoracic Doppler echocardiography predicts late remodelling in

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1531Coronary Artery Disease/Coronary Flow Reserve and Intermediate Stenosis Severity

reperfused anterior myocardial infarction. J Am Soc Echocardiogr2004;17:750–755.

0. Rigo F, Gherardi S, Galderisi M, Pratali L, Cortigiani L, Sicari R,Picano E. The prognostic impact of coronary flow reserve assessed byDoppler echocardiography in non-ischemic dilated cardiomyopathy.Eur Heart J 2006;27:1319–1323.

1. Rigo F, Gherardi S, Galderisi M, Sicari R, Picano E. The independentprognostic value of contractile and coronary flow reserve determinedby dipyridamole stress echocardiography in patients with idiopathicdilated cardiomyopathy. Am J Cardiol 2007;99:1154–1158.

2. Sicari R, Rigo F, Ossena G, Gherardi S, Pasanisi E, Cortigiani L,Picano E. The additive prognostic value of wall motion abnormalitiesand coronary flow reserve during dipyridamole stress echo (abstr).Circulation 2006;2150.

3. Marwick T, D’Hondt AM, Baudhuin T, Willemart B, Wijns W, DetryJM, Melin J. Optimal use of dobutamine stress for the detection andevaluation of coronary artery disease: combination with echocardiog-raphy or scintigraphy, or both? J Am Coll Cardiol 1993;22:159–167.

4. Sicari R, Cortigiani L, Bigi R, Landi P, Raciti M, Picano E. Theprognostic value of pharmacological stress echo is affected by con-comitant anti-ischemic therapy at the time of testing. Circulation
2004;109:2428–2431.
5. Pingitore A, Picano E, Colosso MQ, Reisenhofer B, Gigli G, LucariniAR, Petix N, Previtali M, Bigi R, Chiaranda G, et al. The atropinefactor in pharmacologic stress echocardiography. Echo Persantine(EPIC) and Echo Dobutamine International Cooperative (EDIC) StudyGroups. J Am Coll Cardiol 1996;27:1164–1170.

6. Picano E. Economic and biological costs of cardiac imaging. Cardio-vasc Ultrasound 2005;3:13–20.

7. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, Jacobs AK, Kern MJ, KingSB III, Morrison DA, O’Neil WW, Schaff HV, Whitlow PL, et al.ACC/AHA/SCAI 2005 guideline update for percutaneous coronaryintervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines(ACC/AHA/SCAI Writing Committee to Update 2001 Guidelinesfor Percutaneous Coronary Intervention). Circulation 2006;113:166 –286.

8. Kern MJ, Lerman A, Bech JW, De Bruyne B, Eeckhout E, Fearon WF,Higano ST, Lim MJ, Meuwissen M, Piek JJ, et al. Physiologicalassessment of coronary artery disease in the cardiac catheterizationlaboratory: a scientific statement from the American Heart Associ-ation Committee on Diagnostic and Interventional Cardiac Cathe-terization, Council on Clinical Cardiology. Circulation 2006;114:
1321–1341.

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Comparison of Diagnostic Accuracy of 64-Slice ComputedTomography Coronary Angiography in Women

Versus Men With Angina Pectoris

W. Bob Meijboom, MDa,b, Annick C. Weustink, MDa,b, Francesca Pugliese, MDa,b,Carlos A.G. van Mieghem, MDa,b, Nico R. Mollet, MD, PhDa,b, Niels van Pelt, MDa,b,

Filippo Cademartiri, MD, PhDb, Koen Nieman, MD, PhDa, Eleni Vourvouri, MD, PhDa,b,Eveline Regar, MD, PhDa, Gabriel P. Krestin, MD, PhDb, and Pim J. de Feyter, MD, PhDa,b,*

We compared the diagnostic accuracy of 64-slice computed tomographic (CT) coronaryangiography to detect significant coronary artery disease (CAD) in women and men. The64-slice CT coronary angiography was performed in 402 symptomatic patients, 123 womenand 279 men, with CAD prevalence of 51% and 68%, respectively. Significant CAD,defined as >50% coronary stenosis on quantitative coronary angiography, was evaluatedon a patient, vessel, and segment level. The sensitivity and negative predictive value todetect significant CAD was very good, both for women and men (100% vs 99%, p � NS;100% vs 98%, p � NS), whereas diagnostic accuracy (88% vs 96%; p <0.01), specificity(75% vs 90%, p <0.05), and positive predictive value (81% vs 95%, p <0.001) were lowerin women. The per-segment analysis demonstrated lower sensitivity in women comparedwith men (82% vs 93%, p <0.001). The sensitivity in women did not show a difference inproximal and midsegments, but was significantly lower in distal segments (56% vs 85%, p<0.05) and side branches (54% vs 89%, p <0.001). In conclusion, CT coronary angiographyreliably rules out the presence of obstructive CAD in both men and women. Specificity andpositive predictive value of CT coronary angiography were lower in women. The sensitivityto detect stenosis in small coronary branches was lower in women compared with
men. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:1532–1537)
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omputed tomographic coronary angiography (CTCA) is aapidly evolving coronary imaging technique, and a poten-ial alternative to established noninvasive tests for coronaryrtery disease (CAD). The diagnostic accuracy of CTCA inomen per se has not been investigated, but is extrapolated

rom reports that were performed in populations largelyonsisting of men.1–9 Although earlier data suggested a dis-repancy between men and women with regard to the diag-ostic performance of ischemia-driven tests, recent reportssing contemporary exercise electrocardiographic (ECG)esting, stress echocardiography, and gated single-photonmission computed tomography myocardial perfusion im-ging refute these earlier conclusions, and state similariagnostic results for both women and men.10–16 Apart fromarying age, disease prevalence and severity, additionalnatomic and physiologic differences, including body com-osition, heart rate, coronary calcium, and coronary diam-ter size, between men and women may affect the diagnos-ic performance of CTCA. The purpose of this study was toscertain the diagnostic accuracy of CTCA in women versus

Departments of aCardiology, Thoraxcenter and bRadiology, Erasmusniversity Medical Center, Rotterdam, The Netherlands. Manuscript re-

eived April 2, 2007; revised manuscript received and accepted May 31,007.

wE-mail address: [email protected] (P.J. de Feyter).

en with chest pain to detect or exclude the presence ofbstructive CAD.

ethods

uring a 24-month period 402 patients with acute or stablehest pain symptoms who were referred for conventionaloronary angiography (CCA) were included in the study.o patients with a history of percutaneous coronary inter-ention or coronary artery bypass surgery, impaired renalunction (serum creatinine �120 �mol/L), persistent ar-hythmias, and known intolerance to iodinated contrast ma-erial were included. CCA was performed before or afterTCA and served as the standard of reference. The institu-

ional review board of the Erasmus MC Rotterdam ap-roved the study, and all subjects gave informed consent.

Patients with a heart rate �65 beats/min received addi-ional � blockers (50/100 mg metoprolol) 1 hour before theT examination. All scans were performed on a 64-slice CT

canner with a gantry rotation time of 330 ms, a temporalesolution of 165 ms, and a spatial resolution of 0.4 mm3

Sensation 64; Siemens, Forchheim, Germany). For the cor-nary calcium score, a low-dose, nonenhanced scan waserformed with the following, standardized parameters: 32

2 slices per rotation; individual detector width of 0.6 mm,30-ms rotation time, 3.8-mm/rotation table feed, 120-kVube voltage, 150-mAs tube current, with activated prospec-ive x-ray tube modulation. The CTCA scan was performed
ith identical parameters except for a higher tube current
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1533Coronary Artery Disease/CTCA in Women Versus Men

etween 850 and 960 mAs without prospective ECG x-rayube modulation. The radiation exposure was estimated us-ng dedicated software (ImPACT, version 0.99x, St.eorge’s Hospital, Tooting, London, United Kingdom). A5-ml bolus of iomeprol (Iomeron, 400 mg/ml; Bracco,ilan, Italy) was injected intravenously into an antecubital

ein at 5 ml/s. A bolus-tracking technique was used toonitor the arrival of contrast in the coronary arteries. The

can was started once the contrast material in the ascendingorta reached a predefined threshold of �100 Hounsfieldnits.

Datasets were reconstructed immediately after the scanollowing a stepwise outline. Images were obtained duringhalf x-ray tube rotation, resulting in an effective temporal

esolution of 165 ms. To acquire optimal motion-free im-ges, images were reconstructed by retrospective ECG gat-ng. Initially, a single dataset was reconstructed during theid-to-end-diastolic phase (350 ms before the next R wave

r at 65% of the RR interval). In case of insufficient imageuality of �1 coronary segments, additional datasets wereeconstructed in the diastolic phase (between 250 and 450s before the next R wave or between 60% and 70% of theR interval). In case of persistent artifacts related to coro-ary motion, a second reconstruction approach was carriedut. Datasets were reconstructed during the end-systolichase using an absolute forward or percentage techniquebetween 250 and 400 ms after the previous R wave oretween 25% and 35% of the RR interval). In 34% of the

able 1atient demographics (n � 402)

ariable

ge (yrs)*alcium score (Agatston score)† 1ody mass index (kg/m2)*eart rate (beats/min)*revalence of obstructive coronary artery diseasetypical angina pectorisypical angina pectorisnstable angina pectorison–ST–segment elevation myocardial infarctionypertension‡

ypercholesterolemia§

iabetes mellitus#

ctive smokerrevious smokerody mass index �30 kg/m2

revious myocardial infarctiononventional coronary angiographyAbsence of coronary diseaseNonsignificant diseaseSingle-vessel diseaseMultivessel disease

* Mean � SD.† Median and quartiles. Values are numbers (percent), unless otherwis

ariables were tested with unpaired 2-sided Student’s t test. If not normalValues are significant if �0.05.‡ Blood pressure �140/90 mm Hg or treatment for hypertension.§ Total cholesterol �180 mg/dl or treatment for hypercholesterolemia.# Treatment with oral antidiabetic medication or insulin.

atients (137 of 402) end-systolic reconstructions were used o

or image analysis. If necessary, multiple datasets of aingle patient were used separately to obtain optimal imageuality of all available coronary segments.

All scans were carried out within 1 week before or afterTCA. One experienced cardiologist, who was unaware of

he CTCA results, identified and analyzed all coronary seg-ents according to the modified 17-segment Americaneart Association classification.17 Regardless of diameter

ize, all segments were included for comparison withTCA. Segments were classified as normal (smooth parallelr tapering borders), nonsignificantly stenosed (wall irreg-larities or �50% narrowed), or significantly stenosed�50% narrowed). Stenoses were evaluated in the worstiew, and classified as significant if the lumen diametereduction was �50% as measured by a validated quantita-ive coronary angiographic algorithm (CAAS, Pie Medical,

aastricht, The Netherlands).18

For each patient the total calcium score was measured,nd expressed using the Agatston score.17 Two experienced,linded observers evaluated the CTCA data on an offlineorkstation (Leonardo, Siemens, Forchheim, Germany).he axial source images, as well as multiplanar or curved

eformatted reconstructions and maximum intensity projec-ions, were used to evaluate the CT angiograms and assesshe presence of significant segmental stenosis. Segmentsere scored positive for significant CAD if there was �50%iameter reduction of the lumen by visual assessment. Seg-ents distal to an occluded segment were excluded. Inter-

en23)

Men(n � 279)

p Value

11 58 � 11 �0.01373) 207 (18–530) �0.055.0 27.0 � 3.6 NS7 58 � 8 �0.001

%) 190 (68%) �0.01%) 99 (35%)

NS%) 107 (38%)%) 36 (13%)%) 37 (13%)%) 138 (49%) �0.05%) 161 (58%) NS%) 28 (10%) �0.05%) 99 (35%) �0.05) 20 (7%) NS

%) 64 (23%) NS%) 27 (10%) NS

%) 42 (15%)

�0.05%) 47 (17%)%) 91 (33%)%) 99 (35%)

ated. Categorical variables were tested with chi-square test. Continuousbuted, continuous variables were compared with the Mann-Whitney test.

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Descriptive statistics were performed for coronary seg-ents, vessels, and patients. The diagnostic performance ofTCA for the detection of significant stenoses in the coro-ary arteries with quantitative coronary angiography (QCA)s the standard of reference is presented as sensitivity,pecificity, positive and negative predictive values. Preci-ion of the diagnostic parameters is presented using a 95%onfidence interval (CI). Chi-square tests were performed tohow significant differences in diagnostic accuracy. Positivend negative likelihood ratios are given. The likelihoodatio incorporates both the sensitivity and specificity of aest and provides a direct estimate of how much a test resultill change the odds of having a disease. Post-test odds cane calculated by multiplying the pretest odds (pretest prob-bility/[1 � pretest probability]) by the positive likelihoodatio (sensitivity/[1 � specificity]) and negative likelihoodatio ([1 � sensitivity]/specificity). Post-test probability cane recalculated by using the following formula: (post-testrobability � post-test odds/[1 � post-test odds]).

A subanalysis was performed between the 2 genders.ategorical characteristics are expressed as numbers andercentages, and compared between the 2 groups with thehi-square test. Continuous variables are expressed as mean

SD and compared with an unpaired 2-sided Student’s test when normally distributed. When not normally distrib-ted, continuous variables are expressed as medians (25th to5th percentile range) and compared using the nonparamet-ic Mann-Whitney test. p Values �0.05 were consideredtatistically significant.

An additional sensitivity analysis was done to investigate

able 2verall diagnostic performance of 64-slice computed tomographic corona

ariable Womenn% (95% CI), n/n

atient levelSensitivity 100% (93–100) 63/63Specificity 75% (62–85) 45/60Positive predictive value 81% (70–88) 63/78Negative predictive value 100% (93–100) 45/45Diagnostic accuracy 88% (82–94) 108/123� Likelihood ratio 4.00 (2.58–6.20)� Likelihood ratio 0 (0-/)essel levelSensitivity 94% (87–98) 93/99Specificity 87% (83–90) 342/393Positive predictive value 65% (56–72) 93/144Negative predictive value 98% (96–99) 342/348Diagnostic accuracy 88% (86–91) 435/492� Likelihood ratio 7.24 (5.58–9.40)� Likelihood ratio 0.07 (0.03–0.15)egment levelSensitivity 82% (74–88) 111/136Specificity 94% (93–95) 1,551/1,64Positive predictive value 53% (46–60) 111/208Negative predictive value 98% (98–99) 1,551/1,57Diagnostic accuracy 93% (92–94) 1,662/1,78� Likelihood ratio 13.87 (11.25–17.09)� Likelihood ratio 0.20 (0.14–0.28)

Diagnostic performance and predictive value with corresponding likelihond men. Chi-square test was used for categorical variables. p Values we

he effect of nesting, as repeated assessments within the t

ame patient were made that were not independent obser-ations. Inter- and intraobserver variabilities for the detec-ion of significant coronary stenosis were determined by �tatistics.

esults

he analysis comprised 123 women and 279 men (Table 1).n average women were older (62 � 11 vs 58 � 11 years,�0.01). Hypertension and diabetes were more frequent inomen, with no significant difference for body mass index.here were more active smokers among men. Women had

ower disease prevalence (51% vs 68%, p �0.01), whichas defined as having �1 significant stenosis. The severity

nd extent of obstructive CAD was significantly lower inomen compared with men (p �0.05), with fewer casesf multivessel disease (24% vs 35%, p �0.05), andore nonobstructive lesions on CTCA (26% vs 17%,�0.05). There was a nonsignificant trend toward fewer

bsence of CAD on CTCA in women (23% vs 15%, p �.06). Furthermore, the calcium score was lower in women146 [0 to 373] vs 207 [18 to 530], p �0.05). During the CTcan, women had a significantly higher heart rate than men:1 � 7 vs 58 � 8 beats/min, p �0.001). Additional �lockers before CT scanning were administered to 73% ofomen (90 of 123) and 70% of men (196 of 279) (p � NS),ecreasing the mean heart rate from 69 � 10 to 61 � 7eats/min and from 69 � 11 to 58 � 8 beats/min, respec-ively.

The estimated radiation exposure using prospective x-ray

ography

Menn% (95% CI), n/n

p Value

99% (96–100) 188/190 NS90% (81–95) 80/89 �0.0595% (91–98) 188/197 �0.00198% (91–100) 80/82 NS96% (94–98) 268/279 �0.019.78 (4.70–14.25) —0.01 (0–0.05) —

97% (95–99) 307/315 NS84% (82–87) 676/801 NS71% (66–75) 307/432 NS99% (98–99) 676/684 NS88% (86–90) 983/1,116 NS6.25 (5.31–7.34) —0.03 (0.02–0.06) —

93% (91–96) 400/428 �0.00192% (91–93) 3,249/3,523 �0.0559% (56–63) 400/674 NS99% (99–99) 3,249/3,277 �0.0592% (92–93) 3,523/3,951 NS

12.02 (10.70–13.50) —0.07 (0.05–0.10) —

s of 64-slice CTCA for the detection of �50% stenosis on QCA in womenficant if values �0.05. Values in parentheses represent 95% CIs.

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as 1.8 and 1.4 mSv and the estimated radiation exposureor the contrast-enhanced scan without prospective x-rayube modulation was calculated as 17.0 and 13.4 mSv,hich is in line with previous reports.19

The diagnostic performance of CTCA for detecting sig-ificant stenoses on a patient-based analysis is detailed inable 2. All women (63 of 63) and 99% of men (188 of 190)ith significant CAD on CTCA were correctly identified by

omputed tomography (Figures 1 and 2). Fifteen women

igure 1. A maximum intensity projected CTCA image (A) depicts thenatomy of the right coronary artery. In the mid right coronary artery, aoncalcified obstructive coronary stenosis is visualized (arrow) with prox-mally and distally nonobstructive calcified plaques. Three curved multi-lanar reconstructed images confirm the significant lesions (arrow) from 3rthogonal projections (C, D, E), which was confirmed by CTCA (B).

igure 2. A volume-rendered CTCA image (A) reveals the anatomy of theight coronary artery. Two orthogonal curved multiplanar reconstructedmages (B, C) and a maximum intensity projected image (D) disclose aormal coronary artery without obstructive or nonobstructive plaques,hich was confirmed by CTCA (E).

25%, 15 of 60) and 9 men (10%, 9 of 89) with nonsignif- o

cant CAD were incorrectly classified as having significantoronary stenoses by CT.

In women, specificity (75% vs 90%, p �0.05), positiveredictive value (81% vs 95%, p �0.001), and overallccuracy (88% vs 96%, p �0.01) were significantly lowerompared with men. Agreement between CTCA and QCAn a per-patient (no or any disease) level for women anden was good (� value 0.75) and very good (� value 0.91).The diagnostic performance of CTCA for the detection

f significant coronary stenosis on a vessel-based analysis isetailed in Table 2. In women, 2 significantly diseased rightoronary arteries, 1 left anterior descending coronary artery,nd 3 diseased circumflex coronary arteries were incorrectlylassified as nonsignificantly diseased. In men, significantoronary stenosis in 2 right coronary arteries, 2 left anteriorescending coronary arteries, and 4 circumflex coronaryrteries were missed. Significant left main disease was iden-ified in all patients. Fifty-one and 125 nonobstructive ves-els were overestimated in women and men and scored asalse positives. The diagnostic accuracy was equal inomen and men. Agreement between CTCA and QCA onper-vessel level was both good for women and men (�

alue 0.69, 0.74).After exclusion of anatomically absent segments (833)

nd segments distal to an occlusion (266), 5,735 of 6,834otentially available segments (with a maximum of 17 seg-ents per patient) could be included for comparison withCA. No segments were excluded for reasons of calcifica-

ion or poor image quality. The overall sensitivity and spec-ficity of CTCA for the detection of significantly stenosedoronary segments was 91% and 93%. Sensitivity wasower in women (82% vs 93%, p �0.001). Also, the spec-ficity (94% vs 92%, p �0.05) and negative predictive value98% vs 99%, p �0.05) showed a small, but significantifference between men and women (Table 2).

The performance of CTCA was similar between men andomen in the proximal and middle segments (Table 3).owever, in the distal segments (56% vs 85%, p �0.05) and

ide branches, more lesions were not detected in womensensitivity 54% vs 89%, p �0.001; negative predictivealue 97% vs 99%, p �0.05). The specificity (96% vs 93%,�0.05) was slightly higher in women. Inter- and intraob-

erver variabilities for detection of a significant stenosis peregment had � values of 0.70 and 0.72, respectively. Agree-ent between CTCA and QCA on a per-segment level was

ood both for women and men (� value 0.61, 0.68). Toxclude the possible confounding effect of nesting, randomelection of a single segment per patient was done and theiagnostic accuracy for detecting significant artery diseaseesulted in a sensitivity 92% (44 of 48; 95% CI 79 to 97),pecificity 93% (331 of 356; 95% CI 90 to 95), positiveredictive value 64% (44 of 69; 95% CI 51 to 75), negativeredictive value 99% (331 of 335; 95% CI 97 to 100).

iscussion

e demonstrated that the sensitivity of 64-slice CTCA toetect significant CAD was almost equally high in womennd men (100% vs 99%) due to the very low occurrence ofalse-negative outcomes. Therefore, the diagnostic accuracy
f 64-slice CTCA to rule out the presence of significant

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bstructive CAD was equally high in women and men andnegative CT scan reliably obviates the need for further

ownstream evaluation with invasive coronary angiogra-hy. The lower prevalence of CAD in women, with a trendoward more nonsignificant CAD (p � 0.06) likely contrib-ted to the overestimation of coronary stenosis severity andhus resulted in lower specificity (75% vs 90%).

The segment-based diagnostic accuracy of CTCA per-ormed on a site-by-site analysis (segmental analysis)ompared with CTCA revealed a more complex outcome.he sensitivity to detect a stenosis was lower in women

han in men. The overall reduced sensitivity was mainlyaused by the lower sensitivity of CTCA to detect coro-ary obstructions in distal coronary segments and sideranches. This may be partly explained by the combina-ion of a milder stenosis severity and smaller size of theoronary arteries in women than in men. However, thisutcome does not affect the reliability to rule out theresence of significant CAD in case of a negative CTcan, because on a segment-based analysis the over-helming majority of these segments have no significantAD, and the calculation of the negative predictive value

s almost not affected by the higher occurrence of false-egative outcomes.

The studied patients were not a prospective, consecutiveroup of patients. However, selection was not based onarticular patient demographics, but rather on the availabil-ty of the 64-slice CT scanner for the examination of cardiacatients.

Fundamental limitations of cardiac computed tomogra-hy include the use of radiation, potentially nephrotoxicontrast media, and the need to use � blockers in patientsith a fast heart rate. The substantial radiation exposure of4-slice CTCA for women (17 mSv) and men (13.4 mSv)

able 3iagnostic performance of 64 slice computed tomography coronary angio

Womenn% (95% CI), n/n

nalysis of proximal segmentsSensitivity 96% (84–99) 44/46Specificity 92% (89–94) 411/44Positive predictive value 56% (44–67) 44/79Negative predictive value 100% (98–100) 411/4nalysis of midsegmentsSensitivity 93% (81–98) 43/46Specificity 91% (87–94) 285/31Positive predictive value 60% (47–71) 43/72Negative predictive value 99% (97–100) 285/2nalysis of distal segmentsSensitivity 56% (31–79) 9/16Specificity 97% (94–98) 364/37Positive predictive value 43% (23–66) 9/21Negative predictive value 98% (96–99) 364/37nalysis of side branchesSensitivity 54% (34–72) 15/28Specificity 96% (94–97) 491/51Positive predictive value 42% (26–59) 15/36Negative predictive value 97% (96–99) 491/50

Chi-square test was used for categorical variables. p Values were signi

ompared with CCA (3 to 6 mSv) is of concern.19 In this

tudy prospective ECG x-ray tube modulation, which canignificantly reduce radiation exposure, was not applied.his technique limits the possibility of reconstructing im-ges in the end-systolic phase. In our study, end-systolicatasets provided better image quality in 34% of patients.urthermore, the use of prospective ECG x-ray tube mod-lation requires a regular heart rhythm throughout the scan.n case of an extra-systole, the use of prospective ECG x-rayube modulation can miss-trigger the x-ray pulse, limitinghe possibility to edit valuable reconstruction window data-ets during high-dose scanning.

1. Leschka S, Alkadhi H, Plass A, Desbiolles L, Grunenfelder J,Marincek B, Wildermuth S. Accuracy of MSCT coronary angiographywith 64-slice technology: first experience. Eur Heart J 2005;26:1482–1487.

2. Raff GL, Gallagher MJ, O’Neill WW, Goldstein JA. Diagnostic ac-curacy of noninvasive coronary angiography using 64-slice spiralcomputed tomography. J Am Coll Cardiol 2005;46:552–557.

3. Leber AW, Knez A, von Ziegler F, Becker A, Nikolaou K, Paul S,Wintersperger B, Reiser M, Becker CR, Steinbeck G, Boekstegers P.Quantification of obstructive and nonobstructive coronary lesions by64-slice computed tomography: a comparative study with quantitativecoronary angiography and intravascular ultrasound. J Am Coll Cardiol2005;46:147–154.

4. Mollet NR, Cademartiri F, van Mieghem CA, Runza G, McFadden EP,Baks T, Serruys PW, Krestin GP, de Feyter PJ. High-resolution spiralcomputed tomography coronary angiography in patients referred fordiagnostic conventional coronary angiography. Circulation 2005;112:2318–2323.

5. Ropers D, Rixe J, Anders K, Kuttner A, Baum U, Bautz W, DanielWG, Achenbach S. Usefulness of multidetector row spiral computedtomography with 64- � 0.6-mm collimation and 330-ms rotation forthe noninvasive detection of significant coronary artery stenoses. Am JCardiol 2006;97:343–348.

6. Schuijf JD, Pundziute G, Jukema JW, Lamb HJ, van der Hoeven BL,de Roos A, van der Wall EE, Bax JJ. Diagnostic accuracy of 64-slicemultislice computed tomography in the noninvasive evaluation of

depending on segment location

Menn% (95% CI), n/n

p Value

98% (93–99) 130/133 NS91% (87–92) 891/983 NS59% (52–65) 130/228 NS

100% (99–100) 891/894 NS

96% (90–98) 133/139 NS88% (86–91) 575/650 NS64% (57–70) 133/208 NS99% (98–100) 575/581 NS

85% (74–93) 53/62 �0.0596% (94–97) 754/786 NS62% (51–72) 53/85 NS99% (98–99) 754/763 NS

89% (81–95) 84/94 �0.00193% (92–95) 1,029/2,104 �0.0553% (45–61) 84/59 NS99% (98–100) 1,029/1,039 �0.05

values �0.05. Values in parentheses represent 95% CIs.

graphy

6

13

4

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6

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4

significant coronary artery disease. Am J Cardiol 2006;98:145–148.

1

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1

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7. Nikolaou K, Knez A, Rist C, Wintersperger BJ, Leber A, Johnson T,Reiser MF, Becker CR. Accuracy of 64-MDCT in the diagnosis ofischemic heart disease. AJR 2006;187:111–117.

8. Fine JJ, Hopkins CB, Ruff N, Newton FC. Comparison of accuracy of64-slice cardiovascular computed tomography with coronary angiog-raphy in patients with suspected coronary artery disease. Am J Cardiol2006;97:173–174.

9. Ehara M, Surmely JF, Kawai M, Katoh O, Matsubara T, Terashima M,Tsuchikane E, Kinoshita Y, Suzuki T, Ito T, Takeda Y, Nasu K,Tanaka N, Murata A, Suzuki Y, Sato K. Diagnostic accuracy of64-slice computed tomography for detecting angiographically signifi-cant coronary artery stenosis in an unselected consecutive patientpopulation: comparison with conventional invasive angiography. CircJ 2006;70:564–571.

0. Gibbons RJ, Balady GJ, Bricker JT, Chaitman BR, Fletcher GF,Froelicher VF, Mark DB, McCallister BD, Mooss AN, O’Reilly MG,et al. ACC/AHA 2002 guideline update for exercise testing: summaryarticle: a report of the American College of Cardiology/AmericanHeart Association Task Force on Practice Guidelines (Committee toUpdate the 1997 Exercise Testing Guidelines). Circulation 2002;106:1883–1892.

1. Kwok Y, Kim C, Grady D, Segal M, Redberg R. Meta-analysis ofexercise testing to detect coronary artery disease in women. Am JCardiol 1999;83:660–666.

2. Kim C, Kwok YS, Heagerty P, Redberg R. Pharmacologic stresstesting for coronary disease diagnosis: a meta-analysis. Am Heart J2001;142:934–944.

3. Mieres JH, Shaw LJ, Hendel RC, Miller DD, Bonow RO, Berman DS,Heller GV, Bairey-Merz CN, Cacciabaudo JM, Kiess MC, et al.American Society of Nuclear Cardiology consensus statement: TaskForce on Women and Coronary Artery Disease—the role of myocar-dial perfusion imaging in the clinical evaluation of coronary artery
disease in women [correction]. J Nucl Cardiol 2003;10:95–101.
4. Santana-Boado C, Candell-Riera J, Castell-Conesa J, Aguade-Bruix S,Garcia-Burillo A, Canela T, Gonzalez JM, Cortadellas J, Ortega D,Soler-Soler J. Diagnostic accuracy of technetium-99m-MIBI myocar-dial SPECT in women and men. J Nucl Med 1998;39:751–755.

5. Mieres JH, Shaw LJ, Arai A, Budoff MJ, Flamm SD, Hundley WG,Marwick TH, Mosca L, Patel AR, Quinones MA, et al. Role ofnoninvasive testing in the clinical evaluation of women with suspectedcoronary artery disease: consensus statement from the Cardiac Imag-ing Committee, Council on Clinical Cardiology, and the Cardiovas-cular Imaging and Intervention Committee, Council on CardiovascularRadiology and Intervention, American Heart Association. Circulation2005;111:682–696.

6. Klocke FJ, Baird MG, Lorell BH, Bateman TM, Messer JV, BermanDS, O’Gara PT, Carabello BA, Russell RO Jr., Cerqueira MD, et al.ACC/AHA/ASNC guidelines for the clinical use of cardiac radionu-clide imaging—executive summary: a report of the American Collegeof Cardiology/American Heart Association Task Force on PracticeGuidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guide-lines for the Clinical Use of Cardiac Radionuclide Imaging). J Am CollCardiol 2003;42:1318–1333.

7. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M, Jr.Detrano R. Quantification of coronary artery calcium using ultrafastcomputed tomography. J Am Coll Cardiol 1990;15:827–832.

8. Austen WG, Edwards JE, Frye RL, Gensini GG, Gott VL, GriffithLS, McGoon DC, Murphy ML, Roe BB. A reporting system onpatients evaluated for coronary artery disease. Report of the AdHoc Committee for Grading of Coronary Artery Disease, Councilon Cardiovascular Surgery, American Heart Association. Circula-tion 1975;51:5– 40.

9. Hausleiter J, Meyer T, Hadamitzky M, Huber E, Zankl M, MartinoffS, Kastrati A, Schomig A. Radiation dose estimates from cardiacmultislice computed tomography in daily practice: impact of differentscanning protocols on effective dose estimates. Circulation 2006;113:
1305–1310.

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Clinical and Angiographic Correlates of Short- and Long-TermMortality in Patients Undergoing Coronary Artery Bypass Grafting

Rajendra H. Mehta, MD, MSa,b,*, Emily Honeycutt, MBIa,b, Linda K. Shaw, MSa,b,Carmelo A. Milano, MDb, Peter K. Smith, MDb, Robert A. Harrington, MDa,b,

and Michael H. Sketch, Jr., MDb

Differences in the clinical and angiographic factors associated with short- and long-termoutcomes in patients undergoing coronary artery bypass grafting (CABG) are less known.Accordingly, differences were examined in clinical and angiographic correlates of short-and long-term mortality after CABG in 8,229 patients undergoing initial CABG enrolledin the Duke Cardiovascular Disease Database (1995 to 2002). Logistic regression and Coxproportional hazard modeling were performed to determine independent correlates of30-day and long-term mortality. Death occurred in 2.4% at 30 days and 17.6% beyond 30days at a median follow-up of 6 years in patients who underwent CABG. Multivariablemodels identified older age, lower left ventricular ejection fraction, lower or higher bodymass index, cerebrovascular disease, lack of internal mammary artery use, and lowercholesterol to be associated with increased risk of both events. Although hemodynamicstatus (preoperative myocardial infarction, New York Heart Association class, and cardio-genic shock), female gender, and minority race were associated with 30-day death; co-morbid conditions (serum creatinine, chronic lung disease, diabetes, previous heart failure,peripheral vascular disease, and left main disease) were associated with increased long-term (beyond 30 days) death (c indexes 0.76 and 0.79 for the short- and long-term mortalitymodels, respectively). In conclusion, our study suggested that correlates of acute andlong-term death were different in patients undergoing CABG. These differences should bekept in context when counseling patients undergoing CABG and may help facilitatetargeted strategies to improve short- and long-term mortality risks after CABG. © 2007
Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:1538–1542)
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ultiple previous investigations reported risk factors forhort-term mortality after coronary artery bypass graftingCABG), allowing estimation of a patient’s individual riskf postoperative death based on multiple preoperative clin-cal and angiographic factors.1–6 Fewer studies have fo-used on risk factors for long-term mortality.7,8 However,o previous study evaluated differences in clinical and an-iographic features for short- and long-term mortality. Ac-ordingly, the purpose of the present study was to examinend thereby provide insights into differences in clinical andngiographic correlates of short- and long-term mortality inatients undergoing CABG.

ethodsPatient population and data collection: Using the

uke Cardiovascular Disease Databank, we identified pa-ients who underwent an isolated first CABG using cardio-ulmonary bypass from January 1, 1995, to December 31,002. We excluded patients with previous cardiac surgery,

aDuke Clinical Research Institute and bDuke University Medical Cen-er, Durham, North Carolina. Manuscript received May 19, 2007; revisedanuscript received and accepted June 18, 2007.

Dr. Mehta was supported by the Duke Clinical Research Institute,urham, North Carolina.

(E-mail address: [email protected] (R.H. Mehta).

oncurrent valve surgery, and surgery for congenital heartisease. A total of 8,229 patients met the study criteria andormed the basis of this analysis.

Definitions and follow-up: Hypertension, diabetes, dys-ipidemia, peripheral vascular disease, and presenting heartailure were ascertained from that reported as present orbsent on the data collection form. Renal insufficiency wasefined as serum creatinine �1.5 mg/dl or dependence onialysis therapy. After CABG, patients were followed up atmonths, 1 year, and annually thereafter using telephone

ontact, mailed questionnaire, and National Death Indexearch for mortality status and other adverse events. Mor-ality (all cause) was ascertained from the time of the indexABG and included death in hospital. Information fromlinic visits and rehospitalization was also evaluated toscertain follow-up and end-point determination. The meth-ds used by the Cardiovascular Databank were describedreviously.9–11 Considering all intervals and all patients,ollow-up was 99.2% complete.

Statistical analysis: Summary statistics are presented asrequencies and percentages for categorical variables andedians with interquartile range (25th to 75th percentiles)

or continuous variables. Unadjusted hazard ratio (HR)lots with 95% confidence intervals (CIs) were constructedo further visualize variable significance for long-term death
�30 days). Before modeling, we imputed missing values
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1539Coronary Artery Disease/Predicting Mortality After CABG

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able 1aseline clinical and angiographic characteristics of patients undergoing coronary artery bypass grafting

haracteristic Overall(n � 8,229)

Dead at 30 days p Value

No(n � 8,031)

Yes(n � 198)

ge (yrs) 64 (56–72) 64 (56–72) 71 (63–78) �0.0001omen (%) 31% 31% 47% �0.0001

aucasian race (%) 73% 73% 59% �0.0001eight (cm) 172 (163–178) 172 (164–178) 167 (160–175) �0.0001eight (kg) 82 (72–94) 82 (72–94) 78 (65–90) 0.0001

ody mass index (kg/m2) 28 (25–31) 28 (25–31) 27 (24–32) 0.0130ypertension (%) 67% 67% 72% 0.1435iabetes mellitus (%) 32% 33% 38% 0.1242iabetes mellitus, insulin use (%) 25% 25% 39% 0.0398urrent/remote smoker (%) 43% 43% 36% 0.0411istory of dyslipidemia (%) 49% 50% 36% 0.0002ngina pectoris (%) 77% 77% 74% 0.3855revious myocardial infarction (%) 42% 42% 55% 0.0003revious myocardial infarction �24 h of CABG (%) 3.9% 4.0% 3.6% 0.7031revious PCI (%) 88% 88% 89% 1.0000revious heart failure (%) 15% 14% 33% �0.0001hronic obstructive lung disease (%) 10% 10% 14% 0.1984revious stroke (%) 10% 10% 19% �0.0001erebrovascular disease (%) 11% 11% 22% �0.0001eripheral arterial disease (%) 15% 15% 17% 0.4179enal insufficiency (%) 3.7% 3.7% 5.6% 0.1737reatinine �3.0 mg/dl (%) 2.1% 2.0% 4.5% �0.0001resenting characteristicsNew York Heart Association functional class �3 (%) 9.9% 9.5% 26% �0.0001Resuscitation (%) 0.3% 0.3% 0.5% 0.4825Sustained atrial or ventricular arrhythmia (%) 2.8% 2.7% 6.1% 0.0048Cardiogenic shock (%) 1.5% 1.4% 6.1% �0.0001ngiographic featuresLeft ventricular ejection fraction (%) 54 (43–63) 54 (43–63) 49 (35–60) �0.0001�2 coronary arteries narrowed 94% 94% 96% 0.1592Left main coronary artery narrowing 21% 21% 29% 0.0146�2 grafts placed 79% 79% 78% 0.5086Internal mammary artery graft 94% 94% 88% 0.0005Status of the procedure (emergent/emergent salvage) 3.2% 3.1% 7.6% 0.0016

Values expressed as median (interquartile range) or percent.

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or body mass index, left ventricular ejection fraction, andreatinine; all had a missing rate �15%. Imputation wasone using the Markov chain Monte Carlo method. For0-day mortality, we used logistic regression analysis,hereas for long-term mortality, we used Cox proportionalazard modeling. Variables were assessed for clinical sig-ificance in unadjusted models before multivariable testing.inearity of continuous and ordinal variables was assessed

o determine whether model assumptions were valid, andariables were transformed as appropriate to satisfy thisssumption. Candidate variables for multivariable survivalodels included age, gender, race, body mass index, history

f peripheral vascular disease, history of cerebrovascularisease, diabetes, heart failure, dyslipidemia, hypertension,istory of myocardial infarction, chronic lung disease, car-iogenic shock, family history of coronary artery disease,reprocedure creatinine level, previous percutaneous coro-ary intervention (PCI), left ventricular ejection fraction,eft main disease, use of internal mammary artery conduit,umber of grafts placed, procedural status, year of proce-ure, and extent of coronary artery disease. After backwardelection, only variables with a significant (p �0.05) asso-iation with mortality were included in the final model. Oddatios and 95% CIs were constructed to provide estimates ofisk posed by individual clinical variables on 30-day mor-ality. Similarly, HRs and 95% CIs were constructed forong-term mortality. The c statistic was calculated to eval-ate model discrimination. Finally, both models were inter-ally validated using the technique of bootstrap resampling.ne hundred samples of 100% were drawn at random with

eplacement for this purpose. Model c index was derived forach sample and mean c index with 95% CIs were calcu-ated for the 2 models. All other analyses were performedsing SAS statistical software (SAS Institute, Cary, North

igure 2. Baseline characteristic–unadjusted HRs for death beyond 30 daysn patients undergoing CABG. BMI � body mass index; IMA � internalammary artery; MI � myocardial infarction.

arolina). c

esultsPatients and baseline clinical and angiographic char-

cteristics: Of 8,229 patients undergoing CABG who wereligible for this study, 198 (2.4%) died within 30 days.dditionally, of 8,031 patients who survived 30 days, 1,417

17.6%) died at a median follow-up of 6 years. Figure 1hows unadjusted Kaplan-Meier survival estimates foratients after CABG, with significant event rates at bothhort- and long-term follow-up. Table 1 lists distributions ofaseline clinical and angiographic features of patients whourvived compared with those who died within 30 days afterABG. Compared with surviving patients, those who diedy 30 days were significantly older, more likely to beomen, and had lower body mass index and significantlyigher co-morbid conditions, such as insulin-requiring dia-etes mellitus, previous myocardial infarction, previouseart failure, previous cerebrovascular disease, and in-reased serum creatinine �3.0 mg/dl. Hemodynamic insta-ility, suggested by the presence of cardiogenic shock andigher New York Heart Association functional class, waslso more frequently observed in those who died within 30ays. Surgery was more likely to be performed as emergentr emergent salvage procedure in patients who died com-ared with those who survived beyond 30 days. Left ven-ricular dysfunction and left main coronary artery diseaseere more common in patients who died than those who

urvived. Finally, an internal mammary artery conduit wassed less frequently in patients who died by 30 days.

Figure 2 shows unadjusted HRs and 95% CIs for asso-iation of baseline clinical characteristics and death beyond0 days. As shown, most clinical and angiographic featuresssociated with early death (30 days) were also associatedith hazard of long-term mortality. However, co-morbid

onditions, such as chronic obstructive lung disease, diabe-es (both insulin- and non–insulin-requiring), renal insuffi-iency, peripheral vascular disease, and hypertension werelso more prevalent in patients who died after 30 days.onversely, history of smoking and signs of hemodynamic

nstability (cardiogenic shock) were similar in patients whoied compared with those who survived after 30 days.

Multivariable models for 30-day and long-term (beyond0 days) mortality: Independent correlates of 30-day andong-term mortality are listed in Table 2 in descending orderf chi-square values. Both models showed reasonably goodiscriminatory power to differentiate between patients whoied versus those who survived, with c indexes of 0.76 and.79 for short- and long-term models, respectively. Boottrap validation confirmed good internal validity of the 2odels, with mean c indexes of 0.76 (95% CI 0.72 to 0.79)

nd 0.79 (95% CI 0.78 to 0.80) for 30-day and long-termortality, respectively.Increasing age, decreasing left ventricular ejection frac-

ion, body mass index, cerebrovascular disease, and lack ofnternal mammary artery use were associated with greaterisk of short- and long-term mortality. Although hemody-amic status (preoperative myocardial infarction, New Yorkeart Association class, and cardiogenic shock), femaleender, and non-Caucasian race were associated with in-reased risk of 30-day death; co-morbid conditions (serum
reatinine, chronic obstructive lung disease, diabetes, pre-

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1541Coronary Artery Disease/Predicting Mortality After CABG

ious congestive heart failure, peripheral vascular disease,nd left main disease) were more likely to be associatedith death beyond 30 days.

iscussion

isk assessment of patients undergoing CABG is an integralart of routine clinical practice. Physicians are often re-uired to characterize the risk before a CABG procedure ingiven patient so that an informed decision can be made,

lternative strategies can be discussed and/or applied, andteps can be taken to modify risk factors (if possible) torovide the best milieu for an optimal and better outcome.n addition, risk models are helpful in comparing outcomesn observational studies, as well as allowing for assessmentf case-mix–adjusted mortality, often a primary criterion forudging the quality of care provided by a cardiac surgeonnd/or an institution.

Multiple studies have focused on developing and testingisk models based on baseline clinical variables for short-erm (in-hospital) mortality.1–6 Fortunately, short-term mor-ality after CABG is an uncommon event (�4%)12 as aesult of the growing surgical experience and advances innesthetic and surgical techniques. However, patients un-ergoing CABG continue to experience adverse events,ncluding death, beyond the acute phase. Fewer studiesvaluated clinical correlates of long-term mortality.7,8 Fur-hermore, it was less clear from previous studies whetherlinical and angiographic factors associated with increasedisk of short- and long-term mortality differed.

Our data supported the findings of previous studies thathort-term mortality is low, but that even those who under-ent the procedure at a very large and highly experienced

ertiary center continued to experience long-term events.ur study provides an important and unique previouslyissing insight into the differences in clinical and angio-

raphic correlates of short- and long-term mortality. Bothodels were similar in their ability to explain the variation

n risk of death, suggested by their similar c indexes. Certainactors (older age, lower or higher body mass index, lowereft ventricular ejection fraction, cerebrovascular disease,

able 2ndependent correlates of death up to and beyond 30 days after coronary

0-d Death WaldChi-square

Odds Ratio 95%

ge (/10-yr increase) 33.1 1.58 1.35–ew York Heart Association class 15.9 1.33 1.16–on-Caucasian race 13.5 1.75 1.30–ardiogenic shock 12.8 3.31 1.72–erebrovascular disease 11.7 1.86 1.30–emale sex 9.5 1.60 1.19–ody mass index �28 kg/m2 8.9 0.92 0.87–ypercholesterolemia 8.4 0.64 0.47–eft ventricular ejection fraction (%) 7.8 0.98 0.97–ody mass index �28 kg/m2 6.5 1.05 1.01–reoperative myocardial infarction 5.9 1.45 1.07–nternal mammary artery use 4.2 0.62 0.39–

Index 0.7

yperlipidemia, and lack of internal mammary artery con- d

uit) were found to be important risk factors for both short-nd long-term death and were consistent with those showny previous studies.1–8 The only exception was the associ-tion of hyperlipidemia with lower short- and long-termortality. It is likely that hyperlipidemia is a marker of

etter nutritional status, explaining this relation. Other fac-ors were found to be specifically related to short- or long-erm death, but not both events. These additional factors forhort-term mortality can be lumped into 2 main groups,amely, patient demographics (female gender and minorityace) and hemodynamic status (preoperative myocardial in-arction, cardiogenic shock, and New York Heart Associa-ion class). Similarly, the additional risk factors for long-erm mortality can also be categorized into 2 main groups,amely, patient co-morbid conditions (diabetes, chronic ob-tructive lung disease, previous congestive heart failure,eripheral vascular disease, and increasing creatinine) andngiographic characteristic (left main coronary artery dis-ase). Clearly, these findings that female gender, minorityace, and hemodynamic status affect short-term mortality,hereas co-morbid conditions and left main disease affect

ong-term outcomes, are intuitive and consistent with pre-ious observations, thereby meriting little further discus-ion.1–8

Our findings may have some clinical implications. Al-hough gender and race clearly are nonmodifiable, specificauses of hemodynamic instability can be targeted. Thus,apid revascularization of patients with hemodynamic insta-ility (with immediate opening of the infarct-related arterysing percutaneous catheter-based intervention if neededhile awaiting surgery in patients with preoperative myo-

ardial infarction or cardiogenic shock), better myocardialreservation technique, intra-aortic balloon pump, andhorter pump time may all potentially help improve short-erm mortality. Conversely, tight glycemic control, aggres-ive treatment of patients with congestive heart failure andeft ventricular systolic dysfunction, and arresting the ag-ressive atherosclerotic process using secondary preventionnd lifestyle and behavioral modification may have a greaterotential for impacting on long-term outcomes.13 Our study

ypass grafting

Death Beyond 30 days WaldChi-square

HR 95% CI

Age (/10-yr increase) 411.2 1.62 1.54–1.69Serum creatinine (mg/dl) 227.0 1.23 1.19–1.26Left ventricular ejection fraction (%) 153.5 0.98 0.98–0.98Chronic obstructive pulmonary disease 76.7 1.29 1.22–1.36Diabetes mellitus 52.1 1.40 1.28–1.53Previous heart failure 49.1 1.46 1.32–1.63Peripheral vascular disease 34.7 1.38 1.24–1.54Cerebrovascular disease 29.1 1.38 1.23–1.55Body mass index �28 kg/m2 23.4 1.03 1.02–1.04Hypercholesterolemia 22.7 0.81 0.74–0.88Body mass index �28 kg/m2 20.3 0.96 0.94–0.98Left main disease 12.2 1.20 1.08–1.32Internal mammary artery use 7.4 0.81 0.69–0.94c Index 0.79

artery b

CI

1.841.522.356.392.652.160.970.870.991.081.950.98

oes not provide data supporting these speculations and

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mphasizes the need for future investigation addressing thisssue.

No previous study has focused on examining differencesn clinical correlates of short- and long-term mortality inatients undergoing CABG, making this aspect of our studynique compared with other studies that evaluated only riskactors associated with short- and long-term mortality inhese patients. The major contribution of the present study ishat it highlights the 2-phase risk of CABG. Importantly, aspeculated by us, it provides the basis for 2-phase riskodification with inherently different strategies specifically

argeting the differential risk factors in each phase. Further-ore, all recent data suggest that the PCI versus CABG

urvival curves diverges over time, indicating that theABG advantage, at least in patients with multivessel cor-nary disease, is related to the second phase risk. However,ecision making in patients with multivessel coronary arteryisease seemed to inevitably focus on the first phase risk ofABG in comparison to PCI. This cognitive dissociation ofause and immediate effect versus cause and delayed effectn this cohort of patients is an important component of theCI versus CABG issue today. Thus, our data could serve asfoundation to study and compare with CABG the 2-phase

isk of the complementary therapy, PCI for multivesseloronary artery disease.

Our analysis was retrospective and observational andaution needs to be exerted when inferring causation. Thenfluence of unmeasured variables and adherence to medi-ations and goals of lifestyle changes (smoking cessation,xercise, weight reduction, and dietary modification) afterischarge could not be assessed. These factors and variationn adherence to treatment goals are likely to have a signif-cant influence on long-term mortality. However, it remainso be examined how they would attenuate the prognosticignificance of the clinical and angiographic factors foundn our studies to be related to mortality. External validationf our study from a single-center experience is needed innother data set of patients involving a wide variety ofnstitutions to increase its generalizability.

1. Loop FD, Lytle BW, Cosgrove DM, Stewart RW, Goormastic M,
Williams GW, Golding LA, Gill CC, Taylor PC, Sheldon WC. Influ-
ence of the internal-mammary-artery graft on 10-year survival andother cardiac events. N Engl J Med 1986;314:1–6.

2. O’Connor GT, Plume SK, Olmstead EM, Coffin LH, Morton JR,Maloney CT, Nowicki ER, Tryzelaar JF, Hernandez F, Adrian L;Northern New England Cardiovascular Disease Study Group. A re-gional prospective study of in-hospital mortality associated with cor-onary artery bypass grafting. JAMA 1991;266:803–809.

3. Edwards FH, Grover FL, Shroyer AL, Schwartz M, Bero J. TheSociety of Thoracic Surgeons National Cardiac Surgery Database:current risk assessment. Ann Thorac Surg 1997;63:903–908.

4. Hannan EL, Kumar D, Racz M, Siu AL, Chassin MR. New YorkState’s Cardiac Surgery Reporting System: four years later. Ann Tho-rac Surg 1994;58:1852–1857.

5. Magovern JA, Sakert T, Magovern GJ Jr., Benckart DH, BurkholderJA, Liebler GA, Magovern GJ Sr. A model that predicts morbidity andmortality after coronary artery bypass graft surgery. J Am Coll Cardiol1996;l28:1147–1153.

6. Grover FL, Johnson RR, Marshall G, Hammermeister KE. Factorspredictive of operative mortality among coronary artery bypass sub-sets. Ann Thorac Surg 1993;56:1296–1306.

7. Thourani VH, Weintraub WS, Stein B, Gebhart SS, Craver JM, JonesEL, Guyton RA. Influence of diabetes mellitus on early and lateoutcome after coronary artery bypass grafting. Ann Thorac Surg 1999;67:1045–1052.

8. Lytle BW, Loop FD, Cosgrove DM, Ratcliff NB, Easley K, Taylor PC.Long-term (5–12 years) serial studies of internal mammary artery andsaphenous vein grafts. J Thorac Cardiovasc Surg 1985;89:248–258.

9. Califf RM, Harrell FE Jr., Lee KL, Rankin JS, Hlatky MA, Mark DB,Jones RH, Muhlbaier LH, Oldham HM Jr., Pryor DB. The evolution ofmedical and surgical therapy for coronary artery disease: a 15-yearperspective. JAMA 1989;261:2077–2086.

0. Harris PJ, Harrell FE Jr., Lee KL, Rosati RA. Nonfatal myocardialinfarction in medically treated patients with coronary artery disease.Am J Cardiol 1980;46:937–942.

1. Mehta RH, Honeycutt EF, Peterson ED, Granger CB, Halabi AR,Shaw LK, Califf RM, Harrington RA, Sketch MH. Impact of internalmammary artery conduit on long-term outcomes following percutane-ous intervention of saphenous vein graft. Circulation 2006;114:I396–I401.

2. PREVENT IV Investigators. Efficacy and safety of edifoligide, an E2Ftranscription factor decoy, for prevention of vein graft failure follow-ing coronary artery bypass graft surgery—PREVENT IV: a random-ized controlled trial. JAMA 2005;294:2446–2454.

3. Eagle KA, Guyton RA, Davidoff R, Edward FH, Ewy GA, Gardner TJ,Hart JC, Herrmann HC, Hillis LD, Hutter AM Jr., et al. ACC/AHA2004 guideline update for coronary artery bypass graft surgery: areport of the American College of Cardiology/American Heart Asso-ciation Task Force on Practice Guidelines (Committee to Update the1999 Guidelines for Coronary Artery Bypass Graft Surgery). Ameri-can College of Cardiology. Available at: http://www.acc.org/clinical/
guidelines/cabg/cabg.pdf. Accessed January 7, 2007.
http://www.acc.org/clinical/guidelines/cabg/cabg.pdf

http://www.acc.org/clinical/guidelines/cabg/cabg.pdf

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Progression of Coronary Artery Calcium in Type 1Diabetes Mellitus

Tina Costacou, PhDa, Daniel Edmundowicz, MDb, Catherine Prince, MPHa,Baqiyyah Conway, MPHa, and Trevor J. Orchard, MBBCh, MMedScia,*

Coronary artery calcium (CAC) has been previously associated with atherosclerotic plaquedisease and coronary events. Thus, identifying predictors of CAC progression may providenew insights for early risk-factor intervention and subsequent reduction of the rates of moresevere atherosclerotic disease. The aim of this study was to identify risk factors for CACprogression and evaluate whether risk-factor change was related to CAC progression in acohort of patients with type 1 diabetes mellitus (DM). Participants in the Pittsburgh EDCStudy, a prospective investigation of childhood-onset type 1 DM, who underwent 2 electronbeam tomographic screenings 4 years apart were selected for study (n � 222). CAC wascalculated using the Agatston method of scoring, and progression was defined as anincrease >2.5 in the square root–transformed CAC score. Adjusting for DM duration andinitial CAC score, body mass index (BMI; odds ratio [OR] 1.13, 95% confidence interval[CI] 1.01 to 1.26), non–high-density lipoprotein cholesterol (OR 1.01, 95% CI 1.003 to1.03), and albumin excretion rate (OR 1.30, 95% CI 1.03 to 1.63) were associated with CACprogression. When considering change in risk factors, an increase in BMI (OR 1.38, 95% CI1.10 to 1.72) was also associated with CAC progression after adjustment. In conclusion, inthis cohort with type 1 DM, in addition to baseline BMI, non–high-density lipoproteincholesterol, albumin excretion rate, and all known coronary artery disease risk factors,weight gain further added to the prediction of CAC progression. Thus, weight control, inaddition to lipid and renal management, may help retard atherosclerosis progression inpersons with type 1 DM. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:
1543–1547)
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lectron beam tomography is a noninvasive method touantify the extent of calcium formation in the coronaryrteries. Coronary artery calcium (CAC) measured usinglectron beam tomography can be used as an indicator oftherosclerotic burden.1 Furthermore, in persons with type 1iabetes mellitus (DM), CAC has been previously corre-ated with coronary artery disease.2 Thus, identifying mod-fiable risk factors associated with CAC progression mayrovide new targets for early intervention and potentiallyecrease rates of more severe atherosclerotic disease. How-ver, with the exception of the CAC in Type 1 DM (CACTI)tudy,3–6 we were not aware of other investigations ofredictors of CAC progression in persons with type 1 DM.e therefore aimed to identify risk factors for CAC pro-

ression and evaluate whether risk-factor change was re-ated to CAC progression in a cohort with type 1 DM.ltimately, on sufficient follow-up and cardiovascular

vents, we will assess whether progression is a better pre-ictor of events than baseline score and thus whether CACrogression can be used for monitoring.

aDepartment of Epidemiology, Graduate School of Public Health, andCardiovascular Institute, School of Medicine, University of Pittsburgh,ittsburgh, Pennsylvania. Manuscript received March 8, 2007; revisedanuscript received and accepted June 17, 2007.

This work was supported by Grant DK34818 from the National Insti-utes of Health, Bethesda, Maryland.

*Corresponding author: Tel.: 412-383-1032; fax: 412-383-1020.
lE-mail address: [email protected] (T.J. Orchard).

ethods

articipants for this evaluation were selected from the Pitts-urgh Epidemiology of Diabetes Complications (EDC)tudy cohort, a prospective investigation of childhood-onset

ype 1 DM now entering its 20th year of follow-up. TheDC Study has been previously described in detail.7 Briefly,

he diagnosis was made in participants before their 17thirthday or they were seen within 1 year of such diagnosist Children’s Hospital of Pittsburgh, Pennsylvania, from950 to 1980. Although clinically based, this population haseen shown to be representative of the type 1 DM popula-ion in Allegheny County, Pennsylvania.8 Baseline exami-ations for the EDC Study were conducted from 1986 to988, when the cohort’s mean age was 28 years and diabe-es duration was 19 years. Participants were subsequentlynvited to biennial examinations. At the 10-year follow-upxamination (1996 to 1998), electron beam tomographiccreening was made available first to all participants aged30 years and subsequently to all those �18 years. A total

f 304 participants underwent electron beam tomographiccreening2; 228 also underwent repeated scanning approxi-ately 4 years later. The University of Pittsburgh Institu-

ional Review Board approved the study protocol.All complications and risk factors were assessed at the

ime of the 2 electron beam tomographic screenings, the firstf which occurred during the 10-year follow-up examina-ion (1996 to 1998), and the second, approximately 4 years
ater. Before each biennial clinic visit, participants were sent
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uestionnaires concerning demographic, health care, medi-al history, and physical activity information. An evermoker was defined as a person who smoked �100 ciga-ettes during their lifetime. Intensive insulin therapy wasefined as �3 insulin injections/day or insulin pump use.epressive symptoms were assessed using the Beck De-ression Inventory.9 Hypertension was defined as bloodressure �140/90 mm Hg or current antihypertensive med-cation treatment.

CAC was assessed using electron beam tomography with

able 1aseline characteristics and coronary artery calcium progression

articipant characteristics Overall(n � 222; 110 progre

Stable Prog

ge (yrs) 34.1 � 6.5 41.6 �M duration (yrs) 25.8 � 6.4 32.1 �omen 62 (55.4%) 56 (5aist–hip ratio 1.00 � 1.2 1.03 �

MI (kg/m2) 24.6 � 3.4 25.5 �eight (m) 167.8 � 8.3 167.9 �eight (kg) 69.4 � 10.8 71.2 �

ver smoked (n) 34 (30.4%) 38 (3stimated glucose disposal rate (mg/kg/min) 8.0 � 2.0 7.1 �emoglobin A1c (%) 8.3 � 1.3 8.2 �emoglobin A1c quartiles (%)�7.3 24 (21.4%) 29 (27.3–�8.2 32 (28.6%) 24 (28.2–�9.0 27 (24.1%) 26 (2�9.0 29 (25.9%) 31 (2emoglobin A1c � median (8.2%) 56 (50.0%) 57 (5

ntensive insulin therapy 44 (40.4%) 38 (3

ntensive insulin therapy and check bloodglucose �3 times/d†

29 (27.4%) 21 (2

nsulin (/kg body weight/d) 0.67 � 0.19 0.64 �ystolic blood pressure (mm Hg) 111.3 � 13.2 120.5 �iastolic blood pressure (mm Hg) 69.8 � 8.7 70.1 �ypertension 16 (14.3%) 37 (3ngiotensin-converting enzyme inhibitor use 22 (19.6%) 29 (2lood pressure medication use 0 (0.0%) 5 (4igh-density lipoprotein (mg/dl) 55.9 � 14.2 54.0 �ow-density lipoprotein (mg/dl) 110.6 � 28.3 190.4 �riglycerides (mg/dl)†‡ 91.0 � 44.3 107.4 �on–high-density lipoprotein (mg/dl) 126.9 � 31.4 142.5 �otal cholesterol (mg/dl) 182.9 � 31.6 196.5 �eck Depression Inventory†‡ 5.3 � 6.8 6.9 �ulse rate (beats/min) 71.5 � 10.8 70.0 �hite blood cell count (� 103/mm2) 6.6 � 1.8 7.0 �

oronary artery disease 12 (10.7%) 27 (2

erum creatinine (mg/dl)‡ 0.98 � 0.75 1.1 �lbumin excretion rate (�g/min)‡ 89.9 � 334.9 140.2 �vert nephropathy 18 (16.1%) 33 (3

Values expressed as mean � SD or sample size (percent). For overweighor the progressor group (p � 0.05); for overweight men, 0.67 for the sta

* p �0.05.† Sample size for intensive insulin therapy (�3 insulin injections/day) w

egular (�3 times/day) blood glucose testing, 209 (106 nonprogressors, 10onprogressors, 95 progressors); and for Beck Depression Inventory, 213

‡ Logarithmically transformed before statistical testing.

GE-Imatron ultrafast computed tomographic scanner (GE- t

matron, San Francisco, California). Scans were triggeredy electrocardiographic signals at 80% of the RR intervalnd obtained in 3-mm contiguous sections of the heart. CACas calculated using the Agatston method,10 and progres-

ion was defined as an increase �2.5 in the square root–ransformed CAC score11 because this transformation pro-ided the best fit. Previous use of a suggested modification12

o address the potential systematic bias of increased calciumcores in those with a higher body mass index (BMI) did noteem to significantly alter scoring. Although use of a phan-

Men(n � 104; 54 progressed)

Women(n � 118; 56 progressed)

Stable Progressed Stable Progressed

34.2 � 5.8 40.1 � 7.1* 33.9 � 7.1 43.1 � 6.5*26.1 � 5.9 31.1 � 6.8* 25.5 � 6.8 33.0 � 6.8*

1.1 � 1.3 1.1 � 1.2 0.79 � 0.07 0.80 � 0.0524.7 � 2.8 26.4 � 3.1* 24.6 � 3.8 24.4 � 4.2

174.1 � 5.8 174.4 � 7.4 162.7 � 6.3 161.5 � 6.774.9 � 9.7 80.3 � 11.2* 65.0 � 9.6 63.8 � 11.717 (34.0%) 19 (35.2%) 17 (27.4%) 19 (33.9%)7.3 � 1.7 6.3 � 2.1* 8.6 � 2.0 7.8 � 2.28.4 � 1.2 8.3 � 1.3 8.1 � 1.4 8.2 � 1.3

8 (16.0%) 15 (27.8%) 16 (25.8%) 14 (25.0%)15 (30.0%) 12 (22.2%) 17 (27.4%) 12 (21.4%)12 (24.0%) 9 (16.7%) 15 (24.2%) 17 (30.4%)15 (30.0%) 18 (33.3%) 14 (22.6%) 13 (23.2%)27 (54.0%) 27 (50.0%) 29 (46.8%) 30 (53.6%)13 (26.5%) 20 (38.5%) 31 (51.7%) 18 (34.0%)

p � 0.069 (18.8%) 10 (20.0%) 20 (34.5%) 11 (20.8%)

0.70 � 0.20 0.72 � 0.22 0.65 � 0.18 0.55 � 0.19*113.6 � 12.2 122.2 � 18.4* 109.4 � 13.9 119.0 � 16.4*72.9 � 8.4 76.0 � 13.4 67.4 � 8.2 64.2 � 9.4

6 (12.0%) 19 (35.2%)* 10 (16.1%) 18 (32.1%)*12 (24.0%) 15 (27.8%) 10 (16.1%) 14 (25.0%)0 (0.0%) 2 (3.7%) 0 (0.0%) 3 (5.4%)

48.8 � 10.1 47.5 � 11.2 61.6 � 14.7 60.5 � 14.4114.9 � 26.9 118.8 � 30.1 106.4 � 28.8 120.7 � 38.0*

97.3 � 51.0 120.5 � 66.6* 86.1 � 38.1 93.0 � 40.6131.7 � 30.7 147.3 � 32.7* 122.3 � 31.4 138.0 � 39.8*180.5 � 30.1 194.8 � 33.7* 184.0 � 32.5 198.6 � 41.7*

3.7 � 6.8 5.9 � 6.6* 6.8 � 6.6 7.7 � 7.072.7 � 11.3 69.6 � 8.9 70.5 � 10.5 70.4 � 9.5

6.8 � 2.1 6.8 � 1.8 6.4 � 1.5 7.2 � 2.2*4 (8.0%) 13 (24.1%) 8 (12.9%) 14 (25.0%)

p � 0.03 p � 0.090.97 � 0.30 1.1 � 0.67 0.93 � 0.83 1.1 � 0.71

* 152.3 � 478.8 163.2 � 332.5* 40.2 � 120.1 120.0 � 360.8*9 (18.0%) 16 (29.6%) 9 (14.5%) 17 (30.4%)*

en, insulin dose per body weight was 0.64 for the stable group versus 0.51up versus 0.76 for the progressor group (p � 0.09).

(109 nonprogressors, 105 progressors); for intensive insulin therapy andessors); for low-density lipoprotein cholesterol and triglycerides, 201 (106onprogressors; 105 progressors).

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1545Preventive Cardiology/Calcification Progression in Type 1 Diabetes

opulation, we did not find that it added to longitudinalnalyses within our study. Electron beam tomographic re-ults were made available to participants and their physi-ians, and cardiovascular risk factor decrease was stressedor those with significant CAC. Additional evaluation wasecided upon by participants’ physicians, although a cardi-logist was available for consultation. Coronary artery dis-ase was defined as EDC physician-diagnosed angina, myo-ardial infarction confirmed using Q waves on anlectrocardiogram (Minnesota codes 1.1 or 1.2) or hospitalecords, angiographic stenosis �50%, revascularization, orschemic electrocardiographic changes (Minnesota codes.3, 4.1 to 4.3, 5.1 to 5.3, and 7.1).

Original hemoglobin A1 (1986 to 1998) and A1c (1998 to004) were converted to Diabetes Control and Complica-ions Trial (DCCT) standard hemoglobin A1c values usingegression formulas derived from duplicate analyses (DCCTemoglobin A1c � [0.83 * EDC hemoglobin A1] � 0.14;CCT hemoglobin A1c � [EDC hemoglobin A1c � 1.13]/.81). Cholesterol and triglycerides were measured enzy-atically.13,14 High-density lipoprotein cholesterol was de-

ermined using a modified15 heparin and manganesehloride precipitation technique of the Lipid Research Clin-cs method.16 Low-density lipoprotein cholesterol was cal-ulated using the Friedewald equation.17 Non–high-densityipoprotein cholesterol was calculated as total minus high-ensity lipoprotein cholesterol. Estimated glucose disposalate (insulin sensitivity) was estimated using a regressionquation derived from hyperinsulinemic euglycemic clamptudies in 24 participants chosen to represent the full spec-rum of insulin resistance as represented by insulin resis-ance risk factors.18 White blood cell count was obtainedsing a counter S-plus IV (Coulter Electronics, Hialeah,lorida).

Serum and urinary albumin were measured using immu-onephelometry,19,20 and creatinine was assayed using anctachem 400 Analyzer (Eastman Kodak Co., Rochester,ew York), which, unlike picric acid–based methods, doesot overestimate creatinine concentrations in persons with

able 2ogistic regression–derived odds ratios (95% confidence interval) linking

isk Factors ModE

quare root of baseline CAC scoreM duration (yrs)MI (kg/m2)emoglobin A1c (%)

nsulin dose per body weightypertension*ystolic blood pressure (mm Hg)igh-density lipoprotein cholesterol (mg/dl)on–high-density lipoprotein cholesterol (mg/dl)hite blood cell count (� 103/mm2)lbumin excretion rate (�g/min)†

ngiotensin-converting enzyme inhibitor use*kaike information criterion

* Dichotomous variable (yes/no) is included in model 1, whereas years of† Logarithmically transformed.EBT � electron beam computed tomographic.

M.21 Overt nephropathy was defined as albumin excretion s

ate �200 �g/min in 2 of 3 timed urine collections or, in thebsence of urine, serum creatinine �153 �mol/L (�2 mg/l) or renal failure or renal transplantation.

Variables not following a normal distribution were logransformed (i.e., triglyceride concentration, Beck Depres-ion Inventory, serum creatinine, and albumin excretionate). When normality was not achieved by transformationi.e., for change in BMI; low-density lipoprotein, non–high-ensity lipoprotein, and total cholesterol; Beck Depressionnventory; and serum creatinine), nonparametric proceduresere used. Student’s t test and chi-square (or Fisher’s exact,

s appropriate) tests were used to examine univariate asso-iations, whereas multiple logistic regression models wereonstructed to assess significant predictors of CAC progres-ion, as well as the predictive value of risk factor change. Tovaluate the effect of risk factors during the 10 years up tohe initial CAC measurement on progression, analyses werelso conducted using updated means of risk factors. Dataere analyzed using SAS, version 9.1 (SAS Institute, Cary,orth Carolina). Results were considered significant at p0.05.

esults

f 304 patients who underwent the first electron beamomography, 22 (7.2%) died, whereas another 54 (17.8%)id not return for a second electron beam tomography.ompared with participants with repeated electron beam

omography, those who did not return for a second electroneam tomography had higher hemoglobin A1c (p � 0.03)nd white blood cell counts (p � 0.01) and were morensulin resistant (p � 0.003), but had similar CAC scores atrst assessment (p � 0.85). Of 228 participants with 2lectron beam tomographic scans obtained, 222 had fullnformation on the covariates examined. Their characteris-ics by progression of CAC are listed in Table 1. Surpris-ngly, glycemic control was not related to CAC progressionn this cohort, and there was no evidence of a thresholdffect. Generally, similar univariate risk factors were ob-

progression to specified predictors (n � 222)

isk Factors at Firstn (1996–1998)

Model 2: Updated Means of RiskFactors (1986–1998)

(1.25–1.66) 1.44 (1.24–1.67)(1.04–1.17) 1.10 (1.04–1.17)(1.01–1.26) 1.24 (1.07–1.44)lected Not selectedade available Not selectedlected 1.44 (1.12–1.82)lected Not selectedade available Not selected1.003–1.03) 5.82 (0.96–35.22)lected Not selected(1.03–1.63) Not selectedade available 0.68 (0.49–0.93)81.685 179.075

nsion or angiotensin-converting enzyme inhibitor use is used in model 2.

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atness and the Beck Depression Inventory were associatedith CAC progression only in men. Interestingly, althoughaseline hemoglobin A1c was not in itself related to CACrogression, a greater proportion of nonprogressors used3 insulin injections/day in women (p � 0.07). However,

he proportion on intensive insulin therapy who also regu-arly monitored their blood glucose (�3 times/day) did notiffer significantly (p � 0.14).

In multivariable logistic regression analyses, the finalodel included DM duration, baseline calcification level,MI, non–high-density lipoprotein cholesterol, and albu-in excretion rate (Table 2, model 1) as significant predic-

ors of CAC progression. These results were not alteredhen analyses were restricted to persons free of cardiovas-

ular disease (n � 183; 83 progressors). When logisticegression was conducted separately for men and women,ith the exception of baseline CAC score (odds ratio [OR].51, 95% confidence interval [CI] 1.22 to 1.86), BMI washe only significant predictor of CAC progression in menOR 1.31, 95% CI 1.09 to 1.59), whereas in women, sig-ificant risk indicators included baseline CAC score (OR.46, 95% CI 1.20 to 1.77), duration of DM (OR 1.13, 95%I 1.04 to 1.23), non–high-density lipoprotein cholesterol

OR 1.02, 95% CI 1.001 to 1.04), and albumin excretionate (OR 1.63, 95% CI 1.11 to 2.40). The final model usingpdated mean values of risk factors from study initiation torst electron beam tomographic scan is listed in Table 2model 2). Although results were similar to those using riskactors from the time of the first electron beam tomographiccan, years with hypertension and years of angiotensin-onverting enzyme inhibitor use also became significant,hereas albumin excretion rate was no longer selected.In assessing change in risk factors (follow-up � base-

ine) by CAC progression, generally, greater increases inMI and weight and greater decreases in lipids (caused by

ncreased use of lipid-lowering medication) were noted forrogressors. Despite greater use of hypertension medicationn progressors, no differences were observed in blood pres-ure levels. Again, change in hemoglobin A1c was notelated to CAC progression in this cohort (not shown).ogistic models were constructed for 182 patients with

isk-factor data available at both baseline and follow-up.nivariately significant change variables were included in

ogistic regression models, adjusting for DM duration, base-

able 3ogistic regression–derived odds ratios (95% confidence interval)

inking calcium progression to change in specified predictors (n � 182;1 progressors)

ovariates Final Model

quare root of baseline CAC score 1.34 (1.17–1.53)M duration (yrs) 1.18 (1.09–1.29)MI (kg/m2) 1.16 (1.02–1.32)on–high-density lipoprotein cholesterol (mg/dl) 1.02 (1.003–1.03)og albumin excretion rate (�g/min) 1.25 (0.98–1.61)hange in BMI (kg/m2) 1.38 (1.10–1.72)hange in non–high-density lipoprotein (mg/dl) Not selectedhange in log albumin excretion rate (�g/min) Not selectedkaike information criterion 145.523

ine CAC level, and baseline level of the change variable r

not shown). Only change (increase) in BMI was signifi-antly associated with CAC progression. This associationas stronger in men than women (ORs for a unit increase inMI 1.76 [95% CI 1.17 to 2.65] and 1.28 [95% CI 0.997 to.65], respectively; p for interaction � 0.08). Including, 1 attime or in backward elimination, univariately significant

hange variables to model 1 from Table 2, change in BMIas the only significant change covariate (final model listed

n Table 3).

iscussion

n this cohort with a long duration of type 1 DM, consistentaseline predictors of CAC progression were BMI, non–igh-density lipoprotein cholesterol, and albumin excretionate, all recognized coronary artery disease risk factors. DMuration was also a predictor of CAC progression. In ex-mining the value of risk factor change on CAC progres-ion, we found that only increase in BMI was associatedith CAC progression.Contrary to a previous report on CAC progression by the

ACTI Study3 and another of lower calcium prevalence inhe primary prevention cohort from the DCCT/Epidemiol-gy of Diabetes Interventions and Complications (EDIC),22

lycemic control was not related to CAC progression in thisohort and we were not able to identify a threshold. In theate 1990s, glycemic control was far from optimal in EDCarticipants; only 14.0% of the study cohort kept hemoglo-in A1c �7.0%. Nevertheless, the proportion who pro-ressed was similar, if not slightly higher, in those withptimal glycemic control compared with those with higheremoglobin A1c (58.1% vs 48.2%; p � 0.31). Snell-Ber-eon et al3 also reported increased risk of CAC progressionith higher insulin dose in overweight persons. This rela-

ion differed for the women and men in the EDC Study. Inontrast to CACTI results, both insulin dose (47.0 vs 39.4;� 0.17) and dose of insulin per body weight (0.64 vs 0.51;� 0.05) were slightly increased in overweight womenho did not progress despite similar insulin sensitivity,easured using estimated glucose disposal rate. However,

one of these relations was significant after adjustment foruration of DM and baseline CAC score. However, as inACTI,3 there was an indication of lower insulin units (55.6s 64.0; p � 0.06) and insulin dose per body weight (0.67s 0.76; p � 0.09) in overweight men who did not progressompared with progressors, even after adjustment for DMuration and baseline CAC score.

Despite the small sample size, analyses of risk factorhange in relation to CAC progression identified BMI as thenly covariate for which increases seemed to increase riskf CAC progression. No considerable decrease in hemoglo-in A1c was observed during follow-up in either group0.07-U increase for the stable group vs 0.19-U decrease forhe progressing group). Thus, hemoglobin A1c change wasot associated with progression. Nevertheless, we previ-usly showed that although baseline hemoglobin A1c wasot related to coronary artery disease incidence, hemoglobin1c increases during the follow-up period increased risk ofisease.23 Together, these findings might suggest that he-oglobin A was not related to the underlying atheroscle-
1c
otic process, but rather to the precipitation of events.

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1547Preventive Cardiology/Calcification Progression in Type 1 Diabetes

CACTI investigators previously reported that adiponec-in levels were inversely associated with CAC progressionn persons with type 1 DM and nondiabetic adults.4 Unfor-unately, data for adiponectin are not currently available inhis subset of the EDC population, although we also previ-usly observed a relation between adiponectin and inci-ence of coronary artery disease.24 Two additional reportsrom CACTI also identified a marker of T-cell activation,oluble interleukin-2 receptor and the APOA4 Gln360Hisolymorphism, as risk factors for CAC progression in per-ons with type 1 DM.5,6 However, information for theseolymorphisms are not available in EDC. Thus, their effectould not be assessed.

Study limitations included risk factor differences be-ween those with and without a repeated electron beamomographic scan. Despite similar baseline CAC scores, ifhose without a repeated scan had a greater rate of CACrogression, it is likely that the true relation between riskactors and CAC progression is stronger than observed here.t also is possible that, depending on initial CAC score,atients’ physicians intervened to manage risk factors. Asreviously reported,25 additional cardiac testing increasedith increasing initial CAC score. Such management mayave led to weaker associations between baseline risk fac-ors and CAC progression, although evaluation of risk-actor change addressed this problem.

Our ultimate goal is to identify the rate of progressionhat best predicts subsequent cardiovascular events. Al-hough sufficient follow-up and events have not yet oc-urred to fully address this issue, a very preliminary lookuggests that in our population, CAC score is the best singleredictor of CAD events (OR 8.57, 95% CI 1.16 to 50.27or CAC score �100).26 Approximately 9% of our popula-ion developed this risk level during the 4-year period.

1. Janowitz WR, Agatston AS, Kaplan G, Viamonte M Jr. Differences inprevalence and extent of coronary artery calcium detected by ultrafastcomputed tomography in asymptomatic men and women. Am J Car-diol 1993;72:247–254.

2. Olson JC, Edmundowicz D, Becker DJ, Kuller LH, Orchard TJ.Coronary calcium in adults with type 1 diabetes: a stronger correlate ofclinical coronary artery disease in men than in women. Diabetes2000;49:1571–1578.

3. Snell-Bergeon JK, Hokanson JE, Jensen L, MacKenzie T, Kinney G,Dabelea D, Eckel RH, Ehrlich J, Garg S, Rewers M. Progression ofcoronary artery calcification in type 1 diabetes: the importance ofglycemic control. Diabetes Care 2003;26:2923–2928.

4. Maahs DM, Ogden LG, Kinney GL, Wadwa P, Snell-Bergeon JK,Dabelea D, Hokanson JE, Ehrlich J, Eckel RH, Rewers M. Lowplasma adiponectin levels predict progression of coronary artery cal-cification. Circulation 2005;111:747–753.

5. Wadwa RP, Kinney GL, Ogden L, Snell-Bergeon JK, Maahs DM,Cornell E, Tracy RP, Rewers M. Soluble interleukin-2 receptor as amarker for progression of coronary artery calcification in type 1 dia-betes. Int J Biochem Cell Biol 2006;38(5–6):996–1003.

6. Kretowski A, Hokanson JE, McFann K, Kinney GL, Snell-BergeonJK, Maahs DM, Wadwa RP, Eckel RH, Ogden LG, Garg SK, et al. The
apolipoprotein A-IV Gln360His polymorphism predicts progression of
coronary artery calcification in patients with type 1 diabetes.Diabetologia 2006;49:1946–1954.

7. Orchard TJ, Dorman JS, Maser RE, Becker DJ, Drash AL, Ellis D,LaPorte RE, Kuller LH. Prevalence of complications in IDDM by sexand duration: Pittsburgh Epidemiology of Diabetes ComplicationsStudy II. Diabetes 1990;39:1116–1124.

8. Wagener DK, Sacks JM, LaPorte RE, MacGregor JM. The Pittsburghstudy of insulin-dependent diabetes mellitus: risk for diabetes amongrelatives of IDDM. Diabetes 1982;31:136–144.

9. Beck AT, Garbin MG. Psychometric properties of the Beck DepressionInventory: 25 years of evaluation. Clin Psychol Rev 1988;8:77–100.

0. Agatston AS, Janowitz WH, Hildner FJ, Zusmer NR, Viamonte M Jr.,Detrano R. Quantitation of coronary artery calcium using ultrafastcomputed tomography. J Am Coll Cardiol 1990;15:827–832.

1. Hokanson JE, MacKenzie T, Kinney G, Snell-Bergeon JK, Dabelea D,Ehrlich J, Eckel RH, Rewers M. Evaluating changes in coronary arterycalcium: an analytic method that accounts for interscan variability.AJR 2004;182:1327–1332.

2. Raggi P, Callister TQ, Cooil B. Calcium scoring of the coronary arteryby electron beam CT: how to apply an individual attenuation thresh-old. AJR 2002;178:497–502.

3. Allain CC, Poon LS, Chan CSG, Richmond W, Fu PC. Enzymaticdetermination of total serum cholesterol. Clin Chem 1974;20:470–475.

4. Bucolo G, David H. Quantitative determination of serum triglyceridesby the use of enzymes. Clin Chem 1973;19:476–482.

5. Warnick GR, Albers JJ. Heparin-MN(2�) quantitation of high densitylipoprotein cholesterol: an ultrafiltration procedure for lipemic sam-ples. Clin Chem 1978;24:900–904.

6. National Institutes of Health, Department of Health Education andWelfare. Lipid Research Clinics Program. Washington, DC: US Gov-ernment Printing Office, 1975.

7. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concen-tration of low-density lipoprotein cholesterol in plasma, without use ofthe preparative ultracentrifuge. Clin Chem 1972;18:499–502.

8. Williams KV, Erbey JR, Becker DJ, Arslanian S, Orchard TJ. Canclinical factors estimate insulin resistance in type 1 diabetes? Diabetes2000;49:626–632.

9. Ellis D, Buffone GJ. A new approach to the evaluation of proteinuricstates. Clin Chem 1977;23:666–670.

0. Ellis D, Coonrod BA, Dorman JS, Kelsey SF, Becker DJ, Avner ED,Orchard TJ. Choice of urine sample predictive of microalbuminuria inpatients with insulin-dependent diabetes mellitus. Am J Kidney Dis1989;4:321–328.

1. Assadi FK, John EG, Fornell L, Rosenthal IM. Falsely elevated serumcreatinine concentration in ketoacidosis. J Pediatr 1985;107:562–564.

2. Cleary PA, Orchard TJ, Genuth S, Wong ND, Detrano R, BacklundJY, Zinman B, Jacobson A, Sun W, Lachin JM, et al; DCCT/EDICResearch Group. The effect of intensive glycemic treatment on coro-nary artery calcification in type 1 diabetic participants of the DiabetesControl and Complications Trial/Epidemiology of Diabetes Interven-tions and Complications (DCCT/EDIC) Study. Diabetes 2006;55:3556–3565.

3. Prince KT, Costacou T, Orchard TJ. Glycemia and cardiovascular riskin type 1 diabetes: reconciling conflicting results [abstract]. Diabetes2006;55(suppl 1):1A.

4. Costacou T, Zgibor JC, Evans RW, Otvos J, Lopes-Virella MF, TracyRP, Orchard TJ. The prospective association between adiponectin andcoronary artery disease among individuals with type 1 diabetes. ThePittsburgh Epidemiology of Diabetes Complications Study. Diabeto-logia 2005;48:41–48.

5. Huskey ND, Edmundowicz D, Orchard TJ. Electron beam computedtomography and coronary artery calcification; recipients attitudes andactions [abstract]. Diabetes 2004;53(suppl 2):S283A.

6. Orchard TJ, Costacou T, Edmundowicz D. Coronary calcification as apredictor of coronary artery disease in type 1 diabetes (abstr). Circu-
lation 2006;113:247.

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Effect of Withdrawal of Pravastatin Therapy on C-Reactive Proteinand Low-Density Lipoprotein Cholesterol

Pim van der Harst, MD, PhDa,b,*, Folkert W. Asselbergs, MD, PhDb, Hans L. Hillege, MD, PhDd,Stephan J.L. Bakker, MD, PhDc, Adriaan A. Voors, MD, PhDb, Dirk J. van Veldhuisen, MD, PhDb,

and Wiek H. van Gilst, PhDa, for the PREVEND-IT Investigators

In addition to lowering cholesterol, statins effectively lower C-reactive protein (CRP)levels. The effects of withdrawal from long-term statin therapy on CRP are unknown. Thisstudy examined the effect of withdrawal from 4 years of statin treatment on CRP. Weprospectively evaluated the effects of withdrawal from pravastatin (40 mg) treatment onCRP levels in 566 subjects who participated in a randomized, placebo-controlled trial.Median (interquartile range) CRP levels before randomization were 1.29 mg/L (0.63 to 2.73)and mean low-density lipoprotein (LDL) cholesterol was 4.06 � 0.92 mmol/L. Four yearsafter randomization, placebo-treated patients (n � 266) had a nonsignificant 9% increasein CRP, whereas there was a 12% decrease (p � 0.001) in the pravastatin-treated patients(n � 300). LDL cholesterol only decreased in pravastatin-treated patients (�27%;p <0.001). Withdrawal from pravastatin led to a significant increase in both CRP and LDLcholesterol to approximately pretreatment levels (p <0.05 and <0.001, respectively).Changes in CRP after withdrawal from pravastatin could not be predicted by the changein LDL cholesterol. The difference between the pravastatin and placebo groups in terms ofchange in CRP by withdrawal was consistent and persisted in analysis corrected for bodymass index, smoking status, blood pressure, and baseline levels of total cholesterol, LDLcholesterol, high-density lipoprotein cholesterol, or triglycerides. In conclusion, withdrawalfrom pravastatin treatment resulted in an increase in CRP to approximately baseline levels,which is not related to the increase in LDL cholesterol. © 2007 Elsevier Inc. All rights
reserved. (Am J Cardiol 2007;100:1548–1551)
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t is unknown whether statin-related reduction in C-reactiverotein (CRP) is only present during therapy, or whether itnduces long-lasting changes and a structural reduction ofhe activity of the inflammatory process linked to athero-clerosis. We prospectively addressed this issue in 566 sub-ects who were randomly assigned to receive either prava-tatin or placebo and were followed for 3 additional monthsfter completion of a 4-year intervention trial. Specifically,n an a priori basis, we aimed to analyze the change of CRPnd low-density lipoprotein (LDL) cholesterol after statinithdrawal. In addition, we studied potential clinical and

Departments of aExperimental Cardiology, bCardiology, and cInternaledicine, and dTrial Coordination Center, University Medical Centerroningen, University of Groningen, Groningen, The Netherlands. Manu-

cript received April 30, 2007; revised manuscript received and acceptedune 12, 2007.

This study is financially supported by Grant E.013 of the Dutch Kidneyoundation, Grant 99.103 of the Dutch Heart Foundation, and by annrestricted grant of Bristol-Myers Squibb. Dr. van der Harst is supportedy the Innovational Research Incentives Scheme program of the Nether-ands Organisation for Scientific Research, NWO VENI, Grant 916.76.170nd is a research fellow of the Netherlands Heart Foundation, Grant006T003 and the Interuniversitair Cardiologisch Instituut NederlandICIN). Dr. Asselbergs is a research fellow of the Netherlands Heartoundation, Grant 2003T010. Dr. van Veldhuisen is an Established Inves-

igator of the Netherlands Heart Foundation, Grant D97-017.*Corresponding author: Tel: 31 (0)503632810; fax: 31 (0)503632812.

�E-mail address: [email protected] (P. van der Harst).


iochemical correlates related to rebound of CRP after sta-in withdrawal.

ethods

ubjects were derived from the Prevention of Renal and Vas-ular Endstage Disease Intervention Trial (PREVEND-IT).he PREVEND-IT study was an investigator-initiated, single-enter, double blind, randomized, placebo-controlled trial with2-by-2 factorial design. Subjects were randomized to fosino-ril 20 mg or matching placebo and pravastatin 40 mg oratching placebo. The design and principal results of theREVEND-IT study have been reported previously.1 Inrief, the PREVEND-IT study was a primary preventionrial of cardiovascular disease conducted among 864 pa-ients with microalbuminuria (15 to 300 mg/24 hours),lood pressure of �160/100 mm Hg and not using antihy-ertensive medication, total cholesterol levels of �8.0mol/L or �5.0 mmol in case of previous myocardial

nfarction, and not using lipid-lowering medication. Thetudy was approved by the institutional review board and allarticipants provided written informed consent.

For this analysis, we defined achieved LDL and CRPevels as the values obtained at 4 years of treatment. Wentended a per protocol analysis. Patients in whom open-abel statin treatment was initiated or who discontinuedtudy pravastatin/placebo medication (self-reported) werexcluded. In addition, patients with �1 CRP measurement
10 mg/L were excluded. Of the 864 patients originally
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1549Preventive Cardiology/Statin Withdrawal on CRP and LDL

andomized in the PREVEND-IT study, 25 subjects diedefore the withdrawal period, 29 had open-label statin treat-ent initiated, 168 discontinued study medication before

he 4 years of treatment, 34 had �1 CRP value missing, and2 patients had �1 CRP value �10 mg/L, leaving 566ubjects (66%) for the present analysis. Of these 566 sub-ects, 300 patients (53%) had been randomized to pravasta-in and 266 (47%) to placebo.

As part of the protocol, plasma samples were obtained at thend of study and 3 months after withdrawal from study med-cation. Stored frozen blood samples from both 4 years and.25 years were analyzed simultaneously in a core facility.igh-sensitivity CRP was determined by nephelometry with a

hreshold of 0.156 mg/L and intra- and interassay coefficientsf variation of �4.4% and 5.7%, respectively (Dade Behringiagnostic, Marburg, Germany).2,3 All measurements wereerformed without knowledge of treatment assignment.

Differences between treatment groups were evaluated bytudent’s t test or chi-square test, when appropriate. Devi-tions from a Gaussian distribution were tested by theolmogorov-Smirnov test. Non-normally distributed vari-

bles were transformed by natural logarithm. Pearson cor-elation coefficients (verified nonparametrically by Spear-an’s correlation) were used to test the association of CRPith other lipid parameters. Data are presented as mean �D or as median and interquartile ranges (25th to 75thercentiles), depending on the distribution of the data. Aalue of p �0.05 (2-tailed) was considered statisticallyignificant. To examine the changes in CRP and LDL,tandard linear regression analyses were used to adjust forge, gender, baseline value, and assignment to fosinopril orlacebo. All analyses were performed using SPSS version2.0 software (SPSS, Inc., Chicago, Illinois).

esults

here were 566 patients on study treatment at 4 years whoere included in the present study (66% of the initial study

ohort). At study entry, before randomization, total choles-erol was 5.78 � 1.02 mmol/L, LDL cholesterol 4.06 �.92 mmol/L, high-density lipoprotein (HDL) cholesterol

able 1linical characteristics after four years of treatment

ariable Placeb(n � 26

ge (yrs) 54.1 �en 173 (65aucasian 258 (97moking statusNever 78 (29Past 89 (34Current 99 (37iabetes mellitus 8 (3%lood pressure (mm Hg)Systolic 129 �Diastolic 76 �ody mass index (kg/m2) 26.1 �rinary albumin excretion (mg/24 h)* 20.8 [12.7–

* Median (interquartile range).

.01 � 0.31 mmol/L, and CRP 1.29 mg/L (0.63 to 2.73). C

linical characteristics after 4 years after randomization areresented in Table 1. There were no significant differencesetween groups in terms of age, blood pressure, body massndex, smoking status, and prevalence of diabetes. Overall,oth clinical and biochemical characteristics among patientsn this analysis at baseline and 4 years were very similar tohose in the PREVEND-IT population as a whole.1

Compared with baseline, placebo-treated patients had aonsignificant 9% increased and pravastatin-treated patientsad a 12% decreased CRP (p � NS and p � 0.001, respec-ively; Figure 1). LDL cholesterol in placebo-allocated pa-ients remained unchanged after 4 years, but was 27% de-reased in pravastatin-treated patients (p � NS and�0.001, respectively; Figure 1). After 4 years of treat-ent, we observed a small correlation in placebo-treated

ubjects between CRP and total cholesterol (r � 0.149; p �.016) and high-density lipoprotein (HDL) cholesterol (r �0.147; p � 0.017), but not between CRP and LDL cho-

esterol (r � 0.089; p � NS). In pravastatin-allocated sub-ects, we observed only a small correlation between CRPnd total cholesterol (r � 0.181; p � 0.002) and LDLholesterol (r � 0.155; p � 0.008), but not between CRPnd HDL cholesterol (r � �0.069; p � NS). Thus, duringravastatin treatment, �3% of the variance in achieved CRPevels was explained by the variance in achieved LDLevels. In addition, the percentage change in CRP was notelated to the change in total or LDL cholesterol.

Withdrawal of pravastatin after 4 years of treatmentignificantly increased in both LDL cholesterol (p �0.001)nd CRP (p �0.05) in pravastatin-treated subjects to ap-roximately pretreatment levels (Figure 1). In linear regres-ion stratified for pravastatin treatment, we could not predicthe change of CRP with the change of LDL cholesterol. Theifference between pravastatin versus placebo groups inerms of change in CRP by withdrawal was consistent andersisted in linear regression analysis sequentially correctedor body mass index, smoking status, blood pressure, andaseline levels of total cholesterol, LDL cholesterol, HDLholesterol, and triglycerides. In placebo-allocated patients,RP levels after withdrawal were highly correlated with

Pravastatin(n � 300)

p Value

55.8 � 11.2 0.29211 (70%) 0.18285 (95%) 0.64

0.8683 (28%)99 (33%)

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RP levels before withdrawal (r � 0.72; p �0.001). This

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as comparable to the association over time observed forotal cholesterol, LDL cholesterol, and HDL cholesterolr � 0.78; r � 0.75; r � 0.78, all p �0.001, respectively).

iscussion

his is the first study to prospectively study the effect oftatin discontinuation on CRP levels in a large population.he present study demonstrates that withdrawal of prava-tatin after 4 years of treatment results in an increase in CRPevels to approximately pretreatment levels within 3 months.he increase in CRP after withdrawal was not associated with

he increase of LDL cholesterol and therefore might be inde-endent of the lipid-lowering efficacy of pravastatin. Theresent study also confirms that the magnitude of CRP reduc-ion during pravastatin treatment is not related to the magnitudef achieved LDL reduction.4,5

A few, small previous studies reported a rebound effect

igure 1. Relative mean � SEM change in LDL cholesterol and CRP afteryears of treatment and after 3 months of withdrawal of placebo and

ravastatin. Compared with baseline, pravastatin treatment resulted in aignificant reduction in LDL cholesterol and CRP at 4 years (p �0.001 and� 0.001, respectively). Withdrawal resulted in a significant increase inDL cholesterol and CRP in pravastatin-treated patients (p �0.001 and�0.05).

f statin withdrawal on CRP.6–8 However, these studies

ere not randomized or placebo-controlled, and only in-olved a few patients. It was recently suggested that statinherapy might affect structural vascular remodeling andegression of atherosclerosis.9 Inflammation is recognizeds an important contributor to the development and progres-ion of atherosclerosis.10 The efficacy of statin treatment toower CRP levels and presumably inflammation in humansas been well described.4,5,11 Compelling evidence showshat high CRP levels are a strong predictor of cardiovascularvents in apparently healthy subjects12,13, but also in pa-ients with myocardial infarction,14 stable or unstable an-ina, and after coronary conventional balloon angioplasty15

r stent implantation.16 In addition to inflammation, otherechanisms might be involved.17,18

Several studies have suggested that the nonadherence oftatins in typical populations is likely to substantially un-ermine their efficacy in reducing cardiovascular morbiditynd mortality.19–22 Two-year adherence rates of statin ther-py for primary prevention has been reported to be as low as5%.22 Discontinuation of statin treatment after onset ofymptoms of acute coronary syndrome has been associatedith increased cardiac risk.23,24 Our data underline the im-ortance of continuing statin therapy once initiated and isonsistent with the general belief that nonadherence leads toorsening of the condition being treated.25

The limitations of our study merit some consideration.f the initial PREVEND-IT trial, we followed 566 (66%)

ubjects for the present analysis. Although baseline andlinical characteristics did not differ between this popula-ion and the overall population, our selection may have leado bias in the data. All patients in this study were microalbu-inuric, and did not comply to the current indication for

tatin treatment, and thus are not representative of a typicaltatin-treated population. Our population merely providedhe opportunity to evaluate discontinuation of statin treat-ent, as we consider it unethical in patients with an indi-

ation for statin treatment. Compliance to statin therapy waself-reported, and thus the effects might have been under-stimated. However, the median changes observed in theata were stable in analyses stratified by cardiovascular riskactors. To limit any potentially confounding effects due toutlying values, we chose to exclude from our analysisndividuals with CRP levels �10 mg/L at �1 measure-ents.

cknowledgment: We thank Dade Behring (Marburg, Ger-any) for supplying equipment (Behring Nephelometer II)

nd analytes for the determination of high-sensitivity CRPnd urinary albumin. We thank Jacko J. Duker and Janneke.J.T. van der Wal-Hanewald for their elaborate work and

echnical support.

1. Asselbergs FW, Diercks GF, Hillege HL, van Boven AJ, Janssen WM,Voors AA, de Zeeuw D, de Jong PE, van Veldhuisen DJ, van GilstWH. Effects of fosinopril and pravastatin on cardiovascular events insubjects with microalbuminuria. Circulation 2004;110:2809–2816.

2. van der Harst P, Voors AA, Volbeda M, Buikema H, van VeldhuisenDJ, van Gilst WH. Usefulness of preoperative C-reactive protein andsoluble intercellular adhesion molecule-1 level for predicting future
cardiovascular events after coronary artery bypass grafting. Am JCardiol 2006;97:1697–1701.

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1551Preventive Cardiology/Statin Withdrawal on CRP and LDL

3. van der Harst P, Asselbergs FW, Buikema H, Voors AA, vanVeldhuisen DJ, van Gilst WH. Effects of C-reactive protein andcholesterol on responsiveness in vitro of the internal thoracic artery toangiotensin II in patients having coronary artery bypass grafting. Am JCardiol 2006;98:751–753.

4. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-termeffects of pravastatin on plasma concentration of C-reactive protein.The Cholesterol and Recurrent Events (CARE) Investigators. Circu-lation 1999;100:230–235.

5. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH,Pfeffer MA, Braunwald E, the Pravastatin or Atorvastatin Evaluationand Infection Therapy-Thrombolysis in Myocardial Infarction. C-Reactive protein levels and outcomes after statin therapy. N EnglJ Med 2005;352:20 –28.

6. Lee KT, Lai WT, Chu CS, Tsai LY, Yen HW, Voon WC, Sheu SH.Effect of withdrawal of statin on C-reactive protein. Cardiology 2004;102:166–170.

7. Yip HK, Youssef AA, Chua S, Hung WC, Chen YH, Yeh KH, Wu CJ,Hang CL. Re-elevation of high-sensitivity C-reactive protein but notthe von Willebrand factor after withdrawing atorvastatin therapy inpatients with unstable angina undergoing coronary artery stenting. IntHeart J 2006;47:501–509.

8. Huang CY, Wu TC, Lin WT, Leu HB, Lin CP, Lin SJ, Chen JW.Effects of simvastatin withdrawal on serum matrix metalloproteinasesin hypercholesterolaemic patients. Eur J Clin Invest 2006;36:76–84.

9. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, VogelRA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMariaAN. Effect of intensive compared with moderate lipid-lowering ther-apy on progression of coronary atherosclerosis: a randomized con-trolled trial. JAMA 2004;291:1071–1080.

0. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med1999;340:115–126.

1. van der Harst P, Voors AA, van Gilst WH, Bohm M, van VeldhuisenDJ. Statins in the treatment of chronic heart failure: biological andclinical considerations. Cardiovasc Res 2006;71:443–454.

2. Ridker PM, Hennekens CH, Roitman-Johnson B, Stampfer MJ, AllenJ. Plasma concentration of soluble intercellular adhesion molecule 1and risks of future myocardial infarction in apparently healthy men.Lancet 1998;351:88–92.

3. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein andother markers of inflammation in the prediction of cardiovasculardisease in women. N Engl J Med 2000;342:836–843.

4. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S,Flaker GC, Braunwald E. Inflammation, pravastatin, and the risk of
coronary events after myocardial infarction in patients with average
cholesterol levels. Cholesterol and Recurrent Events (CARE)Investigators. Circulation 1998;98:839 – 844.

5. Buffon A, Liuzzo G, Biasucci LM, Pasqualetti P, Ramazzotti V,Rebuzzi AG, Crea F, Maseri A. Preprocedural serum levels of C-re-active protein predict early complications and late restenosis aftercoronary angioplasty. J Am Coll Cardiol 1999;34:1512–1521.

6. Walter DH, Fichtlscherer S, Sellwig M, Auch-Schwelk W, Schach-inger V, Zeiher AM. Preprocedural C-reactive protein levels andcardiovascular events after coronary stent implantation. J Am CollCardiol 2001;37:839–846.

7. Brouilette SW, Moore JS, McMahon AD, Thompson JR, Ford I, Shep-herd J, Packard CJ, Samani NJ. Telomere length, risk of coronary heartdisease, and statin treatment in the West of Scotland Primary PreventionStudy: a nested case-control study. Lancet 2007;369:107–114.

8. van der Harst P, van der Steege G, De Boer RA, Voors AA, Hall AS,Mulder MJ, van Gilst WH, van Veldhuisen DJ, MERIT-HF Study Group.Telomere length of circulating leukocytes is decreased in patients withchronic heart failure. J Am Coll Cardiol 2007;49:1459–1464.

9. Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weinstein MC, AvornJ. Long-term persistence in use of statin therapy in elderly patients.JAMA 2002;288:455–461.

0. Blackburn DF, Dobson RT, Blackburn JL, Wilson TW, Stang MR,Semchuk WM. Adherence to statins, beta-blockers and angiotensin-converting enzyme inhibitors following a first cardiovascular event: aretrospective cohort study. Can J Cardiol 2005;21:485–488.

1. Eagle KA, Kline-Rogers E, Goodman SG, Gurfinkel EP, Avezum A,Flather MD, Granger CB, Erickson S, White K, Steg PG. Adherenceto evidence-based therapies after discharge for acute coronary syn-dromes: an ongoing prospective, observational study. Am J Med 2004;117:73–81.

2. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy inelderly patients with and without acute coronary syndromes. JAMA2002;288:462–467.

3. Spencer FA, Fonarow GC, Frederick PD, Wright RS, Every N, Gold-berg RJ, Gore JM, Dong W, Becker RC, French W. Early withdrawalof statin therapy in patients with non-ST-segment elevation myocardialinfarction: national registry of myocardial infarction. Arch Intern Med2004;164:2162–2168.

4. Fonarow GC, Wright RS, Spencer FA, Fredrick PD, Dong W, EveryN, French WJ. Effect of statin use within the first 24 hours of admis-sion for acute myocardial infarction on early morbidity and mortality.Am J Cardiol 2005;96:611–616.

5. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med
2005;353:487–497.

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Comparison of C-Reactive Protein Levels in PatientsWho Do and Do Not Develop Atrial Fibrillation

During Electrophysiologic Study

Bahar Pirat, MD*, Ilyas Atar, MD, Cagatay Ertan, MD, Huseyin Bozbas, MD, Oyku Gulmez, MD,Haldun Müderrisoglu, MD, and Bulent Ozin, MD

C-reactive protein (CRP) was increased in patients with atrial fibrillation (AF). The aim ofthis study was to evaluate CRP after inducing AF in 39 patients undergoing electrophysi-ologic study (EPS). After a diagnostic EPS, programmed atrial stimulation with 3 extrastimuli from the right atrium was performed in all patients. CRP was measured before and6 and 24 hours after the procedure. Patients in whom AF was induced were monitored for24 hours. AF was induced in 18 of 39 patients. Twenty-one patients without a tachyar-rhythmia constituted the control group. Groups were similar with regard to age, gender,incidences of hypertension and diabetes, and history of coronary artery disease. On aver-age, AF lasted 4.8 hours, and spontaneous conversion to sinus rhythm was observed in allpatients. There were no statistically significant differences with respect to baseline and6-hour CRP values between groups. However, mean CRP at 24 hours was significantlyhigher in patients with AF compared with controls (10 � 11 and 3.9 � 4.2 mg/L; p � 0.04).In conclusion, induction of AF during EPS led to increased CRP. This finding suggestedthat increased CRP may be the consequence of AF. © 2007 Elsevier Inc. All rights
reserved. (Am J Cardiol 2007;100:1552–1555)
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ecently, evidence emerged implicating inflammation asossibly contributing to structural remodeling of the atriand initiation or maintenance of atrial fibrillation (AF).1,2

nflammatory infiltrates were shown in atrial biopsy speci-ens from patients with lone AF resistant to drug therapy.3hus, research focused mainly on the relation between the

ncidence and recurrence of AF and an inflammatoryarker, C-reactive protein (CRP). Although there were con-

roversial data, many studies reported that increased CRPas associated with an increased incidence of AF.4–8 CRPas also shown to be a predictor of AF recurrence.9–12

owever, it was unclear whether CRP and the inflammatorytate contributed to occurrences of AF or AF induced thencrease in CRP. In this study, we explored the effect of AFevelopment on CRP in patients who were in sinus rhythmnd underwent electrophysiologic study (EPS).

ethods

he study was approved by the ethics committee of Baskentniversity, Ankara, Turkey, and all patients gave informed

onsent before enrollment. All patients referred for EPS fromuly 2003 to September 2006 to evaluate sinus node function,trioventricular conduction, syncope of undetermined origin,

Faculty of Medicine, Department of Cardiology, Baskent University,nkara, Turkey. Manuscript received April 23, 2007; revised manuscript

eceived and accepted June 14, 2007.This study was supported by institutional and departmental resources,

nkara, Turkey.*Corresponding author: Tel.: 90-312-212-6868-1419; fax: 90-312-223-

333.
CE-mail address: [email protected] (B. Pirat).

r palpitations with no documented arrhythmias were eligibleor the study. Patients with permanent AF, acute or chronicnflammatory diseases, malignancies, and chronic liver or renalisease, and those who underwent surgery within the previous0 days or experienced an acute coronary syndrome within therevious month were excluded from the study. Subjects forhom an ablation procedure had been planned based on areviously documented arrhythmia were not enrolled in thetudy. Patients in whom a supraventricular tachycardia otherhan AF or ventricular tachycardia was induced during EPSere also excluded from the study.Each subject underwent a physical examination and pro-

ided a detailed medical history. Medications and symp-oms were noted. Results of echocardiograms performedefore EPS were reviewed. Left ventricular end-diastolicnd end-systolic diameters, anteroposterior diameter of theeft atrium, and the presence or absence of left ventricularypertrophy, valvular heart disease, and regional wall mo-ion abnormality were recorded. Systolic dysfunction wasefined as ejection fraction �50%. Patients who had im-aired relaxation and pseudonormal and restrictive fillingatterns were considered to have diastolic dysfunction, asreviously described.13

Blood samples were obtained from a peripheral vein justefore the EPS for CRP, erythrocyte sedimentation rate,omplete blood count, and creatinine analysis. Measure-ent of serum CRP was repeated at 6 and 24 hours after the

rocedure. CRP was determined using the immunoturbidi-etric method with a PP modular autoanalyzer (Rocheiagnostica GmbH, Mannheim, Germany).For EPS, 4 standard 5Fr sheaths were inserted, 3 through

he femoral vein and 1 through the left internal jugular vein.
atheters were positioned in the right atrium, right ventricle,
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1553Arrhythmias and Conduction Disturbances/Atrial Fibrillation and C-Reactive Protein

oronary sinus, and at the His bundle region. After routineiagnostic EPS, programmed atrial stimulation with 3 extratimuli from the right atrium was performed in all patients tonduce AF. AF was defined as episodes of AF that lasted �5

inutes. Patients who developed AF were monitored using aelemetry system. Duration of AF was recorded for each sub-ect. Electrical cardioversion was planned if spontaneous car-ioversion to sinus rhythm was not observed 24 hours afterPS. Patients without an inducible tachyarrhythmia constituted

he control group.Variables with normal distribution were compared using

aired and unpaired t tests. Differences between groups foronhomogenously distributed parameters were tested usingann-Whitney U and Wilcoxon’s tests. Clinical character-

stics of the groups were compared using chi-square test. Atepwise forward logistic regression analysis was performedo determine independent parameters associated with AF.ariables are presented as mean � SD. p Values of �0.05

able 1aseline characteristics of the control and atrial fibrillation (AF) groups

ariable Control Group(n � 21)

AF Group(n � 18)

ge (yrs) 46 � 14 53 � 12en 10 (48%) 10 (55%)

ystolic blood pressure (mm Hg) 119 � 10 126 � 12iastolic blood pressure (mm Hg) 73 � 9 75 � 8ypertension 4 (20%) 6 (33%)iabetes mellitus 1 (5%) 2 (11%)yperlipidemia* 8 (40%) 6 (33%)moker 5 (25%) 7 (39%)oronary artery disease 3 (15%) 3 (17%)alvular heart disease† 4 (21%) 7 (41%)istory of paroxysmal AF 3 (15%) 5 (28%)Blockers 5 (26%) 9 (50%)

alcium channel blockers 1 (5%) 2 (11%)ngiotensin-converting enzymeinhibitors or angiotensinreceptor blockers

4 (21%) 5 (28%)

igoxin — 1 (5%)ntiarrhythmics 1 (5%) 3 (16%)

Values expressed as number (percent) or mean � SD.* Total cholesterol � 200 mg/dl, low-density lipoprotein cholesterol130 mg/dl, or triglycerides �150 mg/dl or use of a lipid-lowering agent.† Trace, mild, or mild to moderate mitral or aortic regurgitation.

able 2chocardiographic findings of the control and atrial fibrillation (AF)roups at baseline


AF Group(n � 18)

eft ventricular end-diastolic diameter (mm) 46 � 4 47 � 3eft ventricular end-systolic diameter (mm) 30 � 3 31 � 3ractional shortening (%) 34 � 3 33 � 2jection fraction (%) 57 � 7 58 � 4egional wall motion abnormality 4 (19%) 3 (16%)eft ventricular dysfunction 4 (22%) 2 (11%)eft ventricular hypertrophy 8 (44%) 7 (41%)eft atrial size (mm) 34 � 4 36 � 3iastolic dysfunction 2 (11%) 4 (23%)

ere considered statistically significant. Analyses were per-

ormed using SPSS software (Statistical Package for theocial Sciences, version 11.0; SSPS Inc., Chicago, Illinois).

esults

total of 210 patients were screened for inclusion and exclu-ion criteria, and 39 patients met these criteria. AF was inducedn 18 subjects and no tachyarrhythmia was induced in 21ubjects. Patients had otherwise normal electrophysiologicndings. There were no statistically significant differencesith respect to age, gender, and clinical characteristics betweenroups. Systolic blood pressures of patients with AF wereigher compared with patients in the control group during therocedure (p � 0.04). Baseline characteristics of the groups areisted in Table 1. Echocardiographic findings were similaretween groups, including left atrial size (Table 2).

The most frequent indication for EPS was palpitations,hich was present in 24 patients. Eleven subjects were

tudied for syncope of undetermined cause. Two patientsad a history of ventricular tachycardia, and 2 patients hadolff-Parkinson-White syndrome.Mean duration of AF was 4.8 � 5.3 hours (minimum 0.3,

aximum 20). Spontaneous conversion to sinus rhythm wasbserved in all patients. No patient experienced hemodynamicompromise in response to AF that needed cardioversion.

Baseline plasma CRP, erythrocyte sedimentation rate,hite blood cell count, and creatinine were not statisticallyifferent between groups (Table 3). CRP at 24 hours wasignificantly higher in patients with AF compared withhose in the control group (10 � 11 and 3.9 � 4.2 mg/L,� 0.04; Figure 1). A significant increase from baseline to

4 hours was observed for CRP in both groups (Figure 2).Multivariable regression analysis using systolic blood

ressure, left atrial dimension, and CRP at 6 and 24 hoursielded significant associations between AF and CRP at 6ours (� � �1.540, SE 0.755, p � 0.041) and CRP at 24ours (� � 1.527, SE 0.693, p � 0.028).

iscussion

he present study showed that baseline CRP did not differetween patients with and without inducible AF. In thisow-risk population, for the occurrence of AF, baseline CRPid not predict initiation of AF. However, compared withatients in sinus rhythm, subjects with inducible AF hadigher CRP at 24 hours.

able 3aseline and follow-up inflammatory markers of the control and atrialbrillation (AF) groups


AF Group(n � 18)

p Value

rythrocyte sedimentationrate (mm)

9.8 � 4.9 6.9 � 5.8 NS

hite blood cell count (/�l) 6,704 � 984 7,453 � 1,592 NSRP, baseline (mg/L) 2.8 � 3.8 4.5 � 5.4 NSRP, 6 h (mg/L) 2.6 � 2.1 6.1 � 6.6 NSRP, 24 h (mg/L) 3.9 � 4.2 10 � 11 0.04

ncrease in CRP, baseline to24 h (mg/L)

1.1 � 1.3 5.6 � 7.0 0.006

Our study showed for the first time that increased CRP

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ould be more a consequence of AF than an initiating factor.lood samples for the measurement of CRP were obtained

ust before the initiation of AF, when all patients were ininus rhythm. Comparison of CRP at baseline and during4-hour follow-up let us elucidate that AF initiated annflammatory process. However, serial CRP analyses wereot performed after restoration of sinus rhythm. Demonstra-ion of a decrease in CRP in patients with sinus rhythmould be more valuable to establish a cause-and-effect re-ation between AF and inflammation. Our study groupsere similar with respect to confounding parameters, such

s age, gender, left atrial diameter, and prevalence of hy-ertension or coronary artery disease. Multivariable regres-ion analyses determined that CRP at 24 hours was thendependent predictor of AF.

Several studies focused on the association between CRP,uccess of electrical cardioversion, and recurrence of

igure 1. CRP in the control and AF groups at baseline and 6 and 24 hoursfter EPS. *p � 0.04 compared with the control group CRP at 24 hours.

igure 2. Change in CRP from baseline to 6 and 24 hours after EPS in theontrol and AF groups. Error bars, SE. *p � 0.02 compared with CRP ataseline; †p � 0.003 compared with CRP at baseline; ‡p � 0.001 comparedith CRP at baseline.

F.9,11,12 A recent meta-analysis suggested that increased

aseline CRP was associated with higher risk of AF recur-ence after successful cardioversion.14 Watanabe et al11 re-orted that CRP was an independent predictor of successfulardioversion for AF and maintenance of sinus rhythm afterardioversion. They also showed that restoration of sinushythm decreased CRP, and AF recurrence resulted in in-reased CRP. In a study by Acevedo et al,5 CRP signifi-antly increased in patients with AF compared with con-rols, and at 1-year follow-up, mean CRP was still higher inatients who remained in AF compared with those whoonverted to sinus rhythm. These investigators stated thathe increase in CRP in patients with AF could be an expres-ion of the inflammatory process associated with left atrialnd ventricular remodeling because CRP also correlatedith left atrial enlargement and left ventricular dysfunction.hese results complement our data showing that AF initi-ted an inflammatory process. However, the mechanism ofctivation of inflammation by AF remains unclear. It washown that a high rate of AF may increase atrial wallension and may induce oxidative damage leading to com-lement and proinflammatory cytokine activation.15 Thesehanges may contribute to the persistence of AF and furtherggravate AF, although inflammation might not be the pri-ary event. In addition to electrical remodeling, which

eads to the concept of “AF begets AF,”16 sustained inflam-ation also may result in perpetuation of the arrhythmia.In our study, an increase in CRP levels was observed in

oth study groups at 24 hours compared with baseline.here was evidence that ablation procedures, percutaneousoronary intervention, and even uncomplicated diagnosticoronary angiography can induce a systemic inflammatoryesponse.17–19 In our study, the EPS itself might have causedhe increase in CRP in control subjects and partly in patientsith AF.Our study had several limitations. The small number of

atients precluded us from learning more about the effectsf confounding variables on CRP. The small number ofatients was caused by difficulty finding subjects who metnclusion and exclusion criteria in a population undergoingPS. The duration of AF was short (mean 4.8 hours), and allatients spontaneously converted to sinus rhythm. There-ore, we were unable to clarify with certainty whether highRP influenced the conversion rate to sinus rhythm. Fol-

ow-up for our study also was short (24 hours), which didot allow us to monitor the change in CRP after conversiono sinus rhythm.

1. Allessie M, Ausma J, Schotten U. Electrical, contractile and structuralremodeling during atrial fibrillation. Cardiovasc Res 2002;54:230–246.

2. Chung MK, Martin DO, Sprecher D, Wazni O, Kanderian A, CarnesCA, Bauer JA, Tchou PJ, Niebauer MJ, Natale A, Van Wagoner DR.C-reactive protein elevation in patients with atrial arrhythmias: inflam-matory mechanisms and persistence of atrial fibrillation. Circulation2001;104:2886–2891.

3. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A.Histological substrate of atrial biopsies in patients with lone atrialfibrillation. Circulation 1997;96:1180–1184.

4. Dernellis J, Panaretou M. Effects of C-reactive protein and the thirdand fourth components of complement (C3 and C4) on incidence ofatrial fibrillation. Am J Cardiol 2006;97:245–248.

5. Acevedo M, Corbalan R, Braun S, Pereira J, Navarrete C, Gonzalez I.
C-reactive protein and atrial fibrillation: “evidence for the presence of

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1555Arrhythmias and Conduction Disturbances/Atrial Fibrillation and C-Reactive Protein

inflammation in the perpetuation of the arrhythmia.” Int J Cardiol2006;108:326–331.

6. Anderson JL, Allen Maycock CA, Lappe DL, Crandall BG, Horne BD,Bair TL, Morris SR, Li Q, Muhlestein JB. Frequency of elevationof C-reactive protein in atrial fibrillation. Am J Cardiol 2004;94:1255–1259.

7. Buob A, Jung J, Siaplaouras S, Neuberger HR, Mewis C. Discordantregulation of CRP and NT-proBNP plasma levels after electrical car-dioversion of persistent atrial fibrillation. Pacing Clin Electrophysiol2006;29:559–563.

8. Ellinor PT, Low A, Patton KK, Shea MA, MacRae CA. C-reactiveprotein in lone atrial fibrillation. Am J Cardiol 2006;97:1346–1350.

9. Malouf JF, Kanagala R, Al Atawi FO, Rosales AG, Davison DE,Murali NS, Tsang TS, Chandrasekaran K, Ammash NM, FriedmanPA, Somers VK. High sensitivity C-reactive protein: a novel predictorfor recurrence of atrial fibrillation after successful cardioversion. J AmColl Cardiol 2005;46:1284–1287.

0. Hatzinikolaou-Kotsakou E, Tziakas D, Hotidis A, Stakos D, Floros D,Papanas N, Chalikias G, Maltezos E, Hatseras DI. Relation of C-re-active protein to the first onset and the recurrence rate in lone atrialfibrillation. Am J Cardiol 2006;97:659–661.

1. Watanabe E, Arakawa T, Uchiyama T, Kodama I, Hishida H. High-sensitivity C-reactive protein is predictive of successful cardioversionfor atrial fibrillation and maintenance of sinus rhythm after conversion.Int J Cardiol 2006;108:346–353.

2. Wazni O, Martin DO, Marrouche NF, Shaaraoui M, Chung MK,
Almahameed S, Schweikert RA, Saliba WI, Natale A. C reactive
protein concentration and recurrence of atrial fibrillation afterelectrical cardioversion. Heart 2005;91:1303–1305.

3. Nishimura RA, Tajik AJ. Evaluation of diastolic filling of left ventriclein health and disease: Doppler echocardiography is the clinician’sRosetta Stone. J Am Coll Cardiol 1997;30:8–18.

4. Liu T, Li G, Li L, Korantzopoulos P. Association between C-reactiveprotein and recurrence of atrial fibrillation after successful electricalcardioversion: a meta-analysis. J Am Coll Cardiol 2007;49:1642–1648.

5. Mihm MJ, Yu F, Carnes CA, Reiser PJ, McCarthy PM, Van WagonerDR, Bauer JA. Impaired myofibrillar energetics and oxidative injuryduring human atrial fibrillation. Circulation 2001;104:174–180.

6. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillationbegets atrial fibrillation. A study in awake chronically instrumentedgoats. Circulation 1995;92:1954–1968.

7. Richter B, Derntl M, Marx M, Lercher P, Gossinger HD. Therapy withangiotensin-converting enzyme inhibitors, angiotensin II receptorblockers, and statins: no effect on ablation outcome after ablation ofatrial fibrillation. Am Heart J 2007;153:113–119.

8. Saleh N, Svane B, Jensen J, Hansson LO, Nordin M, Tornvall P. Stentimplantation, but not pathogen burden, is associated with plasmaC-reactive protein and interleukin-6 levels after percutaneous coronaryintervention in patients with stable angina pectoris. Am Heart J 2005;149:876–882.

9. Goldberg A, Zinder O, Zdorovyak A, Diamond E, Lischinsky S,Gruberg L, Markiewicz W, Beyar R, Aronson D. Diagnostic coronaryangiography induces a systemic inflammatory response in patients
with stable angina. Am Heart J 2003;146:819–823.

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Acute Effects of His Bundle Pacing Versus Left Ventricularand Right Ventricular Pacing on Left Ventricular Function

Luigi Padeletti, MDa, Randy Lieberman, MDb, Jan Schreuder, MDc, Antonio Michelucci, MDa,Andrea Collella, MDa, Paolo Pieragnoli, MDa, Giuseppe Ricciardi, MDa, William Eastman, MSd,

Sergio Valsecchi, PhDd, and Douglas A. Hettrick, PhDd,*

Dual-chamber pacing with His bundle pacing has theoretical advantages over conventionalright ventricular (RV) apical pacing. We compared indexes of left ventricular (LV) functionduring acute dual-chamber pacing from the His bundle and other RV and LV pacing sites.Twelve patients (6 men; 63 � 11 years) with a standard indication for electrophysiologicstudy were included. Average QRS duration was 100 � 19 ms. Ejection fraction was 48 �15%. A pressure–volume catheter was positioned in the left ventricle through the femoralarterial access. Pressure–volume loops were collected during atrial (AAI) and dual-cham-ber overdrive pacing at 82 � 15 beats/min after 2 minutes of hemodynamic stabilization.Ventricular pacing catheter position was randomized between the RV apex, RV septal, andfree wall portions of the outflow tract, LV free wall, and His bundle. His bundle capture wasverified from surface electrocardiographic morphometry using standard criteria. Atrioven-tricular delay was set to the P wave–His duration �10 ms to minimize the effects of fusion(96 � 22 ms). LV only pacing, but not His pacing, resulted in improved stroke work andstroke volume compared with alternate site RV pacing. No changes in �dP/dt, LVend-systolic pressure. LV end-diastolic pressure, or cycle efficiency, were observed betweenRV pacing sites. In conclusion, acute His bundle pacing did not improve LV functioncompared with alternate site RV pacing and may be inferior to LV pacing. © 2007
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ight ventricular (RV) apical pacing has been shown tocutely reduce left ventricular (LV) function.1–3 These re-uctions may be associated with less than optimal outcomess reported in patients with RV apical pacing in severalotable clinical trials.4–8 In contrast to RV apical pacing,is bundle pacing takes advantage of the intrinsic conduc-

ion system and may offer an attractive alternative becauseontractile dyssynchrony may be avoided.9–12 Recent inves-igations have reported improved acute LV function andong-term benefits with His pacing using commerciallyvailable pacing systems.13,14 RV septal, LV, and biven-ricular pacing have also been proposed as alternatives toV apical pacing. In this investigation, we compared in-exes of LV function during acute dual-chamber pacingrom the His bundle and other RV and LV pacing sites touantify the relative changes in LV function associated withlternatives to RV apical pacing using pressure–volumelane analysis.

ethods

he experimental design was approved by the Institutionaleview Boards at the Careggi Hospital and Detroit Medicalenter, and all subjects provided written informed consent.

aUniversity of Florence, Florence, Italy; bHarper Hospital, Detroit,ichigan; cSan Raffaele Hospital Milan, Italy; and dMedtronic, Inc. Min-

eapolis, Minnesota. Manuscript received April 23, 2007; revised manu-cript received and accepted June 19, 2007.

QE-mail address: [email protected] (D. Hettrick).

atients with indications for electrophysiologic examinationere studied as part of a broader trial of alternate siteentricular pacing.3 Subjects were excluded from analysis ifhey had a previously implanted device, valvular insuffi-iency or stenosis, or measured QRS duration �125 ms. AFr, 12-electrode combination high fidelity micromanome-er-conductance catheter (CD Leycom, Zoetermeer, Theetherlands) was positioned in the LV apex through the

emoral arterial access.15 Pressure–volume loops were col-ected after 2 minutes of right atrial appendage (AAI pacingode) and dual-chamber overdrive pacing. A Swan-Ganz

atheter was placed in the proximal pulmonary artery fromhe femoral vein for the determination of pulmonary arteryressure and stroke volume. Parallel conductance volumeor conductance volume calibration was assessed by injec-ion of 10 ml of hypertonic saline (6%) into the pulmonaryrtery as previously described.15 Absolute LV volumes werealculated by matching effective conductance stroke vol-me with simultaneously measured thermodilution strokeolume and by subtracting parallel conductance from totalolume. Temporary or permanent pacing electrodes wereositioned in the RV apex, RV outflow tract free wall, RVutflow tract septum, LV free wall, and His bundle. The LVead was positioned transvenously in the epicardial lateral orosterolateral LV wall through the coronary sinus usingtandard resynchronization therapy techniques. Lead loca-ion was confirmed from fluoroscopic inspection and elec-rocardiographic morphometry using previously publishedriteria.12,13,16 His bundle capture was verified by paced
RS duration and morphometry identical to intrinsic QRS
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1557Arrhythmias and Conduction Disturbances/LV Function During His Pacing

igure 1. Raw hemodynamic data including electrocardiogram (ECG), LVolume, LV pressure, LV dP/dt, and LV pressure volume loops for 1atient during control (AAI) pacing (left) and during His pacing (right).he electrocardiographic waveforms were recorded directly from the con-uctance catheter. No changes in the QRS morphology were observed.owever, changes in dP/dt, LV pressure morphometry, global LV volume

ignal, and the combined LV pressure–volume signal are apparent. Notehat preload (LV end-diastolic volume) is lower during His pacing. This
ay be due in part to relatively shorter AV delays that limit total LV filling. A
otals 63 � 11 6 (men) 100 � 19 48 � 15 4 5

igure 2. Example pressure volume data from 1 patient during alternate siteacing. In this patient, His pacing compared well with other RV pacingites but not as well with LV pacing. Note the decreased end-systolic

igure 3. QRS duration for various pacing modalities. QRS duration wasonger during RV and LV pacing compared with His and atrial pacing.RS duration was similar between His and atrial pacing. ap �0.05 versus
AI; bp �0.05 versus His.
able 1atient demographics and history

atient Age (yrs)/Sex QRS (ms) EF (%) Cardio-myopathy

CongestiveHeart

Failure

CoronaryArteryDisease

Hyper-tension

MyocardialInfarction

AtrialArrhythmia

VentricularArrhythmia

1 44F 124 45 Yes No Yes Yes Yes No Yes2 51M 100 30 No Yes No No Yes Yes No3 52F 70 66 No No No No No No Yes4 59M 102 59 No Yes Yes Yes Yes No Yes5 61M 120 37 Yes Yes Yes No No No No6 62F 88 20 Yes Yes No Yes No Yes No7 64F 90 58 No No No Yes No Yes No8 65M 130 50 No No Yes No No No No9 69M 110 40 Yes No Yes No Yes No No0 74M 80 50 No No No No No No No1 75F 108 45 No Yes Yes Yes No No Yes2 83F 80 70 No No No No No No No

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uration and morphometry (Figure 1).17 No leads wereermanently placed in the His. Atrioventricular (AV) delayas set to the P wave–His duration �10 ms to minimize theossible effects of fusion.

QRS duration was calculated using standard electrocar-iographic leads. LV pressure, volume, and function wereveraged during 8 to 10 beats at end expiration from the rawV pressure and conductance volume data using commer-ially available software (Conduct NT, Leycom). LV strokeork was calculated as the area of the steady-state pressure–

igure 4. Changes in parameters of LV systolic function during variousacing modalities. His and RV free wall pacing resulted in decreased strokeork (A) and stroke volume (B) compared with AAI. Strike volume was

ower for His and all RV sites compared with LV pacing. RV apical andV septal pacing resulted in decreased LV dP/dt (C) compared with AAIacing. ap �0.05 versus AAI; bp �0.05 versus LV free wall.

olume diagram. The time constant (�) of isovolumic relax- s

tion was determined assuming a non-zero asymptote.lobal cycle efficiency was calculated as previously de-

cribed3,18 using the formula: cycle efficiency � strokeork/[(�LV pressure) � (�LV volume)]. This index quan-

ifies distortions in the pressure–volume diagram, presum-bly due to asynchronous LV contraction. The calculationssumes that ideal synchronous contraction produces a cy-le efficiency value of 1.0.

All hemodynamic data obtained during dual-chamberacing with a different ventricular pacing site were com-ared using 1-way analysis of variance for repeated mea-

igure 5. Changes in LV hemodynamics and efficiency during variousacing modalities. No changes in LV end-systolic pressure (A) were ob-erved between groups. LV free wall pacing resulted in a significantncrease in LV end-diastolic pressure (B). Cycle efficiency (C) was alsoimilar between pacing sites. ap �0.05 versus AAI.

ures. A Student’s Neuman-Keuls test was used for post hoc

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1559Arrhythmias and Conduction Disturbances/LV Function During His Pacing

omparisons. A p value �0.05 was considered significant.ata are presented a mean � SD.

esults

emographic data are listed in Table 1. The average pacingate was 82 � 15 beats/min. Average QRS duration was00 � 19 ms. The programmed paced AV delay was6 � 22 ms. Figures 1 and 2 show raw data from individualatients. QRS duration (Figure 3) was similar between AAI85 � 12 ms) and His (92 � 11 ms) pacing, but significantlyp �0.05) longer during RV and LV pacing. LV onlyacing, but not His pacing, resulted in improved strokeork and stroke volume compared with alternate site RVacing (Figure 4). LV pacing resulted in a significant in-rease in LV end-diastolic pressure. No changes in �dP/dt,V end-systolic pressure, LV end-diastolic pressure, orlobal cycle efficiency were observed between RV pacingites (Figure 5). Additional hemodynamic parameters areisted in Table 2. His pacing resulted in lower cardiacutput, compared with AAI and LV, and lower magnitudedP/dtmin compared with AAI.

iscussion

he results of this study suggest that, despite retainingntrinsic QRS duration, direct His pacing with a short AVelay resulted in decreased LV function compared with AAInd LV pacing and LV function similar to RV pacing. LVacing was equivalent to AAI. His pacing and all RV pacingites resulted in decreased stroke work and stroke volumeompared with AAI and LV pacing.

Several studies have confirmed the feasibility of long-erm His bundle pacing with conventional pacing systems inoth animals9,10,19 and humans.11,13 Deshmukh and col-eagues12 observed a reduction in LV dimensions and im-roved cardiac function with His bundle pacing in patientsith chronic atrial fibrillation and dilated cardiomyopathy.cchetta et al14 also observed that permanent para-Hisianacing is feasible and allows an improvement in functionaltatus and mitral regurgitation during long-term follow-upompared with conventional RV apical pacing. However,hese studies primarily compared His with RV pacing butot to LV pacing or to intrinsic conduction. We recentlyeported that RV pacing worsens LV function in patientsith and without LV dysfunction unless the RV pacing site

s optimized. Furthermore, LV and biventricular pacingreserved LV function in patients with normal ejectionraction and improved LV function in patients with ejection

able 2emodynamic effects of ventricular pacing

AAI HIS

ardiac output (L/min) 4.9 � 2.2 3.6 � 1.5*,†

elaxation time constant (ms) 40 � 12 46 � 18eak negative LV dP/dt (mm Hg/s) �1,265 � 507 �1,123 � 453*V end-diastolic volume (ml) 163 � 63 151 � 57

Data are presented as mean � SD; n � 12.* p �0.05 versus AAI; † p �0.05 versus LV; ‡ p�0.05 versus His.

raction �40%.3 The present results further indicate that His

acing may not necessarily produce acute beneficial hemo-ynamic effects. Optimization of His pacing may depend onoading conditions and appropriate AV delay. Although LVnd-diastolic volume was not significantly different be-ween LV and His pacing in this small population (Table 2),V end-diastolic pressure was higher (Figure 5). Further-ore, individual patient data (Figures 1 and 2) also suggest

lightly improved preload during LV pacing. Whether acutemprovements in LV function lead to long-term improve-ents remains uncertain, but recent investigations into

iventricular pacing suggest that they may.20

The present results also provide additional evidence dis-uting the contention that a QRS duration �120 ms is aurrogate for LV dyssynchrony.21 QRS duration is currently

prerequisite for cardiac resynchronization therapy, andarrowing the QRS is often considered a surrogate markeror optimal RV pacing site.7 However, our results indicatehat reduced LV function during His pacing was associatedith a narrow QRS duration. In addition, a wide QRSuration occurred with reduced LV function during RVacing, and a wide QRS was observed with improved LVunction during LV pacing. Therefore, QRS duration maye of little value in predicting both ventricular synchronynd LV function.

The present results should be interpreted within the con-traints of the trial limitations. We studied a population ofatients with and without a history of congestive heartailure and with variable ejection fraction (Table 1). There-ore, our data were underpowered to perform comparisonsf patients with or without preexisting LV dysfunction. Weid not evaluate the effect of increased or decreased heartate on His pacing. However, we maintained a constanteart rate for all pacing sites, including control atrial pacing.e did not optimize AV delay at any pacing site, but pacedith AV delay �10 ms than the atrial pace to His interval.owever, this definition may still allow relative amounts of

ntrinsic AV conduction to occur between sites, especiallyetween the left ventricle and His bundle. Although, QRSuration during His pacing was similar in both morphometryFigure 1) and duration (Figures 1 and 3) to atrial pacing, it isossible that some RV capture occurred in some patients.

cknowledgment: We thank Paola Cardano, Sara Over-aard, Katie Reichardt, and Amy Skaleski for their excellentssistance in data collection and analysis.

1. Kass DA, Chen CH, Curry C, Talbot M, Berger R, Fetics B, Nevo E.

V Apical RV Free Wall RV Septal LV

4.5 � 2.3‡ 3.9 � 1.8*,† 4.1 � 2.2† 5.0 � 2.245 � 13 44 � 12 46 � 18 42 � 11

,149 � 440* �1,117 � 395* �1,141 � 419* �1,116 � 414*158 � 62 160 � 65 162 � 61 160 � 66

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Improved left ventricular mechanics from acute VDD pacing in pa-

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tients with dilated cardiomyopathy and ventricular conduction delay.Circulation 1999;99:1567–1573.

2. Auricchio A, Stellbrink C, Block M, Sack S, Vogt J, Bakker P, KleinH, Kramer A, Ding J, Salo R, et al. Effect of pacing chamber andatrioventricular delay on acute systolic function of paced patients withcongestive heart failure. The Pacing Therapies for Congestive HeartFailure Study Group. The Guidant Congestive Heart Failure ResearchGroup. Circulation 1999;99:2993–3001.

3. Lieberman R, Padeletti L, Schreuder J, Jackson K, Michelucci A,Colella A, Eastman W, Valsecchi S, Hettrick DA. Ventricular pacinglead location alters systemic hemodynamics and left ventricular func-tion in patients with and without reduced ejection fraction. J Am CollCardiol 2006;48:1634–1641.

4. Andersen HR, Nielsen JC, Thomsen PE, Thuesen L, Mortensen PT,Vesterlund T, Pedersen AK. Long-term follow-up of patients from arandomized trial of atrial versus ventricular pacing for sick-sinussyndrome. Lancet 1997;350:1210–1216.

5. Connolly SJ, Kerr CR, Gent M, Roberts RS, Yusuf S, Gillis AM, SamiMH, Talajic M, Tang AS, Klein GJ, Lau C, Newman DM. Effects ofphysiologic pacing versus ventricular pacing on the risk of stroke anddeath due to cardiovascular causes. Canadian Trial of PhysiologicPacing Investigators. N Engl J Med 2000;342:1385–1391.

6. Lamas GA, Lee KL, Sweeney MO, Silverman R, Leon A, Yee R,Marinchak RA, Flaker G, Schron E, Orav EJ, Hellkamp A, et al, ModeSelection Trial in Sinus-Node Dysfunction. Ventricular pacing ordual-chamber pacing for sinus-node dysfunction. N Engl J Med 2002;346:1854–1862.

7. Tse HF, Yu C, Wong KK, Tsang V, Leung YL, Ho WY, Lau CP.Functional abnormalities in patients with permanent right ventricularpacing: the effect of sites of electrical stimulation. J Am Coll Cardiol2002;40:1451–1458.

8. Wilkoff B, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H,Kutalek SP, Sharma A, Dual Chamber and VVI Implantable Defibril-lator Trial Investigators. Dual-chamber pacing or ventricular backuppacing in patients with an implantable defibrillator; The dual chamberand VVI implantable defibrillator (DAVID) trial. JAMA 2002;288:3115–3123.

9. Karpawich PP, Gates J, Stokes KB. Septal His-Purkinje ventricularpacing in canines: a new endocardial electrode approach. Pacing ClinElectrophysiol 1992;15:2011–2015.

0. Mabo P, Scherlag BJ, Munsif A, Otomo K, Lazzara R. A technique forstable His bundle recording and pacing: electrophysiological andhemodynamic correlates. Pacing Clin Electrophysiol 1995;18:
1894–1901.
1. Amitani S, Miyahara K, Sohara H, Kakura H, Koga M, Moriyama Y,Taira A, Nagano S, Miura N, Misumi K, Sakamoto H. ExperimentalHis-bundle pacing: histopathological and electrophysiological exami-nation. Pacing Clin Electrophysiol 1999;22:562–566.

2. Deshmukh P, Casavant DA, Romanyshyn M, Anderson K. Permanent,direct His bundle pacing: a novel approach to cardiac pacing inpatients with normal His-Purkinje activation. Circulation 2000;101:869–877.

3. Zanon F, Baracca E, Aggio S, Pastore G, Boaretto G, Cardano P,Marotta T, Rigatelli G, Galasso M, Carraro M, Zonzin P. A feasibleapproach for direct His-bundle pacing using a new steerable catheter tofacilitate precise lead placement. J Cardiovasc Electrophysiol 2006;17:29–33.

4. Occhetta E, Bortnik M, Magnani A, Francalacci G, Piccinino C,Plebani L, Marino P. Prevention of ventricular desynchronization bypermanent para-Hisian pacing after atrioventricular node ablation inchronic atrial fibrillation: a crossover, blinded, randomized study ver-sus apical right ventricular pacing. J Am Coll Cardiol 2006;47:1938–1945.

5. Baan, J, Van Der Velde ET, De Bruin HG, Smeenk GJ, Koops J, VanDuk AD, Temmerman D, Senden J, Buis B. Continuous measurementof left ventricular volume in animals and humans by conductancecatheter. Circulation 1984;70:812–823.

6. Lieberman R, Grenz D, Mond HG, Gammage MD. Selective sitepacing: defining and reaching the selected site. Pacing Clin Electro-physiol 2004;27(II):883–886.

7. Cantu F, De Filippo P, Cardano P, De Luca A, Gavazzi A. Validationof criteria for selective His bundle and para-hisian permanent pacing.Pacing Clin Electrophysiol 2006;29:1326–1333.

8. Varma C, O’Callaghan P, Mahon NG, Hnatkova K, McKenna W,Camm AJ, Rowland E, Brecker SJ; Effect of multisite pacing onventricular coordination. Heart 2002;87:322–328.

9. Sweeney MO, Shea JB, Fox V, Adler S, Nelson L, Mullen TJ, Belk P,Casavant D, Sheldon T. Randomized pilot study of a new atrial-basedminimal ventricular pacing mode in dual-chamber implantable cardio-verter-defibrillators. Heart Rhythm 2004;1:160–167.

0. Steendijk P, Tulner SA, Bax JJ, Oemrawsingh PV, Bleeker GB, vanErven L, Putter H, Verwey HF, van der Wall EE, Schalij MJ. Hemo-dynamic effects of long-term cardiac resynchronization therapy: anal-ysis by pressure-volume loops. Circulation 2006;113:1295–1304.

1. Leclercq C, Faris O, Tunin R, Johnson J, Kato R, Evans F, Spinelli J,Halperin H, McVeigh E, Kass DA. Systolic improvement and mechan-ical resynchronization does not require electrical synchrony in thedilated failing heart with left bundle-branch block. Circulation 2002;
106:1760–1763.

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Usefulness of High-Speed Rotational Coronary VenousAngiography During Cardiac Resynchronization Therapy

Dan Blendea, MD, PhDb, Moussa Mansour, MDa, Ravi V. Shah, MDa, Jeffrey Chung, MDa,Veena Nandigam, MDa, E. Kevin Heist, MD, PhDa, Theofanie Mela, MDa, Vivek Y. Reddy, MDa,

Robert Manzke, PhDc, Craig A. McPherson, MDb, Jeremy N. Ruskin, MDa, andJagmeet P. Singh, MD, PhDa,*

Standard coronary venous angiography (SCVA) provides a static, fixed projection of thecoronary venous (CV) tree. High-speed rotational coronary venous angiography (RCVA) isa novel method of mapping CV anatomy using dynamic, multiangle visualization. Thepurpose of this study was to assess the value of RCVA during cardiac resynchronizationtherapy. Digitally acquired rotational CV angiograms from 49 patients (mean age 69 � 11years) who underwent left ventricular lead implantation were analyzed. RCVA, which usesrapid isocentric rotation over a 110° arc, acquiring 120 frames/angiogram, was comparedwith SCVA, defined as 2 static orthogonal views: right anterior oblique 45° and left anterioroblique 45°. RCVA demonstrated that the posterior vein–to–coronary sinus (CS) angle andthe left marginal vein–to–CS angle were misclassified in 5 and 11 patients, respectively,using SCVA. RCVA identified a greater number of second-order tributaries with diameters>1.5 mm than SCVA. The CV branch selected for lead placement was initially identifiedin 100% of patients using RCVA but in only 74% of patients using SCVA. RCVA showedthat the best angiographic view for visualizing the CS and its tributaries differed signifi-cantly among different areas of the CV tree and among patients. The area of the CV treethat showed less variability was the CS ostium, which had a fairly constant relation withthe spine in shallow right anterior oblique and left anterior oblique projections. In conclu-sion, RCVA provided a more precise map of CV anatomy and the spatial relation of venousbranches. It allowed the identification of fluoroscopic views that could facilitate cannula-tion of the CS. The final x-ray view displaying the appropriate CV branch for leftventricular lead implantation was often different from the conventional left anterioroblique and right anterior oblique views. RCVA identified the target branch for leadimplantation more often than SCVA. © 2007 Elsevier Inc. All rights reserved. (Am J
Cardiol 2007;100:1561–1565)
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eft ventricular (LV) lead placement in a suitable branch of theoronary venous (CV) system along the dyssynchronous wallf the left ventricle is an important determinant of responsive-ess to cardiac resynchronization therapy.1,2 Given the vari-bility of the CV anatomy,3,4 selecting an optimal and techni-ally accessible branch for LV lead placement can often behallenging. The most frequently used method of imaginghe coronary veins is CV angiography.5,6 Standard CV an-iography (SCVA) provides 2 orthogonal, static views ofhe coronary vein, occasionally leading to suboptimal de-ineation of the origins, angulations, and courses of theenous tributaries. High-speed rotational CV angiographyRCVA) represents a novel mode of acquiring angiographicmages of the coronary veins in a dynamic, multiangle

aCardiac Arrhythmia Service, Department of Medicine, Massachusettseneral Hospital, Harvard Medical School, Boston, Massachusetts; bCar-iology Division, Bridgeport Hospital, Yale University School of Medi-ine, Bridgeport, Connecticut; and cPhilips Research North America, Clin-cal Sites Research Program, Boston, Massachusetts. Manuscript receivedpril 20, 2007; revised manuscript received and accepted June 13, 2007.

nE-mail address: [email protected] (J.P. Singh).

ashion.7 The purposes of the present study were to (1) useultiangle visualization to define the best angiographic

iews to profile different parts of the CV system to poten-ially facilitate LV lead implantation and (2) compareCVA with SCVA in imaging the CV tree.

ethodsPatients: The present study was approved by the local

nstitutional review board. Forty-nine consecutive patientsho underwent RCVA before LV lead implantation for

ardiac resynchronization therapy were included in thetudy. All patients had conventional indications for cardiacesynchronization therapy (depressed LV systolic functionith symptomatic New York Heart Association class III or

V heart failure; Table 1). Cardiac resynchronization ther-py devices were implanted as described in previous majortudies.8,9 The LV lead was placed into the lateral vein orosterior vein and in 1 case in an anterolateral branch of thenterior interventricular vein. No lead was placed in theiddle cardiac vein. InSync (Medtronic, Inc., Minneapolis,innesota), Contak Renewal (Guidant Corporation, India-

apolis, Indiana), and Atlas (St. Jude Medical, Inc., St. Paul,

www.AJConline.org

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innesota) cardiac resynchronization therapy devices weremplanted.

CV angiography: As described previously, RCVA (Alluraper FD10; Philips Medical Systems, Best, The Netherlands)ses rapid isocentric rotation over a 110° arc, from a rightnterior oblique 55° to a left anterior oblique 55° projectionFigure 1) in 4 seconds, acquiring 120 frames/angiogram.7 Noranial or caudal angulations were used. Forty milliliters ofiluted contrast was injected slowly to completely opacify theoronary sinus (CS) and its tributaries before commencementf rotational imaging. Retrograde venography was performedith balloon occlusion of the CS. In 7 cases, the occlusion of

he CS was not complete, but sufficient filling of the CS and itsrst- and second-degree tributaries was achieved to allow mea-urements. Radiation exposure during a rotational angiographys comparable with that during standard angiography of theame duration.10–12

RCVA versus SCVA: The data obtained from RCVAere compared with the data obtained from SCVA. SCVAas defined as 2 static perpendicular views, right anteriorblique 45° and left anterior oblique 45°, with completepacification of the CV tree, derived from the series of themages acquired during RCVA. The images, in Digital Im-ging and Communications in Medicine format, were ana-yzed using the OSIRIX version 2.7.1 open source software

able 1aseline characteristics of the patients (n � 49)

ariable Value

ge (yrs) 69 � 11en 39

irst-time implantation 65%schemic cardiomyopathy 61%ypertension 61%iabetes mellitus 37%RS duration before implantation (ms) 149 � 27V ejection fraction 21 � 8%V end-diastolic diameter by echocardiography (mm) 62 � 10erum creatinine at implantation (mg/dl) 1.39 � 0.49

igure 1. Frames obtained from a rotational coronary venous angiogram.uring a rapid isocentric rotation over a 110° arc from a right anteriorblique (RAO) 55° projection to a left anterior oblique (LAO) 55° projec-ion, 120 frames are acquired in 4 seconds.

ackage.13 The following parameters were evaluated: (1) 4

he presence of the CS and first-order tributaries (only thoserst-order tributaries of the CS with diameters �2 mm were

ncluded), (2) the angulation between the CS and the first-rder tributaries joining the CS (an acute angle was defineds �90°), (3) the number of second-order tributaries of theS with diameters �1.5 mm, (4) the tortuosity of the

econd-order tributaries of the CS (a tortuous vessel wasefined as one with a complete U-turn in its course along theV wall), and (5) the ability of RCVA and SCVA to

dentify the CV branch in which the lead was finally placedconducted in 31 patients in whom precise postimplantationine angiographic information on final lead position wasvailable).

Multiangle visualization of the CV tree: The best an-iographic view for mapping the CV tree was defined as theiew that offered the least amount of foreshortening andessel overlap. We also determined angiographic views thatrojected the CS ostium over different bony structures, thusffering potential landmarks for CS cannulation. Specifi-ally, we assessed the relation of the CS ostium to differentegments of the spine and to the diaphragm in the 33atients (mean age 69 � 11 years; 8 women) withoutertebral deformities. The diameters of the vessels and theistances from the CS ostium to different landmarks wereeasured after calibration of the quantitation software using

he known diameter (8Fr or 9Fr) of the CS guide catheter.mages were reviewed twice by the same investigator (DB)n a blinded fashion. To minimize potential learning effects,eadings were separated by 8 weeks, and the results of therst review were not available at the second reading. Theeasurement error was considered the absolute difference

etween the 2 readings for the same patient. Intraobserverariability was assessed in 10 patients as percentage mea-urement error by dividing the measurement error by theverage of the 2 measurements for each patient, and theesults were averaged for the entire group of patients. In-raobserver variability for the best angiographic view was

able 2omparative analysis of coronary venous angiograms using rotationalersus standard venography

ariable RCVA SCVA SCVAMisdiagnosis

ngulationAcute CS–to–posterior

vein angle10 8 5

Acute CS–to–lateralvein angle

10 21 11

ortuosityTortuous posterior vein 6 4 2Tortuous lateral vein 12 4 8ributariesPosterior vein tributaries

with diameters �1.5mm

0.8 � 0.8 0.5 � 0.7* —

Lateral vein tributarieswith diameters �1.5mm

1.23 � 1.07 0.63 � 0.85† —

* p � 0.0565 RCVA versus SCVA; † p �0.0001 RCVA versus SCVA.

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1563Heart Failure/Rotational Coronary Venous Angiography During CRT

Statistical analysis: Continuous variables were com-ared using the 2-tailed paired Student’s t test using Stataersion 8.2 for Macintosh (StataCorp LP, College Station,exas). A statistical difference of p �0.05 was consideredtatistically significant. Data are expressed as mean � SD.

esultsRCVA versus SCVA: There was no difference between

CVA and SCVA in identifying the CS and its first-orderributaries. The CS, the middle cardiac vein, and the anteriornterventricular vein were visualized in all 49 patients byCVA and SCVA. At least 1 prominent (diameter �2 mm)osterior vein was seen in 33 patients (67%), and �1 promi-ent lateral vein was seen in 44 patients (89%). Using RCVAs a gold standard, we found that the angulations were oftenisinterpreted by SCVA (Table 2). SCVA underestimated theS–to–posterior vein angle in 2 patients (misclassifying it as

igure 2. Underestimation of the CS–to–lateral vein angle by standard rightn right anterior oblique (RAO) 45° (A) and left anterior oblique (LAO) 45°B) projections. (C) Using a different view, RAO 20°, from the rotationalenogram, the angle was correctly identified as obtuse. This subsequentlyllowed the implantation of a LV lead in that branch.

igure 3. The view that allowed advancement of the pacing lead in theateral vein was different from the 2 views (A, B). The CS–to–lateral veinunction and the initial segment of the lateral vein were not well separatedrom the CS body (the segment between the 2 green arrowheads). Duringotational angiography, a view was identified, right anterior oblique (RAO)°, that better showed the course of the initial part of the lateral vein (C)nd facilitated the advancement of the pacing lead (D). LAO � left anteriorblique.

cute) and overestimated the angle in 3 patients (misclassifying v

t as obtuse). SCVA consistently underestimated the CS–to–ateral vein angle in 11 patients. An example of a case in whichhe CS–to–lateral vein angle appeared acute in SCVA viewsut was correctly identified as obtuse by RCVA is depicted inigure 2. Increased tortuosity of the posterior vein and of the

ateral vein (which potentially hampers the efforts of advanc-ng the pacing lead) was missed in 2 and 8 patients, respec-ively, by using only SCVA (Table 2). RCVA identified areater number of second-order CS tributaries with diameters1.5 mm than SCVA (p � 0.056 for posterior vein tributaries,�0.0001 for lateral vein tributaries). The branch in which theV lead was eventually placed at the end of the implantationad been initially identified in all 31 patients in whom infor-ation about final lead position was available, using RCVA

ut in only 23 of the patients (74%) using the conventionalCVA. The RCVA view that facilitated placement of the LV

ead was often very different from the conventional views usedn SCVA (Figure 3).

Multiangle visualization of the CV tree: The angula-ions that allowed the best view for different areas of the CVree are shown in Figure 4. The angulations that best visualizedhe same CV area varied widely among patients. Technically,lacement of the LV lead into its ultimate position requiresdvancement of the lead in the CS and its subsequentositioning into the lateral vein or posterior vein. In thisight, there were striking differences in the angiographicrojections that optimally visualized the path of the LVead. Advancement of the lead in the proximal CS wasptimal in an left anterior oblique 44 � 9° view. Viewinghe lateral vein–to–CS junction was variable, with the bestngiographic view being left anterior oblique 1 � 21° (nearosteroanterior) projection. Guiding the lead into the sec-nd-order lateral vein branches to fix it in its final positionas best facilitated in the right anterior oblique 14 � 20°rojection. Similar differences in the projection angle forannulation and then fixing the lead into the tributaries ofhe posterior vein were observed (Figure 4). The multiangle

igure 4. Horizontal box plot depicting the distribution among patients ofhe best angiographic views for the different segments of the coronaryenous system. AIV � anterior interventricular vein; LAO � left anteriorblique; LMV � left marginal vein; MCV � middle cardiac vein; PA �osteroanterior; PV � posterior vein; RAO � right anterior oblique.

isualization by RCVA allowed evaluation of the relation of

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S ostium projection with different landmarks possiblyseful for CS ostium cannulation (Figure 5). In the rightnterior oblique 48 � 7° projection, the fluoroscope beamas nearly parallel to the CS plane, the CS ostium wasisualized “en face,” and the CS guiding catheter wastraight. By progressively rotating the camera to right ante-ior oblique 14 � 12°, left anterior oblique 3 � 13°, and leftnterior oblique 19 � 13°, the CS ostium was projectedver the left edge of the spine, the middle of the spine, andhe right edge of the spine, respectively. In the verticalirection, the CS ostium was projected 3 � 10 mm abovehe inferior border of the T-10 vertebral body. The relationf the CS ostium with the dome of the left hemidiaphragmas more variable; the projection was 10 � 16 mm above

he landmark.

iscussion

his study shows for the first time that multiangle visual-zation of the CV tree via rotational venography is a usefulmaging modality for LV lead placement. Compared withtandard venography, high-speed rotational venography re-uces vessel overlap and foreshortening, thereby more pre-isely identifying the takeoff and angulation of the posteriornd lateral CV branches, as well as better defining theecond-degree tributaries. Furthermore, RCVA also enablesynamic visualization of different segments of the CV tree,hich is critical in facilitating the technical component ofegotiating the CV anatomy in placing a LV lead. This isspecially significant in light of the interpatient difference inhe optimal projections for visualization of CV anatomy. Byffering a multiangle visualization of the CV system,CVA allowed the identification of several fluoroscopiciews that might facilitate the cannulation of the CS ostiumuring cardiac resynchronization therapy.

In light of the possibility of prolonged procedural timeor LV lead placement,14–16 and the difficulty in identifyinghe best site for resynchronization,14 visualization of theardiac venous system is of paramount importance for suc-essful cardiac resynchronization therapy.15

The results of our study also showed that SCVA mis-lassified the angle between the CS and first-order tributar-es used for the LV lead implantation, posterior veins andateral veins, in 5 and 11 patients, respectively. RCVA,

igure 5. Horizontal box plot depicting the distribution among patients ofhe angiographic views that displayed the CS ostium in relation to theifferent landmarks. Abbreviations as in Figure 4.

ffering multiple views of the CV tree from multiple angles, m

an better identify the angulations of the various branches.n acute angle between the CS and its tributaries is known

o hamper advancing the lead into the optimal position,5,14

urther suggesting that RCVA may better delineate CVnatomy, facilitating LV lead advancement and placement.

Another finding of this study was that RCVA allowed theisualization of more second-degree CS tributaries withiameters �1.5 mm. This is likely due to reducing vesselverlap and foreshortening by multiangle visualization ofhe CV tree. The enhanced ability of RCVA to resolvemaller branches of the CS was further supported by thebservation that RCVA correctly identified the first- orecond-order branch in which the LV lead was eventuallylaced in 100% of patients, compared with SCVA, whichemonstrated the corresponding branch in only 74% ofatients. With the development of newer, smaller caliberacing leads and the ability to resolve smaller venousranches,17 along with the implementation of a more sys-ematic, segmental classification of the second-degree trib-taries of the CV,4 RCVA may play an increasing role inelping electrophysiologists access areas of the LV wallore appropriate for resynchronization.18,19

Given the anatomic variability in the CS,3,6 it is noturprising that visualizing different aspects of the CS anat-my requires a wide range of views. Indeed, given that theuccess of percutaneous LV lead placement is highly de-endent on technical factors, including accessing the CS andlacing the LV lead in an optimal position, RCVA may bemore fruitful imaging modality for maximizing the suc-

ess of LV lead placement.One of the segments of the CV tree that showed less

ariability in its anatomic position was the CS ostium. Inur group of patients with dilated cardiomyopathy and with-ut vertebral deformities, the CS ostium imaged in shallowight anterior oblique and left anterior oblique views wasrojected over the spine in close proximity to the inferiororder of the T-10 vertebral body. In a steeper right anteriorblique projection (right anterior oblique 48 � 7°), the CSstium was displayed en face, the fluoroscopic beam beinglmost parallel to the CS and great cardiac vein plane, andhe catheter that cannulated the CS maintained a linearhape (as opposed to a J shape in the other views). Inddition to intracardiac electrograms, these fluoroscopicandmarks might be used for CS cannulation. Several land-arks for CS ostium cannulation have been previously

roposed,20 but their accuracy has not been well studied inatients with dilated cardiomyopathy, in whom atrial andentricular dilatation may impede successful CS catheter-zation.

Rotational venography affords the possibility of reformat-ing the myriad 2-dimensional orthogonal projections into a-dimensional reconstruction of the CV anatomy in total.7,21 Inurn, overlaying echocardiographic information onto 3-dimen-ional reconstructions of the CV anatomy may finally integratenatomy and functional information, thereby allowing optimalV lead placement. Another possible application for RCVAould be during percutaneous transvenous mitral annuloplasty,or which multiple fluoroscopic views are needed to preciselyefine the CV anatomy.22 Other imaging methods, such as
ultislice computed tomography, have also shown promising

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1565Heart Failure/Rotational Coronary Venous Angiography During CRT

esults in defining the anatomy of the CV tree,23 but their roleeems to be limited to preprocedural evaluation.

One of the limitations of our study was the fact that weompared 2 conventional views with the entire rotationalun from which they were derived. This was done to limithe amount of contrast used and offered the advantage thatach patient was his or her own control. As a consequencef this study design, it was not possible to prospectivelyvaluate the impact of RCVA on the lead implantationtrategy and outcome. Also, LV lead implantation was suc-essful in all patients. Static orthogonal views of left ante-ior oblique 45° and right anterior oblique 45° were used foromparison, on the basis of current practices and to create aorm of standardized comparison with RCVA. Another lim-tation of the study was the fact that we used a subjectiveetermination of the best angiographic view. However, thentraobserver variability for this measurement was �5%.

e tried to minimize parallax and magnification errors ineasuring dimensions by using for calibration of the quan-

itation software the tip of the CS guide catheter situated inlose proximity to the structures being measured. AlthoughCVA provides multiangle visualization, skilled implantinghysicians can often draw on their experience to create a-dimensional perspective of the anatomy from standard-view CV angiography.

cknowledgment: We thank Jianping Chevalier, from Car-iac Arrhythmia Service, Massachusetts General Hospital,or her excellent assistance in digital data acquisition androcessing.

1. Daubert JC, Ritter P, Le Breton H, Gras D, Leclercq C, Lazarus A,Mugica J, Mabo P, Cazeau S. Permanent left ventricular pacing withtransvenous leads inserted into the coronary veins. Pacing Clin Elec-trophysiol 1998;21:239–245.

2. Leclercq C, Cazeau S, Le Breton H, Ritter P, Mabo P, Gras D, PavinD, Lazarus A, Daubert JC. Acute hemodynamic effects of biventricu-lar DDD pacing in patients with end-stage heart failure. J Am CollCardiol 1998;32:1825–1831.

3. von Ludinghausen M. The venous drainage of the human myocardium.Adv Anat Embryol Cell Biol 2003;68:I–VIII, 1–104.

4. Singh JP, Houser S, Heist EK, Ruskin JN. The coronary venousanatomy: a segmental approach to aid cardiac resynchronization ther-apy. J Am Coll Cardiol 2005;46:68–74.

5. Meisel E, Pfeiffer D, Engelmann L, Tebbenjohanns J, Schubert B,Hahn S, Fleck E, Butter C. Investigation of coronary venous anatomyby retrograde venography in patients with malignant ventricular tachy-cardia. Circulation 2001;104:442–447.

6. Gilard M, Mansourati J, Etienne Y, Larlet JM, Truong B, Boschat J,Blanc JJ. Angiographic anatomy of the coronary sinus and its tribu-taries. Pacing Clin Electrophysiol 1998;21:2280–2284.

7. Mansour M, Reddy VY, Singh J, Mela T, Rasche V, Ruskin J.Three-dimensional reconstruction of the coronary sinus using rota-
tional angiography. J Cardiovasc Electrophysiol 2005;16:675–676.
8. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C,Garrigue S, Kappenberger L, Haywood GA, Santini M, et al. Effectsof multisite biventricular pacing in patients with heart failure andintraventricular conduction delay. N Engl J Med 2001;344:873–880.

9. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E,Kocovic DZ, Packer M, Clavell AL, Hayes DL, et al. Cardiac resyn-chronization in chronic heart failure. N Engl J Med 2002;346:1845–1853.

0. Orlov MV, Hoffmeister P, Chaudhry GM, Almasry I, Gijsbers GH,Swack T, Haffajee CI. Three-dimensional rotational angiography ofthe left atrium and esophagus-A virtual computed tomography scan inthe electrophysiology lab? Heart Rhythm 2007;4:37–43.

1. Rigattieri S, Ghini AS, Silvestri P, Tommasino A, Ferraiuolo G,Palamara A, Loschiavo P. A randomized comparison between rota-tional and standard coronary angiography. Minerva Cardioangiol2005;53:1–6.

2. Akhtar M, Vakharia KT, Mishell J, Gera A, Ports TA, YeghiazariansY, Michaels AD. Randomized study of the safety and clinical utility ofrotational vs. standard coronary angiography using a flat-panel detec-tor. Catheter Cardiovasc Interv 2005;66:43–49.

3. Rosset A, Spadola L, Pysher L, Ratib O. Informatics in radiology(infoRAD): navigating the fifth dimension: innovative interface formultidimensional multimodality image navigation. RadioGraphics2006;26:299–308.

4. Alonso C, Leclercq C, d’Allonnes FR, Pavin D, Victor F, Mabo P,Daubert JC. Six year experience of transvenous left ventricular leadimplantation for permanent biventricular pacing in patients with ad-vanced heart failure: technical aspects. Heart 2001;86:405–410.

5. Daoud EG, Kalbfleisch SJ, Hummel JD, Weiss R, Augustini RS, DuffSB, Polsinelli G, Castor J, Meta T. Implantation techniques andchronic lead parameters of biventricular pacing dual-chamber defibril-lators. J Cardiovasc Electrophysiol 2002;13:964–970.

6. Kautzner J, Riedlbauchova L, Cihak R, Bytesnik J, Vancura V. Tech-nical aspects of implantation of LV lead for cardiac resynchronizationtherapy in chronic heart failure. Pacing Clin Electrophysiol 2004;27:783–790.

7. Hansky B, Vogt J, Gueldner H, Lamp B, Tenderich G, Krater L,Heintze J, Minami K, Horstkotte D, Koerfer R. Left heart pacing—experience with several types of coronary vein leads. J Interv CardElectrophysiol 2002;6:71–75.

8. Butter C, Auricchio A, Stellbrink C, Fleck E, Ding J, Yu Y, HuvelleE, Spinelli J. Effect of resynchronization therapy stimulation site onthe systolic function of heart failure patients. Circulation 2001;104:3026–3029.

9. Heist EK, Fan D, Mela T, Arzola-Castaner D, Reddy VY, Mansour M,Picard MH, Ruskin JN, Singh JP. Radiographic left ventricular-rightventricular interlead distance predicts the acute hemodynamic re-sponse to cardiac resynchronization therapy. Am J Cardiol 2005;96:685–690.

0. Davis LM, Byth K, Lau KC, Uther JB, Richards DA, Ross DL.Accuracy of various methods of localization of the orifice of thecoronary sinus at electrophysiologic study. Am J Cardiol 1992;70:343–346.

1. Movassaghi B, Rasche V, Grass M, Viergever MA, Niessen WJ. Aquantitative analysis of 3-D coronary modeling from two or moreprojection images. IEEE Trans Med Imaging 2004;23:1517–1531.

2. Webb JG, Harnek J, Munt BI, Kimblad PO, Chandavimol M, Thomp-son CR, Mayo JR, Solem JO. Percutaneous transvenous mitral annu-loplasty: initial human experience with device implantation in thecoronary sinus. Circulation 2006;113:851–855.

3. Jongbloed MR, Lamb HJ, Bax JJ, Schuijf JD, de Roos A, van der WallEE, Schalij MJ. Noninvasive visualization of the cardiac venous sys-tem using multislice computed tomography. J Am Coll Cardiol 2005;
45:749–753.

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Role of Multislice Computed Tomography for Preprocedural Evaluation BeforeRevision of a Chronically Implanted Transvenous Left Ventricular Lead

Angelo Auricchio, MD, PhDa,*, Antonio Sorgente, MDa, Jagmeet P. Singh, MD, PhDb,Francesco Faletra, MDa, Cristina Conca, MDa, Giovanni B. Pedrazzini, MDa, Elena Pasotti, MDa,

Francesco Siclari, MDc, and Tiziano Moccetti, MDa

The purpose of this study was to determine the feasibility of multislice computed tomog-raphy (MSCT) to assess the coronary sinus (CS) and its tributaries in patients who areundergoing cardiac resynchronization therapy and need a left ventricular (LV) lead revi-sion. Preprocedural imaging modality, which may enable delineation of the cardiac venousanatomy in patients who need LV lead replacement, has not yet been evaluated. Tenpatients with heart failure with previously implanted cardiac resynchronization therapydevices, who presented with worsening heart failure, were studied with MSCT and tissueDoppler imaging echocardiography before LV lead replacement. MSCT was performed toevaluate patency of the CS and coronary veins, and tissue Doppler imaging echocardiog-raphy assessed the region and the magnitude of mechanical dyssynchrony. An excellentconcordance in the vein diameter, location, and status between MSCT and angiographywas found. Apart from the need to perform a venoplasty in 1 patient and an unsuccessfullead explantation in another patient, all other anatomic issues were correctly predicted byMSCT. CS or vein occlusion were present in 4 patients, and in 3 of them surgical LV leadreplacement was performed. Identification of a patent venous system enabling successfultransvenous lead implantation was possible in 2 patients. Direct visualization of theproximity of the target vein to the phrenic nerve and the diaphragm guided lead selectionand position in 4 patients. In conclusion, MSCT may be used to delineate the coronaryvenous anatomy in patients in whom LV lead replacement is needed to help strategizewhether a transvenous or transthoracic approach may be preferred for LV lead
revision. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:1566–1570)
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ultislice computed tomography (MSCT) has become anmportant diagnostic tool for noninvasive evaluation of car-iovascular structures. Earlier reports have examined theole of MSCT as a preprocedural tool to assess the coronaryenous anatomy before implantation of a cardiac resynchro-ization therapy (CRT) device.1–3 There are no data regard-ng the role of MSCT as a preprocedural tool to visualize theoronary venous tree in patients who have a preexistingRT device. The aim of this study was to evaluate the

easibility of MSCT to assess the coronary sinus (CS) andts tributaries in patients with a CRT device who need a leftentricular (LV) lead revision.

ethods and Results

en patients with heart failure with previously implantedRT devices, who presented with worsening heart failureue to different lead issues, were studied with MSCT beforeV lead revision (Table 1). The LV lead needed revision forither a loss of LV capture or an excessive increase in LV

Divisions of aCardiology and cCardiac Surgery, Fondazione Cardio-entro Ticino, Lugano, Switzerland; and bCardiac Resynchronization Ther-py Program, MGH Heart Center & Cardiac Arrhythmia Service, Massachu-etts General Hospital, Harvard Medical School, Boston, Massachusetts.

anuscript received April 20, 2007; revised manuscript received andccepted June 14, 2007.

bE-mail address: [email protected] (A. Auricchio).

ead threshold (with no safety margin) in 4 patients, leadnsulation defect in 3, intolerable phrenic nerve stimulationn 2, and lead dislodgment in another patient.

Imaging was performed the day before CRT systemeplacement. A 64-detector scanner (Lightspeed VCT, Gen-ral Electric, Milwaukee, Wisconsin) was used, with imagecquisitions obtained at end-expiration and gated to theRS complex. Iodinated contrast was given as a test bolus

20 ml) to time peak LV filling. Subsequently, 70 to 80 mlf contrast followed immediately by a 50-ml saline solutioneach administered at 4 ml/min) was delivered through theeripheral vein using a dual-barrel injector. Scanning waserformed from cardiac base to apex during single breath-old in 1.25-mm steps (pitch � 0.3 to 0.38, kVP � 120,A � 300, gantry rotation time � 0.5 second). Image

onstruction using commercial software (General Electricdvantage) involved editing the sequential images to re-ove all structures except atria, ventricles, and the epicar-

ial coronary veins. Visualization of the left phrenic nerveas done according to Berkmen et al.4 The estimated coursef the left phrenic nerve was superimposed. Multidimensionaleconstruction was performed by coalescing these images (atnd-diastole) and presented from an extracardiac vantage view.

Transthoracic echocardiography was performed on theame day as MSCT. A commercial system (Vivid 7, Gen-ral Electric Vingmed Ultrasound AS, Horten, Norway) wassed. Digital tissue Doppler cine loops from 3 consecutive
eats were obtained from short-axis views to encompass
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1567Heart Failure/Role of MSCT in LV Lead Replacement

pical, mid, and basal levels of the left ventricle, at depth of2 to 20 cm with a velocity range of �16 cm/s and frameates of 72 to 154 per second. Data were digitally recordednd assessed offline using commercial software (EchoPACC, version 6.0.1; General Electric Vingmed UtrasoundS). Tissue Doppler imaging (TDI) was performed using

pical views for the long-axis motion of the ventricles asescribed elsewhere.5 Two-dimensional echocardiogra-hy with TDI color imaging views (apical 4-chamber,-chamber, and long-axis views) were optimized forulse repetition frequency, color saturation, sector size,nd depth and were allowed the highest possible frameate. At least 3 consecutive beats were stored, and themages were analyzed offline with the aid of a custom-zed software package (EchoPac 6.0.1; Vingmed–Generallectric). Myocardial velocity curves were reconstitutedffline using the 6-basal and 6-midsegmental model inhe left ventricle as previously described. The peak myo-ardial velocity during the ejection phase (Sm) and theime to peak Sm (Ts) were measured with reference to theRS complex.At the time of lead replacement, coronary venous an-

iography was performed, paying attention to acquire im-ges with similar angulation to those taken during firstmplantation. Digital venous angiograms were analyzed off-ine by operators blinded to the MSCT procedure using aalidated automated edge detection system (CMS 5.2;EDIS Medical Imaging Systems, Leiden, The Nether-

ands). The outer diameter of contrast-filled catheter wassed for calibration, the luminal diameter of the CS, andelected coronary veins were measured in the same viewefore CRT and at the time of LV lead replacement. Alleasurements were performed in triplicate by 2 indepen-

igure 1. Angiographic and computed tomographic images of a patient (no.) with a pacing lead inserted into the CS occluding the vessel. (A)omputed tomographic image of both pacing lead into CS and defibrilla-

ion lead in the vena cava superior and right ventricle. (B) three-dimen-ional volume rendering of the left anterior descending (LAD) treated with atent and 2 tiny coronary veins, magnified in (E). (C and D) Retrogradecclusive CS angiography after removal of the pacing lead. The distal CS isccluded and collateral veins are displayed; in addition, 2 lateral veins areisible, which corresponded to computed tomographic imaged veins (E).

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Agreement (interobserver and intermethod) was assessedsing Lin’s concordance correlation coefficient and its 95%onfidence interval (CI) and with the Bland and Altmanethod.6,7 The 95% CI of the limits of agreement were also

omputed. To account for the intrapatient correlation (pre-RT and post-CRT) of measures when computing 95%Is, bootstrapped SEs (1,000 replications) were calcu-

ated while clustering on patients. Continuous variablesere tested by analysis of variance for repeated measures.ata were analyzed using SPSS for Windows, version0.0.7 (SPSS Inc., Chicago, Illinois) and Stata 9.2 (Stataorporation, College Station, Texas). A 2-sided p value of.05 was considered statistically significant.

igure 2. Retrograde occlusive angiography of CS (A) shows an inferior anead (B). At the time of lead revision, there was a complete occlusion of thRAO] view 28°). After advancing a 0.014-inch guidewire into the vein, ahich resulted into vessel opening and good anterograde flow (F). A new

igure 3. Three-dimensional volume rendering anticipated in this patient (nssue, which was solved by surgical implantation of a pacing lead. THD �

Mean treatment time was 25.8 � 11.6 months. The w

oss of CRT in our study population resulted in worsen-ng of heart failure symptoms, change in functional classf �1 New York Heart Association class, as well as in andverse remodeling process and increase in the severityf mitral regurgitation. Compared with the initial-month response to CRT, the loss of CRT resulted in aecrease in LV ejection fraction by �5 absolute points15 � 6%, p �0.001) and an increase in mitral regurgi-ation by �1 in about 70% of the patients (p �0.001).he most mechanically delayed region of the left ventri-le, as assessed by TDI measurements, was found in therea of the defective LV lead in nearly all patients (Table). The readability of the MSCT images in certain views

l vein; the latter was selected for implantation of a transvenous left pacing(C) left anterior oblique ([LAO] view 28°) and (D) (right anterior oblique-mm (diameter/length) balloon was used to dilate the vein at 10 atm (E),lead was implanted in this vessel (patient number 7).

). Close proximity of phrenic nerve to the lateral vein and potential pacinghold.

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1569Heart Failure/Role of MSCT in LV Lead Replacement

antly interfere with evaluation of the coronary venousree (Figures 1 to 3).

To validate the accuracy of MSCT images, retrograde-view (left anterior oblique 30° and right anterior oblique0°) CS angiography was performed in all cases at the timef LV lead replacement. A good concordance between theiameter of the veins measured at the time of the first LVead implantation and that measured at the time of LV leadeplacement (Table 1) was obtained. The number and loca-ion of detectable first-order venous branches by retrogradengiography were similar to that visualized by MSCT. Inddition, there was a strong correlation between the diam-ter of the CS at its origin (r � 0.96, p �0.001), target veinor LV lead (r � 0.93, p �0.001), and anterior vein (r �.97, p �0.001) measured by quantitative angiographicnalysis and MSCT scanning. MSCT showed the occlusionf the distal part of CS in 1 patient (Figure 1) and occlusionf a coronary vein in 3 (Figure 2). In all of the patients, theein diameter at the time of the first implantation was �2.5m (Table 1). These findings were confirmed on retrograde

enous angiography, after lead extraction.No specific extraction tools have been used to facilitate

ead extraction, which was possible in all but 1 patientithout any issue. Based on MSCT findings, in all 4 patientsith CS or vein occlusion, a surgical lead implantation was

xpected to be necessary. However, in 1 patient a newransvenous LV lead was placed in a previously shownccluded vein after performing venoplasty (Figure 2).

The left phrenic nerve was visualized in only 5 patients,nd in 3 of them it was close to the target vein (Figure 3).n 1 patient, MSCT assessment of the vein size, length, andelation with the phrenic nerve position guided lead selec-ion and successful CRT implantation; in the other 2 pa-ients, their preference to undergo another transvenous LVmplantation trial first was the reason for the transvenouspproach, which as anticipated, was unsuccessful. Closeroximity of the inferior vein to the diaphragm has beennticipated by MSCT, but again patient preference to un-ergo another transvenous LV implantation trial first washe reason for the transvenous approach, which failed.

Finally, in 2 patients, patency of the target vein wasvident and no issues were expected. A second uneventfulransvenous lead implantation was achieved. In 1 of theseatients, the delayed mechanical area was large enough andould be reached by implanting the lead in another vein. Ofote, the 2 situations incorrectly predicted by MSCT wereue to a successful venoplasty with lead repositioning andn unsuccessful lead explantation. A steroid-eluting bipolaread was implanted through a minimal lateral thoracotomyn all of those patients requiring surgical placement. LV leadeplacement was uneventful in all patients.

iscussion

his is the first report providing detailed description of theardiac venous anatomy in patients previously treated withRT. To date no other report has shown the feasibility ofSCT in assessing patency of coronary veins after long-

erm implantation of transvenous leads for LV pacing.Electron beam computed tomography and multidetector

ow computed tomography enable 3-dimensional recon- o

truction of tomographic images of the beating heart androvide a detailed, minimally invasive definition of theoronary venous anatomy.1–3,8,9 MSCT has the potential torovide important information on patency of the venousystem, proximity to a phrenic nerve, concordance of theenous branch with the segment of dyssynchrony, and lu-inal diameter of a suitable vein, enabling the development

f a preprocedural implant strategy. The diameter of the CSnd its tributary measured in our patients was similar tohat has been reported in the literature.2,8,9 The vesseliameter remained stable over the time after the initialmplantation and the measurement done by retrograde an-iography correlated well with those obtained by MSCT. Itas been proposed that comprehensive computed tomo-raphic evaluation of the coronary venous anatomy beforemplantation of a CRT device could help determine theuitability of the patient for transvenous LV pacing from anown venous tributary over the desired location before annvasive procedure is undertaken.10 However, precisenowledge of coronary vein anatomy, lumen patency of thearget vessel, and relation with other extracardiac structuresuch as phrenic nerve and diaphragm is even more impor-ant when LV lead replacement is scheduled. Only MSCT as

noninvasive imaging technique can be used for preoper-tive evaluation of CRT patients with LV lead issues. Ourxperience confirms that MSCT scanning is feasible even inhe presence of transvenous LV lead with an acceptablemaging quality. We have shown that in several cases ofbstruction of side branch or distal occlusion of the CS mayollow the implantation of the LV lead. Thus, not only lackf suitable side branches,2,3,8,9,11 but also obstruction andstial narrowing may complicate LV lead revision. There ishigh likelihood that the need for LV lead replacementsill increase during the ensuing years. Mechanical stress

eading to lead fracture or insulation defect typically occurfew years after long-term implantation for conventional

acing leads. Nearly all of our cases occurred �2 years afterhe first lead implantation.

As result of intermittent or complete loss of CRT,V mechanical function deteriorated, which, however,romptly recovered after lead revision. The importance ofatching delayed area of activation with lead pacing is well

stablished,12,13 and this is possible in many patients witheart failure undergoing CRT. The possibility to find anccluded CS or the side branch used at the time of firstmplantation may be the most significant limiting factor forroviding optimal CRT when replacing the LV lead. Thus,recise assessment of venous anatomy before LV leadeplacement by MSCT along with evaluation of the magni-ude and extension of mechanical dissynchrony by echocar-iography may be particularly helpful in decision mak-ng.14,15 As a consequence of this multi-imaging diagnosticpproach, surgical lead placement may become the first-linepproach in a subset of patients, which may offset thedditional x-ray exposure and contrast dye load due toSCT procedure.The MSCT may be used to identify patients who do not

ave additional cardiac venous side branches, and thereforeay benefit from an epicardial lead placement using ainimal invasive surgical approach.16 In addition, the site

f latest LV activation, where the LV lead should ideally be

patmitTbts

1

1

1

1

1

1

1


laced, can be evaluated for the presence of suitable venousnatomy preceding LV lead replacement. Visualization ofhe phrenic nerve, especially in patients without previous

ajor cardiac surgery and its relation to the target vein,s of great importance for selecting the proper implanta-ion strategy for transvenous and surgical approaches.hus, based on these findings, the clinician can decideeforehand whether a transvenous or a surgical (lateralhoracotomy or minimal invasive) approach for lead po-itioning is preferred.

1. Gerber TC, Sheedy PF, Bell MR, Hayes DL, Rumberger JA, Behren-beck T, Holmes DR, Jr., Schwartz RS. Evaluation of the coronaryvenous system using electron beam computed tomography. Int J Car-diovasc Imaging 2001;17:65–75.

2. Jongbloed MR, Lamb HJ, Bax JJ, Schuijf JD, de Roos A, van der WallEE, Schalij MJ. Non invasive visualization of the cardiac venoussystem using multislice computed tomography. J Am Coll Cardiol2005;45:749–753.

3. Tada H, Kurosaki K, Naito S, Koyama K, Itoi K, Ito S, Ueda M,Shinbo G, Hoshizaki H, Nogami A, Oshima S, Taniguchi K. Three-dimensional visualization of the coronary venous system using multi-detector row computed tomography. Circulation J 2005;69:165–170.

4. Berkmen YM, Davis SD, Kazam E, Auh YH, Yankelevitz D, GirgisFG. Right phrenic nerve: anatomy, CT appearance, and differentiationfrom the pulmonary ligament. Radiology 1989;173:43–46.

5. Yu CM, Fung JW, Zhang Q, Chan CK, Chan YS, Lin H, Kum LC,Kong SL, Zhang Y, Sanderson JE. Tissue Doppler imaging is superiorto strain rate imaging and postsystolic shortening on the prediction ofreverse remodeling in both ischemic and nonischemic heart failureafter cardiac resynchronization therapy. Circulation 2004;110:66–73.

6. Bland JM, Altman DG. Statistical methods for assessing agreementbetween two methods of clinical measurement. Lancet 1986;1:
307–310.
7. Lin LI-K. A concordance correlation coefficient to evaluate reproduc-ibility. Biometrics 1989;45:255–268.

8. Mao S, Shinbane JS, Girsky MJ, Child J, Carson S, Oudiz RJ, BudoffMJ. Coronary venous imaging with electron beam computed tomo-graphic angiography: three-dimensional mapping and relationshipwith coronary arteries. Am Heart J 2005;150:315–322.

9. Abbara S, Cury RC, Nieman K, Reddy V, Moselewski F, Schmidt S,Ferencik M, Hoffmann U, Brady TJ, Achenbach S. Noninvasive eval-uation of cardiac veins with 16-MDCT angiography. Am J Roentgenol2005;185:1001–1006.

0. Goitein O, Lacomis JM, Gorcsan III J, Schwartzman D. Left ventric-ular pacing lead implantation: potential utility of multimodal imageintegration. Heart Rhythm 2006;3:91–94.

1. Singh JP, Houser S, Heist EK, Ruskin JN. The coronary venousanatomy: a segmental approach to aid cardiac resynchronization ther-apy. J Am Coll Cardiol 2005;46:68–74.

2. Murphy RT, Sigurdsson G, Mulamalla S, Agler D, Popovic ZB,Starling RC, Wilkoff BL, Thomas JD, Grimm RA. Tissue synchroni-zation imaging and optimal left ventricular pacing site in cardiacresynchronization therapy. Am J Cardiol 2006;97:1615–1621.

3. Singh JP, Fan D, Heist EK, Alabiad CR, Taub C, Reddy V, MansourM, Picard MH, Ruskin JN, Mela T. Left ventricular lead electricaldelay predicts response to cardiac resynchronization therapy. HeartRhythm 2006;3:1285–1292.

4. Tse HF, Lee KL, Wan SH, Yu Y, Hoersch W, Pastore J, Zhu Q,Kenknight B, Spinelli J, Lau CP. Area of left ventricular regionalconduction delay and preserved myocardium predict responses tocardiac resynchronization therapy. J Cardiovasc Electrophysiol 2005;16:690–695.

5. Penicka M, Bartunek J, De Bruyne B, Vanderheyden M, Goethals M,De Zutter M, Brugada P, Geelen P. Improvement of left ventricularfunction after cardiac resynchronization therapy is predicted by tissueDoppler imaging echocardiography. Circulation 2004;109:978–983.

6. Joshi S, Steinberg JS, Ashton RC, Jr., Balaram S, Fischer A, DeRoseJJ, Jr. Follow-up of robotically assisted left ventricular epicardial leadsfor cardiac resynchronization therapy. J Am Coll Cardiol 2005;46:
2358–2359.

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Prognostic Usefulness of Anemia and N-Terminal Pro-BrainNatriuretic Peptide in Outpatients With Systolic Heart Failure

Morten Schou, MDa,*, Finn Gustafsson, MDb, Caroline N. Kistorp, MDa, Pernille Corell, MDa,Andreas Kjaer, MDc,d, and Per R. Hildebrandt, MDe

N-terminal pro-brain natriuretic peptide (NT–pro-BNP) and anemia are predictors ofoutcome in systolic heart failure. It is currently unclear how these 2 markers interact inparticular with regard to the prognostic information carried by each risk marker. Wetherefore tested the hypothesis that anemia (World Health Organization criteria, hemo-globin levels <7.5 mmol/L for women and <8.0 mmol/L for men) and NT–pro-BNP areassociated and evaluated how a possible association affects the prognostic value of eachrisk marker. Clinical data from 345 patients with systolic heart failure were obtainedprospectively at the baseline visit to our heart failure clinic (inclusion criterion left ven-tricular ejection fraction <0.45, no exclusion criteria). Follow-up was 30 months (median),and 70 events (mortality) occurred. Prevalence of anemia was 27%. In a multivariatelogistic regression model, anemia (p � 0.041) was closely associated with NT–pro-BNPlevels above the median (1,381 pg/ml) after adjustment for traditional confounders (leftventricular ejection fraction, age, body mass index, atrial fibrillation, chronic kidneydisease). In an adjusted Cox proportional hazard model, the 2 parameters were associatedwith mortality after adjustment for traditional confounders (hazard ratio for anemia 1.73,95% confidence interval 1.06 to 2.83, p � 0.029; hazard ratio for NT–pro-BNP >1,381pg/ml 2.68, 95% confidence interval 1.58 to 4.66, p <0.001). Patients with anemia and highNT–pro-BNP levels had a fivefold increased risk for mortality (hazard ratio 4.77, 95%confidence interval 2.47 to 9.18, p <0.001). In conclusion, anemia is closely associated withNT–pro-BNP in patients with systolic heart failure, and anemia and NT–pro-BNP carryindependent prognostic information. Patients with anemia and high levels of NT–pro-BNPhave a markedly increased mortality risk. © 2007 Elsevier Inc. All rights reserved. (Am
J Cardiol 2007;100:1571–1576)
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nemia1–5 and natriuretic peptides6,7 are strong risk markersn patients with systolic heart failure, but currently it is notlear how a possible association would affect the prognosticalue of each variable. Thus far, this has been studied onlyn patients with acute dyspnea,8,9 advanced heart failure,10

nd in a selected group of patients awaiting cardiac trans-lantation.11 The relation between anemia and natriureticeptides in a broader population with systolic heart failureherefore calls for further clarification, and the present studyested the hypothesis that anemia and N-terminal pro–brainatriuretic peptide (NT–pro-BNP) levels are associated inatients with systolic heart failure and evaluated how aossible association affects the prognostic value of theseisk markers.

aDepartment of Cardiology and Endocrinology, Frederiksberg Univer-ity Hospital, Frederiksberg; bDepartment of Cardiology, The Heart Cen-re, and cDepartment of Clinical Physiology and Nuclear Medicine, TheET Centre, Rigshospitalet University Hospital; and dCluster for Molecu-

ar Imaging, University of Copenhagen, Copenhagen; and eDepartmentf Cardiology, Roskilde University Hospital, Roskilde, Denmark. Manu-cript received April 15, 2007; revised manuscript received and acceptedune 13, 2007.

Dr. Schou is supported by Research Grant 200207135A-321 from theopenhagen Hospital Corporation, Copenhagen, Denmark.

*Corresponding author: Tel: 45-38-16-43-24; fax: 45-38-16-43-59.
rE-mail address: [email protected] (M. Schou).

ethods

atients (n � 345) in the present study were includedrospectively from our heart failure clinic at Frederiksbergniversity Hospital, Copenhagen, Denmark.12 The clinicas been operating since 1999 and data used for the presenttudy were collected from January 2000 to April 2005.atients with known systolic heart failure (left ventricularjection fraction [LVEF] �0.45 by echocardiography) cane referred to the clinic. At the baseline visit, all patientsere examined by a physician and the following informa-

ion was obtained: medical history, medication, New Yorkeart Association (NYHA) classification based on patient

nformation, physical examination including measurementsf height and weight, blood pressure and heart rate at rest,-ray of the heart and lungs, and electrocardiogram. Dataere entered in real time in the database program Hjerter-lus.12 Venous blood samples to determine serum-sodium,erum-potassium, serum-creatinine, and blood-hemoglobinere drawn in all patients, and if the patients accepted,T–pro-BNP was also analyzed. NT–pro-BNP testing was

pproved by the ethical committee of Copenhagen (KF1-019699), and informed consent was obtained accordingo Helsinki Declaration II.

After �8-hour overnight fast and 15-minute rest, venouslood was drawn into tubes containing ethylenediaminetet-
aacetic acid (hemoglobin and NT–pro-BNP) and heparin
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sodium, potassium, and creatinine) and (1) promptly cen-rifuged at 4°C (3,000 rpm in 10 minutes), and plasma wasnalyzed the same day, or (2) stored as frozen plasma at80°C in aliquots.Plasma concentrations of sodium and potassium (Integra

00, Diamond Diagnostics, Holliston, Massachusetts) andreatinine13 and hemoglobin (Sysmex XE 2100 TOA Med-cal Electronics, Kobe, Japan) were analyzed on the sameay. Plasma concentrations of NT–pro-BNP were analyzedn the Elecsys 2010 platform14 by an electrochemilumines-ence method with intra- and interassay variation coeffi-ients �3%. The analytical range is 5 to 35,000 pg/ml.nalyses were performed on the same day or on at a laterate using frozen samples (first 197 patients). Storinglasma samples at �20°C does not affect the plasma level

able 1aseline characteristics according to absence or presence of anemia (n �

ariables

ge (yrs)enomeneight (cm)eight (kg)

ody mass index (kg/m2)uration of heart failure (mos)iabetes mellitushronic kidney diseaseT–pro-BNP �1,381 pg/mlinus rhythmtrial fibrillationther rhythmVEF (%)eart rate (beats/min)ystolic arterial pressure (mm Hg)GFR (ml/min/1.73 m2)YHA class IYHA class IIYHA class IIIYHA class IV

schemic cardiomyopathydiopathic dilatated cardiomyopathyypertensive cardiomyopathylcoholic cardiomyopathyalvular cardiomyopathyther cardiomyopathy or unknownodium (mmol/L)otassium (mmol/L)emoglobin (mmol/L)T–pro-BNP (pg/ml)ngiotensin-converting enzyme inhibitors/angiotensin II receptor blockadblockers

pironolactone antagonistsigoxinoop diureticsspirinarfarin

lopidogrel

Data are presented as median (range) or number of patients (percentage

f NT–pro-BNP.15 w

Estimated glomerular filtration rate (eGFR) was calcu-ated from the 4-component Modification of Diet in Renalisease equation incorporating age, race, gender, and serum

reatinine level: eGFR � 186 � (serum creatinine [milli-rams per deciliter])�1.154 � (age [years])�0.203. Foromen and African-Americans (none in our cohort), theroduct of the equation has to be multiplied by correctionactors of 0.742 and 1.21, respectively.16 Anemia was de-ned according to the World Health Organization (hemo-lobin level �8.0 mmol/L [13 g/dl] in men, hemoglobinevel �7.5 mmol/L [12 g/dl] in women) and chronic kidneyisease was defined according to the National Kidney Foun-ation (GFR �60 ml/min/1.73 m2 for �3 months).

At the end of the study (July 1, 2005) information onital status was obtained from the Danish Personal Registry,

Anemia p Value

Present(n � 95)

Absent(n � 250)

75 (34–92) 69 (41–91) �0.00160 (68%) 175 (70%) 0.64230 (32%) 75 (30%) 0.642

171 (147–192) 173 (149–192) 0.22770 (39–104) 80 (42–138) �0.00124 (14–41) 27 (14–43) �0.001

5 (0–180) 6 (0–168) 0.46830 (32%) 53 (21%) 0.02652 (55%) 70 (28%) �0.00167 (71%) 105 (42%) �0.00159 (62%) 182 (73%) 0.14231 (33%) 58 (23%) 0.1425 (5%) 10 (4%) 0.142

30 (10–45) 30 (10–45) 0.82472 (43–112) 75 (41–112) 0.050

130 (85–200) 130 (90–230) 0.97059 (22–111) 70 (22–129) �0.00114 (15%) 30 (12%) 0.16959 (62%) 162 (65%) 0.16920 (21%) 55 (22%) 0.1692 (2%) 3 (1%) 0.169

52 (56%) 137 (55%) 0.51614 (15%) 32 (13%) 0.5167 (7%) 23 (9%) 0.5163 (3%) 20 (8%) 0.5169 (9%) 13 (5%) 0.516

10 (10%) 25 (10%) 0.516138 (122–148) 138 (118–145) 0.6914.1 (3.1–5.2) 4.0 (2.7–6.0) 0.1547.3 (5.6–8.0) 9.0 (7.6–11.4) �0.001

2,889 (27–35,000) 1,022 (21–31,713) �0.00173 (77%) 198 (79%) 0.68143 (45%) 128 (51%) 0.35415 (16%) 43 (17%) 0.78124 (25%) 40 (16%) 0.05670 (74%) 150 (60%) 0.01540 (42%) 95 (38%) 0.42917 (18%) 38 (15%) 0.5786 (6%) 18 (7%) 0.749

345)

e

hich registers all deaths within 2 weeks. No patients were

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1573Heart Failure/Anemia and NT–Pro-BNP and Outcome in Systolic Heart Failure

ost to follow-up. Median follow-up time was 30 monthsrange 3 to 69). Baseline characteristics of patients, groupedccording to absence or presence of anemia, are presenteds percentages for dichotomous variables and means (me-ians) and ranges for continuous variables. Baseline char-cteristics were compared between medians with chi-squareest for discrete variables and unpaired t tests (parametric)nd Mann-Whitney U test (nonparametric) for continuousariables, as appropriate. In Cox proportional hazardsodel, associations between absence or presence of anemia

nd NT–pro-BNP considered as a dichotomous variablebove and below the median (1,381 pg/ml), respectively,nd mortality were evaluated. Survival curves were gen-rated using Kaplan-Meier estimates, and differences inurvival were compared using log-rank test. Multivariateodels were fitted according to the absence or presence of

nemia and level of NT–pro-BNP. Assumptions underlyinghe Cox proportional hazards model (proportional hazards,ack of interaction, and linearity of continuous variables)ere tested and found valid unless otherwise indicated.YHA class did not fulfill the criteria for linearity, but thenal model, �2 log-likelihood ratio, and parameter esti-ates for anemia and NT–pro-BNP were not affected by

ategorization of NYHA class. Likelihood ratio statisticsere performed due to the close association between ane-ia and NT–pro-BNP. Multivariate logistic regression anal-

ses were performed for the relation between NT–pro-BNPnd absence or presence of anemia. A p value �0.05 wasonsidered statistically significant (2-sided). Analyses wereade using SAS 9.1.4 (SAS Institute, Cary, North Caro-

ina).

esults

aseline characteristics are presented in Table 1 accordingo presence or absence of anemia. Prevalence of anemia was

NT

-pro

BN

P /

pg/m

l

14000

12000

10000

8000

6000

4000

2000

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AnaemiaNormal Hgb Levels

P < 0.001

igure 1. NT–pro-BNP levels grouped according to presence (n � 95) orbsence (n � 250) of anemia (Mann-Whitney test, p �0.001). Hgb �emoglobin.

7%. Patients with anemia had an increased frequency of f

iabetes mellitus and chronic kidney disease, had a lowerody mass index, were older, used loop diuretics andigoxin more frequently, and had higher levels of NT–pro-NP (Figure 1).

Anemia was an independent predictor for NT–pro-BNPevels being above the median after adjustment for tradi-ional confounders (Table 2). In contrast, NT–pro-BNP lev-ls above the median were not an independent predictor ofnemia (Table 2).

In Cox proportional hazard models, anemia and NT–pro-NP were independent predictors of mortality (Table 3 andigures 2 and 3). There was no interaction (p � 0.338)mong anemia, NT–pro-BNP, and mortality. Patients withnemia and NT–pro-BNP levels above the median had avefold increased risk of dying (Table 4). We did notbserve any interaction among cause of systolic dysfunc-ion, anemia, and outcome (p � 0.445).

Because anemia and NT–pro-BNP were closely associ-ted and may reflect volume overload, we also evaluatedheir prognostic value by likelihood ratio statistics (Table). Anemia and NT–pro-BNP added prognostic informationo a model including LVEF and NYHA class. Anemia alsodded significant prognostic information to a model includ-ng NT–pro-BNP, and NT–pro-BNP added highly signifi-ant additional information to a model including anemia.

We observed a higher event rate in patients with anemian � 95, 29 events) compared with patients with normalemoglobin levels (n � 250, 41 events, 119 vs 67 events per,000 patient-years of follow-up, p �0.001) and a highervent rate in patients with levels of NT–pro-BNP above theedian (n � 172, 47 events) compared with patients with

evels of NT–pro-BNP below the median (n � 173, 23vents, 118 vs 50 events per 1,000 patient-years of follow-p, p �0.001). Furthermore, we observed that patients withnemia and NT–pro-BNP levels below the median had aignificantly increased event rate compared with patientsith normal hemoglobin levels and NT–pro-BNP levelselow the median (Table 4).

iscussion

he novel findings of the present study are that anemia andigh NT–pro-BNP levels are closely associated in patientsith systolic heart failure and that anemia and NT–pro-BNP

arry independent prognostic information. Patients withnemia and high levels of NT–pro-BNP have a markedlyncreased risk of dying.

We observed a prevalence of anemia of 27%. This prev-lence of anemia is in the same range as the prevalenceeported from the Candesartan in Heart Failure: Assessmentf Reduction in Mortality and Morbidity17 (CHARM; 25%)nd Trandolapril Cardiac Evaluation (TRACE)18 (25%)tudies and in the same range as new onset of anemia in thearvedilol or Metropolol European Trial [COMET] study19

27% to 28.1%). These studies also used World Healthrganization criteria to define anemia. In accordance with

he findings in these trials, anemia in our cohort was asso-iated with increased age, lower body mass index, diabetesellitus, and chronic kidney disease (Tables 1 and 2).The data clearly show that patients with systolic heart

ailure and anemia have higher levels of NT–pro-BNP than

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atients with systolic heart failure and normal hemoglobinevels. However, patients with systolic heart failure andnemia are older, have a lower body mass index, and havelower eGFR. Therefore, a multivariate analysis adjusted

or these known confounders was performed. The associa-ion remained significant (Table 2). Hence, the associationetween anemia and NT–pro-BNP levels above the medianppears not to be caused by confounding of traditionalariables associated with NT–pro-BNP. The physiologicechanism responsible for the association is not known, but

ossible explanations include hypoxemia20 or subclinicaluid retention resulting in hemodilution.21,22 However, it isnknown whether it is anemia that predicts NT–pro-BNPevels or vice versa due to long-term inflammation associ-ted with neurohormonal activity in systolic heart failure.23

onsequently, a logistic regression analysis with anemia asresponse variable was performed (Table 2). In this anal-

able 2ultivariate logistic regression models

esponse Variable Explanatory Variables PaE

T–pro-BNP �1,381 pg/ml* LVEF �Atrial fibrillationChronic kidney diseaseBody mass index �Anemia

nemia† AgeDiabetes mellitusChronic kidney diseaseBody mass index �

* The variables age, diabetes mellitus, angiotensin-converting enzymepironolactone, ischemic heart disease, and diuretics were eliminated by b

† The variable NT–pro-BNP was eliminated by backward elimination.

able 3ox proportional hazard models

ariable Hazard Ratio

odel 0: including LVEF and NYHA classificationLVEF 1.02NYHA classification 1.75odel 1: adding anemia to model 0

LVEF 1.03NYHA classification 1.72Anemia 2.23odel 2: adding NT–pro-BNP to model 0

LVEF 1.04NYHA classification 1.90NT–pro-BNP �1,381 pg/ml 3.01odel 3: adding anemia and NT–pro-BNP to model 0

LVEF 1.04NYHA classification 1.87Anemia 1.73NT–pro-BNP �1,381 pg/ml 2.68

Likelihood ratio that follows a chi-square distribution. The following vaody mass index. These variables were therefore not used in model 0 (on* Significantly different from model 0 (p �0.001, 1 DF).† Significantly different from model 0 (p �0.001, 1 DF).‡ Significantly different from model 1 (p �0.001, 1 DF) and significanDF � degree of freedom.

sis, levels of NT–pro-BNP above the median did not pre- d

ict anemia after adjustment for traditional confounders,ndicating that the inverse association is stronger. Diabetesellitus significantly predicted anemia after adjustment for

hronic kidney disease (Table 2), which may be explainedy kidney disease not involving glomeruli, but more distalarts of the nephron.24

Anemia and NT–pro-BNP were associated with mortal-ty in a adjusted Cox proportional hazard model (Table 3),uggesting that anemia carries prognostic information inde-endently of NT–pro-BNP and vice versa. Furthermore,nemia and NT–pro-BNP carried additive prognostic infor-ation in our cohort (Table 4). This contradicts the results

eported by Gardner et al11 in transplantation candidates, buts in accord with results of a short-term study reported byalli et al,10 where brain natriuretic peptide rather thanT–pro-BNP was used. The reason our results differ from

he results reported by Gardner et al11 is not obvious, but

SE OddsRatio

95% ConfidenceInterval

p Value

0.017 0.94 0.91–0.97 �0.0010.332 5.37 2.80–10.3 �0.0010.291 2.73 1.55–4.82 �0.0010.030 0.92 0.87–0.98 0.0070.327 1.95 1.03–3.71 0.0410.018 1.06 1.02–1.09 0.0030.348 3.79 1.91–7.48 �0.0010.305 2.06 1.13–3.74 0.0180.380 0.87 0.81–0.94 �0.001

tors/angiotensin II receptor blockers, NYHA classification, � blockers,d elimination.

5% Confidence Interval p Value DF �2 Log-Likelihood

1.00–1.05 0.0501.18–2.59 0.005

2 715.13*1.00–1.06 0.0611.17–2.52 0.0011.38–3.60 0.006

3 695.37†

1.28–2.84 0.0101.01–1.07 0.0021.84–5.41 �0.001

4 690.77‡

1.01–1.06 0.0131.26–2.78 0.0021.06–2.84 0.0291.58–4.55 �0.001

were eliminated by backward elimination from model 3: age, eGFR, andd models can be compared).

rent from model 2 (p �0.05, 1 DF).

rameterstimate

0.0611.6801.0050.0810.6680.0541.3290.7210.136

inhibiackwar

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ifferent study populations (patients with clinical heart fail-

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F(1,381 pg/ml, log-rank test, p �0.001).

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† Significantly different from all others (p �0.001, p � 0.040, and p � 0.021,

1575Heart Failure/Anemia and NT–Pro-BNP and Outcome in Systolic Heart Failure

re primarily in NYHA class I to II versus transplantationandidates) may offer an explanation. An association be-ween hemoglobin levels and NT–pro-BNP has not beeneported from the large Valsartan Heart Failure (Val-eFT)25 and Carvedilol Prospective Randomized Cumula-

ive Survival (COPERNICUS)26 databases, and it has noteen tested in larger populations whether NT–pro-BNP lev-ls and anemia are associated and how a possible associa-ion affects the prognostic value of each risk marker. In ourtudy and in the study by Ralli et al,10 anemia in patientsith low levels of natriuretic peptides was not associatedith increased mortality (Table 4). It is noteworthy that thisnding has been observed in 2 single-center studies relyingn analysis of separate natriuretic peptides with differenturations of follow-up. However, in our study, the obser-ation may be explained by lack of statistical power (type IIrror) because the sample size was 28 in that particularubgroup. The event rate per 1,000 patient-years was sig-ificantly increased in patients with anemia and NT–pro-NP levels below the median (Table 4) and we did notbserve any interaction (see Results).

The following limitations were observed. It cannot beefinitely concluded whether the association between NT–ro-BNP and anemia reflects an association with anemia pere and/or plasma volume. We have not analyzed othereurohormones, cytokines, or hematinic levels (vitamin12, folate, mean cell volumes, hematocrit or iron stores,nd ferritin or erythropoietin levels); consequently, the sub-ype of anemia cannot be characterized in our patients,lthough Witte et al27 observed that only few patients withystolic heart failure have hematinic deficiency. Neurohor-onal blockade is titrated up and sometimes withdrawn

ver time in the heart failure clinic, which may have af-ected our results regarding the prognostic value of anemiand NT–pro-BNP. Age,28 eGFR,29 and body mass index30

ere not associated with mortality after adjustment forT–pro-BNP and anemia in the Cox proportional hazardodels, and LVEF and atrial fibrillation were not associatedith anemia16 in this single-center study, which may be due

o lack of statistical power. We observed a prevalence ofnemia of 27%, which is in the same range as the prevalencef anemia in multicenter trials. Furthermore, our observedvent rates remained similar to those observed in theHARM program.16 These observations may be explainedy selection bias because only 73% of our patients acceptedeasurement of NT–pro-BNP and 77% of our patients were

n NYHA class I to II. The prevalence of anemia and eventates in an unselected clinical cohort with heart failure

pValue

No. ofPatients

No. ofEvents (%)

Event Rate/1,000Patient-Years of Follow-up

— 144 16 (11%) 400.051 28 7 (25%) 107*

�0.001 106 25 (24%) 106*�0.001 67 22 (33%) 126†

l (p �0.001, 1-way analysis of variance).

igure 2. Kaplan-Meier plot according to presence (n � 95) or absence

igure 3. Kaplan-Meier plot according to median level of NT–pro-BNP

able 4djusted hazard ratios for N-terminal pro-brain natriuretic peptide and anemia

ariable HazardRatio

95% ConfidenceInterval

o anemia and NT–pro-BNP �1,381 pg/ml 1.00 —nemia and NT–pro-BNP �1,381 pg/ml 2.43 1.00–5.93o anemia and NT–pro-BNP �1,381 pg/ml 3.14 1.66–5.94nemia and NT–pro-BNP �1,381 pg/ml 4.77 2.47–9.18

Adjusted for LVEF and NYHA classification.* Significantly different from no anemia and NT–pro-BNP level �1,381 pg/m

respectively, 1-way analysis of variance).

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onsisting of, e.g., patients with primarily NYHA class IIIo IV heart failure, may be even higher. Our data do notrovide much insight into the relation among natriureticeptides, anemia, and outcome in this subgroup of patients.hether patients with systolic heart failure, anemia, and

igh NT–pro-BNP levels should be treated intensively re-ains to be determined. Currently, a combination of anemia

nd NT–pro-BNP can be used for risk stratification.

cknowledgment: The excellent assistance in the heartailure clinic by nurses Per H. Nielsen, Hanne Bartholdy,nna Marie Jensen, Birgitte Carlsen, and Louise Fly Jensen

s acknowledged.

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2. Lindenfeld J. Prevalence of anemia and effects on mortality in patientswith heart failure. Am Heart J 2005;149:391–401.

3. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, BorensteinJ. Anemia is associated with worse symptoms, greater impairment infunctional capacity and a significant increase in mortality in patientswith advanced heart failure. J Am Coll Cardiol 2002;39:1780–1786.

4. Maggioni AP, Opasich C, Anand I, Barlera S, Carbonieri E, GonziniL, Tavazzi L, Latini R, Cohn J. Anemia in patients with heart failure:prevalence and prognostic role in a controlled trial and in clinicalpractice. J Card Fail 2005;11:91–98.

5. O’Meara E, Murphy C, McMurray JJ. Anemia and heart failure. CurrHeart Fail Rep 2004;1:176–182.

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7. Doust JA, Pietrzak E, Dobson A, Glasziou P. How well does B-typenatriuretic peptide predict death and cardiac events in patients withheart failure: systematic review. BMJ 2005;330:625–632.

8. Wu AHB, Omland T, Knudsen CW, McCord J, Nowak RM, HollanderJE, Duc P, Storrow AB, Abraham WT, Clopton P, Maisel AS,McCullough PA. Relationship of B-type natriuretic peptide and ane-mia in patients with and without heart failure: a substudy from theBreathing Not Properly (BNP) Multinational Study. Am J Hematol2005;80:174–180.

9. Baggish AL, van Kimmenade R, Bayes-Genis A, Davis M, LainchburyJG, Frampton C, Pinto Y, Richards AM, Januzzi JL. Hemoglobin andN-terminal pro–brain natriuretic peptide: Independent and synergisticpredictors of mortality in patients with acute heart failure. Results fromthe International Collaborative of NT-proBNP (ICON) Study. ClinChim Acta 2007;381:145–150.

0. Ralli S, Horwich TB, Fonarow GC. Relationship between anemia,cardiac troponin I, and B-type natriuretic peptide levels and mortalityin patients with advanced heart failure. Am Heart J 2005;150:1220–1227.

1. Gardner RS, Chong KS, Morton JJ, McDonagh TA. N-terminal brainnatriuretic peptide, but not anemia, is a powerful predictor of mortalityin advanced heart failure. J Card Fail 2005;11(suppl):S47–S53.

2. Galatius S, Gustafsson F, Nielsen PH, Atar D, Hildebrandt PR. Anintegrated approach to diagnosis and therapeutic management of pa-tients with systolic heart failure in the Copenhagen metropolitan area.Am Heart J 2002;144(suppl):E2.

3. Junge W, Wilke B, Halabi A, Klein G. Determination of referenceintervals for serum creatinine, creatinine excretion and creatinineclearance with an enzymatic and a modified Jaffe method. Clin ChimActa 2004;344:137–148.

4. Sokoll LJ, Baum H, Collinson PO, Gurr E, Haass M, Luthe H, Morton
JJ, Nowatzke W, Zingler C. Multicenter analytical performance eval-
uation of the Elecsys proBNP assay. Clin Chem Lab Med 2004;42:965–972.

5. Olsen MH, Hansen TW, Christensen MK, Gustafsson F, Rasmussen S,Wachtell K, Borch-Johnsen K, Ibsen H, Jorgensen T, Hildebrandt P.N-terminal pro brain natriuretic peptide is inversely related to meta-bolic cardiovascular risk factors and the metabolic syndrome. Hyper-tension 2005;46:660–666.

6. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A moreaccurate method to estimate glomerular filtration rate from serumcreatinine: a new prediction equation. Modification of Diet in RenalDisease Study Group. Ann Intern Med 1999;130:461–470.

7. O’Meara E, Clayton T, McEntegart MB, McMurray JJ, Lang CC,Roger SD, Young JB, Solomon SD, Granger CB, Ostergren J, et al.Clinical correlates and consequences of anemia in a broad spectrum ofpatients with heart failure: results of the Candesartan in Heart Failure:Assessment of Reduction in Mortality and Morbidity (CHARM) Pro-gram. Circulation 2006;113:986–994.

8. Valeur N, Nielsen OW, McMurray JJ, Torp-Pedersen C, Kober L.Anemia is an independent predictor of mortality in patients with leftventricular systolic dysfunction following acute myocardial infarction.Eur J Heart Fail 2006;8:577–584.

9. Komajda M, Anker SD, Charlesworth A, Okonko D, Metra M, DiLenarda A, Remme W, Moullet C, Swedberg K, Cleland JG, Poole-Wilson PA. The impact of new onset anemia on morbidity and mor-tality in chronic heart failure: results from COMET. Eur Heart J2006;27:1440–1446.

0. Goetze JP, Gore A, Moller CH, Steinbruchel DA, Rehfeld JF, NielsenLB. Acute myocardial hypoxia increases BNPgene expression. FASEBJ 2004;18:1928–1930.

1. Androne AS, Katz SD, Lund L, LaManca J, Hudaihed A, HryniewiczK, Mancini DM. Hemodilution is common in patients with advancedheart failure. Circulation 2003;107:226–229.

2. Westenbrink BD, Visser FW, Voors AA, Smilde TD, Lipsic E, NavisG, Hillege HL, van Gilst WH, van Veldhuisen DJ. Anemia in chronicheart failure is not only related to impaired renal perfusion and bluntederythropoietin production, but to fluid retention as well. Eur Heart J2007;28:166–171.

3. Okonko DO, Anker SD. Anemia in chronic heart failure: pathogeneticmechanisms. J Card Fail 2004;10(suppl):S5–S9.

4. Thomas MC, Tsalamandris C, Macisaac R, Jerums G. Functionalerythropoietin deficiency in patients with type 2 diabetes and anemia.Diabet Med 2006;23:502–509.

5. Masson S, Latini R, Anand IS, Vago T, Angelici L, Barlera S, MissovED, Clerico A, Tognoni G, Cohn JN. Direct comparison of B-typenatriuretic peptide (BNP) and amino-terminal proBNP in a large pop-ulation of patients with chronic and symptomatic heart failure: theValsartan Heart Failure (Val-HeFT) data. Clin Chem 2006;52:1528–1538.

6. Hartmann F, Packer M, Coats AJ, Fowler MB, Krum H, Mohacsi P,Rouleau JL, Tendera M, Castaigne A, Anker SD, et al. Prognosticimpact of plasma N-terminal pro-brain natriuretic peptide in severechronic congestive heart failure: a substudy of the Carvedilol Prospec-tive Randomized Cumulative Survival (COPERNICUS) trial. Circu-lation 2004;110:1780–1786.

7. Witte KK, Desilva R, Chattopadhyay S, Ghosh J, Cleland JG, ClarkAL. Are hematinic deficiencies the cause of anemia in chronic heartfailure? Am Heart J 2004;147:924–930.

8. Gustafsson F, Torp-Pedersen C, Seibaek M, Burchardt H, Kober L, forthe DIAMOND Study Group. Effect of age on short and long-termmortality in patients admitted to hospital with congestive heart failure.Eur Heart J 2004;25:1711–1717.

9. Hillege HL, Nitsch D, Pfeffer MA, Swedberg K, McMurray JJ, YusufS, Granger CB, Michelson EL, Ostergren J, Cornell JH, et al. Renalfunction as a predictor of outcome in a broad spectrum of patients withheart failure. Circulation 2006;113:671–678.

0. Gustafsson F, Kragelund CB, Torp-Pedersen C, Seibaek M, BurchardtH, Akkan D, Thune JJ, Kober L, for the DIAMOND Study Group.Effect of obesity and being overweight on long-term mortality incongestive heart failure: influence of left ventricular systolic function.
Eur Heart J 2005;26:58–64.

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Quantitative Assessment of Severity of Mitral Regurgitationby Serial Echocardiography in a Multicenter Clinical Trial

of Percutaneous Mitral Valve Repair

Elyse Foster, MDa,*, Hal S. Wasserman, MDb, William Gray, MDb, Shunichi Homma, MDb,Marco R. Di Tullio, MDb, Leonardo Rodriguez, MDc, William J. Stewart, MDc,

Patrick Whitlow, MDc, Peter Block, MDd, Randy Martin, MDd, John Merlino, MDd,Howard C. Herrmann, MDe, Susan E. Wiegers, MDe, Frank E. Silvestry, MDe,

Andrew Hamilton, MDf, Alan Zunamon, MDf, Kimberly Kraybill, MDg, Ivor L. Gerber, MDh,Sarah G. Weeks, MDa, Yan Zhang, MDa, and Ted Feldman, MDf

The aims of the echocardiographic substudy of this multicenter trial were to evaluatethe use of quantitative assessment of mitral regurgitation (MR) severity using serialechocardiography and to assess the efficacy of percutaneous mitral valve repair.Previous surgical repair studies did not use quantitative echocardiographic methods.Results of a percutaneous mitral valve repair clip device in a core echocardiographiclaboratory were evaluated. Published parameters for quantifying MR were used in asystematic protocol to qualify patients for study entry and evaluate treatment efficacyat discharge and 6 months after clip repair. Baseline results were presented for 55patients, and follow-up results, for 49. Ninety-eight percent of required echocardio-graphic studies were submitted to the core laboratory, and >85% of required measure-ments were possible. At baseline, mean regurgitant volume was 54.8 � 24 ml, regur-gitant fraction was 46.9 �16.2%, effective regurgitant orifice area was 0.71 � 0.40 cm2,and vena contracta width was 0.66 � 0.20 cm. Based on a severity scale of 1 to 4, mean colorflow grade was 3.4 � 0.7, and mean pulmonary vein flow was 2.8 � 1.2. In patients with aclip at 6 months, all measurements of MR severity were significantly decreased versusbaseline, with mean regurgitant volume decreased from 50.3 to 27.5 ml (change �22.8 ml;p <0.0001), regurgitant fraction from 44.6% to 28.9% (change �15.7%; p <0.0001), colorflow grade from an average of 3.4 to 1.8 (change �1.6; p <0.0001), and pulmonary veinflow from 2.8 to 1.8 (change �1.0; p <0.0018). In conclusion, quantitative assessment ofMR is feasible in a multicenter trial, and percutaneous mitral repair with the MitraClipproduces a sustained decrease in MR severity to moderate or less for >6 months. © 2007
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new percutaneous method of mitral valve repair using alip (MitraClip device; Evalve Inc., Menlo Park, California)o achieve leaflet apposition to treat mitral regurgitationMR)1–3 was recently described. A phase I safety and fea-ibility trial with MitraClip (Endovascular Valve Edge-to-dge Repair Study [EVEREST] I) was initiated and initial

esults recently were reported.3,4 Evaluation of new medical

aDepartment of Cardiology, University of California, San Francisco,alifornia; bColumbia University, New York, New York; cThe Clevelandlinic, Cleveland, Ohio; dEmory University, Atlanta, Georgia; eUniversityf Pennsylvania, Philadelphia, Pennsylvania; fEvanston Hospital, Evan-ton, Illinois; gSwedish Medical Center, Seattle, Washington; and hAuck-and City Hospital, Auckland, New Zealand. Manuscript received April 17,007; revised manuscript received and accepted June 14, 2007.

This study was supported by a grant from Evalve, Inc., Menlo Park,alifornia.

*Corresponding author: Tel.: 415-353-9156; fax: 415-353-8687.E-mail address: [email protected]

aClinical Trial Registration: www.clinicaltrials.gov, Evalve no. 0301.


evices demands the rigor of core laboratory assessment offficacy. The American Society of Echocardiography pub-ished guidelines for the quantitation of MR that were neverpplied in a therapeutic trial.5 The EVEREST I protocolequired core laboratory assessment of MR at baseline andollow-up using American Society of Echocardiography cri-eria to qualify MR for study entry and evaluate treatmentfficacy. The 2 primary aims of the echocardiographic sub-tudy of the EVEREST I trial were to show the feasibility ofystematic quantitative assessment of MR severity usingerial echocardiography in a multicenter clinical trial andpply these methods to assess the effect of MitraClip ther-py to reduce the severity of MR from baseline to 6-monthollow-up.

ethodsMitral valve repair device and procedure: The Evalve

itraClip device and the procedural technique for cliplacement were previously described in detail.3 Using aransseptal approach, the clip was implanted, and the
mount of MR reduction was assessed using echocardiog-
www.AJConline.org

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aphy. If MR reduction was not satisfactory, the clip wasepositioned. When adequate control of MR was achieved,he clip was deployed. A second clip could be placed ifnsufficient MR improvement was achieved using 1 clip.

Patient selection: Inclusion criteria were based on pub-ished guidelines for therapy for patients with valvular heartisease.6 Patients with moderate to severe or severe MRho were symptomatic or asymptomatic with compromised

eft ventricular (LV) function (LV ejection fraction �60%nd/or LV end-systolic dimension �45 mm) were selected.ll patients were candidates for elective mitral valve sur-ery. An integrative echocardiographic analysis was used toetermine MR grade, and anatomic criteria were evaluatedor suitability of the percutaneous approach.

Six parameters of MR severity were measured. The 2 ofhese considered qualitative were color flow Doppler (CFD)

igure 1. Parasternal short-axis view shows 2-dimensional image on theeft and CFD on the right, with the jet originating from the central 2/3 ofhe coaptation line corresponding to the point of leaflet dropout on the-dimensional image (arrow).

able 1itral regurgitation grade criteria

ariable Mild (1�) M

FD Small central �4 cm2 or�10% of LA area

Moderator 10%area

ulmonary vein flow Systolic dominant Diastolicegurgitant volume (ml) �30egurgitant fraction (%) �30%

Data based on American Society of Echocardiography published guidreviously applied in a therapeutic trial.5

LA � left atrial; PV � pulmonary vein.

able 2linical features (n � 55)

ge (yrs) 68 � 14en 32 (58%)iabetes mellitus 11 (20%)ypertension 39 (71%)hronic obstructive pulmonary disease 7 (13%)istory of congestive heart failure 29 (53%)trial fibrillation 17 (31%)ew York Heart Association class III/IV 24 (44%)

Values expressed as mean � SD, number (percent), or number ofatients.

et characteristics and pulmonary vein flow pattern, and the p

considered quantitative were vena contracta width, regur-itant volume, regurgitant fraction, and effective regurgitantrifice area (EROA; Table 1). To qualify for the study,verall MR severity was required to be moderate to severer severe (3� or 4�) using multiple criteria. Additionally,he primary pathologic state had to originate from the cen-ral anterior and posterior leaflets (Figure 1). When a flaileaflet segment was present, the width and length of theegment were measured.

Echocardiographic evaluation of MR: Detailed echo-ardiographic protocols and face-to-face training were pro-ided for participating centers. We report results of MRssessments at baseline, discharge, 30 days, and 6 months.ena contracta width and EROA were not applied previ-usly for a double-orifice valve and were not included in theostclip analysis. On follow-up echocardiograms, CFD jet,ulmonary vein flow pattern, regurgitant volume, and re-urgitant fraction were analyzed and a composite MR scoreas assigned (Table 1).6

Echocardiographic analysis: CFD jet characteristics andulmonary vein flow pattern were graded on a scale of mild1�) to severe (4�) based on specified characteristics (Table). Vena contracta width was measured on a magnifiedarasternal long-axis view.7 EROA was measured using theroximal isovelocity surface area at the point in systole of itsaximal diameter and the peak velocity of the continuous-ave MR jet. To qualify for enrollment, EROA was required

o be �0.3 cm2.5 LV volumes were measured using the biplaneethod of discs. Regurgitant volume was calculated by sub-

racting the forward stroke volume from total LV stroke vol-me, where total LV stroke volume � LV end-diastolic vol-me � LV end-systolic volume. Forward stroke volume waserived using Doppler methods as the product of the velocity–ime integral in the LV outflow tract and the area of the LVutflow tract.8 Regurgitant fraction was calculated as regurgi-ant volume/total stroke volume. In patients in atrial fibrilla-ion, pulmonary vein flow pattern was rated only when theow signal was predominantly systolic (1�) or systolic floweversal was observed (4�).

A single trained sonographer performed all core labora-ory echocardiographic measurements. When possible, eachchocardiographic measurement was made 3 times. Allchocardiograms were reviewed by a single echocardiogra-

(2�) Moderate to Severe(3�)

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l 4–6 cm2

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ant All diastolic Systolic reversal4 45–59 �609% 40%–49% �50%

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1579Valvular Heart Disease/Echocardiography in Percutaneous Mitral Valve Repair

ssigned. When color flow grade differed between theonographer and echocardiographer, a third reviewer wasonsulted to reach a consensus.

Study end points: The primary end point of the study,cute safety at 30 days, was met and was previouslyeported.3 Efficacy was defined after clip deployment as

R severity of moderate (2�) or less.

Statistical analysis: To assess interobserver variability,second observer repeated measurements on 20 of the

creening echocardiograms. Descriptive statistics were cal-ulated and are presented as proportions (for categoricalariables) or mean � SD (for continuous variables).hanges in overall MR score, CFD jet characteristics, pul-onary vein flow pattern, regurgitant volume, and regurgi-

ant fraction from baseline to 6 months were analyzed usingaired t tests. All analyses were performed using the SAStatistical software package (version 9.1; SAS Institute,ary, North Carolina). Two-sided p �0.05 were considered

tatistically significant.

esults

ifty-five patients underwent the percutaneous procedure at

Figure 2. Flowchart shows out

1 institutions. Clinical features of the 55 patients enrolled f

re listed in Table 2. The cause of MR was degenerative in7 patients (85%) and functional in 8 patients (15%). Of the7 patients with degenerative MR, there was flail or pro-apse of P2 in 34 (72%), A2 in 3 (7%), and bileaflet prolapsen 10 (21%). The clip was implanted in 49 of 55 patients89%; Figure 2). At discharge, 44 of 49 patients (90%) whonderwent implantation with the clip experienced a reduc-ion of �1 MR grade. Two additional patients had MR

2� at discharge. However, because their MR was notssessed at baseline, the extent of MR reduction at discharges unknown. Forty-two of 49 clip recipients (86%) had MR

2� at discharge, and 31 (74%) had 1� MR. One deathnrelated to the clip occurred at 2 months.

The number of echocardiographic studies submitted to theore laboratory compared with the total number required by therotocol at each period was 53 of 55 (97%) at baseline, 48 of8 (100%) at discharge, 46 of 47 (98%) at 30 days, and 40 of1 (98%) at 6 months. Only 4 required echocardiograms wereot submitted for analysis; 2 at baseline, 1 at 30 days, and 1 atmonths after clip implantation. Overall, 187 of 191 protocol-

equired echocardiographic studies (98%) were available fornalysis. In an additional 22 screening examinations performedefore the baseline studies, adequate analysis could be per-

of patients through 6 months.

ormed for most protocol parameters.

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Of 187 baseline and 6-month follow-up echocardiogramsubmitted to the core laboratory for analysis, data werevailable for most parameters used to rate MR severityTable 3). Pulmonary vein flow measurements were theost difficult to interpret, which was related to the occur-

ence of atrial fibrillation in 31% of patients. Overall MReverity grade was able to be determined in 98.4% of ana-yzed echocardiographic studies. Between 2 separate ob-ervers, there was concordance in CFD jet characteristics in9 of 20 screening echocardiograms and 13 of 15 for pul-onary vein flow pattern. The 4 quantitative variables wereeasured by 2 observers and showed strong correlations

etween measurements (Table 4). There was a small, butignificant, difference between readers in regurgitant frac-ion, for which, when further classified categorically fromild to severe, 16 of 19 (84%) remained in the same

ategory of severity.For the 22 screening studies available, mean EROA was

.71 � 0.40 cm2 (n � 18), mean vena contracta width was

.66 � 0.20 cm (n � 22), mean regurgitant volume was 5024 ml (n � 23), and mean regurgitant fraction was 45 �

6% (n � 23). Forty-four of 49 patients who underwent clip

ischarge, 30-day and 6-mo Follow-Up(n � 134; 48 � 46 � 40)

Total(n � 187)

132 (98.5%) 184 (98.4%)110 (82.1%) 156 (83.4%)111 (82.8%) 157 (84.0%)134 (100%) 187 (100%)101 (75.4%) 141 (75.4%)

Pearson p Value Difference (mean � SD) t Test p Value

�0.0001 �0.01 � 0.10 0.6981�0.0001 2.74 � 9.73 0.2362�0.0001 3.47 � 5.17 0.0089�0.0001 �0.01 � 0.08 0.7053

ith a clip implant and matched data available and from baseline to 6

r 44Baseline

MR Evaluation from Baseline to Discharge for 37Patients With Clip Remaining and Matched Data at

Baseline and 6 Mo

p* n Baseline 6 Mo Change p* Value

�0.0001 37 3.5 � 0.6 1.8 � 1.0 �1.7 � 1.0 �0.0001�0.0001 31 50.3 � 21.5 27.5 � 18.6 �22.8 � 17.5 �0.0001�0.0001 31 44.6 � 13.6 28.9 � 15.3 �15.7 � 16.5 �0.0001�0.0001 37 3.4 � 0.7 1.8 � 0.9 �1.6 � 1.0 �0.0001�0.0001 21 2.8 � 1.2 1.8 � 1.1 �1.0 � 1.2 0.0012

e or baseline to 6 months.

igure 3. Representative echocardiogram shows MR reduction assessedsing spatial mapping: 4-chamber view (A) in systole, shows severe MR onFD at baseline before clip implantation, (B) in systole on the discharge

ransthoracic echocardiogram, shows mild central MR on CFD after clipmplantation, and (C) in diastole, shows inflow through the created double

able 3vailable data points for analysis on baseline and follow-up echocardiograms

Baseline(n � 53)

D

R grade 52 (98.1%)egurgitant volume 46 (87.0%)egurgitant fraction 46 (87.0%)FD grade 53 (100%)

able 4eproducibility of quantitative variables between readers 1 and 2

n Pearson Correlation (95% CI)

ena contract diameter 19 0.80 (0.54–0.92)egurgitant volume 19 0.89 (0.73–0.96)egurgitant fraction 19 0.94 (0.85–0.98)ffective regurgitant orifice area 16 0.97 (0.90–0.99)

able 5itral regurgitation (MR) evaluation from baseline to discharge for 44 patients wonths for 37 patients with a clip remaining and matched data available

MR Evaluation from Baseline to Discharge foPatients With Clip Implant and Matched Data at

and Discharge

n Baseline Discharge Change

verall MR 44 3.5 � 0.6 1.5 � 0.8 �2.0 � 0.8egurgitant volume (ml) 28 54.8 � 24.0 26.8 � 16.8 �28.0 � 15.7egurgitant fraction (%) 28 46.9 � 16.2 27.8 � 14.3 �19.2 � 10.8FD (grade) 44 3.4 � 0.7 1.6 � 0.9 �1.8 � 1.0ulmonary vein flow (cm/s) 27 2.8 � 1.2 1.3 � 0.5 �1.6 � 1.2

Values expressed as mean � SD unless noted otherwise.

mplantation had matched data at baseline and discharge

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Table 5). There was a significant reduction in mean overallR grade, CFD jet characteristics, pulmonary vein flow,

egurgitant volume, and regurgitant fraction. A representa-ive echocardiogram showing MR reduction assessed usingpatial mapping is shown in Figure 3. In the 42 patients whonderwent clip implantation who showed reduction in MReverity to �2� at discharge, there was greater improve-ent in all measures of MR severity.At 6 months, 39 of 49 patients who underwent clip

mplantation had follow-up echocardiographic studies sub-itted to the core laboratory (Figure 2). Follow-up echo-

ardiograms were not required for the 7 patients who re-uired surgery after clip deployment for residual (n � 2) orecurrent (n � 5) MR. Surgical removal of the clip wasescribed previously.9 Three additional 6-month echocar-iographic studies were not submitted (1 death, 2 missing).hrough 6 months, 37 of 49 patients (75.5%) who under-ent clip implantation (and not explantation) had a �1rade reduction in MR from baseline (Figure 4). Two ad-itional patients had 1� MR at 6 months; however, becauseheir MR was not assessed at baseline, the extent of MReduction at 6 months is unknown. Mean MR, regurgitantolume, regurgitant fraction, pulmonary vein flow, andFD jet characteristics were significantly reduced for these7 patients (Table 5). Figure 5 shows regurgitant volumend regurgitant fraction data.

Separate analyses comparing baseline with discharge

igure 4. Baseline and 6-month MR severity in patients who had a clipemaining at 6 months.

nd 6 months were also performed for the 47 patients n

ith degenerative MR and the 8 patients with functionalR. Patients with degenerative MR experienced reduc-

ions in mean overall MR grade, CFD jet characteristics,ulmonary vein flow, regurgitant volume, and regurgitantraction that were consistent with values reported for theverall population, and all reductions remained statisti-ally significant. Patients with functional MR showed theame degree of change as the overall population, but becausef the small sample size, the change did not reach statisticalignificance. Forty-one patients were free from surgery andontinued to have the implanted clip in place at 6 months. Inhe final analysis of the 39 core laboratory–reviewed echocar-iograms for patients with a clip remaining at 6 months, overallR grade was rated mild (1�) in 20 (51%), moderate (2�) in

0, moderate to severe (3�) in 6, and severe (4�) in 3 patients.

iscussion

hese echocardiographic results from the first humanrial of percutaneous mitral valve repair represent the firstlinical trial for treatment of patients with MR to reportprospective, systematic, and integrative approach to the

nalysis of MR severity at baseline and follow-up thatncluded quantitative parameters. This echocardiographicnalysis shows the feasibility of a systematic standard-zed echocardiographic protocol to evaluate baseline en-ry criteria and efficacy of MR reduction in a multicenterlinical trial.

A recent American Society of Echocardiography state-ent on the use of echocardiography in clinical trials

ecommended that the “change in magnitude of valvularegurgitation should utilize quantitative methods when-ver possible.”10 For this trial, the echocardiographicore laboratory developed a detailed standardized echo-ardiographic protocol for participating sites. A MR se-erity rating was able to be determined for 98.4% ofatients. Of the total number of possible measurements ofFD jet characteristics, pulmonary vein flow, regurgitantolume, and regurgitant fraction, �85% were obtained.ulmonary vein flow was the most difficult parameter tovaluate because of contamination by the MR jet onransthoracic echocardiograms and the independent influ-nce of atrial fibrillation on flow characteristics. Strongorrelations were shown between measurements by 2eparate observers for the quantitative measures of MReverity, and very high concordance was found relative toetermination of the category of severity. This reproduc-bility shows the viability of a core echocardiographicaboratory for the consistent evaluation of echocardio-rams collected for a controlled clinical trial.

The importance of the integrative approach is exem-lified in the mitral valve replacement or repair stratumf the Acorn Clinical Trial,11 in which patients withilated cardiomyopathy and MR were randomly assignedo surgery with or without the use of a cardiac supportevice. In this multicenter trial, the core laboratory eval-ation of baseline MR severity differed markedly fromhat of the enrolling sites because �40% of enrolledatients had moderate or less MR at baseline, with 7.4%aving no detectable MR. This study also emphasized the
eed for clear enrollment criteria that did not rely solely

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n qualitative evaluation of MR severity. Most previousherapeutic reports that evaluated the efficacy of surgicalntervention on MR severity were single-center observa-ional studies. Limited criteria were used to quantitate

R, and independent review by a core laboratory wasacking. The few studies that reported MR recurrencefter repair surgery failed to specify echocardiographicethods.12–15

Both vena contracta width and EROA are well-vali-ated methods to measure MR severity,16 –18 but neitheras previously applied to a double-orifice valve and

herefore were used only as screening criteria. Theethod used to measure regurgitant volume and regurgi-

ant fraction is independent of valve morphologic char-cteristics. As such, these parameters can be used toeasure MR severity before and after therapeutic inter-

entions that alter valve morphologic characteristics. Theimitations of these measurements are predominantlyechnical because they rely on adequate volumetric LVeasurements. In cases in which the endocardial defini-

ion was suboptimal, investigators were encouraged tose left-sided contrast agents.

Of 39 patients with a clip remaining at 6 months, 30ad a durable reduction in MR of �2� at 6 months. Aortion of the early failures of this novel device werevoided later in the study as a result of rapid proceduralearning. Outcomes were not dependent on whether theause was degenerative or functional MR. The referencetandard for MR reduction was mitral valve surgery withither repair or replacement of the valve. For the purposef comparison, MR data concerning mitral valve repairould be most relevant. Quantitative echocardiographic

Baselin

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100

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Figure 5. Baseline and 6-month regurgitant volume and regurgitant fr

ata that examined MR recurrence after surgery were not e

vailable, and few qualitative reports were available.lameng et al13 reported results for 242 patients whonderwent mitral valve repair for degenerative mitralalve disease. The yearly recurrence of more than mildR (�1/4) was approximately 8%/year, and more thanoderate (�2/4) was approximately 4%/year. In another

ecent report, the success of surgical edge-to-edge repairith annuloplasty for anterior leaflet pathologic states

ompared favorably with quadrangular resection withnnuloplasty for posterior leaflet pathologic states, with90% freedom from reoperation for up to 14 years.19 At

ast echocardiographic examination, there was mild or noR in 90% of both groups and 2� MR in 8% of each

roup. In another study, Maisano et al20 reported 81atients with edge-to-edge repair without annuloplasty.n 76 patients at a mean follow-up of 4 years, echocar-iographic data showed that 35 of 76 (45%) had mild oro MR, 24 of 76 (31%) had moderate MR, 9 of 76 (12%)ad moderate to severe MR, and 8 of 76 (11%) had severeR.15 Without quantitative analysis, results of these

tudies cannot be compared with the present study. Directomparison between percutaneous repair and surgicalepair using the quantitative methods for assessing MReverity in a core laboratory setting as described hereust await results of the ongoing prospective randomized

rial EVEREST II.The limitations of this study were predominantly re-

ated to technical limitations of the method used, whichre well understood and can be overcome with diligentxamination.5 Measurement of EROA assumed a planaralve surface and was more accurate with a central thanccentric jet.21 The CFD evaluation of MR was influ-

6 Months

75th

rcentileMedian 25th

Percentile75th

Percentile

63 22 16 38

53 27 20 39

100

80

60

40

20

0BaselineRF 6MonthRF

Regurgitant Fraction

Baselinen = 31

6 Monthsn = 31

P=0.0001*

n patients with matched data who had a clip remaining at 6 months.

e

Pe

Reg

urgi

tant

Fra

ctio

n (%

)

nced by instrument settings, driving pressure, and wall

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onstraint. Measurements of regurgitant volume and re-urgitant fraction required accurate measurement of LVolumes and LV outflow tract. An additional limitationas the inability to blind readers to placement of the clip.This study clearly showed that a systematic quantitative

R assessment approach according to American Society ofchocardiography guidelines was feasible in a prospectiveulticenter trial. Determination of MR severity could be

eliability and reproducibly obtained.

cknowledgments: The authors acknowledge the technicalontributions of Esperanza Viloria, BS.

1. Fann JI, St Goar FG, Komtebedde J, Oz MC, Block PC, Foster E,Butany J, Feldman T, Burdon TA. Beating heart catheter-based edge-to-edge mitral valve procedure in a porcine model: efficacy and heal-ing response. Circulation 2004;110:988–993.

2. St Goar FG, Fann JI, Komtebedde J, Foster E, Oz MC, Fogarty TJ,Feldman T, Block PC. Endovascular edge-to-edge mitral valve repair:short-term results in a porcine model. Circulation 2003;108:1990–1993.

3. Feldman T, Wasserman HS, Herrmann HC, Gray W, Block PC,Whitlow P, St Goar FG, Rodriguez L, Silvestry F, Schwartz A, et al.Percutaneous mitral valve repair using the edge-to-edge technique:six-month results of the EVEREST phase I clinical trial. J Am CollCardiol 2005;46:2134–2140.

4. Cohn LH. Percutaneous mitral valve repair with the edge-to-edgetechnique: a surgeon’s perspective. J Am Coll Cardiol 2005;46:2141–2142.

5. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD,Levine RA, Nihoyannopoulos P, Otto CM, Quinones MA, Rakowski H,et al. Recommendations for evaluation of the severity of native valvularregurgitation with two-dimensional and Doppler echocardiography. J AmSoc Echocardiogr 2003;16:777–802.

6. Bonow RO, Carabello B, de Leon AC, Edmunds LH, Fedderly BJ,Freed MD, Gaasch WH, McKay CR, Nishimura RA, O’Gara PT,O’Rourke RA, Rahimtoola SH, et al. ACC/AHA guidelines for themanagement of patients with valvular heart disease. Executive sum-mary. A report of the American College of Cardiology/AmericanHeart Association Task Force on Practice Guidelines. Circulation1998;98:1949–1984.

7. Hall SA, Brickner ME, Willett DL, Irani WN, Afridi I, Grayburn PA.Assessment of mitral regurgitation severity by Doppler color flowmapping of the vena contracta. Circulation 1997;95:636–642.

8. Blumlein S, Bouchard A, Schiller NB, Dae M, Byrd BF, Ports T,Botvinick EH. Quantitation of mitral regurgitation by Doppler echo-
cardiography. Circulation 1986;74:306–314.
9. Dang NC, Aboodi MS, Sakaguchi T, Wasserman HS, ArgenzianoM, Cosgrove DM, Rosengart TK, Feldman T, Block PC, Oz MC.Surgical revision after percutaneous mitral valve repair with a clip:initial multicenter experience. Ann Thorac Surg 2005;80:2338 –2342.

0. Gottdiener JS, Bednarz J, Devereux R, Gardin J, Klein A, ManningWJ, Morehead A, Kitzman D, Oh J, Quinones M, et al. AmericanSociety of Echocardiography recommendations for use of echo-cardiography in clinical trials. J Am Soc Echocardiog 2004;17:1086–1119.

1. Acker MA, Bolling S, Shemin R, Kirklin J, Oh JK, Mann DL, JessupM, Sabbah HN, Starling RC, Kubo SH. Mitral valve surgery in heartfailure: insights from the Acorn Clinical Trial. J Thorac CardiovascSurg 2006;132:568–577.

2. Braunberger E, Deloche A, Berrebi A, Abdallah F, Celestin JA, Mei-moun P, Chatellier G, Chauvaud S, Fabiani JN, Carpentier A. Verylong-term results (more than 20 years) of valve repair with Carpenti-er’s techniques in nonrheumatic mitral valve insufficiency. Circulation2001;104:I8–I11.

3. Flameng W, Herijgers P, Bogaerts K. Recurrence of mitral valveregurgitation after mitral valve repair in degenerative valve disease.Circulation 2003;107:1609–1613.

4. McGee EC, Gillinov AM, Blackstone EH, Rajeswaran J, Cohen G,Najam F, Shiota T, Sabik JF, Lytle BW, McCarthy PM, Cosgrove DM.Recurrent mitral regurgitation after annuloplasty for functional isch-emic mitral regurgitation. J Thorac Cardiovasc Surg 2004;128:916 –924.

5. Maisano F, Caldarola A, Blasio A, De Bonis M, La Canna G, AlfieriO. Midterm results of edge-to-edge mitral valve repair without annu-loplasty. J Thorac Cardiovasc Surg 2003;126:1987–1997.

6. Kizilbash AM, Willett DL, Brickner ME, Heinle SK, Grayburn PA.Effects of afterload reduction on vena contracta width in mitral regur-gitation. J Am Coll Cardiol 1998;32:427–431.

7. Enriquez-Sarano M, Avierinos JF, Messika-Zeitoun D, Detaint D,Capps M, Nkomo V, Scott C, Schaff HV, Tajik AJ. Quantitativedeterminants of the outcome of asymptomatic mitral regurgitation.N Engl J Med 2005;352:875–883.

8. Pu M, Vandervoort PM, Greenberg NL, Powell KA, Griffin BP,Thomas JD. Impact of wall constraint on velocity distribution inproximal flow convergence zone. Implications for color Dopplerquantification of mitral regurgitation. J Am Coll Cardiol 1996;27:706–713.

9. De Bonis M, Lorusso R, Lapenna E, Kassem S, De Cicco G, TorraccaL, Maisano F, La Canna G, Alfieri O. Similar long-term results ofmitral valve repair for anterior compared with posterior leaflet pro-lapse. J Thorac Cardiovasc Surg 2006;131:364–370.

0. Maisano F, Schreuder JJ, Oppizzi M, Fiorani B, Fino C, Alfieri O. Thedouble orifice technique as a standardized approach to treat mitralregurgitation due to severe myxomatous disease: surgical technique.Eur J Cardiothorac Surg 2000;17:201–15.

1. Simpson IA, Shiota T, Gharib M, Sahn DJ. Current status of flowconvergence for clinical applications: is it a leaning tower of “PISA”?
J Am Coll Cardiol 1996;27:504–509.

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Valve Structure and Survival in Quinquagenarians Having Aortic ValveReplacement for Aortic Stenosis (�Aortic Regurgitation) With Versus WithoutCoronary Artery Bypass Grafting at a Single US Medical Center (1993 to 2005)

William Clifford Roberts, MDa,b,d,*, Jong Mi Ko, BAd, Giovanni Filardo, PhD, MPHe,f,Albert Carl Henry, MDc, Robert Frederick Hebeler, Jr, MDc, Edson Hoi-Kam Cheung, MDc,

Gregory John Matter, MDc, and Baron Lloyd Hamman, MDc

The purpose of this study was to determine the effect of simultaneous coronary arterybypass grafting (CABG) and the influence of valve structure on both early and late survivalin quinquagenarians having aortic valve replacement (AVR) for aortic stenosis (AS) (withor without aortic regurgitation). We analyzed survival and valve structure in 120 quinqua-genarians having AVR for AS from 1993 through 2005 at Baylor University MedicalCenter, including 44 (37%) with and 76 (63%) without simultaneous CABG. Of the 120patients, 2 (2%) died within 30 days of operation and none from 31 to 60 days postoper-atively. Fifteen other patients (13%) died from >60 days to up to 13 years postoperatively.The unadjusted survival analysis showed that late survival was significantly better in theunicuspid/bicuspid valve structure group than in the tricuspid valve structure group(log-rank test p � 0.001), but that it was not affected by gender (male vs female),preoperative severity of the AS (transvalvular peak pressure gradient >50 vs <50 mm Hg),or by performance of CABG. The aortic valve was congenitally unicuspid in 18 patients(15%), congenitally bicuspid in 84 (70%), and 3-cuspid in 18 (15%). In conclusion, aorticvalve structure affected the unadjusted late survival in quinquagenarians undergoing AVRfor AS, but concomitant CABG, gender, and transvalvular peak systolic gradient had no
effect. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:1584–1591)
pv

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e recently described aortic valve structure and early andate survival in 9 nonagenarians, in 196 octogenarians, in24 septuagenarians, and in 289 sexagenarians having aor-ic valve replacement (AVR) for aortic stenosis (AS) ataylor University Medical Center from 1993 to 2005.1–4

he present report focuses on aortic valve structure andurvival in 120 quinquagenarians having AVR for AS at theame medical center in the same time frame.

ethods

rom January 1993 through December 2005, a total of,112 patients underwent AVR for AS (with or withoutortic regurgitation) with or without simultaneous CABGnd without mitral valve replacement at Baylor Universityedical Center. Of the 1,112 patients, 120 (11%) were aged

0 to 59, and they are the subject of this report. Theperatively excised aortic valve in each patient was submit-ed to the surgical pathology section and all 120 valves werexamined and described by 1 of us (WCR). The valves were

aDepartments of Internal Medicine (Division of Cardiology), bPathol-gy, and cCardiothoracic Surgery, and the dBaylor Heart and Vascularnstitute, Baylor University Medical Center, Dallas, Texas 75246; and theInstitute for Health Care Research and Improvement, Baylor Health Careystem and the fDepartment of Statistical Science, Southern Methodistniversity, Dallas, Texas. Manuscript received July 27, 2007; revisedanuscript received and accepted August 6, 2007.

*Corresponding author: Tel: 214-820-7911, Fax: 214-820-7533.
tE-mail: [email protected] (W.C. Roberts).

hotographed by JMK. Since 1998, all operatively excisedalves have been weighed by 1 of us (WCR).

The echocardiographic and hemodynamic data in the 120uinquagenarians were collected by JMK from the cardio-ascular computer database (Apollo Advance C/S, version.2.13, LUMEDX Corp., Oakland, California) and from theedical records. Information regarding death of any patientas obtained from 2 sources: (1) early death informationas obtained from the medical record, and (2) post-hospitaleath information was obtained and confirmed from theocial Security Death Index.

Echocardiographic data preoperatively were available to usn 50 patients (42%). Cardiac catheterization data were avail-ble to us in most patients: peak transvalvular pressure gradi-nts in 74 patients (62%), mean transvalvular pressure gradi-nts in 70 (58%), aortic valve area in 76 patients (63%), andeft ventricular ejection fraction in 56 patients (47%). Mostatients in whom cardiac catheterization data were not avail-ble to WCR and JMK were referred directly to a cardiovas-ular surgeon. These patients had hemodynamic and coronaryngiographic studies before being referred to Baylor Univer-ity Medical Center, but the data are not available to us.

Means, standard deviations (SD), and percentages werealculated to describe the study cohort (n � 120). Due to theow number of deaths (n � 2), short-term mortality analysisas not conducted. To investigate late survival, we ex-

luded patients who died within 60 days of AVR (n � 2).his left 118 patients for analysis of late survival. Patientsith unicuspid and bicuspid valve structure were grouped

ogether in the analysis of long-term mortality. Log-rank
est statistics were computed to compare unadjusted sur-
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1585Valvular Heart Disease/AVR for AS in Quinquagenarians

ival curves for the variables of interest. UnadjustedKaplan-Meier) plots were also generated. Statistical anal-sis was performed using SigmaStat Version 2.0 (SPSSnc., Chicago, Illinois) and SAS version 9.1 (SAS Institute,ary, North Carolina).

This study was approved by Institutional Review Board

able 1linical and valve structure information in the 120 quinquagenarians havi

imultaneous coronary artery bypass grafting

Year Number ofAVRs for

AS atBUMC

Number ofQuinguagenarians

Age (year)Range (mean)

Men W

993 31 2 52, 53 (53) 2994 50 1 51 1995 44 6 51–59 (56) 6996 56 8 51–59 (56) 4997 51 8 50–58 (54) 5998 68 6 51–59 (55) 5999 110 11 50–57 (54) 9000 112 14 51–59 (55) 11001 98 8 51–59 (54) 6002 110 9 52–58 (55) 7003 136 15 50–59 (55) 7004 120 17 50–59 (55) 9005 126 15 50–59 (55) 12

1,112 120 50–59 (55) 84(11%) (70%)

*Includes only patients surviving �60 days after valve replacement.†Two patients died 11 and 12 days after operation.‡Number of patients in whom the valve was weighed.AS � aortic stenosis; AVR � aortic valve replacement; BAV � b

ndeterminate; M � man; TAV � tricuspid; UAV � unicuspid; W � wo

able 2omparison of the 120 quinquagenarians having aortic valve replacementrafting

ear Without Coro

Number Having AVR(M:W)

Length of Stay* (days)Range (mean � SD)

Total

(M:W)

993 2 (2:0) 7, 8 (7.50 � 0.71) 0994 1 (1:0) 6 0995 1 (1:0) 7 0996 4 (3:1) 5–14 (7.50 � 4.36) 1 (1:0)997 5 (3:2) 5–31 (12.50 � 12.48) 3 (2:1)998 3 (3:0) 4–5 (4.33 � 0.58) 0999 9 (7:2) 3–7 (5.22 � 1.30) 2 (2:0)000 6 (4:2) 3–14 (7.67 � 4.08) 1 (0:1)001 4 (4:0) 4–5 (4.50 � 0.58) 0002 7 (5:2) 4–13 (7.43 � 3.10) 0003 11 (5:6) 4–11 (6.82 � 2.56) 0004 12 (6:6) 4–11 (5.58 � 2.11) 0005 11 (9:2) 3–8 (5.00 � 1.55) 0

76 (53:23) 3–31 (6.41 � 3.80) 7 (5:2)(63%) (9%)

*These data only include early survivors.— � no information available or not applicable; AVR � aortic valve

t Baylor University Medical Center. p

esults

ata in the 120 quinquagenarians are summarized in Tablesand 2. The native stenotic aortic valve was replaced withbioprosthesis in 30 (25%) patients and with a mechanicalrosthesis in the remaining 90 (75%) patients. Of the 120

ic valve replacement for isolated aortic stenosis with or without

CoronaryArteryBypassGrafting

Died Interval (years) AVR-Death*Range (mean � SD)

�60 days �60 days

0 0 0 —0 0 0 —5 0 2 9.19, 11.53 (10.36 � 1.65)4 0 1 3.833 1 2 6.95, 9.60 (8.28 � 1.87)3 1 0 —2 0 2 6.59, 7.02 (6.81 � 0.30)8 0 4 2.79–5.79 (4.63 � 1.42)4 0 2 0.18, 0.31 (0.25 � 0.09)2 0 0 —4 0 1 0.365 0 0 —4 0 1 0.21

44 2† 15 0.18–11.53 (4.95)(37%) (2%) (13%)

BUMC � Baylor University Medical Center; DC � discharge; I �

tic stenosis without-vs-with simultaneous coronary artery bypass

rtery Bypass Grafting

ied UAV (M:W) BAV (M:W) TAV (M:W)

days �60 days

W) (M:W)

— 0 2 (2:0) 0— 0 1 (1:0) 0— 0 1 (1:0) 0

1 (1:0) 1 (1:0) 3 (2:1) 0:0) 2 (1:1) 3 (2:1) 1 (0:1) 1 (1:0)

— 1 (1:0) 2 (2:0) 02 (2:0) 1 (1:0) 8 (6:2) 01 (0:1) 0 4 (3:1) 2 (1:1)

— 2 (2:0) 2 (2:0) 0— 0 7 (5:2) 0— 1 (1:0) 7 (2:5) 3 (2:1)— 3 (1:2) 9 (5:4) 0— 2 (2:0) 9 (7:2) 0

:0) 6 (4:2) 14 (11:3) 56 (38:18) 6 (4:2)) (8%) (18%) (74%) (8%)

ent; M � man; W � woman.

ng aort

omen

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icuspid;

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atients, 84 (70%) were men and 36 (30%) were women.

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imultaneous CABG was performed in 44 (37%) patientsFigure 1). Of the 2 patients dying within 60 days of AVR,

died 11 days and the other patient 12 days after theperation. In total, 2 (2%) patients died �60 days of AVRnd an additional 15 patients (13%) at later periods. Of theatients surviving �60 days, follow-up information was

able 1continued)

Aortic Value Structure

UAV(M:W)

BAV(M:W)

TAV(M:W)

Unicuspid

Men Women

0 2 (2:0) 0 — —0 1 (1:0) 0 — —

2 (2:0) 1 (1:0) 3 (3:0) — —1 (1:0) 7 (3:4) 0 — —3 (2:1) 4 (2:2) 1 (1:0) — —1 (1:0) 4 (4:0) 1 (0:1) 7.70 —1 (1:0) 10 (8:2) 0 3.33 —

0 10 (8:2) 4 (3:1) — —2 (2:0) 4 (3:1) 2 (1:1) 3.93, 4.17 (4.05) —

0 9 (7:2) 0 — —1 (1:0) 9 (3:6) 5 (3:2) 4.07 —4 (1:3) 11 (6:5) 2 (2:0) 5.03 2.22–4.30 (3.183 (3:0) 12 (9:3) 0 1.72–5.44 (3.58) —

18 (14:4) 84 (57:27) 18 (13:5) 1.72–7.70 (4.33) 2.22–4.30 (3.18(15%) (70%) (15%) 9‡ 3‡

able 2continued)

With Coronary A

Number Having AVR(M:W)

Length of Stay* (days)Range (mean � SD)

Total �

(M:W) (

0 — —0 — —

5 (5:0) 4–7 (5.80 � 1.30) 2 (2:0)4 (1:3) 5–11 (6.75 � 2.87) 03 (2:1) 4–6 (5.00 � 1.00) 03 (2:1) 4–7 (5.50 � 2.12) 1 (1:0) 12 (2:0) 5, 12 (8.50 � 4.95) 08 (7:1) 5–21 (9.63 � 6.63) 3 (3:0)4 (2:2) 9–61 (27.75 � 24.38) 2 (1:1)2 (2:0) 6, 13 (9.50 � 4.95) 04 (2:2) 4–8 (6.00 � 1.83) 1 (0:1)5 (3:2) 6–19 (10.40 � 5.03) 04 (3:1) 7–12 (9.00 � 2.16) 1 (0:1)

44 (31:13) 4–61 (9.72 � 9.61) 10 (7:3) 1(37%) (23%)

vailable in all 118 patients. As of December 2006, 103 f

86%) have survived from 1.05 to 13.52 years (mean 5.53 �.33) (Figure 2). Log-rank test results indicated that lateurvival curves were statistically equivalent for men andomen (p � 0.43, n �118), for patients with low peak

ransvalvular gradient (�50 mm Hg) and high peak trans-alvular gradients (�50 mm Hg) (p � 0.08, n � 73), and

ic Value Weight (g) Range (mean)

Bicuspid Tricuspid

Men Women Men Women

— — — —— — — —— — — —— — — —— — — —

4–4.50 (3.18) — — 1.700–5.50 (3.54) 0.90, 2.36 (1.63) — —4–4.40 (2.62) 2.94, 3.49 (3.22) 1.23–2.63 (1.81) 1.725–4.14 (3.24) 4.97 1.19 2.209–5.06 (3.48) 1.52, 1.99 (1.76) — —9–2.20 (1.61) 1.12–4.94 (2.38) 1.71–1.77 (1.75) 1.74, 1.80 (1.77)5–4.25 (3.58) 0.73–2.99 (1.86) 1.48, 1.57 (1.53) —0–6.44 (3.15) 1.53–2.04 (1.74) — —9–6.44 (3.14) 0.73–4.97 (2.23) 1.19–2.63 (1.66) 1.70–2.20 (1.83)

47‡ 21‡ 9‡ 5‡

ypass Grafting

UAV (M:W) BAV (M:W) TAV (M:W)

�60 days

(M:W)

— — — —— — — —

2 (2:0) 2 (2:0) 0 3 (3:0)— 0 4 (1:3) 0— 0 3 (2:1) 00 0 2 (2:0) 1 (0:1)

— 0 2 (2:0) 03 (3:0) 0 6 (5:1) 2 (2:0)2 (1:1) 0 2 (1:1) 2 (1:1)

— 0 2 (2:0) 01 (0:1) 0 2 (1:1) 2 (1:1)

— 1 (0:1) 2 (1:1) 2 (2:0)1 (0:1) 1 (1:0) 3 (2:1) 09 (6:3) 4 (3:1) 28 (19:9) 12 (9:3)(20%) (9%) (64%) (27%)

Aort

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Died

60 days

M:W)

——0——(1:0)—00

—0—0

(1:0)(2%)

or patients having simultaneous CABG and patients not

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aving CABG (p � 0.35, n � 118). The unadjusted analysisndicated that late survival curves were statistically differentor patients with a unicuspid/bicuspid and tricuspid valvetructure (p � 0.001, n � 118). Figures 3 and 4 show thenadjusted survival Kaplan-Meier plots comparing patientsith versus without simultaneous CABG and those withnicuspid/bicuspid versus 3-cuspid aortic valves.

Length of stay in the hospital in the 118 patients whourvived the operative period ranged from 3 to 61 days

igure 1. Number of quinquagenarians having aortic valve replacement for aithout simultaneous coronary bypass grafting.

igure 2. Number of quinquagenarians surviving and not surviving aortic vypass grafting) at Baylor University Medical Center 1993 to 2005 (followear of operation.

mean 7.62) and in the 2 who died early, 11 and 12 days, H

espectively. Hospital stay in 43 having simultaneousABG averaged 3 days longer than in the 75 not havingABG (4 to 61 days [mean 9.72 � 9.61] vs 3 to 31 days

mean 6.41 � 3.80], respectively, crude p � 0.001).The transvalvular peak systolic pressure gradient in the

atients without simultaneous CABG averaged 62 � 27 mmg and in patients having concomitant CABG, 50 � 24 mmg, (crude p � 0.45); the mean systolic pressure gradients

anged from 13 to 91 mm Hg (average 50) and 10 to 77 mm

lve stenosis at Baylor University Medical Center 1993 to 2005 with versus

lacement for aortic stenosis (with or without simultaneous coronary artery0 December 2006). Most of the deaths occurred 1 or more years after the

ortic va

alve rep-up to 3

g (average 40) (crude p � 0.52), respectively; the calcu-

lar1(

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ts with


ated aortic valve area, from 0.40 to 1.66 cm2 (mean 0.75)nd from 0.40 to 1.24 cm2 (mean 0.79) (crude p � 0.04),espectively; and the left ventricular ejection fraction from0% to 75% (mean 53) and from 15% to 68% (mean 49)crude p � 0.34), respectively.

Figure 3. Kaplan-Meier survival curves comparing patients receiving

Figure 4. Kaplan-Meier survival curves comparing patien

Another tool providing some evidence of the severity of u

he AS is gained by the weight of the operatively excisedalves.5–8 (Previous studies have shown that men with ASave heavier valves than women and that congenitally uni-uspid and bicuspid stenotic aortic valves are heavier than-cuspid stenotic aortic valves.5–8) The operatively excised

neous coronary artery bypass grafting with patients not receiving it.

uni/bicuspid and patients with tricuspid valve structures.

nicuspid aortic valves in the 9 men in the present study

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anged from 1.72 to 7.70 g (mean 4.33); the bicuspid valvesn the 47 men, from 0.89 to 6.44 g (mean 3.14), and thericuspid aortic valves in the 9 men, from 1.19 to 2.63 gmean 1.66). In contrast, the 3 unicuspid valves in womeneighed 2.22, 3.03, and 4.30 g (mean 3.18); the bicuspidalves in the 21 women, from 0.73 to 4.97 g (mean 2.23),nd the tricuspid aortic valves in the 5 women, from 1.70 to.20 g (mean 1.83). Of the 120 patients, 18 (15%) hadongenitally unicuspid aortic valves, 84 (70%) congenitally

igure 5. Number of quinquagenarians surviving and not surviving aortic va� simultaneous coronary artery bypass grafting) at Baylor University Meccurred 1 or more years after the year of operation.

2

1

1

1

0

1

2

3

4

5

1993 1994 1995 1996 1997 1998

Ye

Nu

mb

er o

f P

atie

nts

Alive

Dead

(n=18)

igure 6. Number of quinquagenarians surviving and not surviving aorimultaneous coronary artery bypass grafting) at Baylor University Mediccurred 1 or more years after the year of operation.

icuspid, and 18 (15%), 3-cuspid valves (Figures 5 to 7). s

iscussion

he present study focused on a large group of quinquage-arians having AVR for AS at the same US medical centeruring a recent 13-year period. Early mortality analysis�60 days) was not possible because only 2 of the 120atients died early. Unadjusted analysis indicated that gen-er, preoperative severity of the AS, or performance ofimultaneous CABG had no effect on late survival. Late

acement for aortic stenosis involving a unicuspid and bicuspid aortic valveenter 1993 to 2005 (follow-up to 30 December 2006). Most of the deaths

3

2

1

5

2

2000 2001 2002 2003 2004 2005

eration

e replacement for aortic stenosis involving a tricuspid aortic valve (�ter 1993 to 2005 (follow-up to 30 December 2006). Most of the deaths

lve repldical C

1999

ar of Op

tic valvcal Cen

urvival, however, was significantly better in patients with

ua

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Fgiat


nicuspid/bicuspid valves than in patients with tricuspidortic valves.

The positive features of the present study include aelatively large number of quinquagenarians, relativelyong post-AVR follow-up, preoperative hemodynamicata in most patients, and knowledge of aortic valvetructure and weight. That all valves were examined byhe same individual (WCR) produced uniformity notvailable if valve structure was that recorded in the op-

igure 7. Photographs of 4 operatively excised stenotic aortic valves: (A) Cradient was 60 mm Hg, the calculated aortic valve area, 0.90 cm2, and thn whom the valve weighed 1.75 g. (C) Congenitally bicuspid valve from 5ortic valve area, 0.74 cm2, and the valve weight, 2.20 g. (D) Tricuspid vahe calculated aortic valve area, 0.89 cm2, and the valve weight, 1.76 g.

rative note by a number of different cardiac surgeons, i

ach of whom might have different views of what con-tituted a congenitally malformed or a 3-cuspid aorticalve with fusion of 1 or more aortic valve commissures.WCR has been a student of aortic valve structure for40 years.) The negative features of the present study

nclude lack of information on preoperative and postop-rative symptoms and functional class, on early postop-rative complications, co-morbidities, late quality of life,umbers of epicardial coronary arteries narrowed �50%

itally unicuspid valve from a 50-year-old man in whom the mean systolicweight, 4.07 g. (B) Congenitally bicuspid valve from a 50-year-old man

old man in whom the peak systolic gradient was 18 mm Hg, the calculatedm a 59-year-old man in whom the peak systolic gradient was 38 mm Hg,

ongene valve9-year-lve fro

n diameter, and causes of late death postoperatively.

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. Roberts WC. Ko JM. Matter GJ. Aortic valve replacement for aorticstenosis in nonagenarians. Am J Cardiol 2006;98:1251–1253.

. Roberts WC, Ko JM, Garner WL, Filardo G, Henry AC, Hebeler RF Jr,Matter GJ, Hamman BL. Valve structure and survival in octogenarianshaving aortic valve replacement for aortic stenosis (�aortic regurgita-tion) with versus without coronary artery bypass grafting at a single USmedical center (1993 to 2005). Am J Cardiol 2007;100:489–495.

. Roberts WC, Ko JM, Filardo G, Henry AC, Hebeler RF JR, Cheung EH,Matter GJ, Hamman BL. Valve structure and survival in septuagenar-ians having aortic valve replacement for aortic stenosis (�aortic regur-gitation) with versus without coronary artery bypass grafting at a singleUS medical center (1993 to 2005). Am J Cardiol 2007;100:1157–1165.

. Roberts WC, Ko JM, Filardo G, Henry AC, Hebeler RF JR, Cheung EH,Matter GJ, Hamman BL. Valve structure and survival in sexagenarianshaving aortic valve replacement for aortic stenosis (�aortic regurgita-tion) with versus without coronary artery bypass grafting at a single US
medical center (1993 to 2005). Am J Cardiol 2007;100:1286–1292.
. Roberts WC, Ko JM. Weights of operatively excised stenotic unicuspid,bicuspid, and tricuspid aortic valves and their relation to age, sex, bodymass index, and presence or absence of concomitant coronary arterybypass grafting. Am J Cardiol 2003;92:1057–1065.

. Roberts WC, Ko JM. Relation of weights of operatively excised stenoticaortic valves to preoperative transvalvular peak systolic pressure gra-dients and to calculated aortic valve areas. J Am Coll Cardiol 2004;44:1847–1855.

. Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, andtricuspid aortic valves in adults having isolated aortic valve replacementfor aortic stenosis, with or without associated aortic regurgitation. Cir-culation 2005;111:920–925.

. Roberts WC, Ko JM, Hamilton C. Comparison of valve structure, valveweight, and severity of the valve obstruction in 1849 patients havingisolated aortic valve replacement for aortic valve stenosis (with orwithout associated aortic regurgitation) studied at 3 different medical
centers in 2 different time periods. Circulation 2006;114:422–429.

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Depression, Anxiety, and Quality of Life in Patients WithObstructive Hypertrophic Cardiomyopathy Three Months

After Alcohol Septal Ablation

Eva R. Serber, PhDa,*, Samuel F. Sears, PhDa, Christopher D. Nielsen, MDc,William H. Spencer III, MDc, and Karen M. Smith, MDb

Patients with obstructive hypertrophic cardiomyopathy are presumed to have poor qualityof life (QOL) and distress related to their cardiac symptoms and functional limitations.Alcohol septal ablation (ASA) is designed to improve heart function and reduce cardiacsymptoms. The purpose of this study was to examine psychosocial factors and QOL inpatients with obstructive hypertrophic cardiomyopathy before and 3 months after ASA.Twenty-two adult participants (mean age 57 � 14 years, 59% women, 100% Caucasian,67% married) were recruited during their initial evaluations or scheduled index hospital-izations for ASA. Psychosocial and medical measures were collected before and 3 monthsafter ASA. The results indicated that before ASA, 57% of patients reported clinically relevantlevels of depression (Center for Epidemiologic Studies Depression Scale score >16), symptomsof anxiety, and reduced QOL. Repeated-measures analyses of variance revealed that ASAis an effective procedure in reducing disease severity (i.e., peak left ventricular outflow tractgradient, septal thickness, posterior wall thickness) (p � 0.001 to 0.05), depression (p �0.005), and anxiety (p � 0.029) and improving cardiac-specific QOL (p < 0.001) andgeneric physical health-related QOL (p � 0.009). Changes in satisfaction with life,optimism, and generic mental health-related QOL were not significant (p � 0.143 to0.899). In conclusion, significant psychological distress and compromised well-beingwere present in this sample of pre-ASA patients with obstructive hypertrophic cardio-myopathy. After ASA, significant reductions in psychological distress and improve-ments in well-being and echocardiographic parameters indicating disease severity weredemonstrated. These results suggest that patients perceived broad health benefits fromASA in short-term follow-up. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol
2007;100:1592–1597)
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lcohol septal ablation (ASA) is still a relatively new treat-ent for patients with obstructive hypertrophic cardiomy-

pathy (HC), and therefore, evaluating the procedure from aiopsychosocial perspective can determine whether ASA isn effective treatment from a patient’s point of view.ealth-related quality of life (QOL) has been examined,ith results indicating improvement in QOL from before to

fter ASA.1 Little is known about other psychologicalactors, such as depression, anxiety, life satisfaction, andptimism. In the present study, we examined if there werehanges in psychosocial parameters (i.e., depression, anxiety,atisfaction with life, and optimism) and QOL in patients withbstructive HC from before to 3 months after ASA.

aDepartment of Clinical Health Psychology and bDivision of Cardio-ascular Medicine, University of Florida, Gainesville, Florida; and cDivi-ion of Cardiology, Medical University of South Carolina, Charleston,outh Carolina. Manuscript received March 5, 2007; revised manuscripteceived and accepted June 13, 2007.

cE-mail address: [email protected] (E.R. Serber).

ethods

here were 22 adult participants with obstructive HC fromsites: Shands Teaching Hospital at the University of Flor-

da (n � 9) and the Medical University of South Carolinan � 13). Patients were recruited during their initial outpa-ient clinic evaluations or scheduled index hospitalizationsor ASA. To be eligible for ASA, patients had to meet theollowing criteria: asymmetrical septal hypertrophy, septalall thickness �1.6 cm or a septal wall/posterior wall ratiof 1.3, systolic anterior motion of the mitral valve contrib-ting to the obstruction, and peak left ventricular outflowract (LVOT) gradient at rest �30 mm Hg or peak provokedVOT gradient �50 mm Hg.2 In addition, many investiga-

ional studies include a criterion of New York Heart Asso-iation functional class �3,3 which was also observed athese 2 centers. Patients were excluded from the study ifhey were aged �18 years, were not able to read and writenglish, or could not complete the 3-month follow-up as-essment.

After approval was received from the institutional reviewoard at each of the sites, consecutive patients were re-ruited and provided informed consent after checking intoheir outpatient cardiology medical clinics. After written
onsent was obtained, the participants completed a packet of
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1593Cardiomyopathy/Psychological Well-Being in Hypertrophic Cardiomyopathy

esearch questionnaires examining QOL and psychologicalactors (baseline). Participants completed the questionnairesn their own while at the clinics. The packets were returnedefore leaving the clinics on the same day, and participantsere then followed prospectively. Standard clinical care forSA follow-up is 3 months after ASA, and at that time, the

ame research questionnaires were readministered to thearticipants during their routine clinic visits. The question-aires used in the present study were part of a researchacket that took approximately 30 minutes to complete.nformation was also obtained from medical records (in-luding echocardiographic data) available through the pa-ients’ residing institutions of care. For ethical reasons,uring standard clinical care or the research protocol, if aatient needed (i.e., depression score �26 or reported sev-ral depressive symptoms during evaluation) or requestedsychological services, an appropriate referral was made.o control for treatment effects, throughout the study, par-

icipants were asked if they had or were currently receivingsychotherapy or other forms of psychiatric treatment.

A background information questionnaire (designed byroject staff members) was included at each of the patients’ssessments. This measure is a brief self-report tool toacilitate the collection of demographic information from

able 1emographic information and medical histories of patients withbstructive hypertrophic cardiomyopathy collected before alcohol septalblation (n � 22)

ariable n Mean � SD or %

ge (yrs) 22 57 � 14en 9 41%aucasian 22 100%ingle 4 19%eparated/divorced/widowed 3 14%arried/remarried/living with

partner14 67%

ave children (yes) 15 71%mployed full-time 9 41%omemaker/unemployed 3 14%isability/financial assistance 4 18%etired 6 27%igh school education 7/17 41%ore than high school

(undergraduate degree)7/17 41%

ore than undergraduate degree 3/17 18%ncome�$29,999 5/19 26%$30,000–$59,999 8/19 42%�$60,000 6/19 32%ngina pectoris 17 77%itral regurgitation 16 73%eart failure 13 59%oronary artery disease 8 36%trial fibrillation 4 18%yocardial infarction 1 5%entricular tachycardia 1 5%acemaker 2 9%mplantable cardioverter defibrillator 2 9%revious ASA procedures 3 14%

linic visits and medical records. C

A medical record review form (designed by project staffembers) was used to collect medical information from

atients’ medical records to facilitate data collection. Infor-ation was collected at baseline and at 3-month follow-up,

btained from the patients’ echocardiograms and clinicotes.

The Short Form-12 Health Survey (SF-12)4 is a genericeasure of health status and was used to measure generalOL. The SF-12 can be separated into 2 components: phys-

cal component summary and mental component summary,hich are comparable and highly correlated with Shortorm-36 Health Survey scores (range 0.63 to 0.97).4,5 Test-etest reliability in the United States was 0.89 for the phys-cal component summary and 0.77 for the mental compo-ent summary.5 Additionally, internal consistency has beenemonstrated to be 0.77 and 0.80, respectively.6

The Minnesota Living With Heart Failure Questionnaire7

as used to measure cardiac-specific QOL. It includes com-onents of symptom distress and function.8 Scores rangerom 0 to 105. Lower scores indicate less disability fromymptoms or, in other words, better QOL. The outcomeariable was the total score. Cronbach’s � for the full scales 0.87.9

The Center for Epidemiologic Studies Depression ScaleCES-D)10 is a 20-item self-report measure that assessesepression symptomatology. Respondents indicate how fre-uently they have experienced each symptom in the pasteek. The total score can range from 0 to 60 and reflects theumber of depressive symptoms and their duration. In theeneral population, a standard cut-off score of 16 can besed to indicate clinically significant symptoms of depres-ion.10 Heart disease and primary care research has demon-trated that CES-D scores can be grouped into 3 depressionlassifications: mild or subclinical symptoms (0 to 15),oderate symptoms (16 to 26), and severe symptoms

�26), which has shown to be clinically useful.11,12 The

able 2urrent medical information of patients with obstructive hypertrophicardiomyopathy before alcohol septal ablation, including proceduralata (n � 22)

ariable Mean � SD Minimum Maximum

eart rate (beats/min) 77 � 14 49 110ystolic blood pressure (mm Hg) 134 � 20 87 160iastolic blood pressure

(mm Hg)68 � 11 46 86

jection fraction (%) 70 � 8 55 85entricular septal thickness

(mm)20 � 6 14 36

eft ventricular posterior wallthickness (mm)

14 � 4 9 22

eak LVOT gradient at rest(mm Hg)

66 � 40 0 150

eak provoked LVOT gradient(mm Hg)

108 � 57 20 210

o. of arteries injected 1 � 0.3 1 2thanol administered (ml)First 2 � 0.7 1 4Second* 2 � 0 2 2

* n � 2.

ES-D has a high internal reliability coefficient of 0.85.

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The Revised State Trait Personality Inventory–Traitcale13 is a self-report measure used to assess dispositionalnxiety. In the present study, we used the first 3 subscalesanxiety, anger, and depression) of the original measureexcluding the curiosity subscale). With the 30 items, totalcores range from 30 to 120, with higher scores indicatinggreater presence of dispositional anxiety, anger, and de-

ression.14 This measure was selected for research purposesecause the State-Trait Anxiety Inventory was used as partf standard clinical psychology care when indicated.

The Satisfaction With Life Scale15 was designed to as-ess overall satisfaction with life. It is a 5-item measure withossible scores ranging from 5 to 35. Higher scores indicatereater satisfaction with life. Strong reliability has beenemonstrated (Cronbach’s � � 0.87), and 2-month test-

igure 1. Changes in scores from the Satisfaction With Life Scale, the Liferientation Test–Revised (optimism), and the physical component sum-ary and mental component summary scale scores from the Short Form-12ealth Survey (SF-12) from before to 3 months after ASA. Higher scores

ndicate better functioning. *p �0.05; **p �0.01.

able 3ean scores across time from before to three months after alcohol septal

ariable Before ASA(mean � SD

iomedicalPeak LVOT gradient at rest† (mm Hg) 66 � 40Peak provoked LVOT gradient† (mm Hg) 108 � 57Ventricular septal thickness† (mm) 20 � 6Left ventricular posterior wall thickness* (mm) 14 � 4Heart rate (beats/min) 78 � 15Systolic blood pressure (mm Hg) 136 � 18Diastolic blood pressure (mm Hg) 69 � 11sychosocialDepression† 22 � 15Anxiety* 61 � 22Life satisfaction 22 � 9Optimism 16 � 6Cardiac-specific QOL† 54 � 27Physical health summary†,‡ 30 � 7Mental health summary†,‡ 43 � 13

* p �0.05; † p �0.01.‡ Short Form-12 Health Survey scale (n � 14).

etest reliability is 0.82. w

The Life Orientation Test–Revised16 is a 6-item self-eport questionnaire (with 4 additional filler items) thatssesses generalized expectancies for positive comparedith negative outcomes. The range of scores is 0 to 24, withigher scores indicating more positive dispositions. Theife Orientation Test–Revised has an acceptable reported

eliability value of 0.78. Test-retest reliability of the instru-ent has been shown across 4 to 28 months to range from

.56 to 0.79.16

All analyses were performed with the statistical softwareackage SPSS version 14.0 (SPSS, Inc., Chicago, Illinois).escriptive analyses were first conducted on the sample ofatients with obstructive HC before ASA. Categorical vari-bles are reported as percentages and continuous variabless mean � SD. Repeated-measures analyses of variance

igure 2. Changes in scores from the Center for Epidemiologic Studiesepression Scale, the Revised State Trait Personality Inventory–Traitcale, and the Minnesota Living With Heart Failure Questionnaire fromefore to 3 months after ASA. Lower scores indicate better functioning.OL � quality of life. *p �0.05; **p �0.01.

n (n � 22)

3 Months AfterASA (mean � SD)

Effect Size(Hedges’s g)

ObservedPower

22 � 23 1.33 99%35 � 29 1.56 99%16 � 6 0.56 94%13 � 3 0.50 50%73 � 10 0.38 33%

135 � 22 0.05 5%71 � 9 0.20 18%

14 � 11 0.65 58%54 � 17 0.34 60%22 � 9 0.02 5%17 � 6 0.13 15%28 � 25 1.00 99%40 � 12 1.05 80%48 � 14 0.36 30%

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onths after ASA. Pillai’s trace F is reported because it ismore conservative F test. Significance was set at � � 0.05;xact p values for each analysis are reported in the “Results”ection and the tables. Effect sizes were calculated usingedges’s g, which includes an adjustment for small sampleias.17 Observed power is reported from the repeated-mea-ures analysis of variance results and is included to provideetter estimates for future investigations, because this was ailot study. Sufficient power to reject the null hypothesis isonsidered to be 0.80 (80%).

esults

hirty-four participants enrolled in the study and completedaseline questionnaires. Twelve participants were lost to fol-ow-up because they did not return to the clinics for theirtandard cardiology clinic follow-up appointments and there-ore did not receive and complete the packet of question-aires, nor did they undergo echocardiography. Reasons forttrition included no-shows and cancellations for-month follow-up appointments (15% [n � 5]) and lossor unknown reasons (21% [n � 7]). There were noifferences between completers and noncompleters onre-ASA demographic, medical, or psychosocial vari-bles (p � 0.09 to 0.89).

All data reported include the 22 participants who completeduestionnaires before and 3 months after ASA (mean age 57 �4 years). Participants were all Caucasian, predominantly women59%), and predominantly married (67%). See Table 1 foromplete demographic information and cardiac histories.any patients had co-morbid cardiac conditions in addition

o and/or related to obstructive HC. The most common werengina, mitral regurgitation, and heart failure, all of whichre typical for patients diagnosed with obstructive HC. Noatient had a previous myectomy, and 86% of the sampleeported medication management only. There were no pre-ious cardiac arrests. See Table 2 for current medical dataefore ASA, as well as procedural data for ASA. Thereere no significant differences in demographic, medical, orsychosocial variables between participants at the Univer-ity of Florida and those at the Medical University of Southarolina.

Approximately 41% of participants reported mild or sub-linical levels of depressive symptoms (CES-D score �16).owever, 19% reported moderate or clinically relevant

ymptoms (CES-D score 16 to 26), and 38% reported severeepressive symptoms (CES-D score �26). On the basis ofelf-report, 18% reported that they were currently receivingsychotherapy. The percentage of patients with obstructiveC who were receiving some kind of psychiatric treatment

therapy or medication), obtained by self-report or medicalhart review, was 46%.

The average follow-up time was 3.5 � 0.85 months,ongruent with the design of the study (i.e., 3-month follow-p), and corresponded to the treatment plan of standardlinical intervention care. Several significant interventionffects were found from before to 3 months after ASA, withll changes demonstrating improvements. See Table 3 foreans, SDs, effect sizes, and observed power across time

or biomedical, psychosocial, and QOL indexes. Figure 1
llustrates changes in life satisfaction, optimism, and generic d
hysical and mental health-related QOL from before to 3onths after ASA. Figure 2 illustrates changes in depres-

ion, anxiety, and cardiac-specific QOL from before to 3onths after ASA. To determine whether improvements in

ariables were due solely to improved disease state (i.e.,eak LVOT gradient at rest), difference scores (beforeSA � 3 months after ASA) were calculated among out-

ome variables. Then, using these newly created scores,eak LVOT gradient at rest was correlated with psychoso-ial, generic, and cardiac-specific QOL scores. The onlyignificant relation was that between the change in thehysical component summary of the SF-12 and the changen LVOT gradient at rest (rp � �0.597, p � 0.041). Thisuggests that improvement in LVOT gradient was not solelyictating the reductions in depression and improvements inOL. Correlating baseline scores, there were no significant

elations with LVOT gradient at rest, and therefore, it wasot used as a covariate in the repeated-measures analyses ofariance.

As expected, according to the purpose of ASA, the med-cal outcomes of peak LVOT gradient at rest (Pillai’s trace[1, 19] � 27.85, p � 0.001) and peak provoked LVOTradient (Pillai’s trace F[1, 14] � 31.68, p � 0.001) de-reased dramatically. There were significant improvementsn ventricular septal thickness (Pillai’s trace F[1, 16] �3.91, p � 0.002) and left ventricular posterior wall thick-ess (Pillai’s trace F[1, 15] � 4.40, p � 0.053). There wereo significant changes in heart rate or in systolic and dia-tolic blood pressure (p � 0.129 to 0.869).

Among the psychosocial variables, there was a signifi-ant intervention effect for depression (Pillai’s trace F[1,0] � 10.150, p � 0.005). In terms of the prevalence rate oflinically relevant depression, those who reported clinicallyelevant depression at baseline (57%) reduced to 28%. Anx-ety also demonstrated a significant reduction in symptomsrom before to 3 months after ASA (Pillai’s trace F[1, 20] �.562, p � 0.029). There were no significant interventionffects for satisfaction with life (p � 0.899) and optimismp � 0.346). There were also no changes in psychological andsychiatric treatments (p � 0.332 to 0.579) (see Table 4 forates before and after ASA).

Similarly to medical outcomes, cardiac-specific QOL

able 4ummary of psychiatric history of patients before and three months afterlcohol septal ablation

ariable (No/Yes) Before ASA 3 MonthsAfter ASA

ast psychotherapy (SR) 1 (5%) 3 (15%)ast psychotropic medications (SR) 5 (23%) 4 (18%)urrent psychotherapy (SR) 4 (18%) 5 (23%)urrent psychotropic medications (SR) 4 (18%) 5 (23%)ntidepressant prescription (CR) 5 (23%) 6 (27%)nxiolytic prescription (CR) 5 (23%) 6 (27%)verall treatment (SR or CR) 10 (46%) 11 (50%)ES-D score �16, overall treatment(SR or CR)

11/22 (50%) 4/7 (57%)

There were no significant changes over time (p � 0.082 to 1.000).CR � chart review; SR � self-report.

emonstrated highly significant improvements from before

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o 3 months after ASA. Examining scores on the Minnesotaiving With Heart Failure Questionnaire, cardiac-specificOL improved (Pillai’s trace F[1, 20] � 26.47, p � 0.001).dditionally, scores of physical health (physical component

ummary) on the SF-12 significantly improved (Pillai’srace F[1, 13] � 9.24, p � 0.009). There was no significantntervention effect for the mental health scale (mental com-onent summary) (p � 0.143).

iscussion

his study demonstrated that significant psychological dis-ress and compromised well-being were present in a samplef patients with obstructive HC before ASA. After ASA,ignificant reductions in psychological distress and diseaseeverity (measured using echocardiographic parameters)nd improvements in well-being were established, suggest-ng that patients perceived broad health benefits from ASAn short-term follow-up. Although these data do not addresshe recent dialogue regarding the long-term outcomes ofSA or ASA compared with myectomy,18,19 these data

onfirm the medical evidence that the procedure providesesirable patient outcomes at least in the short-term.

The reductions in depression and anxiety and improve-ents in QOL after ASA warrant further examination andust be interpreted with caution, because this was a small

nd highly select sample of patients with obstructive HC.here are several possible reasons for the improvements in

he current sample. First, their obstructive HC conditionay have been so severe and disruptive that any reduction

n symptoms was perceived as an improvement, and subse-uently, depression and anxiety were reduced and QOL wasmproved. Second, patients experiencing reductions inymptoms are able to engage in more activities, have fewerimitations or impairments, and enjoy their lives more fully,t least relative to before ASA. Third, cardiac symptomsnd psychological symptoms can be difficult to distinguishor patients and health care providers. Cardiac symptomsre reduced, and patients interpret their distress symptomsiminishing. Hypervigilance of symptoms is particularlyommon in cardiac patients,20 which may have been thease in this highly select sample of patients with obstructiveC. A placebo effect could be considered, but a placeboould not change echocardiographic parameters. Patient

elf-report may be influenced by cognitive dissonance,21 asychological theory that suggests that conflicts betweenehavior and beliefs create a sense of discomfort, such thatatients choosing to undergo a relatively new procedure willerceive their post-ASA health status favorably so that it isongruent with all that they have experienced (i.e., diseaseeverity and procedure).

This study was limited by its quasi-experimental designnd its sample size. There was a high attrition rate. Despiteoderate to large effect sizes for most of the variables, the

sychosocial variables were much lower in power relativeo the echocardiographic variables used for disease severity.t was the latter on which this study was powered. Notably,ven with the low power, significant differences stillmerged among some of the psychosocial data. It is be-ieved that this sample is representative of patients with
bstructive HC who undergo ASA, because patients were
ecruited from 2 independent institutions. However, theample may not be representative of all patients with ob-tructive HC or of patients with obstructive HC choosingther treatment options. All patients in this study wereeverely ill and symptomatic, seeking out a relatively newreatment.

In conclusion, the primary contribution of this research iso broaden the range of health outcomes of this medicalntervention and to stimulate future investigators to beginocusing on psychosocial outcomes in addition to traditionaledical end points.

cknowledgment: We thank Christine N. Slifka, RN,SN, research and clinical nurse coordinator at Medicalniversity of South Carolina, and Gwen M. Thomas, RN,

linical coordinator, and Evette Hutchinson, interventionalardiology assistant at the University of Florida, withouthom patient recruitment and data collection would notave been possible.

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Prevalence of an Increased Ascending and Descending Thoracic Aorta DiameterDiagnosed by Multislice Cardiac Computed Tomography in Men Versus Womenand in Persons Aged 23 to 50 Years, 51 to 65 Years, 66 to 80 Years, and 81 to 88

Years

Sarah Kaplan, MDa, Wilbert S. Aronow, MDa,*, Hoang Lai, MDa, Albert J. DeLuca, MDa,Melvin B. Weiss, MDa, Hajir Dilmanian, MDa, David Spielvogel, MDb,

Steven L. Lansman, MD, PhDb, and Robert N. Belkin, MDa

The prevalence of increased ascending thoracic aortic diameter (AAD) and increaseddescending thoracic aortic diameter (DAD) diagnosed using multislice cardiac computedtomography was investigated in 624 consecutive patients at an academic cardiology prac-tice in 2006. Increased AAD (>3.7 cm) was present in 71 of 361 men (20%) and in 23 of263 women (9%) (p <0.001). Increased DAD (>3.0 cm) was present in 26 of 339 men (8%)and in 8 of 258 women (3%) (p <0.02). Increased AAD was present in (1) 7 of 96 patients(7%) aged 23 to 50 years, (2) 22 of 234 patients (9%) aged 51 to 65 years, (3) 53 of 263patients (20%) aged 66 to 80 years, and (4) 12 of 31 patients (39%) aged 81 to 88 years(p <0.005 comparing groups 3 and 1; p <0.001 comparing groups 4 and 1, groups 4 and2, and groups 3 and 2; p <0.02 comparing groups 4 and 3). Increased DAD was presentin (1) 0 of 96 patients (0%) aged 23 to 50 years, (2) 5 of 227 patients (2%) aged 51 to65 years, (3) 21 of 244 patients (9%) aged 66 to 80 years, and (4) 8 of 30 patients (27%)aged 81 to 88 years (p <0.005 comparing groups 3 and 1, groups 3 and 2, and groups4 and 3; p <0.001 comparing groups 4 and 1 and groups 4 and 2). In conclusion, menhave a higher prevalence of increased AAD and DAD than women, and increasing ageincreases the prevalence of increased AAD and DAD. © 2007 Elsevier Inc. All rights
reserved. (Am J Cardiol 2007;100:1598 –1599)
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here are limited data on measurements of the diameterf the ascending and descending thoracic aorta by mul-islice computed cardiac tomography (CT). Hager et al1

tudied 70 adults and Hannuksela et al2 studied 77 adultssing CT. We are reporting the prevalence of enlargedscending thoracic aortic diameter (AAD) in 624 consecu-ive outpatients seen at an academic cardiology practiceuring 2006 and the prevalence of enlarged descendinghoracic aortic diameter (DAD) in 597 of these 624 patients96%) who underwent multislice CT for clinical indications.

e are also reporting the prevalence of enlarged AAD andAD in men versus women and in different age groups.

ethods and Results

ix hundred twenty-four consecutive outpatients at an aca-emic cardiology practice underwent multislice CT for clin-cal indications in 2006. Clinical consent for performing CTas obtained from all 624 patients. Of the 624 patients, CTas performed because of positive stress test results in 154atients (25%), because of chest pain in 303 patients (49%),ecause of evaluation of coronary artery disease in 153

aDepartment of Medicine, Cardiology Division, and bDepartment ofurgery, Division of Cardiothoracic Surgery, New York Medical College,alhalla, New York. Manuscript received May 15, 2007; revised manu-

cript received and accepted June 18, 2007.*Corresponding author: Tel: 914-493-5311; fax: 914-235-6274.

nE-mail address: [email protected] (W.S. Aronow).


atients (25%), and because of miscellaneous cardiac con-itions in 14 patients (2%). Multislice CT was performedsing a 64-slice Siemens Somatom Sensation Cardiac scan-er (Siemens Medical Solutions, Forcheim, Germany). Pa-ients were pretreated with oral and/or intravenous � block-rs to achieve heart rates �65 beats/min. The test bolusechnique was used to determine scan timing. Contrast vol-me was determined by scan time and flow rate. Flow ratesf 4 to 6 ml/s were used. Scan collimation was 32 � 0.6 cm,ith dual focal spots for each detector row to allow 64 sliceser rotation.3,4 Rotation time was 330 ms, pitch factor 0.2,ube voltage 120 mV, and effective mAs 750 to 850. Elec-rocardiographic pulsing was used to reduce radiation dose.ated data were reconstructed at 5% intervals from 30% to5% of the RR interval, with 0.6-mm slice thickness and.4-mm increments, for the purpose of coronary artery anal-sis. A large window view to include the descending aortat these reconstruction parameters was used to evaluate thehoracic aorta.

All studies were reviewed by 1 of 2 cardiologistsxperienced in CT. Orthogonal measurements of the as-ending and descending thoracic aorta were generallybtained in axial views at the level of the bifurcation ofhe pulmonary artery. The full extent of each vessel wasoutinely evaluated on review of axial images, or in otherrojections if necessary. If an abnormal dimension that wasarger than that obtained at the level of the pulmonary arteryifurcation was noted, this value was recorded. There was
ot, however, a systematic effort to otherwise record max-
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1599Miscellaneous/Ascending and Descending Thoracic Aortic Diameter

mal dimensions at other sites of the aorta. Measurementsf AAD were obtained in 624 of 624 patients (100%) andf the DAD in 597 of 624 patients (96%). AAD �3.7 cmas considered enlarged.1 DAD �3.0 cm was considered

nlarged.1

Student’s t tests were used for the analysis of continuousariables. Chi-square tests were used for the analysis ofichotomous variables.

Enlarged AAD was present in 94 of 624 patients (15%),nd enlarged DAD was present in 34 of 597 patients (6%).able 1 lists the prevalence of increased AAD and of in-reased DAD in men compared with women. Table 1 alsoists levels of statistical significance.

Table 2 lists the prevalence of increased AAD in patientsged 23 to 50, 51 to 65, 66 to 80, and 81 to 88 years. Tablealso lists levels of statistical significance. Table 2 lists the

able 1revalence of increased ascending thoracic aorta diameter and of

ncreased descending thoracic aorta diameter in men versus women

iameter of Aorta Men Women p Value

ncreased ascending portion* 71/361 (20%) 23/263 (9%) �0.001ncreased descending portion† 26/339 (8%) 8/258 (3%) �0.02

* Increased ascending portion �3.7 cm.† Increased descending portion �3.0 cm.

able 2revalence of increased ascending thoracic aortic diameter and increasedescending thoracic aortic diameter in patients aged 23 to 50, 51 to 65,6 to 80, and 81 to 88 years

ge Group (yrs) Increased AAD* Increased DAD†

1) 23–50 7/96 (7%) 0/96 (0%)2) 51–65 22/234 (9%) 5/227 (2%)3) 66–80 53/263 (20%) 21/244 (9%)4) 81–88 12/31 (39%) 8/30 (27%)

* p �0.005 comparing groups 3 and 1; p �0.001 comparing groups 4nd 1, groups 4 and 2, and groups 3 and 2; p �0.02 comparing groups 4nd 3.

† p �0.005 comparing groups 3 and 1, groups 3 and 2, and groups 4 and; p �0.001 comparing groups 4 and 1 and groups 4 and 2.

revalence of increased DAD in patients aged 23 to 50, 51

o 65, 66 to 80, and 81 to 88 years. Table 2 also lists levelsf statistical significance.

iscussion

ager et al1 measured diameters of the thoracic aorta usingT in 46 men and 24 women aged 17 to 89 years. These

nvestigators found that men had slightly larger diametershan women, and all diameters increased with age. Hannuk-ela et al2 found similar results in 77 adults studied usingT. The strongest correlation seen with thoracic aorta di-meter was with age.2

The data from the present study in a population referredor CT showed that increased AAD diagnosed by multisliceT was present in 20% of 361 men and in 9% of 263omen (p �0.001). Increased DAD was present in 8% of39 men and in 3% of 258 women (p �0.001).

The present study showed that the prevalence of in-reased AAD in a population referred for CT signifi-antly increased with age and was present in 7% of 96atients aged 23 to 50 years, in 9% of 234 patients aged1 to 65 years, in 20% of 263 patients aged 66 to 80ears, and in 39% of 31 patients aged 81 to 88 years. Therevalence of increased DAD also increased with age andas present in none of 96 patients aged 23 to 50 years, in% of 227 patients aged 51 to 65 years, in 9% of 244atients aged 66 to 80 years, and in 27% of 30 patientsged 81 to 88 years.

Patients with enlarged but not aneurysmal AAD or DADhould be followed more closely. The radiation dose asso-iated with CT is considerable and must be considered inerforming follow-up CT.

. Hager A, Kaemmerer H, Rapp-Bernhardt U, Blucher S, Rapp K, Bern-hardt TM, Galanski M, Hess J. Diameters of the thoracic aorta through-out life as measured with helical computed tomography. J ThoracCardiovasc Surg 2002;123:1060–1066.

. Hannuksela M, Lundqvist S, Carlberg B. Thoracic aorta—dilated ornot? Scand Cardiovasc J 2006;40:175–178.

. Raff GL, Gallagher JM, O’Neill W. Diagnostic accuracy of noninvasivecoronary angiography using 64-slice spiral computed tomography. J AmColl Cardiol 2005;46:552–557.

. Leber AW, Becker A, Knez A, von Ziegler F, Sirol M, Nikolaou K,Ohnesorge B, Fayad ZA, Becker CR, Reiser M, et al. Accuracy of64-slice computed tomography to classify and quantify plaque volumesin the proximal coronary system: a comparative study using intravas-
cular ultrasound. J Am Coll Cardiol 2006;47:672–677.

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Responsiveness to Dobutamine Stimulation in Patients With LeftVentricular Apical Ballooning Syndrome

Satomi Fujiwara, MDa,*, Yasuchika Takeishi, MDb, Shogen Isoyama, MDc, Go Aono, MDa,Kaname Takizawa, MDa, Hidehiko Honda, MDa, Tatsushi Otomo, MDa, Mikio Mitsuoka, MDa,Yuko Itoh, MDa, Masayoshi Terashima, MDa, Isao Kubota, MDb, and Taiichiro Meguro, MDa

To investigate the underlying mechanisms of the left ventricular (LV) apical ballooningsyndrome, we evaluated the functional responsiveness to dobutamine stimulation in pa-tients with the syndrome. Over a 22-month period, 11 consecutive patients with the apicalballooning syndrome were referred to our institution. All 11 patients were women and 57to 85 years of age (mean 73 � 10). Among them, 10 patients underwent low-dose dobut-amine echocardiography within 24 hours after admission (17 � 8 hours). Echocardiogra-phy was repeated in the convalescent phase (48 � 33 days) to assess functional outcome.In the resting state, all patients showed akinetic wall motion in the midportion of the leftventricle and apical left ventricle. After low-dose dobutamine infusion, akinetic wallmotion detected at rest did not show any improvement despite the hypercontractile basalLV wall. In the convalescent phase, LV dysfunction was not observed on echocardiographyin all 11 patients. The LV apical ballooning syndrome has a unique feature that reversibledysfunction lacks functional amelioration during dobutamine administration. In conclu-sion, this finding suggests that the pathophysiologic mechanisms of the syndrome appear tobe distinct from those of myocardial stunning after transient ischemia, and catecholamine-mediated cardiac toxicity may play a role in the development of the syndrome. © 2007
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his study sought to assess the functional responsiveness toobutamine stimulation in patients with the left ventricularLV) apical ballooning syndrome. For this purpose, low-ose dobutamine echocardiography (LDDE) was performedithin 24 hours of admission, and the presence of contrac-

ile reserve in response to dobutamine was examined inatients with the syndrome.

ethods

rom October 1, 2004, to July 31, 2006, 11 consecutiveatients with the LV apical ballooning syndrome were re-erred to our institution. The LV apical ballooning syn-rome was diagnosed according to the following criteria1:1) transient akinetic wall motion in the midportion of theeft ventricle and apical left ventricle; (2) absence of ob-tructive coronary artery disease or acute plaque rupture;nd (3) electrocardiographic changes of ST-segment el-vation, pathologic Q-wave development, and/or diffuse-wave inversion. All patients underwent coronary angiog-

aphy and left ventriculography soon after admission. Two-imensional echocardiography in the resting state and dur-ng low-dose dobutamine administration (5 to 10 �g/kg/in) was carried out within 24 hours of admission. All

aDivision of Cardiology, Heart Center, Sendai Kosei Hospital, Sendai;First Department of Internal Medicine, Yamagata University School of

edicine, Yamagata; and cTohoku Bunka Gakuen University, Sendai,apan. Manuscript received April 7, 2007; revised manuscript receivedune 2, 2007; and accepted June 13, 2007.

nE-mail address: [email protected] (S. Fujiwara).

atients underwent the second echocardiographic study atest in the convalescent phase (48 � 33 days). The clinicalharacteristics of the patients and electrocardiographic andchocardiographic data are shown in Tables 1 and 2, re-pectively. All 11 patients were women, 57 to 85 years ofge (mean 73 � 10). One patient (patient 8 in Tables 1 and 2)as excluded from LDDE as a result of intraventricularressure gradients of �30 mm Hg. Written informedonsent was obtained from all patients, and the institu-ional review board on human research approved thetudy protocol.

LDDE was carried out with a Vivid 3 ultrasound systemith a 2.5-MHz transducer (GE Healthcare, Milwaukee,isconsin) as previously described.2 The patients were

tudied in the left lateral decubitus position in the restingtate and during the last 3 minutes of each dobutaminenfusion level. The parasternal long- and short-axis viewsnd apical 4- and 2-chamber views were recorded in allatients. After the resting images were obtained, dobut-mine infusion was started at the initial dose of 5 �g/kg/minor 5 minutes and then increased to 10 �g/kg/min for andditional 5 minutes. Echocardiographic studies were re-eated during dobutamine infusion. Blood pressure andlectrocardiograms were monitored throughout the study.o patients were on �-blocker therapy at the time of do-utamine echocardiography.

LV regional wall motion and systolic wall thickeningere evaluated semiquantitatively by 2 experienced observ-

rs who were unaware of patients’ clinical data. A 4-pointcoring system was used for evaluating wall motion: 0,
ormal; 1, hypokinetic; 2, severely hypokinetic; and 3,
www.AJConline.org

Table 1Clinical characteristics of the patients

PatientNo.

Age (yrs)/Sex

InitialSymptom

Onset toAdmission

(h)

Admission toLDDE (h)

BP(mm Hg)

HR(beats/min)

Stress Event Peak CK(IU)

Initial Treatment Co-morbidity

1 57/F Chest pain 7 16 176/97 69 NR 54 Nitrates, calcium antagonist Hypertension2 60/F Chest pain 16 21 154/84 75 “Awful experience” 132 Nitrates None reported3 65/F Chest pain 2.5 4 73/45 90 “Fierce argument” 229 Dobutamine, nitrates,

respirator, IABPHyperlipidemia

4 70/F Palpitation, nausea 2 20 120/71 78 “Tragic news” 251 � blocker, ACE inhibitor,diuretics

Hypertension

5 72/F Chest pain 3 20 149/107 78 NR 187 Nitrates, calcium antagonist Variant angina6 74/F Chest discomfort 48 20 122/75 77 “Frustrating work

situation”176 Nitrates, calcium antagonist Hypertension

7 77/F Abdominal pain,appetite loss

17 2 67/41 104 Cachexia (systemiccomplication)

2,851 Dobutamine, albumin, volumereplacement

Dehydration, malnutrition

8 80/F Appetite loss 2.5 Not performed 124/51 68 Pyrexia (pulmonarycomplication)

377 Nitrates, aspirin Pleuritis

9 81/F Chest pain 3.5 24 140/102 106 NR 57 Dobutamine, antibiotics,diuretics, calcium antagonist

Hypertension, renal failure,rheumatoid arthritis

10 85/F Dyspnea, chestpain

13.5 22 114/61 69 Acute dyspnea(pulmonary disease)

470 Calcium antagonist,antibiotics, � stimulant TTS

Hypertension, pneumonia,bronchial asthma

11 85/F Chest pain 3 24 148/63 73 NR 166 hANP, diuretics, ARB Hypertension

ACE � angiotensin-converting enzyme; ARB � angiotensin receptor blocker; BP � blood pressure; CK � creatine kinase; hANP � human atrial natriuretic peptide; HR � heart rate; IABP � intra-aorticballoon pump; NR � not reported; TTS � transdermal therapeutic system.

1601M

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kinetic/dyskinetic. Dysfunctional wall motion showing anmprovement in the functional score of �1 during dobut-mine infusion was defined as positive functional respon-iveness to dobutamine indicating myocardial viability. Anyifferences in interpretation were resolved by consensus

Rest Dobutamine 3-month

Rest Dobutamine 3-month

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igure 1. Echocardiograms and left ventriculograms of a patient with apicalallooning syndrome (patient 3 in Tables 1 and 2). (A) Echocardiographicmages in end-diastole (upper panels) and end-systole (lower panels) atest (left), during dobutamine infusion (middle), and at 3-month (right).pical long-axis views are shown. (B) Left ventriculograms in end-diastole

upper panels) and end-systole (lower panels) at rest (left), during dobut-mine infusion (middle), and at 3 months (right). Both demonstrate apicalnd midventricular akinesia, i.e., apical ballooning at rest. Apical andidventricular akinesia shows no functional improvement during dobut-

mine administration. Wall motion abnormalities completely disappear atmonths on echocardiography and left ventriculography. ED � end-

iastole; ES � end-systole.

able 2lectrocardiographic and echocardiographic data

atiento.

Initial ECG

1 Tall peaked T-wave in V2–V5, ST-segment depression in II, II2 Poor R progression, T-wave inversion in II, III, aVF, V3–V6

3 Tall peaked T-wave in V2–V4

4 AF, ST-segment elevation in V3–V6, T-wave inversion in II, II5 T-wave inversion in V2–V6

6 ST-segment elevation in II, III, aVF, V3–V6

7 ST-segment elevation in II, III, aVF, V3–V6, Q-wave in V3–V6

8 Q-wave in II, III, aVF, V2–V5, T-wave inversion in V2–V4

9 Q-wave and ST elevation in V2–V3, T-wave inversion in V4–V0 ST-segment elevation in V2–V6, Q-wave in V3–V5, long QT in1 CRBBB, ST-segment elevation in V4–V6, ST-segment depress

AF � atrial fibrillation; CRBBB � complete right bundle branch bloentricular ejection fraction; LVOT � left ventricular outflow tract; LVP

etween 2 observers. 7

The data are reported as means � SD. Continuous variablesere compared by the Wilcoxon signed-rank test (StatViewersion 5.0; SAS, Cary, North Carolina). A p value �0.05 wasonsidered significant.

esults

igure 1 shows echocardiograms and left ventriculogramsn a patient with the LV apical ballooning syndrome (patient 3n Tables 1 and 2) in the resting state, during 10 �g/kg/minobutamine infusion, and 3 months after onset. Echocardi-graphy and left ventriculography revealed wall motioncores of 3 in the midportion of the left ventricle and apicaleft ventricle, i.e., apical ballooning. Left ventriculographyuring dobutamine administration was also performed inhis patient. Wall motion scores of 3 in the midportion of theeft ventricle and apical left ventricle did not change duringobutamine infusion. Wall motion abnormalities disap-eared on echocardiography and left ventriculography at 3onths (Figure 1).LDDE was performed at a mean of 17 � 8 hours after

dmission. All 10 patients could tolerate dobutamine infu-ion at the dose of 10 �g/kg/min. Heart rate (75 � 12 vs3 � 10 beats/min, p � 0.005), systolic blood pressure (106 �4 and 59 � 15 vs 113 � 28 and 61 � 12 mm Hg, p �.047), and pressure gradients in the LV outflow tract (11 �vs 15 � 7 mm Hg, p � 0.005) were significantly increaseduring dobutamine administration. No patients developedV outflow obstruction of �30 mm Hg during dobutaminedministration measured with continuous-wave Dopplermaging.

All patients exhibited wall motion scores of 3 in theidportion of the left ventricle and apical left ventricle at

est. After dobutamine administration, wall motion scores ofdetected at rest did not change despite the hypercontractileasal LV wall in all patients.

The second echocardiographic study was performed at aean of 48 � 33 days later. No functional abnormalitiesere detected in all patients. LV ejection fraction signifi-

antly improved in the convalescent phase (49 � 13% vs

IVS(mm)

LVPW(mm)

LVOT PG(mm Hg)

LVEF

Acute (%) Chronic (%)

8 8 �10 65 7011 10 �10 54 7112 10 11 45 7312 11 �10 31 6111 12 �10 53 738 8 �10 61 729 8 11 66 728 9 31 36 72

15 13 �10 27 6813 10 �10 55 75

II, aVF 10 11 14 49 70

G � electrocardiogram; IVS � intraventricular septum; LVEF � leftft ventricular posterior wall; PG � pressure gradient.

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1603Miscellaneous/Dobutamine and Apical Ballooning Syndrome

iscussion

o our knowledge, we have demonstrated for the first time thateversible dysfunction in patients with apical ballooning syn-rome had no functional responsiveness to dobutamine stim-lation. LDDE failed to detect viable myocardium in all pa-ients with the LV apical ballooning syndrome.

This study provides insight into the underlying patho-hysiologic mechanisms of apical ballooning syndrome.ote et al,3 who first reported this syndrome, proposedultivessel coronary spasm and subsequent myocardial

tunning as the pathogenic factor. Kurisu et al4 also de-cribed 17 patients with this syndrome, of whom 11 exhib-ted provocative or spontaneous coronary spasm. However,he clinical presentation of the syndrome is substantiallyifferent from variant angina. Sublingual nitroglycerin isot effective for chest pain, and moreover, treatment with �lockers, which potentially exacerbates coronary spasm,an even improve the outcome of the syndrome.5 Althoughe did not provoke coronary vasospasm, we confirmed the

bsence of atherosclerotic coronary disease or coronaryasospasm even while ST-segment elevation was present.n the 4 series of earlier reports from Japan,4,6–8 provocativeultivessel coronary vasospasm was observed only in 13 of

3 patients (18%) with the syndrome. Moreover, the extentf peculiar wall motion abnormalities in the syndrome isnconsistent with the territory of a single coronary artery,nd even cannot be explained by multivessel coronary ter-itories. Thus, coronary spasm seems to be a co-morbidityather than the causal disease. Sharkey et al9 performedardiac magnetic resonance imaging and found no delayedadolinium hyperenhancement in 21 of 22 patients with theyndrome, consistent with viable myocardium and the ab-ence of myocardial infarction. Given these findings, coro-ary artery disease, including coronary vasospasm, does notxplain the clinical spectrum of apical ballooning syn-rome. Furthermore, if coronary artery disease was associ-ted with the underlying mechanisms of the syndrome,DDE must have detected reversible dysfunction in theresent study. The sensitivity and negative predictive valuef LDDE to detect viable myocardium were 0% in apicalallooning syndrome. These findings were distinct fromhose of reversible dysfunction observed in patients withoronary artery disease.10,11 It has also been demonstratedhat coronary flow reserve was reduced in apical ballooningyndrome, indicating impairment of coronary microcircula-ion, such as microvascular spasm.12,13 However, it remainsnclear whether microvascular dysfunction is the primaryause of the syndrome or an epiphenomenon. Moreover, its unlikely that this phenomenon would influence the resultsf the present study because reversible dysfunction witheduced coronary flow can also be detected by LDDE.11

The treatment of apical ballooning syndrome remainshiefly empirical. Although we administered dobutamine inatients with hemodynamic compromise, an intra-aorticalloon pump should have been used because dobutamineid not improve LV dysfunction, and moreover dobutaminean induce LV outflow obstruction in this syndrome.9,14,15

In the present study, 6 of 11 patients (55%) had a historyf hypertension. In earlier reports,7–9,16 the prevalence of
ypertension ranged from 14% to 71% in apical ballooning
yndrome. It remains unclear whether a history of hyper-ension can be a risk factor for apical ballooning syndrome.

In keeping with previous reports,3–9,12–16 we found atriking preponderance of apical ballooning syndrome foromen of advanced age who had LV dysfunction confined

o the apex and midportion of the left ventricle. The expla-ations for these issues are unresolved by this study.

1. Bybee KA, Kara T, Prasad A, Lerman A, Barsness GW, Wright RS,Rihal CS. Systematic review: transient left ventricular apical balloon-ing: a syndrome that mimics ST-segment elevation myocardial infarc-tion. Ann Intern Med 2004;141:858–865.

2. Fujiwara S, Takeishi Y, Hirono O, Fukui A, Okuyama M, YamaguchiS, Ito M, Kaneko K, Shishido T, Miyamoto T, et al. Reverse redistri-bution of Tc-99m sestamibi after direct percutaneous transluminalcoronary angioplasty in acute myocardial infarction: relationship withwall motion and functional response to dobutamine stimulation. NuclMed Commun 2001;22:1223–1230.

3. Dote K, Sato H, Tateishi H, Uchida T, Ishihara M. Myocardial stun-ning due to simultaneous multivessel coronary spasms: a review of 5cases. J Cardiol 1991;21:203–214.

4. Kurisu S, Sato H, Kawagoe T, Ishihara M, Shimatani Y, Nishioka K,Kono Y, Uemura T, Nakamura S. Tako-tsubo-like left ventricular dys-function with ST-segment elevation: a novel cardiac syndrome mimickingacute myocardial infarction. Am Heart J 2002;143:448–455.

5. Kyuma M, Tsuchihashi K, Shinshi Y, Hase M, Nakata T, Ooiwa H,Abiru M, Hikita N, Adachi T, Shoji T, Fujise Y, Shimamoto K. Effectof intravenous propranolol on left ventricular apical ballooning with-out coronary artery stenosis (Ampulla cardiomyopathy), three cases.Circ J 2002;66:1181–1184.

6. Tsuchihashi K, Ueshima K, Uchida T, Ohmura N, Kimura K, Owa M,Yoshiyama M, Miyazaki S, Haze K, Ogawa H, Honda T, Hase M, KaiR, Morii I. Transient left ventricular apical ballooning without coro-nary artery stenosis: a novel heart syndrome mimicking acute myo-cardial infarction. J Am Coll Cardiol 2001;38:11–18.

7. Abe Y, Kondo M, Matsuoka R, Araki M, Dohyama K, Tanio H.Assessment of clinical feature in transient left ventricular apical bal-looning. J Am Coll Cardiol 2003;41:737–742.

8. Akashi YJ, Nakazawa K, Sakakibara M, Miyake F, Koike H, SasakaK. The clinical features of Takotsubo cardiomyopathy. Q J Med2003;96:563–573.

9. Sharkey SW, Lesser JR, Zenovich AG, Maron MS, Lindberg J, Longe TF,Maron BJ. Acute and reversible cardiomyopathy provoked by stress inwomen from the United States. Circulation 2005;111:472–479.

0. Smart SC, Sawada S, Ryan T, Segar D, Atherton L, Berkovitz K,Bourdillon PDV, Feigenbaum H. Low-dose dobutamine echocardiog-raphy detects reversible dysfunction after thrombolytic therapy ofacute myocardial infarction. Circulation 1993;88:405–415.

1. Perrone-Filardi P, Pace L, Prastaro M, Piscione F, Betocchi S, SquameF, Vezzuto P, Soricelli A, Indolfi C, Salvatore M, Chiariello M.Dobutamine echocardiography predicts improvement of hypoperfuseddysfunctional myocardium after revascularization in patients with cor-onary artery disease. Circulation 1995;91:2556–2565.

2. Nishikawa S, Ito K, Adachi Y, Katoh S, Azuma A, Matsubara H.Ampulla (Takotsubo) cardiomyopathy of both ventricles: evaluation ofmicrocirculation disturbance using Tc-99m tetrofosmin myocardialsingle photon emission computed tomography and Doppler guide wire.Circ J 2004;68:1076–1080.

3. Citro R, Galderisi M, Maione A, Innelli P, Provenza G, Gregorio G.Sequential transthoracic ultrasound assessment of coronary flow re-serve in a patient with Tako-tsubo syndrome. J Am Soc Echocardiogr2006;19:1402 e5–e8.

4. Merli E, Sutcliffe S, Gori M, Sutherland GGR. Takotsubo cardiomy-opathy: new insights into the possible underlying pathophysiology.Eur J Echocardiogr 2006;7:53–61.

5. Previtali M, Repetto A, Scuteri L. Dobutamine induced severe mid-ventricular obstruction and mitral regurgitation in left ventricular api-cal ballooning syndrome. Heart 2005;91:353.

6. Wittstein IS, Themann DR, Lima JAC, Baughman KL, Schulman SP,Gerstenblith G, Wu KC, Rade JJ, Bivalacqua TJ, Champion HC.
Neurohumoral features of myocardial stunning due to sudden emo-tional stress. N Engl J Med 2005;352:539–548.

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he Corrected Values for Durationnd Frequency of Angina ataseline in the Clinical Outcomestilizing Revascularization andggressive Drug Evaluation TrialIn reanalyzing the data for our quality-

f-life report from the Clinical Outcomestilizing Revascularization and Aggres-

ive Drug Evaluation (COURAGE)rial, we found evidence of an error inhe way angina frequency was quanti-ed at baseline for the study populations a whole. This affects our previousublication of the report on baselineharacteristics that appeared in the Jan-ary 15, 2007, issue of the Americanournal of Cardiology.1

In the process of quantifying the av-rage number of angina episodes pereek for the study population, an initialinary classification was used to assesshe presence (1) or absence (0) of an-ina. Because 12% of patients did notave angina at baseline, all patientsith 0 integers were inadvertently re-oved from the denominator such thathen the angina frequency assessmentas made, the mean number of epi-

odes was inadvertently reported as 10er week. This is correct for the subsetf patients with angina, but it is incor-ect as the mean number of angina ep-sodes per week for the entire studyopulation. The correct mean numberf weekly angina attacks for all 2,287atients is 6 episodes per week. A re-ised version of Table 2 is includedere. Although there is some variability

*Letters (from the United States) concerning aarticular article in The American Journal of Car-iology� must be received within 2 months of therticle’s publication, and should be limited (withare exceptions) to 2 double-spaced typewritten

Vages. Two copies must be submitted.

002-9149/07/$ – see front matter © 2007 Elsevier I

n the frequency of angina between Vet-rans Affairs and United States non–eterans Affairs sites, none of these

hanges are statistically significantmong the 3 health care sectors.

We apologize for this unfortunateversight.

William E. Boden, MD

Buffalo, New York

Robert A. O’Rourke, MD

San Antonio, Texas

Koon K. Teo, MB, BcH, PhD

Hamilton, Ontario, Canada

William S. Weintraub, MD

Newark, Delaware11 July 2007

. Boden WE, O’Rourke RA, Teo KK, HartiganPM, Maron DJ, Kostuk W, Knudtson M, DadaM, Casperson P, Harris CL, et al. The evolvingpattern of symptomatic coronary artery diseasein the United States and Canada: baseline char-acteristics of the Clinical Outcomes UtilizingRevascularization and Aggressive Drug Eval-uation (COURAGE) trial. Am J Cardiol 2007;99:208–212.

doi:10.1016/j.amjcard.2007.07.009

orrectionIn “Comparison of Access-Related

leeding Complications in Women

able 2 (revised)aseline angina values

Durati

Mean � SD

MT 23 � 46CI � OMT 24 � 53anadian 26 � 48nited States non-VA 23 � 53A 21 � 50

OMT � optimal medical therapy; PCI � peffairs.

ersus Men Undergoing Percutaneous

nc. All rights reserved.

oronary Catheterization Using the Ra-ial Versus Femoral Artery,”1 in theay 1, 2007, issue of the American

ournal of Cardiology, the bleedingefinitions were incorrectly printed.he correct paragraph is as follows:

“Puncture-related bleedings were de-ned as major if associated with any of

he following: (1) retroperitoneal hema-oma and/or death; (2) required surgicalntervention (vascular closure or localompartment decompression); (3) re-uired blood transfusions; (4) hemoglo-in concentration loss �4 g/dl; or (5) aocal hematoma involving �50% of theurface of the limb, associated with se-ere patient discomfort and requiring arolonged hospital stay. All other punc-ure-related hemorrhages were consid-red minor.”

Christian Pristipino, MD

Rome, Italy20 July 2007

. Pristipino C, Pelliccia F, Granatelli A, PasceriV, Roncella A, Speciale G, Hassan T, RichichiG. Comparison of access-related bleedingcomplications in women versus men undergo-ing percutaneous coronary catheterization us-ing the radial versus femoral artery. Am J Car-diol 2007;99:1216–1221.

Frequency

Median Mean � SD Median

5.0 6 � 12 3.05.0 6 � 9 3.06.0 6 � 11 3.03.0 7 � 16 3.04.0 5 � 7 3.0

aneous coronary intervention; VA � Veterans

on

rcut

doi:10.1016/j.amjcard.2007.07.011

www.AJConline.org

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The American Journal of Cardiology - lib.ajaums.ac.irlib.ajaums.ac.ir/booklist/297258.pdf · Pim van der Harst, Folkert W. Asselbergs, Hans L. Hillege, Stephan J.L. Bakker, Adriaan