Our previous research has shown that having isch-emia in distal LV segments is predictive of a future MIor cardiac death (hazard ratio 6.18). If a subject hadischemia in the basal or middle regions without isch-emia in the apex, then the hazard ratio was smaller(1.44) and not significantly different from a ratio of1.0. We recognize that in this previous study thenumber of patients with isolated basal or middle seg-mented ischemia was relatively small (21 of 92 pa-tients with ischemia). For this reason, a study thatfollows a larger number of patients with isolated basalor middle segment ischemia is required to determinethe prognostic significance of ischemia in these seg-ments. The potential clinical importance of a prognos-tic difference in distal versus isolated basal or middlesegmental ischemia is high. Coronary artery revascu-

larization procedures are frequently performed in pa-tients with inducible myocardial ischemia during car-diac stress tests. Perhaps patients with inducibleischemia in the LV apex should be considered formore aggressive risk reduction strategies.

1. Hundley W, Morgan T, Neagle C, Hamilton C, Rerkpattanapipat P, Link K.Magnetic resonance imaging determination of cardiac prognosis. Circulation2002;106:2328–2333.2. Cerqueira M, Weissman N, Dilsizian V, Jacobs A, Kaul S, Laskey W, PennellD, Rumberger J, Ryan T, Verani M. Standardized myocardial segmentation andnomenclature for tomographic imaging of the heart. Circulation 2002;105:539–542.3. Hundley W, Hamilton C, Thomas M, Herrington D, Salido T, Kitzman D,Little W, Link K. Utility of fast cine magnetic resonance imaging and display forthe detection of myocardial ischemia in patients not well suited for secondharmonic stress echocardiography. Circulation 1999;100:1697–1702.4. Bishop YMM, Fienberg SE, Holland PW. Discrete Multivariate Analysis:Theory and Practice. Cambridge, MA: MIT Press, 1975:147–148, 364–365.

In-Stent Restenosis and Lesion Morphology in PatientsWith Acute Myocardial Infarction

Atsushi Tanaka, MD, Takahiko Kawarabayashi, MD, Yoshiharu Nishibori, MD,Hiroki Oe, MD, Masashi Namba, MD, Yukio Nishida, MD, Daiju Fukuda, MD,

Kenei Shimada, MD, and Junichi Yoshikawa, MD

We investigated the correlation between lesion mor-phology with preintervention intravascular ultrasoundand in-stent restenosis in 72 patients with acute myo-cardial infarction (AMI). Multivariate logistic regressionanalysis showed that the presence of ruptured plaquewas the only predictive factor of in-stent restenosis afterprimary stenting for AMI. �2003 by Excerpta Med-ica, Inc.

(Am J Cardiol 2003;92:1208–1211)

Primary or adjunctive coronary stenting for acutemyocardial infarction (AMI) improves patient

outcomes.1–6 However, the problematic clinical con-dition, in-stent restenosis, has not yet been solved. Itis, therefore, very important in the clinical setting tobe able to predict which lesions are at high risk forrestenosis before commencing percutaneous coronaryintervention (PCI). We previously reported that pre-intervention intravascular ultrasound (IVUS) is able toidentify lesion plaque morphology in the acute phaseof AMI.7–9 The aim of this study was to investigate thecorrelation between lesion morphology identified bypreintervention IVUS and in-stent restenosis in pa-tients with AMI.

• • •Our study population consisted of 83 consecutive

patients with AMI who underwent preinterventionIVUS and were successfully recanalized with primaryintracoronary stenting within 12 hours of symptomonset. We excluded 3 patients who had previous myo-cardial infarction, 2 patients with bypass failure, 2patients with subacute thrombosis, and 4 patients inwhom adequate IVUS images could not be obtained.Ultimately, a total of 72 patients (72 lesions) whounderwent both preintervention IVUS and follow-upcoronary angiography after 6 months were includedfor analysis in this study. Diagnosis of AMI wasdetermined from the presence of �30 minutes contin-uous chest pain, ST-segment elevation of �2.0 mm on�2 contiguous electrocardiographic leads, and a morethan threefold increase in serum creatine kinase levels.The study protocol was approved by the ethics com-mittee of Baba Memorial Hospital. We also obtainedwritten informed consent from all the participantsbefore coronary angiography.

Coronary angiography in all patients was per-formed using a 6Fr Judkins-type catheter via the fem-oral approach. All patients received an intravenousbolus injection of 10,000 IU of heparin and intracoro-nary isosorbide dinitrate (2 mg) before angiography.After completion of diagnostic coronary angiography,all patients were evaluated with IVUS before PCI. TheIVUS catheter (UltraCross or Atlantis, Boston Scien-tific CVIS, Fremont, California) was carefully ad-vanced distal to the lesion under fluoroscopic guid-ance. It was then pulled back automatically from thedistal portion at 0.5 mm/s, facilitating observation ofthe lesion with a contrast medium suitable for IVUSimaging.8 IVUS images were recorded on S-VHS

From Baba Memorial Hospital, Sakai; and Department of InternalMedicine and Cardiology, Graduate School of Medicine, Osaka CityUniversity, Osaka, Japan. Dr. Tanaka’s address is: Department ofCardiology, Baba Memorial Hospital, 4-244, Hamadera-funao-choHigashi, Sakai, 592-8555 Japan. E-mail: m4497147@msic.med.osaka-cu.ac.jp. Manuscript received April 23, 2003; revised manu-script received and accepted July 25, 2003.

1208 ©2003 by Excerpta Medica, Inc. All rights reserved. 0002-9149/03/$–see front matterThe American Journal of Cardiology Vol. 92 November 15, 2003 doi:10.1016/j.amjcard.2003.07.034

video for off-line analysis. Primary intracoronarystenting was performed according to established con-ventions either with or without balloon predilatation.The angiographic criteria of �25% residual diameterstenosis was used to determine the end point of theinterventional procedure. After PCI, IVUS evaluationwas repeated. Three thousand units of heparin wereadministered every hour during the procedure to main-tain an activated clotting time of �300 seconds. AfterPCI, intravenous infusion of heparin was continuedfor �24 hours to maintain an activated clotting time of180 to 200 seconds. We also administered antiplatelettherapy (aspirin 80 mg/day and ticlopidine 200 mg/day). Follow-up coronary angiography was performed6 months after PCI. For the purposes of this study,restenosis was defined as �50% diameter stenosis asseen with quantitative coronary angiography on thefollow-up coronary angiograms. Patients were dividedinto 2 groups—a restenosis group and a nonrestenosisgroup—according to the results of quantitative coro-nary angiography.

The morphologic features identi-fied by IVUS were analyzed and in-terpreted by 2 experienced indepen-dent observers (DF and KS) who wereblinded to the angiographic and clin-ical data. Lesion morphology andmeasurements of preinterventionIVUS were determined according tothe American College of CardiologyClinical Expert Consensus Documenton Standards for Acquisition, Mea-surement and Reporting of Intravas-cular Ultrasound Studies.10 Fissurewas defined as an abrupt, focal, orsuperficial break in the linear continu-ity of the plaque that extended in aradial direction. Dissection was de-fined as rupture of the plaque thatcreated �1 neolumina. Computerplanimetry (TapeMeasure, IndecSystems, California) was used tomeasure external elastic membranecross-sectional area at the lesion siteand at both proximal and distal ref-erence segments. Incidences of le-sion external elastic membranecross-sectional area larger than theproximal reference external elasticmembrane cross-sectional area weredefined as positive remodeling.11 Wedefined the IVUS criteria for identi-fying plaque rupture in AMI as: (1)lesions with fissure/dissection, or (2)lesions with no visual evidence offissure/dissection but in which infu-sion of saline or contrast mediumconfirmed communication betweenthe vascular lumen and the plaque.Figure 1 shows some typical imagesof lesions with plaque rupture andnonrupture in the setting of AMI.

Coronary angiograms were reviewed separately by2 independent observers (YN and MN) who wereunaware of the IVUS findings. Thrombolysis In Myo-cardial Infarction criteria were used to evaluate thedegree of perfusion.12 Collaterals were graded accord-ing to Rentrop et al’s classification,13 with good col-lateral flow defined as grade 2 or 3. Angiographicthrombus was defined as a filling defect seen in mul-tiple projections surrounded by contrast in the absenceof calcification. Quantitative coronary angiographywas performed using the CMS-QCA system (CMS-MEDIS, Medical Imaging Systems, Leiden, TheNetherlands).

Results are expressed as mean � SD values forcontinuous variables. Qualitative data are presented asnumbers (percentages). Continuous variables werecompared using Student’s t test, and categorical datawith Fisher’s exact test. A multivariate logistic regres-sion model was used to identify predictors of in-stentrestenosis. Independent variables included in themodel were age, male gender, diabetes mellitus,

FIGURE 1. Preintervention IVUS images of AMI lesions. (A) A typical preinterventionIVUS image of a ruptured plaque. This eccentric plaque ruptured at the shoulder(white arrow). (B) Preintervention IVUS image with no visible feature of rupturedplaque. The image shows a concentric lesion with several highly echoic layers ontop of the other, like the rings of a tree.

TABLE 1 Clinical Characteristics and Clinical Results

VariableRestenosis Group

(n � 16)Nonrestenosis group

(n � 56) p Value

Age (yrs) 62 � 5.9 64 � 11 0.57Men 14 (88%) 41 (73%) 0.33Coronary risk factors

Systemic hypertension 9 (56%) 33 (59%) 0.99Diabetes mellitus 6 (38%) 11 (20%) 0.18Smoker 13 (81%) 39 (70%) 0.53Hypercholesterolemia(�220 mg/dl)

8 (50%) 36 (64) 0.39

Killip class 0.741 13 (81%) 48 (86%)2 2 (13%) 4 (7%)3 0 2 (4%)4 1 (6%) 2 (4%)

Preinfarction angina pectoris 14 (88%) 34 (61%) 0.07Onset to recanalization time (min) 2.9 � 1.7 4.7 � 4.6 0.13Peak creatine kinase levels (IU/L) 2,889 � 2,015 2,318 � 2,213 0.40

Data are presented as mean � SD or number (percent).

BRIEF REPORTS 1209

smoking, final stent inflation pressure, presence ofeccentric plaque, presence of plaque rupture, positiveremodeling, and post-stent plaque area. A p value�0.05 was considered statistically significant.

Primary stent implantation was successful in all pa-tients. Glycoprotein IIb/IIIa inhibitors were not used inthis study, as these agents are not available in Japan.Angiographic restenosis was seen in 16 of the 72 patients(22%). Patient characteristics and clinical results for bothgroups are listed in Table 1. Angiographic findings andacute procedural results are presented in Table 2. Coro-nary artery lesions were observed with IVUS in all

patients without any serious proce-dural complications. The IVUS find-ings are listed in Table 3. Rupturedplaque was observed significantlymore frequently in the restenosis groupthan in the nonrestenosis group. De-spite there being no differences inpost-stent minimal lumen area be-tween groups, residual plaque area out-side the stent was significantly largerin the restenosis group than in the non-restenosis group. Multivariate logisticregression analysis showed that thepresence of ruptured plaque was theonly independent predictive factor ofin-stent restenosis after reperfusion inpatients with AMI.

• • •In this study, we present our find-

ings that angiographic restenosis af-ter primary stenting in patients withAMI is correlated with preinterven-tion IVUS lesion morphology. Ourangiographic restenosis rate (22%) isvery similar to those in both arms ofa previous large multicenter study14

that investigated primary stenting forAMI with (20.8%) and without(23.8%) the benefit of glycoproteinIIb/IIIa inhibitors. In the setting ofstable angina pectoris, previous stud-ies have demonstrated that the mech-anism of stent restenosis is mainlydue to in-stent neointimal prolifera-tion.15,16 Therefore, minimal stentarea or percent diameter stenosis arepowerful predictors of angiographicrestenosis and target vessel revascu-larization after stenting.17–19 How-ever, in this study, we found no dif-ferences in final minimal lumen areaor percent diameter stenosis; theseparameters did not correlate with an-giographic restenosis. Recently, 1pathologic study revealed that arte-rial injury or penetration of the stentinto lipid core induces arterial in-flammation, which is associated with

increased neointimal growth.20 IVUS may not be ableto identify small ruptures or small necrotic core. We,however, are prepared to speculate that the inflamma-tory components of the ruptured plaque, mainly thelipid core, that remain outside the stent may be re-sponsible for increasing the inflammatory response,resulting in a high level of neointimal proliferationafter stent implantation for AMI.

1. Saito S, Hosokawa FG, Kim K, Tanaka S, Miyake S. Primary stent implan-tation without coumadin in AMI. J Am Coll Cardiol 1996;28:74–81.2. Stone GW, Brodie BR, Griffin JJ, Costantini C, Morice MC, St Goar FG,Overlie PA, Popma JJ, McDonnell J, Jones D, O’Neill WW, Grines CL. Clinical

TABLE 2 Angiographic Findings and Procedural Results

Restenosis Group(n � 16)

Nonrestenosis Group(n � 56) p Value

Infarct-related coronary artery 0.99Left descending 7 (44%) 29 (52%)Left circumflex 1 (6%) 3 (5%)Right 8 (50%) 24 (43%)

TIMI flow grade 0 at initialangiogram

9 (56%) 29 (52%) 0.78

Good collateral flow 8 (50%) 18 (32%) 0.24Angiographic thrombus 4 (25%) 5 (9%) 0.10No. of stents per lesion 1.1 � 0.3 1.3 � 0.5 0.33Multiple stents 2 (13%) 13 (23%) 0.49Stent size (mm) 3.3 � 0.4 3.4 � 0.4 0.24Final stent inflation pressure

(atm)7.9 � 2.3 8.1 � 2.4 0.82

Balloon-to-artery ratio 1.14 � 0.3 1.27 � 0.3 0.11Preintervention reference size

(mm)2.9 � 0.6 2.7 � 0.7 0.23

Preintervention minimal lumendiameter (mm)

0.30 � 0.4 0.32 � 0.5 0.83

Preintervention diameterstenosis (%)

90 � 13 88 � 18 0.74

Post-stent minimal lumendiameter (mm)

3.4 � 0.6 3.6 � 0.6 0.25

Post-stent diameter stenosis(%)

22.1 � 17.2 16.2 � 12.0 0.12

Data are presented as mean � SD or number (percent).TIMI � Thrombolysis In Myocardial Infection.

TABLE 3 Intravascular Ultrasound (IVUS) Findings

Restenosis Group(n � 16)

Nonrestenosis Group(n � 56) p Value

Preintervention IVUSEccentric 8 (50%) 31 (55%) 0.78Ruptured plaque 11 (69%) 21 (38%) 0.04

Fissure/dissection 7 (44%) 19 (34%)Confirmed by IVUS contrast 4 (25%) 2 (4%)

Superficial calcium 7 (44%) 26 (46%) 0.99Deep wall calcium 5 (31%) 24 (43%) 0.56Positive remodeling 3 (19%) 14 (25%) 0.75Reference EEM CSA (mm2) 16.3 � 4.4 15.5 � 4.3 0.50Lesion EEM CSA (mm2) 13.7 � 4.4 14.1 � 4.3 0.77

Post-stent IVUSMinimal lumen area (mm2) 7.7 � 2.5 7.2 � 2.2 0.46Plaque area outside stents (mm2) 11.5 � 3.9 9.1 � 3.4 0.02Percent area stenosis 40.8 � 11.6 45.1 � 10.4 0.16

Data are presented as mean � SD or number (percent).EEM CSA � external elastic membrane cross-sectional area.

1210 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 92 NOVEMBER 15, 2003

and angiographic follow-up after primary stenting in acute myocardial infarction:the Primary Angioplasty in Myocardial Infarction (PAMI) stent pilot trial. Cir-culation 1999;99:1548–1554.3. Antoniucci D, Santoro GM, Bolognese L, Valenti R, Trapani M, Fazzini PF.A clinical trial comparing primary stenting of the infarct-related artery withoptimal primary angioplasty for acute myocardial infarction: results from theFlorence Randomized Elective Stenting in Acute Coronary Occlusions(FRESCO) trial. J Am Coll Cardiol 1998;31:1234–1239.4. Maillard L, Hamon M, Khalife K, Steg PG, Beygui F, Guermonprez JL,Spaulding CM, Boulenc JM, Lipiecki J, Lafont A, et al. A comparison ofsystematic stenting and conventional balloon angioplasty during primarypercutaneous transluminal coronary angioplasty for acute myocardial infarc-tion. STENTIM-2 Investigators. J Am Coll Cardiol 2000;35:1729 –1736.5. Grines CL, Cox DA, Stone GW, Garcia E, Mattos LA, Giambartolomei A,Brodie BR, Madonna O, Eijgelshoven M, Lansky AJ, O’Neill WW, Morice MC.Coronary angioplasty with or without stent implantation for acute myocardialinfarction. Stent Primary Angioplasty in Myocardial Infarction Study Group.N Engl J Med 1999;341:1949–1956.6. Stone GW, Grines CL, Cox DA, Garcia E, Tcheng JE, Griffin JJ, GuagliumiG, Stuckey T, Turco M, Carroll JD, Rutherford BD, Lansky AJ, The Con-trolled Abciximab and Device Investigation to Lower Late AngioplastyComplications (CADILLAC) Investigators. The Controlled Abciximab andDevice Investigation to Lower Late Angioplasty Complications (CADILLAC)Investigators. Comparison of angioplasty with stenting, with or withoutabciximab, in acute myocardial infarction. N Engl J Med 2002;346:957–966.7. Fukuda D, Kawarabayashi T, Tanaka A, Nishibori Y, Taguchi H, Nishida Y,Shimada K, Yoshikawa J. Lesion characteristics of acute myocardial infarction:an investigation with intravascular ultrasound. Heart 2001;85:402–406.8. Tanaka A, Kawarabayashi T, Taguchi H, Nishibori Y, Sakamoto T, Nishida Y,Yoshikawa J. Use of preintervention intravascular ultrasound in patients with acutemyocardial infarction. Am J Cardiol 2002;89:257–261.9. Tanaka A, Kawarabayashi T, Nishibori Y, Sano T, Nishida Y, Fukuda D, ShimadaK, Yoshikawa J. No-reflow phenomenon and lesion morphology in patients withacute myocardial infarction. Circulation 2002;105:2148–2152.10. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, PintoFJ, Rosenfield K, Siegel RJ, Tuzcu EM, Yock PG. American College of Cardi-ology clinical expert consensus document on standards for acquisition, measure-ment and reporting of intravascular ultrasound studies (IVUS). A report of the

American College of Cardiology Task Force on Clinical Expert ConsensusDocuments. J Am Coll Cardiol 2001;37:1478–1492.11. Kaji S, Akasaka T, Hozumi T, Takagi T, Kawamoto T, Ueda Y, Yoshida K.Compensatory enlargement of the coronary artery in acute myocardial infarction.Am J Cardiol 2000;85:1139–1141.12. The TIMI IIIB Investigators. Effects of tissue plasminogen activator and acomparison of early invasive and conservative strategies in unstable angina andnon-Q-wave myocardial infarction. Results of the TIMI IIIB Trial. Thrombolysisin Myocardial Ischemia. Circulation 1994;89:545–556.13. Rentrop KP, Cohen M, Blanke H, Phillips RA. Changes in collateral channelfilling immediately after controlled coronary artery occlusion by an angioplastyballoon in human subjects. J Am Coll Cardiol 1985;5:587–592.14. Stone GW, Grines CL, Cox DA, Garcia E, Tcheng JE, Griffin JJ, Guagliumi G,Stuckey T, Turco M, Carroll JD, Rutherford BD, Lansky AJ, The ControlledAbciximab and Device Investigation to Lower Late Angioplasty Complications(CADILLAC) Investigators. Comparison of angioplasty with stenting, with or with-out abciximab, in acute myocardial infarction. N Engl J Med 2002;346:957–966.15. Hoffmann R, Mintz GS, Dussaillant GR, Popma JJ, Pichard AD, Satler LF,Kent KM, Griffin J, Leon MB. Patterns and mechanisms of in-stent restenosis. Aserial intravascular ultrasound study. Circulation 1996;94:1247–1254.16. Mudra H, Regar E, Klauss V, Werner F, Henneke KH, Sbarouni E, TheisenK. Serial follow-up after optimized ultrasound-guided deployment of Palmaz-Schatz stents. In-stent neointimal proliferation without significant reference seg-ment response. Circulation 1997;95:363–370.17. Kasaoka S, Tobis JM, Akiyama T, Reimers B, Di Mario C, Wong ND,Colombo A. Angiographic and intravascular ultrasound predictors of in-stentrestenosis. J Am Coll Cardiol 1998;32:1630–1635.18. Kobayashi Y, De Gregorio J, Kobayashi N, Akiyama T, Reimers B, Finci L,Di Mario C, Colombo A. Stented segment length as an independent predictor ofrestenosis. J Am Coll Cardiol 1999;34:651–659.19. Mercado N, Boersma E, Wijns W, Gersh BJ, Morillo CA, de Valk V, van EsGA, Grobbee DE, Serruys PW. Clinical and quantitative coronary angiographicpredictors of coronary restenosis: a comparative analysis from the balloon-to-stent era. J Am Coll Cardiol 2001;38:645–652.20. Farb A, Weber DK, Kolodgie FD, Burke AP, Virmani R. Morphologicalpredictors of restenosis after coronary stenting in humans. Circulation 2002;105:2974–2980.

Plasma Endothelin-1 Levels After Coronary Stentingin Humans

Marco V. Wainstein, MD, DSc, Sandro C. Goncalves, MD, MSc,Alcides J. Zago, MD, DSc, Raquel Zenker, Renata Burttet, Guilherme de B. Couto,

Fabiana Tomazi, and Jorge P. Ribeiro, MD, DSc

Endothelin (ET)-1 levels were analyzed in patientswho underwent elective coronary stenting. There wasa significant increase in systemic ET-1 levels immedi-ately after the procedure, which is probably a markerof endothelial dysfunction that is associated with ar-terial injury. However, there was no association be-tween ET-1 levels and in-stent restenosis inhumans. �2003 by Excerpta Medica, Inc.

(Am J Cardiol 2003;92:1211–1214)

Despite the recent introduction of drug-elutingstents,1 restenosis remains a major limitation of

coronary stenting. Endothelin (ET)-1 is a powerful

vasoconstricting and proliferative substance2 that isresponsible for most of the enhanced vasoconstrictionin atherosclerotic plaque.3 There may be a role forET-1 as an early participant in and marker for coro-nary endothelial dysfunction in humans.4 Animal aswell as human balloon-injury models of restenosishave implicated ET-1 in this process.5,6 However, theresponse of plasma ET-1 levels after coronary stentingis still disputed. Although endothelin A (ET(A)) re-ceptor antagonist administration during coronarystenting results in a tendency to decrease restenosis,7the role of ET-1 in the pathogenesis of in-stent reste-nosis has not been established in humans. Therefore,the aim of this study was to evaluate the change inplasma ET-1 levels in patients who underwent coro-nary stenting and to determine if there is an associa-tion between ET-1 levels and the occurrence of in-stent restenosis 6 months after coronary stenting.

• • •Patients referred for elective percutaneous coro-

nary stenting between January and July 2002 wereinvited to participate in the study. The indication for

From the Cardiology Division, Hospital de Clınicas de Porto Alegre;and the Department of Medicine, Faculty of Medicine, Federal Uni-versity of Rio Grande do Sul, Porto Alegre, Brazil. This study wassupported by a grant from the Brazilian Research Council (CNPq),Brasilia, Brazil. Dr. Wainstein’s address is: Cardiology Division, Hos-pital de Clınicas de Porto Alegre, Rua Ramiro Barcelos 2350,90035–003, Porto Alegre, RS, Brazil. E-mail: mvwainstein@uol.com.br. Manuscript received April 10, 2003; revised manuscriptreceived and accepted July 15, 2003.

1211©2003 by Excerpta Medica, Inc. All rights reserved. 0002-9149/03/$–see front matterThe American Journal of Cardiology Vol. 92 November 15, 2003 doi:10.1016/j.amjcard.2003.07.035