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orphological Characteristics of Culprittheromatic Plaque Are Associated Withoronary Flow After Thrombolytic Therapy

ew Implications of Optical Coherence Tomography From a Multicenter Study

onstantinos Toutouzas, MD,* Elefterios Tsiamis, MD,* Antonios Karanasos, MD,*aria Drakopoulou, MD,* Andreas Synetos, MD,* Costas Tsioufis, MD,*imitrios Tousoulis, MD,* Periklis Davlouros, MD,† Dimitrios Alexopoulos, MD,†onstantina Bouki, MD,‡ Thomas Apostolou, MD,‡ Christodoulos Stefanadis, MD*

thens, Patras, and Piraeus, Greece

bjectives This study investigated the association between morphological characteristics of culprittheromatic lesions as assessed by optical coherence tomography and Thrombolysis In Myocardialnfarction (TIMI) flow grade after thrombolysis in patients with ST-segment elevation myocardial in-arction (STEMI).

ackground Although several variables have been found to predict coronary flow after thromboly-is in patients with STEMI, the impact of culprit lesion morphology has not been studied.

ethods Fifty-five patients with STEMI from 3 tertiary centers that were treated with thrombolysisnd underwent optical coherence tomography examination in the culprit lesion between 24 and8 h after thrombolysis were included in the study. Patients were categorized on the basis of TIMIow grade into patients with TIMI flow grade 3 versus TIMI flow grade �2.

esults Patients with TIMI flow grade �2 had plaques with more lipid quadrants than patientsith TIMI flow grade 3 (p � 0.001), and presented with greater incidence of plaque rupture (p �

.001). Mean minimal cap thickness was greater in patients with patent arteries than in patientsith impaired flow (87 � 26 �m vs. 48 � 18 �m, p � 0.0001). Minimal cap thickness was indepen-ently associated with TIMI flow grade.

onclusions The morphological characteristics of the culprit atheromatic lesion in patients with STEMIre associated with coronary flow after thrombolysis. The lipid content, the existence of rupture, andainly the thickness of the fibrous cap are associated with the outcome of thrombolysis. (J Am Collardiol Intv 2010;3:507–14) © 2010 by the American College of Cardiology Foundation

rom the *First Department of Cardiology, Athens Medical School, Hippokration Hospital, Athens, Greece; †Department ofardiology, Patras University Hospital, Rion, Patras, Greece; and the ‡Second Department of Cardiology, General Hospital ofikea, Piraeus, Greece.

anuscript received December 21, 2009; revised manuscript received February 1, 2010, accepted February 5, 2010.

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rimary percutaneous coronary intervention is the mostffective method of treatment of ST-segment elevationyocardial infarction (STEMI) (1). Despite the effective-

ess of percutaneous coronary intervention in STEMI (2),hrombolysis remains the most used reperfusion treatment.everal variables have been identified as independent pre-ictors of flow and clinical outcome of patients withTEMI after thrombolysis (3,4). Angiographic patency isn important predictor of mortality after thrombolysis5–7). Although the impact of these variables on flow haseen extensively investigated, the role of morphologicalharacteristics of the culprit atheromatic plaque has noteen studied.The major limitation for investigating a possible associ-

tion of the morphology of the culprit plaque with theutcome of thrombolysis has been the low resolution ofvailable imaging methods. By intracoronary optical coher-nce tomography (OCT) we can accurately measure thehickness of the fibrous cap, estimate the lipid content, anddentify plaque ruptures and coronary thrombi (8–10).

We hypothesized that OCTexamination could provide accu-rate quantitative data regardingthe morphology of the athero-matic plaques in patients withSTEMI. The aim of this multi-center study was to investigatea possible association betweencertain morphological charac-teristics of the culprit athero-matic plaque of patients withSTEMI and coronary flow afterthrombolysis.

ethods

e prospectively enrolled 59 consecutive patients sufferingrom STEMI admitted in 3 tertiary centers that werereated with thrombolysis with tenecteplase within 6 h fromymptom onset in hospitals without percutaneous coronaryntervention facility. All patients had received at admissiontandard antiplatelet and antithrombotic therapy with aspi-in (100 mg) and clopidogrel (300-mg loading dose and 75g daily) and unfractionated heparin (60 U/kg loading dose

ollowed by intravenous infusion of 12 U/kg) and werecheduled for coronary angiography between 24 and 48 hfter thrombolysis. No glycoprotein IIb/IIIa inhibitors weresed between admission and catheterization. Patients wereivided into 2 groups according to Thrombolysis In Myo-ardial Infarction (TIMI) flow grade; patients with TIMIow grade 3 and patients with TIMI flow grade �2.Patients with cardiogenic shock, intracranial hemorrhage,

enal insufficiency, mechanical complications or recurrent

bbreviationsnd Acronyms

ET � angiographicallyvident thrombus

CT � fibrous cap thickness

CT � optical coherenceomography

TEMI � ST-segmentlevation myocardialnfarction

IMI � Thrombolysis Inyocardial Infarction

ngina after thrombolysis, and left main coronary artery

isease were excluded. All patients provided written in-ormed consent before inclusion in the study, and the studyas approved by the institutional ethics committee.Aspiration thrombectomy was performed with an aspiration

atheter (Export, Medtronic, Minneapolis, Minnesota) if theatients had TIMI flow grade 0 to 1 in the culprit vessel. Thespiration of thrombus was completed when flow was restored.

Thereafter, OCT image acquisition was performed in theulprit lesion, before any balloon dilation and stent deploy-ent. The treatment of the culprit lesion was left to the

perator’s discretion. Demographic and clinical data wereollected prospectively.

The analysis of clinical, angiographic, and OCT data waserformed in the laboratory of First Department of Cardi-logy, Athens Medical School. Analysis of OCT imagesas blinded from the clinical and angiographic data. The

ollowing analyses were performed:

Angiographic analysis: Quantitative coronary angiogra-phy, TIMI flow grade assessment, and TIMI framecount measurement were performed after the procedureas previously described (11–13).Thrombus burden: Intracoronary thrombus was angio-graphically identified and scored in 5 grades (G0 to G5)as previously described (14). Angiographically evidentthrombus (AET) was defined as the presence of throm-bus burden G2 or higher.

CT image acquisition. The OCT study was performedsing the LightLab OCT system (M3 LightLab system,mageWire, Westford, Massachusetts). We used the con-

Table 1. Baseline Clinical Characteristics

TIMI Flow Grade 3 TIMI Flow Grade <2 p Value

n 25 30

Age, yrs 58.6 � 13.0 62.1 � 10.1 0.28

Sex, male (%) 22 (88.0) 28 (93.3) 0.65

Time to thrombolysis, h 3.1 � 0.99 3.07 � 0.90 0.91

Time from thrombolysisto catheterization, h

33.16 � 6.06 33.90 � 6.91 0.68

Risk factors

Smoking history 15 (60.0) 20 (66.7) 0.78

Hypertension 15 (60.0) 15 (50.0) 0.59

Hyperlipidemia 18 (72.0) 20 (66.7) 0.78

Diabetes mellitus 10 (40.0) 15 (50.0) 0.59

Family history 9 (36.0) 10 (33.3) 0.99

Drugs from admissionto catheterization

Statins 26 (86.7) 22 (88.0) 0.99

Angiotensin-convertingenzyme inhibitorsor angiotensin IIantagonists

24 (80.0) 19 (76.0) 0.75

All values are expressed as n, mean � SD, or n (%).

TIMI � Thrombolysis In Myocardial Infarction.

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inuous flushing technique, which can acquire images ofimilar quality with the balloon occlusion technique (15,16).he image-wire (0.019 inches) was positioned in the target

essel, distally to the culprit lesion and automatically pulledack at 3 mm/s with simultaneous manual infusion ofontrast medium (Iodixanol 320, Visipaque, GE Health-are, Cork, Ireland) from the guiding catheter for 3 to 6 s,ith an infusion rate of approximately 2 to 3 ml/s, allowing

or displacement of the blood from the artery during thecquisition period. The operator could repeat the injectionn case of poor imaging quality. Images were acquired fromhe target segment involving the lesion and the proximalnd distal reference sites, and stored digitally for offlinenalysis (16).CT image analysis. Acquired images were analyzed by 2

ndependent investigators using previously validated criteria

Table 2. Angiographic Characteristics

TIMI Flow Grad(n � 25)

TIMI flow grade 3

n 25

CTFC 21.84 � 6.02

Quantitative coronary angiography

RD, mm 2.93 � 0.34

MLD, mm 0.76 � 0.25

DS, % 74.4 � 7.10

Lesion length 7.72 � 1.59

Culprit vessel

LAD 10 (40.0)

LCx 4 (16.0)

RCA 11 (44.0)

Segment of culprit lesion

Proximal 8 (32.0)

Middle 15 (60.0)

Distal 2 (8.0)

Calcium 4 (16.0)

Eccentricity 14 (56.0)

AET 5 (20.0)

Thrombus burden

Grade 0 15 (60.0)

Grade 1 5 (20.0)

Grade 2 5 (20.0)

Grade 3 0 (0)

Grade 4 0 (0)

Grade 5 0 (0)

AHA/ACC lesion classification

A 2 (8.0)

B1 12 (48.0)

B2 11 (44.0)

C 0 (0)

All values are expressed as n, mean � SD, or n (%). *Calculated with M

AET � angiographically evident thrombus; ACC � American Colleg

frame count; DS � diameter stenosis; LAD � left anterior descending

right coronary artery; RD � reference diameter; TIMI � Thrombolysis In Myoc

or OCT plaque characterization (17,18). Frames with poormage quality were excluded from the analysis. Plaquenalysis included analysis of all images within the lesionithout normal vessel morphology. Lipid content was

stimated in a semiquantitative manner by measuring therc of the lipid pool (quadrants) at the site of the greatestrc. Every plaque with lipid content in �2 quadrants wasonsidered lipid-rich (17).

Measurement of minimal fibrous cap thickness (FCT)as performed: 1) at the thinnest part overlying a lipid pool

minimal FCT) throughout the lesion, and also in rupturedlaques; and 2) at the thinnest part of the cap in the rupturedite of the culprit plaque (ruptured FCT). For the lattereasurement, plaque rupture was defined as the consistent

resence of the fibrous cap discontinuity in �3 consecutiverames. In ruptured plaques, residual fibrous cap was iden-

TIMI Flow Grade <2(n � 30) p Value

0 1 2

6 9 15

— — 44.13 � 11.87 �0.0001

2.89 � 0.5 0.68

0.66 � 0.24 0.12

77.2 � 7.20 0.15

7.86 � 1.82 0.77

0.44

16 (53.3)

2 (6.7)

12 (40.0)

0.12

11 (36.7)

11 (36.7)

8 (26.7)

9 (30.0) 0.34

18 (60.0) 0.79

14 (46.7) 0.05

0.02*

12 (40.0)

4 (13.3)

1 (3.3)

7 (23.3)

0 (0)

6 (20)

0.06

0 (0)

7 (23.3)

22 (73.3)

1 (3.3)

itney test.

rdiology; AHA � American Heart Association; CTFC � corrected TIMI

LCx � left circumflex artery; MLD � minimal lumen diameter; RCA �

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ified as a flap between the arterial lumen and the cavity ofhe plaque, and its thickness was measured at the thinnestart (ruptured FCT). For all FCT measurements, theverage of 3 measurements was recorded.

In all cases of plaque rupture, the incidence of plaquesuptured at cap shoulder or distally to the minimal lumenite, the length of the rupture, and the distance between theupture and the site of the minimal lumen diameter wereecorded.

Thin-cap fibroatheroma was defined as a lipid-richlaque with FCT �65 �m (17). Presence of thrombus andupture was also recorded. Intracoronary thrombus wasdentified as a medium-reflectivity mass protruding into theessel lumen discontinuous from the surface of the vesselall (10,19).tatistical analysis. Statistical analysis was performed usingtatView (version 5.0.1, SAS Institute Inc., Cary, Northarolina). Data are expressed as mean � SD for continuous

ariables and as percentages for categorical variables. Dif-erences between groups were assessed with the chi-squareest or Fisher exact test for categorical variables, and forontinuous variables with Student t, Mann-Whitney U,ruskal-Wallis, or analysis of variance tests as appropriate.orrelation between 2 continuous variables was calculatedith the Pearson correlation test. A receiver operating

haracteristic curve analysis was performed in order todentify a cut-off value of FCT for predicting TIMI flowrade 3. Unadjusted logistic regression models were esti-ated in order to identify clinical, angiographic, and OCT

arameters associated with TIMI flow grade 3. We consid-red p � 0.05 to indicate statistical significance. All clinical,ngiographic, and OCT factors that were considered sig-ificant in the univariate analysis were entered in theultivariate logistic regression analysis. Hosmer-Lemeshow

Table 3. Plaque Characteristics

TIMI Flow Grade 3(n � 25)

TIMI Flow Grade <2(n � 30) p Value

Number of lipid quadrants 0.0007*

0 0 0

1 5 (20.0) 1 (3.3)

2 12 (48.0) 7 (23.3)

3 6 (24.0) 8 (26.7)

4 2 (8.0) 14 (46.7)

Lipid-rich plaque 20 (80.0) 29 (96.7) 0.08

TCFA 4 (16.0) 24 (80.0) �0.0001

Minimum fibrous cap thickness,�m (plaque)

87 � 26 48 � 18 �0.0001

Rupture 6 (24.0) 21 (70.0) 0.001

OCT-detected thrombus 15 (60.0) 21 (70.0) 0.57

All values are expressed as n, mean � SD, or n (%). *Calculated with Mann-Whitney U test.

OCT � optical coherence tomography; TCFA � thin-cap fibroatheroma; TIMI � Thrombolysis In

Myocardial Infarction.

tatistic was calculated to evaluate model’s goodness-of-fit.

ollinearity of the independent variables was tested usinghe correlation matrix of the estimates. Collinear variablesere excluded from the model.

esults

aseline characteristics of the patients. We obtained OCTmaging from 59 patients. Four patients (6.8%) were ex-luded from the study due to inadequate image acquisitionsin 2 of those patients [TIMI flow grade 0] plaque mor-hology could not be evaluated due to great thrombusurden and in 2 patients [TIMI flow grades 2 and 3]ecause of insufficient flushing). Mean time from pain onseto start of thrombolysis was 3.08 � 0.97 h. Twenty-fiveatients had TIMI flow grade 3, 15 had TIMI flow grade 2,nd 15 patients had TIMI flow grades 0 to 1. The clinicalharacteristics of the patients are summarized in Table 1.here were no significant differences between the 2 groups.ngiographic results. The angiographic characteristics ofhe patients are summarized in Table 2. Increased thrombusurden was associated with reduced flow (Table 2).CT image analysis. All culprit plaques (n � 55) were

uccessfully visualized without any complication or adversevent during the procedure. Frames rejected due to poormage quality constituted �10% of acquired frames, andhe vast majority concerned sites located near the refer-nce sites.

Table 3 summarizes the findings from the OCT exami-ation. Minimal FCT was increased in patients with TIMIow grade 3 (p � 0.0001) (Table 3, Fig. 1). Furthermore,uptured lesions were more common in patients with TIMIow grade �2 (p � 0.001). The number of lipid quadrants

Figure 1. Minimal Cap Thickness and TIMI Flow Grade

Box plots of minimal fibrous cap thickness in patients with Thrombolysis InMyocardial Infarction (TIMI) flow grade �2 and in patients with TIMI flowgrade 3 at the culprit vessel. Minimal cap thickness was greater in patientswith TIMI flow grade 3 (p � 0.0001). The bottom of the box representsthe first quartile and the top of the box represents the third quartile, withthe line in the box representing the median. Whiskers represent 10th and
90th percentiles.

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as significantly higher in the culprit plaques of patientsith TIMI flow grade �2 (p � 0.001). No significantifferences were found in the incidence of thrombus be-ween the 2 groups (Table 3, Figs. 2 and 3).

We further investigated the association of plaque char-cteristics with the TIMI flow grade. For patients withIMI flow grades 0 or 1, minimal FCT was 41 � 7 �m; foratients with TIMI flow grade 2, 55 � 23 �m; and forhose with TIMI flow grade 3, 87 � 26 �m (p � 0.0001).n patients with TIMI flow grades 2 or 3, a correlation wasound between corrected TIMI frame count and the mini-al FCT (r � –0.423, p � 0.01) (Fig. 4). There were more

uptures in patients with TIMI flow grades 0 to 1 than inatients with TIMI flow grades 2 or 3 (n � 13, 86.7% forIMI flow grades 0 to 1; n � 8, 53.3% for TIMI flow grade; n � 6, 24% for TIMI flow grade 3; p � 0.001).oreover, the number of lipid quadrants was greater in

atients with TIMI flow grades 0 to 1 than in patients withIMI flow grades 2 or 3 (p � 0.001).In patients with ruptured plaques, both minimal FCT

nd ruptured FCT were greater in patients with TIMI flowrade 3 (83 � 35 �m vs. 41 � 10 �m, p � 0.0001; 100 �3 �m vs. 57 � 15 �m, p � 0.0001) (Fig. 5). Furthermore,inimal FCT was strongly correlated with the rupturedCT (r � 0.815, p � 0.0001). In ruptured plaques, thereere no differences between the group of TIMI flow gradesto 2 and the group of TIMI flow grade 3 regarding the

Figure 2. Representative OCT Study of a Patient With TIMI Flow II

Representative optical coherence tomography (OCT) images of the culprit lesioin the left anterior descending artery. Acquisition of the OCT image was perfolesion with OCT. The arrow shows the site of the rupture. (C) Minimal lumen(D) Thrombus (arrow) adjacent to the vessel wall. (E, F) Plaque disruption (yemeasurement of the ruptured cap thickness (white arrows). (G) Measurement
the minimal FCT (arrows) in a neighboring fibrous cap. GW � guidewire; L � lipid p
ean length of the rupture (3.43 � 2.24 mm vs. 2.81 �.06 mm, p � 0.53), the mean distance from the site of thereatest stenosis (2.69 � 2.00 mm vs. 3.35 � 2.69 mm, p �.47), the incidence of patients with plaque ruptured at thelaque shoulder (57% vs. 50%, p � 0.99), and the incidencef plaques ruptured distally to the minimal lumen site (62%s. 67%, p � 0.99).

The lesions were categorized into 4 groups according tohe presence or not of thin cap (�65 �m), plaque rupture,nd lipid-rich plaque. Two or more characteristics werebserved in 86.7% (26 of 30) of patients with TIMI flowrade �2, compared with only 28% (7 of 25) of patientsith TIMI flow grade 3 (p � 0.0001). Accordingly, �1

haracteristic was observed in 72% (18 of 25) of patientsith TIMI flow grade 3, compared with 13.3% (4 of 30) ofatients with TIMI flow grade �2 (p � 0.0001) (Fig. 6).Sensitivity-specificity analysis revealed that cap thickness has

ery good discriminating ability in classifying patients intoatients with TIMI flow grade 3 and patients with TIMI flowrade �2 (area under the curve � 0.885, p � 0.001).oreover, a value �78.5 �m is optimal in discriminating

atients into 2 groups (sensitivity � 80%, specificity � 90%).The univariate logistic regression analysis, using TIMI

ow grade 3 as a dependent variable, showed that theariables that predicted TIMI flow grade 3 were AET (oddsatio [OR]: 0.286; 95% confidence interval [CI]: 0.085 to.963), the presence of plaque rupture (OR: 0.135; 95% CI:

patient with TIMI flow grade 2. (A) Coronary angiogram of the culprit lesionin the segment defined by the lines. (B) Longitudinal view of the culpritth predominantly fibrotic plaque and a small lipid pool at 11th to 3rd hour.rrow) at the area of a lipid pool demonstrated in consecutive frames ande associated with the ruptured site fibrous cap (arrows). (H) Measurement of

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.041 to 0.452), the number of lipid quadrants (OR: 0.318;5% CI: 0.160 to 0.632), and the minimal FCT (OR for0-�m increase: 2.078; 95% CI: 1.433 to 3.177). In theultivariate logistic regression analysis (Table 4), we in-

luded the presence of AET, the presence of plaque rupture,he number of lipid quadrants, and the minimal FCT. Throm-us burden was not entered in the multivariate analysis, as itas collinear with AET. Only the minimal FCT of the plaqueas independently associated with TIMI flow grade 3 (OR for0-�m increase: 1.84; 95% CI: 1.23 to 2.76).

iscussion

he main findings of the present study indicate that lesionsf patients with STEMI and TIMI flow grade 3 afterhrombolysis have greater minimal FCT, reduced incidencef plaque rupture, and less lipid quadrants. In this study, thessociation of specific morphologic plaque characteristicsith the outcome of thrombolysis is reported.Although thrombolysis reduces mortality, only about half

f the patients achieve normal flow after thrombolysis (1).

Figure 3. Representative OCT Study of a Patient With TIMI Flow Grade 3

Representative OCT images of the culprit lesion of a patient with TIMI flow gradeAcquisition of the OCT image was performed in the segment defined by the linesthe thinnest cap (arrows) measuring 120 �m is also located. (D) Small thrombus

everal predictors of coronary blood flow following throm- s

olytic administration have been suggested (3,4). However,he impact of morphological characteristics of the culpritesion on blood flow restoration has not been studied,ossibly due to the lack of high-resolution imaging meth-ds. Lately, the use of OCT allows accurate fibrous capeasurement due to its excellent spatial resolution, although

he limited penetration of OCT permits partial plaqueomponent characterization (9,10,17,18,20,21).

The increased concentration of tissue factor has beenssociated with failed thrombolysis (22), and the findings ofhe current study can be interpreted by the increased tissueactor content. In this study, the morphological factorsssociated with blood flow after thrombolysis were thehickness of fibrous cap, the lipid content, and the presence ofupture. Although FCT was the only independent variablessociated with TIMI flow grade 3, the other 2 variables werelso predictive, as indicated in the univariate analysis. Previoustudies have shown an increased number of macrophages inuptured plaques with thin fibrous cap and increased lipidontent (18). In addition, macrophage concentration has been

Coronary angiogram of the culprit lesion in the left anterior descending artery.ongitudinal view of the culprit lesion with OCT. (C) Minimal lumen site, wherents (arrow) in the lumen. Abbreviations as in Figure 2.

3. (A). (B) L

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Recent studies revealed that the specific morphologicalharacteristics are included in the definition of thin-capbroatheroma (18). Indeed, the majority of lesions (64%)ith impaired flow had thin cap �65 �m, plaque with2 lipid quadrants, and rupture. Interestingly, 100% of

atients with TIMI flow grades 0 to 1 had �2 of theentioned characteristics. These findings stress the im-

ortance of plaque morphology in target vessel patencyfter thrombolysis.

Moreover, an interaction of the lipid content and theupture with the minimal FCT may explain our findings

Figure 4. TIMI Frame Count and Minimal Cap Thickness

Correlation of the corrected Thrombolysis In Myocardial Infarction (TIMI)frame count with the minimal fibrous cap thickness.

Figure 5. Ruptured Cap Thickness and TIMI Flow Grade

Box plots of the ruptured fibrous cap thickness (FCT) in patients withThrombolysis In Myocardial Infarction (TIMI) flow grade �2 and in patientswith TIMI flow grade 3. Ruptured FCT was greater in patients with TIMIflow grade 3 (p � 0.0001). The bottom of the box represents the firstquartile and the top of the box represents the third quartile, with the linein the box representing the median. Whiskers represent 10th and 90th
percentiles.
21). All patients with impaired flow had �90 �m, and 80%f them had �50 �m minimal FCT. Although the rupturedCT was also greater in patients with TIMI flow grade 3,e cannot exclude the possibility that adjacent thin fibrous

aps within the culprit lesions are associated with reducedatency after thrombolysis.In our study, in 50.9% of the total cohort and in 76% of

atients with TIMI flow grade 3 no rupture was identified.n these patients, the pathogenesis of the infarction mighte attributed to other mechanisms, such as erosion oralcific nodule (18), or could be related to plaque ruptureot detectable by OCT, despite OCT having the greatestotential for rupture identification (10).tudy limitations. An OCT examination was performedithin 48 h from thrombolysis, and reocclusion of a patent

rtery after thrombolysis could be possible. However, clinicallyvident reocclusion was eliminated on the basis of our exclu-ion criteria. Moreover, spontaneous reperfusion cannot bexcluded. Nevertheless, whether thrombolysis was pharmaceu-ical or spontaneous was beyond the scope of this study.

Figure 6. Prevalence of Morphological Characteristics According toTIMI Flow Grade

Diagram showing the characteristics of the culprit atheromatic plaque (thincap [�65 �m], lipid-rich plaque, and plaque rupture) according to TIMIflow grade: 0 � no characteristics; 1 � 1 characteristic; 2 � co-existence of2 characteristics; 3 � presence of all 3 characteristics. TIMI � ThrombolysisIn Myocardial Infarction.

Table 4. Multivariate Analysis of the Factors Associated WithTIMI Flow Grade 3 Following Thrombolysis

Variable Odds Ratio 95% CI p Value

AET 0.43 0.08–2.21 0.36

10-�m increase of minimumfibrous cap thickness

1.84 1.23–2.76 0.003

Rupture 0.52 0.21–1.37 0.44

Number of lipid quadrants 0.54 0.2–1.42 0.19

CI � confidence interval; other abbreviations as in Table 2.

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A difference in the incidence of thrombus was foundetween angiography and OCT, possibly due to the in-reased sensitivity of OCT. However, the clinical signifi-ance of OCT-detected thrombus is not known yet.

Aspiration thrombectomy was performed in patients withIMI flow grades 0 to 1 prior to OCT examination foretter visualization, as performed in previous studies10,21). Although aspiration may modify the morphologyf the culprit plaques, and the number of ruptures wasncreased in patients with TIMI flow grades 0 to 1, theonclusions of our study seem not to be affected as: 1) thereas a difference in minimal FCT even between patientsith TIMI flow grades 2 and 3, in whom thrombectomyas not performed; and 2) the aspirated plaque components,

ncluding thrombus and lipid (24), might underestimate theesults of the present study. Finally, previous studies haveemonstrated that the predominant plaque characteristicsre not affected by thrombolysis (25).

onclusions

he results of the current study showed that the morpho-ogical characteristics of the culprit atheromatic lesion inatients with acute myocardial infarction are associated withoronary flow after thrombolysis. Although several knownactors affect the outcome of thrombolysis in acute myocar-ial infarction, certain morphological factors of the athero-atic plaque, and mainly the thickness of the fibrous cap,

eed to be considered.

eprint requests and correspondence: Dr. Konstantinos Tout-uzas, Department of Cardiology, Athens Medical School, 26araoli and Dimitriou Street, Holargos, Athens 15562, Greece.-mail: [email protected].

EFERENCES

1. Weaver WD, Simes RJ, Betriu A, et al. Comparison of primarycoronary angioplasty and intravenous thrombolytic therapy for acutemyocardial infarction: a quantitative review. JAMA 1997;278:2093–8.

2. Laster SB, O’Keefe JH Jr., Gibbons RJ. Incidence and importance ofthrombolysis in myocardial infarction grade 3 flow after primarypercutaneous transluminal coronary angioplasty for acute myocardialinfarction. Am J Cardiol 1996;78:623–6.

3. Gibson CM, Murphy S, Menown IB, et al. Determinants of coronaryblood flow after thrombolytic administration. TIMI Study Group.Thrombolysis in Myocardial Infarction. J Am Coll Cardiol 1999;34:1403–12.

4. Lundergan CF, Reiner JS, McCarthy WF, Coyne KS, Califf RM, RossAM. Clinical predictors of early infarct-related artery patency followingthrombolytic therapy: importance of body weight, smoking history,infarct-related artery and choice of thrombolytic regimen: theGUSTO-I experience. Global Utilization of Streptokinase and t-PAfor Occluded Coronary Arteries. J Am Coll Cardiol 1998;32:641–7.

5. Lenderink T, Simoons ML, Van Es GA, Van de Werf F, VerstraeteM, Arnold AE. Benefit of thrombolytic therapy is sustained through-out five years and is related to TIMI perfusion grade 3 but not grade 2
flow at discharge. The European Cooperative Study Group. Circula-tion 1995;92:1110–6. t
6. Anderson JL, Karagounis LA, Becker LC, Sorensen SG, Menlove RL.TIMI perfusion grade 3 but not grade 2 results in improved outcomeafter thrombolysis for myocardial infarction. Ventriculographic, enzy-matic, and electrocardiographic evidence from the TEAM-3 Study.Circulation 1993;87:1829–39.

7. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMImyocardial perfusion grade to mortality after administration of throm-bolytic drugs. Circulation 2000;101:125–30.

8. Jang IK, Bouma BE, Kang DH, et al. Visualization of coronary athero-sclerotic plaques in patients using optical coherence tomography: compar-ison with intravascular ultrasound. J Am Coll Cardiol 2002;39:604–9.

9. Regar E, Schaar JA, Mont E, Virmani R, Serruys PW. Opticalcoherence tomography. Cardiovasc Radiat Med 2003;4:198–204.

0. Kubo T, Imanishi T, Takarada S, et al. Assessment of culprit lesionmorphology in acute myocardial infarction: ability of optical coherencetomography compared with intravascular ultrasound and coronaryangioscopy. J Am Coll Cardiol 2007;50:933–9.

1. Gibson CM, Sandor T, Stone PH, Pasternak RC, Rosner B, SacksFM. Quantitative angiographic and statistical methods to assess serialchanges in coronary luminal diameter and implications for atheroscle-rosis regression trials. Am J Cardiol 1992;69:1286–90.

2. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase Ifindings. TIMI Study Group. N Engl J Med 1985;312:932–6.

3. Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: aquantitative method of assessing coronary artery flow. Circulation1996;93:879–88.

4. Gibson CM, de Lemos JA, Murphy SA, et al. Combination therapywith abciximab reduces angiographically evident thrombus in acutemyocardial infarction: a TIMI 14 substudy. Circulation 2001;103:2550–4.

5. Kataiwa H, Tanaka A, Kitabata H, et al. Head to head comparisonbetween the conventional balloon occlusion method and the non-occlusion method for optical coherence tomography. Int J Cardiol 2009Aug 5 [E-pub ahead of print].

6. Prati F, Cera M, Ramazzotti V, et al. From bench to bedside: a noveltechnique of acquiring OCT images. Circ J 2008;72:839–43.

7. Jang IK, Tearney GJ, MacNeill B, et al. In vivo characterization ofcoronary atherosclerotic plaque by use of optical coherence tomogra-phy. Circulation 2005;111:1551–5.

8. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of thevulnerable plaque. J Am Coll Cardiol 2006;47:C13–8.

9. Prati F, Regar E, Mintz GS, et al. Expert review document onmethodology, terminology, and clinical applications of optical coher-ence tomography: physical principles, methodology of image acquisi-tion, and clinical application for assessment of coronary arteries andatherosclerosis. Eur Heart J 2010;31:401–15.

0. Kume T, Akasaka T, Kawamoto T, et al. Measurement of the thicknessof the fibrous cap by optical coherence tomography. Am Heart J2006;152:755.e1–4.

1. Tanaka A, Imanishi T, Kitabata H, et al. Morphology of exertion-triggered plaque rupture in patients with acute coronary syndrome: anoptical coherence tomography study. Circulation 2008;118:2368–73.

2. Ragni M, Cirillo P, Pascucci I, et al. Monoclonal antibody againsttissue factor shortens tissue plasminogen activator lysis time andprevents reocclusion in a rabbit model of carotid artery thrombosis.Circulation 1996;93:1913–8.

3. Moreno PR, Bernardi VH, Lopez-Cuellar J, et al. Macrophages,smooth muscle cells, and tissue factor in unstable angina. Implicationsfor cell-mediated thrombogenicity in acute coronary syndromes. Cir-culation 1996;94:3090–7.

4. Suzuki N, Kozuma K, Kyono H, et al. Angiographic and clinicalcharacteristics associated with the removable plaque components bymeans of thrombectomy catheters in patients with myocardial infarc-tion. Cardiovasc Revasc Med 2007;8:236–42.

5. Van Belle E, Lablanche JM, Bauters C, Renaud N, McFadden EP,Bertrand ME. Coronary angioscopic findings in the infarct-relatedvessel within 1 month of acute myocardial infarction: natural historyand the effect of thrombolysis. Circulation 1998;97:26–33.

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