The Clinical Significance of Echo Signal The Clinical Significance of Echo Signal Attenuation on Intravascular Ultrasound in Attenuation on Intravascular Ultrasound in Patients with Coronary Artery DiseasePatients with Coronary Artery Disease

Name : Shigeki Kimura , MD1) 　 Tsunekazu Kakuta, MD2) Taishi Yonetsu, MD2) Asami Suzuki, MD2) Yoshito Iesaka, MD2)

　　 　　　 Hideomi Fujiwara, MD2) Mitsuaki Isobe, MD1)

1)Department of Cardiovascular Medicine, Tokyo Medical and Dental

University, Tokyo, Japan

2)Division of Cardiology, Cardiovascular Center, Tsuchiura Kyodo Hospital,

Ibaraki, JapanPresented in part at the Annual Scientific Sessions 2005, AHA, Dallas

S Kimura, T Kakuta, et al. Circ Cardiovasc Intervent. 2009;2:444-454.

Presenter Disclosure InformationPresenter Disclosure Information

Name : Shigeki Kimura, MD, Tsunekazu Kakuta, MD Taishi Yonetsu, MD, Asami Suzuki, MD Yoshito Iesaka, MD, Hideomi Fujiwara, MD Mitsuaki Isobe, MD

Nothing to Disclose Related to This Presentation

Backgrounds1 Backgrounds1

Atherosclerotic plaque that shows echo signal attenuation (EA) without associated bright echoes is sometimes observed by intravascular ultrasound (IVUS), although its clinical significance remains unclear.

Circ J. 2007;71:648-653

Okura et al. reported that atherosclerotic plaque with ultrasonic attenuation (EA) may be related to a transient deterioration in coronary flow during PCI in patients with acute coronary syndrome (ACS)

Backgrounds 2Backgrounds 2A recent IVUS study reported that high level CRP, angiographic thrombus, deteriorated initial coronary flow, greater plaque burden, positive remodeling and plaque rupture were associated with attenuated plaque, and post-PCI no-reflow were frequent in ACS lesions with attenuated plaque. No attenuated plaque was observed in lesions with stable angina pectoris.

JACC Cardiovasc Interv.2009;2:65-72

Several histopathological studies suggested that the presence of microcalcification and lipid rich plaque components might be associated with echo attenuation.

Acute Cardiac Care. 2006;8 110-112J Cardiol 2007 50 (4) 223-228

AimsAims

To investigate the impact of EA on coronary perfusion and clinical outcome after PCI in patients with coronary artery disease.

Further, to evaluate the pathological features of plaque with EA obtained by DCA

Method 1Method 1Six hundred and eighty seven lesions in 687 consecutive patients (535 men and 152 women) who underwent preintervention IVUS were investigated.

Exclusion: *in-stent restenotic lesions *bypass graft lesions *multiple culprit lesions *heavily calcified lesions *lesions treated with Rotablator or distal protection devices

Method 2Method 2Quantitative coronary angiography was performed with a CMS-MEDIS system (Medis Medical Imaging System, Leiden, The Netherlands)

Coronary flow was assessed according to Thrombolysis in Myocardial infarction (TIMI) flow grade and corrected TIMI frame count (CTFC)

Angiographic no reflow was defined as TIMI grade 0-2

Myocardial perfusion was assessed by the myocardial blush grade (MBG)

Method 3Method 3IVUS : Commercially available IVUS system, 40-MHz

Boston Scientific Corporation/SciMed Automatic pullback of 0.5mm/s Plaque morphologies were qualitatively and quantitatively analyzed by two experienced observer according to the AmericanCollege of Cardiology Clinical Expert Consensus Document on IVUS

The culprit lesion was defined as the site of the smallest lumen and the reference site was set at the most normal looking region within 10mm proximal to it

J Am Coll Cardiol. 2001; 37:1478-1492

Methods 4Methods 4Definition of echo signal attenuation on IVUSIVUS findings showing ultrasound signal attenuation without very high intensity echo reflectors that involved >90 degrees of the vessel circumference and involved of >1mm

Method 5Method 5All lesions were divided into two groups. (Group A: lesions with EA, Group NA: lesions without EA)

Between the two groups, the differences in patient characteristics and lesion morphologies were compared.

By subgroup analysis, 60 DCA samples (30 with EA and 30 without EA) underwent pathological examination

Coronary flow after PCI and clinical outcome were compared between the two groups (DCA lesions were excluded from the analysis of coronary flow)

Method 6Method 6

The relationship between no reflow (TIMI 0-2) after PCI, EA and other variables (clinical characteristics, coronary risk factors, lesion morphologies on IVUS, angiographic characteristics, interventional strategies, and medications) was evaluated by multivariate logistic regression analysis

Methods 7Methods 7

DCA was performed with IVUS guidance

Directional removal of the plaque with EA was intended

DCA samples were immediately immersion-fixed in 10% 　　　 buffered formalin and embedded in paraffin

These segments were stained with hematoxilin-eosin, Von Kossa stain and immunostaing with an anit-CD 68 antibody (M814 DAKO)

Pathological assessment

Methods 8Methods 8In each lesion, the percent areas of the following 4 tissues were measured and averaged: (1) fibrous tissue (few cells and dense collagen fibers) (2) lipid-rich atheromatous tissue (foam cells, cholesterol clefts, and acellular debris) (3) hypercellular tissue (a loose connective tissue matrix containing numerous stellate cells) (4) thrombus (fibrin deposits)

Circulation.2000;102:2180–2184

Lipid rich atheromatous tissue

Fibrous tissue Hypercellular tissue

Thrombus

Methods 9Methods 9In addition, the presence of the following components was semi-quantitativelygraded (0; absent, 1:sparse, and 2 abundant) and the mean grade for each lesion was calculated: macrophages, cholesterol clefts, hemosiderin, microcalcification (small

calcium flecks <50 µ in diameter), and dense calcification (larger calcified masses

Macrophages Cholesterol cleft

Hemosiderin

Microcalcification

Dense calcification

Age (yrs) 66±14 64±12 ns 66±11 65±10 nsFemale gender 33 (22.5%) 38(20.1%) ns 19 (19.4%) 62 (24.5%) nsCurrent Smoker 67 (45.6%) 82 (43.4%) ns 31 (31.6%) 73 (28.9%) nsDiabetes mellitus 54 (36.7%) 56 (29.6%) ns 34 (34.7%) 115 (45.5%) nsHyperlipidemia 67 (45.6%) 96 (50.8%) ns 54 (55.1%) 160 (63.2%) nsHypertention 95 (64.6%) 124 (65.6%) ns 71 (72.5%) 179 (70.8%) nsPrevious myocardial infarction 18 (12.2%) 24 (12.7%) ns 50 (51.0%) 108 (42.7%) nsAspirin use 46 (31.3%) 73 (38.6%) ns 84 (85.7%) 231 (91.3%) nsTiclopidine use 34 (23.1%) 48 (25.4%) ns 60 (61.2%) 167 (66.0%) nsStatins use 38 (25.9%) 44 (23.3%) ns 45 (45.9%) 141 (55.7%) ns

Patient characteristics

A (n=147) NA (n=189) P

ACS: acute coronary syndrome, SAP: stable angina pectoris

A : echo attenuation, NA: non-attenuation

EA was detected in 245 lesions (35.7%)The frequency of EA was significantly higher in ACS than in SAP (43.8% in ACS vs. 27.9% in SAP, p<0.001)

Results 1Results 1

A (n=98) NA (n=253)P

ACS (336) SAP (351)

LAD/RCA/LCX/LMT 76/51/20/0 86/70/25/8 ns 19/46/26/7 102/87/53/11 p<0.05 B2/C* 106 (72.1%) 129 (68.3%) ns 50 (51.0%) 148 (58.5%) nsPre-RD (mm) 3.0 ± 0.7 2.8 ± 0.6 p<0.05 2.9 ± 0.6 2.8 ± 0.6 p<0.05 Pre-MLD (mm) 0.9 ± 0.6 0.9 ± 0.6 ns 1.4 ± 0.4 1.4 ± 0.4 nsLesion length (mm) 18.0 ± 5.8 17.5 ± 5.9 ns 16.5 ± 5.1 16.2 ± 5.7 ns LV EF<40% 20 (13.6%) 17 ( 9.0%) ns 7 ( 7.1%) 18 ( 7.1%) nsPre-TIMI** (0~2) 92 (62.6%) 107 (56.6%) ns 4 ( 4.1%) 11 ( 4.3%) ns

A (n=147) NA (n=189) P

ACS: acute coronary syndrome, SAP: stable angina pectoris, A : echo attenuation, NA: non-attenuationLAD, left anterior descending artery; RCA, right coronary artery; LCX, left circumflex artery; LMT, left main trunk

*Lesion complexity was assessed according to the modified classification of the ACC/AHA. **TIMI: Thrombolysis in Myocardial Infarction (TIMI) flow gradeRD: reference diameter, MLD: minimal lumen diameter, EF: ejection fraction

Results 2Results 2

A (n=98) NA (n=253)P

ACS SAP

Angiographic lesion characteristics

Reference EEM CSA 18.2 ± 6.4 16.3 ± 4.9 p<0.01 16.4 ± 4.7 14.5 ± 5.2 p<0.01 (mm2) Lesion EEM CSA 18.9 ± 5.7 15.2 ± 5.2 p<0.001 16.8 ± 5.4 12.8 ± 4.6 p<0.001 (mm2)Lesion lumen CSA 2.1 ± 0.7 2.2 ± 0.8 ns 2.5 ± 1.0 2.3 ± 1.0 ns (mm2)Lesion plaque area 16.7± 5.5 13.1 ± 5.0 p<0.001 14.3 ± 5.4 10.5 ± 4.1 p<0.001 (mm2)Lesion plaque burden* 88.5 86.0 p<0.001 84.4 81.6 p<0.001 (%) (85.9 to 91.0) (80.4 to 89.4) (81.0 to 88.8) (77.0 to 85.6)

Results 3Results 3

ACS: acute coronary syndrome, SAP: stable angina pectoris, A : echo attenuation, NA: non-attenuation

EEM: external elastic membrane, CSA: cross sectional area

*Plaque area divided by (EEM-CSA) x100, presented as medians with interquartile ranges.

Quantitative Coronary Ultrasound

A (n=147) NA (n=189) P A (n=98) NA (n=253)P

ACS SAP

Positive remodeling 81 (55.1%) 44 (23.3%) p<0.001 44 (44.9%) 59 (23.3%) p<0.001

Eccentricity 125 (85.0%) 132 (69.8%) p<0.05 86 (87.8%) 188 (74.3%) p<0.01

Thrombus 78 (53.1%) 105 (55.6%) ns 　 8 ( 8.2%) 7 ( 2.8%)

p<0.05

Lipid core 39 (26.5%) 37 (19.6%) ns 22 (22.4%) 26 ( 10.3%) p<0.01

Ruptured plaque 83 (56.5%) 110 (58.2%) ns 23 (23.5%) 41 (16.2%) ns

Mild Calcification* 71 (48.3%) 37 (19.6%) 　 p<0.001 50 (51.0%) 71 (28.1%)

p<0.001

Results 4Results 4

ACS: acute coronary syndrome, SAP: stable angina pectoris

A : echo attenuation, NA: non-attenuation

*presence of Mild Calcification was defined as having calcification with less than 90 ゜ in IVUS

Lesion Morphologies in IVUS

A (n=147) NA (n=189) A (n=98) NA (n=253)P

ACS SAPP

Baseline Final

ACS

A NA A NA

SAP

P<0.001

NSP=0.03

30.2

29.5

8.5

31.8

38.9

26.8

10.3

24.0

78.3

19.42.3

96.0

4.0

95.3

3.51.2

95.4

4.2 0.4

94.2

4.71.1

98.7

1.3

TIMI flow grade during PCI

Results 5Results 5NS

A NA A NA

TMG 0

TMG 1

TMG 2

TMG 3

100

80

60

0

%

40

20

100

80

60

0

%

40

20

Results 6Results 6

Group A

Group NA

60

ACS SAP60

40 40

20 20

0 0

% %

NS

51.1

43.4

10.1

0.6

NS

P<0.001

2.3 1.33.5

0.0

P<0.001

Frequencies of inadequate coronary flow during PCI (CTFC>40)

Baseline Final Baseline Final

MBG 0

MBG 1

MBG 2

MBG 3

Baseline Final

ACS

A NA A NA

SAP

A NA A NA

NS P<0.001

NS

20.1

23.3

17.1

39.5

27.4

25.7

11.4

35.5

45.7

42.6

6.2

64.6

33.1

87.2

9.31.2

85.7

11.82.1

67.4

31.4

89.0

11.0

Myocardial blush grade during PCI

5.5 2.3

2.3 0.4 1.2

P<0.001

Results 7Results 7100

80

60

0

%

40

20

100

80

60

0

%

40

20

Results 8Results 8

Group A

Group NA

60

Procedural MN* Procedural MI**

60

40 40

20 20

0 0

% %

48.9

19.8

32.6

P<0.001 P<0.05

17.0

4.99.3

3.0

P<0.01

Frequencies of Peri-Procedural Myocardial Damage

UAP SAP UAP SAP

16.9

P<0.05

*Myocardial necrosis: elevation of creatine kinase after PCI above the 99th percentile of the

reference range

**Myocaridal infarction: elevation of creatine kinase after PCI by more than 3 times the uppser

limit of the reference range

Fatal arrhythmia 3 ( 2.5) 0 ( 0.0) ns 0 ( 0.0) 0 ( 0.0) nsCHF* 9 ( 7.6) 3 ( 1.9) p<0.05 4 (4.8) 3 (1.3) nsDisabling stroke 1 (0.8) 0 ( 0.0) ns 0 (0.0) 0 (0.0) nsReinfarction 1 (0.8) 0 (0.0) ns 0 (0.0) 1 (0.4) nsIschemic TVR** 9 (7.6) 7 (4.4) ns 1 (1.2) 7 (3.1) nsCardiac surgery 0 (0.0) 1 (0.6) ns 1 (1.2) 0 (0.0) nsCardiac death 0 (0.0) 0 (0.0) ns 0 (0.0) 0 (0.0) nsMACE † 9 (7.6) 7 (4.4) ns 1 (1.2) 7 (3.1) nsTotal Cardiac Events‡ 20 (16.8) 10 (6.3) p<0.01 5 (6.0) 9 (3.9) ns

Results 9Results 9

ACS: acute coronary syndrome, SAP: stable angina pectoris, A : echo attenuation, NA: non-attenuation

*congestive heart failure, ** target vessel revascularization, †Cardiac death, ischemic TVR, or reinfarction.‡MACE, cardiac surgery, fatal arrhythmia, congestive heart failure, or unstable angina

Clinical outcome During 1 Year of Follow-up

A (n=119) NA (n=159) A (n=84) NA (n=229)P

ACS SAP

P

Frequency of TIMI 0-2 after PCI (%) Variable Factor Present Factor Absent OR (95% CI) P

Baseline TIMI 0 to 2 15.6 2.4 7.47 (3.60 to 15.48) p<0.001Echo signal attenuation 15.4 2.4 7.29 (3.52 to 15.11) p<0.001Acute coronary syndrome 11.5 2.5 5.12 (2.34 to 11.23) p<0.001Primary aspiration 15.0 3.7 4.55 (2.40 to 8.62) p<0.001Ruptured plaque 12.7 3.1 4.47 (2.25 to 8.88) p<0.001Thrombus (IVUS) 14.4 3.8 4.27 (2.26 to 8.88) p< 0.001Large reference area* 10.8 2.9 4.07 (1.92 to 8.64) p<0.001Current smoker 11.4 4.4 2.77 (1.48 to 5.20) p<0.001Ejection fraction <40% 15.0 6.0 2.77 (1.26 to 6.09) 0.02Large plaque burden† 9.9 3.8 2.75 (1.38 to 5.46) 0.003Positive remodeling 11.2 4.7 2.54 (1.36 to 4.74) 0.003Lipid core 11.1 6.0 1.97 (0.98 to 3.97) 0.055LAD 9.3 5.4 1.80 (0.97 to 3.35) 0.061Long lesion** 8.6 5.1 1.76 (0.93 to 3.33) 0.08Previous MI 3.7 8.2 0.43 (0.19 to 0.98) 0.058Statins 3.7 8.9 0.39 (0.18 to 0.82) 0.02Ticlopidine 2.7 10.6 0.23 (0.11 to 0.51) p<0.001Aspirin 3.3 13.9 0.21 (0.11 to 0.41) p<0.001

*reference area: > median **Lesion length > median, ACS: acute coronary syndrome

Results 10 Univariate analysis for worse coronary flow after PCI

Variable Coefficient Standard Error OR(95% CI) P

Baseline TIMI0-2 1.78 0.38 5.91 (2.79~12.51) 　 p<0.001

Echo signal attenuation 1.72 0.38 5.59 (2.64~11.85) p<0.001

Large reference area* 1.12 0.40 3.08 (1.40~ 6.76) 0.005

*plaque area > median, OR: odds ratio, CI: confidence interval,

TIMI: Thrombolysis in Myocardial Infarction(TIMI) flow grade

Results 11 Multivariate analysis for worse coronary flow after PCI

Results 12Mean Percentage Area of Each Plaque Component

60

74.5

40

9.5

2020.5

00

%

18.5

0.72.4

P<0.001

P<0.01

Atheromatous tissue

55.7

Fibrous tissue

Hypercellular tissue

Thrombus

ns

P<0.05

80

Group A

Group NA

Macrophages 1.2±0.8 0.7±0.7 p<0.01

Cholesterol clefts 1.5±0.7 0.8±0.7 p<0.001

Hemosiderin 0.7±0.8 0.3±0.6 ns

Microcalcification 1.4±0.8 0.8±1.0 p<0.01

Dense calcification 0.7±0.9 0.8±0.9 ns

Results 13Results 13Comparison of the mean grade of each plaque component

With EA Without EA P

Representative case (Female, 62 y.o)

Target lesion was detected in left circumflex artery.

DCA was performed. Stent was implanted.

Echo signal attenuation was detected.

Pre DCAPost DCA

Lipid rich plaque Microcalcium deposit, cholesterol clefts and acellular debris were observed.

Pathological findingsH-E

Presented at the Annual Scientific Sessions 2005 of the American Heart Association, Dallas

The plaque was strongly stained by CD 68, CD36, Berlin Blue, CRP-8, respectively

CD 68

CD 36

Berlin Blue

CRP-8

Presented at the Annual Scientific Sessions 2005 of the American Heart Association, Dallas

In SummaryEA was significantly more frequent in the culprit lesions of ACS than in those of SAP

Coronary flow and myocardial perfusion after PCI were worse and the frequency of myocardial damage was higher in patients with either ACS or SAP whose culprit lesion showed EA on IVUS

Multivariate analysis revealed a significant association between no reflow after PCI and EA along with a baseline TIMI grade 0-2 and a large reference area by IVUS

EA was predominantly found in lesions from vessels with a large reference diameter and significant plaque burden. Lesions with EA showed a high frequency of positive remodeling, eccentricity, and mid calcification<90 degrees

Histopathological examination of specimens obtained by DCA revealed a significantly higher prevalence of lipid-rich plaque, macrophage infiltration, cholesterol clefts, thrombus, and microcalcification in lesions with EA than in those without

*

*

*

*

*

S Kimura, T Kakuta, et al. Circ Cardiovasc Intervent. 2009;2:444-454.

Conclusion

EA was detected in 35.7% of the culprit plaques, and was more common in patients with ACS than with SAP.

Detection of EA in culprit lesions was a strongindependent predictor of no reflow after PCI.

EA might indicate that a lesion contains high-risk plaque components that are susceptible to distal embolization.

S Kimura, T Kakuta, et al. Circ Cardiovasc Intervent. 2009;2:444-454.