invasive diagnosticinvasive diagnostic ik-kyung jang, md, phd associate professor of medicine ......

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Invasive Diagnostic

Ik-Kyung Jang, MD, PhD

Associate Professor of MedicineHarvard Medical School

Massachusetts General Hospital

Angioplasty Summit 2008

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Stable vs Vulnerable Plaque

• Low lipid conc. • High lipid conc.• Thick fibrous cap • Thin fibrous cap• Low mΦ density • High mΦ density

Stable Plaque Vulnerable Plaque

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Current Technology for VP Identification

Non invasive- CTA- MR

Invasive- Anatomic- Physiologic

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Intravascular Modalities

IVUSAngioscopyIV MROCT

ThermographySpectroscopy

Anatomic Information

Biochemical Information

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Intravascular Modalities

IVUSAngioscopyIV MR OCT


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IVUS

• Echolucency

• Remodeling

• Distensibility

LesionProximal Ref

Diastole Systole

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IVUS

• Echolucency

• Remodeling

• Distensibility

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Prevalence of Echolucent Area on IVUS

Yamagishi et al. JACC 2000

66.7

83.3

4.421.1

ACS Non-ACS

(%)

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Echolucent Area: Unstable vs stable angina

Schoenhagen et al. Circulation 2000

0%

10%

20%

30%

40%

50%

Echolucent Echodense Mixed Calcified

Unstable Stable

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Echolucency

• Previous histological studies have demonstrated that the discrimination of lipid is inconsistent using greyscale images alone.– Palmer et al. Eur Heart J., 1999– Peters et al. J Am Soc

Echocardiogr., 1994– Peters et al. Circulation, 1994

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IVUS vs OCT (n = 145)

100100.01.82 quadrant lipid

9393.922.71 quadrant lipid

8897.06.3Superficial lipid

9597.017.9Deep lipid

PPV (%)Specificity (%)Sensitivity (%)

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IVUS

• Echolucency

• Remodeling

• Distensibility

Lesion

Proximal Reference

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Vascular remodeling:Unstable vs stable angina

Schoenhagen et al. Circulation 2000

0%10%20%30%40%50%60%70%

PositiveRemodeling

Absence ofRemodeling

NegativeRemodeling

Unstable Stable

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IVUS

• Echolucency

• Remodeling

• Distensibility

Diastole

Systole

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Arterial DistensibilityResults

Lipid Rich Mixed Fibrous PNumber 7 6 16

EEM CSA (mm2) 16.1 ± 7.2 16.9 ± 4.6 17.1 ± 0.4 NSLumen CSA (mm2) 7.2 ± 1.4 8.5 ± 3.6 8.5 ± 0.4 NSPlaque Volume (mm2) 8.9 ± 5.2 8.4 ± 3.5 8.6 ± 2.9 NS

Distensibility 2.8 ± 1.8 1.7 ± 0.9 1.0 ± 0.8 0.004Index (mmHg-1)

MacNeill & Jang

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IVUS

• Echolucency

• Remodeling (Plaque volume)

• Distensibility

LesionProximal Ref

Virtual Histology

Palpography

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FIBROUS

FIBROLIPIDIC

CALCIUM

LIPID CORE

MEDIA

VH Legend

Virtual Histology™ IVUS

Classification Tree

M a xP < -2 5.05T yp e: C ol la ge n

# of RO Is : 5

M a xP > -2 5.05T yp e: C ol la ge n

# of RO Is : 2 6

Int < -28 .65# of RO Is : 3 1

Int < -14 .8T yp e: C ol la ge n

# of RO Is : 5

Int > -14 .8T yp e: C ol la ge n

# of RO Is : 5

F at M a xP < 21 .04 5# of RO Is : 1 0

F at M a xP > 21 .04 5T yp e: C ol la ge n

# of RO Is : 1 7

M B F < -6 5.0 9# of RO Is : 2 7

Int < -4.1 95T yp e: C al c iu m

# of RO Is : 6

Int > -4.1 95T yp e: C ol la ge n

# of RO Is : 5

M B F > -6 5.0 9# of RO Is : 1 1

F at M a xP < 30 .03# of RO Is : 3 8

M a xP < -1 6.09 5T yp e: C ol la ge n

# of RO Is : 6

F at M a xP < 34 .27 5T yp e: N ecr otic

# of RO Is : 6

M B F < -6 6.6 6T yp e: F ib ro Li pi di c

# of RO Is : 5

M B F > -6 6.6 5T yp e: C ol la ge n

# of RO Is : 5

M a xP < -1 2.14 5# of RO Is : 1 0

M a xP > -1 2.14 5T yp e: F ib ro -Li pi di c

# of RO Is : 5

F at M a xP > 34 .27 5# of RO Is : 1 5

M a xP < -9 .9 15# of RO Is : 2 1

F at M a xP < 35 .5T yp e: C ol la ge n

# of RO Is : 8

F at M a xP > 35 .5T yp e: C ol la ge n

# of RO Is : 9

M a xP > -9 .9 15# of RO Is : 1 7

M a xP > -1 6.09 5# of RO Is : 3 8

F at M a xP > 30 .03# of RO Is : 4 4

Int > -28 .65# of RO Is : 8 2

M B F < -5 5.6 95# of RO Is : 1 13

M i nP < -1 7 .9 15T yp e: C ol la ge n

# of RO Is : 5

M B F < -5 3.1 5T yp e: C al ciu m

# of RO Is : 8

M B F > -5 3.1 5T yp e: C al ciu m

# of RO Is : 2 0

M i nP > -1 7.9 15# of RO Is : 2 8

M B F > -5 5 .6 95# of RO Is : 3 3

1 46# of RO Is :

TR E ER O OT

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THIS IS THE PROBLEM !

ID (IVUS Defined) TCFAs

MP Margolis, MD, PhD

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What is VH IVUS: VH slice thickness

300 µm

Longitudinal axis

MP Margolis, MD, PhDMP Margolis, MD, PhD

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Histology slice thickness

4 µm

300 µm


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The Effect of Slice Thickness on VH Plaque Composition

Histopathology; Calcified FA

4 µm 4 µm 4 µm

300 µm

VH IVUS, Calcified FA

4 µm


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Effect of Lesion Thickness on VH Plaque Composition

220 µm

4 µm4 µm 4 µm4 µm 4 µm

20 µm 20 µm120 µm 60 µm

Histopathology: FA on right

Histopathology: Calcified TCFA on left

Lesion Analysis by Histopathology: Calcified TCFA

Calcified TCFA FA

VH IVUS:Calcified TCFA


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What is the “Gold Standard” for In-Vivo “histology”? Histopathology or Pathologists?

Example 1

Pathologists 1(March 2006)Pathologists 1(March 2006) Pathologists 2 (Aug 2006)Pathologists 2 (Aug 2006) Pathologists 3 (Sept Pathologists 3 (Sept 2006)2006)


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19) CCF 05104 B2Single Single

LesionLesion

PIT FA FA

Pathologists 1(March 2006)Pathologists 1(March 2006) Pathologists 2 (Aug 2006)Pathologists 2 (Aug 2006) Pathologists 3 (Sept Pathologists 3 (Sept 2006)2006)

2D ALAS

FA


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7) CCF 05065 B2Single Single

LesionLesion

Pathologists 1(March 2006)Pathologists 1(March 2006) Pathologists 2 (Aug 2006)Pathologists 2 (Aug 2006) Pathologists 3 (Sept 2006)Pathologists 3 (Sept 2006)

FC Ca FA FA

2D ALAS

Ca FA


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SOFT

HARD

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Sensitivity and Specificity: in vitro

Sensitivity = 88%Specificity = 89%⇒

Schaar JA, et al. Circulation 2003

Elastogrampositive

Elastogramnegative

Histologypositive 20 3 23

Histologynegative 4 27 31

24 30 54

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Smooth muscle cells

heavymediumminornone

Stra

in(%

)Strain and tissue components

p < 0.006p < 0.0001

3.0

2.5

2.0

1.5

1.0

.5

0.0

Macrophages

Stra

in(%

)1312326N =

3,0

2,5

2,0

1,5

1,0

,5

0,0

heavymediumminornone

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Invasive Imaging Modalities



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The frequency of yellow plaque

0

10

20

30

40

50

60

70

80

AMI RMI OMI UA SAMizuno et al. Lancet 1991

(%)

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Incidence of ACS: Angioscopic Finding

Uchida et al. Am Heart J 1995

68.4

7.63.3

0

10

20

30

40

50

60

70

Yellow Glistening(9/13)

Yellow (2/26)

White (4/118)

(%)

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Top-spin® intracoronary MR catheter

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100µ

100µ

100µ

CD68Movat’s

Vulnerable plaque

Thick cap fibroatheroma

Stable plaque

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Correlation of lipid fraction determined by ic MR and histology

Fibrous Necrotic coreFoam cells

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In vivo thermal heterogeneity within human atherosclerotic coronary arteries

Stefanadis et al. Circulation 1999

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Risk of Adverse Cardiac Events

Stefanadis et al. JACC. 2001

40Stefanadis et al. J Mol Cell Cardiol. 2000

Clinical Presentation and the Temperature Difference: hsCRP

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Atorvastatin and Plaque Temperature

Stefanadis et al. Eur Heart J

StatinsNo statin

Tem

pera

ture

diff

eren

ce

2.5

2.0

1.5

1.0

.5

0.0

-.5

P<0,001

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Toutouzas et al reported correlation between temperature and expansive remodeling and MMP-9 concentration.

Verheye et al showed that temperature heterogeneity was reduced after change from high to low-cholesterol diet in rabbits.

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IVUSAngioscopyOCTIV MR


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Near-IR Spectra of Human Aortic Samples

PlaqueRepeat plaque

Cholesterol

Collagen

Repeatnormal

Normal

Wavelength

Abs

orpt

ion

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889593Negative predictive value

866890Positive predictive value

899393Specificity

847790Sensitivity

Inflam-mation

Thincap

Lipid pool

All values in %.

Characterization of plaque histology by NIR spectroscopy (ex vivo, no blood, no motion)

Moreno P et al. Circulation 2002

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InfraReDx Spectroscopy System

• Three components: console, PBR, catheter (3.2 Fr, monorail, 0.014” compatible)

• Automatically scans artery

• Spectra processed by algorithm and displayed to user as a chemical image of lipid rich plaque probability (“Chemogram”)

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Comparison of Chemogram with Histology

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SPECTACL: No Lipid Signal at Culprit

NIR End

NIR Start

Culprit

• 55y, M

• BMI 32.4 kg/m2

• Prog Angina

•+DM, HTN, Chol

Culprit

Lahey Clinic

Lahey Clinic

Culprit

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SPECTACL: Lipid Signal at Culprit

Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center

NIR End

NIRStart

Culprit

Culprit

Culprit• 71y, M

• BMI 28.3 kg/m2

• MI (<72 hrs)

• HTN

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SPECTACL: Other Areas of Interest

William Beaumont Hospital

William Beaumont Hospital

NIR Start

NIR End

Culprit

Culprit

• 59y, F

• Atypical CP

• HTN, Chol, +FH

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Multiple views of lipid-rich plaque probability

3-D Mesh

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Intermediate Stenoses Caused by Lipid-rich vsFibrotic Plaques: Detection by NIR Spectroscopy

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“Lipid Burden Index”

• Measure of overall Plaque Burden– Potentially useful as measure of risk or of pharmacologic

treatment efficacy

• Fraction of Chemogram image pixels above probability of 0.6– Scaled from 0 to 1000

• 0.85 AUC vs. fibroatheroma presence (0.79 – 0.91)

4

143

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169 172 178 184 202 213 272 295 298 312 322

184

126 127 129 138 138 143 145 145 150 156 157

133 160 162

72 73 74 78 80 81 84 86 87 87 9677 102 106

58 58 59 62 63 64 65 66 67 68 6960 71 71

38 39 40 42 43 43 45 46 47 48 5041 53 54

23 26 27 29 34 34 35 35 36 36 3627 37 38

10 11 11 15 16 17 19 19 20 21 2313 23 23

3 3 4 4 5 5 6 7 7 8 84 9 10

0 0 0 0 0 0 1 1 1 2 20 3 3

LRP Burden Index Mosaic

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Ex Vivo Study Results

.96NPV.97SPEC

.88PPV.87SENS

.95NPV1.0SPEC1.0PPV.95SENS

.97NPV.94SPEC

.81PPV.92SENS

Fibrous

Calcific

Lipid pool

Interobserver k = 0.88, Intraobserver k = 0.91

Yabushita, .. Jang, Bouma, Tearney. Circulation 2002

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0

50

100

150

200

250

300

350

400

450

500

0 100 200 300 400 500OCT measurement ( )탆

y = 1.02x+3.8r = 0.89p < 0.0001

Correlation between OCT and histology

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Linear NSD vs. CD68

100% (60 -100%)SPEC100% (70-100%)SENS

CD68 % area > 10 % -NSD cutoff 6.2%

Tearney, .. Jang, Bouma. Circulation 2003

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Stable vs Vulnerable Plaque

• Low lipid conc. • High lipid conc.• Thick fibrous cap • Thin fibrous cap• Low m Φ density • High mΦ density

Stable Plaque Vulnerable Plaque

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Plaque Characterization

• Goal: Determine plaque characteristics in various presentations of CAD

• Methods– Patients with CAD; N=57– OCT imaging culprit/remote lesions– OCT: 3.0 F catheter 8 cc saline purge

• Analysis– Clinical presentation:

• AMI (20)• ACS (20)• SAP (17)

– Two OCT readers consensus– Cap thickness– Macrophage density (~NSD)

Culprit Lesion

Remote Lesion

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Cap Thickness

4753.8

102.6

0

20

40

60

80

100

120

140

160M

in. C

ap T

hick

ness

AMIACSSAP

P < 0.02

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Prevalence of TCFA

Jang et al. Circulation 2005

45%

18%

65%

0%

10%

20%

30%

40%

50%

60%

70%

80%TC

FA P

erce

nt

AMIACSSAP

P < 0.01

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Macrophage Density for Acute and Stable Clinical Syndromes

• Cap macrophage density is higher in acute clinical syndromes in both culprit and remote sites

*P < 0.001*

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Limitations of OCT

1. Need to create blood free zone

2. No scanning capability

3. Shallow penetration depth

4. No functional information

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Intravascular Diagnostics for VP

Modality Resolution Penetration Cap Lipid Inflam Use

IVUS 100 um good + ++ - +++

Angioscopy - poor + ++ - +

IV MR 160 um poor + ++ ++ +

OCT 10 um poor +++ +++ ++ +

Thermography - poor - - +++ ++

Spectroscopy - poor + ++ ++ +

Modality Resolution Penetration Cap Lipid Inflam Use

IVUS 100 um good + ++ - +++

Angioscopy - poor + ++ - +

IV MR 160 um poor + ++ ++ +

OCT 10 um poor +++ +++ ++ +

Thermography - poor - - +++ ++

Spectroscopy - poor + ++ ++ +

Modified from MacNeill and Jang. ATVB 2003

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Ideal Invasive Diagnostics for VP

Combination of imaging and physiologic test

- OCT + thermography- OCT + spectroscopy- IV MR + thermography

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Invasive Diagnostics for VP

Questions1. Can one justify the invasive

diagnostic tests?- invasive- high cost- pt acceptability as a screening tool

2. Which patients?3. When to perform the tests?4. When to treat the lesions??

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Optimal Medical PreventionOptimal Medical Prevention

Cannon et al. NEJM 2004; 350: 1495–1504.

26.3% vs.

22.4%at 2y

PROVEPROVE--IT TrialIT Trial

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Invasive Diagnostics for VP

Inherent limitations

1. Local information (systemic disease)

2. Superficial information

3. Difficulty in sampling the same site

4. Gold standard (??) – validation problem

5. Only when a local therapy is viable!!

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Acknowledgements

Cardiology DivisionOC RaffelS. ChiaH. YabushitaM. Takano

M. Kawasaki A. Low D. DeJosephI. McNulty J. Healy

Wellman Laboratories of Photomedicine

B.E. Bouma S.H. Yun G.J. Tearney

Dept. of PathologyS. Houser

Dept. of Radiology

T. Brady U. HoffmannS. Abbara S. Achenbach

invasive diagnosticinvasive diagnostic ik-kyung jang, md, phd associate professor of medicine ......

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