Vulnerable Plaque:Vulnerable Plaque: Anatomic Features Linked to

Future Events

Renu Virmani, MD,CVPath Institute,

Gaithersburg, MD, USAGaithersburg, MD, USA

Natural History of Atherosclerosis• Systemic factors –

dyslipidemia, diabetes mellitus, smoking, hypertension, age and gender, hsCRP, Lp‐PLA2, etc.

• Local factors –branch points, e.g. carotid bifurcation, abdominal aorta just 

above bifurcation, coronary branch point, and arch vessels at take off are the sites of atherosclerosis manifestationtake off, are the sites of atherosclerosis manifestation.

• Thrombosis –occurs in the coronary arteries at focal points and is mostoccurs in the coronary arteries at focal points and is most 

often seen in the proximal segments of the three main coronary arteries (systemic coagulation factors play a role), y ( y g p y ),and occur at sites where there are underlying plaque characteristic that result in thrombosis.

Branch points are the sites of atherosclerosis and occur in areas of low shearoccur in areas of low shear

Left Coronary arteryCarotid Artery

A CLow shear

High shearBlood flow

Non-Progressive and Progressive Coronary PlaquesCoronary Plaques

non-progressive progressive

adaptive intimalhi k i

Intimalh

pathologicintimalthi k i f

thin-capfibroatheroma

NC

thickening xanthoma thickening fibroatheroma fibroatheroma

NC FC

lipid pool necrotic corep p

early late necrosis

Lesions with ThrombiLesions with Thrombi

• Plaque Rupture• Plaque Rupture• Plaque ErosionPlaque Erosion• Calcified NoduleCalcified Nodule

Causes of Coronary ThrombosisCauses of Coronary ThrombosisCalcified noduleCalcified noduleRuptureRupture ErosionErosion

RuptureSite

NCTh

ThThNC

Site

ThTh NCTh

Th Th

Th

Th

Virmani R, et al. Arterioscler Thromb Vasc Biol 2000;20:1262

Gross and Light Microscopicf

ANC

Features of Plaque RuptureTh

60% of Thrombi in Sudden Coronary Death occur

NC D FB

form Plaque Rupture

ThTh

NC D F

T cells SMCs

ThTh

T cells SMCs

C E G

NC

ThMΦ HLA‐DR

Fig 3-1

Th

LDA

Thrombus Propagation in Plaque Rupture

1mmLD

LAD

Proximal fibrin-richpropagated thrombusPlatelet-rich

thrombusB thrombusB

Proximal

D

ProximalPropagated Thrombus

C

Platelet

Carstairs’

Platelet

FibrinPlatelets

Fig. 3‐15

Plaque erosion in a 33 year old female complaining of

Plaque Erosion: 30-35% of thrombi in SCD

Plaque erosion in a 33 year‐old female complaining of chest pain for two‐weeks and discharged from the emergencyroom with a diagnoses of anxiety.

A CB

NC

ED F

MΦSMCs

T‐cells PLT FibrinT cells PLT Fibrin

Calcified NoduleBA

Calcified NoduleBA

*

**

**NoduleNodule*

*

**

*

Fibrin

CalcifiedCalcifiedplate

Frequency 2-7% of SCD Older individuals usually Men Frequency 2-7% of SCD, Older individuals, usually Men, equally common in tortuous right and left coronary arteries

Clinical and Morphologic Difference in Plaques Associated Clinical and Morphologic Difference in Plaques Associated with Luminal Thrombiwith Luminal Thrombi

Plaque rupture Plaque erosion

Th

LumenLumen

ThTh

Necrotic coreTh

60% thrombi in SCDM>F, Older, Ca++Eccentric = concentricG % i

30-35% thrombi in SCDM=F, youngerUsually eccentricL % i

2-7% thrombi in SCD, calcified plates, M>F, older,

id RCA &LADGreater % stenosisMacs, T cells, HLA-DR

Lesser % stenosisSMC rich, proteoglycans

mid RCA &LADUsually eccentricStenosis variableNod les of calci mNodules of calcium

Plaque rupture with mild stenosis and nonPlaque rupture with mild stenosis and non‐‐

Proximal

Plaque rupture with mild stenosis and nonPlaque rupture with mild stenosis and non‐‐occlusive thrombus: a mechanism by which occlusive thrombus: a mechanism by which plaques progress from an asymptomatic to plaques progress from an asymptomatic to  Th

symptomatic phasesymptomatic phase9mm

Rupture site 

Th

Th

3mm6mm

Th

NC

Healed Healed lesions lead to plaque lesions lead to plaque progressionprogressionHealed plaque rupture

NC NC

Multiple healed rupturep p

Healed Rupture Causes “Luminal Narrowing”and “Negative Remodeling”

C

mm

2

Healed ruptureAcute rupture

IEL, 

Burke, A P et al. Circulation.2001;103:9364-940

Remodeling in Varying CoronaryLesion MorphologiesLesion Morphologies

A.

5

4

NCMedial SMC loss

pected

 IEL

ue area)

4

3

2

1

IEL‐Exp

(/plaq 0

‐1

‐2

osion

Stab

le

oma

hage

pture

pture

sion

‐3

Ero S

n cap athe

ro

que he

morrh

Acute rup

Healed rup

Total occlus

Medial SMCapoptosis

Thi

Pla q

Thi Fib th A Pl R

Frequency and Location of Unstable Lesions: Thin-cap Atheromas, Acute and Healed Ruptures in the Coronary Circulation

504540

Thin-cap Fibroatheromaer

oma’

%)

Acute Plaque Rupture

’

504540

3156

40353025Fi

broa

thqu

ency

(%

Rup

ture

’en

cy (%

) 40353025 17 1526

Total Lesions= 68Total Lesions= 131

2015105Th

in-C

ap

Freq

‘Pla

que

Freq

ue 2015105

1526 23

11

5 650

‘T

Healed Plaque Rupture

50

50 pLAD

1 2 1 15 62 2

61

ture

’(%

)

50454035

pLADpRCpLCxLM

Total Lesions= 136

61

aled

Rup

teq

uenc

y 30252015

LOMdRCdLADdLCx

Total Lesions= 136

23 23

‘Hea Fr

151050

126 6 4 1 Kolodgie et al. Current Opinion

in Cardiology 2001;16:285

Relationship of Fibrous Cap Thickness to Macrophage Infiltration

P = 0 03

MMP‐1MMP‐2MMP‐3

CollagenLamininFibronectinSIKVAV

5

6

Kp-

1

P   0.03P = 0.06 MMP‐7

MMP‐8MMP‐9

LPSIL‐1βTNFα

SIKVAVEMMPRIN

3

4

ean

for %

MMP‐10MMP‐12MMP‐14TIMP 1

1

2

Cel

l Me TIMP‐1

TIMP‐2TIMP‐3PS

0

5 μm

 

0 μm

 

0 μm 0 μm

MMP‐2MMP‐14TIMP‐2

s than

 65

66 ‐20

0

201 ‐3

00

than

 300

MMP‐2TIMP‐2

Less 2

More  SMC death

Unstable plaqueModified from Newby AC.  ATVB 2008

PS = P‐Selectin

Development of Necrotic Core

The Necrotic Core“graveyard of dead M s”graveyard of dead M s

Thr

NC

Ruptured plaque atRuptured plaque at area of thinned fibrous cap

inflammation

Necrotic Core

stress on fibrous coppCoagulation thrombosis

proteases

T

Adaptive Intimal Thickening

P th l i I ti l Thi k iSmooth muscle cell

proliferationdeath (apoptosis MacrophagesMacrophages

Pathologic Intimal Thickening

death (apoptosismicrocalcification

Extracellular lipid (lipid pool) ± luminal macrophages

MacrophagesMacrophages

Inflammation – T-cells Macrophage

Infiltration into LP,apoptosis

Fibroatheroma ( ± calcification)

(early and late)Macrophage infiltration

“Fatty streak”“Fatty streak”Thin cap fibroatheroma

Macrophage infiltration(proteolytic enzymes)

Hemorrhage (red cell membrane)

Plaque rupture

Associated with lesion regression

Microcalcificationof macrophages + iron Flow disturbances

Lesion enlargement – asymptomatic or symptomatic

Histomorphometric Analysis of Plaque Componentp

Pit (no Macs)) Pit (+ Macs)) Early FA) Late FA)

Macrophage (KP-1.CD68))

In-Situ End Labeling (DNA fragmentation, apoptosis))

Phagocytosis efficiency of apoptotic cells (AC) in advanced atherosclerotic plaque and human tonsils

Carotid plaque Tonsil

TUNNEL (AC, red)

CD 68CD 68 (macrophages, blue)

TonsilAtherosclerotic plaque

100 The radio of free ACversus phagocytized AC was 19 timeshi h i th

100

80

60

100

80

60

tic cells

phages*

***

higher in athero‐sclerotic plaques as compared to human tonsil

40

20

40

20

0

% apo

ptot

% m

acrop

******

***

*

human tonsil

Free        uptake                        1AC       2AC      >2AC

0 0

Schrijvers DM et al. ATVB,2007

Thin‐cap FibroatheromaRecent Intraplaque Hemorrhage is seen atRecent Intraplaque Hemorrhage is seen at 

Multiple sites in Patients Dying SCDFrequency of Plaque

A BFrequency of Plaque 

Hemorrhage

a bbrupture erosion Severe CAD

(>75%)

Morphometric Analysis of Hemorrhagic Events in Human

Hemorrhagic Pericarditis

GpA MΦVulnerable Plaque

WFFMΦNC

G A

Plaque TypeGpAScore Iron

Necrotic Core(mm2)

MΦ(mm2)

vWFFeMΦ GpA

PIT no core(n=129)FA early core(n 79)

( ) ( )0.09±0.04

0.23±0.07

0.07±0.05

0.17±0.08

0.0

0.06±0.02

0.002±0.001

0.018±0.004(n=79)FA late core(n=105)TCFA(n=52)

*0.94±0.11

*1 60±0 20

*0.41±0.09

*1 24±0 24

*0.84±0.08

*1 95±0 30

*0.059±0.007

*0 142±0 016(n=52) 1.60±0.20 1.24±0.24

Values are reported as the means±SE, *p<0.001 versus early core.  The number in parenthesis represent thenumber of lesions examined;the total number= 365.  MΦ = macrophages

1.95±0.30 0.142±0.016

Kolodgie FD, et al. New Engl J Med 2003

Gross pictures of Plaque RuptureGross pictures of Plaque Rupture and TCFA

Rupture TCFA Fibroatheroma

Thr LumenLumen

Lumen

Thr

NC

NC+Hemorrhage

Ca++NC Ca++

Can we better characterize the differences between these three types of plaques?

Plaque Rupture           Thin cap fibroatheroma Fibroatheroma ‐SP

three types of plaques?

Ca2+

Histomophological Comparison of PR, TCFA and FARupture TCFA FARupture(N=100)

TCFA(N=101)

Rupture+TCFAFA

(N=105)P value

Prox/Mid 66/34 68/33 134/67 70/35 0.98

EEL, mm2 16.0 ± 6.1 14.0 ± 5.9 15.2 ± 6.3 11.6 ± 4.5 <0.0001

IEL, mm2 14.2 ± 5.9 12.4 ± 5.5 13.5 ± 6.0 10.1 ± 4.0 <0.0001

Lumen, mm2 3.2 ± 2.7 3.6 ± 2.4 3.5 ± 2.9 2.5 ± 1.8 0.0014

Plaque Area, mm2 11.0± 5.0 8.8 ± 4.4 10.0 ± 4.9 7.6 ± 3.3 <0.0001mm

%Stenosis 78 ± 14 71 ± 14 75 ± 15 76 ± 14 0.50

Total NC Area, 4 37± 4 09 2 26± 1 98 3 38± 3 43 1 33±1 00 0 0001

,mm2 4.37± 4.09 2.26± 1.98 3.38± 3.43 1.33±1.00 <0.0001

Total Cal Area, mm2 0.58 ±0.99 0.50±0.94 0.54±0.97 0.46±0.81 0.46mm2

Total Mφ Area, mm2 0.53± 0.44 0.31 ± 0.36 0.43 ± 0.42 0.12 ± 0.16 <0.0001

Cap thickness, mm

0.03 ± 0.01 0.04 ± 0.02 0.03 ± 0.02 0.40 ± 0.19 <0.0001

e

Mild stenosis Moderate stenosis Severe stenosis

Plaque Rupture and TCFA with Varying Luminal Stenosis

e R

uptu

re

NCNC

NCThr Thr Thr

A B C

Plaq

ueD E F

TCFA NC NC

NC

D E F

NC

80

50

60

70

80

41.0%

55.2%

51.1%

69.6%Rupture

10

20

30

40N

3.8%10.2%

38.6%

5.9%

24.5%

FA

TCFA

03.8%

<50% 50-75% >75% <50% 50-75% >75% <50% 50-75% >75%

FA TCFA PR

% Stenosis Categories within Plaque Type% Stenosis Categories

FA

% Stenosis

FA RuptureTCFA

Incidence of TCFA, Rupture, Stable Plaque Stratified by Remodeling (IEL)y g ( )

TCFA Rupture Fibroatheroma

NC Area (mm2)

0‐1.01.0‐2.5

50 50 50

ce (%

) 1.0 2.52.5‐

0 0 0

cide

nc

Mφ ( 2)

0 0 0

50 50 50

Inc Mφ (mm2)

0‐0.10.1‐0.30 3‐0.3

0 0 0

0‐9 9‐13 13‐ 0‐9 9‐13 13‐ 0‐9 9‐13 13‐

IEL (Remodeling)

Recursive Partitioning Analysis (RPA)  of Coronary arteries by Fibrous cap thickness  and % Stenosis 

Fib hFibroatheromaVulnerable PlaqueRuptured Plaque

Narula J, Nakano M, et al. Submitted JACC

Recursive Partitioning Analysis (RPA) of Coronary arteries by Macrophage Infiltrationand Necrotic core

Fib hFibroatheromaVulnerable PlaqueRuptured Plaque

Narula J, Nakano M, et al. Submitted JACC

Partitioning Analysis : %Stenosis 

Partitioning Analysis : %Stenosis 50‐

Plaque Type Area

y>75%

Plaque Type Area

y75%

q yp

Rupture 0.7977

TCFA 0.5790

Rupture 0.8484

TCFA 0.6979

SP 0.8363 SP 0.8133

Independent risk factors for “rupture”Independent Morphological Predictor of Rupture

50‐75% cross‐sectional stenosisMovat

D68

 ropahge)

C(M

acr

P Value Odds Ratio 95% CI

Cap thickness 0.005 0.35 0.16 – 0.69p

%NC 0.02 2.0 1.1 – 3.7

%Macrophage 0.052 1.8 0.99 – 3.2 

Post‐Statin

Imaging Strategies for the Assessment of High‐Risk Plaque Characteristics, including CapThickness (OCT), Necrotic Core (CT‐ low attenuation plaque [LAP]), and Inflammation (FDG‐PET)

Post‐Statin

Pre‐Statin

Motoyama S, et al JACC 2009; Courtesy Jagat Narula, MD, PhD

Summary: Atherosclerosis( )Plaque rupture is a main cause of thrombosis (65‐70%), 

while other minor causes include erosion (30%) and calcified nodule (2 5%)calcified nodule (2‐5%).

Risk factors are predictive of specific plaque typesb d b l d lDiabetes and metabolic syndrome play an important 

role in CAD l bl l ( ) l k l l fVulnerable plaques (TCFA) is a likely precursor lesions of 

rupture. ib hi k i h b di i i fFibrous cap thickness is the best discriminator of 

vulnerable plaque and plaque rupture from stable lesionsM h i fil i i d i iMacrophage infiltration, necrotic core, and positive 

remodeling are important parameters to identify if we are to recognize these lesion prior to clinical manifestationto recognize these lesion prior to clinical manifestation.

AcknowledgmentsFunding

CVPath Instit te

FundingCVPath Institute Inc.

CVPath Institute, Inc.

CVPath InstituteMasataka Nakano, MDFumiyuki Otsuka, MD, PhD ,Saami Yazdani, PhDFrank D Kolodgie, PhDElena Ladich, MDS i Y d i PhDSaami Yazdani, PhDRuss JonesRobert Kutz, MSEd Acampado DVMEd Acampado, DVMYouhui Liang, MDAbebe Atiso, HTMichael Cooper

Washington DC

Michael CooperJinky BeyerGiselle MagsalinHedwig Avallone HTHedwig Avallone, HTLila Adams, HTHengying Ouyang, MD