PathologyPathology ofof VulnerableVulnerable PlaquePlaque AngioplastyAngioplasty SummitSummit 20052005 TCTTCT AsiaAsia Pacific,Pacific, Seoul,Seoul, AprilApril 2828--30,30, 20052005

Renu Virmani, MD CVPath, A Research Service of the International Registry of Pathology Gaithersburg, MD Plaque Morphology of Thrombi in SCD Plaque Rupture 55 - 60% th th

Plaque Erosion th 30 - 35% th

Calcified Nodule 2 -7 %

th ClinicalClinical andand MorphologicMorphologic DifferenceDifference inin PlaquesPlaques AssociatedAssociated withwith LuminalLuminal ThrombiThrombi Plaque rupture Plaque erosion Calcified nodule

Lumen Lumen Th Th Th Necrotic core

45-55% thrombi in 35-40% thrombi in 4-7% thrombi in SCD SCD SCD, calcified plates M>F, Older, Ca++ M=F, younger M>F, older, mid Eccentric = Usually eccentric RCA concentric Lesser % stenosis Usually eccentric Greater % stenosis SMC rich, Stenosis variable Macs, T cells,HLADr proteoglycans Nodules of bone A NC Gross and Light Microscopic Th Features of Plaque Rupture 60% of Thrombi in Sudden Coronary Death Are form Plaque Rupture B NC D F

Th

SMCs T cells C E G NC

Th MΦ HLA-DR Fig 3-1 Plaque erosion in a 33 year-old female complaining of chest pain for two-weeks and discharged from the emergency room with a diagnoses of anxiety.

A B C

NC SMCs MΦ D E F

T-cells PLT Fibrin Development of Human Coronary Atherosclerosis Pathologic Intimal Intimal intimal Fibrous Thin-cap thickening xanthoma thickening cap atheroma Fibroatheroma

NC LP NC FC

Smooth muscle cells Calcified plaque Macrophage foam cells Hemorrhage Extracellular lipid Thrombus Cholesterol clefts Healed thrombus Necrotic core Collagen What is a Vulnerable Plaque?

• Plaque morphology underlying luminal thrombi represents a vulnerable plaque – Thin-cap Fibroatheroma – Plaque rupture – Pathologic intimal thickening Plaque – Fibroatheroma Erosion – Calcified plates with bone formation – Calcified nodule - surface thrombus Thin cap Fibroatheroma is a Precursor lesions of Plaque Rupture TCFA Plaque Rupture *Ruptured cap Th Thin fibrous nc cap ? th * nc Thin-Cap Atheroma (Vulnerable Plaque) Components • Necrotic core • Thin fibrous cap (< 65 µm) • Cap infiltrated by macrophages and lymphocytes • Cap composition – type 1 collagen and few smooth muscle cells A Non-Hemodynamically Limiting Thin-cap Fibroatheroma

A B C NC NC

Movat H&E D E

Fig 2-2 MΦ SMCs Morphologic Characteristics of Plaque Rupture and Thin-cap Fibroatheromas

Necrotic Fibrous cap MΦs SMCs T- Calcification Plaque type Core (%) Thickness (µm) (%) (%) lymph Score

Rupture 34±17 23±19 26±20 0.002±0.004 4.9±4.3 1.53±1.03

Thin-cap Fibroatheroma 23±17 <65µm 14±10 6.6±10.4 6.6±10.4 0.97±1.1

P value 0.01 0.005 ns ns 0.014

Mean values are represented ± standard deviation. Abbreviations: MΦs= macrophages, SMCs= smooth muscle cells, T-lymph= T-lymphocytes

Kolodgie F, et al. Current Opinion in Cardiology 2001;16:285 Morphological Variants of the Thin-Cap Fibroatheroma

Insignificant Large eccentric Large concentric Healed Plaque burden necrotic core necrotic core Rupture(s)

NC NC NC NC

NC NC NC

Kolodgie F, et al. Current Opinion in Cardiology 2001;16:285 Vulnerable Plaque Characteristics

AB

Type of plaque 90 50 80 45 70 40 35 60 30 50 25 40 20 30 15 % thin cap atheroma % thin 20 10 10 5 0 0 90 % cross sectional area luminal narrowing ≥ <50% 75-89 50-74% rupture thin cap healed rupture healed

hemorrhage Cross sectional luminal narrowing fibrous atheroma Mean % x-sectional area 80% of thin cap atheromas occur in arteries For TCFA is 60% with < 75% x-sectional area luminal narrowing (<50% diameter reduction) Distribution of Ruptures and Thin-Cap Atheromas by Plaque Area or Lipid Core Size A B 73 ± 13%* 45 45 40 40 77 ± 16%* ± 35 77 15%* 35 30 79 ± 13%* 30 71 ± 13%* 25 25 20 20 81 ± 9%* 78 ± 12%* (n= 90)

15 82 ± 9%* (n= 90) 15 10 10 5

Plaque Ruptures (%) 5 0 Plaque Ruptures (%) 0 % <10 %10-25 %25-50 >50% area<1 area 1-3 area 3-5 area > 5 Lipid core as % plaque area Cross sectional lipid core area, mm2 C D 45 65 ± 15%* 45 71 ± 17%* 40 40 ± 35 74 15%* 35 30 30 65 ± 17%* 25 25 ±

77 9%* n= 106)

n= 106) 20 20 76 ± 14%* 78 ± 12%* 15 ± 15 77 13%* 10 10 5 5 0 0 Thin-Cap Fibroatheromas (%) Thin-Cap Fibroatheromas (%) % <10 %10-25 %25-50 >50% area<1 area 1-3 area 3-5 area > 5 Fig 2-8 * = mean cross sectional area luminal narrowing DoDo TCFAsTCFAs leadlead toto plaqueplaque progressionprogression ?? Movat pentachrome

Sirius red Sirius red with polarized light Mean % Stenosis Increases with Number of Prior Rupture Sites but the Increase with Each New Rupture is Small (<20%)

90 Healed Rupture Sites Acute Rupture Sites 100 80 90 70 80 60 70 50 60 40 50 30 40 30 Mean % stenosis Mean % stenosis 20 20 10 10 0 0 1 2 3 4 A 0 1 2 3 4 Number of prior ruptures, B Number of prior ruptures, healed rupture sites acute rupture sites

Burke, A P et al. Circulation 2001;103:9364-940 PercentagePercentage ofof CrossCross--SectionalSectional--AreaArea NarrowingNarrowing byby PlaquePlaque MorphologyMorphology

A B P= 0.05 Thin Acute Healed cap rupture rupture

50 46 45 43 38 40 36 35 37 N=12 N=19 35 30 27

25 22 X-SCA Narrowing (%) Occlusive Non-Occlusive 0 20 18 Thrombus 20 15 C

10 40 45 60 Total Sections (%) 5

40 0 35 80

30 < 50 100 < 50 < 50 25 50- 74 50- 74 50- 74 75-100 75-100 75-100 20 15 Cross-Sectional-Area Narrowing (% ) 10 5 0 Fig 2-6 -New lumen lumen (%) Old 1234 No. Healed Ruptures Necrotic core size, sum mm2, independent of plaque area, morphometrically determined, at maximal luminal narrowing of 3 major epicardial arteries

P=0.01 2

6 P=0.03 5

4

3

2

1

0 Mean necrotic core area mm Normal TC/HDL-C TC/HDL-C > 7 TC/HDL-C >5, <7 Relationship of Fibrous Cap Thickness to Macrophage Infiltration

P = 0.03 6 P = 0.06 5

4

3

2 Cell Mean for % Kp-1

1

0 m m m m µ µ µ µ 66 - 200 201 - 300 Less than 65 More than 300 Correlation of Fibrous Cap Thickness and Macrophage Infiltration

16 R2 = .117 14 P = <0.001 12 10 8

% kp-1 6 4 2 0 -2 -100 0 100 200 300 400 500 600 Fibrous cap thickness mm Relationship of Fibrous Cap Thickness to Underlying Percent Necrotic Core

40 35 30 25 20 15

% Necrotic Core 10 5 0 m m m m µ µ µ µ 66 - 200 201 - 300 Less than 65 More than 300 Correlation of X-Ray Calcification with Plaque type

A B Speckled LM

RCA

LAD

C Fragmented D Diffuse CalcifiedCalcified MatrixMatrix DeterminedDetermined HistologicallyHistologically Severe Coronary Artery Disease, n=36, 64+14 yrs Coronary Arteries Serially Sectioned 3

2.5

2

1.5

1

Mean calcification score calcification Mean .5

0 erosion rupture Thin cap fibroatheroma healed rupture thickening Pathologic intimal Proportion and types of “unstable” plaques, by approximate distance from ostium

60 proximal 50 n mid

o

i t distal u 40

b

i

r

t

s i 30

d

% 20

10

0 Fibro- hemorrhage thin cap acute healed atheroma into plaque rupture rupture Frequency and Location of Unstable Lesions: Thin-cap Atheromas, Acute and Healed Ruptures in the Coronary Circulation Thin-cap Fibroatheroma Acute Plaque Rupture 50 50 45 45 31 56 40 40 35 Total Lesions= 131 35 Total Lesions= 68 30 30 25 25 17 26 15 20 23 20 Frequency (%) 15 15 11 Frequency (%) 10 ‘Plaque Rupture’ 10 ‘Thin-Cap Fibroatheroma’ 5 5 6 5 22 1 2 11 0 0 Healed Plaque Rupture 50 pLAD 61 45 pRC 40 pLCx 35 LM 30 Total Lesions= 136 LOM 25 dRC 20 23 23 dLAD 15 dLCx

Frequency (%) 12

‘Healed Rupture’ 10 6 5 6 Kolodgie F, et al. Current Opinion 4 1 0 in Cardiology 2001;16:285 P=0.009 A. P=0.01 4 P=0.04 3.5 P=0.05 3 2.5 Frequency of Thin-Cap 2 Fibroatheromas 1.5 1 by Decades .5 Mean Number of TCFAs Mean Number 0 30’s 40’s 50’s 60’s 70’s B. 6 No acute MI 5 With acute MI 4

3

2

1 Mean Number of TCFAs Fig 2-7 0 30’s 40’s 50’s 60’s 70’s Number of Thin-Cap Atheromas in Various Coronary Syndromes in Males and Females

4 Male 3.5 Female 3 2.5 2 1.5 1 Mean Number of

Thin-Cap Atheromas .5 0 MI SCD Incidental Erosion

Fig 2-11 Frequency of thin cap atheroma, by mechanism of death

3

2.5

2

1.5

1

.5

Number of thin cap atheromas 0 erosion noncoronary stable plaque acute rupture healed rupture LCx Plaque rupture

A nc RCA LCx C nc E Thin cap Fibro- atheroma F nc th nc B G Thin cap fibroatheroma

nc D LAD nc E F 43-year old WM collapsed at work and could not be resuscitated. Fig. 11 Comparison of the Length, Necrotic Core Area and % Necrotic core/plaque Area

Dimensions Fibroatheroma Thin-cap Plaque Atheroma Rupture Length, mm, 6 mm (range 8 mm (range 9 mm (range mean/Range 1-18 mm) 2-16 mm) 2.5-22 mm) Necrotic core 1.2 ± 2.2 1.7 ± 1.1 3.8 ± 5.5 area mm2

% necrotic 15 ± 20 % 23 ± 17 % 34 ± 17 % core/plaque area Serial Sections of a Thin-Cap Fibroatheroma Cut 250 mm apart ABCD

EFGH

Fig 2-16 Serial Coronary Sections (mm) Demonstrating Multiple Vulnerable Plaques and Rupture Sites Proximal LCx A B C D

0.2 0.5 1.1 1.7

E F G H

1.9 2.22.5 2.7 Distal I J K L

3.0 3.3 3.6 3.9 IEL-Expected IEL (mm2) A. Remodeling in VaryingCoronary -1 0 1 2 3

Erosion

Stable Lesion Morphologies

Thin cap atheroma Plaque hemorrhage Acute rupture Healed rupture

Total occlusion

IEL-Expected IEL

(/plaque area) B. -3 -2 -1 1 2 3 4 5 0

Erosion Stable

Thin cap atheroma Plaque hemorrhage Acute rupture

Healed rupture Total occlusion Mean Number of Thin Cap Fibroatheromas and Serum Cholesterol in Men

P=0.001 P=0.001 P=0.02 P=0.02 1.8 Total Population 1.6 1.4 Whites 1.2 Blacks 1 0.8 0.6 0.4 0.2 0 TC<210 TC>210 TC >210 All cases mg/dl & or mg/dl& Fig 2-17 ratio<5 ratio>5 ratio >5 Mean Number of Thin-Cap Fibroatheromas in 51 Women with SCD and Severe Coronary Disease A Comparison of Risk Factors Age Cholesterol

1.4 1.4 1.2 1.2 1.0 1.0 0.8 0.8 P<0.0001 P=0.03 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 <50 yrs >50 yrs Normal TC >210 mg/dl Diabetes Smoking ratio>5

1.0 1.0

0.8 0.8 P=0.2 >10 GlyHgb P=0.09 0.6 0.6

0.4 0.4 Normal 0.2 0.2 0.0 0.0 Non- Smoker Fig 2-18 Glycohemoglobin Smoker Serum hs-CRP correlated with Immunohistochemical staining intensity of Plaques and with TCFA CRP CRP staining Mean number intensity of of thin cap plaques* atheroma Low CRP group 2.9 +0.5 0.95 +0.22 (<1.0µg/mL)

High hs-CRP 6.2+0.6 3.0 +0.3 group (>3.2µg/mL) *Grading of staining intensity was assessed on macrophages and Lipid core. A quantitative score of 0 to 4 was applied to each. A sum of the 2 scores resulted in overall grading system of 0 to 8 Thin Cap Fibroatheroma- A plaque vulnerable to rupture ?

9Definition 9Frequency is higher in AMI than SCD, >males than females 9Higher prevalence in the presence of high TC, low HDL-C, high TC/HDL-C ration, high hs CRP (>3.2 mg/dl) 9Location in SCD, proximal and mid LAD, RCA, and LCX 9Length 2-22 mm ( mean 8 mm) 9% luminal narrowing (80% of TCFAs occur in lesions <50% diameter stenosis) 9% necrotic core is <25% of plaque area in 70% of TCFAs 9Calcification is not a marker of TCFA