Plaque progresion and instability - critical insights from ...Plaque Burden ‐‐‐ 232.4 248.1...
Transcript of Plaque progresion and instability - critical insights from ...Plaque Burden ‐‐‐ 232.4 248.1...
Plaque Progression and Instability:Critical Insights from PathologyCritical Insights from Pathology
Renu Virmani, MDRenu Virmani, MDCVPath Institute
Gaithersburg, MD, USAg, ,
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 MicroscopicA
NC g pFeatures of Plaque RuptureTh
60-65% 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
Plaque erosion in a 33 year old female complaining of
Plaque Erosion: 30-35% of thrombi in SCDPlaque 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, T2D and Prediabetes, 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 Calcified noduleCalcified nodule
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 platesM>F, older, mid RCA, LADU ll iGreater % stenosis
Macs, T cells, HLA-DR
Lesser % stenosisSMC rich, proteoglycans
Usually eccentricStenosis variableNodules of bone
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
1
2
Mean % stenosis increases with number of prior rupture sites
is
80
90
90100
is
% s
teno
s
50
60
70
60
7080
% s
teno
s
Mea
n %
20
30
40
304050
Mea
n %
M
0
10
20
1 2 3 40
10
20
M
Number of prior ruptures, healed rupture sites
1 2 3 4A 0 1 2 3 4
Number of prior ruptures, acute rupture sites
B
Burke, A P et al. Circulation 2001;103:9364-940
IntimalIntimal IntimalIntimal FibrousPathologicintimal Thin cap
Progression of Human Coronary AtherosclerosisVirmani R, et al. ATVB2000;20:1262
IntimalIntimalthickeningthickening
IntimalIntimalxanthomaxanthoma
Fibrouscap atheroma
intimal thickening
Thin‐capFibroatheroma
NC
NCEL FC
Calcified noduleRuptureErosion
NoduleNCHealed Rupture
ThThThTh NCNCTh
Nodule
FCTh
C 2+
ThTh
Ca2+
ThTh ThThThTh
Development of Necrotic Corep
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 Progressive Coronary LesionsCoronary Lesions
Pit (no Macs)) Pit (+ Macs)) Early FA) Late FA)
Differential Expression of Differential Expression of HyaluronanHyaluronan andandVersicanVersican in the Developing Necrotic Corein the Developing Necrotic Core
Fibroatheroma ‘Early’ Necrosis
VersicanVersican in the Developing Necrotic Corein the Developing Necrotic CoreA B
Fibroatheroma Early Necrosis
NC
MΦ bHABR Versican
C D
Thin‐cap Fibroatheroma ‘Late’ Necrosis
NC
bHABR VersicanMΦ
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
Morphologic Characteristics of Plaque Rupture and Thin‐cap Fibroatheromas
Plaque typeNecroticCore (%)
Fibrous capThickness (µm)
MΦs(%)
SMCs(%)
T‐lymph
CalcificationScorePlaque 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‐capFibroatheroma 23±17 <65µm 14±10 6.6±10.4 6.6±10.4 0.97±1.1
P value 0.01 0.005
Mean values are represented ± standard deviation. Abbreviations: MΦs= macrophages,SMCs= smooth muscle cells, T‐lymph= T‐lymphocytes
ns ns 0.014
SMCs smooth muscle cells, T lymph T lymphocytes
Kolodgie F, et al. Current Opinion in Cardiology 2001;16:285
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
Intraplaque HemorrhageIntraplaque Hemorrhage, Oxidant Stress & Plaque Vulnerability
A Evidence that Human Coronary Plaques Express a Latent Proangiogenic Phenotype
I
MNormal artery with adventitial Vv Fibroatheroma with severe
Intraplaque hemorrhageULEX E.
B
MIFibroatheroma with
HemNCMITortuous and Abnormal Vv
HemNC
C
Fibroatheroma withLeaky Vv ( i l h h )(peri‐vascular hemorrhage)
)
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
Necrotic Core FormationMechanism(s) and MoleculesMechanism(s) and Molecules
Early Necrosis
• Early foam cell apoptosis (via ER stress path
engulfment:y p p ( p
• Clearance by phagocytosis (efferocytosis)
d f ti lf t ( )defective engulfment: (molecular genetic causation studies in mice)
Late Necrosis Hemorrhagic NecrosisExcess foam cell apoptosis
Defective efferocytosis
Excess• free cholesterol• free hemoglobin (Hb)y
1) Fas ligand (apoptosis stimulating fragment)
2) transglutaminase-2 3) lactadherin
g ( )• macrophages
efferocytosis3) lactadherin4) Mertk (Mer receptor tyrosine kinase)
efferocytosis
Role of Vasa Vasorum in the leakage of RBC into the plaque d h ti tiand macrophage activation
vWf ‐‐VEGF + ang‐1 vWf
iNOS0202
HboxLDL
Lp‐PLA2
HbiNOS
HO‐1
FeHaptoglobin
ICAM
A t ti
oxLDLCD163
CeroidHaptoglobin1‐1 or 1‐2 genotype
Apoptotic bodies
oxRBC↑IL‐6+MCP‐1
Free CholesteroloxLDL
↓phagocytosis Haptoglobin
↓phagocytosis of apoptotic bodies
Foam cellsoxLDLoxRBC
p g yGeneotype 2‐2 vs.1‐1 or 1‐2associated with greater iron in plaque (46% vs.12%) among T2D
Development of Calcified Nodulep
Patients dying from Sudden coronary Death:Extent of Coronary calcification by decades
80
100
120um
sco
re
BlacksWhites
2.5
3
nsc
ore
40
60
80
ary
calc
iu
1.5
2
calc
ifica
tion
0
20
40
Cor
on
0
.5
1
Mea
n
0
thirt
ies
fort
ies
fiftie
s
sixt
ies
seve
ntie
s 0
oath
erom
a
Thin
cap
rupt
ure
eros
ion
led
rupt
ure
gic
intim
alni
ng
fibro
heal
Path
olo
thic
ken
Radiograph Movat Stain Ground Section (40 µm)
Ca++Ca++
Eruptive Calcified Nodule with Thrombosis in a Heavily
LMy
Calcified Coronary Artery
LAD LCX
RCA
LAD LCX
66 ld hit66 year old white manH/O hypertension, prediabetic and BMI 34 7LM prox LCX
prediabetic, and BMI 34.7 LM
Th
Eruptive Calcified Nodule with ThrombosisA B CCalcified plate
Fibrous cap
Nodule
CD61Movat 100 μm1.0 mmMovat 200 μm
Th
D E F
Osteoclast-like cell
N d l
CD68Fibrin II H&E 200 μm100 μm100 μm
Nodule Nodule
The Role of Risk Factors in SCD patients St bl C l ifi d
ControlN=163
Stableplaquen=131
Rupturen=84
Erosionn=45
Calcified nodulesN=8
Age 46 54 49 45 57
Male 118 (72%) 102 (78%) 78 (90%) 29 (64%) 6 (88%)
R %Bl k 75 (46%) 46 (35%) 21 (24%) 16 (36%) 2 (25%)Race %Black 75 (46%) 46 (35%) 21 (24%) 16 (36%) 2 (25%)
BMI 28.4 28.3 29.4 26.7 31.8
HbA1c 6 6 7 5 7 2 7 0 7 0*HbA1c 6.6 7.5 7.2 7.0 7.0*
Hx of HTN 35 (21%) 61 (47%) 27 (31%) 9 (20%) 5 (63%)
Smoker 64 (39%) 63 (48%) 53 (60%) 33 (73%) 7 (88%)( ) ( ) ( ) ( ) ( )
T. Chol 202 208 258 211 208
HDL 46 41 37 39 42
T.Chol/HDL 5.3 5.8 7.7 5.9 5.4
Healed MI 1 (1%) 76 (58%) 37 (42%) 11 (24%) 4 (50%)
Plaque Burden ‐‐‐ 232.4 248.1 178.9 258
* Out of 8 case, 4 were DM, and 2 were Pre‐DM.
Distribution of Atherosclerotic Coronary Disease
LAD LCx RCA
Calcified nodule with thrombusNodular calcificationFibocalcific plaqueThin‐cap fibroatheromaTotal occlusionTotal occlusionPathological intimal thickening
A C
Nodular Calcification without ThrombosisA C
B D
Plaque RuptureHealed Plaque
RuptureFibrocalcific
PlaquePlaque Fissure
Th
C l ifi d
Calcified Nodule with l i l th b
Calcified Plate F t ti
Nodular C l ifi ti
Calcifiedplate
luminal thrombusFragmentation Calcification
Fibrin
Calcified Plate Nodules of calcium Medial
Fibrin
Luminal thrombusfragmenationfrom artery torturocityand beating heart
Nodules of calciumDestroying the media destruction
Luminal thrombussurrounded by Fibrin and platelet
Inflammation: The Road toPl P iPlaque Progression
Summary:• The earliest lesion of plaque progression is Pathologic Intimal
thickening
Summary:
thickening.• PIT, lipid pool is converted to necrotic core from
macrophages infiltration and apoptosis leading to earlymacrophages infiltration and apoptosis leading to early necrotic core formation.
• Late necrotic core is likely the result of defective efferocytosisy yas well as plaque hemorrhage which contribute to free cholesterol within necrotic core
• Inflammation continues to increase as plaques progress and is maximum in plaque rupture.
Summary: Thrombosis( )Plaque rupture is a main cause of thrombosis (65‐70%),
while other minor causes include erosion (30%) and calcified nodule (4 7%)calcified nodule (4‐7%).
Vulnerable plaques (TCFA) is a likely precursor lesions of rupture Macrophage infiltration play an important role inrupture. Macrophage infiltration play an important role in modification of plaque vulnerability.
Plaque hemorrhage from “leaky” vasa vasorum is anPlaque hemorrhage from leaky vasa vasorum is an important contributor to the enlargement of the necrotic corecore.
Calcified nodules is another substrate for thrombosis, especially in elderly male individuals with high plaqueespecially in elderly male individuals with high plaque burden, tortuous arteries, diabetes , metabolic syndrome, hypertension, and smoking.yp , g
A k l d t• Masataka Nakano, M.D.
Acknowledgments• Fumiyuki Otsuka, M.D.
• Frank Kolodgie, Ph.D.
• Aloke V. Finn, M.D.
• Elena Ladich, M.D.
• Ed Acampado, D.V.M.
• Robert Kutz, M.S.,
• You‐hui Liang, M.D.
• Erica Pacheco, M.S.,
• Hedwig Avallone
• Lila AdamsLila Adams
• Russ Jones
• Abebe AtisoAbebe Atiso
• Rosalind Mathew