andrew newby wei-chunhuang, nick jenkins, sarah george ... · does vulnerable plaque predict mi in...
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Pathogenesis of vulnerable plaque
Andrew NewbyWei-chun Huang, Nick Jenkins, Sarah George, Jason Johnson, Karina di Gregoli, Buket Reel,
Rebecca Salter, Graciela Sala-Newby
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Questions
• What is a vulnerable plaque?• What effect does it have in patients?• What are the mechanisms?• Is there an animal model?• What can we do about it?
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Atherosclerotic plaque is a highly prevalent, slowly developing cause of angina pectoris
and a risk factor for MI and stroke
Stary HC An Atlas of Atherosclerosis
10 200 40+ years
Type II Type IIII Type IV
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Stroke and MI (heart attack) are mainly caused by plaque rupture or endothelial erosion
Plaque rupture – 85% of male MI
Davies, MJ Heart 2000; 83:361-6
Surface erosion- 40% of female MI- smokers
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Vulnerable plaque - definitions and assumptions
• Plaque with a high probability to rupture or erode hence provoke thrombosis
• Predictor of MI and stroke• Similar structural characteristics as plaques
with recent thrombus• Formed by similar mechanisms as other
plaques only more so!Are these assumptions valid?
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Does Vulnerable Plaque predict MIIn 697 STEMI patients, thin-cap fibroatheromas were more likely to give rise to MACE in next 3 years.However, most MACE were new episodes of anginaMI was too infrequent for statistical powerVulnerable plaque was a good predictor of subsequent MACE but the situation for MI is still unclear.
Stone, NEJM;364:226
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Transient ischaemic attacks predicts stroke – carotid endarterectomy
Ulcerated plaque with thrombus
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What features of VP are predictive?
In 818 carotid plaques from AtheroExpress• Haemorrhage and micro-vessels were
predictors of MACE• Lipid core size, macrophages, smooth
muscle cells and collagen were not predictive
Hellings, Circulation 2010;121:1941
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Why does plaque rupture occur?
Davies MJ Circulation Heart 2000; 83:361-6
Plaque rupture like bridge collapse results from the chance interplay of
intrinsic weakness and external forces
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Factors that influence MI and stroke
Coagulation factorsSmoking, infections(size of thrombus)
Haemodynamicsi.e. flow patternsBlood pressure
Blood
Cap weakeningReduced endothelial adhesion (erosion)
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What makes plaque likely to rupture?
Thin fibrous cap (<65 μm), large lipid core, lots of foam cells, loss of collagen from the cap or core, microvesselsDavies, M Circulation 1996; Falk, E JACC 2006;47:C7-12
Thincap
Foamy macrophages
Apoptosis2ndary necrosis
Large core
No collagen
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How do mechanical factors influence MI?
Hypertension, arterial stiffness =increased pressure wave = high stress
Weak shoulder= High strain
Big lipid core = high strain
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Fibrous plaque Cap thins byproteolysis
Thin, weak cap
TensileStrength
Young Arterial stiffening, hypertension
Running for the bus
Arterial pulse wave= Strain on plaque cap
Statins
BP lowering
Why do plaques rupture when they do?
Low stress on cap High stress on cap Cap ruptures
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Extent of thrombosis determines severity of outcome
Partial occlusion – NSTEMI
Davies, MJ Heart 2000; 83:361-6
Total occlusion – STEMI
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IFNg
Mo
Th1
F C
INTIMA
LUMEN
SMC
SMC
SMCMEDIA
SMC
Foamcell
Autoantigens promote T-cell activation
-
-
-
-
--
ox-LDL
++
© Bristol Heart
InstituteTCC, T-cell chemokines, CXCL9, 10, 11, CD40L, OX40L
CX3CLCCL5
HSP60
CD16 +/-HSP60
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Mo
F C
INTIMA
LUMEN
SMC
MEDIA
SMC
FoamCell (M1)
Various damage associated molecular patterns are recognised by Toll-like receptors
-
-
© Bristol Heart
Institute
TLL
CD16 +/-
TLL, Toll-like ligands esp TLR2, Monaco C.Circulation. 2009;120(24):2462-2469.
Cell injury, altered matrix components
ox-LDL
++
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ox-LDL
Mo
INTIMA
LUMEN
SMC
MEDIA
SMC
FoamCellapoptosis
Foam cell and smooth muscle apoptosis and matrix remodelling ensues
-
-
++
© Bristol Heart
Institute
T
Lipid dropletsApoptotic bodiesCholesterol crystals
SMC apoptosis- -
- -
- -
CD16 +/-
Free cholesterol activates the inflammasomeDuewell, P et al. Nature, 2010;464:1357-61
IL-1α
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Low collagen
Foam cells
Foam cells make proteasesthat destroy collagen
van der Wal Cardiovasc Res 1999;41:334-344
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0
5
10
15
20
25
30
MM
P 1
MM
P 3
MM
P 1
2
MM
P 1
4
TIMP 3
Pro
tein
levels
(arb
itra
ry u
nit
s)
FCM NFM
Which proteases are important -rabbit foam cells
*
*
*
**
Chase et al. ATVB 2002;22:765-771
MMP-10 , -25 should be added
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What about MMP-12, MMP-14 and TIMP-3 in man?
Gerard PasterkampVincent Scholtes
AtheroExpress Biobank (n>2000)
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Staining and controls
MMP-14 IgG
COX-2 IgG
MMP-12 IgG
NF-kB IgG
CD206 IgG
TIMP-3 IgG
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Histological correlates of macrophage MMP-12, MMP-14 and TIMP-3 expression
Johnson, Jenkins et al, unpublished
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Correlation between parameters
Collaboration with Vincent Scholtes and Gerard Pasterkamp
MMP-14 TIMP-3P value rho P value rho
Collagen semiquantitative
0.000 -.409 .019 .283
SMC semiquantitative
0.000 -.623 .000 .475
SMC quantitative 0.000 -.466 .021 .283% fat / atheroma 0.000 .665 0.001 -.402
Macrophage semiquantitative
0.000 .567 0.000 -.441
Macrophage quantitative
0.026 .453 0.009 -.316
Thrombus NS .018 -.286
Stable
Un-stable
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MMP-14 TIMP-3
MMP-14 TIMP-3
MMP-14 and TIMP-3 don’t co-localise
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MMP-12 and MMP-14 don’t co-localise
Johnson, Jenkins et al, unpublished
NCSR
CD68 CD68
MMP-12 MMP-14
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Hypoxia and MMP-12 expression in vivo
Sala-Newby, Johnson et al, unpublished
CD68
A
CD68
B
Merged
FMMP-12
D
HIF-1α
EDAPI
C
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Outcome studies
• Plaques from 236 patients following endarterectomy.
• 3 year follow up. • Primary outcome was any vascular event or
vascular intervention. • Sections stained for MMP-12, MMP-14 or TIMP-3
and CD68. • Ratio positive for MMP-12, MMP-14 or TIMP-3
was quantified.
Scholtes, et al, JAHA, in press
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Areas of interest show a wide variation or MMP-12 positivity
Scholtes, et al, JAHA, 2012
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Macrophage MMP-12 expression associates with poor prognosis
Composite endpoint
Scholtes, et al, JAHA, 2012
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Macrophage MMP-12 expression associates with poor prognosis
Too much MMP-12 can kill you!Scholtes, et al, JAHA, 2012
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Is there an animal model?
ReproducibleQuickEasyCheapPublishable
Near to human Highly predictive
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Sites of predilection are similar
Cheng Circulation.2006;113:2744 –2753
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< 10 m
Size matters!3.5 mm
< 65 μm
< 10 μm
Thombus volume 1000 times lessJackson et al ATVB 2007; 27:714
0.5 mm
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Plaque rupture or intraplaquehaemorrhage?
200 times smaller, less PAI-1= quicker thrombolysisJackson et al ATVB 2007; 27:714
‘The most worrisome difference between the pathology in the mouse and the pathology of human disease is the absence of fibrin formation either within the lesion or within the lumen’. Rosenfeld ATVB 2000;20:2587
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BCA, 8 week high-fat diet
Johnson JL et al, Circulation 2005;111:1422.
62% of all animals: 1.05 buried caps/plaqueNeither occur in aortic sinus
p<.000001
19/23
4/27
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ApoE-/-:MMP-12+/+
ApoE-/-:MMP-12-/-
Plaque area(x103 mm2)
116 12 56 7*
Buried fibrouslayers
1.33 0.21 0.55 0.14*
SMC (%)
9 1 23 3*
Macrophage (%) 32 4 15 4*
Johnson et. al. PNAS 2005;102:15575-80
MMP-12 may reduce plaque stability by increased
macrophage migration
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PO O
NH
O
NO
HN
O
CONH2
C
C
OO
O O
Cl
RXP470.1
P1’
Jason JohnsonBHF, IRF
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Effect on plaque progression
0
50
100
150
200
250
300
Control (8 weeks) Control (12 weeks) MMP-12 inhibitor
*
Are
a (
mm
2 x
10
3)
Johnson JL et. al. Arterioscler Thromb Vasc Biol. 2011;31:528-535
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Vulnerable plaque – what can we do about it?
• Reduce all known risk factors (life style changes, quit smoking, statin, BP lowering)
• Reduce thrombotic consequences (aspirin)• Prophylactic angioplasty?• Decrease plaque inflammation (NHR,
cytokine/ chemokine inhibitors, immunotherapy)
• Prevent apoptosis (?)• Prevent loss of collagen (protease inhibitor)