Pathogenesis and Pathologic Features of …Plaque Rupture →Fatal Thrombosis Europe ≈Asia ≈USA...
Transcript of Pathogenesis and Pathologic Features of …Plaque Rupture →Fatal Thrombosis Europe ≈Asia ≈USA...
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Erling Falk, Seoul, April 28, 2006
PathogenesisPathogenesis andandPathologicPathologic Features Features ofof
Vulnerable Vulnerable PlaquePlaque
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++stentstent
D, 1 hour later:
LAD LAD occlusionocclusion & & AMIAMI→→ stentingstenting
Romagnoli et al. Circulation 2006;113:e61-2
58-year-old man with recent inferolateral MIA,C: LCx culprit B: LAD 50% stenosis
→→ stenting stenting nonsignificantnonsignificant
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Circulation 2006;113:e61-2
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definitiondefinitionpathogenesispathogenesispathologicpathologic featuresfeatures
Vulnerable plaques
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NomenclatureNomenclature1. 1. PlaquePlaque disruptiondisruption2. 2. UnstableUnstable plaqueplaque3. Vulnerable 3. Vulnerable plaqueplaque4. 4. PlaquePlaque rupturerupture5. 5. HighHigh--riskrisk plaqueplaque6. 6. CulpritCulprit plaqueplaque7. 7. PlaquePlaque fissurefissure
NextNext page:page:8. 8. PlaquePlaque erosionerosion
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Circulation 2003107:2068-71
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EHJ 2004;25:1077-82
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Schaar et al. Eur Heart J, June 2004
Thrombosis-proneplaque
Development of atherosclerosis and progression to thrombosis and clinical events
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definitiondefinitionpathogenesispathogenesispathologicpathologic featuresfeatures
Vulnerable plaques
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N N EnglEngl J Med 1999 Jan;340:115J Med 1999 Jan;340:115--2626
Seattle, March 18, 1999Seattle, March 18, 1999
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NEJM 2005NEJM 2005352:1685352:1685--9595
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Glass, Witztum.Cell 2001;104:503-16
Atherogenesis: inflammation fueled by lipidmacrophagemacrophage recruitmentrecruitment
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Glass, Witztum.Cell 2001;104:503-16
Atherogenesis: inflammation fueled by lipidchrchr. . inflammatoryinflammatory –– immunoimmuno –– proliferativeproliferative diseasedisease
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Glass, Witztum.Cell 2001;104:503-16
NecroticNecrotic corecore::TheThe graveyardgraveyardofof deaddead macrmacr
Athero-thrombosis: plaque rupture ~75%necroticnecrotic corecore, , thinthin fibrousfibrous capcap, inflammation, inflammation
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Plaque rupture: role of macrophages
thrombusthrombus
necroticnecrotic corecore
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thrombusthrombus
necroticnecrotic corecore
Plaque rupture: role of macrophages
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capcapcapcapmacrophagesmacrophagesat at rupturerupture sitesite(MMP, TF)(MMP, TF)
Plaque rupture: role of macrophages
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1460 thrombosed coronary plaquesplaqueplaque rupturerupture
Patients Age n Rupture StudyHospital, ? ? 19 19 = 100% Chapman-1965Hospital, ? ? 17 17 = 100% Constantinides-1966Hospital, AMI+SCD 58 y 40 39 = 98% Friedman-1966Hospital, AMI 62 y 88 71 = 81% Bouch-1970Hospital, AMI 66 y 91 68 = 75% Sinapius-1972Coroner, SCD 53 y 20 19 = 95% Friedman-1973Hospital, AMI 67 y 76 69 = 91% Horie-1978Hospital, AMI 67 y 49 40 = 82% Falk-1983Coroner, SCD <65 y 32 26 = 81% Tracy-1985Med.exam, SCD <70 y 61 39 = 64% El Fawal-1987Hospital, AMI 83 52 = 63% Yutani-1987Coroner, SCD? ? 85 71 = 84% Richardson-1989Hospital, AMI 63 y 20 12 = 60% van der Wal-1994Coroner, SCD (all?) ? 202 143 = 71% Davies-1997, updateHospital, AMI 69 y 291 218 = 75% Arbustini-1999Hospital, AMI 61 y 61 56 = 92% Shi-1999Hospital, AMI 69 y 100 81 = 81% Kojima-2000Med.exam, SCD 48 y 125 74 = 59% Virmani-2000, update
1460 1114 = 76%76% Worldwide
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Plaque Rupture → Fatal Thrombosisacuteacute MI MI ≈≈ suddensudden deathdeath
Patients Age n Rupture StudyHospital, ? ? 19 19 = 100% Chapman-1965Hospital, ? ? 17 17 = 100% Constantinides-1966Hospital, AMI+SCD 58 y 40 39 = 98% Friedman-1966Hospital, AMI 62 y 88 71 = 81% Bouch-1970Hospital, AMI 66 y 91 68 = 75% Sinapius-1972Hospital, AMI 67 y 76 69 = 91% Horie-1978Hospital, AMI 67 y 49 40 = 82% Falk-1983Hospital, AMI 83 52 = 63% Yutani-1987Hospital, AMI 63 y 20 12 = 60% van der Wal-1994Hospital, AMI 69 y 291 218 = 75% Arbustini-1999Hospital, AMI 61 y 61 56 = 92% Shi-1999Hospital, AMI 69 y 100 81 = 81% Kojima-2000
935 742 = 79% Acute MICoroner, SCD 53 y 20 19 = 95% Friedman-1973Coroner, SCD <65 y 32 26 = 81% Tracy-1985Med.exam, SCD <70 y 61 39 = 64% El Fawal-1987Coroner, SCD? ? 85 71 = 84% Richardson-1989Coroner, SCD (all?) ? 202 143 = 71% Davies-1997, updateMed.exam, SCD 48 y 125 74 = 59% Virmani-2000, update
525 372 = 71% Sudden death
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Plaque Rupture → Fatal ThrombosisEuropeEurope ≈≈ AsiaAsia ≈≈ USAUSA
Patients Age n Rupture StudyHospital, AMI 62 y 88 71 = 81% Bouch-1970Hospital, AMI 66 y 91 68 = 75% Sinapius-1972Hospital, AMI 67 y 49 40 = 82% Falk-1983Med.exam, SCD <70 y 61 39 = 64% El Fawal-1987Coroner, SCD? ? 85 71 = 84% Richardson-1989Hospital, AMI 63 y 20 12 = 60% van der Wal-1994Coroner, SCD (all?) ? 202 143 = 71% Davies-1997, updateHospital, AMI 69 y 291 218 = 75% Arbustini-1999
887 662 = 75% EuropeHospital, AMI 67 y 76 69 = 91% Horie-1978Hospital, AMI 83 52 = 63% Yutani-1987Hospital, AMI 61 y 61 56 = 92% Shi-1999Hospital, AMI 69 y 100 81 = 81% Kojima-2000
320 258 = 81% AsiaHospital, ? ? 19 19 = 100% Chapman-1965Hospital, ? ? 17 17 = 100% Constantinides-1966Hospital, AMI+SCD 58 y 40 39 = 98% Friedman-1966Coroner, SCD 53 y 20 19 = 95% Friedman-1973Coroner, SCD <65 y 32 26 = 81% Tracy-1985Med.exam, SCD 48 y 125 74 = 59% Virmani-2000, update
253 194 = 77% USA
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Plaque Rupture → Fatal Thrombosisageage
Patients Age n Rupture StudyHospital, ? ? 19 19 = 100% Chapman-1965Hospital, ? ? 17 17 = 100% Constantinides-1966Hospital, AMI 83 52 = 63% Yutani-1987Coroner, SCD? ? 85 71 = 84% Richardson-1989Coroner, SCD (all?) ? 202 143 = 71% Davies-1997, update
406 302 = 74% Age unknownHospital, AMI 62 y 88 71 = 81% Bouch-1970Hospital, AMI 66 y 91 68 = 75% Sinapius-1972Hospital, AMI 67 y 76 69 = 91% Horie-1978Hospital, AMI 67 y 49 40 = 82% Falk-1983Med.exam, SCD <70 y 61 39 = 64% El Fawal-1987Hospital, AMI 63 y 20 12 = 60% van der Wal-1994Hospital, AMI 69 y 291 218 = 75% Arbustini-1999Hospital, AMI 61 y 61 56 = 92% Shi-1999Hospital, AMI 69 y 100 81 = 81% Kojima-2000
837 654 = 78% >60 yearsCoroner, SCD <65 y 32 26 = 81% Tracy-1985Hospital, AMI+SCD 58 y 40 39 = 98% Friedman-1966Coroner, SCD 53 y 20 19 = 95% Friedman-1973Med.exam, SCD 48 y 125 74 = 59% Virmani-2000, update
217 158 = 73% <60 years
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Plaque Rupture → Fatal Thrombosissexsex
Sex n Rupture Study pMale 37 32 = 86% Falk-1983
134 113 = 84% Davies-1997184 151 = 82% Arbustini-1999 .000474 63 = 85% Kojima-2000 .08 → .494 64 = 68% Virmani-2000, update
523 423 = 81%Female 12 8 = 67% Falk-1983
27 16 = 59% Davies-1997107 67 = 63% Arbustini-199926 18 = 69% Kojima-200031 10 = 32% Virmani-2000, update
203 119 = 59%
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Plaque Rupture → Coronary Thrombosis
men ~~80%80%women ~60%~60%
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Thrombosis not caused by plaque rupture
Thrombus
LipidLipid
FibrosisFibrosis
Erosionmen ~~20%20%women ~40%~40%
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definitiondefinitionpathogenesispathogenesispathologicpathologic featuresfeatures
Vulnerable plaques
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*Kolodgie, Virmani et al. Heart 2004;90:1385-91
Ruptured
Intact
thrombusthrombus
•
•••••••
•
•••••
•••
corecore
capcapMacrophages in plaque
• Plaque area ~11 mm2
• Macr area ~ 0.14 mm2*
<2% <2% ofof plaqueplaque areaarea
*TCFA, Kolodgie, ..., Virmani. NEJM 2003;349:2316-25
••
••
••
••
•
••••
••
•
••
• Coronary Atherosclerosisrupturedruptured vsvs intactintact plaqueplaque
Necrotic core↑• ~34% of plaque area*
• ~3.8 mm2 & ~9 mm long*
FibrousFibrous capcap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**
•• macrophagesmacrophages↑↑, , ~26% ~26% ofof capcap**
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Carotid Atherosclerosis & Strokeeendarterectomndarterectomyy specimenspecimen
macrophagesmacrophages??
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Carotid Plaque → Stroke ~ CAD → AMI
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Carotid Plaque → Stroke ~ CAD → AMI
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SymptomaticSymptomatic plaquesplaques, n=106, n=106
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3.3 mm
MacrophagesMacrophages red (CD68+): ~1% to 1.8%red (CD68+): ~1% to 1.8%
J Vasc Surg 2002;35:137-45
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Gene expression in carotid plaques
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Adams et al. ATVB 2006;26:319-25
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Adams et al. ATVB 2006;26:319-25
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Adams et al. ATVB 2006;26:319-25
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Symptomatic Carotid Atherosclerosismacrophagemacrophage densitydensity: <: <22--3%3%
~acellular
macrmacrfibrosisfibrosis
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*Kolodgie, Virmani et al. Heart 2004;90:1385-91
Ruptured
Intact
thrombusthrombus
•
•••••••
•
•••••
•••
corecore
capcap
Coronary Atherosclerosisrupturedruptured vsvs intactintact plaqueplaque
Necrotic core↑• ~34% of plaque area*
• ~3.8 mm2 & ~9 mm long*
FibrousFibrous capcap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**
•• macrophagesmacrophages↑↑, ~26% , ~26% ofof capcap**
•• smoothsmooth musclemuscle cellscells↓↓ ((apoptosisapoptosis))•• thrombusthrombus↑↑Expansive remodeling↑
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Gregg W. Stone, TCT Asia PacificSatellite Lecture, April 26, 2006Satellite Lecture, April 26, 2006
“What we do in the cath. lab.do not prevent heart attack or death”
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*Kolodgie, Virmani et al. Heart 2004;90:1385-91
Ruptured
Intact
thrombusthrombus
•
•••••••
•
•••••
•••
corecore
capcap
Coronary Atherosclerosisrupturedruptured vsvs intactintact plaqueplaque
Necrotic core↑• ~34% of plaque area*
• ~3.8 mm2 & ~9 mm long*
FibrousFibrous capcap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**
•• macrophagesmacrophages↑↑, ~26% , ~26% ofof capcap**
•• smoothsmooth musclemuscle cellscells↓↓ ((apoptosisapoptosis))•• thrombusthrombus↑↑Expansive remodeling↑Angiogenesis↑
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A B
C D
Barger et al.VisualizationVisualization ofof vasavasavasorumvasorum and and neovascularizationneovascularization ofatherosclerotic coronaryarteries by cinematography ofsiliconesilicone injectioninjection in cleared human hearts.
Vasa vasorum wererarely seen in normal arteries.In contrast, ….
NEJM 1984;310:175-7
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A B
C D
Barger et al.Panel B, later:
Long, parallel vasavasorum in theadventitia.
NEJM 1984;310:175-7
vasavasavasorumvasorum
lumenlumen
plaqueplaque LADLAD vasavasavasorumvasorum
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A B
C D
Barger et al.Panels C & D, with furtherfilling:
Rich capillary networkconfined to the plaque,= adventitia-derived
neovascularization
•• LeakyLeakyexudationexudation
•• FragileFragilehemorrhagehemorrhage
LowerLower edgeedge ofof plaqueplaqueneoneo--
vascularizationvascularization
neoneo--vascularizationvascularization
plaqueplaque
lumenlumen
vasavasavasorumvasorum
vasavasavasorumvasorum
LADLAD
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Human Pathol 1995;26:450-6
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Human Pathol2005;36;330-40
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*Kolodgie, Virmani et al. Heart 2004;90:1385-91
Ruptured
Intact
thrombusthrombus
•
•••••••
•
•••••
•••
corecore
capcap
Coronary Atherosclerosisrupturedruptured vsvs intactintact plaqueplaque
Necrotic core↑• ~34% of plaque area*
• ~3.8 mm2 & ~9 mm long*
FibrousFibrous capcap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**
•• macrophagesmacrophages↑↑, ~26% , ~26% ofof capcap**
•• smoothsmooth musclemuscle cellscells↓↓ ((apoptosisapoptosis))•• thrombusthrombus↑↑Expansive remodeling↑Angiogenesis↑• intraplaque hemorrhage
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*Kolodgie, Virmani et al. Heart 2004;90:1385-91
Ruptured
Intact
thrombusthrombus
•
•••••••
•
•••••
•••
corecore
capcap
Coronary Atherosclerosisrupturedruptured vsvs intactintact plaqueplaque
Necrotic core↑• ~34% of plaque area*
• ~3.8 mm2 & ~9 mm long*
FibrousFibrous capcap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**
•• macrophagesmacrophages↑↑, ~26% , ~26% ofof capcap**
•• smoothsmooth musclemuscle cellscells↓↓ ((apoptosisapoptosis))•• thrombusthrombus↑↑Expansive remodeling↑Angiogenesis↑• intraplaque hemorrhagePerivascular inflammation
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Virmani et al. ATVB 2005;25:2054-61
Intima
Media
Adventitia
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Coronary Atherosclerosisrupturedruptured vsvs intactintact plaqueplaque
Necrotic core↑• ~34% of plaque area*
• ~3.8 mm2 & ~9 mm long*
FibrousFibrous capcap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**
•• macrophagesmacrophages↑↑, ~26% , ~26% ofof capcap**
•• smoothsmooth musclemuscle cellscells↓↓ ((apoptosisapoptosis))•• thrombusthrombus↑↑Expansive remodeling↑Angiogenesis↑• intraplaque hemorrhagePerivascular inflammationCalcification↓ & spotty
*Kolodgie, Virmani et al. Heart 2004;90:1385-91
Ruptured
Intact
thrombusthrombus
•
•••••••
•
•••••
•••
corecore
capcap
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Coronary Plaque Vulnerabilitycalcium calcium stabilizesstabilizes plaquesplaques??
0
10
20
30
40
50
60
70
Fibrous tissueAtheromatous coreCalcium
Infarct-Related Coronary Arteries: Composition of Stenosis >75%
Gertz SD, Roberts WC. Am J Cardiol 1990;66:1368-72
% ofPlaque
Intact Ruptured
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Plaque heterogeneity
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Plaque heterogeneity among patientsdissimilardissimilar syndromessyndromes
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macrophagesmacrophages ((CD68+CD68+):): redred
Coronary atherectomy: non-ST↑ MI culprit
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0
5
10
15
Macrophages in Culprit Lesion
StableAngina
UnstableAngina
Non-Q-waveMI
Moreno, Falk, Palacios et al. Circulation 1994;90:775-8
% of Plaque
3% 13% 14%n=8
n=8n=10
Coronary Plaque Inflammationmacrophagemacrophage densitydensity
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0
5
10
15
Macrophages in Culprit Lesion
StableAngina
UnstableAngina
Non-Q-waveMI
Moreno, Falk, Palacios et al. Circulation 1994;90:775-8
% of Plaque
3% 13% 14%n=8
n=8n=10
Coronary Plaque Inflammationmacrophagemacrophage densitydensity
not specific
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Heart 1996;76:312-6
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Plaque heterogeneity among patients((dis)similardis)similar syndromessyndromes
Considerable overlap between
1. Chr. stable angina,1. Chr. stable angina, n=28n=282. 2. UnstableUnstable angina, angina, n=18n=183. 3. AcuteAcute rest angina,rest angina, n=12n=12
van der Wal et al. Heart 1996;76:312-6
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contrast
thrombusthrombuscapcap rupturerupture
necroticnecrotic corecore
collagencollagenCaCa
Plaque heterogeneity within a personplaquesplaques nextnext to to eacheach otherother
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Vulnerable PlaqueA A disasterdisaster waitingwaiting to to happenhappen
Atherosclerosis is a generalizeddisease with (multi)focal
manifestations
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Vulnerable PlaqueA A disasterdisaster waitingwaiting to to happenhappen
HowHow manymany VP?VP?Can we find them?Can we find them?
Can we treat them and prevent heart attack?Can we treat them and prevent heart attack?
Atherosclerosis is a generalizeddisease with (multi)focal
manifestations
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Madjid et al. ATVB 2004;24:1775-82
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Coronary Atherosclerosistargetstargets for for imagingimaging
Necrotic core↑• ~34% of plaque area*
• ~3.8 mm2 & ~9 mm long*
FibrousFibrous capcap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**
•• macrophagesmacrophages↑↑, ~26% , ~26% ofof capcap**
•• smoothsmooth musclemuscle cellscells↓↓ ((apoptosisapoptosis))•• thrombusthrombus↑↑Expansive remodeling↑Angiogenesis↑• intraplaque hemorrhagePerivascular inflammationCalcification↓ & spotty
*Kolodgie, Virmani et al. Heart 2004;90:1385-91
Ruptured
Intact
thrombusthrombus
•
•••••••
•
•••••
•••
corecore
capcap