Vulnerable Plaque

Erling Falk, Denmark

Potential Targets forImaging of Vulnerable Plaques

EHJ 2004;25:1077-82

Santorini declaration

Schaar et al. Eur Heart J, June 2004

Development of atherosclerosis and progression to thrombosis and clinical events

Schaar et al. Eur Heart J, June 2004

Thrombosis-proneplaque

Development of atherosclerosis and progression to thrombosis and clinical events

Plaque Rupture → Coronary Thrombosis

men ~~80%80%women ~60%~60%

Plaquerupture

Thrombosis-prone = high-risk = vulnerable plaque

Ruptured

Non-ruptured

Fatal Coronary ThrombiPrecipitated by Plaque Rupture

Total AMI + SCD 1,460 1,114 = 76% Worldwide

Falk. JACC 2006;47:C7-12

Coronary Thrombosisplaque ruptureplaque rupture• men ~80%• women ~60%

Coronary Atherosclerosisruptured vs intact plaqueruptured vs intact plaque

Ruptured

Intactlumen

Coronary Atherosclerosisruptured vs intact plaqueruptured vs intact plaque

Plaque sizePlaque size↑↑

Ruptured

Intactlumen

Coronary Atherosclerosisruptured vs intact plaqueruptured vs intact plaque

Plaque sizePlaque size↑↑Necrotic core↑• ~34% of plaque area*

• ~3.8 mm2 & ~9 mm long*

*Kolodgie, Virmani et al. Heart 2004;90:1385-91

Ruptured

Intact

corecore

lumen

0

10

20

30

40

50

60

70

FibrosisNecrotic CoreCalcium

Gertz SD, Roberts WC. Am J Cardiol 1990;66:1368-72

% of plaque area

Intact Ruptured

Coronary Plaque Rupturenecrotic core in intact necrotic core in intact (stenotic)(stenotic) vs ruptured plaquesvs ruptured plaques

32%

12%

Heart 2004;90:1385-91

(stenotic)

Mean (SD)

Heart 2004;90:1385-91

(stenotic)

Mean (SD)

Overlap: Necrotic core >10% of an average stable plaque

Coronary Atherosclerosisruptured vs intact plaqueruptured vs intact plaque

Plaque sizePlaque size↑↑Necrotic core↑• ~34% of plaque area*

• ~3.8 mm2 & ~9 mm long*

Fibrous capFibrous cap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**

*Kolodgie, Virmani et al. Heart 2004;90:1385-91

Ruptured

Intact

corecore

capcap

lumen

Heart 2004;90:1385-91

Mean (SD)

Coronary Atherosclerosisruptured vs intact plaqueruptured vs intact plaque

Plaque sizePlaque size↑↑Necrotic core↑• ~34% of plaque area*

• ~3.8 mm2 & ~9 mm long*

Fibrous capFibrous cap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**

•• macrophagesmacrophages↑↑, , ~26% of cap~26% of cap**

*Kolodgie, Virmani et al. Heart 2004;90:1385-91

Ruptured

Intact

•••••••

•

•••••

•••

corecore

capcap

lumen

•

Coronary Atherosclerosisruptured vs intact plaqueruptured vs intact plaque

Plaque sizePlaque size↑↑Necrotic core↑• ~34% of plaque area*

• ~3.8 mm2 & ~9 mm long*

Fibrous capFibrous cap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**

•• macrophagesmacrophages↑↑, , ~26% of cap~26% of cap**

*Kolodgie, Virmani et al. Heart 2004;90:1385-91

Ruptured

Intact

•

•••••••

•

•••••

•••

26%

hypocellular

hypocellular

cap

core

lumen

•• •••••••

••••

••

••

acellularacellular

26%

Ca

fibrosisfibrosis

Lp-PLA2

Mean ~ SDMean ~ SD

Kolodgie, …, Virmani. Lp-associated PLA2 … .ATVB 2006;26:2523-9

Heart 1996;76:312-6

Plaque inflammation: considerable overlap(dis)similar syndromes(dis)similar syndromes

Considerable overlap between

1. Chr. stable angina,1. Chr. stable angina, n=28n=282. Unstable angina, 2. Unstable angina, n=18n=183. Acute rest angina,3. Acute rest angina, n=12n=12

van der Wal et al. Heart 1996;76:312-6

Plaque rupture: role of inflammation

thrombusthrombus

necrotic corenecrotic core

thrombusthrombus

necrotic corenecrotic core

Plaque rupture: role of inflammation

capcapcapcapmacrophagesmacrophagesat rupture siteat rupture site(MMP, TF)(MMP, TF)

Plaque rupture: role of inflammation

Coronary Atherosclerosisruptured vs intact plaqueruptured vs intact plaque

Plaque sizePlaque size↑↑Necrotic core↑• ~34% of plaque area*

• ~3.8 mm2 & ~9 mm long*

Fibrous capFibrous cap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**

•• macrophagesmacrophages↑↑, ~26% of cap, ~26% of cap**

•• smooth muscle cellssmooth muscle cells↓↓ (apoptosis)(apoptosis)

Ruptured

Intact

•

•••••••

•

•••••

•••

corecore

capcap

lumen

Coronary Atherosclerosisruptured vs intact plaqueruptured vs intact plaque

Plaque sizePlaque size↑↑Necrotic core↑• ~34% of plaque area*

• ~3.8 mm2 & ~9 mm long*

Fibrous capFibrous cap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**

•• macrophagesmacrophages↑↑, ~26% of cap, ~26% of cap**

•• smooth muscle cellssmooth muscle cells↓↓ (apoptosis)(apoptosis)

Ruptured

Intact

•

•••••••

•

•••••

•••

corecore

capcap

lumen0

10

20

30

40

50

60

Stable Vulnerable Disrupted

% of plaque/cap

Core Cap Macr Cap SMC

Davies et al. Br Heart J 1993;69:377-81

AortaAorta

Heart 2004;90:1385-91

Mean (SD)

Coronary Atherosclerosisruptured vs intact plaqueruptured vs intact plaque

Plaque sizePlaque size↑↑Necrotic core↑• ~34% of plaque area*

• ~3.8 mm2 & ~9 mm long*

Fibrous capFibrous cap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**

•• macrophagesmacrophages↑↑, ~26% of cap, ~26% of cap**

•• smooth muscle cellssmooth muscle cells↓↓ (apoptosis)(apoptosis)•• thrombusthrombus↑↑

Ruptured

Intact

•

•••••••

•

•••••

•••

corecore

capcap

lumen

thrombus

Fatal Coronary ThrombiPrecipitated by Plaque Rupture

Total AMI + SCD 1,460 1,114 = 76% Worldwide

Falk. JACC 2006;47:C7-12

Coronary Atherosclerosisruptured vs intact plaqueruptured vs intact plaque

Plaque sizePlaque size↑↑Necrotic core↑• ~34% of plaque area*

• ~3.8 mm2 & ~9 mm long*

Fibrous capFibrous cap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**

•• macrophagesmacrophages↑↑, ~26% of cap, ~26% of cap**

•• smooth muscle cellssmooth muscle cells↓↓ (apoptosis)(apoptosis)•• thrombusthrombus↑↑Expansive remodeling↑

*Kolodgie, Virmani et al. Heart 2004;90:1385-91

Ruptured

Intact

•

•••••••

•

•••••

•••

corecore

capcap

lumen

thrombus

No correlation!

Circ 1996;94:928-31

Coronary Remodeling & Plaque Vulnerabilitypositive but weak correlation with lipid core and macrpositive but weak correlation with lipid core and macr

Varnava, Mills, Davies. Circ 2002;105:939-43

Coronary Remodeling & Plaque Vulnerabilitypositive but weak correlation with lipid core and macrpositive but weak correlation with lipid core and macr

Varnava, Mills, Davies. Circ 2002;105:939-43

Coronary Atherosclerosisruptured vs intact plaqueruptured vs intact plaque

Plaque sizePlaque size↑↑Necrotic core↑• ~34% of plaque area*

• ~3.8 mm2 & ~9 mm long*

Fibrous capFibrous cap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**

•• macrophagesmacrophages↑↑, ~26% of cap, ~26% of cap**

•• smooth muscle cellssmooth muscle cells↓↓ (apoptosis)(apoptosis)•• thrombusthrombus↑↑Expansive remodeling↑Angiogenesis↑• intraplaque hemorrhage

*Kolodgie, Virmani et al. Heart 2004;90:1385-91

Ruptured

Intact

•

•••••••

•

•••••

•••

corecore

capcap

lumen

thrombus

A B

C D

Barger et al.Panels C & D, with further filling:

Rich capillary network confined to the plaque,= adventitia-derived

neovascularization

•• LeakyLeakyexudationexudation

•• FragileFragilehemorrhagehemorrhage

Lower edge of plaqueLower edge of plaqueneoneo--

vascularizationvascularization

neoneo--vascularizationvascularization

plaqueplaque

lumenlumen

vasavasavasorumvasorum

vasavasavasorumvasorum

LADLAD

NEJM 2003 Dec;349:2316-25

Human Pathol 1995;26:450-6

Human Pathol2005;36;330-40

Coronary Atherosclerosisruptured vs intact plaqueruptured vs intact plaque

Plaque sizePlaque size↑↑Necrotic core↑• ~34% of plaque area*

• ~3.8 mm2 & ~9 mm long*

Fibrous capFibrous cap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**

•• macrophagesmacrophages↑↑, ~26% of cap, ~26% of cap**

•• smooth muscle cellssmooth muscle cells↓↓ (apoptosis)(apoptosis)•• thrombusthrombus↑↑Expansive remodeling↑Angiogenesis↑• intraplaque hemorrhagePerivascular inflammation

*Kolodgie, Virmani et al. Heart 2004;90:1385-91

Ruptured

Intact

•

•••••••

•

•••••

•••

corecore

capcap

lumen

thrombus

Coronary artery from patient with AMI(peri)adventitial inflammation(peri)adventitial inflammation

Kohchi et al. Circulation 1985:71:709-16

iemiemmediamedia

adventitiaadventitia

intimaintima

B lymphocytes, plasma cells, macrophagesB lymphocytes, plasma cells, macrophagesGK Hansson, 1996

Coronary Atherosclerosisruptured vs intact plaqueruptured vs intact plaque

Plaque sizePlaque size↑↑Necrotic core↑• ~34% of plaque area*

• ~3.8 mm2 & ~9 mm long*

Fibrous capFibrous cap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**

•• macrophagesmacrophages↑↑, ~26% of cap, ~26% of cap**

•• smooth muscle cellssmooth muscle cells↓↓ (apoptosis)(apoptosis)•• thrombusthrombus↑↑Expansive remodeling↑Angiogenesis↑• intraplaque hemorrhagePerivascular inflammationCalcification↓ & spotty

*Kolodgie, Virmani et al. Heart 2004;90:1385-91

Ruptured

Intact

•

•••••••

•

•••••

•••

corecore

capcap

lumen

thrombus

Ca

Sangiorgi G et al. JACC 1998;31:126-33

Plaque

Lumen

Coronary Calcium: ~Plaque, ≠Lumen

0

10

20

30

40

50

60

70

FibrosisNecrotic CoreCalcium

Gertz SD, Roberts WC. Am J Cardiol 1990;66:1368-72

% of plaque area

Intact Ruptured

Coronary Plaque Rupturecalcification in intact calcification in intact (stenotic)(stenotic) vs ruptured plaquesvs ruptured plaques

5%15%

Coronary Atherosclerosisruptured vs intact plaqueruptured vs intact plaque

Plaque sizePlaque size↑↑Necrotic core↑• ~34% of plaque area*

• ~3.8 mm2 & ~9 mm long*

Fibrous capFibrous cap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**

•• macrophagesmacrophages↑↑, ~26% of cap, ~26% of cap**

•• smooth muscle cellssmooth muscle cells↓↓ (apoptosis)(apoptosis)•• thrombusthrombus↑↑Expansive remodeling↑Angiogenesis↑• intraplaque hemorrhagePerivascular inflammationCalcification↓ & spotty

*Kolodgie, Virmani et al. Heart 2004;90:1385-91

Ruptured

Intact

•

•••••••

•

•••••

•••

corecore

capcap

lumen

thrombus

Ca

Coronary Atherosclerosistargets for imagingtargets for imaging

Plaque sizePlaque size↑↑Necrotic core↑• ~34% of plaque area*

• ~3.8 mm2 & ~9 mm long*

Fibrous capFibrous cap•• thinknessthinkness↓↓, ~23 , ~23 µµm m (95% <65 (95% <65 µµm)m)**

•• macrophagesmacrophages↑↑, ~26% of cap, ~26% of cap**

•• smooth muscle cellssmooth muscle cells↓↓ (apoptosis)(apoptosis)•• thrombusthrombus↑↑Expansive remodeling↑Angiogenesis↑• intraplaque hemorrhagePerivascular inflammationCalcification↓ & spotty

*Kolodgie, Virmani et al. Heart 2004;90:1385-91

Ruptured

Intact

•

•••••••

•

•••••

•••

corecore

capcap

lumen

thrombus

Ca

Madjid et al. ATVB 2004;24:1775-82

Vulnerable plaque(s) → Vulnerable patient

Carotid Atherosclerosisendarterectomi specimensendarterectomi specimens

Carotid Plaque → Stroke ~ CAD → AMI

Carotid Plaque → Stroke ~ CAD → AMI

Symptomatic plaques, n=106Symptomatic plaques, n=106

1 mm

CD68+ macr: red

Grønholdt MLM et al. J Vasc Surg 2002;35:137-45n=106

Symptomatic Carotid Plaquesmacr ~1.6% of plaque area macr ~1.6% of plaque area ((≠≠ plasma hsCRP)plasma hsCRP)

1 mm

CD68+ macr: red

Symptomatic Carotid Plaqueslipidlipid--rich core ~40% of plaque arearich core ~40% of plaque area

Grønholdt MLM et al. J Vasc Surg 2002;35:137-45n=106

Verhoeven et al, Stroke 2006;37:2054-60

Macr density: ~0.4% of plaque

Verhoeven et al, Stroke 2006;37:2054-60

PET-FDG

Macrin plaque

JACC 2006;48:1818 –24

Neurosurgery 2006;59(S3):219-27

Virmani R et al. Neurosurgery 2006;59(S3):219-27

Ruptured plaquecarotid (carotid (vs vs coronary)coronary)

Virmani R et al. Neurosurgery 2006;59(S3):219-27

Ruptured plaquecarotid (carotid (vs vs coronary)coronary)

Virmani R et al. Neurosurgery 2006;59(S3):219-27

Ruptured plaquecarotid (carotid (vs vs coronary)coronary)

Vessel size (blood flow)↑Plaque size↑Plaque ulceration (defect+thrombus)↑Total occlusion↓ & thromboembolism↑

Virmani R et al. Neurosurgery 2006;59(S3):219-27

Ruptured plaquecarotid (carotid (vs vs coronary)coronary)

Vessel size (blood flow)↑Plaque size↑Plaque ulceration (defect+thrombus)↑Total occlusion↓ & thromboembolism↑

Plaque rupture (vs erosion)↑• symptomatic 74% (asymptomatic: 32%)

Virmani R et al. Neurosurgery 2006;59(S3):219-27

Ruptured plaquecarotid (carotid (vs vs coronary)coronary)

Vessel size (blood flow)↑Plaque size↑Plaque ulceration (defect+thrombus)↑Total occlusion↓ & thromboembolism↑

Plaque rupture (vs erosion)↑• symptomatic 74% (asymptomatic: 32%)

Plaque hemorrhage↑↑↑

Virmani R et al. Neurosurgery 2006;59(S3):219-27

Ruptured plaquecarotid (carotid (vs vs coronary)coronary)

Vessel size (blood flow)↑Plaque size↑Plaque ulceration (defect+thrombus)↑Total occlusion↓ & thromboembolism↑

Plaque rupture (vs erosion)↑• symptomatic 74% (asymptomatic: 32%)

Plaque hemorrhage↑↑↑Necrotic core size• ruptured ~ intact plaques (vs coronary)

Virmani R et al. Neurosurgery 2006;59(S3):219-27

Ruptured plaquecarotid (carotid (vs vs coronary)coronary)

Vessel size (blood flow)↑Plaque size↑Plaque ulceration (defect+thrombus)↑Total occlusion↓ & thromboembolism↑

Plaque rupture (vs erosion)↑• symptomatic 74% (asymptomatic: 32%)

Plaque hemorrhage↑↑↑Necrotic core size• ruptured ~ intact plaques (vs coronary)

Cap thickness↑• ruptured: 72 µm (vs 23 µm in coronary)• symptomatic: 270 ± 300 µm• asymptomatic: 500 ± 500 µmCap inflammation↓• ruptured: 14 ± 11% (vs 26% in coronary• symptomatic: 1114 ± 1104 macr• asymptomatic: 385 ± 622 macr