vulnerable plaque - summitmd.comvulnerable plaque pathophysiology, detection, and intervention...
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Vulnerable PlaquePathophysiology, Detection, and Intervention
Erling Falk, Denmark
VP: A Local Problem or Systemic Disease
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Vulnerable PlaquePathophysiology, Detection, and Intervention
Erling Falk, Denmark
VP: A Local Problem in a Systemic Disease
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Vulnerable PlaquePathophysiology, Detection, and Intervention
Erling Falk, Denmark
VPs: Local Problems in a Systemic Disease?
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Am J Cardiol 1990;65:2F-6F. Review
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Ca: 8%Ca: 8%
NecrosisNecrosis16%16%
FibrosisFibrosis68%68%
Infl: 8%Infl: 8%
Plaques causing >75% stenosis by histology
Roberts et al (Falk. JACC 2006;47:C7-12)
Atherosclerosis: chronic smoldering inflammationplaque composition
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N Engl J Med 1999 Jan;340:115N Engl J 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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NCEP ATP III, 2002
Non-coronary atherosclerosisCHD risk equivalent
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NCEP ATP III, 2002
Non-coronary atherosclerosisCHD risk equivalent
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Circulation 2004;110:227-239
Acute coronary syndromeveryvery high risk
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Cannon et al. NEJM 2004:350:1495-504
PROVE IT – TIMI 22: statin after stabilized ACS
Despite profound lipid lowering in ACS¼¼ come back with a new event within 30 mcome back with a new event within 30 m
(standard) (intensive)
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Falk. JACC 2006;47:C7-12
Atherosclerosissystemic disease with focal manifestations
VP→Thrombosis
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Falk. JACC 2006;47:C7-12
Atherosclerosissystemic disease with focal manifestations
VP/culpritOne?Few?Many?
VP→Thrombosis
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Am J Cardiol 2006;98(suppl):3Q-9Q
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Am J Cardiol 2006;98(suppl):3Q-9Q
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Mauriello et al. JACC 2005;45:1585-93
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Plaque rupture (14/16 thrombi = 87.5%) → AMI<2 TCFA per patient
16 patients
Mauriello et al. JACC 2005;45:1585-93
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Plaque rupture (14/16 thrombi = 87.5%) → AMI<2 TCFA per patient
16 patients
Mauriello et al. JACC 2005;45:1585-93
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<2 TCFAper patient
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Cannon et al. NEJM 2004:350:1495-504
PROVE IT – TIMI 22: statin after stabilized ACS
Despite profound lipid lowering in ACS¼¼ come back with a new event within 30 mcome back with a new event within 30 m
(standard) (intensive)
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Ruptured Plaquestotal +thrombus
47 patients1 103 40 83 patients2 211 102
1 Falk E. Br Heart J 1983;50:127-342 Frink RJ. J Inv Cardiol 1994;6:173-85
Plaque rupture in fatal CAD2-3 per patient, including culprit
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Atheroma-related Plaque Rupturedisease no thrombus +thrombus
69 persons: no 6 ( 9%) 060 persons: + 10 (17%) 3 mural (5%)
Davies MJ et al. Eur Heart J 1989;10:203-8
Plaque rupture in non-cardiac death, n=129relatively rare (vs CAD)
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NEJM 1984;310:1137-40
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• 115 thrombi in 74 patients• 103 (90%)(90%) of these had plaque fissuring
NEJM 1984;310:1137-40
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Curr Opin Cardiol 2001;16:285-292
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Plaque rupture → CAD~1.3 TCFA per patient
Kolodgie, …, Virmani. Curr Opin Cardiol 2001;16:285-292
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Plaque rupture → CAD~1.3 TCFA per patient
Kolodgie, …, Virmani. Curr Opin Cardiol 2001;16:285-292
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Thin-cap fibroatheroma & ruptureprox LAD: “hot spot”
TCFA Plaque Rupture
Healed Rupture
Kolodgie, …, Virmani. Curr Opin Cardiol 2001;16:285-292
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LAD
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VP and ruptured plaques”… relatively infrequent … limited, focal distribution…”
AHA, Nov 2006; abstract 251
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VP and ruptured plaques”… relatively infrequent … limited, focal distribution…”
AHA, Nov 2006; abstract 251
50 hearts (33 CVD)
• TCFA, Vulnerable Plaque n=23 (0.46 per heart)• Ruptured plaques n=19 (0.38 per heart)
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Targeting Vulnerable Plaquemedical whack-a-mole?
1. Origin• speed of development
2. How long does a VP persist?3. Fate
• healing without thrombosis• silent rupture/thrombosis• acute ischemic event (ACS, stroke)
Thrombosis-prone plaques
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Targeting Vulnerable Plaquemedical whack-a-mole?
1. Origin• speed of development
2. How long does a VP persist?3. Fate
• healing without thrombosis• silent rupture/thrombosis• acute ischemic event (ACS, stroke)
Thrombosis-prone plaques
Acne. NEJM 2005;352:1463-72
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Plaque Rupture → Coronary Thrombosis
men ~~80%80%women ~60%~60%
Plaquerupture
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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%
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Coronary Atherosclerosisruptured vs intact plaqueruptured vs intact plaque
Ruptured
Intactlumen
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Coronary Atherosclerosisruptured vs intact plaqueruptured vs intact plaque
Plaque sizePlaque size↑↑
Ruptured
Intactlumen
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Circulation 1996;94:2662-6
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Circulation 1996;94:2662-6
ANGIOGRAPHYluminal narrowing
(diameter reduction)
IVUS/HISTOLOGYwall disease (plaque)
B:Wall: 50% X-sectional↓Lumen: normal
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Circulation 1996;94:2662-6
ANGIOGRAPHYluminal narrowing
(diameter reduction)
IVUS/HISTOLOGYwall disease (plaque)
B:Wall: 50% X-sectional↓Lumen: normal
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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
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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%
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Heart 2004;90:1385-91
(stenotic)
Mean (SD)
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Heart 2004;90:1385-91
(stenotic)
Mean (SD)
Overlap: Necrotic core >10% of an average stable plaque
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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
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Heart 2004;90:1385-91
Mean (SD)
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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
•
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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
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Mean ~ SDMean ~ SD
Kolodgie, …, Virmani. Lp-associated PLA2 … .ATVB 2006;26:2523-9Lp-PLA2
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Heart 1996;76:312-6
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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 inflammation: considerable overlap(dis)similar syndromes
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Lp-PLA2
Mean ~ SDMean ~ SD
Kolodgie, …, Virmani. Lp-associated PLA2 … .ATVB 2006;26:2523-9
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Mean ~ SDMean ~ SD
Kolodgie, …, Virmani. Lp-associated PLA2 … .ATVB 2006;26:2523-9Lp-PLA2
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Mean ~ SDMean ~ SD
Kolodgie, …, Virmani. Lp-associated PLA2 … .ATVB 2006;26:2523-9Lp-PLA2
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Mean ~ SDMean ~ SD
Kolodgie, …, Virmani. Lp-associated PLA2 … .ATVB 2006;26:2523-9Lp-PLA2
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AHA Nov 2006
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AHA Nov 2006
TCFA+RP relationshipPlaque component predictor bivariate
• plaque size + +• necrotic core size + +• inflammation (macr) + -
Conclusion: Plaque area and necrotic core determine the likelihood of plaque rupture
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Plaque rupture: role of inflammation
thrombusthrombus
necrotic corenecrotic core
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thrombusthrombus
necrotic corenecrotic core
Plaque rupture: role of inflammation
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capcapcapcapmacrophagesmacrophagesat rupture siteat rupture site(MMP, TF)(MMP, TF)
Plaque rupture: role of inflammation
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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
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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
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Heart 2004;90:1385-91
Mean (SD)
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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
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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
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No correlation!
Circ 1996;94:928-31
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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
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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
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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
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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
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NEJM 2003 Dec;349:2316-25
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Human Pathol 1995;26:450-6
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Human Pathol2005;36;330-40
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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
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HELAD, 50 FDied of AMI
Adventitial lymphocyte infiltration
Plaque (AHA Type V)
MediaAdv.
Lymphocytes
Søren Dalager
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AHA Nov 2006
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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
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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%
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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
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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
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Madjid et al. ATVB 2004;24:1775-82
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Circulation 2006;114:2390-2411
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Circulation 2006;114:2390-2411
TCFA = thin-cap fibroatheroma (the most frequent VP)
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Circulation 2006;114:2390-2411
TCFA = thin-cap fibroatheroma (the most frequent VP)