Vulnerable PlaquePathophysiology, Detection, and Intervention

Erling Falk, Denmark

VP: A Local Problem or Systemic Disease

Vulnerable PlaquePathophysiology, Detection, and Intervention

Erling Falk, Denmark

VP: A Local Problem in a Systemic Disease

Vulnerable PlaquePathophysiology, Detection, and Intervention

Erling Falk, Denmark

VPs: Local Problems in a Systemic Disease?

Am J Cardiol 1990;65:2F-6F. Review

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

N Engl J Med 1999 Jan;340:115N Engl J Med 1999 Jan;340:115--2626

Seattle, March 18, 1999Seattle, March 18, 1999

NEJM 2005NEJM 2005352:1685352:1685--9595

NCEP ATP III, 2002

Non-coronary atherosclerosisCHD risk equivalent

NCEP ATP III, 2002

Non-coronary atherosclerosisCHD risk equivalent

Circulation 2004;110:227-239

Acute coronary syndromeveryvery high risk

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)

Falk. JACC 2006;47:C7-12

Atherosclerosissystemic disease with focal manifestations

VP→Thrombosis

Falk. JACC 2006;47:C7-12

Atherosclerosissystemic disease with focal manifestations

VP/culpritOne?Few?Many?

VP→Thrombosis

Am J Cardiol 2006;98(suppl):3Q-9Q

Am J Cardiol 2006;98(suppl):3Q-9Q

Mauriello et al. JACC 2005;45:1585-93

Plaque rupture (14/16 thrombi = 87.5%) → AMI<2 TCFA per patient

16 patients

Mauriello et al. JACC 2005;45:1585-93

Plaque rupture (14/16 thrombi = 87.5%) → AMI<2 TCFA per patient

16 patients

Mauriello et al. JACC 2005;45:1585-93

<2 TCFAper patient

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)

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

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)

NEJM 1984;310:1137-40

• 115 thrombi in 74 patients• 103 (90%)(90%) of these had plaque fissuring

NEJM 1984;310:1137-40

Curr Opin Cardiol 2001;16:285-292

Plaque rupture → CAD~1.3 TCFA per patient

Kolodgie, …, Virmani. Curr Opin Cardiol 2001;16:285-292

Plaque rupture → CAD~1.3 TCFA per patient

Kolodgie, …, Virmani. Curr Opin Cardiol 2001;16:285-292

Thin-cap fibroatheroma & ruptureprox LAD: “hot spot”

TCFA Plaque Rupture

Healed Rupture

Kolodgie, …, Virmani. Curr Opin Cardiol 2001;16:285-292

LAD

VP and ruptured plaques”… relatively infrequent … limited, focal distribution…”

AHA, Nov 2006; abstract 251

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)

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

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

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

Circulation 1996;94:2662-6

Circulation 1996;94:2662-6

ANGIOGRAPHYluminal narrowing

(diameter reduction)

IVUS/HISTOLOGYwall disease (plaque)

B:Wall: 50% X-sectional↓Lumen: normal

Circulation 1996;94:2662-6

ANGIOGRAPHYluminal narrowing

(diameter reduction)

IVUS/HISTOLOGYwall disease (plaque)

B:Wall: 50% X-sectional↓Lumen: normal

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

Mean ~ SDMean ~ SD

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

Heart 1996;76:312-6

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

Lp-PLA2

Mean ~ SDMean ~ SD

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

Mean ~ SDMean ~ SD

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

Mean ~ SDMean ~ SD

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

Mean ~ SDMean ~ SD

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

AHA Nov 2006

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

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

HELAD, 50 FDied of AMI

Adventitial lymphocyte infiltration

Plaque (AHA Type V)

MediaAdv.

Lymphocytes

Søren Dalager

AHA Nov 2006

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

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

Circulation 2006;114:2390-2411

Circulation 2006;114:2390-2411

TCFA = thin-cap fibroatheroma (the most frequent VP)

Circulation 2006;114:2390-2411

TCFA = thin-cap fibroatheroma (the most frequent VP)