Vulnerable Plaque - summitmd.comVulnerable Plaque Pathophysiology, Detection, and Intervention...

Vulnerable PlaquePathophysiology, Detection, and Intervention

Erling Falk, Denmark

VP: A Local Problem or Systemic Disease



VP: A Local Problem in a Systemic Disease



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

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

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

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

TCFA Plaque Rupture

Healed Rupture

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

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


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


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



• ~3.8 mm2 & ~9 mm long*

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


Ruptured

Intact

corecore

capcap

lumen

Heart 2004;90:1385-91

Mean (SD)



• ~3.8 mm2 & ~9 mm long*


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


Ruptured

Intact

•••••••

•

•••••

•••

corecore

capcap

lumen

•



• ~3.8 mm2 & ~9 mm long*


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


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

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


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




• ~3.8 mm2 & ~9 mm long*


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

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

Ruptured

Intact

•

•••••••

•

•••••

•••

corecore

capcap

lumen



• ~3.8 mm2 & ~9 mm long*



•• 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)



• ~3.8 mm2 & ~9 mm long*



•• 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



• ~3.8 mm2 & ~9 mm long*



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


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



• ~3.8 mm2 & ~9 mm long*



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


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



• ~3.8 mm2 & ~9 mm long*



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


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



• ~3.8 mm2 & ~9 mm long*



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


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%



• ~3.8 mm2 & ~9 mm long*





Ruptured

Intact

•

•••••••

•

•••••

•••

corecore

capcap

lumen

thrombus

Ca

Coronary Atherosclerosistargets for imagingtargets for imaging


• ~3.8 mm2 & ~9 mm long*





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)

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