SHAPE Society

1. Plaque Rupture: Definition
Structural failure of the fibrocellular cap11
that
separates an atheromatous core22
from the lumen
of an atherosclerotic artery (ie, lumen ↔ core).
11
cap defect/gapcap defect/gap rupture, fissure, break, tear
not just missing endotheliumnot just missing endothelium
22
lipid-richlipid-rich Greek athere, gruel (soft)
Propensity to rupture
 lipid-rich corelipid-rich core + → +++
no coreno core →→ no capno cap -

2. Plaque Rupture: Definition
Plaque rupture ≠ Plaque disruption
Plaque rupture
Plaque erosion
Endothelial
disruption

3. Plaque Rupture: Definition
Plaque rupture ≠ Plaque disruption
Plaque rupture
Plaque erosion
Endothelial
disruption

4. Cardiovascular Risk Factors
athero-thrombosisathero-thrombosis
Traditional age and sex
cholesterol, LDL vs HDL
diabetes (metabolic syndrome/exercise)
smoking
hypertension
family history
Novel inflammation: CRP, fibrinogen, IL, etc
infection: Cp, CMV, HSV, Hp, ’burden’
homocysteine, folate, B6
coronary calcium: EBCT, IVUS
carotid IMT

5. Plaque Rupture → Fatal Thrombosis
1460 coronary thrombi1460 coronary thrombi
Patients Age n Rupture Study
Hospital, ? ? 19 19 = 100% Chapman-
1965
Hospital, ? ? 17 17 = 100%
Constantinides-1966
Hospital, AMI+SCD 58 y 40 39 = 98% Friedman-1966
Hospital, AMI 62 y 88 71 = 81% Bouch-1970
Hospital, AMI 66 y 91 68 = 75% Sinapius-1972
Coroner, SCD 53 y 20 19 = 95% Friedman-1973
Hospital, AMI 67 y 76 69 = 91% Horie-1978
Hospital, AMI 67 y 49 40 = 82% Falk-1983
Coroner, SCD <65 y 32 26 = 81% Tracy-1985
Med.exam, SCD <70 y 61 39 = 64% El Fawal-1987
Hospital, AMI 83 52 = 63% Yutani-1987
Coroner, SCD? ? 85 71 = 84% Richardson-1989
Hospital, AMI 63 y 20 12 = 60% van der Wal-1994
Coroner, SCD (all?) ? 202 143 = 71% Davies-1997,
update
Hospital, AMI 69 y 291 218 = 75% Arbustini-1999
Hospital, AMI 61 y 61 56 = 92% Shi-1999
Hospital, AMI 69 y 100 81 = 81% Kojima-2000

6. Plaque Rupture → Fatal Thrombosis
EuropeEurope ≈≈ AsiaAsia ≈≈ USAUSA
Patients Age n Rupture Study
Hospital, AMI 62 y 88 71 = 81% Bouch-1970
Hospital, AMI 66 y 91 68 = 75% Sinapius-
1972
Hospital, AMI 67 y 49 40 = 82% Falk-1983
Med.exam, SCD <70 y 61 39 = 64% El Fawal-
1987
Coroner, SCD? ? 85 71 = 84% Richardson-
1989
Hospital, AMI 63 y 20 12 = 60% van der Wal-
1994
Coroner, SCD (all?) ? 202 143 = 71% Davies-1997,
update
Hospital, AMI 69 y 291 218 = 75% Arbustini-
1999
887 662 = 75% Europe
Hospital, AMI 67 y 76 69 = 91% Horie-1978
Hospital, AMI 83 52 = 63% Yutani-1987
Hospital, AMI 61 y 61 56 = 92% Shi-1999
Hospital, AMI 69 y 100 81 = 81% Kojima-2000
320 258 = 81% Asia

7. Plaque Rupture → Fatal Thrombosis
AsiaAsia:: JapanJapan ≈≈ ChinaChina
Patients Age n Rupture Study
Hospital, AMI 62 y 88 71 = 81% Bouch-1970
Hospital, AMI 66 y 91 68 = 75% Sinapius-
1972
Hospital, AMI 67 y 49 40 = 82% Falk-1983
Med.exam, SCD <70 y 61 39 = 64% El Fawal-
1987
Coroner, SCD? ? 85 71 = 84% Richardson-
1989
Hospital, AMI 63 y 20 12 = 60% van der Wal-
1994
Coroner, SCD (all?) ? 202 143 = 71% Davies-1997,
update
Hospital, AMI 69 y 291 218 = 75% Arbustini-
1999
887 662 = 75% Europe
Hospital, AMI 76 69 = 91% Horie-
Japan
Hospital, AMI 83 52 = 63% Yutani-
Japan
Hospital, AMI 61 56 = 92% Shi-
China
Hospital, AMI 100 81 = 81% Kojima-

8. Plaque Rupture → Fatal Thrombosis
hospitalhospital ≈≈ coroner/med.exam.coroner/med.exam.
Patients Age n Rupture Study
Hospital, ? ? 19 19 = 100% Chapman-
1965
Hospital, ? ? 17 17 = 100%
Constantinides-1966
Hospital, AMI+SCD 58 y 40 39 = 98% Friedman-
1966
Hospital, AMI 62 y 88 71 = 81% Bouch-1970
Hospital, AMI 66 y 91 68 = 75% Sinapius-
1972
Hospital, AMI 67 y 76 69 = 91% Horie-1978
Hospital, AMI 67 y 49 40 = 82% Falk-1983
Hospital, AMI 83 52 = 63% Yutani-1987
Hospital, AMI 63 y 20 12 = 60% van der Wal-
1994
Hospital, AMI 69 y 291 218 = 75% Arbustini-
1999
Hospital, AMI 61 y 61 56 = 92% Shi-1999
Hospital, AMI 69 y 100 81 = 81% Kojima-2000
935 742 = 79% Hospital
Coroner, SCD 53 y 20 19 = 95% Friedman-
1973
Coroner, SCD <65 y 32 26 = 81% Tracy-1985
Med.exam, SCD <70 y 61 39 = 64% El Fawal-

9. Plaque Rupture → Fatal Thrombosis
acute MIacute MI ≈≈ sudden deathsudden death
Patients Age n Rupture Study
Hospital, ? ? 19 19 = 100% Chapman-
1965
Hospital, ? ? 17 17 = 100%
Constantinides-1966
Hospital, AMI+SCD 58 y 40 39 = 98% Friedman-
1966
Hospital, AMI 62 y 88 71 = 81% Bouch-1970
Hospital, AMI 66 y 91 68 = 75% Sinapius-
1972
Hospital, AMI 67 y 76 69 = 91% Horie-1978
Hospital, AMI 67 y 49 40 = 82% Falk-1983
Hospital, AMI 83 52 = 63% Yutani-1987
Hospital, AMI 63 y 20 12 = 60% van der Wal-
1994
Hospital, AMI 69 y 291 218 = 75% Arbustini-
1999
Hospital, AMI 61 y 61 56 = 92% Shi-1999
Hospital, AMI 69 y 100 81 = 81% Kojima-2000
935 742 = 79% Acute MI
Coroner, SCD 53 y 20 19 = 95% Friedman-
1973
Coroner, SCD <65 y 32 26 = 81% Tracy-1985
Med.exam, SCD <70 y 61 39 = 64% El Fawal-

10. Plaque Rupture → Fatal Thrombosis
age of deceasedage of deceased
Patients Age n Rupture Study
Hospital, ? ? 19 19 = 100% Chapman-
1965
Hospital, ? ? 17 17 = 100%
Constantinides-1966
Hospital, AMI 83 52 = 63% Yutani-1987
Coroner, SCD? ? 85 71 = 84% Richardson-
1989
Coroner, SCD (all?) ? 202 143 = 71% Davies-1997,
update
406 302 = 74% Age
unknown
Hospital, AMI 62 y 88 71 = 81% Bouch-1970
Hospital, AMI 66 y 91 68 = 75% Sinapius-
1972
Hospital, AMI 67 y 76 69 = 91% Horie-1978
Hospital, AMI 67 y 49 40 = 82% Falk-1983
Med.exam, SCD <70 y 61 39 = 64% El Fawal-
1987
Hospital, AMI 63 y 20 12 = 60% van der Wal-
1994
Hospital, AMI 69 y 291 218 = 75% Arbustini-
1999
Hospital, AMI 61 y 61 56 = 92% Shi-1999
Hospital, AMI 69 y 100 81 = 81% Kojima-2000
837 654 = 78% >60 years

11. Plaque Rupture → Fatal Thrombosis
sexsex
Sex n Rupture Study
p
Male 37 32 = 86% Falk-1983
134 113 = 84% Davies-1997
184 151 = 82% Arbustini-
1999 .0004
74 63 = 85% Kojima-2000
.08 → .4
94 64 = 68% Virmani-
2000, update
523 423 = 81%
Female 12 8 = 67% Falk-1983
27 16 = 59% Davies-1997
107 67 = 63% Arbustini-
1999
26 18 = 69% Kojima-2000
31 10 = 32% Virmani-
2000, update

12. Plaque Rupture → Fatal Thrombosis
sexsex && ageage
Sex Age, y n Rupture Study
Male >41, all 37 86% Falk-
1983
<50 7 86%
-------------
+12 Females 50-70 22 82%
-------------
>70 20 80%
-------------
Male ~47 59 69%
Burke-1997
unrelated to age

13. Plaque Rupture → Fatal Thrombosis
sexsex && ageage
Sex Age, y n Rupture Study
Male >41, all 37 86% Falk-
1983
<50 7 86%
-------------
+12 Females 50-70 22 82%
-------------
>70 20 80%
-------------
Male ~47 59 69%
Burke-1997
unrelated to age

14. Plaque Rupture → Coronary Thrombosis
burden of CHDburden of CHD
*MI + fatal CHD. AHA 2002 Heart and Stroke Statistical Update.
Annual heart attacks in the US: 1,107,000*
• Men 668,000
Women,
• ≥45 y
430,000
• <45 y 9,000
39%
<1%
60%

15. Plaque Rupture → Coronary Thrombosis
burden of CHDburden of CHD
Annual heart attacks in the US: 1,107,000
Plaque erosionPlaque erosion
is the major substrate
for thrombosis in
premenopausal women.
Burke et al. Am Heart J 2001
39%
60%
~1%

16. Plaque Rupture → Coronary Thrombosis
burden of CHDburden of CHD
Annual heart attacks in the US: 1,107,000
Plaque erosionPlaque erosion
is the major substrate
for thrombosis in
premenopausal women.
Burke et al. Am Heart J 2001
Plaque rupturePlaque rupture
is the major substrate
in postmenopausal
women and men
~1%

17. Fatal Thrombosis: Rupture vs Non-rupture
ageage && sexsex
Rupture
+ - Study
p
Age, mean
53 y 44 y Farb-1996
<.02
68 y 70 y Arbustini-
1999 NS
69 y 71 y Kojima-2000
NS
Male 48 y 45 y Burke-1997
NS

18. Fatal Thrombosis: Rupture vs Non-rupture
ageage && sexsex
Rupture
+ - Study
p
Age, mean
53 y 44 y Farb-1996
<.02
68 y 70 y Arbustini-
1999 NS
69 y 71 y Kojima-2000
NS
Male 48 y 45 y Burke-1997
NS

19. Fatal Thrombosis: Rupture vs Non-rupture
whites vs blackswhites vs blacks
Rupture
+ - Study
p
Race
Race was not significantly (p>0.4)
associated with plaque rupture in men*
*Burke AP et al. N Engl J Med 1997;336:1276-82

20. Fatal Thrombosis: Rupture vs Non-rupture
hypercholesterolemiahypercholesterolemia
Rupture
+ - Study
p
Cholesterol
Male
mg/dlmg/dl 262 220 Burke-1997
.003
totaltotal::HDLHDL 8.5 5.0 Burke-1997
.003
Female
mg/dlmg/dl 270 188 Burke-1998
.007
totaltotal::HDLHDL 6.2 6.0 Burke-1998
NS

21. Fatal Thrombosis: Rupture vs Non-rupture
hypertensionhypertension
Rupture
+ - Study
p
Hypertension
22% 11% Burke-1997
NS
38% 22% Burke-1998
NS
56% 58% Kojima-2000
NS

22. Fatal Thrombosis: Rupture vs Non-rupture
diabetes mellitus ~ type 2diabetes mellitus ~ type 2
Rupture
n + - Study
p
Diabetes
8 13% 33% Falk-1983
41 11% 64% Davies-1996,
Circ
57 61% 42% Kojima-2000
NS
GlycoHgb
59 7.9% 6.9% Burke-1997
NS

23. Fatal Thrombosis: Rupture vs Non-rupture
diabetes mellitus ~ type 2diabetes mellitus ~ type 2
Rupture
n + - Study
p
Diabetes
8 13% 33% Falk-1983
41 11% 64% Davies-1996,
Circ
5757 61%61% 42%42% Kojima-2000Kojima-2000
NSNS
GlycoHgb
5959 7.9%7.9% 6.9%6.9% Burke-1997Burke-1997
NSNS

24. Fatal Thrombosis: Rupture vs Non-rupture
cigarette smokingcigarette smoking
Rupture
+ - Study
p
Smokers
71% 83% Burke-1997
NS
50% 78% Burke-1998
NS
62% 26% Kojima-2000
.04

25. Fatal Thrombosis: Rupture vs Non-rupture
local flow and shearlocal flow and shear
Rupture
+ - Study
p
Stenosis, mean
area, %area, % 91 93 Falk-1983
NS
78 70 Farb-1996
<.03
77 70 Burke-1998
NS
76 70 Kojima-
2000 NS
diameter, %diameter, % 39 64 Davies-

26. Fatal Thrombosis: Rupture vs Non-rupture
plaque calcificationplaque calcification
Rupture
+ - Study
p
Calcification
69% 23% Farb-1996
.002

27. Plaque Rupture → Fatal Thrombosis
exertion and sudden deathexertion and sudden death
Coronary thrombosis in men
n Rupture
Study
Acute exertion
+ 19 89%
Burke*
- 51 53%
--------
*Burke et al. JAMA 1999;281:921-26

28. Coronary Thrombosis: Virchow’s triad
pathogenesispathogenesis
Local Systemic = Blo
substrate flow coag.–plts.–fibr.lysis
queque
uptureupture +++ +
on-ruptureon-rupture + +++ +++

29. Coronary Thrombosis: Virchow’s triad
therapytherapy
Local Systemic = Blo
substrate flow coag.–plts.–fibr.lysis
queque
uptureupture +++ +
on-ruptureon-rupture + +++ +++
Statins ASA, clopidogrel, warfarin, etc.
? ?

30. Coronary Thrombosis: Virchow’s triad
therapytherapy
Local Systemic = Blo
substrate flow coag.–plts.–fibr.lysis
queque
uptureupture +++ +
on-ruptureon-rupture + +++ +++
Statins ASA, clopidogrel, warfarin, etc.
? ?
Additive?Additive?Additive?Additive?

31. lipid-rich core
thrombus
cap
cap