The document discusses several factors that are considered predictors of plaque vulnerability, including luminal narrowing, plaque volume and composition, fibrous cap thickness, and plaque inflammation. It reviews studies that show myocardial infarction can develop from previously non-severe lesions and that lipid content, cap thickness, inflammation, and stress factors like circumferential stress are correlated with plaque stability or rupture. In conclusion, the size and composition of the lipid core, thickness and composition of the fibrous cap, and inflammation are well-established predictors of plaque rupture.

1. Revisiting the Basics, Culprit vs. Non-Culprit:
Luminal Narrowing, Plaque Volume, Cap thickness
and plaque inflammation
It is now widely accepted that the main determinant(s) of acute clinical events in
coronary heart disease is the composition of the atherosclerotic lesion. In this
review, we will discuss several plaque characteristics that are considered to be
factors in the plaque vulnerability.
Abstract

2. Abstract (con’t)
Luminal narrowing.
In a classic paper, Ambrose et al, reported that acute myocardial
infarctions frequently developed in lesions that were not considered
stenotic a few months before the ischemic event. Shortly afterwards,
Little et al confirmed these findings. Moreover, in their series, 19 out
of 29 patients had an occluded vessel responsible for their new
myocardial infarction that was less than 50% stenotic in their previous
angiogram, and 28 out of 29 patients had less than 70% narrowing in
their culprit vessel on the first angiogram. In some biomechanical
models, increase of stenosis leads to decrease of peak stress in the
plaque, especially in lipid-rich plaques. It should be remembered,
however, that plaque burden is a strong predictor of vascular events as
demonstrated by a high EBCT score. The plaque burden, however, is
predictive of the patient’s prognosis, not of a particular lesion
progression. Also, a prospective five-year angiographic follow-up of
factors associated with progression of coronary artery disease in the
Coronary Artery Surgery Study showed that initial lesion severity was
predictive of late segment occlusion.

3. Plaques containing a highly thrombogenic lipid-rich core are more at risk for
rupture if the size of the lipid core is large. In studies on aortae of individuals who
died suddenly of coronary artery disease, Davis et al estimated that when lipid
accounted for >40% of the plaques, there is high risk for plaque rupture. It is also
possible that the chemical components of the atheroma are major determinants of
plaque consistency and therefore, of plaque vulnerability. Specifically, liquid
cholesterol esters are softer than crystalline cholesterol. Likewise, higher core
temperature induces core softness, making it less likely for the fibrous cap to bear
the circumferential stress and predisposing it for rupture.
.
Abstract (con’t)
Plaque volume and composition

4. Abstract (con’t)
Fibrous cap thickness.
• Extracellular collagen-rich matrix produced by smooth muscle cells
underlie the cap thickness and strength. The peak circumferential
stress is inversely related to the cap thickness. An important
determinant of cap thickness and composition is the presence or
absence of inflammatory cells, mainly macrophages.

5. Abstract (con’t)
Plaque inflammation (mainly
cap and vicinity).
Disruption of the fibrous cap is usually associated with heavy
infiltration by macrophages and not uncommonly, T-lymphocytes as
well. Macrophages especially may release several matrix-degrading
proteases (MMPs): MMP-1 (collagenases), MMP-2 and 9
(gelatinases) and MMP-3 (stromelysin). Their main role is to degrade
the fibrillar collagen that underlies the skeleton of the fibrous cap. A
word of caution is well advised since Pasterkamp et al showed
significant inflammation of the caps and shoulders of plaques in the
femoral and coronary arteries. Clearly, inflammation is only one of
many parameters, many yet to be reported, that determine plaque
vulnerability.

6. Abstract (con’t)
Summary
In summary, size and composition of the lipid core, thickness
and composition of the fibrous cap, and inflammation within or
in the vicinity of the fibrous cap are well-established predictors
of plaque rupture. Predictors of other forms of lesions
underlying luminal thrombosis (e.g. erosion) are not yet well
characterized.

7. Myocardial infarction frequently develops from
previously non-severe lesions
• Initial percent stenosis of infarct-related artery at restudy of 23
patients with myocardial infarction (Group I), or new occlusions
in 18 patients without myocardial infarctions (Group II). The
degree of stenosis was lower in the infarct group. From Ambrose

8. Relation between severity of the stenosis at the
future infarct site and time from initial
angiography
• There is no relation between severity of the stenosis at the future
infarct site and the time from initial angiography until the development
of the acute myocardial infarction. In addition, severe stenoses were
infrequent in the infarct-related artery on the initial angiogram. From
Little at al. Circulation 1988;78:1157-66

9. Review of studies that examined the severity
of coronary stenosis lesions before the
myocardial infarction
• From Fishbein & Siegel. Circulation 1996;94:2662-6

10. Is the size of the lipid core related to the
degree of vessel stenosis?
The size of the lipid core has no correlation with the severity of the
arterial stenosis. From Davies MJ et al. Br Heart J 1993;69:377-81

11. Plaque lipid content is a marker of
vulnerability
Unstable plaques have a higher lipid content than stable plaques.
From Davies MJ et al. Basic Res Cardiol 1994;89:I:33-9

12. Lipid contents in stable (group A), combined
stable and unstable plaques (B) and unstable
plaques (C).
Although there was considerable overlap between the groups the mean
values were very different. Only one plaque in group A had a value
over 40% while 41 of the 45 plaques in group C exceeded the value
of 40%. From Davies MJ et al. Br Heart J 1993;69:377-81

13. Macrophage and smooth muscle cell contents
of the fibrous cap in stable and unstable
plaques
Lipid-filled macrophages occupy a larger portion of the cap tissue in
unstable plaques. Conversely, the volume of cap tissue occupied by
smooth muscle cells is much smaller in unstable plaques. From Davies
MJ et al. Basic Res Cardiol 1994;89:I;33-9

14. Is cap thickness inversely related to the
maximum circumferential stress?
In arterial models, decreasing cap thickness dramatically increases the
maximum circumferential stress, thus predisposing to plaque rupture.
From Loree et al. Circ Res 1992;71:850-8

15. Is stenosis inversely related to the maximum
circumferential stress?
When a lipid core is present, increasing stenosis severity markedly
decreases the maximum circumferential stress. In the absence of lipid
core, this relationship is not as steep. From Loree et al. Circ Res
1992;71:850-8

16. Why is peak circumferential stress important?
The peak circumferential stress was compared in 12 ruptured
and 12 stable coronary lesions. Peak stresses are significantly
increased in ruptured plaques and are considered an
important factor in the genesis of the rupture. From Cheng et
al. Circulation 1993;87:1179-87

17. Is the plaque rupture site related to the stress
concentration?
There is a very good correlation between the rupture site and
the regions of peak stress concentration. From Cheng et al.
Circulation 1993;87:1179-87

18. Ratio of smooth muscle cells and macrophages
in cap tissue in different plaques settings
Stable plaques are characterized by an excess of smooth muscle
cells. In unstable plaques the ratio reaches unity or less. From
Davies MJ et al. Basic Res Cardiol 1994;89:I-33-9

19. Fibrous cap extracellular matrix and
cellularity in vulnerable plaques
Arterial segment with atheromatous core with heavy staining of picro Sirius red within
the cap confirmed with polarized light microscopy (A and C), and absent staining
for CD68 in the cap and moderate CD68 staining in the shoulder and heavy CD68
staining at the base of the plaque (E) (asterick). Arterial segment with
atheromatous core and thin/local absent picro Sirius red staining of the cap
confirmed by polarized light microscopy (B and D). CD68 staining was heavily

20. Thermal heterogeneity in the coronary
atherosclerotic plaque
Based on earlier studies by Casscells et al showing termal heterogeneity in
ex-vivo atherosclerotic plaques, Stefanadis et al showed that temperature
heterogeneity increases progressively from stable angina to acute
myocardial infarction patients. From Stefanadis et al. Circulation
1999;99:1965-71

21. CONCLUSIONS
• Size and composition of lipid core, thickness and
composition of fibrous cap, and inflammation
within or in the vicinity of the fibrous cap are
well-established predictors of plaque rupture.
• Predictors of other forms of lesions underlying
luminal thrombosis (e.g. erosion) are not as well
characterized.