Abstract

1
Abstract
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.
2
Abstract (cont)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 patients
  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
Abstract (cont)Plaque volume and composition
.
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 gt40 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.
4
Abstract (cont)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 (cont) 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 (cont)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 et al, JACC
  19881256-62
•  
•  

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 1988781157-66

9
Review of studies that examined the severity of
coronary stenosis lesions before the myocardial
infarction

•  
• From Fishbein Siegel. Circulation
  1996942662-6

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
  199369377-81
•  

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 199489I33-9
•  

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 199369377-81
•  
•  

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
  199489I33-9

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
  199271850-8
•  

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 199271850-8

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 1993871179-87

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
  1993871179-87

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 199489I-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
  positive for cap and shoulder (F).

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 1999991965-71
•  
•  

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.
•  
•