SHAPE Society

1. Editorial Slides (A)
VP Watch – September 18, 2002 – Volume 2, Issue 37
The Pathologic Substrate of Coronary Plaque
Erosion
Provided by:
Allard C van der Wal, M.D., Ph.D.
Department of Cardiovascular Pathology
Academic Medical Center, University of Amsterdam, The Netherlands.

2. Plaque disruptions, considered as immediate cause of coronary
thrombosis, may vary in severity from small denudations of
endothelial plaque surface to complex lacerations of the fibrous
cap. Within this wide spectrum 2 major subtypes are recognized
[1]:
- plaque erosion: loss of (large parts of) endothelial surface
of an otherwise intact plaque
- plaque rupture: laceration(s) extending into the inner parts
of the plaque
Backgrounds

3. Backgrounds
The clinical relevance of making such a distinction in subtypes is
supported by several clinicopathological observations, derived
from autopsied patients who died consequent to coronary
thrombosis:
- plaque rupture is found relatively more frequently in men
and often associated with high LDL and low HDL. They
often occur in plaques with lower degree of initial stenosis [2]
- plaque (endothelial) erosions are reported to be more common at
younger age, in women and in diabetic patients. They occur more often
at sites of pre existing high grade stenosis. An association with smoking
is assumed [1,3]

4. Which plaques develop erosions?
- In 1994 we reported 9 thrombosed coronary culprit plaques with surface erosion
associated with accumulation of lipid filled macrophages , T-cells and HLA DR
expressing SMC underneath the trombus [4]. We held secretory products of
inflammatory cells responsible for the onset of endothelial erosion (similar to
the situation in plaque rupture).
- In 1996 Farb et al. showed that plaques rich in smooth muscle cells and
proteoglycans but relatively poor in lipids, macrophages and T-cells can also
develop endothelial erosions followed by trombus formation [5]. A pathogenic
role for the onset of erosion was devoted to thrombogenecity of matrix and
SMC components of these plaques.

5.  As reported in VP Watch of this week, a recent
study published in ATVB [6] by Kolodgi et deals
with the SMC rich type of eroded plaque, as
described earlier by this group of investigators.
 The authors performed a detailed pathologic analysis
of the differential accumulation of matrix proteins
(proteoglycans and hyaluronan) in different types of
culprit plaques (stable, eroded and ruptured) in order
to further explore the thrombogenicity of plaque.

6. - 49 culprit plaques were retrieved from sudden coronary death
patients: 11 had plaque rupture, 20 had erosions and 18
showed a stable plaque composition.
- For imunohistochemical evaluation of the plaque composition
in all cases a large panel of monclonal and polyclonal
antibodies was used, reactive with:
- various differentiation antigens of smooth muscle cells
- inflammatory cells ( macrophages and T-cells)
- platelets and fibrin
- various extracellular matrix proteins: biglycan, versican, decorin,
hyaluronan
Matrix composition of coronary culprit plaques
- Analysis of immunostaining patterns was focused on the
fibrous cap (stable lesions), the plaque thrombus interface
(erosions), or the site of plaque rupture

7. Matrix Composition of Coronary Culprit Plaques Results
Several interesting observations on spatial differences
in culprit plaque composition emerged from this
study:
1. Immunostaining for immature SMC , identified by SM
myosin heavy chain SM1 and SMemb, was found in
erosions and in eroded plaques, whereas SM2 and
smoothelin (expressed on mature SMC was weak or
absent.
2. The adhesion receptor CD44 was localized along the
plaque / thrombus interface in erosions, whereas in
stable and in ruptured plaques it was confined to
inflammatory cells

8. Matrix Composition of Coronary Culprit Plaques Results
3. Each type of culprit lesion showed a unique pattern of
immunostaining for extracellular matrix proteins:
- STABLE PLAQUES: - high versican and biglycan
- low decorin and hyluronan
- collagen I
- ERODED PLAQUES: - high decorin and hyluronan
- low versican qnd hyaluronan
- collagen III
- RUPTURED PLAQUES - all proteoglycans low
- hyaluronan low

9. The present study demonstrates clear differences in accumulation
patterns of proteoglycans and hyaluronan among stable, ruptured
and eroded plaques, and may provide mechanistic insights in the
development of erosion of SMC rich plaques.
The authors postulate that accumulation of hyaluronan could
provide a high risk substrate for thrombus formation , a view
supported by previous in vitro studies:
- Large vessel endothelium has low adherence potential to
Hyaluronan [7]
- Hyaluronan binds to CD44, a receptor mediating adhesion of platelets
[8], and apart from mediating recruitment of inflammatory cells [9],
activates SMC.
-Hyaluronan could promote cell migration by altering the architecture of
fibrin clots [10]
Conclusions

10. Conclusions
On the basis of these considerations the authors propose the
folllowing working hypothesis of potential critical events
leading to this type of plaque erosion:
Selective accumulation of hyaluronan, loss of
surface endothelium and expression of CD44 may
promote thrombosis and the proliferation and
migration of Smooth Muscle Cells.
(Kolodgi et al [6] )

11. Questions:
1. Which mechanisms underlie formation of such an
altered matrix composition associated with plaque
erosion , and particularly, which circumstances
promote accumulation of Hyaluronan?
• Is there a relationship between clinical variables that
predispose for erosive type of plaque complications and the
observed differential accumulation of proteoglycans and
hyaluronan?
2. Regarding the involvement of CD44 expression and
hyaluronan in early stages of woundhealing: do these
changes occur before (in response to earlier acute
events) or shortly after the onset of plaque erosion?

12. Questions:
3. Is there a relationship between the inflammatory
type and the smooth muscle rich type of erosion:
Are they biologically indeed completely different
processes?
or
Are they different expressions of the same process viewed
at different time points in the evolution of plaque erosion
and subsequent repair?

13. [1] Davies MJ. Stability and instability - two faces of coronary atherosclerosis. Circulation
1996:94:2013-2020.
[2] Burke AP, Farb A, Malcome GT et al. Coronary risk factors and plaque morphology in men with
coronary disease who died suddenly. N Engl J Med 1997;336:1276-1282.
[3] M.J. Davies. The pathophysiology of acute coronary syndromes. Heart 2000
[4] van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of
thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process
irrespective of the dominant plaque morphology. Circulation 1994;89:36-44.
[5] Farb A, Burke AP, Tang AL, Liang TY, Mannan P, Smialek J, Virmani R. Coronary plaque
erosion without rupture into a lipid core: a frequent cause of coronary thrombus in sudden
coronary death. Circulation 1996:93:1354-1363
[6] Kolodgi FD, Burke AP, Farb A, Weber DK, K utys R, Wight TN, Virmani R. Differential
accumulation of proteoglycans and hyaluronan in culprit lesions. Arterioscler Thromb Vasc Biol
2002;22:
[7] Lokeshwar VB, Selzer MG. Differences in hyaluronic acid mediated functions and signaling in
arterial , microvessel and vein derived human endothelial cells .J Biol Chem 2000;275:27641-
27649.
[8] Koshiishi, Shizari M Undrhill CB. CD44 can mediate the adhesion of platelets to hyaluronan.
Blood 1994;84:390-396.
[9] Cuff CA, Kothapalli D, Azonnobi I et al. The adhesion receptor CD44 promotes atherosclerosis
by mediating inflammatory cell recruitment and vascular activation J Clin Invest
2001;108:108:1031-1040
[10] Savani RC, Wang C, Yang B et al. Migration of bovine aortic smooth muscle cells after
wounding injury: the role of hyluronan and RHAMM. J ClinInvest 1995;95:1158-1168.
References