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.

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

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]

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.

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.

- 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

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

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

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

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] )

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?

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?

orAre they different expressions of the same process viewed at different time points in the evolution of plaque erosion

and subsequent repair?

[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