The rupture of the fibrous cap is the critical event leading to thromboembolic complications on the luminal surface of advanced atherosclerotic plaques. The factors that set the stage of plaque disruption include progressive cap atrophy with loss of cells and matrix. Unfortunately, these beliefs are hard to test because of a lack of animal models. The investigative team proposes to solve this problem by an interdisciplinary approach combining human tissue and animal model studies of molecular pathways that could underlie this process. In Grant 1 (T. Hatsukami and C.Yuan), they will study, using high resolution magnetic resonance imaging, a cohort of patients with moderate internal carotid artery stenosis. They will test the hypothesis that the fibrous caps of these lesions generally are thick and that thinning of the cap develops after the plaque enlarges and the lumen narrows. They will also determine whether ischemic neurological events or plaque rupture assessed by histological evaluation of excised plaques correlates with fibrous cap thinning. In Grant 2 (A. Clowes and M. Reidy), they will make use of animal models to define the contribution of increased apoptosis and matrix metalloproteinase expression to fibrous cap atrophy. They will attempt to demonstrate in rats that luminal narrowing by a rigid wrap models the state of an advanced human atherosclerotic internal carotid artery and causes cell death and intimal matrix degradation, a process that might depend upon certain secondary stress signaling pathways. In Grant 3 (S.M. Schwartz and D. Dichek), they will define the protease cascade leading to cell death in human lesions and correlate these findings in operative specimens with MR evidence of cap thinning. They will also test the hypothesis that certain fibrous caps do not rupture because of increased expression of anti-apoptotic genes. Finally, they will attempt to diminish or enhance the stability of fibrous caps in apo E deficient mice by gene transfer of select pro- or anti-apoptotic genes. These collaborative studies should provide novel insights into the basic mechanisms underlying fibrous cap atrophy and disruption.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061845-04
Application #
6390186
Study Section
Special Emphasis Panel (ZHL1-CSR-B (S1))
Program Officer
Wassef, Momtaz K
Project Start
1998-09-30
Project End
2003-08-31
Budget Start
2001-09-01
Budget End
2003-08-31
Support Year
4
Fiscal Year
2001
Total Cost
$304,000
Indirect Cost
Name
University of Washington
Department
Surgery
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195