SUBJECT: Ph.D. Dissertation Defense
BY: Karen Hallow
TIME: Monday, June 25, 2007, 1:30 p.m.
PLACE: Whitaker Ford Building, 1103
TITLE: Relationships Between Mechanical Stress and Inflammation in Human Coronary Atherosclerotic Plaque
COMMITTEE: Dr. Raymond Vito, Chair (ME)
Dr. Hamid Garmestani (MSE)
Dr. Rudolph Gleason (ME)
Dr. Robert Guldberg (ME)
Dr. Alexander Rachev (ME)
Dr. Robert Taylor (Emory Med)


Atherosclerotic plaque rupture is the primary cause of death due to cardiovascular disease. The factors directing plaque progression to rupture are poorly understood. It is known that arteries respond to changes in mechanical stress by remodeling, and that remodeling is mediated by the inflammatory response. We hypothesized that spatial relationships exist between the local mechanical environment and markers of inflammation in atherosclerosis, and that these relationships are plaque progression dependent. To test these hypotheses, we analyzed cross-sections at regular intervals along the length of human coronary atherosclerotic arteries. For each cross-section, a 2D heterogeneous finite element model was developed to determine the spatial distribution of stress. In addition, novel techniques for quantifying inflammatory markers at high spatial resolution were used to determine the distributions of inflammatory markers. The distributions of stress and five markers of inflammation activated NF-kB, macrophages, MMP-1, nitrotyrosine, and microvessels - were then compared to determine whether spatial relationships exist. We found that the probability of activated NF-kB expression increases monotonically with increasing stress in all stages of plaque progression. This indicates that the relationship between mechanical stress and NF-kB activation is important throughout the disease process. We found that the relationship between mechanical stress and macrophages depends on the state of progression. In intermediate stages of progression macrophage expression increases with moderate stress but drops off at very high stresses, while in the advanced stage macrophages continue to increase monotonically with stress. We found that MMP-1 increases with stress in stages of progression where active remodeling is occurring, but decreases with stress in mature stable plaque. We found no relationship between mechanical stress and nitrotyrosine or microvessels. Taken together, these results support the role of mechanical stress in instigating and maintaining the inflammatory response, and help explain how mechanical input is able to direct complex biological changes involved in remodeling.