The majority of the acute coronary events are caused by coronary artery segments with minimal luminal disease, but with potentially significant vascular wall inflammation and oxidative stress, leading to plaque vulnerability. It has become apparent that an initial injury at the endothelial surface is the primary trigger for the mechanisms involved, and a role for vascular inflammation and its interaction with oxidative stress continues to emerge. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a novel biomarker for vascular wall inflammation that circulates in the blood bound to both low density (LDL) and high density (HDL) lipoproteins and promotes vascular inflammation. Circulating levels of Lp-PLA2 mass and activity are independent risk factors for cardiovascular events and also associated with coronary endothelial dysfunction. However, the relationships between Lp-PLA2 and early atherosclerotic changes in the coronary arteries, or the contribution of lipoprotein binding to the deleterious potential of Lp-PLA2, have not been elucidated. Our working hypothesis is that local activation of the endogenous Lp-PLA2 plays an integral role in early atherosclerosis, and contributes to the mechanism of coronary endothelial dysfunction and to the structural and mechanical properties that characterize plaque vulnerability. Thus, the current application will characterize prospectively, for the first time, the correlation between the functional, mechanical, and structural vascular wall properties, and the systemic as well as the coronary activity of the Lp-PLA2 pathway, in the coronary circulation. To address our working hypothesis, three Specific Aims are proposed.
Aim I : Hypothesis: The production of Lp-PLA2 mass and activity correlates with the extent of endothelial dysfunction, oxidative stress, and tissue characteristics of plaque vulnerability. We will define the association between the systemic and coronary gradient and production of markers of inflammation and the presence of coronary oxidative stress and endothelial dysfunction in patients with early coronary atherosclerosis.
Aim II : Hypothesis: The distribution of Lp-PLA2 on LDL (vs. HDL) is associated with greater coronary endothelial dysfunction, coronary atherosclerosis, and plaque vulnerability. The distribution pattern of Lp-PLA2 in patients with early coronary atherosclerosis and endothelial dysfunction will be contrasted with that in patients with normal endothelial function.
Aim III : Hypothesis: Long-term inhibition of Lp-PLA2 with a specific inhibitor will result in a reduction in LpPLA2 activity, improvement in coronary endothelial function, and reduced tissue characteristics of plaque vulnerability. We will define the ability of a novel, chronically administered Lp-PLA2 inhibitor to modulate coronary endothelial function and structure. The current application will provide insight into the role of the endogenous Lp-PLA2 pathway in early coronary atherosclerosis and endothelial dysfunction in humans. The current application may also support a novel therapy, beyond the conventional risk factors, for early coronary atherosclerosis in humans.

Public Health Relevance

The majority of heart attacks and death from heart disease occur earlier than the development of blockades in the arteries. One of the reasons is the process of inflammation in the wall of the vessel. The current application is focused on new methods to identify and treat this early process and potential prevents heart attacks and sudden death.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092954-05
Application #
8440774
Study Section
Cardiovascular and Sleep Epidemiology (CASE)
Program Officer
Hasan, Ahmed AK
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$419,435
Indirect Cost
$141,847
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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