Regressing Atherosclerosis by Resolving Plaque Inflammation

  • Fisher, Edward (PI)

Project Details

Description

This proposal is in the area of cardiovascular disease (CVD). Atherosclerosis is the hardening of the arteries, and in many individuals, including those in the military, it is a common cause of heart attacks and strokes. In fact, in the patient population of the Veteran's Affairs (VA) Hospital System, CVD is the leading cause of admission. The numbers supporting CVD as a major cause of death and sickness in these patients include the staggering statistic that since 2005 there have been 434,967 cardiac catheterization procedures including 86,481 percutaneous coronary interventions performed for coronary artery disease (the cause of heart attacks) in 246,967 patients at VA hospitals.

Our research program over the last 15 years has focused on reversing CVD. A number of risk factor reduction therapies are available, such as lowering LDL cholesterol, treating hypertension, smoking cessation, and preventing or controlling diabetes. In general, in any clinical trial, even in those that reduced multiple risk factors at the same time, the heart attack rates never fell by more than 50%. This highlights the need to better understand the underlying processes in the plaques (the cholesterol accumulations) in the coronary arteries that are resistant to current therapies. Furthermore, most treatments begin in people after their first CVD event (which puts them in the secondary prevention category); for those in the primary prevention group, for many a heart attack is the first indication that there is a serious problem and that they have coronary artery disease (CAD). Damage to the heart muscle, which can ultimately lead to debilitating heart failure, is a common result, especially in those 'taken by surprise.' Thus, another goal of our research is to limit the consequences of a heart attack by targeting treatments to the plaques as soon as possible after one occurs.

The proposal is divided into two main parts. In the first, we will intensively study mouse models of human atherosclerosis to get at the root causes of coronary artery disease not fully responding to current therapies. Using models of atherosclerosis regression, we have found that as a plaque in the artery heals, cells in them called macrophages, which contain the cholesterol accumulations, become less inflamed (that is, less likely to cause a plaque to rupture and trigger a blockage of the coronary artery) and some even leave. Our current results implicate certain chemicals naturally made in the body, called cytokines, in causing these beneficial changes in macrophages to happen. Our first goal is to prove this definitively and to find the cells that produce these cytokines and how they re-program the macrophages. In the second part, we will use the new approach called 'nanomedicine' to package into nanoparticles certain factors known to regulate macrophage inflammation and movement. These particles will enter the diseased arteries, where we envision they will rapidly re-program the macrophages, thereby regressing the plaque, which will promote better blood flow and healing. It is also expected that recurrent disease will be reduced.

Overall, the successful completion of the project will provide the preclinical data needed to provide the rationale and scientific basis to design human trials. Given that mouse models of atherosclerosis are the number one discovery tool for CVD in academic institutions and pharmaceutical companies, because of the similar disease process and genetic regulatory mechanisms, we are optimistic that our results will provide a deeper understanding of plaque biology, which in turn will lead to practical applications to meet a serious therapeutic need.

StatusActive
Effective start/end date1/01/15 → …

Funding

  • Congressionally Directed Medical Research Programs: $1,604,144.00

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