The heat that hurts  pg. 5

Talking back to fat

During the past decade, two new classes of drugs were developed to relieve pain and inflammation in patients with rheumatoid arthritis—specific inhibitors of the COX-2 enzyme, and blockers of the pro-inflammatory tumor necrosis factor (TNF). It remains to be seen, however, whether they also will be useful in preventing heart disease.

Although COX-2 is expressed in atherosclerotic lesions, chronic use of high doses of one of the COX-2 inhibitors has been linked to an increase in blood pressure, edema and serious heart problems in some patients. As for TNF-inhibitors, animal studies and at least one report in a patient suggest that TNF blockade may actually destabilize atherosclerotic plaques and precipitate heart attacks.

Statins, the blockbuster cholesterol-lowering drugs, also have anti-oxidant and anti-inflammatory properties that may protect against cardiovascular disease. To test this hypothesis, investigators in the multi-center JUPITER study are administering the statin drug Crestor to participants who have elevated circulating inflammatory markers including CRP, but normal LDL and triglyceride levels.

The newest targets for pharmacological treatment of atherosclerosis may come from studies of how adipose tissue (fat) regulates cholesterol metabolism and inflammation. Fazio and Linton point to recent studies that suggest adipose tissue, composed of fat cells, and macrophages in atherosclerotic plaques lead the inflammatory response in atherosclerosis and cardiovascular disease.

Some genes originally reported to be expressed primarily or exclusively in adipose tissue are also expressed in activated macrophages. Some of these genes, including the fatty acid binding protein aP2, are believed to be involved in insulin resistance, an early hallmark of type II (non-insulin dependent) diabetes. These recent reports suggest inflammation as a critical link between diabetes and atherosclerosis.

Individuals showing symptoms of insulin resistance are more likely to develop cardiovascular disease as well as diabetes. Patients with diagnosed diabetes are at elevated risk for adverse cardiovascular events such as heart attack and stroke. By targeting proteins expressed in fat cells and macrophages that seem to play a dual role in reducing insulin sensitivity and increasing inflammation, new therapies may reduce the incidence of both atherosclerosis and diabetes in at-risk populations.

“I wouldn’t be surprised if we develop a panel of 20-30 genes that we routinely look at in individuals to define and predict risk,” predicts Douglas Vaughan, M.D., chair of Medicine at Northwestern University Feinberg School of Medicine and former chief of Cardiovascular Medicine at Vanderbilt. “It’s going to be a multi-factorial approach that includes … biochemical, physiological and genetic parameters.”

Tale of a thrombus
Endothelium that is injured, in this case by high levels of lowdensity lipoprotein (LDL) cholesterol, releases factors that attract blood cells called monocytes. Once inside the tissue, the monocytes differentiate into macrophages. Part of their job is to sweep up excess cholesterol. As they become engorged with cholesterol, the macrophages take on a foamy appearance, and now are called foam cells.
Interactions between foam cells and white blood cells trigger a chronic inflammatory process. Smooth muscle cells migrate to the arterial wall, proliferate and secrete proteins that form a fibrous plaque. As the foam cells die, the plaque weakens and can rupture. Platelets are attracted to the site of the rupture, and can quickly form a clot that blocks the vessel completely.
Illustrations by Dominic Doyle

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