Using the drug darapladib, researchers at the University of Pennsylvania School of Medicine have inhibited a cholesterol- and immune system-associated protein, thereby reducing the development of heart-disease plaques that may cause death, heart attacks, and strokes in a pig model of atherosclerosis and diabetes. The study appeared online this week in Nature Medicine.

A molecule, ,lipoprotein-associated phospholipase A2 (Lp-PLA2), is connected with low-density lipoproteins (LDLs) circulating in the blood. Elevated levels of Lp-PLA2 in the blood are associated with an increased risk of heart disease events and are related to the development of the necrotic core of plaques. Darapladib specifically inhibits Lp-PLA2.

“The results are exciting,” says Robert L. Wilensky, MD, Director of Experimental Interventional Cardiology and Professor of Medicine at the Penn Cardiovascular Institute. “First, darapladib reduced the overall amount and size of plaques that block the coronary arteries of animals in the study. More importantly, it reduced the number and size of the type of advanced plaques that cause heart attacks and strokes. “

These advanced plaques have a thin cap and large core filled with cellular debris from inflammatory-immune cells that engorge themselves on cholesterol. If unstable plaques come into contact with blood, blood clots that develop from this contact constrict flow, which can lead to stroke and heart attack. Darapladib stabilizes these dangerous plaques by decreasing the size of the core and reducing the number of inflammatory-immune cells present within the plaque. Darapladib also decreased the expression of genes involved in enlisting immune cells involved in the inflammatory response associated with atherosclerosis.

“The aha moment came when we saw the profound difference in plaque composition in animals given medication versus those not given darapladib, although the high cholesterol levels in the pig model remained the same in both groups,” says Wilensky. “This study took cholesterol out of the equation and let us evaluate the effects of inflammation on the development of atherosclerosis.”

Release Date: September 22, 2008
Source: University of Pennsylvania School of Medicine