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Researchers Reduce High-Risk Artery Blockages with New Drug Therapy E-mail
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Using the drug darapladib, researchers have inhibited a cholesterol-and immune system-associated protein, thereby reducing the development of heart-disease plaques that may cause  heart attacks, strokes and even death in a pig model of atherosclerosis and diabetes.

"We've used a model that closely mimics clinical disease," says first author Robert L. Wilensky, MD, Director of Experimental Interventional Cardiology and Professor of Medicine at the Penn Cardiovascular Institute. "The study shows that darapladib is useful in reducing atherosclerosis but more importantly those blockages that are thought to cause death and heart attacks."

Atherosclerosis, or hardening of the arteries, is the most common cause of heart attack, stroke, and death from cardiovascular disease, and has long been thought of as a type of chronic inflammation. An early first step in the build-up of the plaques associated with atherosclerosis is the accumulation of low-density lipoproteins (LDLs), the "bad" cholesterol, on artery walls. When LDLs are oxidized by the body, they attract immune cells and lipids to the site of the build-up.

Problems arise when the plaques grow to form a lesion characterized by a thin fibrous cap and a lipid-filled core of dying cells. These unstable plaques are prone to rupture, which can then lead to heart attack, stroke, and death.

A molecule called lipoprotein-associated phospholipase A2 (Lp-PLA2) is connected with 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 Wilensky. "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."

Recently, darapladib has been tested in a human clinical trial in Europe, which showed similar findings. GlaxoSmithKline (GSK) Inc., who provided the darapladib for the study, is planning a Phase 1 safety and efficacy trial with darapladib in humans in the near future. Penn will be one site in this proposed multi-center clinical trial. This study was supported, in part, by funding from GlaxoSmithKline, over the last two years totaling about $1.5 million, through an industry-academic alliance called the Alternative Drug Discovery Initiative at the Penn School of Medicine. Co-author Emile Mohler, III, has a position on a steering committee as a National Coordinator for the Phase III GSK trial for darapladib. In addition to other Penn co-authors Damir Hamamdzic, Daniel J. Pelchovitz, and Jisheng Yang, colleagues from Thomas Jefferson University, GlaxSmithKline, Southhampton General Hospital (UK), and the University of Washington were also co-authors.

Editors' Note:
Wilensky has a consulting agreement ($2000 over the past year) with GSK for another compound. 

About Heart Disease

Heart disease is a broad term that includes several more specific heart conditions. These conditions include: 
  • Arrhythmias. Irregular, or abnormally fast or slow, beating of the heart. The heart beat is controlled by electrical impulses. When the timing or frequency of these electrical impulses are disrupted, arrhythmias develop. Some arrhythmias are quite serious. An example is ventricular fibrillation, a severely abnormal heart rhythm that causes death unless treated right away by providing an electrical shock to the heart (called defibrillation). Others are less severe but can develop into more serious conditions over time. A particular concern is atrial fibrillation. Atrial fibrillation is rapid, irregular beating of the upper chambers of the heart. The chambers can quiver instead of beating in a regular pattern. Blood is not fully pumped out of them and may pool and clot.
  • Cardiomyopathy. A weakening of the heart muscle or a change in heart muscle structure. It often results in inadequate heart pumping or other heart function abnormalities. These can result from various causes, including prior heart attacks, viral or bacterial infections, and others.
  • Congenital Heart Disease. Malformations of heart structures, present during pregnancy or at birth. These may be caused by genetic factors or by adverse exposures during pregnancy. Examples include holes in the walls that divide the heart chambers, abnormal heart valves, and others. Congenital heart defects can disrupt the normal flow of blood through the heart. Congenital heart defects are the most common type of major birth defect.
  • Coronary Heart Disease (CHD). CHD is the most common type of heart disease. CHD occurs when the coronary arteries, that supply blood to the heart muscle, become hardened and narrowed due to the plaque buildup. The plaque buildup and the narrowing and hardening of the arteries is called atherosclerosis. Plaques are a mixture of fatty substances including cholesterol and other lipids. Blood flow and oxygen supply to the heart can be reduced or even fully blocked with a growing plaque. Plaques may also rupture and cause blood clots that block arteries. CHD can lead to a heart attack. Angina, the most common symptom of CHD can also occur. Angina is chest pain or discomfort that occurs when the heart muscle is not getting enough blood. Irregular heart beats, called arrhythmias, can develop.Over time, CHD can weaken the heart muscle and lead to heart failure, a serious problem where the heart cannot pump blood the way that it should.
  • Heart Attack. A heart attack , also called a myocardial infarction may occur when blood supply to the heart is severely reduced or completely blocked. When blood flow is restricted the heart muscle cells do not receive enough oxygen and begin to die. The more time that passes without treatment to restore blood flow, the greater the damage to the heart. This damage can cause irregular heart rhythms or even sudden cardiac arrest or stopping of the heart beat. Death can result. Coronary artery disease is the chief underlying cause of a heart attack. A less common cause of a heart attack is a severe spasm of a coronary artery that reduces the blood supply to the heart.
  • Heart Failure. This may also be called congestive heart failure or chronic heart failure. Heart failure is a condition where the heart cannot pump enough blood and oxygen to meet the needs of other body organs. Heart failure does not mean that the heart has stopped, but that it cannot pump blood the way that it should. Heart failure is a serious condition. There is no cure for heart failure at this time, except a heart transplant. Once diagnosed, medicines are needed for the rest of the person's life. See our heart failure fact sheet.
  • Peripheral Arterial Disease (PAD). Hardening of the arteries that supply blood to the arms and legs. PAD is usually the result of atherosclerosis, the buildup of plaque and narrowing of the arteries. Blood flow and oxygen to the muscles in the arms and legs can be reduced or even fully blocked. Painful leg muscles, numbness, swelling in the ankles and feet, and weak pulse in the feet are some of the signs and symptoms of PAD.
  • Rheumatic Heart Disease.This condition is damage to the heart valves and other heart structures due to inflammation and scarring caused by rheumatic fever, which occurs from streptococcal infection.Heart disease is an umbrella term for a number of different diseases affecting the heart.Heart disease is a number of abnormal conditions affecting the heart and the blood vessels in the heart.

About Diabetes

Type 2 diabetes is also referred to as non-insulin dependent diabetes mellitus (NIDDM), or adult onset diabetes mellitus (AODM). Type 2 diabetes affects nearly 21 million in the United States and nearly 200 million people worldwide.

Type 2 diabetes is characterized by high levels of blood sugar, caused by the body's inability to utilize insulin to move blood sugar into the cells for energy. In type 2 diabetes, patients can still produce insulin, but do so relatively inadequately for their body's needs, particularly in the face of insulin resistance as discussed above. In many cases this actually means the pancreas produces larger than normal quantities of insulin.

Diabetes is a major cause of heart disease and stroke, as well as the most common cause of blindness, kidney failure and amputations in U.S. adults. 

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