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Heart Disease

Heart Disease

Heart Disease

Description
 Coronary artery disease is a preventable condition in which fatty deposits (atheroma) accumulate in the cells lining the wall of the coronary arteries. These fatty deposits build up gradually and irregularly in the large branches of the two main coronary arteries, which encircle the heart and are the main source of its blood supply. This process is called atherosclerosis which leads to narrowing or hardening of the blood vessels supplying blood to the heart muscle (the coronary arteries). This results in ischemia (inability to provide adequate oxygen) to heart muscle and this can cause damage to the heart muscle. Complete occlusion of the blood vessel leads to a heart attack (myocardial infarction). In the United States, cardiovascular disease is the leading cause of death among both sexes, and coronary artery disease is the commonest cause of cardiovascular disease.

Who is at Risk?
 The following are risk factors for heart disease: family history of coronary artery disease, high blood pressure, or atherosclerosis; smoking; poor nutrition, especially too much fat in the diet; previous heart attack or stroke; obesity; hypertension; elevated cholesterol and/or low level of HDL (high-density lipoprotein); type A personality; lack of exercise; age; and other health problems (such as diabetes). The incidence of Coronary Heart Disease is highest amongst people who are obese. Physically inactive people have about double the risk of Coronary Heart Disease. Men over age 45 and women over age 55 are at greater risk for heart disease.

Sources: Rxmed.Com, United Kingdom Department of Health, American Academy of Family Physicians

Treatment Found For Two Heart Ailments
 For the first time, researchers have found a way to treat two deadly heart ailments that are caused by a protein called transthyretin that folds into an abnormal shape. Although the treatment is tailored for the two forms of heart disease, it is based on principles that may lead to similar therapies for other conditions by misfolded proteins, including Alzheimer"s disease, Parkinson"s disease, adult-onset diabetes and the human form of mad cow disease.

One of the ailments afflicts a million African-Americans and another is found in up to 15 percent of all Americans older than 80. In both diseases, the misfolded protein accumulates into sticky clumps that fatally interfere with heart function. The treatment involves giving patients a sample "small molecule" drug that stops the misfolding process. TSRI Professor Jeffery W. Kelly, Ph.D., the Lita Annenberg Hazen Professor of Chemistry and vice president of academic affairs, carried out the research. Scientists not connected with the research called the findings unusually exciting. Clinical trials are about to begin for the two forms of heart disease caused by misfolded transthyretin.

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Ozone in Our Bodies Linked to Atherosclerosis
 High in the earth"s atmosphere, a layer of ozone helps protect all life on earth from harmful radiation. But ozone produced by our own bodies could be hazardous to our health. In a unique study performed by TSRI, researchers have found that the body itself may be producing ozone. TSRI President Richard A. Lerner, M.D., Lita Annenberg Hazen Professor of Immunochemistry and holder of the Cecil H. and Ida M. Green Chair of Chemistry, and Professor Paul Wentworth, Jr., Ph.D. have found ozone is produced by the human immune system as part of its defense strategy. However, such ozone production could contribute to atherosclerosis, the disease commonly known as hardening of the arteries which increases the risk of heart attacks and strokes.

Heart disease is the most common cause of death in the United States with 878,471 deaths in 2000. Lerner and Wentworth theorize that ozone breaks cholesterol down to produce toxic compounds in the blood, which they"ve given the name atheronals. They found these destructive compounds pervasive in plaques that were surgically removed from patients with atherosclerosis. Atheronals also may contribute to a number of other diseases such as lupus, multiple sclerosis, and rheumatoid arthritis. The presence of atheronals may be a good basis for a diagnostic test of atherosclerosis which would allow early identification of patients at risk of life-threatening heart attacks - and would be a boon to preventive medicine.

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Scientists Report Cryo-em Structure of a Human Platelet Integrin Molecule
 TSRI researchers, led by Mark Yeager, M.D., Ph.D., have published the first detailed three-dimensional model for the human platelet integrin alphaIIbbeta3 - a signaling molecule that is important for activating platelets, which leads to a healthy formation of blood clots in response to a cut as well as clots that obstruct blood flow to healthy tissue. Integrins are a broad class of signaling molecules that affect diverse biological processes such as development, angiogenesis, wound healing, neoplastic transformation, and thrombosis.

Though scientists have known for many years that integrins are important in many physiological processes, detailed structural information on these molecules has been elusive. These results will be relevant for the design of new drugs to treat health conditions in which the formation of blood clots is undesirable, such as during heart attacks and strokes. Medical techniques like balloon angioplasty and intracoronary stent implantation are designed to clear blocked arteries but can also cause the formation of thrombi. In fact, several clinical trials have demonstrated that alphaIIbbeta3 inhibitors have benefit in the medical treatment not only for heart attacks but also during angioplasty and stent treatment.

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Blood Flow Beneath a Microscope
 TSRI Professor Zaverio Ruggeri, M.D., studies the movement of blood cells, particularly platelets - the flat molecule-filled cytoplasmic disks in the blood that are necessary for clotting. He uses the microscopic stage to look at the interaction of platelets with various surfaces encountered in the circulation, and to study the interaction of individual platelets with the endothelial cells and wounds. Ruggeri is interested in the molecular mechanisms that govern clotting because many individuals suffer from diseases relating to these mechanisms, such as bleeding disorders. Another reason scientists are interested in clotting is its potential for therapeutic intervention in vasculature disease. Clotting is an essential physiological process, but at the same time, the blood components that heroically stop bleeding, also nefariously cause diseases such as heart attacks and stroke, which are the most common causes of death in the United States today.

Ruggeri is conducting basic research to address the main disease-causing mechanisms responsible for arterial and venous thrombosis, the clotting of veins and arteries, and is laying the foundation for novel and more efficient therapeutic approaches. Ruggeri and his team study the interaction between vessels and blood platelets, the cell fragments that carry the chemicals the body uses in hemostasis, in which blood clots at a site of injury. Members of the Ruggeri lab are particularly interested in the structures of the adhesion proteins that mediate the formation of blood clots and the receptors on the platelets. Lab members have been solving the structures of these interacting molecules and piecing together how they work. Such detailed knowledge of the three-dimensional structure of these adhesion proteins is indispensable for understanding the differences between normal hemostasis, where bleeding is stopped after a cut, and pathological thrombosis, in which a clot of platelets occludes blood flow and causes cardiovascular disease.

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Research Suggests New Approaches To Atherosclerosis
 A team of researchers at The Scripps Research Institute has determined that a protein called "TLR2" found on the surface of cells lining the arteries of mammals is involved in the disease atherosclerosis - a significant finding because it supports the concept of a therapeutic approach to heart disease aimed at counteracting the effect of TLR2. TSRI Professor Linda Curtiss, Ph.D., and Associate Professor Peter Tobias, Ph.D., elucidated the effect TLR2 has on atherosclerosis, which is to exacerbate the disease. TLR2 is believed to exacerbate the disease through chronic inflammation. New information suggests that infection and inflammation are related to cardiovascular disease, which adds a whole new dimension. Atherosclerosis is a common vascular disease that increases the risk of heart attacks and strokes, which are leading causes of death in the United States. The name comes from the Greek athero (which means gruel or paste) and sclerosis (which means hardness), and, as the name implies, it is a disease that is characterized by a hardening of the arteries over time due to the buildup of plaques - fibrous tissue, calcium, fat, cholesterol, proteins, cells, and other materials - on the inner "endothelial" walls of an artery. High cholesterol is the most obvious risk factor associated with atherosclerosis, but cholesterol is not the complete story. There are plenty of people with high cholesterol who never develop atherosclerosis, and clearly other factors are involved in the development of the disease. But what are these factors?

Over the last several years, evidence has been accumulating that the process of atherosclerosis is linked to infection and inflammation, and a number of infectious agents such as bacteria are known to contribute to high risk for atherosclerosis. In certain rare cases, microbial components have been found in atherosclerotic lesions, and epidemiological evidence suggests that people with chronic infections tend to have more of the disease. The gum disease periodontitis, for instance, is a known risk factor for atherosclerosis. Wanting to investigate how inflammation is linked to atherosclerosis, Curtiss and Tobias turned their sights on a cellular protein called the Toll-like receptor-2 (TLR2), and designed a project to determine if TLR2 is involved in the disease. When Curtiss and Tobias examined the role of TLR2 activation and deletion in mice, they found that TLR2 exacerbates the disease in a distinct way: when you knock out the TLR2 receptor, you have a lot less atherosclerosis. Without TLR2, the mice got less disease; this suggests that normally, when the receptor is there, it is proatherogenic. The work is interesting for several reasons, say the researchers, because it suggests that activation of atherosclerosis may be linked to a natural compound in the body that activates the TLR2 receptor on endothelial cells. If the TLR2 is detecting this natural compound, then identifying these "endogenous ligands" could help in the design of a drug that would block the action of TLR2 and prevent the inflammation that contributes to atherosclerosis. Additionally, the progression of the disease may be linked to activation of macrophages via molecules generated by pathogenic organisms, which may be a common scenario in individuals with chronic inflammatory disorders. Moreover, the research suggests a starting point for further studies into the genetic background of families that are more or less susceptible to atherosclerosis than the general population.

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Study Uncovers New Sensor - A Potential Target For New Therapies For Obesity And Diabetes, And Implications For Heart Disease And Stroke
In a new study, scientists at The Scripps Research Institute and the Genomics Institute of the Novartis Research Foundation (GNF) have described for the first time a glucose activated sensor that acts as a switch to decrease production of endogenous glucose in the liver, and increase conversion of glucose to fat for storage in adipose tissue. This dual action makes the sensor, Liver X Receptor, a potential target for new therapies aimed at obesity and diabetes. The research may also have implications for heart disease and stroke. In the study, glucose is shown to stimulate the activity of the Liver X Receptors (LXR) a and b. The LXRs act as sensors of dietary components, orchestrating the body's response to nutrients such as oxysterols (short-lived derivatives of cholesterol) and controlling gene expression linked to cholesterol and fat metabolism. When you eat, glucose pours into the gut and is recognized by LXR in the liver, which then activates expression of the enzymes that turn excess glucose into triglycerides that are stored as fat. The fact that the study demonstrates that LXR does both - it binds to glucose and it induces fatty acid synthesis - is significant and makes LXR a potential target for diabetes and obesity treatments. Scripps Research Assistant Professor Enrique Saez, Ph.D., led the study

In some recent animal studies, activation of LXRs using synthetic molecules also induced regression of atherosclerosis, the clogging, narrowing, and hardening of the body's large arteries and blood vessels that can lead to stroke, heart attack, and eye and kidney problems. Elevated levels of pathogenic cholesterols, also known to bind LXR, are a primary risk for development of atherosclerosis. The integration of glucose sensing and control of lipogenesis by LXR may explain why low-fat/high-carbohydrate diets induce hypertriglyceridemia [an elevated level of triglycerides in the blood]. LXR can sense surplus glucose, induce fatty acid synthesis, and prompt the liver's export of triglycerides into the bloodstream. Since LXR acts as the body's sensor of a buildup of pathogenic cholesterol, its ability to bind both glucose and oxysterols suggests that LXR may be a link between hyperglycemia and atherosclerosis. In fact, Saez and his colleagues originally looked at LXR as a drug target for atherosclerosis. But when they fed synthetic LXR ligands to mice to induce activation, they discovered that the mice metabolized glucose more effectively and that activation suppressed new production of glucose in the liver.

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