Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-11-01
2003-02-25
Myers, Carla J. (Department: 1634)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S912000
Reexamination Certificate
active
06524795
ABSTRACT:
TECHNICAL FIELD
The present invention relates to kits and methods for the diagnosis and treatment of cardiovascular disorders, and more specifically to kits and methods related to diagnosis of disorders associated with IL-1 genotype patterns.
BACKGROUND OF THE INVENTION
Atherosclerosis (or arteriosclerosis) is the term used to describe progressive luminal narrowing and hardening of the arteries that can result in an aneurysm, ischemia, thrombosis, embolism formation or other vascular insufficiency. The disease process can occur in any systemic artery in the human body. For example, atherosclerosis in the arteries that supply the brain (e.g. the carotids, intracerebral, etc.,) can result in stroke. Gangrene may occur when the peripheral arteries are blocked, and coronary artery disease occurs when the arteries that supply oxygen and nutrients to the myocardium are affected.
Coronary artery disease is a multifactorial disease that results in the deposition of atheromatous plaque and progressive luminal narrowing of the arteries that supply the heart muscle. The atherosclerosis process involves lipid induced biological changes in the arterial walls resulting in a disruption of homeostatic mechanisms that keeps the fluid phase of the blood compartment separate from the vessel wall. Since the normal response to all injury is inflammation, the atherosclerotic lesion shows a complex chronic inflammatory response, including infiltration of mononuclear leukocytes, cell proliferation and migration, reorganization of extracellular matrix, and neovascularization. In fact, the atheromatous plaque consists of a mixture of inflammatory and immune cells, fibrous tissue, and fatty material such as low density lipids (LDL) and modifications thereof, and &agr;-lipoprotein. The luminal narrowing or blockage results in reduced ability to deliver oxygen and nutrients to the heart muscle, producing myocardial infarction, angina, unstable angina, and sudden ischemic death as heart failure. Though occlusion usually progresses slowly, blood supply may be cut off suddenly when a portion of the built-up arterial plaque breaks off and lodges somewhere in an artery to block it temporarily, or more usually, when thrombosis occurs within the arterial lumen. Rupture of the fibrous cap overlaying a vulnerable plaque is the most common cause of coronary thrombosis. Depending on the volume of muscle distal to the blockage during such an attack, a portion of the myocardial tissue may die, weakening the heart muscle and often leading to the death of the individual.
For many years, the most common measure of imminent risk for a heart disease “clinical event”, such as a myocardial infarction or death, was physical blockage of the coronary arteries, as assessed by techniques such as angiography. During the early 80's studies by DeWood and coworkers (N. Engl. J. of Med. (1980) 303:1137-40), revealed that occlusive thrombus was responsible for most cases of acute myocardial infarction. At that time, the prevailing concept was that myocardial infarction resulted from occlusion at a site of high grade stenosis. In 1988, Little et al. (Circulation (1988) 78:1157-66), showed most of the infarctions resulted from a coronary blockage that had previously shown a stenosis of less than 50% on angiography. Therefore, the severity of the coronary stenosis did not accurately predict the location of a subsequent coronary blockage. With these studies the importance of vulnerable atherosclerotic plaque became evident.
It is now clear that rupture at the site of a vulnerable artherosclerotic plaque is the most frequent cause of acute coronary syndromes. Such plaque does not cause high grade stenosis, but may result in acute coronary syndrome, such as unstable angina, myocardial infarction, or sudden death. No methods are currently available that can reliably identify plaques prone to rupture. In fact, development of clinically useful imaging techniques for identifying vulnerable plaques is an active area of research. Some of the methods are being used to identify such plaques include for example, thermography (atherosclerotic plaques show thermal heterogeneity), spectroscopy (used to quantify the amount of cholesterol, cholesterol esters, triglycerides, phospholipids and calcium salts present in small volumes of the coronary arterial tissue), radioisotope scintigraphy (various constituents of vulnerable plaques such as inflammatory cells may be imaged with radioisotope techniques), and detection of inflammatory serum markers such as C-reactive protein levels.
Arterial sites that show acute plaque rupture are characterized by chronic inflammatory components that are not found, or are at much lower levels, in arterial plaques that are stable and unlikely to cause clinical events (Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362:801-809.) (Libby P. Molecular basis of the acute coronary syndromes. Circulation 1995;91:2844-2850). The current published clinical data from many sources clearly demonstrate that various components of inflammation are strong independent influences on the severity and clinical outcomes of coronary artery disease (Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362:801-809.) (Libby P. Molecular basis of the acute coronary syndromes. Circulation 1995;91:2844-2850). In addition, laboratory work has shown that pro-inflammatory mediators are critical elements in the atherosclerosis process (Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362:801-809.) (Libby P. Molecular basis of the acute coronary syndromes. Circulation 1995;91:2844-2850).
The causes and mechanisms of the atheromatous plaque build-up are not completely understood, though many theories exist. One theory on the pathogenesis of atherosclerosis involves the following stages: (1) endothelial cell dysfunction and/or injury, (2) monocyte recruitment and macrophage formation, (3) lipid deposition and modification, (4) vascular smooth muscle cell proliferation, and (5) synthesis of extracellular matrix. According to this theory, the initiation of atherosclerosis is potentially due to a form of injury, possibly from mechanical stress or from chemical stress. How the body responds to this injury then defines whether, and how rapidly, the injury deteriorates into an atherosclerotic lesion. This, in turn, can result in arterial luminal narrowing and damage to the heart tissue which depends on the blood flow of oxygen and nutrients.
For many years, epidemiologic studies have indicated that an individual's genetic composition is a significant risk factor for development of a vascular disease. For example, a family history of heart disease is associated with an increased individual risk of developing coronary artery disease. Lipid and cholesterol metabolism have historically been considered the primary genetic influence on coronary artery disease. For example, deficiency in cell receptors for low-density lipids (LDL), such as in familial hypercholesterolemia, is associated with high levels of plasma LDL and premature development of atherosclerosis (Brown & Goldstein,
Sci.,
191 (4223):150-4 (1976)).
Inflammation is now generally regarded as an important component of the pathogenic process of atherosclerosis (Munro,
Lab Invest.,
58:249-261 (1988); Badimon, et al.,
Circulation,
87:3-16 (1993); Liuzzo, et al.,
N.E.J.M.,
331(7):417-24 (1994); Alexander,
N.E.J.M.,
331(7):468-9 (1994)). Damage to endothelial cells that line the vessels leads to an accumulation of inflammatory cytokines, including IL-1, TNF&agr;, and the release of prostanoids and growth factors such as prostaglandin I
2
(PGI
2
), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and granulocyte-monocyte cell stimulating factor (GM-CSF). These factors lead to accumulation and regulation of inflammatory cells, such as monocytes, that accumulate within the vessel walls. The monocytes then release additional inflammatory mediators, including IL-1
Crossman David C.
Duff Gordon W.
Francis Sheila E.
Kornman Kenneth S.
Stephenson Katherine
Arnold Beth
Foley & Hoag LLP
Interleukin Genetics Inc.
Myers Carla J.
Olesen James T.
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