Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1997-03-10
2001-04-03
Myers, Carla J. (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S023500, C536S024310, C536S024330
Reexamination Certificate
active
06210877
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a presymptomatic assay for early identification of individuals more likely to develop coronary artery disease and related vascular disorders. The invention describes gene-specific, protein-specific, and epitope-specific probes and molecular genetic and biochemical assays.
2. Description of the Background
Coronary Artery Disease
Atherosclerosis (or arteriosclerosis) is the term used to describe progressive luminal narrowing and hardening of the arteries. This disease process can occur in any systemic artery in the human body. For example, atherosclerosis in the arteries that supply the brain 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. This 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. Depending on the volume of muscle distal to the blockage during such an attack, a portion of myocardial tissue may die, weakening the heart muscle and often leading to the death of the individual.
The causes and mechanisms of the atheromatous plaque buildup 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 or not, 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.
Though recent improvements in cardiovascular care have improved the life expectancy of coronary artery disease patients, this has been primarily from improvements in lowering lipid levels, limitation of damage after it has occurred, surgical restoration of blood supply, the suppression of abnormal heart rhythms and prevention of re-infarction. Little improvement has occurred, however, in early prevention of the disease by early diagnosis.
A key problem in treating coronary artery disease is proper diagnosis. Often the first sign of the disease is sudden death due to myocardial ischemia or myocardial infarction. Approximately half of all individuals who die of coronary artery disease die suddenly. Furthermore, for 40-60% of the patients who are eventually diagnosed as having coronary artery disease, myocardial infarction is the first presentation of disease. Unfortunately, approximately 40% of those initial events go unnoticed by the patient. For various reasons, the perception of symptoms by the patient does not correlate well with the total burden of coronary artery disease (Anderson & Kin,
Am. Heart J
. 123(5);1312-23 (1992)).
While the causes of atherosclerosis remain unknown, the proper diagnosis of susceptibility may provide patients sufficient time to reduce their risk of developing coronary artery disease. One method to reduce the risk of coronary artery disease is through alteration of patient lifestyle such as smoking cessation, exercise, weight loss, and stress reduction. Other methods include pharmaceutical intervention to treat hypertension, hypercholesterolemia, and diabetes, as well as the use of aspirin. Finally, genetic therapy promises to treat those rare genetic traits that result in a family history of cardiovascular disease (e.g., altered apolipoprotein metabolism).
The ability to identify high-risk individuals would allow physicians to focus preventive measures on those individuals who may gain the greatest benefit, and would provide strong incentives for those at risk to comply with such approaches.
Correlation of Coronary Artery Disease with Inflammatory Response
Evidence has accumulated to show that coronary artery disease and related vascular disorders may be initiated as a response to some form of injury in the arterial endothelium. The injury may be subtle, or may involve outright endothelial cell denudation. Focal sites of injury lead to increased permeability to plasma constituents and permit blood platelets and monocytes to adhere to endothelial or subendothelial connective tissue. Inflammatory factors released from activated platelets or monocytes then cause migration of smooth muscle cells from the media into the intima, followed by proliferation of these cells. Synthesis of extracellular matrix components by smooth muscle cells leads to accumulation of collagen, elastic fibers and proteoglycans. Monocytes also enter the intima, transform into macrophages, accumulate lipids and contribute to the evolution of the lesion. Single or short-lived injurious events are followed by regeneration of endothelial cells, restoration of endothelial function, and healing of the lesion. However, an abnormal inflammatory event may result in the development of an atheromatous plaque.
For many years epidemiologic studies have indicated that an individual's genetic composition is a significant risk factor for development of coronary artery disease. 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, el al.,
N.E.J.M
. 331(7): 417-24 (1994), Alexander,
N.L.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, TNF, prostaglandin E
2
(PGE
2
), bFGF, and transforming growth factors &agr; and &bgr; (TGF&agr;, TGF&bgr;). All of these inflammatory mediators recruit more inflammatory cells to the damaged area, regulate the behavior of endothelial and smooth muscle cells and lead to the accumulation of atheromatous plaques.
Several inflammatory products, including IL-1&bgr;, have been identified in atherosclerotic lesions or in the endothelium of diseased coronary arteries (Galea, et al.,
Ath. Thromb. Vasc. Biol
. 16:1000-6 (1996)). Also, serum concentra
Crossman David C.
Duff Gordon W.
Francis Sheila E.
Arnold, Esq. Beth E.
Foley Hoag & Eliot LLP
Interleukin Genetics Inc.
Myers Carla J.
Varma, Esq. Anita
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