Animal model for detection of vulnerable plaques

Details Animal model for detection of vulnerable plaques Animal model for detection of vulnerable plaques

2001-01-12

2003-06-17

Jones, Dameron L. (Department: 1611)

Multicellular living organisms and unmodified parts thereof and

Nonhuman animal

The nonhuman animal is a model for human disease

C424S009100

Reexamination Certificate

active

06580016

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the medical diagnosis of arterial disease, and particularly to detection of vulnerable plaque by means of detection of lipid accumulations within the arterial system.
BACKGROUND OF THE INVENTION
Atherosclerotic coronary artery disease is the leading cause of death in industrialized countries. An atherosclerotic plaque is a thickened area in the wall of an artery. Typically, patients who have died of coronary disease may exhibit as many as several dozen atherosclerotic plaques; however, in most instances of myocardial infarction, cardiac arrest, or stroke, it is found that only one of these potential obstructions has, in fact, ruptured, fissured, or ulcerated. The rupture fissure, or ulcer causes a large thrombus (blood clot) to form on the inside of the artery, which may completely occlude the flow of blood through the artery, thereby injuring the heart or brain. A major prognostic and diagnostic dilemma for the cardiologist is how to predict which plaque is about to rupture.
Plaque, a thickening in the arterial vessel wall, results from the accumulation of cholesterol, proliferation of smooth muscle cells, secretion of a collagenous extracellular matrix by the cells, and accumulation of macrophages. Eventually, hemorrhage (bleeding), thrombosis (clotting), and calcification result. The consensus theory is that atherosclerotic plaque develops as a result of irritation or biochemical damage of the endothelial cells.
The endothelial cells which line the interior of the vessel prevent inappropriate formation of blood clots and inhibit contraction and proliferation of the underlying smooth muscle cells. Damage or dysfunction in endothelial cells is typically produced as a result of injury by cigarette smoke, diabetes, high serum cholesterol (especially oxidized low density lipoprotein), hemodynamic alterations (such as those found at vessel branch points), hypertension, some hormonal factors in the plasma (including Angiotensin II, norepinephrine),), certain viruses (herpes simplex, cytomegalovirus) and/or bacteria (e.g., Chlamydia), and other factors as yet unknown. As a result of these gradual injuries to the endothelial cells, an atherosclerotic plaque may grow slowly over many years. However, it is now well documented that if a plaque ruptures, it often grows abruptly by clot formation, occluding the blood vessel.
When plaque rupture develops, there is hemorrhage into the plaque through the fissure where the surface of the plaque meets the bloodstream. Blood coagulates (forms a thrombus) quickly upon contact with the matrix and lipid of the plaque. This blood clot may then grow to completely occlude the vessel, or it may remain only partially occlusive. In the latter case, the new clot quite commonly becomes incorporated into the wall of the plaque, creating a larger plaque.
Plagues at Risk of Rupturing
Given the enormous impact on public health of acute plaque disruption, much research has attempted to identify those factors which increase the likelihood of a plaque becoming destabilized. The term “vulnerable plaque” was coined to denote a lesion at risk of such an abrupt change.
Considerable evidence indicates that plaque rupture triggers 60% to 70% of fatal myocardial infarctions, and that monocyte-macrophages contribute to rupture by releasing metalloproteinases (e.g., collagenases, stromelysin), which can degrade and thereby weaken the overly fibrous cap (Van der Waal, et al.,
Circulation
89:36-44, 1994; Nikkari, et al.,
Circulation
92:1393-1398, 1995, Falk, et al.,
Circulation
92:2033-20335, 1995; Shad, et al.,
Circulation
244, 1995; Davies, et al.,
Br Heart J
53:363-373, 1985; Constantinides,
J Atheroscler Res
6:1-17, 1966). In another 25% to 30% of fatal infarctions, the plaque does not rupture, but beneath the thrombus the endothelium is replaced by monocytes and inflammatory cells (Van der Waal, et al.,
Circulation
89:36-44, 1994; and Farb, et al.,
Circulation
92:1701-1709, 1995). These cells may both respond to and aggravate intimal injury, promoting thrombosis and vasoconstriction (Baju, et al.,
Circulation
89:503-505, 1994).
Unfortunately, neither plaque rupture nor plaque erosion is predictable by clinical means. Soluble markers, such as P-selectin, von Willebrand factor, Angiotensin-converting enzyme, C-reactive protein, D-dimer (Ikeda, et al.,
Circulation
92:1693-1696, 1995; Merlini, et al.,
Circulation
90:61-8, 1994; and Berk, et al.,
Am J Cardiol
65:168-172, 1990) and activated circulating inflammatory cells are found in patients with unstable angina pectoris, but it is not yet known whether these substances predict infarction or death (Mazzone, et al.,
Circulation
88:358-363, 1993). It is known, however, that the presence of such substances cannot be used to locate the involved lesion.
Angiograms may be useful for predicting a vulnerable plaque because low-shear regions opposite flow dividers are more likely to develop atherosclerosis (Ku, et al.,
Arteriosclerosis
5:292-302, 1985). However, most patients who develop acute myocardial infarction or sudden cardiac death have not had prior symptoms, much less an angiogram (Farb, et al.,
Circulation
92:1701-1709, 1995).
Certain angiographic data has revealed than an irregular plaque profile is a fairly specific, though insensitive, indicator of thrombosis (Kaski, et al.,
Circulation
92:2058-2065, 1955). Such plaques are likely to progress to complete occlusion, while others are equally likely to progress, but less often reach the point of complete occlusion (Aldeman, et al.,
J Am Coll Cardiol
22:1141-1154, 1993). Those that do abruptly progress to occlusion actually account for most myocardial infarctions (Ambrose, et al.,
J Am Coll Cardiol
12:56-62, 1988 and Little, et al.,
Circulation
78:1157-1166, 1988).
The size of the plaque occlusion is not necessarily determinative. Postmortem studies show that most occlusive thrombi are found over a ruptured or ulcerated plaque that is estimated to have produced a stenosis of less than 50% of the vessel diameter (Shah, et al.,
Circulation
244, 1995). Such stenoses are not likely to cause angina or result in a positive treadmill test. In fact, most patients who die of myocardial infarction do not have three-vessel disease or severe left ventricular dysfunction (Farb, et al.,
Circulation
92:1701-1709, 1995).
In the vast majority of plaques causing a stenosis less than or equal to 50% in vessel diameter, the surface outline is uniform, but the deep structure is highly variable and does not correlate directly with either the size of the plaque or the severity of the stenosis (Pasterkamp, et al.,
Circulation
91:1444-1449, 1995 and Mann and Davies
Circulation
94:928-931, 1996).
In view of the dependence of vulnerability on the deep structure of the plaque, studies have been conducted to determine the ability to identify plaques likely to rupture using intracoronary ultrasound. It is known that (1) angiography tends to underestimate the extent of coronary atherosclerosis, (2) high echo-density usually indicates dense fibrous tissue, (3) low echo-density is a feature of hemorrhage, thrombosis, or cholesterol, and (4) shadowing indicates calcification (Yock, et al.,
Cardio
11-14, 1994 and McPherson, et al.,
N Engl J Med
316:304-309, 1987). However, recent studies indicate that intra-vascular ultrasound technology currently cannot discriminate between stable and unstable plaque (De Feyter, et al.,
Circulation
92:1408-1413, 1995).
The relation of the deep structure of the plaque to the rupture process is not completely understood, but it is known that the plaques most likely to rupture are those that have both a thick collagen cap (fibrous scar) and a point of physical weakness in the underlying structure. It is also known that plaques with inflamed surfaces or a high density of activated macrophages and a thin overlying cap are at risk of thrombosis (Van der Waal, et al.,
Circulation
89:36-44, 1994; Shah, et al.,
Circulation
244, 1995; Davies, et al.,
Br Heart J
53:363-373, 1

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