Animal model for detection of vulnerable plaques

• US 6,580,016 B2
• Filed: 01/12/2001
• Issued: 06/17/2003
• Est. Priority Date: 12/04/1998
• Status: Expired due to Fees

• Current Assignee: MediVas, LLC
• Original Assignee: MediVas, LLC
• Inventors: Carpenter, Kenneth W., Teirstein, Paul S., Szinai, Istvan, Schwartz, David A.
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US09/760,182
• Publication Number:
  US 20010018042A1
• Time in Patent Office: 886 Days
• Field of Search: 424/9.1, 424/1.11, 424/9.2, 800/9, 800/10, 800/11, 800/12
• US Class Current: 800/9
• CPC Class Codes: A61B 6/4057 by using radiation sources located in the interior of the body A61B6/037 takes precedence
• CPC Class Codes: A61B 6/481 involving the use of contrast agents
• CPC Class Codes: A61B 6/508 for non-human patients
• CPC Class Codes: A61K 49/0442 Polymeric X-ray contrast-enhancing agent comprising a halogenated group
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 49/126 Linear polymers, e.g. dextran, inulin, PEG
• CPC Class Codes: A61K 51/065 conjugates with carriers being macromolecules
• CPC Class Codes: G01N 2400/40 Glycosaminoglycans, i.e. GAG or mucopolysaccharides, e.g. chondroitin sulfate, dermatan sulfate, hyaluronic acid, heparin, heparan sulfate, and related sulfated polysaccharides
• CPC Class Codes: G01N 2800/323 Arteriosclerosis, Stenosis
• CPC Class Codes: G01N 33/92 involving lipids, e.g. cholesterol , lipoproteins, or their receptors steroid hormones G01N33/743

Abstract

The present invention provides in vivo methods for detection of vulnerable plaque in a subject in need thereof. In the invention method the subject is administered a diagnostic amount of a biologically compatible detectable lipid-avid agent, the detectable lipid-avid agent is allowed to penetrate arterial walls and attach to any lipid accumulations of oxidized LDL-cholesterol in arterial walls in the wall of an artery; unbound detectable lipid-avid agent is allowed to clear from the body by natural processes, and the presence of the detectable lipid-avid agent attached to the lipid accumulation in the wall of the artery is detected. Detection of bound lipid-avid agent indicates the presence of a vulnerable plaque and predicts a heightened risk of lethal heart attack or thrombus. The detectable lipid-avid agent is selected for its ability to penetrate arterial walls and bind with oxidized LDL-cholesterol in the lipid accumulation in a vulnerable plaque. Alternatively, macrophage-avid agents, for example a lipid-avid agent attached to a macrophage-specific antibody, can be used in the invention methods. The invention further includes methods for in vitro assays for detecting vulnerable plaque and a porcine animal model of vulnerable plaque useful for testing treatment modalities.

Claims

1. A method for obtaining an animal model of a vulnerable plaque, said method comprising:

locally delivering a lipid containing oxidized LDL directly into one or more blood vessel walls of a live pig while minimizing thrombogenesis so as to form one or more lipid accumulations in the vessel walls, and

allowing the bodily processes of the live pig to react to the lipid accumulations to form one or more structures selected from the group consisting of an accumulation of oxidized low density lipoproteins, a presence of metalloproteinases, local inflammation, inflammatory cell activity, a presence of a collagen cap or fibrous scar, and thrombus found in a human vulnerable plaque.

2. The method according to claim 1 wherein the lipid is delivered into the tunica media of one or both coronary arteries of the pig.

3. The method according to claim 1 wherein the lipid is delivered by means of an intramural delivery catheter.

4. The method according to claim 1 wherein the lipid is contained within an olive oil/albumin coacervate.

5. The method according to claim 1, wherein the method further comprises delivery with the lipid of one or more of the following:

pre-cultured and stimulated monocytes,

stimulated CD-4 lymphocytes in cell suspension,

granulocyte-macrophage colony stimulating factor (GMCF),

vascular cell adhesion molecule (VCAM-1),

monocyte chemoattractant protein (MCP-1),

granulocyte-macrophage colony stimulating factor (GMCF),

interleukin-1 or interleukin 8,

whereby foamy cells and local inflammation are produced adjacent to the lipid accumulations in the vessel walls.

6. The method according to claim 1 wherein the pig is allowed to react to the lipid accumulations for about 28 days to about 3 months.

7. The method according to claim 6 wherein the structures formed are selected from the group consisting of neointimal hyperplasia, medial necrosis, recruitment of macrophages and/or lymphocytes, formation of giant cells, and rupture of the vessel with accompanying clot formation.

8. A porcine model of a vulnerable plaque produced by the method of claim 1.