With 60% of plasma cholesterol being associated with low-density lipoproteins (LDL), reduction in LDLc is one of the primary targets for intervention to reduce cardiovascular disease. However, meta- analyses of available clinical trials have consistently demonstrated that, while the risk for clinical event is reduced with LDLc reduction, the progression of atherosclerosis is not stopped. Many patients continue to have clinical events, including death, in spite of having reached target levels for LDLc. According to the oxidation hypothesis of atherosclerosis, native LDL is not atherogenic. LDL particles that have been oxidatively modified, on the other hand, can be avidly taken up by macrophages leading to the formation of foam cells and plaque instability. We have developed a number of specific and highly sensitive monoclonal antibodies against cysteic acid (oxidized form cysteine), which is one of the most common forms of naturally occurring protein oxidation. Preliminary data using the K2F1.6 clone (deposited with the ATCC PTA-897, US patent 6,953,666B1) indicates that a wide range of positive signals can be detected in high-risk individuals as compared to healthy controls. The objective of this SBIR Phase 1 is to demonstrate the clinical significance of this oxidative marker in a large cohort of patients with and without cardiovascular disease, including documented coronary artery disease. Specimen from three cohorts of patients will be available (1) free-living individuals with and without CAD as characterized from medical history and endothelial dysfunction (brachial artery flow-mediated dilatation), (2) participants in the NIH funded Veterans Twin Heart Study characterized clinically by MRI and endothelial dysfunction, (3) veterans with type 2 diabetes mellitus with and without concomitant CAD who have been treated to LDLc goal. This will be a prospective, nested case-control single-blind study design.
Public Health Relevance: Elevated plasma levels of oxidized LDL may contribute to the risk for future cardiovascular events beyond the traditional risk factors. Using a patent-protected ELISA assay based on a unique monoclonal antibody that recognizes an oxidized cysteine moiety, we propose to define the distribution of this oxidized epitope in three independent cohorts of subjects including healthy controls, patients with type 2 diabetes mellitus and patients with documented CAD.
Public Health Relevance Statement: NARRATIVE Elevated plasma levels of oxidized LDL may contribute to the risk for future cardiovascular events beyond the traditional risk factors. Using a patent-protected ELISA assay based on a unique monoclonal antibody that recognizes an oxidized cysteine moiety, we propose to define the distribution of this oxidized epitope in three independent cohorts of subjects including healthy controls, patients with type 2 diabetes mellitus and patients with documented CAD.
Project Terms: 3-Sulfoalanine; Alanine, 3-sulfo-; Angiogram; Angiography; Antigenic Determinants; Assay; Atheroscleroses; Atherosclerosis; Atherosclerotic Cardiovascular Disease; Award; Binding Determinants; Bioassay; Biologic Assays; Biological Assay; Blood Plasma; Brachial Artery; Cardiac infarction; Cardiovascular; Cardiovascular Body System; Cardiovascular Diseases; Cardiovascular system; Cardiovascular system (all sites); Cell Communication and Signaling; Cell Signaling; Cessation of life; Characteristics; Cholest-5-en-3-ol (3beta)-; Cholesterol; Clinical; Clinical Trial Overviews; Clinical Trials; Clinical Trials, Unspecified; Coronary Arteriosclerosis; Coronary Artery Disease; Coronary Artery Disorder; Coronary Atherosclerosis; Cysteate; Cysteic Acid; Cysteine; Data; Data Pooling; Data Poolings; Death; Deposit; Deposition; Detection; Diabetes Mellitus; Diabetes Mellitus, Adult-Onset; Diabetes Mellitus, Ketosis-Resistant; Diabetes Mellitus, Non-Insulin-Dependent; Diabetes Mellitus, Noninsulin Dependent; Diabetes Mellitus, Slow-Onset; Diabetes Mellitus, Stable; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type II; Diagnostic; Dilatation; Dilatation - action; Disease Progression; Dysfunction; ELISA; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Epidemiology, Personal Medical History; Epitopes; Event; Exhibits; Foam Cells; Framingham Heart Study; Functional disorder; Funding; Future; Goals; Half-Cystine; Hand; Heart; INFLM; Individual; Inflammation; Intervention; Intervention Strategies; Intervention Trial; Intracellular Communication and Signaling; L-Cysteine; LDL; Laboratories; Legal patent; Licensing; Life; Lipoproteins, LDL; Low-Density Lipoproteins; MODY; MR Imaging; MR Tomography; MRI; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Maturity-Onset Diabetes Mellitus; Mediating; Medical History; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Medical Specialities; Meta-Analyses; Meta-Analysis; Moab, Clinical Treatment; Monoclonal Antibodies; Mortality; Mortality Vital Statistics; Myocardial Infarct; Myocardial Infarction; NIDDM; NIH; NMR Imaging; NMR Tomography; National Institutes of Health; National Institutes of Health (U.S.); Non-Insulin Dependent Diabetes; Non-Insulin-Dependent Diabetes Mellitus; Normal Range; Normal Values; Nuclear Magnetic Resonance Imaging; Organ System, Cardiovascular; OxLDL; Oxidative Stress; Participant; Patents; Patients; Personal Medical History; Phase; Physiopathology; Plasma; Prevention; Proteins; Research; Research Design; Research Specimen; Residual; Residual state; Reticuloendothelial System, Serum, Plasma; Risk; Risk Factors; SBIR; SBIRS (R43/44); Serum, Plasma; Signal Transduction; Signal Transduction Systems; Signaling; Single-Blind Study; Small Business Innovation Research; Small Business Innovation Research Grant; Specialties, Medical; Specialty; Specimen; Structure of brachial artery; Study Type; Study, Single-Blind; Symptoms; T2D; T2DM; Technology; Therapeutic; Twin Multiple Birth; Twins; Type 2 diabetes; Type II diabetes; United States National Institutes of Health; Universities; Vascular, Heart; Veterans; Woman; Zeugmatography; active method; adult onset diabetes; atheromatosis; atherosclerotic vascular disease; base; beta-Lipoproteins; beta-Sulfoalanine; biological signal transduction; brachial artery; cardiac infarct; cardiovascular disorder; case control; circulatory system; clinical investigation; clinical significance; clinically significant; cohort; coronary attack; coronary infarct; coronary infarction; diabetes; early detection; gene product; heart attack; heart infarct; heart infarction; high risk; indexing; interventional strategy; ketosis resistant diabetes; macrophage; maturity onset diabetes; medical specialties; men; men's; ox-LDL; oxidation; oxidized LDL; oxidized low density lipoprotein; particle; pathophysiology; prospective; public health relevance; single-blind trial; study design
