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.
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.
