Oxidized LDL pathophysiology and potential as a therapeutic target in atherosclerosis.

Uptake of oxidized and other forms of modified low-density lipoprotein (LDL) drives formation of foam cells, a hallmark of atherosclerotic plaques. Experimental studies demonstrating the proinflammatory and cytotoxic properties of oxidized LDL have led to the concept of LDL oxidation as one key factor in both development and destabilization of atherosclerotic plaques. Such data positioned oxidized LDL as a promising target for prevention or mitigation of atherosclerotic cardiovascular disease. Yet the failure of multiple antioxidants to reduce cardiovascular risk in large randomized clinical trials has hampered this prospect. Such null studies have stimulated interest in an alternative approach: the therapeutic potential of antibodies against oxidized LDL. High levels of IgM against oxidized LDL phospholipids are associated with lower cardiovascular risk and these antibodies function primarily through neutralization and stimulation of clearance of modified LDL. IgG antibodies against aldehyde-modified peptide sequences in apolipoprotein B-100, the signature protein component of LDL, are also associated with lower risk of cardiovascular disease but experimental studies have shown that these antibodies function by locally forming immune complexes with oxidized LDL that limit the inflammatory activity of certain plaque macrophages. A phase 2 pilot study showed that one such antibody, orticumab, reduces an imaging index of local coronary arterial inflammation in patients with psoriasis. Thus, emerging evidence supports the possibility of using oxidized LDL antibodies to limit atherothrombotic disease.