Antibodies to oxidized LDL and LDL-containing immune complexes as risk factors for coronary artery disease in diabetes mellitus

Several groups have published results from clinical studies supporting the involvement of anti-modified LDL antibodies as risk factors for the initiat ion or progression of cardiovascular disease. However, the data published s o far are judged inconclusive because of several contradictory observations concerning the correlation between clinical evidence of arteriosclerosis a nd the levels of antibodies to oxidized LDL (oxLDL Ab). We have previously reported that oxLDL Ab exist both in free form and as antigen-antibody comp lexes (LDL-IC) in patients with insulin-dependent diabetes mellitus (IDDM). The presence of LDL-IC in IDDM patients has important implications: it may interfere with the assay of oxLDL antibodies and the levels of LDL-IC may correlate better with the development of arteriosclerosis than the levels o f free oxLDL antibodies. To clarify these questions baseline samples collec ted from 49 IDDM patients, who subsequently developed coronary artery disea se (CAD) during an 8-year follow-up period, were compared to baseline sampl es from 49 age-, sex-, and duration-matched control IDDM subjects who remai ned free of clinical CAD during an identical follow-up period. The levels o f free oxLDL antibody were significantly lower in the patients who develope d CAD. The same patients had significantly higher concentrations of total c holesterol, apolipoprotein B, and IgA in immune complex-enriched polyethyle ne glycol (PEG;) precipitates. The concentration of IgG was also higher in PEG precipitates from patients who developed CAD, but did not reach statist ical significance. This indicates that patients who develop CAD had higher levels of circulating LDL-IC, a fact that could not be deduced from the mea surement of free oxLDL antibody concentrations. A linear regression analysi s of the correlation between the concentrations of total cholesterol in PEG precipitates, taken as a surrogate measurement of PEG-precipitated oxLDL-I C, and the concentration of free oxLDL antibody in serum showed a statistic ally significant negative correlation (r = -0.229, P = 0.024). Our results support the conclusion that oxLDL-IC may be a risk factor for the developme nt of macrovascular disease in IDDM patients. We also have demonstrated tha t circulating oxLDL-IC interfere with the assay of free oxLDL antibodies. ( C) 1999 Academic Press.