Association between Negatively Charged Low-Density Lipoprotein L5 and Subclinical Atherosclerosis in Rheumatoid Arthritis Patients

L5, the most negatively charged subfraction of low-density lipoprotein (LDL), is implicated in atherogenesis. We examined the relationship between plasma L5 levels and the occurrence of subclinical atherosclerosis in patients with rheumatoid arthritis (RA). Using anion-exchange purification with fast-protein liquid chromatography, we determined the proportion of plasma L5 of LDL (L5%) in 64 RA patients and 12 healthy controls (HC). Plasma L5% and L5 levels were significantly higher in RA patients (median, 1.4% and 1.92 mg/dL) compared with HC (0.9%, p < 0.005; and 1.27 mg/dL, p < 0.05) and further increased in patients with subclinical atherosclerosis (2.0% and 2.88 mg/dL). L5% and L5 levels decreased in patients after 6-months of therapy (p < 0.01). Subclinical atherosclerosis was indicated by plaque and intima-media thickness determined by carotid ultrasonography. Using multivariate analysis, L5% and L5 levels are revealed as the predictors of subclinical atherosclerosis (odds ratio, 4.94 and 1.01; both p < 0.05). Receiver operating characteristic curves showed that cut-off values of L5% ≥ 1.45% and L5 levels ≥ 2.58 mg/dL could predict subclinical atherosclerosis in patients (both p < 0.001). Immunoblotting showed that the expression levels of lectin-like oxidized LDL receptor-1 (LOX-1) was increased in RA patients. Together, our findings suggest that plasma L5% and L5 levels may be predictors of cardiovascular risk in RA patients.