Lipoprotein oxidation may underlie the paradoxical association of low cholesterol with coronary atherosclerotic risk in rheumatoid arthritis

To compare coronary plaque burden, proatherogenic cytokines, oxidized low-density lipoprotein (oxLDL), anti-oxLDL antibodies, lipoprotein(a)-cholesterol, and their relationships in patients with rheumatoid arthritis with low-density lipoprotein cholesterol (LDL-C)<1.8 mmol/L versus ≥1.8 mmol/L. Also, to study differences in inflammation and proprotein convertase subtilisin/kexin type-9 (PCSK9), which impacts LDL clearance, in patients with low versus high LDL-C. Computed tomography angiography evaluated coronary plaque (noncalcified, partially calcified, fully calcified, and high-risk plaque) in 150 patients from a single-center observational cohort. Ox-LDL, anti-oxLDL IgG, lipoprotein(a)-cholesterol, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6, tumor necrosis factor-α (TNF-α) and PCSK9 were measured. Analyses adjusted for Framingham general cardiovascular risk score, statin use, and high-density lipoprotein cholesterol. Patients with LDL-C<1.8 mmol/L versus ≥1.8 mmol/L demonstrated: 1) higher likelihood of per-segment plaque (adjusted-OR = 1.67 [95%CI = 1.10–2.55], p = 0.017) and high-risk plaque presence (adjusted-OR 2.78 [95%CI = 1.06–7.29], p = 0.038); 2) greater anti-oxLDL titers (p = 0.020), which positively associated with TNF-α and likelihood of noncalcified, partially calcified and high-risk plaque presence only in patients with LDL-C<1.8 mmol/L (all p-for-interaction≤0.046); 3) increased lipoprotein(a)-cholesterol content (10.33% [8.11–12.54] versus 6.68% [6.10–7.25], p < 0.001), which positively associated with oxLDL (p < 0.001) and anti-oxLDL (p = 0.036); 4) higher interleukin-6 and PCSK9. No differences in CRP, ESR, or oxLDL were observed. RA patients with LDL-C<1.8 mmol/L had more coronary plaque, higher anti-oxLDL titers and anti-oxLDL associated with plaque only in this group. It is possible the observed paradoxical association of low LDL-C with greater atherosclerosis may be related to higher production of the oxidation-prone lipoprotein(a)-cholesterol and anti-oxLDL antibodies, resulting in increased vascular LDL uptake and plaque formation.