Serum cholesterol loading capacity on macrophages is linked to coronary atherosclerosis and cardiovascular event risk in rheumatoid arthritis

Abstract

Objectives: Cholesterol loading capacity (CLC) describes the ability of serum to deliver cholesterol to cells. It is linked to foam cell formation, a pivotal step in atherosclerotic plaque development. We evaluate the associations of CLC with coronary atherosclerosis presence, burden and cardiovascular risk in patients with rheumatoid arthritis (RA).

Methods: Coronary atherosclerosis (any, high-risk low-attenuation plaque and obstructive plaque) was evaluated with CT angiography in 141 patients. Participants were prospectively followed for 6.0±2.4 years and cardiovascular events including cardiac death, myocardial infarction, unstable angina, stroke, claudication, revascularisation and hospitalised heart failure were recorded. CLC was quantified as intracellular cholesterol in human macrophages after incubation with patient serum.

Results: CLC was not linked to overall plaque presence or burden after adjustments for atherosclerotic cardiovascular disease (ASCVD) score, statin use and low-density lipoprotein cholesterol. However, CLC associated with presence and numbers of any, low-attenuation and obstructive plaques exclusively in biologic disease-modifying antirheumatic drugs (bDMARD) non-users (p for interaction ≤0.018). CLC associated with cardiovascular event risk overall after adjustments for ASCVD and number of segments with plaque (HR=1.76 (95% CI 1.16 to 2.67) per 1 SD increase in CLC, p=0.008). Additionally, bDMARD use modified the impact of CLC on event risk; CLC associated with events in bDMARD non-users (HR=2.52 (95% CI 1.36 to 4.65) per 1SD increase in CLC, p=0.003) but not users.

Conclusion: CLC was linked to long-term cardiovascular event risk in RA and associated with high-risk low attenuation and obstructive coronary plaque presence and burden in bDMARD non-users. Its prospective validation as a predictive biomarker may be, therefore, warranted.

Keywords: arthritis, rheumatoid; atherosclerosis; lipids.

Figure 1

Association of serum CLC with per-segment coronary plaque outcomes for the total sample and stratified by bDMARD use. ORs derived from robust binary logistic regression adjusted for proximal segment location, atherosclerotic cardiovascular disease (ASCVD) score, statin use and LDL-C. bDMARD, biologic disease modifying anti-rheumatic drugs; CLC, cholesterol loading capacity; LDL-C, low-density lipoprotein cholesterol.

Figure 2

Association of serum CLC with per-patient coronary plaque outcomes for the total sample and stratified by bDMARD use. Rate ratios denote the per cent change in number of segments with plaque associated with one SD unit increase in CLC. Rate ratios derived from multivariable negative binomial regression models adjusted for atherosclerotic cardiovascular disease (ASCVD) score, statin use and LDL-C. bDMARD, biologic disease modifying anti-rheumatic drugs; CLC, cholesterol loading capacity; LDL-C, low-density lipoprotein cholesterol.

Figure 3

Coronary plaque burden outcomes across levels of serum CLC stratified by bDMARD use. (A) Coronary artery Calcium score. (B) Predicted number of segments with plaque per patient. (C) Predicted number of high-risk plaque per patient. Dashed lines represent standard errors. bDMARD, biologic disease modifying anti-rheumatic drugs; CLC, cholesterol loading capacity.

Figure 4

Association of serum CLC with cardiovascular event risk. (A) Higher CLC associates with greater cardiovascular risk after adjustments for ASCVD risk score and number of coronary segments with plaque. Red line represents high serum CLC (+1 SD) and black line represents low serum CLC (−1SD). (B) CLC associated with higher cardiovascular event risk in bDMARD nonusers but not in bDMARD users. Solid lines represent bDMARD nonusers and dashed lines represent bDMARD users. Red lines represent high serum CLC (+1 SD) and black lines represent low serum CLC (−1 SD). ASCVD, atherosclerotic cardiovascular disease; bDMARD, biologic disease modifying anti-rheumatic drugs; CLC, cholesterol loading capacity.