The role of systemic inflammation in remnant cholesterol-associated cardiovascular risk: insights from the EPIC-Norfolk study

AIMS: Both plasma levels of remnant cholesterol and low-density lipoprotein (LDL) cholesterol levels are independent risk factors for atherosclerotic cardiovascular disease. However, only remnant cholesterol has consistently been associated with systemic inflammation. In this study, we aimed to assess the extent to which inflammation mediates the effect of remnant and LDL cholesterol on (non)fatal major adverse cardiovascular events (MACE), comprising of coronary artery disease and ischaemic stroke. METHODS AND RESULTS: This prospective study included 16,445 participants without prior atherosclerotic cardiovascular disease from the EPIC-Norfolk study, with a mean age of 58.8 ± 9.1 years, of which 9,357 (56.9%) were women. Every 1 mmol/L higher remnant cholesterol was associated with 29.5% higher high-sensitivity C-reactive protein (hsCRP) levels [95% Confidence Interval (CI): 22.1, 37.4, P < 0.001], whereas LDL cholesterol was not significantly associated with hsCRP levels in the fully adjusted model. Additionally, each 1 mmol/L higher remnant cholesterol was associated with a hazard ratio (HR) of 1.31 (95% CI: 1.14, 1.50, P < 0.001) for MACE, compared with an HR of 1.21 (95% CI: 1.13, 1.31, P < 0.001) for LDL cholesterol. Mediation analysis showed that hsCRP mediated 5.9% (95% CI: 1.2, 10.6%, P < 0.001) of the effect of remnant cholesterol on MACE, whereas hsCRP did not mediate the effect of LDL cholesterol. CONCLUSION: Plasma remnant cholesterol levels are independently associated with systemic inflammation and cardiovascular events. Inflammation, as measured with hsCRP, contributed minorly to the association between remnant cholesterol and MACE. This underscores the need to address both remnant cholesterol and systemic inflammation separately in the clinical management of cardiovascular disease. LAY SUMMARY: This study finds that systemic inflammation does not influence the effect remnant cholesterol has on cardiovascular disease risk, suggesting the importance of addressing both remnant cholesterol and inflammation to manage cardiovascular health.