Systemic inflammation is a minor contributor to remnant cholesterol atherogenicity

Kraaijenhof, J. M.; Kerkvliet, M.; Nurmohamed, N. S.; Grefhorst, A.; Kroon, J.; Wareham, N. J.; Hovingh, G. K.; Stroes, E. S.; Boekholdt, S. M.; Reeskamp, L. F.

doi:10.1101/2024.07.18.604203

bioRxiv · 10.1101/2024.07.18.604203

Systemic inflammation is a minor contributor to remnant cholesterol atherogenicity

Kraaijenhof, J. M.·Kerkvliet, M.·Nurmohamed, N. S.·Grefhorst, A.·Kroon, J.·Wareham, N. J.·Hovingh, G. K.·Stroes, E. S.·Boekholdt, S. M.·Reeskamp, L. F.

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Abstract

BackgroundBoth plasma levels of remnant cholesterol and low-density lipoprotein cholesterol (LDL-C) levels are independent risk factors for atherosclerotic cardiovascular disease. However, only remnant cholesterol has consistently been associated with systemic inflammation. The extent to which inflammation mediates the effect of remnant cholesterol on major adverse cardiovascular events (MACE) remains unclear. Methods and ResultsThis study included 16,445 participants without prior atherosclerotic cardiovascular disease from the EPIC-Norfolk cohort, 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 hsCRP levels (95% Confidence Interval (CI): 22.1, 37.4, p<0.001), whereas LDL-C 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 to a HR of 1.21 (95% CI: 1.13, 1.31, p<0.001) for LDL-C. 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-C. ConclusionsPlasma 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/604203v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@bdbb4org.highwire.dtl.DTLVardef@850ea6org.highwire.dtl.DTLVardef@184f321org.highwire.dtl.DTLVardef@17616fa_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract:C_FLOATNO The study assessed the relationship between remnant cholesterol, systemic inflammation, and MACE risk in 16,445 participants free from atherosclerotic cardiovascular disease from the EPIC-Norfolk cohort. Every 1 mmol/L higher remnant cholesterol was associated with 29.5% higher hsCRP levels (95% CI: 22.1, 37.4, p<0.001), while LDL cholesterol was not significantly associated with hsCRP levels. Additionally, each 1 mmol/L higher remnant cholesterol was associated with a HR of 1.31 (95% CI: 1.14, 1.50, p<0.001) for MACE, compared to a HR of 1.21 (95% CI: 1.13, 1.31, p<0.001) for LDL-C. hsCRP mediated 5.9% (95% CI: 1.2, 10.6%, p<0.001) of the effect of remnant cholesterol on MACE, while it did not mediate the effect of LDL cholesterol. LDL: low-density lipoprotein cholesterol, HR: hazard ratio, CI: confidence interval, MACE: major adverse cardiovascular events. C_FIG

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Kraaijenhof, J. M., Kerkvliet, M., Nurmohamed, N. S., Grefhorst, A., Kroon, J., Wareham, N. J., Hovingh, G. K., Stroes, E. S., Boekholdt, S. M., Reeskamp, L. F.. 2024-07-23. Systemic inflammation is a minor contributor to remnant cholesterol atherogenicity. https://doi.org/10.1101/2024.07.18.604203

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