Low-grade inflammation explains some of the cardiovascular risk associated with high remnant cholesterol
May 2026
In this report from the Copenhagen General Population Study, low-grade systemic inflammation contributes to the increased risk of peripheral artery disease and myocardial infarction associated with elevated remnant cholesterol levels.
Wadstrom BN, Wulff AB, Pedersen KM, Nordestgaard BG. Inflammation may explain part of atherosclerotic cardiovascular disease risk conferred by elevated remnant lipoproteins: a cohort and Mendelian randomization study. Atherosclerosis 2026; doi.org/10.1016/j.atherosclerosis.2026.120772 .
STUDY SUMMARY.
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Objective |
To investigate whether low-grade inflammation explains part of the increased risk of peripheral artery disease (PAD) and myocardial infarction (MI) conferred by elevated remnant lipoproteins. Additionally, the causal effect of elevated remnant lipoproteins on levels of inflammatory cytokines was also tested.
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Study design |
Cohort population study (Copenhagen General Population Study). Mendelian randomization was used to assess the causal effect of elevated remnant lipoproteins on levels of inflammatory cytokines.
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Study population |
90,789 individuals (median age 56 years, 44% men) from the Copenhagen General Population Study without statin use or evidence of infection, cancer, or other severe inflammatory conditions. The causal effects of elevated remnant cholesterol on cytokine levels were estimated in 43,400 individuals aged 40-69 years of genetic European ancestry in the UK Biobank.
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Main study variables
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In the main study analysis based on the Copenhagen General Population Study, the primary endpoints were PAD and MI. Remnant cholesterol was calculated as total cholesterol minus low-density lipoprotein (LDL) cholesterol minus high-density lipoprotein (HDL) cholesterol. Lipoprotein particle subfractions measured with nuclear magnetic resonance (NMR) spectroscopy were also assessed in 24,470 individuals.
In the UK Biobank, genetic scores derived from 44 genetic variants for remnant cholesterol and 73 genetic variants for LDL cholesterol were assessed for effects on cytokine levels.
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Methods |
Cox regression analysis was used to assess the association of remnant cholesterol, LDL cholesterol, remnant particles, and LDL particles with risk of PAD and MI, with and without adjustment for log2-transformed high-sensitivity C-reactive protein (CRP). In the UK Biobank, Mendelian randomization was applied to estimate the causal effects of remnant cholesterol and LDL cholesterol on cytokine levels using the two-stage least-squares method. |
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Results |
Over 15 years of follow up, 1045 individuals had a diagnosis of PAD, and 1966 individuals had an MI. Higher levels of remnant cholesterol and remnant particles were associated with increased risk of PAD and MI, and these associations were attenuated after adjustment for CRP. Low-grade inflammation explained 17% (95% confidence interval 12-22%) of PAD risk and 10% (6-14%) of MI risk associated with elevated remnant cholesterol (Table 1). Similar proportions explained risk associated with remnant particles in the NMR cohort.
Table 1. Risk explained by low-grade inflammation in the association from elevated remnant cholesterol and LDL cholesterol
* Estimate and 95% confidence interval
Mendelian randomization using the UK Biobank showed that higher levels of remnant cholesterol predicted from the genetic score were causally associated with increased levels of CRP, tumor necrosis factor (TNF), TNF-superfamily member 12, interleukin (IL)-16, IL-18, and IL-27; lowered IL-32 levels; but did not change IL-6 or IL-1β levels. Higher LDL cholesterol levels were not associated with higher levels of any of the cytokines.
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Author conclusions |
Low-grade inflammation explained a fraction of the increased PAD and myocardial infarction risk conferred by elevated remnant lipoproteins. Elevated remnant cholesterol may induce low-grade inflammation by increasing levels of TNF rather than IL-6 and IL-1β; future studies should further investigate these potential biological pathways. |
Comment
Previous studies showed that elevated remnant cholesterol causally increases levels of CRP (1), and that elevated CRP is implicated in the association of remnant cholesterol with atherosclerotic cardiovascular disease (ASCVD) (2,3). The current report from the Copenhagen General Population Study aimed to quantify the importance of inflammation in the association from elevated remnants and LDL cholesterol to risk of PAD and MI. The results show that low-grade inflammation explained almost one-fifth of the increased PAD risk and one-tenth of the myocardial infarction risk associated with elevated remnant cholesterol and remnant lipoprotein particles. Additionally, in the UK Biobank analysis, elevated remnant lipoproteins causally increased levels of several cytokines including TNF. The authors therefore suggest that TNF-mediated inflammation may partly mediate the effect of elevated remnant lipoproteins on risk of ASCVD. The study does not, however, provide direct evidence that TNF is the specific cytokine mediating the increased risk of either PAD or myocardial infarction associated with elevated remnant cholesterol.
The size of the cohort, extended follow-up, and use of NMR spectroscopy in a sizable proportion of the cohort to support the remnant cholesterol concentration findings add to the robustness of the study. Furthermore, in the UK Biobank analysis validated cytokines were measured using a high-throughput proteomics assay. The authors do, however, acknowledge several limitations of the study. First, the study reports observational analyses with potential for residual confounding and reverse causation. Additionally, the study evaluated data from individuals of northern European ancestry without a history of ASCVD at baseline who were not receiving lipid-lowering therapy, which may limit the generalizability of the results.
Peripheral artery disease affects over 113 million people worldwide and prevalence is expected to escalate as populations age, with estimates suggesting that worldwide more than 360 million individuals will be affected by 2050 (4). With atherosclerosis accounting for >90% of PAD cases, new therapeutic strategies are needed to reduce the risk of ASCVD. The current findings lend support to a potential role for novel therapeutics capable of substantially lowering remnant cholesterol and associated inflammation.
References
- Varbo A, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation 2013;128:1298–309.
- Doi T, Langsted A, Nordestgaard BG. Dual elevated remnant cholesterol and C-reactive protein in myocardial infarction, atherosclerotic cardiovascular disease, and mortality. Atherosclerosis 2023;379:117141.
- Meng W, Wang C, Xu Z, et al. Association between remnant cholesterol and peripheral artery disease from multiple perspectives. Atherosclerosis 2026:417:120784.
- Qiu X, Hu B, Ke J, et al. Global, regional, and national trends in peripheral arterial disease among older adults: findings from the global burden of disease study 2021. Aging Clin Exp Res 2025;37(1):150.
Key words: Remnant cholesterol; peripheral artery disease; low-grade inflammation; Copenhagen General Population Study
