Remnant cholesterol, inflammation and atherosclerosis

This editorial refers to ‘The role of systemic inflammation in remnant cholesterol associated cardiovascular risk: insights from the EPIC-Norfolk study’, by J. M. Kraaijenhof et al., https://doi.org/10.1093/eurjpc/zwaf037. Remnant cholesterol, which consists of the cholesterol in intermediate density lipoprotein (IDL), very low density lipoprotein (VLDL), and chylomicron remnant particles, is associated with risk of atherosclerotic cardiovascular disease.1 Indeed some, but not all, studies have suggested an even greater association between remnant cholesterol and major adverse cardiovascular events (MACE) than for LDL cholesterol, suggesting that remnants may influence atherosclerosis by mechanisms in addition to the delivery of apoB-containing lipoproteins to the artery wall.1,2 Levels of remnant cholesterol are associated with markers of systemic inflammation,3 but the extent to which inflammation contributes to the atherogenicity of remnant cholesterol has not been previously established. A study by Kraaijenhof et al.4 presents an analysis of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study in which they evaluate the extent to which systemic inflammation mediates the effect of both remnant and LDL cholesterol on major adverse cardiovascular events. To perform this analysis the authors studied individuals in the EPIC-Norfolk prospective cohort study in whom plasma lipid levels were measured. Remnant cholesterol was estimated as the total cholesterol less the sum of HDL cholesterol and LDL cholesterol. In addition, VLDL size was determined by nuclear magnetic resonance spectroscopy. The authors found that every 1 mmol/L increase in remnant cholesterol was associated with a 73% higher high-sensitivity C-reactive protein (hsCRP) with partial attenuation of this effect when components of the metabolic syndrome (diabetes, obesity, and hypertension) were adjusted for. A much weaker association was observed between LDL cholesterol and hsCRP, which was completed abrogated when adjusted for remnant cholesterol. Each 1 mmol/L higher remnant cholesterol was associated with a 1.7-fold increase in the risk of MACE, which was reduced to 1.3 after adjusting for metabolic syndrome, smoking, LDL cholesterol, and apoB. For LDL cholesterol, each 1 mmol/L increase was associated with a 1.2-fold greater risk of MACE. The authors then performed a mediation analysis to estimate the extent to which systemic inflammation, as reflected by hsCRP, explains the observed relationship between remnant cholesterol and risk of MACE. This is a form of logistic regression which asks to what extent does an intermediary variable—in this case, inflammation—contribute to, or ‘mediate’, the association between two other variables (remnant cholesterol and MACE). They found, perhaps surprisingly, that hsCRP explained only 5.9% of the relationship between remnant cholesterol and MACE, with directionally similar findings in men and women. In contrast, there was no mediation of hsCRP on the association of LDL cholesterol and MACE. A discordance analysis stratified by remnant cholesterol and LDL cholesterol provided similar findings, suggesting a minor degree of mediation by hsCRP in the groups with high levels of remnant cholesterol but not in the group with high LDL cholesterol and low remnant cholesterol. This elegant study adds to the existing body of literature, which has demonstrated a robust association between remnant cholesterol and inflammation, as well as between remnant cholesterol and risk of MACE. These data expand previous knowledge on this topic by suggesting that inflammation makes a relatively minor contribution to the atherogenicity of remnant cholesterol. Whether remnant cholesterol has other properties that also contribute to its atherogenicity remains an area of active exploration. For instance, it was recently reported that remnant particles, but not LDL, are associated with peripheral arterial disease, suggesting that specific apoB-containing species may have discrete effects on atherosclerosis in different vascular beds.5 What are the clinical implications of these findings? One is that targeting remnant cholesterol may not reduce inflammation-related cardiovascular risk, suggesting that therapeutic approaches that aim to reduce both apoB and systemic inflammation may be needed to optimally treat our patients. For example, agents that target apoCIII or ANGPTL3 significantly reduce remnant cholesterol, but do not lower the levels of hsCRP,6,7 suggesting that targeted anti-inflammatory therapies may also be required in these patients. Limitations of this analysis need to be considered. First and foremost, remnant cholesterol was calculated, not measured, based on the levels of total cholesterol, HDL cholesterol, and LDL cholesterol, the latter also a calculated value in this cohort. This calculation provides a value that is directly proportional to the triglyceride concentration. Indeed, the authors show that the correlation coefficient between triglycerides and remnant cholesterol was 0.99. Although the analyses were not adjusted for the triglyceride concentration, it seems likely that most of the association between remnant cholesterol and hsCRP or MACE would be largely explained by triglyceride levels. In addition, although hsCRP is a sensitive marker of systemic inflammation, it is possible that other biomarkers of vascular inflammation, such as the perivascular fat attenuation index,8 could provide additional information regarding the role of inflammation as a mediator of remnant cholesterol’s effect on atherosclerotic plaque. Finally, with this type of observational study, residual confounding is always a possibility. In summary, these data expand our understanding of the complex role of remnant cholesterol in atherosclerosis and suggest that inflammation is a significant but quantitatively minor pathway by which it leads to the increased risk of atherosclerotic events. L.R.B. is supported by a Canada Research Chair in Precision Cardiovascular Disease Prevention.

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