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Macrovascular Residual Risk THROUGH LANDMARK STUDY

13 May 2014
Elevated remnant cholesterol is causally associated with inflammation

In this Mendelian randomisation study, elevated levels of both nonfasting remnant cholesterol and low-density lipoprotein (LDL) cholesterol were causally associated with ischaemic heart disease (IHD). However, only elevated nonfasting remnant cholesterol was causally associated with low-grade inflammation.

Varbo A, Benn M, Tybjerg-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;128:1298-1309.
Summary
Comments & References
STUDY SUMMARY
Objective: Remnant cholesterol is the cholesterol contained in triglyceride-rich lipoproteins (TRLs, i.e. LDLs and intermediate-density lipoproteins in the fasting state and these two lipoproteins together with chylomicron remnants in the nonfasting state). This study investigated whether both nonfasting remnant cholesterol and LDL cholesterol levels are causally associated with low-grade inflammation, as characterised by elevated levels of C-reactive protein (CRP), and with IHD.
Study design: Multidirectional Mendelian randomisation design
Study population:

60,608 white individuals of Danish descent (10,668 with IHD) from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease study.

Primary variable:

Causal associations between elevated nonfasting remnant cholesterol, LDL cholesterol and CRP

Methods:

Subjects were genotyped for genetic variants affecting levels of nonfasting remnant cholesterol and LDL cholesterol. In addition, to exclude reverse causation (i.e. that low-grade inflammation, as characterised by elevated CRP levels, may directly result in higher levels of remnant or LDL cholesterol, genetic variants known to increase CRP (i.e. both CRP alleles, and interleukin-6 receptor [IL6R] alleles) were also genotyped. Possible causal associations between nonfasting remnant cholesterol and LDL cholesterol and CRP, and between the lipoproteins and IHD were investigated using a Mendelian randomisation approach. Initially, relationships were evaluated observationally, i.e. subject to confounding and reverse causation, and then using genetic approaches which were not subject to either effects. The study also compared observational and causal associations of elevated nonfasting remnant cholesterol, LDL cholesterol, and CRP with risk of IHD.

Results:

Observational and causal associations between nonfasting remnant cholesterol, LDL cholesterol and CRP are summarised in Table 1. There was a causal association between elevated nonfasting remnant cholesterol and CRP, but not between LDL cholesterol and CRP. There was no evidence of reverse causation as higher levels of CRP did not associate causally with elevated nonfasting remnant cholesterol or LDL cholesterol.

Table 1. Observational and causal associations between lipoproteins and CRP (n= 48,250 subjects from the Copenhagen General Population Study)


Lipoprotein

­ in CRP per 1 mmol/L increase in lipoprotein, (95% CI)

Nonfasting remnant cholesterol

 

Observational data

37% (35–39)

Causal data – CRP alleles

28% (10–48)

 

 

LDL cholesterol

 

Observational data

7% (6-7)

Causal data

No association

Risk estimates for IHD for both observational and causal data for nonfasting remnant cholesterol and LDL cholesterol are summarised in Table 2. There was a causal association between nonfasting remnant cholesterol or LDL cholesterol and IHD; the magnitude of the association was 2-fold higher for remnant cholesterol. Causal associations for nonfasting remnant cholesterol were present even in subjects without diabetes mellitus or obesity.

Table 2. Risk for IHD per 1 mmol/L (39 mg/dL) increase in lipoprotein (combined data from all three Danish studies)


Lipoprotein

Risk estimate* or Odds ratio (95% CI) per 1 mmol/L increase in lipoprotein

Nonfasting remnant cholesterol

 

Observational data

1.3 (1.2–1.4).

Causal data

3.3 (2.1–5.2)

 

 

LDL cholesterol

 

Observational data

1.2 (1.1–1.2)

Causal data

1.8 (1.5–2.2)

* Risk estimate for causal data

Authors’ conclusion: Elevated nonfasting remnant cholesterol is causally associated with low-grade inflammation and with IHD, whereas elevated LDL cholesterol is associated causally with IHD without inflammation.

COMMENT

This study addresses a key question. Statins have been shown to reduce cardiovascular disease (CVD) in individuals with low-grade inflammation even when LDL cholesterol levels were relatively low, as in the JUPITER trial, suggesting a lipoprotein load-independent pleiotropic component of their beneficial effect.1 This might be explained by statins preventing CVD by direct anti-inflammatory effects (either systemic or at the level of the plaque), or alternatively, by lowering LDL cholesterol as well as triglycerides, which represent a marker of TRLs and consequently remnant cholesterol, thereby reducing inflammation.

Both remnant cholesterol and LDL cholesterol are known to be causally associated with IHD,2-4 and this is again confirmed by this study. However, the current study shows that only nonfasting remnant cholesterol is causally associated with low-grade inflammation. These findings are further supported by mechanistic studies.5,6 The lack of causal association between LDL cholesterol and inflammation is novel. However, it is worth noting that previous studies in subjects with familial hypercholesterolaemia, a genetic condition characterised by very high LDL cholesterol levels mostly due to defects in the LDL receptor, have shown either no difference or only slight increases in CRP compared with controls,7,8 which would lend support to the lack of causal association between LDL cholesterol and low-grade inflammation observed by Varbo et al. The study findings are strengthened by the large sample size in a homogeneous population (whites of Danish descent only) and the use of a multidirectional Mendelian randomisation design. These data therefore support the contention that elevated LDL cholesterol causes atherosclerosis without a major inflammatory component, whereas an inflammatory component of atherosclerosis is driven by elevated nonfasting remnant cholesterol.

From the clinical perspective, this study provides additional support for the relevance of a comprehensive LDL- and non-LDL-targeted approach to managing dyslipidaemia to prevent atherosclerosis and CVD. While targeting LDL cholesterol is clearly integral to CVD prevention strategies, patients still remain at high residual risk of CVD events. This high residual CV risk has already been identified by the Residual Risk Reduction Initiative (R3i).9 Given the causal association between remnant cholesterol and low-grade inflammation shown in this study, preventive strategies should also aim to reduce the inflammatory component of atherosclerosis. By implication, therapeutic targeting of TRLs and thus remnant cholesterol is one approach which offers the potential to impact this contributor to residual cardiovascular risk.

References

1. Ridker PM, Danielson E, Fonseca FA et al; JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009;373:1175–82.
2. Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R,Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36.
3. Jørgensen AB, Frikke-Schmidt R, West AS, Grande P, Nordestgaard BG, Tybjærg-Hansen A. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur Heart J 2013;34:1826–33.
4. Baigent C, Keech A, Kearney PM, Blackwell L, et al; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.
5. Twickler TB, Dallinga-Thie GM, Cohn JS, Chapman MJ. Elevated remnant-like particle cholesterol concentration: a characteristic feature of the atherogenic lipoprotein phenotype. Circulation 2004; 109: 1918-25.
6. Nordestgaard BG, Wootton R, Lewis B. Selective retention of VLDL, IDL, and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo: molecular size as a determinant of fractional loss from the intima inner media. Arterioscler Thromb Vasc Biol 1995;15:534–42.
7. Hovland A, Aagnes I, Brekke OL, Flage JH, Lappegård KT. No evidence of impaired endothelial function or altered inflammatory state in patients with familial hypercholesterolemia treated with statins. J Clin Lipidol 2010;4:288–92
8. Real JT, Martínez-Hervás S, García-García AB et al. Circulating mononuclear cells nuclear factor-kappa B activity, plasma xanthine oxidase, and low grade inflammatory markers in adult patients with familial hypercholesterolaemia. Eur J Clin Invest 2010;40:89–94.
9. Fruchart JC, Sacks FM, Hermans MP et al; Residual Risk Reduction Initiative (R3I). The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res 2008;5:319-35.

Key words

residual cardiovascular risk; inflammation; remnant cholesterol; Mendelian randomisation study