Remnant cholesterol: a causal factor in coronary disease

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1 January 2013

There is extensive mechanistic evidence that remnant cholesterol carried in triglyceride-rich lipoproteins is atherogenic. Added to this, the current study shows that remnant cholesterol is causal in ischemic heart disease (IHD). Each 1 mmol/L (39 mg/dl) increase in genetic levels of non-fasting remnant cholesterol was associated with a 2.8-fold increase in causal risk for IHD, independent of high-density lipoprotein cholesterol (HDL-C).

Varbo A, Benn M, Tybjærg-Hansen A et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36

STUDY SUMMARY

Objective

To evaluate whether elevated non-fasting remnant cholesterol, defined as non-fasting total cholesterol – (HDL-C + low-density lipoprotein cholesterol [LDL-C]) is a causal risk factor for IHD, independent of low HDL-C.

Study design

Mendelian randomization design based on observational and genetic data from the Copenhagen General Population Study (CGPS), Copenhagen City Heart Study (CCHS) and the Copenhagen Ischemic Heart Disease Study (CIHDS). Fifteen genetic variants affecting remnant cholesterol alone, remnant cholesterol/HDL-C, LDL-C, or HDL-C were selected.

Study population

In total, 73,513 subjects were genotyped, of whom 11,984 had IHD diagnosed between 1976 and 2010. Characteristics of subjects in each study are summarized.

Variable	CGPS	CCHS	CIHDS
Total N	47,351	10,609	15,553
% female	61%	55%	29%
Median age, yr	55	59	63
% IHD	10%	21%	33%
Lipids (mmol/L)*
Triglycerides	1.4 (1.0–2.1)	1.5 (1.1–2.2)	1.6 (1.1–2.3)
Remnant cholesterol	0.6 (0.4–0.9)	0.7 (0.5–1.0)	0.7 (0.5–1.0)
HDL-C	1.6 (1.3–1.9)	1.5 (1.2–1.9)	1.4 (1.1–1.8)
LDL-C	3.2 (2.6–3.8)	3.7 (3.0–4.5)	3.2 (2.6–3.9)
* median (interquartile range)

Primary variable

Non-fasting remnant cholesterol, calculated as non-fasting total cholesterol – (HDL-C + LDL-C)
IHD, defined as World Health Organization International Classification of Diseases-8th Revision, codes 410-414 and International Classification of Diseases-10th Revision, codes I20-I25

Secondary variables

HDL-C, LDL-C and triglycerides

Methods

For combined control data, Cox proportional hazards regression models were used to estimate hazard ratios for IHD by lipoprotein quintile. Multivariate adjustment was performed for age, sex, smoking, hypertension, time since last meal, time of day for blood sampling, and lipid-lowering therapy. Correction for regression dilution bias was performed using lipoprotein values from 4,253 individuals without lipid-lowering therapy from the CCHS.

One-way analysis of variance was used to compare lipoprotein levels as a function of genotypes in the CGPS, CCHS, and CIHDS controls combined. The following genotypes were combined in 4 groups:

Variants that increased non-fasting remnant cholesterol (TRIB1 rs2954029, GCKR rs1260326, and APOA5 rs651821);
Variants that increased non-fasting remnant cholesterol/decreased HDL-C (LPLrs1801177, LPL G188E, LPL rs268, and LPL rs328)
Variants that decreased HDL-C (LIPC -480C>T, ABCA1, N1800H, and ABCA1 R2144X)
Variants that increased LDL-C (positive control).

Logistic regression was used to evaluate the association of genotypes with observed risk for IHD based on the combined data.

Main results

The key findings are summarized.

A 1 mmol/L (39 mg/dL) increase in genetic levels of remnant cholesterol was associated with:

Causal odds ratio (OR 95%CI) of 2.8 (1.9-4.2)
The observational hazards ratio (HR 95% CI) was 1.4 (1.3-1.5)

A 1 unit increase in the ratio of remnant cholesterol/HDL-C was associated with:

Causal OR of 2.9 (1.9-4.6)
The observational HR 1.2 (1.2-1.3)

A 1 mmol/L (39 mg/dL) decrease in genetic HDL-C levels was associated with:

Causal OR of 0.7 (0.4-1.4)
The observational HR was 1.6 (1.4-1.7)

Positive control:
A 1 mmol/L (39 mg/dL) increase in genetic levels of LDL-C was associated with:

Causal OR of 1.5 (1.3 to 1.6)
The observational HR was 1.1 (1.1 to 1.2

The association between remnant cholesterol and causal risk for IHD was independent of HDL-C

The higher causal odds ratio for remnant cholesterol suggests that lifelong exposure through genetically elevated levels has a larger effect on risk than that suggested from observational data alone

Author's conclusion

The elevated cholesterol content of triglyceride-rich lipoprotein particles causes IHD.
The focus of future intervention studies should be not only on lowering LDL-C levels but also on lowering levels of non-fasting remnant cholesterol and triglyceride-rich lipoproteins

COMMENT

Recent consensus1 has highlighted the importance of triglyceride-rich lipoproteins, typically manifest as elevated plasma triglycerides, often in association with low HDL-C, in atherosclerosis and cardiovascular disease. Failure to show outcome benefits associated with raising HDL-C in recent trials,2 implicates remnant cholesterol in triglyceride-rich lipoproteins rather than HDL-C, in causal risk.
The current study provides direct causal evidence of this association. Based on genotype analysis, each 1 mmol/L (39 mg/dL) genetic increase in remnant cholesterol was associated with a 2.8-fold causal risk for IHD, independent of reduced HDL C. These results support considerable mechanistic evidence that remnant lipoproteins are atherogenic; these lipoproteins are able to cross the endothelial barrier, and are taken up by scavenger receptors into the subendothelial space to promote foam cell formation.3‑5

The study is strengthened by a number of features, including the large number of subjects, lack of bias (due to the nature of the sample, all white subjects of Danish descent), and inclusion of a positive control (LDL-C). The use of a Mendelian randomisation design is another strength. This is a method for testing for a causal effect from observational data in the presence of confounding factors, corresponding to a ‘natural’ randomised trial. However, it is acknowledged6 that because pleiotropic effects of the genetic variants cannot be excluded, the findings need to be confirmed in further studies with additional genetic variants and/or randomized intervention trials.

The study findings are clearly consistent with the focus of the R3i on atherogenic dyslipidemia as an important contributor to cardiovascular risk beyond LDL-C. Moreover, this study adds to emerging consensus that it is elevated triglyceride-rich lipoproteins – rather than low HDL-C- that is the key contributor to this residual cardiovascular risk. The results of this study also lend support to the view7 that alternative lipid targets that better reflect the burden of triglyceride-rich lipoproteins in patients with atherogenic dyslipidemia– such as non-HDL‑C – may be preferable to LDL-C.

In line with the mission statement of the R3i, this paper highlights the need to focus therapeutic intervention beyond LDL-C reduction. With clear evidence of a causal association, targeting remnant cholesterol and triglyceride-rich lipoproteins is essential to reducing the burden of residual cardiovascular risk.

References

1. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61
2. Schwartz GG, Olsson AG, Abt M et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-99.
3. Shaikh M, Wootton R, Nordestgaard BG, et al. Quantitative studies of transfer in vivo of low density, Sf 12-60, and Sf 60-400 lipoproteins between plasma and arterial intima in humans. Arterioscler Thromb 1991;11:569 –77.
4. 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.
5. Nakajima K, Nakano T, Tanaka A. The oxidative modification hypothesis of atherosclerosis: the comparison of atherogenic effects on oxidized LDL and remnant lipoproteins in plasma. Clin Chim Acta 2006;367:36–47.
6. McPherson R. Remnant cholesterol “Non-(HDL-C LDL-C)” as a coronary artery disease risk factor. J Am Coll Cardiol 2013;61:437-9.
7. Rizzo M, Barylski M, Rizvi AA, Montalto G, Mikhailidis DP, Banach M. Combined dyslipidemia: should the focus be LDL cholesterol or atherogenic dyslipidemia? Curr Pharm Des. 2012 Dec 26. [Epub ahead of print]