Register now to R3i !
Your Login
Your Password
Confirm Password  
Your Email
I agree to receive
the R3i newsletter

FOCUS ON...

6 November 2018
More evidence linking remnants with cardiovascular disease

Findings from the ARIC (Atherosclerosis Risk in Communities) study show that both remnant lipoprotein cholesterol (RLP-C) and low-density lipoprotein triglycerides (LDL-TG) levels were predictive of cardiovascular disease and associated with APOE variants.

Saeed A, Feofanova EV, Yu B et al. Remnant-like particle cholesterol, low-density lipoprotein triglycerides, and incident cardiovascular disease. J Am Coll Cardiol 2018;72:156–69.
Summary
Comments & References
STUDY SUMMARY
Objective: To investigate associations of RLP-C and LDL-TG with incident cardiovascular disease (CVD) events and genetic variants in the ARIC (Atherosclerosis Risk In Communities) study
Study design: ARIC is a prospective observational study of middle-aged adults in the USA.
Study population: 9,334 men and women without prevalent CVD at baseline.
Efficacy variables:

·       Incident CVD events, a composite endpoint of coronary heart disease (CHD) events and ischaemic stroke over a 16-year follow-up period.

·       RLP-C and LDL-TG levels

Methods:

LDL-TG and RLP-C were modelled as continuous and categorical variables. Associations with CVD outcomes were determined using Cox proportional hazards modeling, after adjusting for age, sex, and race (Model 1), plus total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, antihypertensive medication use, current smoking, and diabetic status (Model 2), and Model 2 plus log triglycerides (Model 3). Kaplan-Meier survival curves were calculated for CVD outcomes across RLP-C and LDL-TG quartiles. For RLP-C these were defined as 0.4–3.1 (quartile 1), 3.2–5.9 (quartile 2), 6.0–12.2 (quartile 3) and 12.3–259.1 (quartile 4) mg/dL, and for LDL-TG these were defined as 0.7–17.0 (quartile 1), 17.1–22.6 (quartile 2), 22.7–29.6 (quartile 3) and 29.7–104.0 (quartile 4) mg/dL.

Associations between LDL-TG and RLP-C levels and genetic variants in LPL, LIPC, LIPG, APOC3, APOA5, ANGPTL3, ANGPTL4 and APOE were investigated by whole-exome sequencing using single-variant analysis for common variants and gene-based burden tests for rare variants.

Main results:

Both RLP-C and LDL-TG were associated with CVD risk; however, in models adjusted for traditional risk factors including lipids, only LDL-TG was associated with incident CHD and stroke (Table 1).

In genetic analyses, a common APOE variant, rs7412, had the strongest association with LDL-TG and RLP-C.

 

Table 1. Association of RLP-C and LDL-TG with CVD outcomes (modelled as continuous variables)

Outcome

Model

Hazard ratio (95% confidence interval)

p-value

RLP-C

 

 

 

CHD

Model 1

1.26 (1.19–1.34)

<0.001

 

Model 2

0.99 (0.92–1.06)

0.73

 

Model 3

0.85 (0.76–0.96)

0.008

Ischaemic stroke

Model 1

1.18 (1.07–1.30)

0.001

 

Model 2

1.05 (0.93–1.18)

0.46

 

Model 3

0.82 (0.68–1.01)

0.058

CVD

Model 1

1.25 (1.19–1.32)

<0.001

 

Model 2

1.00 (0.94–1.06)

0.97

 

Model 3

0.84 (0.76–0.93)

0.001

LDL-TG

 

 

 

CHD

Model 1

1.97 (1.73–2.24)

<0.001

 

Model 2

1.28 (1.10–1.50)

0.002

 

Model 3

1.27 (1.07–1.50)

0.006

Ischaemic stroke

Model 1

1.64 (1.32–2.04)

<0.001

 

Model 2

1.47 (1.13–1.92)

0.005

 

Model 3

1.36 (1.01–1.82)

0.040

CVD

Model 1

1.94 (1.73–2.17

<0.001

 

Model 2

1.35 (1.17–1.55)

<0.001

 

Model 3

1.31 (1.13–1.53)

<0.001

Authors’ conclusion: RLP-C and LDL-TG levels were predictive of CVD and associated with APOE variants. LDL-TG may represent a marker of dysfunctional remnant lipoprotein metabolism associated with increased CVD risk. Further research is needed to determine whether LDL-TG plays a causal role in CVD and may be a target for therapy.

COMMENT

The association of TG with cardiovascular risk has long been recognized.1,2 TG are, however, merely surrogates for TG-rich lipoproteins and their remnants.3,4 and there is now strong evidence, largely provided by genetic studies, that these intermediate and residual particles of TG metabolism, notably remnant lipoproteins are associated with cardiovascular risk.5-7 Yet, elevated TG may also result in TG-enrichment of LDL, as a result of cholesteryl ester transfer protein–mediated transfer of TG from chylomicrons and very low-density lipoprotein (VLDL) to LDL, in exchange for cholesteryl esters from LDL. Whether elevated numbers of TG-enriched LDLs are also associated with increased cardiovascular risk has not previously been considered.

The results of this analysis from the ARIC study suggest that this is the case, showing an association between LDL-TG levels and cardiovascular risk Moreover, the study data indicate differences in the association of RLP-C or LDL-TG with risk for future cardiovascular events. While both lipoprotein measures were associated with incident cardiovascular events, this association only remained for LDL-TG after adjustment for traditional risk factors including lipids. On the basis of these findings, the authors suggest that inclusion of LDL-TG may have merit for risk assessment in a primary prevention setting, providing additional information beyond traditional risk factors and lipid levels. The findings also provide a rationale for considering LDL-TG as potential therapeutic target for intervention, either with the use of treatments that increase LDL receptor–mediated clearance (e.g., statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors), or those that increase clearance of TG-rich lipoproteins by inhibition of apolipoprotein C-III, inactivation of ANGPTL3, or activation of lipoprotein lipase. However, corroboration of the association of LDL-TG with incident cardiovascular events in other studies is still needed.

References

1. Sarwar N, Danesh J, Eiriksdottir G et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 2007;115:450–8.

2. Austin MA, McKnight B, Edwards KL et al. Cardiovascular disease mortality in familial forms of hypertriglyceridemia: a 20-year prospective study. Circulation 2000;101:2777–82.

3. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease. New insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.

4. Varbo A, Benn M, Nordestgaard BG. Remnant cholesterol as a cause of ischemic heart disease: evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment. Pharmacol Ther 2014;141:358-67.

5. Varbo A, Nordestgaard BG. Remnant cholesterol and triglyceride-rich lipoproteins in atherosclerosis progression and cardiovascular disease. Arterioscler Thromb Vasc Biol 2016;36:2133–5.

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

7. Joshi PH, Khokhar AA, Massaro JM, et al. Remnant lipoprotein cholesterol and incident coronary heart disease: the Jackson Heart and Framingham Offspring Cohort Studies. J Am Heart Assoc 2016;5:e002765.

Key words remnant lipoprotein cholesterol; triglycerides; cardiovascular disease; ARIC study