LDL-triglycerides associated with increased CVD risk
Remnant-like particle cholesterol, low-density lipoprotein triglycerides, and incident cardiovascular disease
Literature - Saeed A, Feofanova EV, Yu B, et al. - JACC 2018; 156-69Introduction and methods
Hypertriglyceridemia is associated with elevated remnant-like particles cholesterol (RLP-C) and triglycerides in low-density lipoproteins (LDL-TG). Although recent studies have focused on the atherogenic effect of RLP-C [1-3], only few data on the association between LDL-TG and CVD risk are available.
This prospective study investigated both the associations of RLP-C and LDL-TG with CVD incidence, and between genetic variants and LDL-TG and RLP-C concentrations. For this purpose, data of 9,334 middle-aged individuals with established CVD from the ARIC (Atherosclerosis Risk in Communities) study were analyzed. Fasting plasma RLP-C and LDL-TG levels were measured and participants were followed for up to 16 years (median: 15.6 years for CVD and CHD and 15.8 years for ischemic stroke). Primary endpoints were coronary heart disease (CHD) and ischemic stroke. Associations between RLP-C, LDL-TG levels and genetic variants were studied in 5,767 European Americans and in 1,857 African Americans by whole-genome sequencing.
Main results
- RLP-C and LDL-TG levels were significantly associated with TG concentrations (r=0.85 and r=0.64 respectively, P<0.0001).
- A significant correlation between RLP-C and LDL-TG levels was found (r=0.5108, P<0.0001).
- RLP-C and LDL-TG were associated with incident CVD risk (HR:1.25, 95%CI: 1.19-1.32, P<0.001 and HR:1.94, 95%CI:1.73-2.17, P<0.001 respectively).
- After adjustment for traditional risk factors and Pooled Cohort Equation (PCE) risk factors, only LDL-TG showed significant associations with incidence of CHD (HR: 1.28, 95%CI: 1.10-1.50), ischemic stroke (HR: 1.47, 95%CI: 1.13-1.92) and CVD (HR: 1.35; 95%CI: 1.17-1.55, P< 0.001).
- LDL-TG showed the greatest improvement in the c-statistic as a measure of predictive value for future CVD risk beyond circulating TG and apolipoprotein B levels, and lead to a significant effect on net reclassification index and integrated discrimination improvement.
- A common genetic APOE variant, rs7412, which determines the APOE ε2 allele status, was strongly associated with LDL-TG and RLP-C (P<5x10-8).
- The APOE ε2/2 haplotype was significantly associated with reduced LDL-TG and increased RLP-C levels (P<0.0001 versus other haplotypes).
Conclusion
Elevated TG concentrations were associated with increased RLP-C and LDL-TG levels, but after adjustment for risk factors only LDL-TG predicted both CHD and ischemic stroke risk. Genetic APOE variants were associated with RLP-C and LDL-TG. Moreover, individuals with the APOE ε2/2 haplotype showed reduced LDL-TG levels. More research is needed to determine whether LDL-TG plays a causal role in CVD and if LDL-TG can act as target in new therapies.
Editorial comment
In the editorial comment, Michael Miller [4] first explains that RLP-C is incorporated by macrophages that gain entry into the arterial wall for foam cell generation. RLP-C thereby promotes atherosclerosis. Also, he explains the cause of elevated LDL-TG levels. Miller notes that the current study widens the atherogenic landscape with their finding of the independent associations of RLPs an LDL-TG and CVD. A limitation of the study is that the investigators were not able to fully adjust for factors that reduce lipase (LPL and/or HL) activity. Poor glycemic control in T2DM, thyroid disease, CKD and non-hypertensive medications were included that may have contributed to elevated LDL-TG levels. Next, he summarizes the most important findings of Saeed and Feofanova: RLP-C and LDL-TG are independently associated with CVD incidence, even after adjustment for traditional risk factors, and the APOE ε2/2 haplotype was significantly associated with elevated RLP-C and reduced LDL-TG levels. He notes that the clinical significance of the association between the APOE variant and higher RLPs and LDL-TG is unclear, as the association with CVD is limited.
The author concludes: ’’To advance LDL-TG as a potential target of therapy, it will be important to validate its role as an independent predictor of CVD in randomized controlled trials. To date however, the sole randomized controlled trial to report LDL-TG, AIM-HIGH, did not identify LDL-TG as a significant predictor of CVD events [5].’’ Fortunately, several ongoing randomized controlled trials [6] (NCT02104817, NCT03071692) may provide such an opportunity.
References
1. Varbo A, Nordestgaard BG. Remnant cholesterol and triglyceride-rich lipoproteins in atherosclerosis progression and cardiovascular disease. Artherioscl Thromb Vasc Biol 2016; 36:2133-5.
2. Varbo A, Benn M, Tybjaerg-Hansen A, Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427-36.
3. 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.
4. Miller M. Low-Density Lipoprotein Triglycerides: Widening the Atherogenic Landscape in CVD Risk Assessment. JACC 2018;72:170-2.
5. Albers JJ, Slee A, Fleg JL, O’Brien KD, Marcovina SM. Relationship of baseline HDL subclasses, small dense LDL and LDL triglyceride to cardiovascular events in the AIM-HIGH clinical trial. Atherosclerosis 2016;251: 531-533.
6. Bhatt DL, Steg PhG, Brinton EA, et al. Rationale and design of REDUCE‐IT: Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial. Clinical Cardiology 2017;40: 1-11.
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