Association of Apolipoprotein B–Containing Lipoproteins and Risk of Myocardial Infarction in Individuals With and Without Atherosclerosis

Abstract

IMPORTANCE Lipid management typically focuses on levels of low-density lipoprotein cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). However, animal models and genetic studies suggest that the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) are both important and that the number of particles is more predictive of cardiac events than their lipid content. OBJECTIVE To determine whether common measures of cholesterol concentration, TG concentration, or their ratio are associated with cardiovascular risk beyond the number of apolipoprotein B (apoB)-containing lipoproteins. DESIGN, SETTING, AND PARTICIPANTSThis prospective cohort analysis included individuals from the population-based UK Biobank and from 2 large international clinical trials, FOURIER and IMPROVE-IT. The median (IQR) follow-up was 11.1 (10.4-11.8) years in UK Biobank and 2.5 (2.0-4.7) years in the clinical trials. Two populations were studied in this analysis: 389 529 individuals in the primary prevention group who were not taking lipid-lowering therapy and 40 430 patients with established atherosclerosis who were receiving statin treatment.EXPOSURES ApoB, non-high-density lipoprotein cholesterol (HDL-C), LDL-C, and TG. MAIN OUTCOME AND MEASURES The primary study outcome was incident myocardial infarction (MI).RESULTS Of the 389 529 individuals in the primary prevention group, 224 097 (58%) were female, and the median (IQR) age was 56.0 (49.5-62.5) years. Of the 40 430 patients with established atherosclerosis, 9647 (24%) were female, and the median (IQR) age was 63 (56.2-69.0) years. In the primary prevention cohort, apoB, non-HDL-C, and TG each individually were associated with incident MI. However, when assessed together, only apoB was associated (adjusted hazard ratio [aHR] per 1 SD, 1.27; 95% CI, 1.15-1.40; P < .001). Similarly, only apoB was associated with MI in the secondary prevention cohort. Adjusting for apoB, there was no association between the ratio of TG to LDL-C (a surrogate for the ratio of TG-rich lipoproteins to LDL) and risk of MI, implying that for a given concentration of apoB-containing lipoproteins, the relative proportions of particle subpopulations may no longer be a predictor of risk. CONCLUSIONS AND RELEVANCEIn this cohort study, risk of MI was best captured by the number of apoB-containing lipoproteins, independent from lipid content (cholesterol or TG) or type of lipoprotein (LDL or TG-rich). This suggests that apoB may be the primary driver of atherosclerosis and that lowering the concentration of all apoB-containing lipoproteins should be the focus of therapeutic strategies.

Elucidating the genetic architecture of DNA methylation to identify promising molecular mechanisms of disease

“…The atherogenic potential of apolipoprotein B-100 has been demonstrated by many studies including MR analysis. [24][25][26][27] Our data are consistent with the notion that DNA methylation contributes to the atherogenicity of LDL and suggest that future studies are needed to examine the exact molecular underpinnings of these observations. Also, in line with these observations, our MR analysis showed that many CVD risk factor-associated CpGs are putatively causal for CVD and CVD risk factors (Supplemental Table 8).…”

Effect of Vupanorsen on Non–High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70

“…These observations have important implications for the potential ability of this mechanism to reduce lipidmediated cardiovascular risk, which largely appears to be a function of the number of ApoB-containing lipoproteins. 4 With regard to safety, there were no confirmed instances of reduced renal function or platelet count with vupanorsen, 2 issues that have been observed with some first-generation antisense oligonucleotides. 16,17 Injection site reactions were more common at higher total monthly doses, as were recall injection site reactions, which have not previously been seen with vupanorsen, but have been reported with mipomersen, an antisense oligonucleotide targeting ApoB.…”

“…These observations have important implications for the potential ability of this mechanism to reduce lipid-mediated cardiovascular risk, which largely appears to be a function of the number of ApoB-containing lipoproteins. 4…”

“…[1][2][3] Evidence suggests that lipid-mediated cardiovascular risk comes from atherogenic Apolipoprotein B (ApoB)-containing lipoproteins, including both cholesterol-rich low-density lipoproteins and triglyceride-rich very-low-density lipoproteins. 4,5 Angiopoietin-like protein 3 (ANGPTL3) inhibits lipases, including lipoprotein lipase, and impairs metabolism of triglyceride-rich lipoproteins. 6 Lower levels of triglycerides and LDL-C have been observed with loss-of-function mutations in the ANGPTL3 gene.…”

Cascade testing for elevated lipoprotein(a) in relatives of probands with high lipoprotein(a)

“…This underscores the importance of lifestyle modification and LLT for mitigating modifiable cardiovascular risk in those who screen positive for Lp(a) [20] . We showed that among 30% of affected relatives initiated on LLT, there were clinically meaningful reductions in plasma concentrations of LDL-cholesterol and apoB-containing lipoproteins [21] . Beyond a higher Lp(a) concentration, those who started LLT were more likely to have FCHL, CH and a higher estimated absolute risk of ASCVD.…”