Apolipoprotein B Particles and Cardiovascular Disease

Abstract

The conventional model of atherosclerosis presumes that the mass of cholesterol within very low-density lipoprotein particles, low-density lipoprotein particles, chylomicron, and lipoprotein (a) particles in plasma is the principal determinant of the mass of cholesterol that will be deposited within the arterial wall and will drive atherogenesis. However, each of these particles contains one molecule of apolipoprotein B (apoB) and there is now substantial evidence that apoB more accurately measures the atherogenic risk owing to the apoB lipoproteins than does low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol.OBSERVATIONS Cholesterol can only enter the arterial wall within apoB particles. However, the mass of cholesterol per apoB particle is variable. Therefore, the mass of cholesterol that will be deposited within the arterial wall is determined by the number of apoB particles that are trapped within the arterial wall. The number of apoB particles that enter the arterial wall is determined primarily by the number of apoB particles within the arterial lumen. However, once within the arterial wall, smaller cholesterol-depleted apoB particles have a greater tendency to be trapped than larger cholesterol-enriched apoB particles because they bind more avidly to the glycosaminoglycans within the subintimal space of the arterial wall. Thus, a cholesterol-enriched particle would deposit more cholesterol than a cholesterol-depleted apoB particle whereas more, smaller apoB particles that enter the arterial wall will be trapped than larger apoB particles. The net result is, with the exceptions of the abnormal chylomicron remnants in type III hyperlipoproteinemia and lipoprotein (a), all apoB particles are equally atherogenic.CONCLUSIONS AND RELEVANCE Apolipoprotein B unifies, amplifies, and simplifies the information from the conventional lipid markers as to the atherogenic risk attributable to the apoB lipoproteins.

High-throughput multivariable Mendelian randomization analysis prioritizes apolipoprotein B as key lipid risk factor for coronary artery disease

“…Our results add to the growing evidence that ApoB is the primary causal determinant for CAD risk amongst lipoprotein measurements [17,18,19]. These results do not invalidate LDL-cholesterol as a causal risk factor for CAD risk.…”

Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis

“…Both LDL cholesterol and triglycerides are carried in atherogenic lipoproteins, each containing an apolipoprotein B molecule. Recent reviews [11,12,60,61] point to apolipoprotein B potentially being the necessary entity for atherosclerosis to occur, for example, through the 'response to retention' hypothesis, in which apolipoprotein-B-containing particles become trapped in the tunica intima of the arterial wall [62]. Our study builds on recent findings [26] to provide further empirical evidence that supports this hypothesis, but our findings do not discredit the causal roles that LDL cholesterol or triglycerides play in vascular disease.…”

“…For example, a naïve interpretation of our findings would be that apolipoprotein B confounds the relationship of LDL cholesterol and triglycerides with risk of CHD, but this would be to neglect evidence gleaned over a century of scientific investigations into atherosclerosis [71]. In our interpretation, these findings from the multivariable MR, together with established physiological principles of lipoprotein structure and composition, are consistent with apolipoprotein B being a critical component in the entrapment of atherogenic lipoprotein particles in the tunica intima in order to initiate and maintain lipid accumulation in the development of atherosclerosis [11,12,60]. Thus, our findings are in keeping with established understanding of the development of atherosclerosis [72] but pinpoint the crucial role of apolipoprotein B in the pathogenesis as a key molecule facilitating the entrapment of atherogenic lipoprotein particles in the intima.…”

“…Each circulating atherogenic lipoprotein particle includes one apolipoprotein B molecule, but the amount of cholesterol (especially in LDL particles) and the amount of triglycerides (especially in very low-density lipoprotein [VLDL] particles) can vary extensively between lipoprotein particles [10][11][12]. Thus, whilst the concentration of LDL cholesterol and triglycerides quantifies the concentration of these lipid substances carried in circulating lipoproteins, they do not precisely quantify the number of atherogenic lipoproteins; in contrast, the concentration of apolipoprotein B molecules is directly proportional to the number of circulating atherogenic particles in the blood [11,12]. Evidence from human genetics supports a causal role of LDL cholesterol, triglycerides, and apolipoprotein B in CHD [13][14][15][16].…”

Lower LDL is better – can this be achieved with CETP inhibition therapy?

“…This is made even more apparent in the fact that the results of the REVEAL trial fit well on the slope of the regression line of non-HDL-C levels (a proxy for apoB) reported in trials of statins, ezetimibe, and PCSK9 inhibitors and the corresponding risk of coronary heart disease (CHD) [18]. This effect is attributed to the fact that apoB plasma concentrations are indicative of the absolute number of LDL particles (one apoB molecule is present per LDL particle) that enter the arterial wall and, thereby, induce and promote ASCVD in proportion to their numbers [9,19].…”