Physiological Bases for the Superiority of Apolipoprotein B Over Low‐Density Lipoprotein Cholesterol and Non–High‐Density Lipoprotein Cholesterol as a Marker of Cardiovascular Risk

Abstract

In 2019, the European Society of Cardiology/European Atherosclerosis Society stated that apolipoprotein B (apoB) was a more accurate marker of cardiovascular risk than low‐density lipoprotein cholesterol (LDL‐C) and non–high‐density lipoprotein cholesterol. Since then, the evidence has continued to mount in favor of apoB. This review explicates the physiological mechanisms responsible for the superiority of apoB as a marker of the cardiovascular risk attributable to the atherogenic apoB lipoprotein particles chylomicron remnants, very low‐density lipoprotein, and low‐density lipoprotein particles. First, the nature and relative numbers of these different apoB particles will be outlined. This will make clear why low‐density lipoprotein particles are almost always the major determinants of cardiovascular risk and why the concentrations of triglycerides and LDL‐C may obscure this relation. Next, the mechanisms that govern the number of very low‐density lipoprotein and low‐density lipoprotein particles will be outlined because, except for dysbetalipoproteinemia, the total number of apoB particles determines cardiovascular risk, Then, the mechanisms that govern the cholesterol mass within very low‐density lipoprotein and low‐density lipoprotein particles will be reviewed because these are responsible for the discordance between the mass of cholesterol within apoB particles, measured either as LDL‐C or non–high‐density lipoprotein cholesterol, and the number of apoB particles measured as apoB, which creates the superior predictive power of apoB over LDL‐C and non–high‐density lipoprotein cholesterol. Finally, the major apoB dyslipoproteinemias will be briefly outlined. Our objective is to provide a physiological framework for health care givers to understand why apoB is a more accurate marker of cardiovascular risk than LDL‐C or non–high‐density lipoprotein cholesterol.

Eradicating Atherosclerotic Events by Targeting Early Subclinical Disease: It Is Time to Retire the Therapeutic Paradigm of Too Much, Too Late

“…44,86 Post hoc analyses of PCSK9i trials have implicated residual circulating apoB-lipoproteins in residual ASCVD event risk, 90,91 as would be expected. 14,68,92 With the rise in overnutrition, obesity, the atherometabolic syndrome, and related conditions, C-TRLs (cholesterol-and triglyceriderich apoB-containing lipoproteins) have become increasingly significant contributors to residual apoB-lipoproteins in plasma during LDL-lowering therapies (Figure 1). 93,94 But similar to the results stratified by CRP concentrations, patients enrolled with end-stage arterial disease who then achieved apoB levels ≤35 mg/dL on PCSK9i still experienced a substantial ASCVD event rate that was over half of the event rate in patients who achieved apoB levels ≥50 mg/dL.…”

“…The approach should stop or minimize any future ASCVD events. Several issues would need to be resolved based on the prespecified imaging end points and on longer-term follow-up: which (if any) plaques will reliably regress or remodel during the induction phase, by how much, how long will the induction phase need to last, whether known factors that exacerbate atherosclerosis will interfere with plaque regression (such as hypertension, tobacco smoking, 147,148 diabetes, [149][150][151] elevated levels of lipoprotein[a], 92 or patient age), and how fast plaques might re-appear. Plaque re-appearance includes the possibility of a rebound suggested by some historic studies of intermittent hypercholesterolemia in animals 152,153 but never examined in the context of recent atherosclerosis regression to my knowledge.…”

“…Rule-out tests have become mainstays of successful, evidence-based management in other medical fields. 176 Using CTA as the current gold standard, discriminatory power can be tested for conventional risk factors for ASCVD events but now including plasma apoB and lipoprotein(a) levels, 92 newly refined polygenic risk scores, 177,178 iliofemoral and carotid ultrasonography for plaque, 104,110 brachial-to-ankle pulse-wave velocity, and a new assay of LDL quality—namely, its susceptibility to sphingomyelinase-induced aggregation ex vivo, that independently predicts future events. 65 Based on these non-CTA parameters, an optimal model can be constructed to discriminate the presence versus the absence of image-evident plaque.…”

Current and Emerging Therapies for Atherosclerotic Cardiovascular Disease Risk Reduction in Hypertriglyceridemia

“…First, HTG reflects elevated TRL concentrations in the circulation and TRL, as with other apoB-containing lipoproteins, are directly atherogenic. In fact, research indicates that nearly all apoB-containing lipoproteins (i.e., those that are small enough to cross the endothelium, with a ~70 nm diameter or less) are approximately equal in atherogenicity on a per particle basis [ 9 ]. Second, high plasma TG concentrations promote several characteristic alterations in the circulating lipoprotein profile that are associated with increased atherogenesis.…”

“…This process directly leads to the cholesterol depletion of LDL and high-density lipoprotein (HDL) particles, reducing their particle size and cholesterol content [ 10 ]. The resulting small-dense LDL particles are more atherogenic than may be expected from their cholesterol content alone, since there are many molecules of apoB for each unit of cholesterol [ 9 ]. Additionally, small cholesterol-depleted HDL particles are more rapidly cleared by the kidneys, further reducing HDL-C and resulting in fewer HDL particles.…”