National Lipid Association published part 1 of guidelines in April 2015. Please find below a key recommendation and rationale regarding ApoB, non-HDL and LDL as root cause of cardiovascular disease. Text has been slightly modified for easier and succinct reading.
An elevated level of cholesterol carried by circulating apo-B–containing lipoproteins (non–HDL-C and LDL-C, termed atherogenic cholesterol) is a root cause of atherosclerosis, the key underlying process contributing to most clinical ASCVD events.
HDL, LDL,IDL, VLDL, and Chylomicrons are the 5 major classes of lipoproteins. Of these, LDL is the predominant cholesterol-carrying lipoprotein comprising ~75% of cholesterol carried by non-HDL particles, with the remaining ~25% of non–HDL-C in triglyceride-rich particles, which include VLDL, IDL, Chylomicrons, and their remnants. Each LDL particle contains a single apo-B100 particle, whereas the major apos of VLDL are apo B100, A4, C(1, 2, and 3), and E. Chylomicron particles contain the same apos as VLDL, except that they also contain apo A (1, 2, and 4), and apo B48 is present instead of apo B100.
It should be noted that clinical laboratories typically report the LDL-C concentration as a calculated value using the Friedewald equation (LDL = total cholesterol – HDL – TGs/5) as long as the triglyceride level is <400 mg/dL. This calculated value includes cholesterol carried by true LDL particles, as well as IDL particles. Also, some particles, mostly in the LDL density range, are covalently bound to apolipoprotein (a). LDL-C estimated by the Friedwald equation also includes cholesterol carried by these lipoprotein (a) [Lp (a)] particles.
Non–HDL-C (calculated as Total-C – HDL-C) represents the sum of cholesterol carried by all potentially atherogenic, apo B-containing lipoprotein particles, including LDL, IDL, Lp (a), VLDL (including VLDL remnants), and chylomicron particles and remnants. The NCEP ATP III acknowledged the importance of non–HDL-C in atherogenesis in 2002, but, at that time, instructions to target non–HDL-C concentration pertained only to individuals with hypertriglyceridemia because it was understood that elevated levels of VLDL cholesterol (VLDL-C) and its remnants are more prevalent in those with hypertriglyceridemia.
However, a substantial body of evidence has since accumulated to support the view that non–HDL-C is more strongly related to risk for ASCVD than LDL-C and that this relationship is evident in those with and without hypertriglyceridemia. Atherosclerosis has been described as a lipid-driven inflammatory disorder of the arterial wall. Atherogenic lipoproteins (LDL and some smaller species of the triglyceride-rich lipoproteins) have the ability to infiltrate the arterial wall thereby initiating atherosclerosis. After entering the arterial wall, the particles bind to pro-retentive extracellular molecules, become trapped, and are modified through oxidation and other processes, which increase their inflammatory properties and their unregulated uptake by macrophages. As the macrophages become engorged with lipid, they form foam cells, and this process triggers a potentiation of the inflammatory response through release of compounds that increase recruitment of additional monocytes and macrophages. The accumulation of foam cells leads to the development of a fatty streak that initiates smooth muscle proliferation. The proliferation of smooth muscle cells creates a fibrous cap or plaque.
As the plaque matures and atherogenic particles continue to infiltrate, lipid-rich areas form within the fibrous plaque. Inflammation triggers processes that weaken the fibrous cap and make the plaque susceptible to rupture. Thus, atherogenic lipoproteins play important roles in the initiation of atherosclerosis, progression to a mature plaque and, eventually, plaque instability and rupture.
When plaque rupture occurs, subendothelial components are exposed to the blood, and luminal thrombosis occurs, which, if sufficiently large, can occlude arterial flow. Atherosclerotic plaque rupture is generally the proximal cause of acute coronary syndromes (eg, myocardial infarction, unstable angina). Epidemiologic studies have demonstrated a strong relationship between serum cholesterol levels and increased ASCVD risk, and, conversely, low rates of ASCVD are associated with low levels of cholesterol.
The importance of LDL-C in ASCVD is corroborated by the existence of familial hypercholesterolemia (FH), an autosomal codominant genetic disorder characterized by very high levels of LDL-C (and LDL particles) and early ASCVD. In patients with FH, the removal of apo B–containing lipoproteins by lipoprotein apheresis has been shown to markedly reduce arterial wall inflammation. Individuals with proprotein convertase subtilisin kexin type 9 (PCSK9) mutations and Niemann-Pick C1-like 1 protein (NPC1L1) polymorphisms, which result in reduced levels of LDL-C throughout life, are associated with markedly reduced risk for ASCVD events.
A causal relationship between triglyceride-rich lipoprotein cholesterol levels (sometimes referred to as ‘‘remnant cholesterol’’ [calculated as Total-Chol – HDL – LDL]) is supported by an association between elevated triglycerides and increased ASCVD risk, as well as by the high risk for ASCVD among individuals with atherogenic dyslipidemia (combination of elevated triglycerides and low HDL-C). Genetic mutations that result in increased circulating levels of triglycerides and triglyceride-rich lipoprotein cholesterol (eg, variants associated with lipoprotein lipase, apo C3, and apo A5) are associated with elevated ASCVD risk.
As discussed in more detail, RCTs of lipid-altering interventions that lower levels of LDL-C and/or triglyceride-rich lipoprotein cholesterol levels have demonstrated reduced ASCVD event risk, further supporting a causal role of apo B–containing lipoproteins in the atherothrombotic process. The relative importance of lowering atherogenic particle concentrations vs. the levels of cholesterol carried by atherogenic particles is incompletely understood. Non–HDL-C has been regularly shown to be a better predictor of ASCVD event risk than LDL-C, which may, at least in part, reflect the stronger relationship between the non–HDL-C concentration and circulating levels of atherogenic particles. Thus, the panel included both LDL-C and triglyceride-rich lipoprotein cholesterol (non–HDL-C is the sum of LDL-C and triglyceriderich lipoprotein cholesterol) as atherogenic cholesterol components.