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A recently published scientific paper shows that measuring cholesterol levels in the blood may not be an optimal tool to predict the risk of cardiovascular events (1). The study is especially important because our confidence in cholesterol, LDL-cholesterol (LDL-C) in particular, has been pretty consistent for a very long time.
The paper, published by Marston and coworkers, underlines the importance of lipoproteins containing apolipoprotein B (apoB) and their key role in the development of atherosclerotic heart disease. The study shows that the risk of myocardial infarction (heart attack) is best captured by the number of apoB-containing particles, independent of their cholesterol or triglyceride content.
Surely, we have known for decades that there is an association between circulating levels of cholesterol and cardiovascular risk. Numerous studies have shown a strong correlation between LDL-C and the risk of coronary heart disease (2,3,4,5). Moreover, cholesterol-lowering drugs have been shown to improve cardiovascular health (6).
So, we have come to believe that we should always aim at lowering LDL-C, whether it be by dietary measures or by drug treatment (7). Our progress, or lack thereof, could then be simply tested by checking the cholesterol numbers.
However, as I have pointed out in several blog posts over the years, relying on LDL-C to predict cardiovascular risk has many pitfalls (7,8,9).
Unfortunately, the deep-rooted and oversimplified cholesterol model of heart disease often leads us off-target and frequently promotes erroneous conclusions. Therefore, the study by Marston and coworkers is of huge importance.
Apolipoprotein B and Cholesterol – The Carrier and the Cargo
Cholesterol is an essential substance for the human body. Our liver constantly generates cholesterol. It is believed that only about 20 percent of the cholesterol in our bloodstream comes from the food we eat, the rest is produced by the liver. (10).
To be able to get to cells and organs, cholesterol has to be transported in the circulation. However, since cholesterol is a fat, it can’t travel in the bloodstream by itself,
The body solves the problem by packaging cholesterol together with proteins (apolipoproteins) that function as carriers, transporting important cholesterol molecules to the cells of the body. These combinations of fats and protein are termed lipoproteins.
The apolipoproteins are the carriers whereas the cholesterol is the cargo.
Different lipoproteins contain different types of apolipoproteins. The type of apolipoprotein present determines the structure and function of the lipoprotein.
There are several classes of apolipoproteins and many subclasses (11).
The amount (mass) of cholesterol in each lipoprotein particle is variable. For example, some LDL particles carry small amounts of cholesterol whereas other particles carry large amounts. Hence, the difference between small and large particles.
Atherogenic Lipoprotein Particles
There are six major types of lipoproteins; chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and Lipoprotein (a).
Evidence shows that lipoproteins play a fundamental role in atherosclerosis.
Some lipoproteins tend to interact with the arterial wall and initiate the cascade of events that leads to atherosclerosis which may progress to atherosclerotic cardiovascular disease (8). These lipoproteins are termed atherogenic.
The presence of apoB determines whether an apolipoprotein is atherogenic or not. Atherosclerosis is only promoted by aboB containing lipoprotein particles.
Trapping of apoB-containing lipoprotein particles within the arterial is a primary cause of atherosclerosis.
The mass of cholesterol within the lipoprotein particle does not influence whether it gets trapped within the arterial wall or not. Thus, the lipoprotein’s atherogenicity is determined by the surface protein, not the cholesterol.
Atherogenic lipoproteins such as LDL, VLDL, and Lp(a), all contain one ApoB100 molecule per particle.
Thus, all atherogenic lipoprotein particles contain one ApoB molecule each. Ergo, we can count the number of atherogenic particles by counting the number of ApoB molecules.
LDL-C, Non-HDL-C or ApoB
A standard serum lipid profile measures the concentration of total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. The LDL-C concentration is usually estimated from these numbers by using the Friedewald equation.
Over the years, LDL cholesterol (LDL-C) has been the most commonly used lipid variable to predict cardiovascular risk (12). However, recent evidence suggests that non-HDL cholesterol (non-HDL-C) may be a better tool for risk assessment (13,14).
Non-HDL-C is calculated by subtracting HDL-C from the total cholesterol. Hence it provides a measure of the amount of cholesterol carried by all lipoproteins except HDL.
Non-HDL-C will give us the amount of cholesterol carried within all atherogenic lipoproteins. In other words, a measure of cholesterol carried by all the “bad” lipoproteins but not the “good” ones (which is only HDL).
Importantly, LDL-C and non-HDL-C do not tell us anything about the number of atherogenic particles. They only provide information about the mass of cholesterol carried by the different types of lipoproteins.
Due to the fact that the mass of cholesterol per particle is variable, LDL-C and non-HDL-C can differ significantly from apoB.
In their recent study, Marston and coworkers provide evidence from a large prospective observational study (the UK biobank) and two large clinical trials (FOURIER and IMPROVE-IT) that cardiovascular risk is best predicted by measurements of apoB.
The study also shows that LDL-C and non-HDL-C are nonsignificant markers of risk when apoB is taken into account.
When cholesterol-depleted particles are present, LDL-C and non-HDL-C will underestimate risk. Conversely, when cholesterol-rich particles are present, LDL-C and non-HDL-C will overestimate risk.
So, it appears that LDL-C and non-HDL-C are unreliable surrogate markers of the number of atherogenic lipoprotein particles. ApoB on the other hand provides a reliable measure of particle number and is currently the best available lipid marker to predict cardiovascular risk.
Interestingly, apoB can be measured inexpensively, and more accurately than LDL-C or non-HDL-C by currently available methods (15).
Why not end the dispute? From now on, measurements of apoB should be used when deciding whom to target and how aggressively to treat people at risk and patients who already have established cardiovascular disease.