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The role of low-density lipoprotein cholesterol (LDL-C) in the evolution of heart disease is fairly well established. In addition, the benefits of pharmacological treatment with agents that lower LDL-C in high-risk patients are well documented.
Lipoproteins are biochemical structures that enable the transport of lipids such as cholesterol in the circulation. LDL-C represents the amount or mass of cholesterol carried by low-density lipoprotein.
The interaction between circulating lipoproteins and the arterial wall is the first step in atherosclerosis and the development of heart disease. However, only some lipoproteins tend to interact with the arterial wall and trigger this bleak cascade of events (1). These lipoproteins are termed atherogenic. Low-density lipoprotein (LDL) is an atherogenic lipoprotein.
Today, there is ample evidence that the number of LDL particles (LDL-P) plays a much stronger role in the development of cardiovascular disease than the mass of cholesterol within these particles. This needs to be clarified because cholesterol mass does not always go hand in hand with the number of particles.
Furthermore, relying on LDL-C has several pitfalls (2). For example, LDL-C is a calculated variable that counts on measurements of total cholesterol, HDL-cholesterol, and triglycerides.
LDL-C does not accurately reflect the number of atherogenic LDL particles. This may explain why a large proportion of patients with cardiovascular disease do not have elevated levels of LDL-C.
Furthermore, clinical trials have shown that many patients who receive treatment with an LDL-C lowering drug and achieve a substantial reduction in LDL-C levels still develop clinical events (eg. heart attack or stroke)(3).
The LDL Particle
Lipoprotein particles are commonly classified according to their density, thus the terms high-density lipoprotein (HDL) and low-density lipoprotein (LDL).
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) (4,5,6,6).
LDL is called low-density lipoprotein because LDL particles tend to be less dense than other lipoprotein particles. Its main function is to deliver cholesterol to cells of the body.
Apolipoprotein B (apoB) is the primary lipoprotein in LDL (7). apoB-containing lipoproteins play a hugely important role in atherosclerosis and heart disease. All atherogenic lipoproteins contain one molecule of apoB.
A key step in the atherosclerotic process is the entrapment of apoB-containing lipoproteins within the arterial wall (8).
The Difference Between LDL-C and LDL-P
There is strong scientific evidence that LDL and other apoB-containing lipoproteins, including VLDL and their remnants, IDL, and LP(a), are directly implicated in the development of atherosclerotic cardiovascular disease (9).
Accordingly, a biochemical marker reflecting the amount of all these atherogenic lipoproteins would be of great clinical value when predicting the risk of heart disease.
However, despite its flaws, the assessment of the amount of cholesterol within LDL particles (LDL-C) is the most commonly used indicator of risk in the clinical world. Furthermore, LDL-C is also used to target therapy in primary as well as secondary prevention of cardiovascular disease.
Here, it is important to underline that LDL and LDL-C are not synonymous. In fact, the cholesterol content of LDL particles varies greatly. Hence, measurements of LDL particle number (LDL-P) maybe of importance (10).
Let’s take an example. Two patients with the same LDL-P may have very different LDL-C, depending on the amount of cholesterol within each LDL particle. However, their risk of developing heart disease may be similar.
Hence, LDL-C is a surrogate measure that only provides a very rough estimate of LDL particle concentration (LDL-P). Studies clearly indicate that the risk for atherosclerosis is more related to the number of LDL particles than the total amount of cholesterol within these particles (11).
It is also important to remember that LDL particles carry other lipid molecules than cholesterol. For example, triglycerides (TG) are also carried within LDL particles. Similar to total cholesterol and LDL-C, there is an association between serum TG and the risk of cardiovascular disease (12).
If the number of TG molecules in an LDL particle is high, there will be less space for cholesterol molecules. Therefore, if TGs are high, it may take many more LDL particles to carry a given amount of cholesterol. Therefore high LDL particle count may be associated with small, cholesterol-depleted, triglyceride-rich particles. Research has shown that high levels of triglycerides are associated with small LDL particle sizes (13).
So, what does all this mean? It means that one person (person A) may have large cholesterol rich LDL particles, while another (person B) may have smaller cholesterol-depleted particles. These two persons may have the same LDL-C concentration. However, person B will have a LDLP. Despite similar levels of LDL-C, person B is at higher risk four future cardiovascular events.
Many studies have suggested that the size of LDL particles may be of importance (14). People whose LDL particles are predominantly small and dense, have a threefold greater risk of coronary heart disease. Furthermore, the large and fluffy type of LDL may actually be protective.
However, keep in mind that the association between small LDL and heart disease reflects an increased number of LDL particles in patients with small LDL. Therefore, the LDL particle count could be more important in terms of risk than particle size in itself.
ApoB and LDL-P both reflect the number of atherogenic lipoprotein particles. However, measurements of ApoB will reflect the number of all atherogenic particles, whereas LDL-P only reflects the number of LDL particles.
Research shows that ApoB and LDL-P are better predictors of cardiovascular disease risk than LDL-C (15).
Discordance is when there is a difference between LDL-C and LDL-P. If LDL-C is high and LDL-P is low, there is discordance. If LDL-C is low and LDL-P is high, there is discordance. If both are low or both high, there is no discordance.
Studies have indicated that if there is discordance between LDL-C and LDL-P, cardiovascular disease risk tracks more closely with LDL-P than LDL-C (15). Specifically, when a patient with low LDL-C has a level of LDL-P that is not equally low, there is a higher “residual” risk. This may help explain the high number of cardiovascular events that occur in patients with normal or low levels of LDL-C.
The “Get With the Guidelines” study published in 2009 reported lipid levels in almost 137 thousand patients with an acute coronary event (16). Almost half of those had admission LDL levels <100 mg/dL (2.6 mmol/L) which may be considered fairly low. Hence, LDL-C did not seem to predict risk in these patients. However, low HDL-C and elevated TG was common among these patients. Low HDL-C and high TG levels are generally associated with higher LDL-P (16).
Among discordant patients in the Framingham Offspring Study the group with the highest risk for future cardiovascular events had high LDL-P and low LDL-C, while the group with the lowest risk had low LDL-P but higher LDL-C (17).
Many patients with metabolic syndrome or type-2 diabetes have discordance where LDL-P is elevated but LDL-C may be close to normal. In these individuals, measurements of LDL-C may underestimate cardiovascular risk. Measurements of ApoB or LDL-P are much more likely to predict risk in these individuals.
Discordance may be an important clinical phenomenon. Sometimes the question of medical therapy in primary prevention arises when there is an intermediate risk, based on LDL-C. In these cases, a low LDL-P level might help to confirm that the risk is indeed low, which might justify avoiding statin therapy.
Statins tend to lower LDL-C more than LDL-P. Many individuals who reach the target for LDL-C with statins, may still have raised LDL-P. This may indicate a higher residual risk despite what is generally defined as adequate treatment.
The article was initially published in 2012
It was revised, updated and republished on August 24, 2022.