The lipid hypothesis, suggesting a causative role for cholesterol in atherosclerotic heart disease is by many considered one of the best proven hypotheses in modern medicine. Measurements of total cholesterol, and the amount of cholesterol bound to different lipoproteins, are commonly used to assess the risk of future cardiovascular events. However, recent research into the role of lipoproteins in atherosclerosis, the role of oxidation and inflammation, has indicated that cholesterol in itself does not cause atherosclerosis. It is only when cholesterol bound to atherogenic lipoproteins becomes trapped within the arterial wall, that it becomes a part of the atherosclerotic process. Certainly, atherosclerosis as we know it will not occur in the absence of cholesterol. Thus, cholesterol is definitively involved, and necessary for atherosclerosis to occur, but so are many other important organic molecules that play a role in health and disease. The necessity of cholesterol does not prove its causative role. So, in order to understand the pathophysiology of atherosclerosis and the role of lipoproteins and inflammation, we may have to loosen our grip on cholesterol, at least for the time being.
Lipoproteins and atherosclerosis
The insolubility of lipids in water poses a problem because lipids must be transported through aqueous compartments within the cell as well as in the blood and tissue spaces. Lipoproteins are biochemical structures that enable transport of lipids throughout the body. A lipoprotein includes a core, consisting of a droplet of triglycerides and/or cholesterlyl esters, a surface layer of phospholipid, unesterified cholesterol and specific proteins (apolipoproteins). Lipoprotein particles are commonly classified according to their density, thus the terms high density lipoprotein (HDL) and low density lipoprotein (LDL). Apolipoprotein B (apoB) is the primary lipoprotein in LDL. ApoB containing lipoproteins play a hugely important role in atherosclerosis. In atherosclerosis aplipoprotein containing lipoproteins become trapped within the arterial wall, even when blood levels of cholesterol are normal.
Atherosclerosis is a complex process. Initially, LDL and other apoB containing lipoproteins enter the arterial wall. Why this happens and why lipoproteins are retained in the wall of the artery is still not completely clear. Chemical substances called proteoglycans play an important role for the retention of apoB containing lipoproteins within the arterial wall. This chemical intrusion then appears to initiate a maladaptive and chronic inflammatory response leading to the formation of an atherosclerotic plaque. Such plaques may cause narrowing of important vessels such as the coronary arteries. A rupture of such a plaque with subsequent thrombosis may lead to an acute occlusion of a coronary artery causing an acute myocardial infarction.
The difference between LDL-C and LDL-P
In the clinical world, an important question is how we can use laboratory measurements to assess individual risk. Calculated, or less frequently measured low density lipoprotein cholesterol (LDL-C ) is the most commonly used marker to assess risk. LDL-C is also used to target therapy in primary as well as secondary prevention of cardiovascular disease. This is partly due to the fact that most of the cholesterol in the blood is carried in LDL´s. Moreover, there appears to be a strong and graded association between LDL-C and the risk for cardiovascular disease. However, LDL-levels may not be correctly assessed by the measurements of cholesterol carried within these particles.
Let me explain this a little bit further. LDL-C is a measurement of the cholesterol mass within LDL-particles. Due to the fact that LDL-C has been traditionally used for so many years to reflect the amount of LDL, LDL-C and LDL have become almost synonymous. This may be quite misleading, because the cholesterol content of LDL particles varies greatly. Thus, LDL-C is a surrogate measure that only provides an estimate of LDL levels. Studies indicate that the risk for atherosclerosis is more related to the number of LDL particles (LDL-P) than the total amount of cholesterol within these particles.
It is also important to remember that LDL particles carry other 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. TG molecules are larger than cholesterol ester molecules. If the number of TG molecules in an LDL-particle is high, there will be less space for cholesterol molecules. Therefore, if triglycerides 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 size.
Now, 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 higher LDL particle number (LDL-P). Despite similar levels of LDL-C, person B is at higher risk four future cardiovascular events. Furthermore, person B will have more small LDL-particles.
Some studies have suggested that the size of LDL-particles may be of importance. 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, it is possible 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. Measurements of ApoB and LDL-P are better predictors of cardiovascular disease risk than LDL-C. Furthermore, ApoB and LDL-P may predict residual risk among individuals who have had their LDL-C levels lowered by statin therapy.
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. Specifically, when a patient with low LDL-C has a level of LDL-P that is not equally low, there is 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.
An analysis of “Get With the Guidelines” data published in 2009 studied almost 137 thousand patients with an acute coronary event. Almost half of those had admission LDL levels <100 mg/dL (2.6 mmol/L). Thus, LDL-C does not seem to be predicting risk in these patients. However, low HDL-C and elevated TG was common among these patients. Low HDL-C and high TG is generally associated with higher LDL-P.
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.
Many patients with the metabolic syndrome or type-2 diabetes have the type of 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 may therefore be helpful in these individuals.
Discordance may be an important clinical phenomenon. Sometimes the question of medical therapy in primary prevention arises when there is 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 residual risk despite what is generally defined as adequate treatment.
Effect of therapies
In general, most methods that lower LDL-C have some ability to lower LDL-P. However, there are some differences. Much has been written about how to lower LDL-C. Most doctors will recommend eating less fat and cholesterol from meat and dairy products. Statin therapy significantly lowers LDL-C. Therapies may affect LDL-P differently. Interventions that will lower LDL-C more than LDL-P include statins, estrogen replacement therapy, some antiretrovirals, and a low-fat, high-carbohydrate diet. Interventions that lower LDL-P more than LDL-C include fibrates, niacin, pioglitazone, omega-3 fatty acids, exercise and Mediterranean and low carbohydrate diets. Although statins lower LDL-P, they may leave a significant number of patients above the LDL-P target.
Patients with high levels of triglycerides and low HDL-C are likely to have high LDL-P despite normal or low LDL-C. Such a lipid profile is typical for individuals with the metabolic syndrome. Studies indicate that these patients may benefit most from low carbohydrate diets and that carbohydrate restriction reduces LDL-P.
LDL-P is not generally used in Europe to assess cardiovascular risk. So far, these measurements have primarily been performed in the United States. Clinical guidelines in Europe still recommend measurements of LDL-C to assess risk. Furthermore, LDL-C is still recommended to assess the effect of statin therapy. However, due to the fact that LDL-C is only a surrogate marker of the availability of atherogenic lipoproteins, its use may be of limited value. Measurements of LDL-P and ApoB are better predictors of cardiovascular risk and provide a better reflection of the atherogenic potential of lipoproteins.