The Difference Between LDL-C and LDL-P

21, Nov, 2012 by

The difference between LDL-C and LDL-PThe 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 magnitude 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

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.

 

 

11 Comments

  1. Very nice post. Thanks clarifying this pretty complicated subject. How convincing is the evidence in your opinion that LDL-P should be the primary parameter to follow? Does it add anything on top of ApoB?

  2. Ed Cooper

    I like your question Reijo. I hope we can get an answer. In my case I have discordance between APO-B and LDL-P. I’d sure like to know how that can happen. My APO-B is low-normal but LDL-P is “high risk” so nothing has been clarified for me as yet.

  3. Doc´s opinion

    Thanks Reijo. The problem with the LDL-P measurements using NMR spectroscopy is that it is still rather expensive. It has been suggested that looking at non-HDL cholesterol (total cholesterol minus HDL cholesterol), HDL-C and triglycerides may be helpful when LDL-P and ApoB are not available. This could be important in patients with the metabolic syndrome, where LDL-C may underestimate risk. Non-HDL cholesterol reflects the cholesterol within all lipoprotein particles currently considered ateherogenic. Many studies have indicated that it is a better predictor of cardiovascular events than is LDL-C. However I still think LDL-P measurements may often give important additive information and I my guess is that it´s use will become more common in the near future. However, the clinical utility of these measurements is still limited because the technique is not widely available and it is relatively expensive.

    In clinical terms, LDL-P does not add much to ApoB. LDL-P measures the number of LDL-particles while ApoB measures the number of all atherogenic particles (chylomicrons, VLDL,IDL,LDL and Lp(a)). Usually 85-90% of ApoB represent LDL-particles.Therefore, in most cases you don´t need ApoB if you have LDL-P available and vice versa.

  4. ED COOPER

    I WAS ABLE TO GET A TEST FROM ONE OF THE “WALK IN” LABS WHERE YOU CAN ORDER YOUR OWN TEST. THIS TEST GAVE ME THE LDL-P ALONG WITH THE STANDARD LIPID RESULTS. THE PRICE WAS ONLY $58. LIPO SCIENCE IS PROVIDING ALL THE NMR RESULTS SO IT DOESN’T REALLY MATTER WHAT LAB DRAWS THE SAMPLE. THEY ARE ALL SENDING IT TO LIPO SCIENCE.
    I DIDN’T GET ANOTHER APO-B FOR THIS PRICE HOWEVER.

  5. “l…HD-CL and triglyserides …important in patients with the metabolic syndrome, where LDL-C may underestimate risk” Have you a solid reference to this statement? Would be very interesting as almost all the fuss is about LDL-C.

  6. Doc´s opinion

    Reijo. Here is a study on the use of Non-HDL cholesterol to predict risk in patients with type-2 diabetes. It is a stronger predictor of risk than LDL-C. Another study arrived at the following conclusion: Non-HDL is a stronger predictor of CHD death among those with diabetes than LDL and should be given more consideration in the clinical approach to risk reduction among diabetic patients. Here is another study comparing ApoB and Non-CHDL cholesterol with LDL-C.
    In this short video Dr. Richard F Wright explains discordance and the populations most likely to be at increased risk despite normal LDL-C. It turns out that that patients with diabetes often have high LDL-P despite normal LDL-C. Here Dr Thomas Dayspring explains why LDL-C is a much worse predictor of risk in insulin resistant patients than ApoB or LDL-P.

  7. bhrdoc

    Excellent post. Here is another study: Cui Y, Blumenthal RS, Flaws JA et al.: Non-High-Density-Cholesterol Level as a Predictor of Cardiovascular Disease Mortality. Arch Intern Med. 161, 1413-1419 (2001).

  8. Hi doc, any thoughts on the usefulness of TG/HDL ratios? I’ve heard that TG is a fairly accurate proxy for ApoB count. Plus TG numbers are easy to obtain. thx!

  9. Doc´s opinion

    @ Richard. Evidence suggests that there is an association between TG/HDL-C ratio and cardiovascular risk. This ratio has also been shown to be associated with insulin resistance. Thus, the higher your TG and the lower your HDL-C, the greater degree of insulin resistance. Therefore it may be particularly helpful in individuals with the metabolic syndrome where the traditional LDL-C often underestimates risk.A TG/HDL-C ratio above 3.5 has often been used as cutoff for identifying insulin resistance. As you say, this ratio is easy to obtain, it is included in the traditional lipid panel, and therefore relatively cheap.

  10. I get asked many times why the arterial wall gets damaged in the first place. I am also asked if this can be reversed – the implication being by non surgical/medicinal means.
    I know smoking, insulin spikes etc. can lead to inflammation, but why does (rhetorical) the wall become weakened before this happens. Age? Yes possibly…… and yet I still seem to need to dig deeper, especially when arterial damage was detected in me at the age of 49 years – not particularly ancient!

    Have you ever considered the Rath – Pauling theory? Explained here by Dr. Dach.
    http://www.drdach.com/Heart_Disease.html

    Curious and also wondering what your treatment regime would be for natural reversal of plaques?

    Clare in Tasmania

  11. As far as I know the only attempt to establish a logical hypothesis of atherosclerosis explaining at least a big chunk of observed data is the one by Drs. Ravnskov and McCully where damage is first inflicted in the vasa vasorum: see for example Infections May Be Causal in the Pathogenesis of Atherosclerosis (available at last International Health News issue). For me confusing correlation with causation (LDL-P hypothesis?) and ignoring how LDL particles jump through supposedly healthy tissue doesn’t cut it.

    This being said I am all in for vitamin D, magnesium, vitamin C, vitamin K2, iodine etc.

Let me know what you think!