Lipidaholics Anonymous Case 2012;13:(1);284 Explaining the unexplainable LDL- P

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Alyson Leona Brooks
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1 1 Lipidaholics Anonymous Case 2012;13:(1);284 Explaining the unexplainable LDL- P A respected cardiologist contacted me about the following dilemma. He has a primary prevention case which is a woman with a TG/HDL axis disorder who has been on chronic statin therapy. Her last two lipid panels did not seem to make sense as lipid concentrations were improving when paradoxically the LDL-P is worsening. Other than lab error is there an explanation In May on Pravastatin 40 mg TC 208 LDL-C = 85 HDL-C = 50 TG = 208 VLDL-C = 41.6 Non-HDL-C = 178 mg/dl LDL-P = 1283 nmol/l Small LDL-P = 1069 nmol/l LDL size = 19.9 nm Lp-IR = 76 Then in November on Pravastatin 40 mg TC = 151 LDL-C = 68 HDL-C = 54 TG =144 VLDL-C = 28.8 Non-HDL-C = 107 mg/dl LDL-P = 1501 nmol/l Small LDL-P = 1115 nmol/l LDL size 20.1 nm LP-IR =67 DAYSPRING DISCUSSION One of these days clinicians will have to stop wasting their time trying to predict what is going on by solely looking at lipid concentrations. We all have to stop being perplexed when LDL-P does not make sense and respect and trust all of the data associating it with risk and be prepared to treat the LDL-P to goal. None of us is really brilliant enough to truly know why the LDL-P is where it is in a given individual So in this case the question is why did the LDL-P increase so much without an obvious cause (often a rising TG and reducing HDL-C), and specifically how can LDL-P go up when the LDL-C and non-hdl-c (both normally surrogates of LDL-P) went down. Clinical chemistry teaches us that when lab values that usually correlate with each other like apob, LDL-P, LDL-C and non-hdl-c for whatever reason do not

2 2 correlate with each other the concentrations are said to be discordant. In virtually every study published where discordance between LDL-P or apob and LDL-C and non-hdl-c was present, risk virtually always more accurately follows apob and especially LDL-P. In the first panel above (May) the LDL-C is at the 10th percentile population cutpoint (meaning 90% of patients would have a higher value and 10% or less a lower value) and the LDL-P at the 40th percentile cutpoint: so there is certainly some discordance. Yet in the second panel the LDL-C is at the 5th percentile population cutpoint (very low risk) whereas the LDL-P is at the 70th percentile cutpoint (approaching high risk value of 80%): the discordance is even worse. As scientists, we should believe the elevated LDL-P and treat accordingly: (more potent statin or perhaps adding ezetimibe to the pravastatin). The answer explaining what is going, meaning understanding the lipid/lipoprotein concentration discordance on lies in having a fairly sophisticated understanding of what a lipoprotein is and how it behaves once it is in plasma. Lipoproteins are not static collections of lipids that never change: in fact they are in a constant state of dynamic remodeling of their core and surface lipid molecule makeup. The graphic below depicts the basic structure of every lipoprotein that exists: a one molecule thick surface of unesterified cholesterol and phospholipids with a core consisting of variable amounts of cholesteryl ester (CE) and TG:

3 3 Quite important is the ratio of TG and cholesteryl ester (CE) in the particle core and how it changes "on the fly." Normally a VLDL has 5 times more TG molecules than CE molecules, an LDL 4 or more times CE than TG and an HDL 10 times or more CE than TG. Anytime and LDL or HDL has less than the normal number of CE molecules in its core, it is by definition a cholesterol-depleted particle. It will always takes more CE-depleted than CE-rich particles to traffic a given cholesterol mass (number of cholesterol molecules). LDL-C is the mass of cholesterol trafficked within all of the LDL particles that exist is a deciliter of plasma. HDL-C is the cholesterol mass within all of the HDLs, irrespective of size that exist in a deciliter of plasma.

4 Something that is not typically measured, LDL-TG or HDL-TG would be the mass of TG trafficked within all of the LDLs or HDLs respectively per deciliter of plasma. What determines a given LDL-P?

4 4 Something that is not typically measured, LDL-TG or HDL-TG would be the mass of TG trafficked within all of the LDLs or HDLs respectively per deciliter of plasma. What determines a given LDL-P? LDL-P is the number of LDL particles that are needed to traffic the cholesterol mass (number of cholesterol molecules) that is within all of the LDL particles per liter of plasma. The volume of a spherical particle is 4/3(pi) radius cubed (to the third power). So how many CE molecules can fit into a single LDL particle? Of course that will depend on not only how big that LDL particle is but it also will depend on what percentage of the particle volume is devoted to cholesteryl ester. No LDL devotes 100% of its core to CE. It allocates some space to TG. Also keep in mind that in molecular terms a TG molecule is much larger than a CE molecule. It will take less TG than CE molecules to fill a given lipoprotein than CE molecules. So even in the face of a seemingly unremarkable TG concentration, TGs can find their uninvited way into LDL and HDL particles. Normally ~10-25% of an LDL is devoted to carry TG and 75-90% to CE: a 4:1 ratio of CE to TG.

5 5 Under normal physiologic conditions, an HDL particle should not carry significant amounts of TG. Below are depicted a normal HDL on the left and a TG-rich HDL on the left

6 There are three ways to deplete an LDL of CE or in other words change a normally CE-rich LDL into a CE-poor LDL. (1) One is to reduce the diameter (radius) of the LDL.

6 6 There are three ways to deplete an LDL of CE or in other words change a normally CE-rich LDL into a CE-poor LDL. (1) One is to reduce the diameter (radius) of the LDL. Thus its takes 40-70% more small LDLs than large LDLs to traffic a given number of CE molecules. So folks, especially those not on a drug, with small LDLs tend to have high LDL-P.

7 (2) If one increases the number of TG molecules per LDL particle, then there will be less room for CE molecules. TG-enrichment of LDLs is associated with CE-depletion.

7 7 (2) If one increases the number of TG molecules per LDL particle, then there will be less room for CE molecules. TG-enrichment of LDLs is associated with CE-depletion. It will require 40-70% more TGrich, CE-poor LDLs (regardless of particle size) to traffic a given cholesterol mass (number of cholesterol molecules) than CE-rich LDLs.

8 (3)Statins lower LDL-C significantly more than they do LDL-P and thus leave LDL particles cholesterol depleted (and thus TG-rich) even when TG levels are normal.

8 8 (3)Statins lower LDL-C significantly more than they do LDL-P and thus leave LDL particles cholesterol depleted (and thus TG-rich) even when TG levels are normal. This is a major reason why statins lower LDL-C more than they do LDL-P. In the slide below, using data from statin trials, the drug rather easily drop LDL-C values to the 20 th percentile population cutpoint but do not approach 20 th percentile

9 9 LDL-P cutpoint. What determines the size of the LDL particle: LDLs have a phospholipid surface (PL) and a TG/CE core. So exposure to a phospholipase or a triglyceridase will hydrolyze (de-esterify) surface PL and core TG to fatty acids (FA) and monoacylglycerols and the LDL will reduce in size. Hepatic lipase is both a triglyceridase and a phospholipase. There are several phospholipases in plasma including endothelial lipase (a pure phospholipase). TG-rich LDLs are thus ripe substrates for triglyceridases like HL or even lipoprotein lipase (LPL). TG-rich LDLs easily become smaller as they lose their core TG and surface PL (lipolysis). If you follow that physiology or pathophysiology just described, those patients with the highest numbers of LDL particles will likely have incredibly CE-depleted LDLs -- i.e. they will have small LDLs that are also TG-rich. Each such particle is not capable of carrying very many CE molecules. How does the LDL acquire the excess TG and lose CE to make room for it? That's easy, it comes from TG rich particles. So TG-rich VLDLs (or chylomicrons in postprandial plasma) exchange or swap their TG for CE within the LDL core, using a lipid transfer protein called cholesteryl ester transfer protein or CETP (also known as apolipoprotein D). When apob particles (VLDLs, IDLs, LDLs, chylomicrons) exchange their core TG and CE (utilizing CETP), the process is called homotypic exchange of neutral lipids. But another type of exchange might also be occurring, namely heterotypic exchange where TG and CE are swapped (via CETP) between apob containing particles (90% of which are LDLs) and apoa-i particles (HDLs). So during every second of every minute that an LDL is in plasma (its plasma residence time) it is constantly acquiring and/or gaining TG or CE. That is its core lipid content changes. The amount of CETP-mediated exchange that occurs today might be different than that tomorrow or nest month. Thus the core composition

10 of particles on one test might be very different from that in particles checked on another occasion. After all an LDL half-life is only 1.5 to 3 days. Want me to make this even more complicated?

10 10 of particles on one test might be very different from that in particles checked on another occasion. After all an LDL half-life is only 1.5 to 3 days. Want me to make this even more complicated? OK - both apolipoprotein F or apolipoprotein C-I inhibit CETP activity. Anybody measure that lately? So how can any clinician know what is going on in the LDL core guess what he or she cannot! Can any real world physician assay LDL-TG hydrolysis or CETP activity - of course not. Is anyone measuring LDL-TG levels? No but it is easily done and perhaps one day soon HD Labs in Richmond will offer that test to all. So how can any provider offer a rational explanation of why a person has an elevated LDL-P -- they cannot. Can a given LDL-P change over time even if medication does not change - obviously it can and does. Can the change in LDL-P always be explained by plasma concentrations of TG, HDL-C, non-hdl-c - NOPE. Many times the cholesterol and particle concentrations are concordant but very often they are not. They may be concordant one time and discordant the next. Since there is no accurate way to predict LDL-P by looking at any lipid parameter whatsoever, we really need LDL-P on every single patient because we know from trial after trial; when the concentrations are discordant, CV risk always follows LDL-P. It is amazing how many lipidologists, never mind docs without that credential, think they can predict LDL- P by looking at lipid (LDL-C, HDL-C, TG) or even subparticle lipid (cholesterol) concentrations offered by some labs. Without any disrespect, anyone believing they can predict LDL-P with any serious degree of accuracy by looking at lipids are delusional. I am personally aware of data that 20 % of folks with an LDL- C < 50 mg/dl who have what is considered normal TG (< 150 mg/dl) and HDL-C (> 40 in men and 50 mg/dl in women) have an LDL-P > 1000 nmol/l. Check out the discordance in this study of T2DM patients with LDL-C < 100 mg/dl and 70 mg/dl. Many still have abnormally high LDL-P.

11 11 Let's hazard an explanation for the LDL-P differences between the two above tests without any obvious change in medication or lifestyle (but how does one really know if lifestyle has been exactly the same 6 months apart- was the carbohydrate intake constant? Any change in carbs especially high fructose corn syrup intake will affect insulin levels, which in turn affect lipase activity, etc., and effect particle core composition. In panel one (May) the TG were quite high and the LDL size was quite small at 19.9 nm. So the small particle size is likely affecting the total LDL-P (vast majority of the particles are small with small LDL-P of 1069 nmol/l). The total LDL-P would have been much higher if pravastatin not been used. Who knows what the LDL-TG level might have been in this woman in May. Who knows what her CETP activity, apof, apoc-i or various lipase activity was? On the follow up lipid panel in November the LDL-P is much higher but the lipid concentrations all look better including the TG. But is a TG of 144 mg/dl really that much better in an insulin resistant patient compared to the original value of 208. If you look at published LDL-P data from Framingham Offspring in metabolic syndrome patients, at a TG level of 150 mg/dl the mean LDL-P was at high risk (> 1600 nmol/l) and at a TG > 200 mg/dl the mean LDL-P was just a tad higher ~ 1700 nmol/l (Circ 2006;113:20-29). Clearly the explanation form the high LDL-P in both cases is small LDLs which likely are still packing too many TG. But the LDL size on the second panel was actually larger but the small LDL-P was higher than that in May. Why would small LDL-P be rising when LDL size was increasing (albeit till in the small range)? The answer lies in what is happening in the particle core. The LDL particles in November are more CE depleted than were the particles in May. The larger LDL size might be explained by an increased LDL-

12 12 TG in November - yet the large TG-rich LDLs might be very CE-depleted (more so than they were in May) and LDL-C goes down and LDL-P goes up. The high LDL-TG might be related to diet, CETP, activity, lipase activity, apof, apoc-i activity, insulin levels -- your guess is as good as mine. All I worry about as a treating clinician is that I now have to be more aggressive in lowering LDL-P as the pravastatin 40 is not cutting it anymore! What happened in the case above is on the second test the LDL core was more CE-depleted than on the second test. Thus LDL-P is up despite the better LDL-C and even the better TG. The more depleted the LDL core is of CE, the higher the LDL-P will be. So even though the lipid concentrations did not change a lot, in fact they improved, the core of the particle is always changing via activity dues to any number of now immeasurable factors. Just a tad bit more for thought: what is nothing I have theorized above is at play? What if as they do, the statin increased expression of PCSK9, the LDL receptor (LDLr) peptidase that shortens the half-life of LDLr? A person with less LDLr expression will not be so efficient at clearing LDL-P and the level rises over time. What if as statins are prone to cause, there is an induced hyperabsorption of cholesterol which by increasing delivery of cholesterol to the liver will cause reduced expression of LDLr and a rising LDL-P. At least we can measure sterol absorption to see if that is at play! Remember the good old days when lipids were so easy and it was all about LDL-C: What dopes we really were. I refer to those as the dark ages. Tragedy is the vast majority of docs are still betting lives on LDL-C. Can the odd error also occur with any lab testing: for sure, but again LDL-P via NMR is the best adjudicated in clinical trials assay we have: it blows away lipid concentrations.

13 13 TAKE HOME POINTS: LDL-P is the number of LDL particles in plasma and it often has no obvious relationship to lipid concentrations. It is mostly related to LDL size, LDL core composition but also LDL particle production and LDL particle clearance. We can easily measure LDL-P and we should. If you cannot get LDL-P, then do apob. One of these days clinicians will have to stop wasting their time trying to predict what is going on by looking at lipid concentrations. We all have to stop being perplexed when LDL- P does not make sense and respect and trust all of the data associating it with risk and we must treat the LDL-P to goal. The next two slides are from the National Lipid Association Biomarker Satement. An article written by myself and Tara Dall which apples all of the above discussion to two patients is available as a free download. Moving beyond LDL-C: incorporating lipoprotein particle numbers and geometric parameters to improve clinical outcomes

Case # 278 Should lipoprotein cholesterol assays disappear?

Case # 278 Should lipoprotein cholesterol assays disappear? Let's get into the case: I was contacted by a provider who states: "I have a 70 year old guy with absolutely no cardiac risk factors except for