May 23, 2012

Cardiovascular Disease

The straight dope on cholesterol – Part V

In this post we’ll address the following concept: Does the size of an LDL particle matter?

Read Time 10 minutes

In Part I, Part II, Part III and Part IV of this series, we addressed these 6 concepts:

     #1What is cholesterol?

     #2What is the relationship between the cholesterol we eat and the cholesterol in our body?

     #3Is cholesterol bad?

     #4 How does cholesterol move around our body?

     #5 How do we measure cholesterol?

     #6How does cholesterol actually cause problems?



Quick refresher on take-away points from previous posts, should you need it:

  1. Cholesterol is “just” another fancy organic molecule in our body but with an interesting distinction: we eat it, we make it, we store it, and we excrete it – all in different amounts.
  2. The pool of cholesterol in our body is essential for life.  No cholesterol = no life.
  3. Cholesterol exists in 2 formsunesterified or “free” (UC) and esterified (CE) – and the form determines if we can absorb it or not, or store it or not (among other things).
  4. Much of the cholesterol we eat is in the form of CE. It is not absorbed and is excreted by our gut (i.e., leaves our body in stool). The reason this occurs is that CE not only has to be de-esterified, but it competes for absorption with the vastly larger amounts of UC supplied by the biliary route.
  5. Re-absorption of the cholesterol we synthesize in our body (i.e., endogenous produced cholesterol) is the dominant source of the cholesterol in our body. That is, most of the cholesterol in our body was made by our body.
  6. The process of regulating cholesterol is very complex and multifaceted with multiple layers of control.  I’ve only touched on the absorption side, but the synthesis side is also complex and highly regulated. You will discover that synthesis and absorption are very interrelated.
  7. Eating cholesterol has very little impact on the cholesterol levels in your body. This is a fact, not my opinion.  Anyone who tells you different is, at best, ignorant of this topic.  At worst, they are a deliberate charlatan. Years ago the Canadian Guidelines removed the limitation of dietary cholesterol. The rest of the world, especially the United States, needs to catch up.  To see an important reference on this topic, please look here.
  8. Cholesterol and triglycerides are not soluble in plasma (i.e., they can’t dissolve in water) and are therefore said to be hydrophobic.
  9. To be carried anywhere in our body, say from your liver to your coronary artery, they need to be carried by a special protein-wrapped transport vessel called a lipoprotein.
  10. As these “ships” called lipoproteins leave the liver they undergo a process of maturation where they shed much of their triglyceride “cargo” in the form of free fatty acid, and doing so makes them smaller and richer in cholesterol.
  11. Special proteins, apoproteins, play an important role in moving lipoproteins around the body and facilitating their interactions with other cells.  The most important of these are the apoB class, residing on VLDL, IDL, and LDL particles, and the apoA-I class, residing for the most part on the HDL particles.
  12. Cholesterol transport in plasma occurs in both directions, from the liver and small intestine towards the periphery and back to the liver and small intestine (the “gut”).
  13. The major function of the apoB-containing particles is to traffic energy (triglycerides) to muscles and phospholipids to all cells. Their cholesterol is trafficked back to the liver. The apoA-I containing particles traffic cholesterol to steroidogenic tissues, adipocytes (a storage organ for cholesterol ester) and ultimately back to the liver, gut, or steroidogenic tissue.
  14. All lipoproteins are part of the human lipid transportation system and work harmoniously together to efficiently traffic lipids. As you are probably starting to appreciate, the trafficking pattern is highly complex and the lipoproteins constantly exchange their core and surface lipids.
  15. The measurement of cholesterol has undergone a dramatic evolution over the past 70 years with technology at the heart of the advance.
  16. Currently, most people in the United States (and the world for that matter) undergo a “standard” lipid panel, which only directly measures TC, TG, and HDL-C.  LDL-C is measured or most often estimated.
  17. More advanced cholesterol measuring tests do exist to directly measure LDL-C (though none are standardized), along with the cholesterol content of other lipoproteins (e.g., VLDL, IDL) or lipoprotein subparticles.
  18. The most frequently used and guideline-recommended test that can count the number of LDL particles is either apolipoprotein B or LDL-P NMR, which is part of the NMR LipoProfile.  NMR can also measure the size of LDL and other lipoprotein particles, which is valuable for predicting insulin resistance in drug naïve patients, before changes are noted in glucose or insulin levels.
  19. The progression from a completely normal artery to a “clogged” or atherosclerotic one follows a very clear path: an apoB containing particle gets past the endothelial layer into the subendothelial space, the particle and its cholesterol content is retained, immune cells arrive, an inflammatory response ensues “fixing” the apoB containing particles in place AND making more space for more of them.
  20. While inflammation plays a key role in this process, it’s the penetration of the endothelium and retention within the endothelium that drive the process.
  21. The most common apoB containing lipoprotein in this process is certainly the LDL particle. However, Lp(a) and apoB containing lipoproteins play a role also, especially in the insulin resistant person.
  22. If you want to stop atherosclerosis, you must lower the LDL particle number.


Concept #7 – Does the size of an LDL particle matter?

There are few, if any, topics in lipidology that generate more confusion and argument that this one.  I’ve been leading up to it all month, so I think the time is here to address this issue head on.  I’ve read many papers and seen many lectures on this topic, but the one that stole my heart was a lecture given by Jim Otvos at the ADA 66th Scientific Sessions in Washington, DC.   Some of the figures I am using in this post are taken directly or modified from his talk or subsequent discussions.

At the outset of this discussion I want to point out two clinical scenarios to keep in mind:

  1. The most lethal lipoprotein disorder is familial hypercholesterolemia, which I have discussed in previous posts.  Such patients all have large LDL particles, but most of these patients die in childhood or early adulthood if not treated with medications to reduce particle number.
  2. Conversely, diabetic patients and other patients with advanced metabolic syndrome have small LDL particles, yet often live well into their 50s and 60s before succumbing to atherosclerotic diseases.

The common denominator is that both sets of patients in (1) and (2) have high LDL-P.  What I’m going to attempt to show you today is that once adjusted for particle number, particle size has no statistically significant relationship to cardiovascular risk.  But first, some geometry.


“Pattern A” versus “Pattern B” LDL

The introduction of gradient gel electrophoresis about 30 years ago is what really got people interested in the size of LDL particles.  There is no shortage of studies of the past 25 years demonstrating that of the following 2 scenarios, one has higher risk, all other things equal.  [This is a big disclaimer and I went back and forth for a while before deciding to include this point.  It is an uncharacteristic oversimplification. If you’ve been reading this blog for a while, you’ll know I’m rarely accused of that sin – but I’m about to be].

Here’s the example: Consider 2 patients, both with the same total content of cholesterol in their LDL particles, say, 130 mg/dL.  Furthermore, assume each has the “ideal” ratio of core cholesterol ester-to-triglyceride (recall from Part I and III of this series, this ratio is 4:1).  I’m going to explain in a subsequent post why this assumption is probably wrong as often as it’s right, but for the purpose of simplicity I want to make a geometric point.

  1. LDL-C = 130 mg/dL, Pattern A (large particles) – person on the left in the figure below
  2. LDL-C = 130 mg/dL, Pattern B (small particles) – person on the right in the figure below

Under the set of assumptions I’ve laid out, case #2 is the higher risk case.  In other words, at the same concentration of cholesterol within LDL particles, assuming the same ratio of CE:TG, it is mathematically necessary the person on the right, case #2, has more particles, and therefore has greater risk.

Bonus concept: What one really must know is how many cholesterol molecules there are per LDL particle.  It always requires more cholesterol-depleted LDL particles than cholesterol-rich LDL particles to traffic cholesterol in plasma, and the number of cholesterol molecules depends on both size and core TG content.  The more TG in the particle, the less the cholesterol in the particle.

So why does the person on the right have greater risk?  Is it because they have more particles?  Or is it because they have smaller particles?

This is the jugular question I want to address today.


Small vs. large particles

If you understand that the person on the right, under the very careful and admittedly overly simplified assumptions I’ve given, is at higher risk than the person on the left, there are only 4 possible reasons:

  1. Small LDL particles are more atherogenic than large ones, independent of number.
  2. The number of particles is what increases atherogenic risk, independent of size.
  3. Both size and number matter, and so the person on the right is “doubly” at risk.
  4. Neither feature matters and these attributes (i.e., size and number) are markers for something else that does matter.

Anyone who knows me well knows I love to think in MECE terms whenever possible.  This is a good place to do so.

I’m going to rule out Reason #4 right now because if I have not yet convinced you that LDL particles are the causative agent for atherosclerosis, nothing else I say matters.  The trial data are unimpeachable and there are now 7 guidelines around the world advocating particle number measurement for risk assessment. The more LDL particles you have, the greater your risk of atherosclerosis.


But how do we know if Reason #1, #2, or #3 is correct?

This figure (one of the most famous in this debate) is from the Quebec Cardiovascular Study, published in 1997, in Circulation.  You can find this study here.


Relative risks

This is kind of a complex graph if you’re not used to looking at these.  It shows relative risk – but in 2 dimensions.  It’s looking at the role of LDL size and apoB (a proxy for LDL-P, you’ll recall from previous posts).  What seems clear is that in patients with low LDL-P (i.e., apoB < 120 mg/dl), size does not matter.  The relative risk is 1.0 in both cases, regardless of peak LDL size.  However, in patients with lots of LDL particles (i.e., apoB > 120 mg/dl), smaller peak LDL size seems to carry a much greater risk – 6.2X.

If you just looked at this figure, you might end up drawing the conclusion that both size and number are independently predictive of risk (i.e., Reason #3, above).  Not an illogical conclusion…

What is not often mentioned, however, is what is in the text of the article:

“Among lipid, lipoprotein,and apolipoprotein variables, apo B [LDL-P] came out as the best and only significant predictor of ischemic heart disease (IHD) risk in multivariate stepwiselogistic analyses (P=.002).”

“LDL-PPD [peak LDL particle diameter] — as a continuous variable did not contribute to the risk of IHD after the contribution of apo B levels to IHD risk had been considered.”

What’s a continuous variable?  Something like height or weight, where the possible values are infinite between a range.  Contrast this with discrete variables like “tall” or “short,” where there are only two categories. For example, if I define “tall” as greater than or equal to 6 feet, the entire population of the world could be placed in two buckets: Those who are “short” (i.e., less than 6 feet tall) and those who are “tall” (i.e., those who are 6 feet tall and taller). This figure shows LDL size like it’s a discrete variable – “large” or “small” – but obviously it is not. It’s continuous, meaning it can take on any value, not just “large” or “small.”  When this same analysis is done using LDL size as the continuous variable it is, the influence of size goes away and only apoB (i.e., LDL-P) matters.

This effect has been observed subsequently, including the famous Multi-Ethnic Study of Atherosclerosis (MESA) trial, which you can read here.  The MESA trial looked at the association between LDL-P, LDL-C, LDL size, IMT (intima-media thickness – the best non-invasive marker we have for atherosclerosis), and many other parameters in about 5,500 men and women over a several year period.

This study used the same sort of statistical analysis as the study above to parse out the real role of LDL-P versus particle size, as summarized in the table below.



This table shows us that when LDL-P is NOT taken into account (i.e., “unadjusted” analysis), an increase of one standard deviation in particle size is associated with 20.9 microns of LESS atherosclerosis, what one might expect if one believes particle size matters.  Bigger particles, less atherosclerosis.

However, and this is the important part, when the authors adjusted for the number of LDL particles (in yellow), the same phenomenon was not observed.  Now an increase in LDL particle size by 1 standard deviation was associated with an ADDITIONAL 14.5 microns of atherosclerosis, albeit of barely any significance (p=0.05).

Let me repeat this point: Once you account for LDL-P, the relationship of atherosclerosis to particle size is abolished (and even trends towards moving in the “wrong” direction – i.e., bigger particles, more atherosclerosis).

Let me use another analysis to illustrate this point again.  If you adjust for age and sex, but not LDL-P [left graph, below], changes in the number of LDL particles (shown in quintiles, so each group shows changes by 20% fractions) seem to have no relationship with IMT (i.e., atherosclerosis).

However, when you adjust for small LDL-P [right graph, below], it becomes clear that increased numbers of large LDL particles significantly increase risk.



I’ve only covered a small amount of the work addressing this question, but this issue is now quite clear.  A small LDL particle is no more atherogenic than a large one, but only by removing confounding factors is this clear.   So, if you look back at the figure I used to address this question, it should now be clear that Reason #2 is the correct one.

This does not imply that the “average” person walking around with small particles is not at risk.  It only implies the following:

  1. The small size of their particles is probably a marker for something else (e.g., metabolic derangement due to higher trafficking of triglycerides within LDL particles);
  2. Unless you know their particle number (i.e., LDL-P or apoB), you actually don’t know their risk.

Let’s wrap it up here for this week.  Next week we’ll address another question that’s probably been on your mind: Why do we need to measure LDL-P or apoB?  Isn’t the LDL-C test my doctor orders enough to predict my risk?



  • At first glance it would seem that patients with smaller LDL particles are at greater risk for atherosclerosis than patients with large LDL particles, all things equal.  Hence, this idea that Pattern A is “good” and Pattern “B” is bad has become quite popular.
  • To address this question, however, one must look at changes in cardiovascular events or direct markers of atherosclerosis (e.g., IMT) while holding LDL-P constant and then again holding LDL size constant.  Only when you do this can you see that the relationship between size and event vanishes.  The only thing that matters is the number of LDL particles – large, small, or mixed.
  • “A particle is a particle is a particle.”  If you don’t know the number, you don’t know the risk.

By NASA Mercury image: JHUAPLVenus image: JPLMars image: HST [Public domain], via Wikimedia Commons

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  1. Another awesome installment. I’m looking forward to the installment that discusses how one can reduce LDL-P, preferably without drugs. Or does that fall under the category of things you can’t do here?

    • Certain gene types. For example, about 25% of the population carries one allele of the apoE3 gene and one copy of apoE4; 1-2% of the population is apoE4/4. I’ll cover this in a subsequent post. Obviously, nutrition plays a role. IR makes things worse.
      There are many blood tests that address this, MPO, Lp-PLA2 are probably the best. Again, I’ll address it later.

    • It’s less about the “tool” (i.e., the statin) and more about the application (i.e., how and when it is used). I’m not here to vilify or vindicate a drug maker. But if you have a hammer, it’s best to use for hitting nails, not cleaning windows. Using statins to lower LDL-C is missing the point.

    • Peter your effort is commendable but your analogy is not the most appropriate. Is not a hammer is the atomic bomb on a process that as you have explain very well is very complex and needed by the entire body. Processes that we knew very little for a disease were the etiology is still not well understood. People are using an atomic bomb that is affecting every cell in the body and the pharmaceutical companies makes them think that they are immunized against CVD, so they can keep their unhealthy living. That for a small reduction of absolute risk of a heart attack, but not mortality. I will not say never like Zoe Harcombe

      But I will try everything else, including holistic medicine before throwing a nuclear bomb on my body and hoping it will not have any other ill effect on the rest of my body on the long run.

      • All fair points, John, and as I said the analogy isn’t perfect, especially at the molecular level. My point was that most doctors use statins to treat LDL-C. As you’ll see in part VI of this series, that is the wrong parameter to treat. In fact, that is part of the reason the efficacy of statins is only “good” and not “great.” Too much noise is being generated by these trials because of the treatment goals. In subsequent posts I’ll try to give readers an idea of how and when statins should be used. Hence, the hammer. True, they probably do much more than “just” block HMG-CoA reductase, but that is the main nail they hit. Very few drugs, do just one thing, but it doesn’t mean they are bad.

  2. Here’s something very interesting… Endothelial dysfunction: the early predictor of atherosclerosis. And it’s got the full text publicly available. 🙂 And it’s written in understandable English! 😀

    Basically, anything that lowers bio-availability of nitric oxide at the endothelium cells will cause the artery to become “leaky” to lipid particles with ApoB proteins and allow the whole process of atherosclerosis to start.

    The triggering factors seem to be hyperglycaemia, hyperlipidemia (with oxLDL), established hypertension, smoking, inflammation, and the inevitable ageing.

    The more I read about these things, the more anti-oxidants seem to be the answer to the decaying vascular health at many levels. Resveratrol keeps popping up, so I’m glad I like my occasional glass of red wine. 🙂

    • Unless you’re drinking 18 glasses of red wine per day (in which case you’ve got bigger issues), the dose of resveratrol you’re getting doesn’t come close to what is reported to have any benefit in the literature, though.

  3. NMR+IF+hs-CRP

    Had blood taken on 5/10 (1 week after my once every 3 week shot of 400mgs Test Cypionate – in a doctors office paid for by my insurance)

    Have been doing IF (16 hour fast – 8 hour feeding window) for appx 5 weeks prior to the blood test.

    hs-CRP was 18.48mg/L – high is anything over 3.0mg/L

    In August 2011 my Cardio CRP (From Quest Labs) was 1.4mg/L

    Could the IF be causing the hs-CRP to spike?

    To the NMR test results – I’m fooling a moderate carb paleo diet. Daily carbs include a mashed sweet potato after my workout and 1 banana and some frozen berries with my protein smoothie (usually a can of high fat coconut milk OR 8 ozs of whole fat grass fed milk and 6-8ozs of whole fat grass fed milk yogurt)

    LDL-P 1500 nmol/L – Boderline High is 1300-1599 nmol/L

    LDL-C 188 mg/dl – High is 160-189 mg/dL

    HDL-C 59 mg/dL S/B >=40 so this is OK

    Triglycerides 36 mg/dL S/B =30.5 so this is low

    Small LDL-P 127 nmol/L S/B 20.5 so this is OK

    LP-IR (Insulin Resistance Score) 6 S/B <=45

    Your thoughts

    • “Could the IF be causing the hs-CRP to spike?”

      Yes, but first I’d ask you if you might have any undiagnosed gum disease you don’t know about. When was the last time you had your teeth cleaned? Do you have any gum pockets? You might have systemic inflammation due to gum disease, leaky gut, an allergy, even too much exercise. If you are overweight with a big apple shape and moobs, it could be your own visceral fat that’s inflaming you. . . many factors at play here, you should try tracking them down 1 by 1 with your doctor, for sure.

  4. It ended up being a VAP that got tested when GammaDynaCare ran my “lipoprotein subfractionation”, including direct LDL, etc. I also got apoB, apoA1 (separate and apart from the VAP which are calculated measures), homocysteine, hsCRP, and all the nitty-gritty in the VAP. I did not get Lp-plA2 which is disappointing (see Mike Cobble’s latest blog post at cobble’s corner). Anyway, I pretty much confirmed I am a hyper-absorber. LDL went off the scale. After initiating rosuvastatin 10 mg OD and cutting out virtually all saturated fat and dietary cholesterol, LDL levels have dropped more than 80%, and triglycerides have continued to go down. So now we are looking at low carb and healthy lean protein food sources. This is pretty much the Lyon Diet Study deja vu all over again (apologies to Yogi Berra). Namely the only RCT ever to show hard endpoint reductions (including cancer) in a nutritional setting. Weight loss has continued and I am glad I did not have to take an intestinal cholesterol blocker (as they are much less evidence-based). From my point of view, unrestricted saturated fat and dietary cholesterol could potentially harm someone with an underlying genetic predisposition to hypercholesterolemia, or a hyper-absorber. You are so right to recommend lipid monitoring – don’t worry what the critics say. If I could recommend three tests in our age/sex cohort then BP testing, lipid testing and a testicular examination would cover >99% of all preventive medicine needs.

  5. Great series, great links with good references.

    I’m 100% on board with the concept that all things equal, LDL-P seems to have a very compelling association with atherosclerosis. A good strategy for people worried about CVD would be to lower your LDL-P. I get that.

    But after reading as many of your references as possible, I have to agree with Vasco about the concept of gradient. I’m not suggesting that this isn’t a plausible explanation, just that there may be other factors involved.

    Relying solely on LDL-P concentration as the key variable in atherosclerosis would essentially suggest ignoring other risk factors that have widely associated with increased heart disease risk, including blood pressure, hba1c, LDLox, HDL, endothelial health, diabetes, smoking, etc.

    You gave two interesting examples at extreme ends of the LDL-P spectrum to make your point. Both are related to LDL-R expression. In one case, FH patients can’t express enough LDL_R and hence clearance is poor. In the other case, an enzyme mutation causes LDL-R to be overactive, resulting in rapid clearance of particles.

    So, is the change in CVD a result of a change in LDL-P, or a change in the half-life of the LDL particle? Increases and decreases in clearance activity will influence the amount of time that LDL-P circulates around in the bloodstream before it gets removed, and will ultimately show up as changes in LDL-P.

    But is it the gradient that is causing LDL-P to stick, or is it the increases in half-life of particles?

    The longer the particle sticks around, the more chance these particles have to interact with vessels and perhaps get stuck. Will these particles get stuck if the vessels are healthy? Another way to think about it… is a damaged particle (oxidized or glycated) more likely to get stuck into the artery (or actually pulled into the artery to protect the endothelial cells)? I think this is the gist of Masterjohn’s arguments, and I think might have a point.

    Anyway, I think the arguments you present make a compelling case that ALL THINGS BEING EQUAL, you would want to have lower LDL-P than higher LDL-P if you want to reduce CVD risk (but prob not infections). But since all things arent equal, can you offset the risks associated with high LDL-P by having lower blood pressure, not smoking, keeping your blood vessels healthy via good glucose control, etc?

    • Interesting question, Ed. Sounds like you’re suggesting that in addition to poor LDL-P clearance leading to increased LDL-P concentration, there could be (another) confounding variable – particle age? If this could be accurately measured it would actually be possible to do the same sort of analysis that was done to parse out size vs. particle count. One could look at age vs. number. So I don’t think the age issue is how you’ve described it. You are just reiterating the gradient model. Remember, these particles are in constant circulation “buzzing” by the endothelium. The only time they stop is when they violate the barrier.
      Poor clearance –> more particles IS the reason for these 2 cases I’ve given. I think you’re suggesting poor clearance –> more particles AND change in particle “quality” AND BOTH may account for the increased risk. That’s a hypothesis worth testing.

  6. One thing that seems abundantly clear from the literature is that the body makes attempts to regulate LDL. The fact that the LDL-P lowering by statins is caused by an upregulation in LDL-R because it senses it is running low on cholesterol (because it cant produce enough and cant pull enough in via extra gut absorption) is an example.

    Now consider this… I’ve searched pubmed for the impact of saturated fats on ldl-receptor expression, and there are a few papers suggesting that saturated fat increases LDL-C concentrations via downregulation in LDL-R. Now why would he body do that? Conversely, increased dietary PUFA intake, upregulate LDL-R expression. Now why would the body do that?

    Maybe there is no good reason, but could it be that the body assumes its safe to send out SFA laden particles into the bloodstream for longer periods of time, while fragile PUFA-packed lipoproteins need to be recycled as quickly as possible?

    So Peter, where do you come out on PUFA vs SFA? If you are in the LDL-P camp, it would suggest favoring PUFA over SFA consumption… but if you are in the big particle, TC/HDL ratio camp, this would favor SFA consumption.

    • I don’t have enough clear data beyond a few studies to really say definitively if PUFA vs. SFA vs. MUFA has a differential impact on LDL-P. Some idea of what they do to LDL-C, and as Dr. Dayspring pointed out, in some cases we know because of specific trails (e.g., EPA, DHA) that they have no impact on LDL-P.

  7. Dr. Attia.

    Good series. Don’t let my quibbles lead you to think I don’t like it. And, much as I have long hoped that big fluffy LDL is no problem, it is time that the paleo – low carb world hear that the evidence points in the other direction. Maybe not irrefutably, but we see the assertion that small LDL is the sole problem all over the place, flat-footed and presented as established fact.

    Which brings me to my quibble. Throughout your series I think you are overstating the role of lipids as the causative agent of athersclerosis. No doubt high LDL-P is associated with significant risk, no doubt. But it isn’t a death sentence, and other factors are very important, and we don’t know how it plays a role or to what degree it is causative.

    Example: You say: “The most lethal lipoprotein disorder is familial hypercholesterolemia, which I have discussed in previous posts. Such patients all have large LDL particles, but most of these patients die in childhood or early adulthood if not treated with medications to reduce particle number.”

    You told LynneC above you would fix statements of this type. Fix that one. If you mean homozygous FH, OK. But 99% of FHers (like LynneC and like me) are heterozygouts, and our FH has perhaps been a survival advantage up to recent times. I have now spent several days looking for proof of various assertions that HtFH is a giant risk for CAD. In some familiies, yes. For me, it is a risk but probably not as bad as smoking, or smoking plus T2DM, or smoking plus LP(a). (My Framingham risk is 9% in next ten years; not that Framingham is that great.)

    I am very anxious to see what you say about statins. Your mentor Dr. Dayspring loves them, even though he has difficulty tolerating them. If LDL-P is the 800-pound-gorilla cause of CAD, how come statins still have a 70% (or higher if you figure that the studies have been biased to find bigger positive effects) residual risk. How come other cholesterol lowering agents don’t seem to reduce CAD? How come statins seem to have the same modest benefits in reducing heart attacks (if not mortality) in people with low LDL numbers as well as high LDL numbers?

    LDL-P is important, but my quibble is that you are overstating its contribution to risk. CAD is a multi-factorial ailment. I look forward to your future posts – my comment here (not seeking a response here) is to suggest to you that you will need nuanced answers.

    • Great points in here. Yes, when I speak about FH, I’m talking about homozygotic patients, not heterozygotic patients. Though, heterozygoes have more risk than “wild type.” To your big question about statins, I would say the biggest problem is that they are — in at least 90% of cases — being used to treat (i.e., lower) LDL-C. As you see in this week’s post, doing this is not a judicious way to use them. I’ll come back to the example I’ve given several times. A hammer is a very good tool for pounding nails into wood. When you start using a hammer to wash your windows — that is, when you use a good tool for a job it wasn’t really made for — the results may not look so good. No doubt statins are great at lowering LDL-C (so many silly analogy is not perfect), but the point is, who cares if they lower LDL-C?

  8. Excellent series. Learning a lot and can’t wait for more. Have a good library of VAP tests now (with ApoB), so will make next test an NMR and see how it compares and what new things I learn.

    That said, as seems to be the case with at least Vasco and Ed, I do not believe you have yet proven the closing emphatic declaration of point #22 – i.e. “Period.” Their questions seem like it points to opportunity for credible further inquiry.

    Whereas you’ve made it clear that inflammation does take place in response to the penetration of the endothelium by an ApoB lipid particle, and whereas it seems plausible that particle concentration gradient is a factor, the issue seems to lie in whether something else is also an important forcing function on the initial attraction/penetration. The leading hypothesis seems to be associated with inflammation, perhaps caused by glucose or infection or some other variable(s).

    So whereas I can see that human experiments are indeed difficult (i.e. the seat belt problem), do you think there is something to learn from animal experiments that explored effects both known inflammatory and anti-inflammatory agents in a controlled setting?

    • I’m not disputing that factors beyond LDL-P can exacerbate the problem of atherosclerosis, and perhaps I’ve misunderstood some of the comments. There is no dispute that inflammation plays a role, but where? Are we suggesting that taking 50 mg of prednisone per day (sure to suppress all inflammation in the body) is going to reduce atherosclerosis? Inflammation is a very diffuse and complex pathway. The reductionist approach does not seem to work. Ask any patient who has had an organ transplant. We need to globally suppress their immune response to prevent organ rejection, and with that comes many other problems.
      I am all for lowering inflammation through food choices, and we certainly see a reduction in diffuse markers of inflammation (e.g., CRP, ESR, WBC) with carb- and especially sugar-restricted diets. So I think glucose and even infectious agents can play a role. But nothing in this arena has been more studied the role of apoB and LDL-P, so perhaps I’m just a bit confused by the opposition to these data. It’s probably my fault for not doing a good enough job explaining it. See if your question still holds after part VI this week.

    • Peter:

      “There is no dispute that inflammation plays a role, but where?”

      Ok, now I see the miscommunication. Uffe Ravnskov and others who are skeptical of the lipid hypothesis and who don’t think cholesterol matters tend as a group to argue that those people you call “LDL discordant” – those who have the worst heart attacks out of the blue – also seem to have very high inflammation. Thus they ask which the better risk marker, the LDL-P, or the inflammation? It’s true that the LDL-P has been better studied, but that doesn’t mean it is actually the better risk marker, right?

      So i think the folks above are trying to ask you if you have thought about this question: which is the better marker? And do you think inflammation needs to be studied more? That’s all. 🙂

      • In large, unsegregated populations, inflammatory markers like hs-CRP, are good markers for cardiovascular disease risk. But, as you’ll see in subsequent posts, it provides little guidance is terms of treatment. If someone has a high hs-CRP, what is the first line of treatment? I’ll get into this more later.

        • Dry sauna!I sit in one for an hour a day over two sessions at 190! Whole grains also lower hs-CRP!I pretty much follow the Okinawa Blue zone diet! I’ve used this blueprint with my clients for 12 years now! I’m 49 and was diagnosed 5 years ago with RA, the 16th in my family since 1950 to be diagnosed! I know what I face everyday and do everything in my power not to get CVD! I’ve lived a healthy lifestyle my entire life, very athletic and very lean 210 9% body fat! My hA1c is 4.5, HDL 70, LDL 120, TG’s 40, CRP 0.5, hsCRP 0.3,Homocysteine 6 Calcium score still luckily Zero and carotids clear! My formula is pretty straight forward, I fast, eat real food, do heavy resistance training mainly through my legs and moderate amounts of cardio, mainly sprinting! I’m a nobody in this group, but I’ll go to my death bed believing the driving force of CVD is through typ2 diabetes and insulin resistance!I believe lifestyle is the benchmark, to longevity, of course with a little luck, mainly being happy and positive and cool to everyone! You can’t supplement or medicate your way to health and wellness! Thank you for your work Peter, I’ve really learned a lot from you over the last 3 years! On a side not, Health care starts with the individual! The doctors, insurance companies and especially big Pharma with manage your sick care! Metabolic syndrome is the greatest epidemic in the history of the world, it makes up 75% of the 3.6 trillion spent on health care! We will get healthier as a nation when we decide to take personal responsibility of our lifestyles! Good health to all!

    • Just getting back on after a busy week…

      Actually, I think the underlying question is a bit different. So far, the evidence seems solid that the process kicked off following invasion of the LDL leads to significant inflammation. It also seems plausible that pre-existing inflammation will likely exacerbate the problem (with which you seem to agree) with LDL-P count as a driving factor (seems logical).

      The question that seems to me worthy of further study is whether some pre-existing state (i.e. inflammation, …?) is a pre-requisite to get the whole thing started. In other words, if there were low/no inflammation, could you do just fine with a high LDL-P? Perhaps there is even a linear correlation – i.e. iso-risk lines that increase safe LDL-P levels as inflammation decreases (realizing latter may be hard to reliably measure)?

      Off to read Part VI 🙂

  9. Dr. Attia thank you for your work. I just want some clarification on some things.

    In your summer video for JumpstartMD you mentioned that your small dense LDLs stayed the same when you went low carb but your large buoyant LDLs increased. You mentioned these large buoyant LDLs being less harmful in that video series one year ago.

    However, now that it is becoming clear that the particle size doesn’t matter and that it’s the actual numbers themselves…doesn’t that mean you were at a higher risk on low carb since you pointed out that your small dense LDL-P stayed the same but your large LDL-P increased making total LDL-P #s increase?

    • Yes, unfortunately, when I was doing my self-experiments I did not know enough about lipidology to know I should have been tracking my LDL-P. That said, we can’t really conclude much from my VAP, since we have no idea what happened to apoB or LDL-P during this change.

  10. Does the VAP test have any place in helping one understand the LDL-P number? On the VAP test they refer to apoB100 (I’m not sure I’m following, but it seems you are using LDL-P and apoB interchangeably?). I think that you are saying the ratio does not matter but perhaps the size does.

    I’m trying to understand if this is supposed to be the same particle being discussed in the post? It says it is being measured, but is it actually just a calculation? I can see that NMR is the way to test next time, but is the VAP useful at all in the absence of an NMR?

    Still trying to sort out the post with my non-science background!

    Many thanks.

    • Nick, the apoB reported in VAP is not actually measured. It’s estimated. Hence, it serves little purpose. I think I addressed in this in part III of this series. If apoB is measured directly, yes, it can be used as a good proxy for LDL-P. Keep up the good work. This will all make sense eventually. It took me a while a learn it well, also.

  11. On my last blood test my apo-b was in the 40 percentile however my ldl-p was high (1800). I thought that there was a direct relationship between the two. Makes me wonder how accurate the blood test were. Is it possible to have this kind of disconnect?

    • Depends if you had a measured apoB or an estimated one (via VAP). If the latter, discordance is more common. If the former, it’s less common but it does happen. In this case, risk tracks LDL-P.

  12. Dr lipid,
    If cholestanol alone is in hyperabsortion range on Crestor with ldlp 95% can zetia decrease ldlp significantly.?

  13. Peter,
    You’re a powerful force for good, keep up the great work! [Same for Dr. Dayspring if he’s reading] Everybody knows you don’t give medical advice over the internet so let me describe a hypothetical situation and ask two questions.

    Imagine a 55ish male, 6ft 240lbs, who’s eaten low-carb/high-fat paleo for a couple of years. He’s still got a stubborn 20 lbs of subcutaneous fat to lose but overall he loves it, has lost weight, is slowly building muscle, feels great etc. Let’s he say takes no medications at all and is generally in mild ketosis (by ketostick measurement). With tight glucose control, he’s winning the war on insulin!

    An educated layman, he’s very interested in health in general and lipid metabolism in particular. So he’s following the discussion and decides to get an NMR, anticipating a moderate to low-risk LDL-P number. He looks at his triglyceride/HDL ratio (110/50 = 2.2) and is happy. Then his jaw hits the floor as he sees an LDL-P count of 2400!

    Hypothetical NMR results:

    LDL-P 2400

    Cholesterol Total 280 mg/dL
    LDL-C 210 mg/dL
    HDL-C 50 mg/dL
    Triglycerides 110 mg/dL

    Small LDL-P 790 nmol/L
    HDL-P (Total) 31.4 umol/L

    LDL Size 21.2 nm

    Here are the two questions:

    1) Does being keto or fat-adapted make a difference? I.e., would a high particle count be ‘risky’ for a glucose-burner but ‘less risky’ or ‘not risky’ for a fat-burner?

    2) How do you lower the number of LDL-P? Would dialing up the carbs (ugh!) and ‘balancing’ the metabolism make sense? Increase carbs, and probably body fat, to lower CVD risk?

    • An LDL-P of 2400 in a person already compliant with a low-sugar, low-carb diet needs medication to be fixed. Likely apoE problem (i.e., 3/4 or 4/4 allele), suggesting multi-drug therapy.

  14. If you already have some artery plaque like many over 50 who have been subjected to the SAD diet do, how low should LDL particle count be? Also, how would you know that your plan of diet and meds to get to the particle goal is actually preventing the further increase in plaque creation in coronary arteries? Also, is reversal possible: we all have seen the Crestor commercials!

    • Yes, this process is partially reversible – both with medication and dietary change. Unfortunately (though not surprisingly) the older you are, the more longstanding the damage, and the greater the damage, the harder it is to reverse.

    • Very true, but there are people in their 80’s and 90’s with very high calcium scores some as high as 1,000, so if CAD not to high for a younger person and progression can at least be stopped there is significant hope that the 40-60 yr old can live event free in to their 80’s or 90’s.
      We will all die one day of either cancer or heart disease; the goal is postpone that until being very old.
      Thanks! Look forward to your thoughts on diet and meds to address this. Am guessing carb restriction of some kind will be in order. Also, be interesting to learn how low LDL particles need to be if there is already some disease.

  15. Goal: Search the earth and find out who has the high LDL-P (Virus): Resident Evil ?)-

    Inoculate said victims with Big Pharma Sta tins and Niacin

    This whole thing is beginning to resemble something from the – ‘Resident Evil’ movie

  16. Great post! Thanks for your hard work. Much appreciated! How is the cook book going? Release date? : )

    • I would like to have something ready in a year…sorry for the delay. I’m having a hard time keeping up with blog, let alone other commitments. I do seem to come up with a few new amazing recipes every week, though.

  17. Hi Peter, I believe you have the kick-off meeting this week. Is this why you changed your name to The Eating Academy? Blessings and success to you all, Maryann

    • Yes, kick-off meeting is on Friday. Name change is actually unrelated, I just haven’t had the time to shift over. I’ll will be migrating this blog onto a separate site called, which I’ll explain in the next few weeks.

    • Hi Maryanne,

      I’d really like to read what you have amassed together regarding Cholesterol, if possible?
      I think I’d appreciate your aim to make laymen’s sense of this often scientifically jargen laden subject.

      Many thanks to you and all who have advanced the subject.

    • I am not sure what you are referring to; did you mean to ask someone else for this information?

  18. Total layman reporting to ask annoying questions:

    If my understanding is correct, familial hypercholesterolemia is caused by a genetic defect resulting in under-expressed and/or functionally compromised LDL receptors on the hepatocytes, meaning that not only will LDL-P be high, but these large-buoyant LDL particles will remain in circulation for much longer than large-buoyant LDL particles in a person without this genetic defect of the LDL receptor, thus prolonging their exposure to oxidative factors in the bloodstream. On the other hand, in diabetics and those with advanced metabolic syndrome, their small-dense LDL particles have intrinsically less affinity for the LDL receptor than large-buoyant LDL particles, and thus will stay in circulation for longer than large-buoyant LDL particles, but still not nearly as long as large-buoyant LDL particles in those with a genetic defect in the LDL receptor. So doesn’t it make perfect sense than those with FH tend to succumb to heart disease much earlier in life than diabetics or advanced metabolic syndrome sufferers, even though they have large-buoyant LDL profiles, and even though under normal circumstances small-dense LDL is more prone to oxidation and thus more atherogenic than large-buoyant LDL? Isn’t the plasma half-life of particles, and by extension their rate of oxidation and glycation, just as important if not more important than particle number?

    • Ted, nothing annoying about this question. You are correct about the phenotype of FH and how their pathology exists, despite large LDL particles. Your second claim, however, is not true. Jim Otvos has very elegantly shown than particle-to-particle, a single small LDL is no more or less atherogenic than a large LDL particle. As you note, of course, small particles are a strong marker for metabolic syndrome and the higher particle count that comes with it.

    • But wouldn’t a small LDL particle’s reduced affinity for the LDL receptor alone make it more atherogenic by virtue of its increased half-life?

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