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The personal blog of Peter Attia, M.D.

The straight dope on cholesterol – Part IV

The straight dope on cholesterol – Part IV


Previously, in Part I, Part II and Part III of this series, we addressed these 5 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?

In this post we’ll continue to build out the story with the next concept:

     #6How does cholesterol actually cause problems?

Asked another way, how does someone end up with a coronary artery that looks like the one in the picture above?

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 (i.e., those patients not on cholesterol-lowering drugs), before changes are noted in glucose or insulin levels.


Concept #6 – How does cholesterol actually cause problems?

If you remember only one factoid from the previous three posts on this topic, remember this: If you were only “allowed” to know one metric to understand your risk of heart disease it would be the number of apoB particles (90-95% of which are LDLs) in your plasma.  In practicality, there are two ways to do this:

  1. Directly measure (i.e., not estimate) the concentration of apoB in your plasma (several technologies and companies offer such an assay). Recall, there is one apoB molecule per particle;
  2. Directly measure the number of LDL particles in your plasma using NMR technology.

If this number is high, you are at risk of atherosclerosis.  Everything else is secondary.

Does having lots of HDL particles help?  Probably, especially if they are “functional” at carrying out reverse cholesterol transport, but it’s not clear if it matters when LDL particle count is low. In fact, while many drugs are known to increase the cholesterol content of HDL particles (i.e., HDL-C), not one to date has ever shown a benefit from doing so.  Does having normal serum triglyceride levels matter? Probably, with “normal” being defined as < 70-100 mg/dL, though it’s not entirely clear this is an independent predictor of low risk. Does having a low level of LDL-C matter?  Not if LDL-P (or apoB) are high, or better said, not when the two markers are discordant.

But why?

As with the previous topics in this series, this question is sufficiently complex to justify several textbooks – and it’s still not completely understood.  My challenge, of course, is to convey the most important points in a fraction of that space and complexity.

Let’s focus, specifically, on the unfortunately-ubiquitous clinical condition of atherosclerosis – the accumulation of sterols and inflammatory cells within an artery wall which may (or may not) narrow the lumen of the artery.

Bonus concept: It’s important to keep in mind that this disease process is actually within the artery wall and it may or may not affect the arterial lumen, which is why angiograms can be normal in persons with advanced atherosclerosis.  As plaque progresses it can encroach into the lumen leading to ischemia (i.e., lack of oxygen delivery to tissues) as the narrowing approaches 70-75%, or the plaque can rupture leading to a thrombosis: partial leading to ischemia or total leading to infarction (i.e., tissue death).

To be clear, statistically speaking, this condition (atherosclerotic induced ischemia or infarction) is the most common one that will result in the loss of your life.  For most of us, atherosclerosis (most commonly within coronary arteries, but also carotid or cerebral arteries) is the leading cause of death, even ahead of all forms of cancer combined.    Hence, it’s worth really understanding this problem.

In this week’s post I am going to focus exclusively on what I like to call the “jugular issue” – that is, I’m going to discuss the actual mechanism of atherosclerosis.   I’m not going to discuss treatment (yet).  We can’t get into treatment until we really understand the cause.

“It is in vain to speak of cures, or think of remedies, until such time as we have considered of the causes . . . cures must be imperfect, lame, and to no purpose, wherein the causes have not first been searched.”

Robert Burton, The Anatomy of Melancholy, 1621

The sine qua non of atherosclerosis is the presence of sterols in arterial wall macrophages.  Sterols are delivered to the arterial wall by the penetration of the endothelium by an apoB-containing lipoprotein, which transport the sterols.  In other words, unless an apoB-containing lipoprotein particle violates the border created by an endothelium cell and the layer it protects, the media layer, there is no way atherogenesis occurs. 

For now, let’s focus only on the most ubiquitous apoB-containing lipoprotein, the LDL particle. Yes, other lipoproteins also contain apoB (e.g., chylomicrons, remnant lipoproteins such as VLDL remnants, IDL and Lp(a)), but they are few in number relative to LDL particles.  I will address them later.

The endothelium is the one-cell-thick-layer which lines the lumen (i.e., the “tube”) of a vessel, in this case, the artery.  Since blood is in direct contact with this cell all the time, all lipoproteins – including LDL particles – come in constant contact with such cells.

So what drives an LDL particle to do something as sinister as to leave the waterway (i.e., the bloodstream) and “illegally” try to park at a dock (i.e., behind an endothelial cell)?  Well, it is a gradient driven process which is why particle number is the key driving parameter.

As it turns out, this is probably a slightly less important question than the next one: what causes the LDL particle to stay there?  In the parlance of our metaphor, not only do we want to know why the ship leaves the waterway to illegally park in the dock, but why does it stay parked there?  This phenomenon is called “retention.”

Finally, if there was some way an LDL particle could violate the endothelium, AND be retained in the space behind the cell (away from the lumen on the side aptly called the sub-endothelial side) BUT not elicit an inflammatory (i.e., immune) response, would it matter?

I don’t know.  But it seems that not long after an LDL particle gets into the sub-endothelial space and takes up “illegal” residence (i.e., binds to arterial wall proteoglycans), it is subject to oxidative forces and as one would expect an inflammatory response is initiated.  The result is full blown mayhem.  Immunologic gang warfare breaks out and cells called monocytes and macrophages and mast cells show up to investigate.  When they arrive, and find the LDL particle, they do all they can to remove it.  In some cases, when there are few LDL particles, the normal immune response is successful.  But, it’s a numbers game.  When LDL particle invasion becomes incessant, even if the immune cells can remove some of them, it becomes a losing proposition and the actual immune response to the initial problem becomes chronic and maladaptive and expands into the space between the endothelium and the media.

The multiple-sterol-laden macrophages or foam cells coalesce, recruit smooth muscle cells, induce microvascularization, and before you know it complex, inflamed plaque occurs. Microhemorrhages and microthrombus formations occur within the plaque. Ultimately the growing plaque invades the arterial lumen or ruptures into the lumen inducing luminal thrombosis. Direct luminal encroachment by plaque expansion or thrombus formation causes the lumen of the artery to narrow, which may or may not cause ischemia.

Before we go any further, take a look at the figure below from an excellent review article on this topic from the journal Circulation – Subendothelial Lipoprotein Retention as the Initiative Process in Atherosclerosis.  This figure also discuss treatment strategies, but for now just focus on the pathogenesis (i.e., the cause of the problem).

In this figure you can see the progression:

  1. LDL particles (and a few other particles containing apoB) enter the sub-endothelium
  2. Some of these particles are retained, especially in areas where there is already a bit of extra space for them (called pre-lesion susceptible areas)
  3. “Early” immune cells initiate an inflammatory response which includes the direct interaction between the LDL particle and proteins called proteoglycans.
  4. The proteoglycans further shift the balance of LDL particle movement towards retention.  Think of them as “cement” keeping the LDL particles and their cholesterol content in the sub-endothelial space.
  5. More and more apoB containing particles (i.e., LDL particles and the few other particles containing apoB) enter the sub-endothelial space and continue to be retained, due to the existing “room” being created by the immune response.
  6. As this process continues, an even more advanced form of immune response – mediated by cells called T-cells – leads to further retention and destruction of the artery wall.
  7. Eventually, not only does the lumen of the artery narrow, but a fibrous cap develops and plaques take form.
  8. It is most often these plaques that lead to myocardial infarction, or heart attacks, as they eventually dislodge and acutely obstruct blood flow to the portion of muscle supplied by the artery.

Early progression

Another way to see this progression is shown in the figure below, which shows the histologic progression of atherosclerosis in the right coronary artery from human autopsy specimens.  This figure is actually a bit confusing until you understand what you’re looking at.  Each set of 3 pictures shows the same sample, but with a different kind of histological stain.  Each row represents a different specimen.

  • The column on the left uses a stain to highlight the distinction between the intimal and media layer of the artery call.  The intima, recall, is the layer just below the endothelium and should not be as thick as shown here.
  • The middle column uses a special stain to highlight the presence of lipids within the intimal layer.
  • The right column uses yet a different stain to highlight the presence of macrophages in the intima and the media.  Recall, macrophages are immune cells that play an important role of the inflammatory cascade leading to atherosclerosis.


What is particularly compelling about this sequence of figures is that you can see the trigger of events from what is called diffuse intimal thickening (“DIT”), which exacerbates the retention of lipoproteins and their lipid cargo, only then to be followed by the arrival of immune cells, which ultimately lead the inflammatory changes responsible for atherosclerosis.


Why LDL-P matters most

You may be asking the chicken and egg question:

Which is the cause – the apoB containing LDL particle OR the immune cells that “overreact” to them and their lipid cargo?

You certainly wouldn’t be alone in asking this question, as many folks have debated this exact question for years.  The reason, of course, it is so important to ask this question is captured by the Robert Burton quote, above.  If you don’t know the cause, how can you treat the disease?

Empirically, we know that the most successful pharmacologic interventions demonstrated to reduce coronary artery disease are those that reduce LDL-P and thus delivery of sterols to the artery. (Of course, they do other things also, like lower LDL-C, and maybe even reduce inflammation.)

Perhaps more compelling is the “natural experiment” of people with genetic alterations leading to elevated or reduced LDL-P.  Let’s consider an example of each:

  1. Cohen, et al. reported in the New England Journal of Medicine in 2006 on the cases of patients with mutations in an enzyme called proprotein convertase subtilisin type 9 or PCSK9 (try saying that 10 times fast).   Normally, this proteolytic enzyme degrades LDL receptors on the liver.  Patients with mutations (“nonsense mutations” to be technically correct, meaning the enzyme is somewhat less active) have less destruction of hepatic LDL receptors.  Hence, they have more sustained expression of hepatic LDL receptors, improved LDL clearance from plasma and therefore fewer LDL particles.  These patients have very low LDL-P and LDL-C concentrations (5-40 mg/dL) and very low incidence of heart disease.  Note that a reduction in PCSK9 activity plays no role in reducing inflammation.
  2. Conversely, patients with familial hypercholesterolemia (known as FH) have the opposite problem.  While there are several variants and causes of this disease, the common theme is having decreased clearance of apoB-containing particles, often but not always due to defective or absent LDL receptors, leading to the opposite problem from above.  Namely, these patients have a higher number of circulating LDL particles, and as a result a much higher incidence of atherosclerosis.

So why does having an LDL-P of 2,000 nmol/L (95th percentile) increase the risk of atherosclerosis relative to, say, 1,000 nmol/L (20th percentile)?  In the end, it’s a probabilistic game.  The more particles – NOT cholesterol molecules within the particles and not the size of the LDL particles – you have, the more likely the chance a LDL-P is going to ding an endothelial cell, squeeze into the sub-endothelial space and begin the process of atherosclerosis.


What about the other apoB containing lipoproteins?

Beyond the LDL particle, other apoB-containing lipoproteins also play a role in the development of atherosclerosis, especially in an increasingly insulin resistant population like ours.  In fact, there is some evidence that particle-for-particle Lp(a) is actually even more atherogenic than LDL (though we have far fewer of them).  You’ll recall that Lp(a) is simply an LDL particle to which another protein called apoprotein(a) is attached, which is both a prothrombotic protein as well as  a carrier of oxidized lipids – neither of which you want in a plaque. The apo(a) also retards clearance of Lp(a) thus enhancing LDL-P levels. It may foster greater penetration of the endothelium and/or greater retention within the sub-endothelial space and/or elicit an even greater immune response.


In summary

  1. The progression from a completely normal artery to an atherosclerotic one which may or may not be “clogged” follows a very clear path: an apoB containing particle gets past the endothelial layer into the sub-endothelial space, the particle and its cholesterol content is retained and oxidized, immune cells arrive, an initially-beneficial inflammatory response occurs that ultimately becomes maladaptive leading to complex plaque.
  2. While inflammation plays a key role in this process, it’s the penetration of the apoB particle, with its sterol passengers, of the endothelium and retention within the sub-endothelial space that drive the process.
  3. The most numerous apoB containing lipoprotein in this process is certainly the LDL particle, however Lp(a) (if present) and other apoB containing lipoproteins may play a role.
  4. If you want to stop atherosclerosis, you must lower the LDL particle number.


(To Part V »)


About the Author:

Peter Attia, M.D., is a physician in private practice in NYC and CA. His practice focuses on longevity and healthspan. His clinical interests are nutrition, lipidology, endocrinology, and a few other cool things.


  1. Dan  May 17, 2012

    Hi Peter, thanks for this highly detailed series. In your conclusion you say that 4. If you want to stop atherosclerosis, you must lower the LDL particle number. Did I miss where you said how this is best done, or is that the subject of a future post?

    • Peter Attia  May 17, 2012

      We’re not there yet…but I’ve given you some hints.

  2. KevinF  May 17, 2012

    Maybe this is beyond the scope of the discussion, but if all that matters is LDL-P, why has it been gospel for some years now, including among many sensible low-carb promoters like Taubes, to make that distinction between supposed benign large fluffy buoyant LDL particles versus the killer small dense LDL particles?

    • Peter Attia  May 17, 2012

      I’ll cover this in a subsequent post. 1,000 large LDL particles are no better or worse than 1,000 small LDL particles.

    • Thomas Dayspring aka "Dr Lipid"  May 17, 2012

      Actually since normally composed large LDLs carry significantly more cholesterol molecules than does a small LDL particle, the larger LDL, particle for particle deliver considerably more sterol molecules to the artery: the most lethal lipid disorder known is familial hypercholesterolemia and those folks have many large LDLs. Homozygotes die in childhood and heterozygotes not treated die in their 20’s and 30’s. Diabetics with their small LDLs dies in their 50’s and 60s. Size is irrelevant as an independent risk factor.
      Please refer to last years Biomarker statement fromn the National Lipid association for a more thorough discussion

  3. medstudent  May 17, 2012

    So you’ve got me thinking a lot with your series on these blood lipids. And I was messing around on Up to Date, doing a little digging. I found this:


    It’s kind of shocking, given that I’ve been thinking that the medical “establishment” as such was entrenched against the Taubesian/Attian view of things (certainly, it’s often what we hear in med school). This is frank exploration of why there is little evidence that reduction in dietary fat consumption is harmful; why increasing carbohydrate consumption may be deleterious; and why many as-yet-unexplored factors may be at play in the major CV diseases of our day. Ultimately the authors recommend less trans & saturated fats–but not the low-fat diet per se, and certainly not a high-carb diet.

    Anyway, like everyone, I’m really interested to see where the rubber meets the road here (connecting your LDL analysis with the high-fat diet).

  4. David Nelsen  May 17, 2012

    The plot thickens (or the artery wall thickens). I have read about some conditions causing the blood to be “Sticky” and I wonder if this is an element in the retention of the particle in the cell wall. Is there a blood viscocity component involved here? Otra articulo magnifico.

    • Peter Attia  May 17, 2012

      This plays no role in atherosclerosis, but DOES play in a role in the generation of the thrombus that actually leads to the occlusion of the lumen of the artery.

  5. lorraine  May 17, 2012

    First off, that atherosclerosis photo is dope.

    Concentration gradient, eh…I’m having a hard time with that. It seems to me (at the moment anyway), that if it was concentration then the total number of all particles would be the factor, and then any particle (even HDL) could penetrate. I know Tara Dall indicated that high levels of any of the particles could create the same problem, but then why is it that the LDL is the one that penetrates? Seems there must be something about apoB, Lp(a) that’s the trouble maker, and then, what is it?

    Seems like once the particle is retained there’s a full blown auto-immune response. Of course this also leads to musing that if there’s a low grade auto-immune response (inflammation) to start out with, does that stack the odds in favor of retention.

    Great post. Thanks again so much. Look forward to reading the papers you linked.

    • Peter Attia  May 17, 2012

      The actual molecule of apoB facilitates the endothelial penetration. Furthermore, LDL particles carry more “cargo” (i.e., cholesterol) to be oxidized in the S-E space.

    • Thomas Dayspring aka "Dr Lipid"  May 17, 2012

      Actually HDLs enter and leave the artery wall all day long. They do not get oxidized as do LDLs and do not bind to arterial wall proteoglycans nor are they internalized by macrophages as do the apoB species.

    • greensleeves  May 18, 2012

      “Actually HDLs enter and leave the artery wall all day long.”

      Why, Dr. Dayspring? Are they picking up unneeded stuff to ferry back to the liver? Why do they have to enter the wall to do that?

    • Peter Attia  May 18, 2012

      I’ll answer for Tom here. Yes, HDL particles function to carry out RCT (reverse cholesterol transport). They must penetrate the endothelium to get into the sub-endothelial space, as that is where the sterols (which are being oxidized) are.

  6. EnglishMajor  May 17, 2012

    Hi Peter:

    Interesting quotation from Burton. And as you know, the book was published in 1621. It’s a minor point, but may I ask why you list the date as 1893?

    Just curious. Thanks for the great work.

    “If you want to stop atherosclerosis, you must lower the LDL particle number. Period.”

    I think you have just convinced me to move to the Ornish diet since as we all know, low-carb and SAD always raises LDL, although low-carb reduces trigs.

    And I guess then we can also conclude that the suggestion to put statins in the drinking water is also very sound. So your writing is very important here. Thanks again!

    • Peter Attia  May 17, 2012

      My source has the quote in 1893. Perhaps he said it before the publication of the book?
      Low-carb always raises LDL????? REALLY??? Do you know the difference between LDL-C and LDL-P? Has my last month of work been for nothing? 🙂
      1. High fat diets DO raise LDL-C — let me repeat LDL-choleserol — in about a third of people.
      2. This is NOT the same as raising LDL-P, and in fact many times LDL-C can go up, while LDL-P goes down for reasons I will explain in a future post.
      3. Statins are a very important class of drug, but not if misused. So, NO, they should not be in the drinking. That’s like saying we should use hammers to clean our windows, wash our floors, and wash our dishes because they are so good at hitting nails. Use the tool for it’s purpose and no more.

      I will absolutely get into statins later, also.

    • greensleeves  May 17, 2012

      Wow Peter you’re responsiveness is really impressive. I think we’re all grateful you take so much time and reply to so many.

      Given your point about the difference between LDL-P and LDL-C, did you then perhaps mean to say “you must lower the LDL-P number.” ????

      Forgive me because I too was confused for a bit by that statement. What part do I need to read again?

      As you know a study just came out from the Lancet today in which they do a meta-analysis arguing seriously to give statins out to everyone, even healthy people, and this study has been met with great acclaim. So I can understand why someone new to the blog might think you are endorsing this study.

      And certainly if you read the newspapers, they are always saying that the Ornish diet is the only proven diet to lower cholesterol and reverse heart disease. It’s hard to “unlearn” this info. 🙂

    • Peter Attia  May 17, 2012

      Go back and look at my post on Why Weight Watchers is a Low Carb Diet to see my commentary on the Ornish study. LDL-P number and “concentration” reduction are sometimes used interchangeably. Sorry for confusion.

  7. Stephen Ferguson  May 17, 2012

    This is very timely. In the newspapers today it appears that the UK Government is about to prescribe statins to all over-50s to cover up the effects of the “heart-unhealthy” high-carb diet that they’ve been pumping down everyone’s throats:

    • Peter Attia  May 17, 2012

      See my previous comment on using a hammer to do all household chores. Not the best solution, unfortunately. Ironically, the people suggesting this don’t actually know WHY one should use statins. Statins are, sadly, prescribed by most MDs to lower LDL-C — which they do very well. Of course, this turns to irrelevant if LDL-P isn’t be lowered also, which it is NOT in at a third of patients.

    • Thomas Dayspring aka "Dr Lipid"  May 17, 2012

      Actualy statins fail to lower LDL-P to goal in upwards of 2/3 (not 1/3) of patients. They achive LDL-C goals with far greater frequency

  8. Roger Butler  May 17, 2012

    As a 62 year old who managed to get through school with next to no science education your articles have been a bit of a stretch, but I have persisted, think I am getting the general idea, and like so many others wish to express my sincere gratitude to you for taking the time and putting in the effort to explain these matters.

    I was planning to wait to the end of the series of articles to avoid raising questions that might prove unnecessary, but having just read your latest post I wonder whether now is an appropriate time to raise some issues that I may well not be the only one puzzling over:
    1. You are now referring to sterols, you have already explained that we do not ingest or produce plant sterols so what are we now talking about in addition to cholesterol?
    2. Why would immune cells (which are presumably so-called because of an immunity giving function) make matters worse by ‘cementing’ apoB containing particles into the sub-endothelial space?
    3. The NMR scans you are so keen on do not seem to be available in the UK (so I suspect also not in many other places outside the USA): this being the case can you give advice as to how we can make the best use we can of the standard lipid panel, e.g. say a bit more about the usefulness of ratios like that of triglycerides to HDL (giving – with all necessary caveats – broad information about good, bad and middling ratios).
    4. If you are going to write about treatment for atherosclerosis, and specifically about statins, for me and many of us I suspect, the issue is not simply do taking statins give us some protection from cardio vascular disease, but how do we begin to quantify our individual situations balancing the benefits against unpleasant side effects. Not to put too fine a point on it, given that we are going to die of something some of us may be willing to up our chances of CVD if that lowers our chances of Alzheimer’s or certain cancers.
    5. Finally, when you get to the end of this series of posts on cholesterol might you turn your attention to the benefits of different sorts of exercise that might realistically be followed by those of us not able or willing to give the time and effort you clearly spend on it.

    • Peter Attia  May 17, 2012

      Roger, glad you’re hanging in there. I know it’s been a long haul in these posts.
      1. Some folks do ingest a lot of plant sterols, so yes, these are included in the group. There is a very important nuance around this, and I’ll address it subsequently.
      2. This response is part of the normal and healthy immune response. Sort of like your friends holding someone down while you try to beat him up (not that you’d ever…)
      3. You’re right. Outside of the US the best thing to is have apoB directly measured, as it’s done by a number of labs. This is the best proxy for LDL-P and is more available.
      4. Correct.
      5. I’ll take it under advisement, but it’s not really something I know a lot about. I wonder if others know so much more about this topic?

    • Bill  September 17, 2012

      Just to come in on the point that LDL-P measurement is not available outside the USA. While this may well be true for the testing itself, that does not mean that the samples cannot be shipped to the USA for testing. At County Pathology (www.countypathology.co.uk) we can ship samples to the USA and our patients benefit from the most recent medical advances in diagnostic testing.

    • Peter Attia  September 17, 2012

      As long as the lab can do accurate apoB measurements, that’s a pretty good proxy. Don’t stress about NMR if it’s not available to you.

  9. Vasco Névoa  May 17, 2012

    Hello Peter.

    First off, thank you immensely for such a dedicated and necessary work of public documentation. We owe you.

    However, I agree with lorraine, I really don’t buy the concentration gradient model.
    In fact, Dr. Ravnskov’s infection and inflammation model makes more sense.

    From the point of view of evolution, how does a mechanism so old and well-established as triglyceride shipping in blood go haywire so easily, and why only in the western diet and lifestyle? this is of course a rhetoric question which tends to go into epidemiological terrain and I won’t have you waste time answering it. 🙂

    But I do have a real question:
    – what do you think of Ravnskov’s model and why wouldn’t it be realistic?

    And another, possibly more important question:
    – Isn’t it likely that the critical defect that originates the whole process is the increased permeability of the endothelium to lipoproteins? I can very easily see an exaggerated permeability problem being initiated by some blood-floating toxin, much like what happens with Gliadin disrupting the intestinal mucosa’s interstitial cell connections. THAT would make sense.

    I sincerely cannot believe that this is merely a question of quantity of particles when the system is so complex, so detailed, and so feedback-loop controlled. Nah. Something else is piercing the surface and paving the way for both the LDLs and other inflammatory particles.

    Sorry for plugging Ravnskov’s work into your blog, but I honestly believe this discussion is pertinent and even critical to understand the causes. I completely agree with you that we can’t design a therapy when we don’t know the causes, and I absolutely disagree on the causes you have transcribed here. 🙂

    Keep pumping that data! We sure need it! 😀

    • Peter Attia  May 17, 2012

      Agree to disagree, BUT I acknowledge that we can’t “prove” it definitely because we can’t actually do controlled trials to individually manipulate the variables. Hence, we’ll always have to rely on slightly indirect information, as we are doing now. Inflammation plays a huge role, but in both normal and abnormal inflammatory states atherosclerosis persists, if LDL particles are retained in the sub-endothelial place. Remember, don’t confuse systemic inflammation for local inflammation. What we’re talking about here is not CRP, we’re talking Lp-PLA2.
      All of the other points you’re discussing are valid, but don’t forget that our ancestors probably didn’t walk around with high LDL-P (or TG) as they lived and ate very different from us.
      However, to say you “absolutely disagree on the causes” I have laid out is a bit over the top. You’re then saying that atherosclerosis has nothing to do with apoB-containing particles carrying sterols into the sub-endothelial space and kicking off a cascade of inflammation?

    • Thomas Dayspring aka "Dr Lipid"  May 17, 2012

      There are several types on endothelial inflammation diseases called arteritis (polymalgia rheumatics, Takayuso’s, etc., that are not associated with atherosclerosis so that kills your premise. The only sine qua non for atherosclerosis is sterols in the artery wall and the only way sterols enter the artery and wind up in macrophages (foam cells) is in apoB containing lipoproteins

    • lorraine  May 17, 2012

      I’m just cogitating here, so this isn’t a question that I’m posting for an answer from Peter per se. I did a bit of a lipids bender last night previous to this post so I’m rolling all of it around in my head.

      So if it’s the volume of the traffic jam of all particles that increases the chance of a crash to the epithelium, but only the apoB-carrying LP (and/or Lp(a) apo(a)) that penetrates, what is it about apoB that signals it to penetrate? I can’t help but think about Dr. Dayspring’s Part II of cholesterol synthesis at Lecturepad, in which he discusses the sterol efflux molecules in the hepatocyte and enterocyte, and says that nature always lets you know what’s up by it’s purposefulness (Jersey paraphrasing), and if we were meant to absorb phytosterols, we wouldn’t have two separate efflux molecules to get rid of them and prevent absorption.

      In this same regard, I’m curious about what’s the purposeful function of apoB when it’s not causing havoc in the arteries. Is there something it’s supposed to do that signals it to enter the intima? My first choice would be that it’s responding to something immunological going on in there, but Figure 2 does seem to indicate that intimal thickening goes on first before lipid penetration and macrophage infiltration (p.s. cool graphics, again, btw).

      However, both Figure 1 and 2 indicate that intima/media thickening seems to be the antecedent to the whole mess, and it’s suggested in the literature that this thickening can be calcification in response to inflammation and cytokine production (e.g., http://cjasn.asnjournals.org/content/3/6/1599.full). Is apoB being signalled by that?

      So to Vasco’s point about infection, or more to my liking, autoimmunity caused by gut permeability. His guy Ravnskov’s (2003) paper on infection is compelling, especially as it relates to LPS binding on LDL.

      The point being that does apoB have a function that’s being signalled by something going on with intimal/medial thickening? For example, is it responding to inflammatory markers or calcium associated with thickening?

      Ok, brain finished. Peter, I don’t know what drives you to provide this high level content (and your time and energy) for free, but I am grateful. I don’t think I’d be pushed this far forward in the current thinking about lipids were it not so well directed by your efforts.

    • Peter Attia  May 17, 2012

      Thanks for understanding.

    • Carol  May 17, 2012

      No, I think he’s disagreeing with the idea that the gradient of LDL-P being the driving force for LDL-P to leave the blood stream and enter the intima. How does LDL-P squeeze by the endothelium? To get into cells it needs to bind to its receptor and then be phagocytosed. What allows it to pass freely between endocytes? Presumably there is a concentration gradient for similar sized particles that are floating around the blood stream all the time, and these aren’t described as ending up in the intima. There has to be a chemotactic signal for the particle to move through the artery wall at the location that it does move across. I think the story makes sense from where you’ve started to tell it, but I don’t think we know what the beginning of the story is yet.

    • Mike N.  May 17, 2012

      I wonder if glucose damages the endothelium to make it more permeable to LDL particles?

    • Peter Attia  May 18, 2012

      It certainly does other things like interfere with hepatic clearance of remnant lipoproteins.

  10. Vasco Névoa  May 17, 2012

    To put it more simply, the model I give most probability of being close to the truth is this:
    Pathogenic invasion of the blood gives rise to two parallel effects:
    – chemical toxicity of the blood, by which some specific toxin acts on the blood vessel wall to increase permeability;
    – feedback-loop up-regulated expression of LDL particles to mop up the blood toxins.
    These two things could easily be happening and be misconstrued as “too much cholesterol sinks into your arteries”.

    The only “proof” I have for this is my own personal anecdote: after being on a “primal” diet and lifestyle for almost a year, I have seen every single serum marker go significantly better except LDL count. All my epidemiologic-derived risk factors are superb (body fat, HDL, TG, BG, whatever) and yet the dammned LDL goes up and down and up and down… correlated only with one thing: the current state of a chronic gut infection I have been fighting for years.
    Sooo… what does this tell you? 🙂

  11. Vasco Névoa  May 17, 2012

    Sorry for hogging the replies, but I just remembered Lukas Tafur’s take on the subject: lots of pathogenic material is found in artherial plaque, which is very indicative to me.
    So you don’t say that I only quote Ravnskov. 😉

  12. Lardlad  May 17, 2012

    So particle size doesn’t matter and we are back to lowering numbers?

    • Peter Attia  May 17, 2012

      Particle size does not matter. The number of LDL particles is the most important feature to understand your risk of atherosclerosis.

    • George Henderson  May 17, 2012

      Yeah but, you can’t easily quantify number of particles from a mass measurement if you don’t know their size.
      Pragmatically, the two things are linked;
      a microgram of LDL-C could be a few big ones or lots of little ones, and it’s easier to weigh it than count them.
      In that regard, size is indeed important.

  13. Bruce  May 17, 2012

    First of all, thanks for the great series on Cholesterol. This installment brings up a question. If the LDL/apoB particle count is all that matters in the formation of atherosclerosis why do we only see placks in the coronary arteries and not the veins?

    • Peter Attia  May 17, 2012

      Great question, Bruce. I think it has to do the fact that veins don’t have muscular walls, the so called “media” layer. This is actually a good bit of evidence for LDL particle RETENTION in the sub-endothelium is vital. No place to hang out –> no need for immune response.

    • Thomas Dayspring aka "Dr Lipid"  May 17, 2012

      Totally different hemodynamic variables in the veins – a very low pressure system and as Peter says the walls of veins are very different than arteries

  14. Bruce Blakely  May 17, 2012

    So this morning in addition to Part IV of this series, we open our newspapers and find:

    Peter, what is your take on the importance of the HDL/LDL ratio? Is there good and bad HDL, as one interviewee expresses in the above cited article? Why should we care about HDL-2 vs HDL-3 (as broken out in the tests in Part III). You mentioned HDL (and other) levels as an indicator of insulin resistance but you really didn’t get into that much.

    Or are you saying we should just focus on LDL-P and forget about HDL?

    • Peter Attia  May 17, 2012

      I commented about the pharmacological benefit of raising HDL-C in this post — no evidence it “works” (i.e., aids in RCT). No value in HDL/LDL and no real reason to care about HDL-2 vs. HDL-3. I did all of my testing with VAP before I understood this topic well enough, unfortunately.

      Low HDL-C is a predictor of risk, but it doesn’t really matter the way apoB does. Once you know apoB (or LDL-P), you can stop worrying about the other things.

    • KevinF  May 17, 2012

      Hope folks are paying attention. Here Peter’s been laying out his case that says, among other things, that HDL doesn’t REALLY matter because it’s something else that matters. Now in the middle of all that comes news that … HDL doesn’t matter, it must be something else that matters — and the world is shocked! I guess they haven’t been following this blog!

  15. Stuart  May 17, 2012

    If baffles me that you are supporting the lipid hypothesis after debunking the diet heart hypothesis. As far as I can see you are confusing correlation with causation just the same but are explaining it with an elaborate, as yet unproven, theory about why LDL particles get into the artery wall in the first place.

    • Peter Attia  May 17, 2012

      Stuart, I actually just acknowledged this point in a previous response today. Since we can’t design a RCT and directly manipulate LDL-P vs. LDL-C vs. some other lipoprotein characteristic, all of our understanding in this topic stems from indirect information. This is the best we can do, so you’ll have to determine for yourself if this level of evidence is good enough to justify a change.
      That said, I’m not sure if you’ve actually read all of the studies on this topic. Nothing I write in my little mickey mouse blog should be a substitute for actually going back and scouring the literature, should you choose to. If you do, I think you’ll have a hard time convincing yourself that apoB-containing lipoproteins do not play a central role in atherosclerosis.
      Put it this way, there are no randomized trials proving beyond a reasonable doubt that you should wear a seat belt, right? There is a lot of observational data *AND* a very compelling mechanistic argument. Is this bulletproof? No way. Are we going ever have randomized data to address this question? Unlikely. But the question is, what will you do the next time you get in a car? Will you put on a seat belt?

      Nutrition is different. We actually do have the ability to manipulate the variable (i.e., food intake) in a controlled manner (and I’m saying nothing about how weak the observational linkages are). You might find my post on red meat helpful, because I address this point and use smoking as an example.

    • lorraine  May 17, 2012

      Stuart, just to clarify the nomenclature, the lipid hypothesis IS the diet heart hypothesis. It states that dietary cholesterol/fat is the cause of heart disease.

      What’s being proposed here (and in the so-called Alternative Hypothesis) is that dietary cholesterol/fat is completely inconsequential, and that it’s not even the cholesterol that’s made by the body that’s the problem, but the carrier molecules – the lipoproteins – that cause injury.

      But when you look at the things that lower the problematic lipoproteins (the LDL-P), it’s all the stuff that also lowers insulin: low carb diet, exercise and metformin. (You can view Tara Dall’s presentation on Advanced Lipid Testing on Lecturepad for this discussion.) Ergo, the Alternative Hypothesis looks to factors that increase insulin as associated with the increase in these carrier lipoproteins.

    • Peter Attia  May 17, 2012

      Thanks for adding some clarification to this obviously complex (but stimulating) discussion.

    • Stuart  May 18, 2012

      I think Daniel Steinberg would disagree with your assessment about “Lipid” vs “Diet Heart”. The lipid hypothesis has always been about LDL particles but confused with cholesterol because cholesterol was a suragate measure that could more easily be measured. I think the evidence more correctly implicates damaged lipoproteins, via both glycated APOb and oxidized polyunsaturated fatty acids in the phospholipid and CE as triggering the immune system cascade. That which damages lipoproteins likely also damages the artery increasing the need for cholesterol to repair the damage. The ideas about LCHF are interesting because clearly there are changes but not all are consistant. For some LDL-C increases and for most particle size increases but LDL-P seems to be inconsistant, even increasing for some.

  16. Vasco Névoa  May 17, 2012

    Quoting Peter:
    “However, to say you “absolutely disagree on the causes” I have laid out is a bit over the top. You’re then saying that atherosclerosis has nothing to do with apoB-containing particles carrying sterols into the sub-endothelial space and kicking off a cascade of inflammation?”

    No, I don’t mean to say. 🙂 I probably over-expressed myself there, so I’ll clarify: I totally disagree that it is the sheer concentration gradient that drives ApoB particles into the vessel wall. Of course, like you said so well, this is all about probabilistic belief, not actual proven fact. Unfortunately.

    And when it comes to the role of inflammation in atherosclerosis, I believe the jury is still out on the whole chicken-and-egg question: which comes first? Could you shed some light on this subject, indicating what factoids we have at our disposal to piece the puzzle together?

    • Peter Attia  May 17, 2012

      It’s basically that any clinical setting where a patient has elevated LDL-P (apoB) circulating, they get more heart disease, independent of inflammatory state. If we could make human knockouts with no immune system, of course, we could give them all the LDL-P in the world and they would not develop atherosclerosis (of course, they would be dead from everything else).
      Let’s ask the more important question: what should we be doing about it?
      If the cause is only inflammation how does this explain FH or nonsense mutations in PCSK9?

    • Bob Johnston  May 17, 2012

      I really enjoy the debate on just how does oxidized LDL get underneath the endothelium.

      My personal favorite is that an artery/endothelium suffers inflammation and the endothelium is breached in places, allowing LDL to be trapped underneath it. But what causes a breach in the endothelium? As Malcolm Kendrick mentions in “The Great Cholesterol Con”, only arteries and not veins will become atherosclerotic. And with veins and arteries being the same structurally, the only difference seems to be what they carry. Arteries are subjected to higher pressures and carry oxygenated blood. My feeling is that the higher pressure could cause more damage and the higher oxygen levels of the blood would tend to oxidize LDL particles that are trapped and continually bathed in the high levels of oxygenated blood.

      So what causes the inflammation and breach of the endothelium? My guess is that the most blame can be laid against elevated blood sugar and elevated insulin levels. I ran across this article the other day by Ron Rosedale (unfortunately with no citations) but he mentions that introducing insulin into a dog’s artery will have it plaque filled in 3 months. I thought this was interesting:

      “But there are certain tissues that aren’t becoming resistant such as your endothelium; the lining of the arteries doesn’t become resistant very readily, so all that insulin is affecting the lining of your arteries.

      If you drip insulin into the femoral artery of a dog, there was a Dr. Cruz who did this in the early 70s by accident, the artery will become almost totally occluded with plaque after about three months.


      So my thinking is that damage to the endothelium by excessive blood sugar, insulin and high pressure creates an opening for LDL to become trapped, bathing the LDL in highly oxygenated arterial blood and becoming oxidized. This causes an immune response and even more damage. Over time, if the underlying reason for the initial inflammation (high insulin and blood sugar) isn’t cured, the process repeats again and again until you have enough crap built up under the endothelium to cause an infarction or stroke when it breaks off. Obviously this description is very simplistic and there’s a ton of other things going on but as an overview I think it’s reasonable.

      I found an essay by Kendrick which goes into more detail.


      Again, I have no idea what’s really correct but it is fun to mull them over and this theory resonates with me a little more than the others.

    • Peter Attia  May 18, 2012

      Arteries and veins are VERY different. Different histology altogether. Whatever the differences, I suspect the sub-endothelial space is a key contributor.

  17. Jeff D  May 17, 2012

    Peter – for a given LDL-C, aren’t particle size and number two sides of the same coin?

  18. Nuno  May 17, 2012

    Sooo… can we do an experiment where we pick a piece of an artery, some blood and a circulating pump, an LDL-P filter and injector, run it at several numbers of LDL-P particles and see what happens?

    As an aside, do those studies record things like blood pressure and heart rate?

    Very accessible article set Peter, congratulations.

    • Peter Attia  May 17, 2012

      It’s a good idea, but I still think it wouldn’t replicate the exact physiologic scenario.

  19. Vasco Névoa  May 17, 2012

    I’m not saying inflammation is the only factor. Obviously there has to be enough LDL around for it to burrow into the wall (and this quantity may or may not be driven up by the inflammation itself, I don’t know).
    I’ll take your word for it when you say that non-inflamed subjects also get atherosclerotic; but isn’t it true that atherosclerosis also happens on people with low cholesterol concentrations?

    One of the problems I see in the CW view of cholesterol is that the vast majority of data seems to come from patients directly involved in CVD and related death – and this smells quite strongly of confirmation bias to me. Studies of people without CVD symptoms show that people do develop atherosclerosis even when they don’t have high cholesterol.
    So, to me, the concentration gradient theory is too simplistic. We’re missing something here.

  20. Samantha  May 17, 2012

    Thank you so much for putting this all together! I know you have done a lot of work to write this and I just wanted you to know that I appreciate it very much.

  21. FrankG  May 17, 2012

    First off many thanks for this excellent. detailed and extensive series.

    You say “If you were only “allowed” to know one metric to understand your risk of heart disease it would be the number of apoB particles…” Can you please say what you consider to be a normal vs. high number of apoB particles?

    If I may offer, it seems that there is still confusion (in some comments) as to the difference between the various LDL particle counts and what most of us see reported by the standard test which is (as I understand it) a VOLUME. So if I correctly follow your reasoning: “1,000 large LDL particles are no better or worse than 1,000 small LDL particles” BUT with the standard test 1,000 large particles would result in an higher LDL-C “number” than 1,000 small particles.

    • Peter Attia  May 17, 2012

      1,000 nmol/L is 20th percentie. 1,200 is about 50th, and 2,000 is about 95th percentile.

  22. Kypros  May 17, 2012

    Is there a correlation between high LP(a) and high LDL-P?

    Can you have very low VLDL-P and high LDL-P?

    Thanks again Peter!

  23. Kypros  May 17, 2012

    and also… are high LP(a) and LDL-P determined largely by genes? How far does nutrition go in lowering them?

    (ignore question if this will be covered in next part) : )

    • Peter Attia  May 17, 2012

      Genes play a huge role, and I am not aware of the correlation between lp(a) and LDL-P. It may exist, but I’m not familiar with these data.

  24. steve  May 17, 2012

    1. High fat diets DO raise LDL-C — let me repeat LDL-choleserol — in about a third of people.
    2. This is NOT the same as raising LDL-P, and in fact many times LDL-C can go up, while LDL-P goes down for reasons I will explain in a future post.

    Be interested in your further exploration of this. In my case high fat diet does raise LDL-C and LDL-P with LDL-P going through the roof! Am guessing that multiple factors at play: high absorption,genetic predisposition to lots of particles and a CETP problem TRG rich cholesterol poor LDL particles. Only thing that changes on high fat is not particle count, but mix of large and small which is irrelevant.
    I believe that gradient process clearly is the issue as is the architecture of the coronary arteries. If you have lots of particles moving through areas where arteries are more narrow, ie LAD
    you are likely to see more damage. Also, the health of the artery itself,particularly as one ages may be less robust( maybe emits less nitric oxide)thereby allowing particles to penetrate the wall. Infection clearly plays a part,but this appears to be after the artery wall has been penetrated with particles that have been glycated more likely to stay and turn in to a plaque instead of being carried out and returned to the liver.
    CRP is not so good a marker; plenty have plaques and coronary events with low CRP.
    Question: Would an atopic allergic person be more prone to CAD? Immune system already overreacts and maybe it does so when particles penetrate the artery wall.
    Great series. Thanks for being so generous with your time on a complex subject

  25. Laura  May 17, 2012

    Is it really that clear that it is only LDL particle number, and not size, that matters? Intuitively, it would seem logical that it would be easier for small, than large, particles to squeeze into the sub-endothelium. Could both size and number matter? Also, I’m curious what it is about ApoB etc that apparently makes LDL particles so much more likely than HDL particles to enter the sub-endothelium.

    • Peter Attia  May 17, 2012

      We’ll cover this in great detail in one of the upcoming posts. If you want a sneak preview, look at MESA data and the work of Jim Otvos.

  26. Bruce Blakely  May 17, 2012

    Peter – I’m confused about two of your replies with regards to particle size. Can you clarify?

    Above in reply to Lorraine you said: “It’s a size issue, also, and you are correct, the actual molecule of apoB facilitates the endothelial penetration.”

    But in reply to Lardlad you said: “Particle size does not matter. The number of LDL particles is the most important feature to understand your risk of atherosclerosis.”

    A role for apoB would make sense – if size was critical then you would have more HDL (smaller than LDL) leaking past the endothelium. I’m unconvinced on the concentration gradient aspect. A table in part III states that a good LDL-P is given as <1000 nmol/L and a risky LDL-P is ?1300 nmol/L. I don't see a less than 2-fold concentration difference driving a significant difference in getting past the endothelium.

  27. Marilyn  May 17, 2012

    Peter, as always, thanks taking on this cholesterol thing. I’m a kindergartner here, so if I ask a silly question or somehow missed information that’s already been given, forgive me and point me to the info.

    –I was interested to see what you said about veins. I remember reading somewhere that when veins are harvested from one part of the body and placed in service as arteries in another part, the veins can become as atherosclerotic as arteries do. Is that incorrect?

    –What causes the excess LDL-P situation in the first place?

    –To what extent does the integrity of the artery wall enter into this problem? Are there (I’m guessing nutritional) factors that make the artery wall not up to the task?

    –Can high blood pressure — perhaps together with excess numbers of particles — be a factor in the particles entering the artery wall?

    • Peter Attia  May 17, 2012

      High BP makes things worse, probably by causing damage to the intima, which creates even more problems with atheroma and plaques generation. I do not know if higher BP drives the gradient further, but I have seen no data to suggest this.

  28. Marilyn  May 17, 2012

    Sorry. Can’t help myself. Does anyone else see stuffed green olives in the first figure above? Maybe we should stop eating them? . . . .

  29. Mike  May 17, 2012

    Quoting from your article,

    “Which is the cause – the apoB containing LDL particle OR the immune cells that “overreact” to them and their lipid cargo? … captured by the Robert Burton quote, above. If you don’t know the cause, how can you treat the disease?”

    Well, I do understand that you are looking for a “cause” but isn’t the cause in this case the thing that stands out or in other words the abnormality? WBC’s are doing their jobs as they should it’s LDL-P that shouldn’t be hanging around in artery walls. Right?


    ” In the end, it’s a probabilistic game. The more particles – NOT cholesterol molecules within the particles and not the size of the LDL particles – you have, the more likely the chance a LDL-P is going to ding an endothelial cell, squeeze into the sub-endothelial space and begin the process of atherosclerosis.”

    And as you stated a bit above this paragraph, that it’s a gradient driven process. So does this mean that even if you have extremely low LDL-P (as in healthy people) LDL-P molecules STILL can penetrate and reside in arteries ? Because normally arteries have a low concentration of LDL-P molecules, so it’s just that you are merely improving “your chances” of not building up too much LDL-P leading to atherosclerosis, right?

    Sorry for the long question!

    • Peter Attia  May 17, 2012

      Less LDL particles, less crossing into the S-E space, less chance of overly robust immune response.

  30. Sam Knox  May 17, 2012

    I remember reading that there is a fluid dynamics component to atherosclerosis. Plaques tend to form in areas where there are “eddies” in the blood flow. This would concentrate apoB particles and also provide a physical impetus for penetration of the epithelium (particles flowing directly at the epithelium instead of alongside).

    If memory serves, this was also offered as an explanation for the appearance of plaques in arteries closest to the heart, where blood flow is fastest, and not in peripheral arteries or veins.

    Excellent article, as usual.

    • Steve Pehnec  May 20, 2012

      If I may invoke Bernoulli here: In a given dynamical system, the pressure is highest where the flow is slowest (i.e., “eddies”), and where the velocity of the flow is highest, pressure is lowest. (This would mean a bigger effect for arteries, where the total energy present in the fluid would be greater than in the veins.) It begins to make sense to me why high BP is a factor in metabolic syndrome. I suspect that other factors, such as the partial pressures of gases dissolved in the blood, may also be complicating variables.

  31. Martin Ankerl  May 17, 2012

    Thanks for all your work! Maybe I’ve missed it somewhere in the text, but how much does LDL-P and LDL-C correlate? I’ve changed my diet to a ketogenic one, and LDL-C has gone up from 117 to 180.

    • Peter Attia  May 17, 2012

      Coming soon.

    • Lardlad  May 17, 2012

      Looking forward to this as well. My LDL has gone up significantly since eating low carb. I now feel like I am driving without a seatbelt.

    • Peter Attia  May 17, 2012

      LDL-C or LDL-P? Remember, only the latter matters.

  32. Harry35  May 17, 2012

    Peter, is there any data on what might constitute an optimum level of LDL-P? There are several studies (Song 1998, Neaton 1992, Waverling-Rijnsburger 1997 & 2003, Razzolini 2008, Cui 2001, Schatz 2001, Schupf 2005, Yang 2008), showing that the all-cause mortality curve vs LDL-C and/or total-C is U-shaped, and there is an optimum LDL-C range somewhere around 100-150 mg/dL. This appears to happen because while CVD risk decreases as LDL-C is lowered, at some point CVD risk is as low as it is going to get, and all-cause mortality increases because of increased risk of cancer, respiratory diseases, accidents, depression, suicide, etc. At low LDL-C levels, these other risks outweigh any further CVD risk reduction. Also, the optimum LDL-C range appears to increase as we get older. It would be interesting if similar data were available for mortality vs LDL-P; do you know of any such studies? Currently, all I’ve seen are statements suggesting that anything below 1000 nmol/L is great, and the lower the better.

    I’m able to achieve quite low LDL-P levels by adding Crestor to a very low-carb, high-fat, high saturated fat diet. At a dose of 10 mg of Crestor, my LDL-P is around 300 and LDL-C is 80 mg/dL. With 5 mg Crestor, LDL-P is around 600 nmol/L and LDL-C is 100. Without any Crestor, LDL-P is 1275, and LDL-C is 175. As mentioned above by Dr. Dayspring, this is the opposite of what most people see, my LDL-P is more sensitive to Crestor than LDL-C is. Reverse discordance, perhaps.

    So my principal concern is, how low is it safe to drive LDL-P? Are there any studies that might show how much LDL-P suppression is too much?

    • Peter Attia  May 17, 2012

      Excellent questions. I will hopefully have time to get to this when we start to discuss a few the other cholesterol-related topics in the pipeline. I actually JUST had a tutorial on this last month from one of the experts in the fields.

    • steve  May 17, 2012

      Harry 35:
      Do you have CAD, family history? Why do you even take Crestor?
      With a particle count of 1275 with an LDL-C of 175 absent CAD or being in a high risk category seems you are in the group of the lucky 25% or so who have lower particle count vs what you would expect given the level of LDL-C.

  33. Eric  May 17, 2012

    For obvious reasons, I am going to assume that the conclusion of this series will suggest the best non-pharmaceutical pathway for reducing LDL-P/apoB and thus risk of CV disease is carbohydrate reduction and ideally a ketogenic diet. Hypothetically, if this would still not reduce LDL-P/apoB to an acceptable range, which treatment do you feel the most current research would support? Is this the appropriate time to take a statin? I am guessing this may be anwered in the next post.

  34. ShottleBop  May 17, 2012

    Waiting for the next installments with bated breath. (I’ve been low-carbing for about 4 years, now, since diagnosed as prediabetic in early 2008. That, plus exercise, has kept my BGs low and me relatively fit. Still, LDL-P and LDL-C are high (last September, LDL-P, per an NMR test, was 1793; LDL-C was 282). Last December, I had a stent inserted into one of my coronary arteries, and my doctor prescribed 80 mgs Lipitor daily. I am extremely concerned about potential side effects of a dose like that, and haven’t started taking it yet.)

  35. Maryann  May 17, 2012

    Dr. Dayspring, I wish you were still taking patients (we live in NJ and we called to become new patients of yours but were told no). Would you know of a lab that we can trust to have the HDL kit for the NMR test drawn? Thank you so very much for all you have taught me in your Specialty Health and Lecturepad segments. You are a great teacher, and like Peter you are a great communicator with a wonderful personality!

  36. Maryann  May 17, 2012

    Thank you Peter for making this understandable. I am looking at an EBT scan with an LAD that has 1 lesion,14.17 volume, and a calcium score of 20.89. Is this atherosclerosis? Is this plaque that burst through the wall into the lumen? Thank you…

    • Peter Attia  May 18, 2012

      Sorry, Maryann. I’m unable to comment on this. Can’t really practice medicine directly like this.

    • Maryann  May 18, 2012

      Hi Peter, I completely understand that; I wasn’t seeking any medical advice. I am trying to be a good student and apply the knowledge. I wanted to know if I understand what you are teaching properly.

    • Peter Attia  May 18, 2012

      The coronary calcium scans are interesting, and probably good for an initial assessment. The risk assessment is heavily based on age. So a score of 15 in a 30 year-old is suggestive of high risk, but the same profile in a 60 year-old is not. They should never be used to follow patients or treatment, though. Unfortunately, some doctors feel this is a good idea.

    • Maryann  May 18, 2012

      So everyone has this process taking place in their bodies, and what we want to do is minimize it; we can’t stop the particles from penetrating, which is why we want lower particle numbers; we want to stop the cascade that leads to breaking through into the lumen. The calcium score is a measurement of plaque that has broken through, and plaque is atherosclerosis, is that right?

    • Peter Attia  May 18, 2012

      Reducing the number of particles reduces the chance they get into the S-E space. The calcium score only tells you about, obviously, calcium. But it can be misleading. As plaques get absorbed, we can actually see a rise in calcium score, despite a reduction in plaque and risk.

  37. George Henderson  May 17, 2012

    Cholesterol (pron. : kol’ester-oal) is one of the myserty substances of the body. We still know very little about its metabolism. It is excreted by the liver in the bile. It is related to the hormones of sex. It increases in the blood of pregant women, and in some kidney diseases, but its function so far is not well understood.

    The Wonderful Story of the Human Body
    By A Well-Known Physician
    (no date but I am guessing 1930s)

  38. steve  May 18, 2012

    I am still unclear of the influence of diet given that most of the cholesterol we find in LDL and particles is made in our body. Saturated fat ingestion seems to increase LDL levels and particle levels for some. Is this due to an increased burden of cholesterol being delivered to the liver? Thanks.

    • Peter Attia  May 18, 2012

      I will try to address this in future posts.

    • Mike C  June 7, 2012

      I am very interested in this as well because I am one of those folks who has seen an increase in LDL from eating low-carb/primal (LDL-P went from 1788 nmol/L to 2112 nmol/L in 8 months while LDL-C had similar values each time, 232 vs. 228 mg/dL). I don’t know what could be the cause(s) other than the diet change but this series has contended that dietary cholesterol isn’t very relevant for those numbers. Previously I wasn’t concerned because I thought I was up-to-date on things with the view that large LDL-P was okay. Maybe I’m not being strict enough on the sugar? I was also recently reading somewhere (I don’t think it was here) that lack of sunlight could create a ‘backlog’ of cholesterol that isn’t being turned into Vitamin D?

      Great series, looking forward to suggestions on how to mitigate.

    • Peter Attia  June 7, 2012

      Hopefully we’ll get to the bottom of these issues with more study. Current data aren’t providing enough individual information on some of these issues.

  39. Dave Seibert  May 18, 2012

    Dr. Attia, First thanks! I am a meteorologist by trade and have always made comparisons between environments. As you wrote about the LDL particles flowing in the serum and how they will become stuck in the endothelium I thought about airflow and how through the right dynamics there is restricted flow due to terrain and how clouds form and persist in locations due to airflow obstruction. An interesting mind twist for me…anyway as you continued with this part:

    >>But it seems that not long after an LDL particle gets into the sub-endothelial space and takes up “illegal” residence (i.e., binds to arterial wall proteoglycans), it is subject to oxidative forces and as one would expect an inflammatory response is initiated. The result is full blown mayhem. Immunologic gang warfare breaks out and cells called monocytes and macrophages and mast cells show up to investigate. When they arrive, and find the LDL particle, they do all they can to remove it. In some cases, when there are few LDL particles, the normal immune response is successful. But, it’s a numbers game. When LDL particle invasion becomes incessant, even if the immune cells can remove some of them, it becomes a losing proposition and the actual immune response to the initial problem becomes chronic and maladaptive and expands into the space between the endothelium and the media.<<

    I could not help but make a connection to folks crossing the borders…our "illegal aliens" not unlike the LDL particles, you analogies were no doubt the key, but it fits! Not condemning either side in our own illegal alien struggles but do you see the analogy between LDL particles setting up shop, and our own human species "aliens"….something that is part of us, but yet we find invading and so try to remove… interesting! And the fight to remove both is much the same!

    Great stuff! Thanks again!


  40. Jim Bowron  May 18, 2012

    A doctor friend whom I referred to this web site sent me a link to a cardio-vascular surgeon who supported (i)the re-balancing of Omega 6 and Omega 3, as well as (ii) the position that the low fat-high carb diet was the major factor in the high level of CVD over the last few decades. His position was that high glucose levels in the blood began the inflammation in the arteries, creating the opening for plaque formation. I haven’t the skills to properly comment on his position, but thought it might add to the discussion. http://www.sott.net/articles/show/242516-Heart-Surgeon-Speaks-Out-On-What-Really-Causes-Heart-Disease

    • Kevin Mobley  May 20, 2012

      Thank you very much. A great intro article to pass to friends.

  41. Jill  May 18, 2012

    Why do particles get past the endothelial layer? Are the endothelial cells like tiles on the floor? If they are stuck down securely nothing can penetrate. Perhaps when Vitamin C is in short supply, the “glue” becomes weak or dissolves. Then LDL violates the endothelium. If we eat too much carbohydrate is the requirement for Vitamin C higher? The heart is active around the clock. Perhaps it pulls itself apart when Vitamin C is in short supply. Is heart disease a symptom of scurvy?

    • Peter Attia  May 18, 2012

      Cellular barriers are actually more complex than “walls” or other structures we tend to anthropomorphize them to. They are dynamic systems. I don’t actually know the answer to your question, but I am unaware of a link between HD and scurvy, and I do know there has never been shown a proven benefit of vitamin C for reducing HD.

  42. steve  May 18, 2012

    Non cholesterol question, but somewhat related. Would it make more sense to eat about 1/2lb to 1lb or so of fatty fish per week vs.daily intake of fish oil? Fish oil is highly susceptible to oxidation particularly at higher levels. I believe the Japanese eat about 2-4 ounces of fish per day.

    • Peter Attia  May 18, 2012

      Depends on the type of fish. Not all equal in n-3, and the larger the fish, the more chance of contamination. A good fish oil supplement uses bait fish to reduce this problem.

  43. Lynne Barrows  May 18, 2012

    I sense a disturbance in the force! I see an enormous crack in the Large/Fluffy LDL wall…

  44. Harry35  May 19, 2012

    Steve, I’m taking Crestor because I have a lot of coronary calcium (1222 Agatston units), it is growing every year, and my carotids are 50% stenosed, so I do have evidence of atherosclerosis. And there is a family history of stroke, although at 80+ years old. If you believe the lipid hypothesis, the best way to arrest plaque growth is to lower LDL. I am somewhat skeptical of this, but there isn’t much downside to Crestor that I have noticed, and even if the lipid hypothesis is wrong, there appear to be pleiotropic benefits to statins.

    • steve  May 19, 2012

      Thanks Harry35:
      If plaque is progressing that is very interesting in light of your low particle count,particularly if it has been low for many years. From Dr.Attia’s writing here one would think that keep particles low and you will preclude material plaque progression. NOt sure that is the case.
      What is your diet like- number of carbs you ingest,etc.
      Hopefully Dr. Attia may get in to a discussion of endothelial dysfunction which might mean more particles at any level penetrate artery wall and contribute to plaque growth in. Particles seem to be the new hot area, and while I agree with their contribution to CAD there are likely other contributing factors,particularly with those with family histories/genetics.
      Thanks again for reply and best wishes for good health.

  45. PeggyC  May 19, 2012

    Dr. Attia, I can definitely tell you your time has not been wasted. This series is amazing and I am so glad you are doing it. I am learning so much! Can’t wait for the next installment. Thank you, Thank you.

  46. joseph  May 19, 2012

    Great article peter. How does exercise (and type of exercise) affect LDL levels?

    • Peter Attia  May 19, 2012

      I’ve never seen convincing data to suggest it does.

  47. Jim  May 19, 2012

    What is the minimal time to retest lipids for apob and LDL-p after making a drug or dietary change?6 weeks?

  48. Papa G  May 19, 2012

    Hi Peter –

    Very interesting facts and arguments from all sides of this controversy.

    I have never fit the Framingham model. I weigh the same as in high school, don’t smoke, have always eaten a mediterranean diet, and am very active (as you know, Peter!). And I never had a high cholesterol count until about 7 years ago. At that time I was diagnosed with Chronic Lymphocytic Leukemia (CLL. It is fairly low-level o far and for that I am very thankful. However, my White Blood Cell count has been above normal for all those years. My research tells me that an elevated WBC is predcivtive of many other health problems,and so I began to wonder if it is a cauasal factor in the genesis of atherosclerosis in otherwise very healthy people because… a high WBC is a form of inflammation.
    I found an article by Professor Coller of the Rockerfeller Institute who wrote there is “reason to believe that leukocytosis directly enhances acute thrombosis and chronic atherosclerosis.” I wrote to him because it seemed strange to me that I have come down with athersclerosis,and I have been looking for the reason. He replied that the epidemiology is very suggestive but that very little work has been done to trace a direct causal relation between elevated WBC counts and Athersoslcerosis. But he feels there is “reason to believe.”
    What are your thoughts on this possible cause of athersclerosis?

    • Peter Attia  May 19, 2012

      Papa G, you are certainly correct that low-normal levels of WBC are correlated with longevity and health, which includes reduced heart disease. WBC is a pretty crude marker, of course, of general inflammation. For example, the first time I swam from Catalina Island to LA I had a friend draw all of my labs right before I jumped in the water, and again 10 hours later at the completion of the swim. My WBC rose from 5 to 20! So clearly the stress of swimming for 10 hours caused some inflammation (a normal level is considered between 4 and 11). There are other, more specific, markers of inflammation as it pertains to atherosclerosis, such as Lp-PLA2, myeloperoxidase, hs-CRP, and fibrinogen. (By the way, we will be checking all of these in you and Billy.) I think it safe to make the following statement: A high number of LDL particles is necessary, though in rare cases probably not sufficient to cause atherosclerosis. A normal (or hyperactive) inflammatory response is also necessary, but along not sufficient to induce atherosclerosis.

      Million dollar question: For *most* folks, which is easier to control to the level necessary to prevent atherosclerosis?

  49. Harry35  May 19, 2012

    Steve, my LDL-P has been low for 4.5 years, with one excursion when I went without Crestor for 3 months. When I started back on Crestor, LDL-P slowly came back down until it was again around 300 18 months after restarting Crestor 10 mg. During the 4.5 years that I’ve been tracking LDL-P and CAC score, CAC has doubled, so I don’t have this under control yet. LDL-P is the most important lipoprotein, but that’s not always enough, it’s just a start.

    I’ve been on warfarin for the past 18 years due to hereditary coagulopathy, so that may have caused my CAC score to increase due to lack of vitamin K2. I’m hoping so, because I switched from warfarin to pradaxa a year ago, and have been supplementing a lot of vitamin K2 since then in hopes of carboxylating every molecule that needs it.

    As far as diet goes, I was on a low-fat Ornish-style diet for 20 years or so, but 3 years ago I found that I am pre-diabetic and can’t tolerate carbs. Since then I’ve been limiting carbs to 30-40 grams/day, protein to 100 g/day, and total fat is 175 g/day. Saturated fat is around 50 g/day, and omega-6 fat is 10-15 g/day, omega-3 is 5-6 g/day. I’m hoping that Feynman, Volek, & Westman are correct that saturated fat is not a problem on a very low-carb diet. So far, my carotid stenosis is stable, but CAC score is going up 15-20%/year, which is not good, because CAC score is the best marker for all-cause mortality out there.

  50. steve  May 20, 2012

    Harry 35: Keep working at it! I think Dr. Attia probably concurs with the the hi sat fat low carb crowd. Not sure i could do 30-40 carb grams a day. The interesting thing for me is the diversity of opinion regarding diet. Several lipidologists i have seen are ok with hi fat- mon and poly, but look askance regarding sat fat. Dr.Dayspring seems to be on board the sat fat is ok viewpoint and when it comes to lipid disorders/knowledge he is about the best.Calcium score is an indicator,but there are many with high calcium scores who do not show arterial closure on agiography. Arterial remodeling can take place. Again, best wishes

  51. JohnJ  May 20, 2012

    Maybe because of receptor GPR109A is involved;


    Maybe is because of MGmin-LDL


    Maybe because heart disease has many factors involved;


    Or maybe you could try less conventional advice first;

    Visit the blog of Dr. William Davis a cardiologist; he has excellent advice on how to treat heart problems.


    That said, here are a number of unconventional ways that can significantly reduce your LDL cholesterol:

    • Ground flaxseed-Similar to oat bran but essentially devoid of digestible carbohydrates, it is a wonderful way to reduce LDL (small and large) and obtain healthy fiber. Use it just as you would oat bran, as a hot cereal or added to other foods.
    • Elimination of wheat products-Yes, that’s right. I know it sounds weird. Elimination of wheat products is an enormously-enormously-effective strategy that reduces the small LDL particles drastically.
    • Avoidance of high-glycemic index foods-Along with wheat, this includes candies, soft drinks, cookies, white potatoes, white rice, etc. This effect develops if small LDL is present.
    • Raw nuts-A really great way to reduce LDL. Nuts got a bad name from the processed, salted, hydrogenated-oil soaked products that dominated supermarket shelves. Instead, look for raw almonds, walnuts, pecans, and pistachios. ¼-1/2 cup per day can yield significant reductions in LDL and do not make you fat, since high fiber and monounsaturated fat content provide a feeling of fullness that diminishes appetite for other foods.
    • Niacin-Yes, yes, I know: The hot-flush effect is annoying. Niacin is vitamin B3 and I have well over a thousand patients taking it. Niacin is as effective as statin drugs in reducing LDL; it’s also the best agent available (after weight loss and elimination of wheat) for reducing the dreaded small LDL particles.

    Or you could try another cardiologist;


    Or other alternatives treatment to statins first;



    • KevinF  May 20, 2012

      JohnJ — gotta say thanks for your flaxseed tip — I keep a bag of ground flax handy but hadn’t quite figured out how to add it into my diet. So just now I mixed a couple tablspoons with boiling water, mixed in a dash of cream, butter and xylitol, and it was just awesome. Like cream of wheat.

    • Pat  May 27, 2013

      A good flax muffin (ground) in the morning is a much nicer way to get a good dose of flax. I could certainly provide the recipe if anyone wants it. I am type 2 diabetic tightly controlling by diet, eating essentially no starch which drives my sugar sky high. The essence of the flax muffin, besides the breadth of nutrition, and as you said is the almost effective absence of carb. thanks.

  52. Jim  May 20, 2012

    Dr Attia,
    A statement you made above sounded like you do not like managing lipids by using serial CAC scores.Am I correct?If so why,besides the radiation?

    • Peter Attia  May 20, 2012

      See previous reasons given in comments. Once you establish risk, what else is it telling you? Not to mention it can be misleading. Also, don’t minimize the risk of radiation.

  53. Harry35  May 20, 2012

    I use serial CAC scores to track atherosclerosis because it is the best non-invasive method of measuring risk. Dr. Budoff did a study of 25,253 patients showing that the risk of all-cause mortality, adjusted for all other known risk factors, rises smoothly from a relative hard coronary event risk of 1 at a CAC score of zero to a risk ratio of 12.5 at a score of > 1000. See http://content.onlinejacc.org/cgi/content/abstract/49/18/1860
    Even tracking stenosis using CTA gives only about a factor of 6 to 7 greater risk between 0 stenosis and >70% stenosis, and the risk doesn’t get much worse going from 30% to >70% stenosis, which doesn’t allow good discrimination with increased stenosis if you have >30% stenosis, which many people have. See http://circ.ahajournals.org/cgi/content/meeting_abstract/122/21_MeetingAbstracts/A17461
    The reason why CAC score is better than stenosis is that CAC score is the best noninvasive measure we have of overall coronary plaque burden, which correlates better with risk than does stenosis, because most heart attacks don’t occur at the point of maximum stenosis, and stenosis can remain the same as plaque burden increases considerably due to positive remodeling, where the artery expands to maintain the same lumen diameter even as plaque grows considerably.

    CAC score is not perfect, because it doesn’t perfectly track vulnerable plaque, but it’s the best marker we currently have for total plaque burden. No noninvasive method we have yet can track plaque necrotic core and atheroma cap thickness, which would likely be a better measure. Also, CAC score can increase when vulnerable lipid-rich plaque is decreasing through calcification stabilizing vulnerable plaque. Finally, CAC score is only approximately reproducible, due to variations in the scan starting point and in interpreting the results. See http://www.ajronline.org/content/185/6/1546.full
    As far as radiation goes, yes, it’s definitely always a consideration. However, a CAC score on an EBCT machine gives about 1 mSv, and on a multislice machine with >128 slices, considerably less than that. Compared to background radiation at around 3 mSv at sea level, that’s not a lot. And compared to a thallium stress test at 25 mSv, it’s very small potatoes.

    • Ed  May 27, 2012

      If you have a high calcium score, why not supplement K2? Its cheap and relatively low toxicity… good discussion here:


    • Peter Attia  May 27, 2012

      It may be cheap and may be well tolerated. This does not imply it actually does anything. It might, but I am not aware of any clinical data saying if you take K2 you will reduce your risk of heart disease. My advice, Ed. Worry about getting LDL-P in the zone, then take care of vit K all the other things.

  54. Martin  May 21, 2012

    Thank you for a fantastic series of articles. i am particularly impressed with the clear summeries you provide. This is science communication at its best.
    One comment. can you PLEASE commment on how hypertension affects all of this? It may be somewhat selfish, but I have been lo carbing and exercising for some years but can only control my hypertension with drugs. How dangerous is hypertension anyway?
    Thanks for your blog and information.

    • Peter Attia  May 21, 2012

      Epidemiologically, hypertension is “bad,” but this comes the standard caveats of epidemiology. Maybe it’s not “bad” but it’s a marker for something ELSE that is. Mechanistically, hypertension probably disrupts the intimal later and accelerates the atherogenic process. My personal believe is that hypertension is not a good thing and should be controlled. Many people, though not all, can do so by greatly reducing carbs.

  55. Debra  May 21, 2012

    That was such a good thought provoking post. I have so many questions but will not unload them yet. The only way science truly advances is with argument, disagreement and copious experimentation. One thing that has always worried me with this routine testing is that venous blood is tested for lipid profiling when it is what is in arterial blood that is more relevant. Obviously sampling arterial blood is a little difficult. Is there any work showing correlation (or not) of lipid measurements between types of blood? (Apologies if you have covered this somewhere.)

    • Peter Attia  May 21, 2012

      Not sure how much of a difference exists, but more importantly, it’s better to calibrate in the form of testing (i.e., venous) that will apply to the masses.

  56. Debbie  May 21, 2012

    Hi Peter,

    What is a coronary calcium score, and is this a useful test if APO-B is elevated?


    • Peter Attia  May 21, 2012

      Speak with your doctor about whether you should have one.

    • Debbie  May 21, 2012

      I understand – thanks. 🙂

  57. steve  May 21, 2012

    What do you consider an acceptable range for BP? I think many say ok up to 130.

    • Peter Attia  May 21, 2012

      Most would suggest systolic below 130, diastolic below about 80-90.

    • Travis Koger  May 22, 2012

      Awesome, 107 and 62 here.

  58. David Nelsen  May 21, 2012

    Peter, finally got my LPL-P score back. I guess I’m disconcordant as LPL-P = 1486 LDL-C = 116. Met with my physician today and she prescribed Niacin. It’s good to know that there can be a disconnect between the Particles and the LDL-C. Will retest in 3 months. Triglycerides were at 33. HDL-C was at 53. I am posting info as a guide to others and not seeking medical advice. 🙂

    • Paul Craigen  July 5, 2012

      What sort of diet did you follow to get these numbers? How about your physical specs, ie height, weight, body fat, age, sex?

      thanks Paul

  59. Debra  May 22, 2012

    Just another comment on previous comments. I think veins grafted on to arteries in by pass surgery become atherosclerotic-although morphology of plaque is different and the intima layer becomes thickened. Also the pulmonary artery can become atherosclerotic despite carrying deoxygenated blood. It is such a complex area but it is good to hear about the current findings.Thanks for this whole series. I am looking forward to what is to come.

  60. Victoria  May 23, 2012

    Is there an advantage to having apoB-containing particles penetrate the endothelium? Is it a beneficial function in small amounts?

    • Peter Attia  May 23, 2012

      I do not know of such an advantage.

  61. Ed  May 24, 2012

    Steve made and interesting comment about location of plaques. Can someone explain the distribution of plaques and how this might tie into the concept of gradients?

    The fact that plaques are not randomly distributed in your circulatory system should provide some clues here, unless you were arguing that the concentration of apoB particles differs in different parts of the circulation.

    If the gradient concept were to apply to the number of particles (perhaps mediated by velocity of those particles) that passes over a specific vascular surface in a given time frame then perhaps that makes more sense.

  62. Diana Attuso  May 31, 2012

    Hi Dr. Attia, I’m trying to keep up with your posts, but I have to admit that I was overwhelmed with the need to ask this question when I read the following statement: “If [your LDL] number is high, you are at risk of atherosclerosis.” My question is: Why? What mechanism makes them lodge in your artery wall? Just having “too many” doesn’t make sense to me. I apologize for asking if you have already covered this. As a follow up I will tell you that I have read in other sources that inflammation of the artery walls (possibly caused by “bad” or too many carbs in our diet) create “ulcers” in which the LDLs become lodged. This made sense. But now that I see how many different kinds of lipoproteins are floating around, my question then becomes “Why this particular type?”, “What’s special about this one?”

    • Peter Attia  June 1, 2012

      Diana, check part IV and V, along with the thread of comments.

  63. art  June 1, 2012

    Tremendous series, Peter. Thank you. A trifling observation: The Anatomy of Melancholy was first published in 1621 (and happens to be, like, the best book ever…).

  64. Ben Greenfield  July 13, 2012

    So based on my understanding, a high Apo-B is correlated to a high LDL particle number, which appears to be the major risk factor for atherosclerosis. However, I have witnessed high Apo-B in nearly EVERY vegetable oil and grain avoiding “healthy” athlete who I’ve had undergo such a test. Based on this, could there be some other mechanism that elevates Apo-B mg/dl, such as response to exercise based inflammation, high utilization and mobilization of free fatty acids in lower carbohydrate consuming athletes, etc.? I’m trying to wrap my head around because I keep seeing this pattern: high LDL, high HDL, low triglycerides, low vLDL-C, low LP(a), low to medium hs-CRP, but HIGH ApoB.

    This ones got me puzzled, so I’m asking the cholesterol genius. 😉

    • Peter Attia  July 13, 2012

      Thanks, Ben, though I look to the “cholesterol geniuses” myself on these. It may depend on training, as you point out. In fact, I did a self-experiment a few months ago, which I’ll write about if I can ever find the time. I checked an LDL-P “resting” one morning. It was about 750 nmol/L, if I recall. 2 weeks later I checked it again after a really hard workout. It was something like 1,350 nmol/L. That’s a difference of the 2nd percentile to the 60th percentile! Why? Well, I have a few ideas, and inflammation, margination of plasma particles, and flux of TG may play a role. In the first test, my TG was 42 mg/dL; on the second it was about 120 — a 3x difference.

      This is a round about way of saying I don’t know what’s going on with exercise, but it did make me start to wonder if super-intense exercise may not be the healthiest thing one can do. Let’s discuss in person in Boston next month!

    • Ben Greenfield  July 13, 2012


      I *suspect* that in a highly active individual on a high fat, low carbohydrate diet, in a state of high lipid metabolism and delivery of cholesterol to peripheral tissues, that high ApoB *may* be normal, and not reflective necessarily of an increased time of LDL particles in circulation (as may be observed in a lower activity, carbohydrate fueled, relatively inactive population).

      This suspicion is mostly fueled by the fact that even with high LDL and ApoB, markers of endothelial damage, like hs-CRP, are rock bottom.

    • Peter Attia  July 13, 2012

      I think you could be right, Ben, but I hope we can one day generate some data to test this hypothesis.

    • justin mcnaughton  May 16, 2014

      I think I’m a perfect example of what you guys are discussing (results below). I don’t take statins at the moment, all I do is 4g of niacin per day, healthy diet, etc. I believe I have HeFH and always get urged by doctors to get on statins. They told me 10 years ago I’d be dead by 30. I’m 34 now. Mom has 450 cholesterol (no heart issues to date), her dad had 450 cholesterol and died @ 90 of a non-heart issue. I don’t know what to do.. but there is something missing from this story:

      LDL CHOLESTEROL 222 =40 MG/DL Final 01
      VLDL CHOLESTEROL 22 <30 MG/DL Final 01
      CHOLESTEROL, TOTAL 284 <200 MG/DL High Final 01
      TRIGLYCERIDES 79 <150 MG/DL Final 01
      NON HDL CHOL. (LDL+VLDL) 243 <160 MG/DL High Final 01
      APOB100-CALC 150 <109 MG/DL High Final 01
      LDL-R (REAL)-C 198 <100 MG/DL High Final 01
      LP(A) CHOLESTEROL 6.0 <10 MG/DL Final 01
      IDL CHOLESTEROL 18 <20 MG/DL Final 01
      REMNANT LIPO. (IDL+VLDL3) 30 10 MG/DL Low Final 01
      HDL-3 (LESS PROTECTIVE) 33 >30 MG/DL Final 01
      VLDL-3 (SMALL REMNANT) 12 <10 MG/DL High Final 01
      LDL1 PATTERN A 37.3 MG/DL Final 01
      LDL2 PATTERN A 63.5 MG/DL Final 01
      LDL3 PATTERN B 86.6 MG/DL Final 01
      LDL4 PATTERN B 10.5 MG/DL
      CRP .23 <1 low risk

  65. Mike A.  July 30, 2012

    Dr. Attia-
    I recently read the Cholesterol Delusion by Dr. Curtis and he outlines many reasons to be skeptical of the Cholesterol Theory of atherosclerosis. I won’t attempt to outline them here, but he seems to theorize that the cholesterol-containing plaque found behind the endothelium could arise there due to the muscle cells, which constrict and relax around the arteries, protruding into the sub-endothelial space. He suggests that the mechanism could be that those cells then deposit the cholesterol which is sometimes, but not always, found in plaque. In short, I’m asking how certain we can be that “unless an apoB-containing lipoprotein particle violates the border created by an endothelium cell and the layer it protects, the media layer, there is no way atherogenesis occurs”, as you state in this post? Thanks for your insights on this. I’m a bit at a loss as I find both of your discussions compelling.

    • Peter Attia  July 31, 2012

      Mike, I can’t really comment on the difference between my argument and Dr. Curtis’ without reading his book.

    • Mike A.  July 31, 2012

      Dr. Attia- I understand and I certainly wouldn’t expect you to, that’s why I tried to confine my question to the point made in your post. I’m just trying to tease out what we can know with certainty, versus what we are theorizing based on the evidence. If we grant that higher levels of LDL-P in the blood are associated with atherosclerosis, it doesn’t seem that it necessarily follows that the cholesterol penetrates the endothelium from the blood. That certainly may be the case, but I wasn’t sure if that was a known fact.

      I have greatly enjoyed this series. Unfortunately, great information like that contained in your posts often leads to more questions.

    • Peter Attia  July 31, 2012

      At the risk of sounding like a schmuck…I obviously don’t subscribe to Dr. Curtis’ theories on this topic, as I’ve just written 30,000 words in 9 blog posts in support of a completely different argument. Keep the following in mind: cholesterol can’t move around the body without a lipoprotein particle transporting it. The only way a sterol can get into the S-E space is if it gets carried there by a lipoprotein.

    • Mike A.  July 31, 2012

      Dr. Attia- I apologize if you think I’m trying to pit you against someone else. That’s not my goal at all. I was merely trying to give you the background as to why I was asking the question. I had read that most cells in the body are capable of producing cholesterol, and that’s why I was asking if it was certain that cholesterol deposits had to arrive in the way that you mentioned. I have no medical training and I’m happy to defer to you. I just was hoping to determine the level of certainty that existed on that point. If anyone sounds like a schmuck when discussing medicine, I’m sure it is me. Please take my comments and questions in the spirit intended. I’m a big fan.


    • Peter Attia  July 31, 2012

      Absolutely, Mike. All but 2 cell types in the body make cholesterol, including muscle cells. The issue isn’t making cholesterol, though. It’s transporting cholesterol in the plasma. We don’t have free muscle cells in our bloodstream carrying cholesterol. Regardless of where cholesterol is made is can ONLY be carried in the bloodstream by a lipoprotein particle. So we’re sort of back to the same point we started with. Hope this helps.

  66. Gerry C  September 3, 2012


    Question for you on LDL particle count: Is particle count higher for an at risk person because they are producing more VLDL (which become LDL) or is it because when they become LDL they hang around longer or could it be either?

    Here is my reasonong: I think that a person with high glucose levels would create more particles because they are producing TG rich and cholesterol depleted particles so they have to produce more of them to get the cholesterol out there? However, what about a person that might be a smoker or have high cortisol levels from stress? Their TG might not necessarily be high. Would they be producing a high VLDL particle count (just not TG rich) or are they just retaining LDL because it is breaching the SE?


    • Peter Attia  September 3, 2012

      Many reasons for high LDL-P. Can be too much VLDL export (usually due to too many TG). Can be poor clearance of LDL particles. Can be too much synthesis and/or absorption of cholesterol, which needs more lipoproteins to traffic.

  67. Julie  September 4, 2012

    Hi Peter!

    I love your blog! I have a question regarding LDL’s: I have been told by my endo that I genetically test as someone who is an ‘over producer’ of cholesterol and that is why, along with the fact I eat a HFLC diet, that my LDL’s are high and I should take statins. I’ve read a lot about statins and feel they aren’t for me based on side effects and minimal testing done on women, not to mention I’ve tried Pravastatin and Red Yeast Rice and both cause nausea and vomiting along with fatigue. So. My question: what effect would a statin have on elevated LDL-P and is it something that would improve my heart health? Why is being an overproducer of cholesterol bad? Wouldn’t that simply be personal biology rather than a pathology? My doctor is trying to scare me into taking a statin but I am refusing Thoughts on this? Thanks!

    • Peter Attia  September 4, 2012

      I’m sorry, I can’t give medical advice.

    • Patrick  September 5, 2012


      Have you actually had the NMR test done? Only asking because to say you have high LDL’s only captures part of the story as you may already know. Those TG’s are pretty high, but what is your HDL? The quick, although incomplete, way to further assess your state is to determine your TG/HDL ratio. If you can get to somewhere around 1 or less, you’re more likely to be better off than the “standard” numbers may represent. As far you being an “overproducer” I think that it would mean you need to be more vigilant in general in monitoring and controlling your levels. Also, if you want to assess any accumulated “damage” thus far, you may want to look into having a calcification test done, which is an easy but good way of taking a look at the level of calcium buildup in the arteries. It’s about $350 or less but well worthwhile. Have your endo refer you to get it done. I would do all of these things prior to taking a statin….which you may discover you don’t really need.

  68. Julie  September 4, 2012

    Btw, my triglycerides are 106. My insulin is 14 so I do have insulin resistance. Thanks!!!

    • J  September 4, 2012

      Hi Julie,
      Do you live anywhere near Wisconsin? Maybe you could consult with Tara Dall–she’s a family practice doc who now specializes in lipidology. On Lecture Pad (there’s a link in Peter’s sidebar under “sites I visit”) she gives some lectures about lipidology. In one of them she describes a couple of case studies where people with insulin resistance and high LDL-P have their LDL-P go down, even back down to normal, on just metformin treatment for the insulin resistance (without statins). Or if you look up her website, maybe her office would have a list of specialists around the country that they recommend. Good luck!

  69. Jared  September 5, 2012


    As a senior in college who is very much interested and obsessed with the health and nutrition world but a bit confused as to where to go after undergraduate college, I was looking for a bit of advice. I would love to be able to study the kind of research you spread on here (so perhaps molecular biology?) or spread the word of real health. However, becoming a dietician seems muddled in the path of conventional wisdom which is not what I want to be forced to tell people. What are your thoughts on what the next best path for me to take would be with my obsessions laying in this kind of work? Thanks

    • Peter Attia  September 5, 2012

      Study what makes you excited beyond belief. The rest will work itself out.

  70. Suzanne  September 6, 2012

    Hi Jared,

    Check out UC Davis’ doctoral program in Nutritional Biology. It sounds right up your alley.

  71. John Nelson  September 10, 2012

    Since the death of Michael Clark Duncan (Green Mile) who for the last few years of his life became a vegetarian, I hear people trying to blame his death on the years of eating so much meat. Of course, I believe that’s BS based on the science I’m discovering in Taubes’ books and on this site. But it does raise an important question…

    If you eat junk for the first 40 years of your life (unlimited sugar, white flour, white rice, etc.) so that plaque starts building up bigtime…but then start eating a high-protein, high-fat, low-carb diet, won’t the bigger fluffier LDL that makes their way to the bloodstream then build up the plaque even faster than the VLDL that high-carb diets throw off? My point being, once the super tiny VLDL has started lodging in the arteries, are we only going to speed up heart disease by eating foods which raise the fluffy cholesterol?

    • John Nelson  September 13, 2012

      nevermind, in reading this through again and through the other comments, I understand it now.

  72. Laura  September 13, 2012

    Is a high LDL-p number always indicative of oxidation and the build up of plaque. My husband has a very high LDL-p number and I have been reading about the correlation between high TSH and high LDL-p… http://perfecthealthdiet.com/category/disease/hypothyroidism/ there are many other articles about this possibility.

    • Peter Attia  September 13, 2012

      Not always, but often.

  73. David Caskey, MD  October 13, 2012

    Good analysis, but you missed the boat on association between cholesterol and causation of disease. I feel that cholesterol and all of its little particle have nothing to do with the production of disease. This is the thought pattern of a number of my fellow cardiologist.

    What causes the problem does have to do with inflammation. What causes the inflammation is unknown. Definitely it is not cholesterol particles. The first question you have to address is “how does an artery repair itself?”. That is something that I have not been able to discern despite much research. The intima of an artery is special tissue and is rich in cholesterol and fat products. I feel that when the intima is disrupted, then fat particles are mobilized to seal the area. Most patients with atherosclerosis have their disease start in the media of and artery and not the intima. The inflammation works to the intima where it can rupture and cause the clotting cascade to begin, thus a clot and thus an MI. This accounts for 80% of MI’s. Only 20% of MI’s are the result of a plaque, which is nothing more than an excessive scar.

    Find the origin of the inflammation and solve it and heart disease goes away. Cholesterol in the modern-day equivalent of leeches and blood-letting.

    • Peter Attia  October 13, 2012

      No doubt inflammation plays a role, but your suggestion that cholesterol doesn’t ignores a lot of information. For example, what do you make of the patients with PCSK9 mutations? What about FH? No changes in inflammation there, so I’m not sure I’ve “missed the boat” as you so effortlessly put it. To be clear, I am not for a moment suggesting inflammation does not play a role — it surely does. But the next logical question, of course, is how to quantify it in a clinically relevant and actionable way?

  74. Raymund Edwards  October 14, 2012

    Peter have you seen this ?.


    Shiel Medical Laboratory is the only clinical laboratory worldwide to offer the Oxidized LDL Triple Marker Test. It is the only blood test available that measures atherosclerotic disease activity in the artery wall.


    “Oxidized LDL – Oxidized LDL is the atherogenic form of LDL. Oxidized LDL is a plaque-speci?c
    lipoprotein which plays a key role in the atherosclerotic disease process, particularly in the deposition
    of cholesterol in the artery wall plaque. Oxidized LDL is found primarily in the atherosclerotic plaque
    and NOT in normal arteries. Oxidized LDL is directly involved in the initiation and progression of
    atherosclerosis: from the early-stage conversion of monocyte/macrophages into cholesterol-laden
    foam cells, to the late-stage development of plaque instability and rupture. “

    • Peter Attia  October 15, 2012

      Tabas in all his writings on atherogenesis has clearly shown apoB oxidation occurs within the artery wall. LDLs are oxidized within then arterial wall: some small amount may escape. But plasma has tons of antioxidants that should rapidly negate them. The folks who market oxLDL will show you data associating oxLDL levels with risk – they of course never adjust for LDL-P.

      According to JAMA. 2008;299(19):2287-2293, “It is generally believed that “fully oxidized LDL” does not exist in the circulation. Blood is rich in antioxidants. In addition, such highly oxidized particles would be rapidly cleared in the liver via scavenger receptors. In contrast, circulating minimally oxidized LDL in which oxidative modification has not been sufficient to cause changes recognized by scavenger receptors was demonstrated. Therefore, all assays for oxidized LDL presumably detect minimally oxidized LDL. This oxidized LDL is only a minor fraction of LDL ranging from 0.001% in healthy controls to approximately 5% in patients with acute coronary events. Because LDL is the substrate for oxidation, concentrations of oxidized LDL correlate with LDL concentrations, and in turn with the cholesterol within LDL.”

    • Raymund Edwards  October 16, 2012

      Thanks Peter .

      Here seems a good overview from Tabas .

      Basic Science for Clinicians
      Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis
      Update and Therapeutic Implications
      Ira Tabas, MD, PhD; Kevin Jon Williams, MD; Jan Borén, MD, PhD

      http://circ.ahajournals.org/content/116/16/1832.full .

    • Raymund Edwards  October 16, 2012

      Very interesting papers in that Journal .

      if the Oxidized LDL Triple Marker Test is not so important

      Having plenty of functional HDL is. ( Keto Diet , Omega 3s , Vitamin D all seem to help )

      Antiinflammatory Properties of HDL

      http://circres.ahajournals.org/content/95/8/764.full .

      “HDL has the capacity to inhibit the oxidative modification of low-density lipoprotein (LDL) in a process that reduces the atherogenicity of these lipoproteins. HDL also possesses other antiinflammatory properties. By virtue of their ability to inhibit the expression of adhesion molecules in endothelial cells, they reduce the recruitment of blood monocytes into the artery wall. These antioxidant and antiinflammatory properties of HDL may be as important as its cholesterol efflux function in terms of protecting against the development of atherosclerosis.”

  75. Raymund Edwards  October 18, 2012

    Interesting …It makes sense that research into hibernating animals living off stored fats should be useful .
    It suggests that the body has evolved to use the stored fats as fuel without causing damage and that high cholesterol under these circumstances is different to High Cholesterol outside a keto or fasted state.


    “Healthy levels for cholesterol or triglycerides in people are both below 200 milligrams per deciliter (200 mg/dL). Black bear levels are almost this low in early summer when cholesterol averages 248 mg/dL and triglycerides come in at a healthy 169 mg/dL. However, by early hibernation, when they’re living off their fat, cholesterol reaches 351 and triglycerides reach 355.

    Is that a problem? No. We made those measurements in healthy wild bears back in our early studies in the 1970’s and 1980’s when we still were using tranquilizers. The amazing thing is that we have never found plaque in the veins of even the oldest wild bears we’ve examined, and we’ve found no evidence of cholesterol gall stones.

    How do bears get away with these high levels and no related problems, even in winter with no exercise? Further tests showed that bears have two secrets.

    Their good cholesterol, HDL is their big number. People exercise and take statin drugs to lower their bad cholesterol (LDL, meaning low density lipoprotein) and raise their HDL. Bears do it without trying.
    The other secret is in the gall bladder. They have a super drug named ursodeoxycholic acid (UDCA), which dissolves gall stones.” .

    • Raymund Edwards  October 19, 2012

      Peter , on this line. Here is a point that am tending to think could be a factor in how the body responds to a ketogenic diet for instance with the response of LDL-P numbers.

      The Epilepsy and Cancer research often stresses that a calorie restricted Keto diet is different to an excess calorie keto diet ( children with epilepsy sometimes ” like the diet too much” and the seizure protection starts to be lost )

      Being On a keto diet .. I have found it easy to enjoy too much , sour cream , cheese and heavy cream. It is very easy to find oneself eating 2000 Calories over what ones energy expenditure would be.

      This does not produce a significant weight problem. Though it does produce a little more body fat.

      But eating 2000 Calories over Energy expenditure .. Can not be the same as Fasting , Hibernation . ( and there is a paper regarding epilepsy specifically on this ) or a restricted or energy or neutral energy Keto diet.

      I have done an experiment cutting out these foods . I have still plenty of energy , I have no more hunger and the little bit of body fat is vanishing.

      Do you think people who find themselves overeating such energy dense foods and ( important ) find their LDL-P Sky high might find benefit from reducing these calories ?

      Fat intake must have it’s own signalling effects.. Especially when That intake is well above energy expenditure.

      I would suggest these spectrum.

      Starvation is nor fasting, fasting is not energy restricted Keto diet and a restricted keto diet is not a energy excess keto diet.

      While all similar , there must be differences too .

      Anti cancer effects
      Anti Seizure effects

      LDL-P ?

      This I think needs researching –> Fat intake must have it’s own signalling effects.. Especially when That intake is well above energy expenditure.

  76. Bryan Walsh  April 3, 2013

    Hey there, Dr. Attia.

    Thanks for such an amazing resources. I love the science-heavy articles and many people are benefiting from your work.

    Quick question . . . has any work been done looking at the ratio of discordance between LDL-P and LDL-C? In other words, there seems to be little question that elevated LDL-P increases ones risk of cardiovascular disease, especially when LDL-C is low, but in your opinion, would one still be at risk for cardiovascular disease if LDL-P were low-normal (eg ~900 nmol/L), but also with severe discordance with LDL-C (~30 mg/dL)?



    • Peter Attia  April 3, 2013

      Bryan, this pathology is a results of the particles, not the discordance, per se. The discordance is problematic (especially in MetSyn) because it prevents adequate risk assessment from just LDL-C. 900 nmol/L is low…probably 15th percentile risk.

  77. Steven  April 24, 2013

    I have been reading about this, and I’m wondering if the beginning of the process is the arterial inflammation?
    For example, eating a high sugar diet. Glucose swimming through your arteries is like scrubbing them with a wire brush which is why insulin is immediately deployed to remove it. But inflammation may occur. In this situation, you have created the slight inflammation that allows the LDL particles to start dumping. Which begins the loop.
    Any thoughts? I’m not a doctor by any stretch of the imagination. Wonderful blog by the way!

    • Peter Attia  April 24, 2013

      Great question, Steven. I really don’t think anyone knows for sure. Bottom line: do what you can do reduce BOTH inflammation AND LDL particle number.

  78. Paz  November 17, 2013

    I usually don’t leave comments, but in this case I think I have to. I was looking for some info about cholesterol, but I couldn’t find any resourse that explain it clearly (there was always some questions that left unanswered, or the info didn’t make any sense)… but then I found your blog, and let me tell you WOW. The information you post is complete and beautifully explained. THANK YOU

  79. Irina  November 25, 2013

    Amazing work, Dr. A!

    I’m 25 and have high cholesterol (including apoB (185), per VAP after 6 weeks on Paleo… will try to get NMR though!)

    Per a previous post: Every cell in the body can produce cholesterol and thus very few cells actually require a delivery of cholesterol…. lipoproteins exist to carry cholesterol where there are insufficiencies
    Question: Why do these insufficencies exist in the first place?

    (B) Any benefit to getting DNA testing done (via 23andme) to assess additional CVD risk?


    • Peter Attia  November 25, 2013

      1. Ask Darwin, I guess. I could speculate, but I don’t know.
      2. I have not seen the value in these shotgun approaches. Very few genes, relative to what are tested, really inform actionable change. I just don’t see the value in these tests, but maybe I’m wrong.

  80. Justin  February 27, 2014


    First of all, thank you so much. Your blog has empowered and inspired me to always ask why and to always research everything. You have sparked in me a fire that loves to look at research and WHY things happen the way they do. Thank you.

    Secondly, a question. As a fat-adapted runner with type 1 diabetes, I often begin exercise with elevated glucose levels. For example, on long runs I start around ~160 mg/dL with no active insulin in my body (I take fast-acting insulin via pump). I do this to prevent hypoglycemia during my run – my BG level does drop to ~90 mg/dL by the end of my run. In regards to cholesterol, is this period of slight hyperglycemia dangerous and likely to instigate the penetration of apoB particles due to the increased presence of glucose molecules within my bloodstream?

    • Peter Attia  February 27, 2014

      The acute danger is hypoglycemia, not changes in apoB

    • Tim  April 17, 2014

      I seriously doubt it’s a gradient affect for LDL particles. If it were you would expect 2 things (if it really mattered):
      Even deposition in every artery always. In other words all the arteries would see reductions in cross section evenly, or at worst in locations (for example) where there are velocity changes, always. Because at that point it is a physical effect and has nothing to do with the health of the artery itself. They physical pressure of the LDL particles on the artery wall push them into it.
      There would be clear numbers above which this effect is seen, always. Once you get above a certain value you get a nice linear rate of deposition, always. The more in the blood, the more deposition we see. You would never, ever, see anyone with high cholesterol be free from heart disease, and you would be very hard pressed to see anyone with low cholesterol with heart disease. You would never see it in random locations, it would be consistent IF it were concentration related. But it isn’t, locations and sizes vary, which means it can’t be predominantly gradient related.

      The damage/repair hypothesis fits much better, and correlates well with explaining diabetic HD rates as well, with sugar being the real culprit (among other things like stress).

      The article you reference ‘Sequence Variations in PCSK9, Low LDL,and Protection against Coronary Heart Disease’ doesn’t prove anything other than you take 3200+ people, and compare them to 26, 60, and 85 people and find that their rates differ by at most 4%. No where close to enough subjects to extrapolate to the general population, regardless of what kind of statistical magic you throw at it, and that 4% difference is MEANINGLESS as a result. Just because that’s the only number of people they could find to test is no excuse to do the study and assume it has meaning.

      The problem is this: You start with the theory that cholesterol is bad, and is associated with heart disease, then when you find out the data doesn’t support it you start looking for reasons why it still should be, so then you say, it must be LDL/HDL, or trig’s, that still doesn’t work so then it’s LDL particle number, etc., next it will be some other variation or ratio, or some new component they’ll try to couple with it because it MUST be a major risk factor, everybody knows this! I believe Occam’s razor applies – the more convoluted and complicated the explanation gets, the less likely it is to be true (or in this case it may be true, but insignificant relative to other factors).

      IF cholesterol LDL/HDL etc., were significant risk factors you wouldn’t be looking at the individual components because it would be just like smoking or exercise. When you start seeing risk factors increase/decrease by 2x-5x you’ve got something to talk about, assuming the risks are not single digit percentages to start off with…

      People want a dietary explanation because it might be one of very few things we feel we can control. Yet when you look across all the different cultures you can find just about every diet has a population that lives long and healthy lives. IF it really mattered, it would be very obvious, and it isn’t, which means it can’t matter nearly as much as we think it does. The human body is an amazing thing, able to eat just about anything and thrive (with the exception of too much sugar, in whatever form). Even then, eating like crap takes 50+ years to kill you…

      Lastly, I just find it illogical to worry about a substance which is primarily produced by the body because it is so essential, and to take steps to reduce it because scientists who don’t truly understand it (if they did we wouldn’t be talking about what matters and what doesn’t) have a theory that *might* suggest it could matter.

      What are the things nobody argues about?
      Don’t smoke
      Exercise regularly
      Get enough sleep
      Reduce/eliminate added sugar

      Everything else is in the noise….

  81. James  July 21, 2014

    Hi Dr [is the 11-th hour non stop, and i’m still reading your blog]

    Pls correct the Robert Burton year he of “Anatomy of Melancholy, nice quote.”
    He lived (8 February 1577 – 25 January 1640)
    You have placed it in XIX cent.
    cheers J.

    • Peter Attia  July 21, 2014

      Thanks, James. I think the year I have is the year the book was published from which I found it. Do you know the exact year?

    • James  July 21, 2014

      You’re welcomed Doc. 1621 – was 1st publishing.
      It was out of print from that time till ~1800., very much in demand.

      No original copy survived, so all reprints are based on 1932.
      As befitting of his time, R.B. was an erudite who studied from
      physiology to astrology. He wrote a lot of latin poetry/ references in it.

      “A-of-Mel” had many admirers from Samuel Johnson [who wrote “The Dictionary” Johnson claimed that he could finish it in 3-years. Academie Francaise used 40 scholars working for 40 yrs to finish theirs:) S-J said: “This is the proportion. 40 x 40 = 1600. As 3 goes to 1600, so is the proportion of an Englishman to a Frenchman”] to Keats, J.L.Borges etc.

    • Peter Attia  July 23, 2014

      Thank you!

  82. Jeff Johnson  July 24, 2014

    Respose to Tim April 17, 2014

    Cultures that do not eat heat processed unnatural polyunsaturated oils – heat processed refined sugars and non-fermented (soaked in water) grains and legumes –

    have almost no heart problems –

    The obvious conclusion being that diet and diet only is the most important thing in controlling risk –

    Also – the LDL particle is composed of thousands of individual molecules – I assume some of these are glycated sugars and some polyunsaturated fats( if these things are in the diet) –

    Opinion only – but in my mind – the glycated sugars with their hard-sharp molecular structures is what cuts into the artery wall and this starts a cascade of events – the polyunsaturated fats just being their act as the muck to help the repair –

    So – the LDL Particle is not their to repair anything – toxic substances it is carrying create the problem and then the repair begins – being fixed or repaired with equally toxic stuff(oxidized polyunsatured oils)

    The point being – no repair would have been needed if substances being carried by the LDL were not there

    There are other factors involved as well – the general integrity of the bodies cells – calcium transport – correct immunne response

    The number of LDL Particles therefore can only act as a guide – and simply implies that the more of them – the better chance the bad players attached to the LDL Particle will cause harm

    If the LDL Particle is carring any virucs-bacteria-fungus-misshaped proteins: an increased foam cell response would occur

    This is just how all this plays out in my mind – The LDL-Particle number between 15 year no cardiac event and those with an event is only on averaged out basis of 3000 people – 1300LDL-P to 1600LDL-P or not a great deal of difference

    Since almost no one gets a test done for soft plaque build-up – a Doctor is left playing a guessing game – where a lousy LDL-P number is his best bet –

    There’s one other theory worth looking at: processed food often contain hundreds of different egg sources(a commercial batch of cookies or bread or Miricle Whip and others containing egge sources from hundreds of different eggs) –

    The possible problem being is that: certain egg proteins enter the blood stream and are certainly capable of attaching themselfs to an LDL-Particle – one egg would not be a problem – it’s the hundred’s of different egg sources that could cause a greater imunne response or some other metabolic havoc –

    The person with the greatest imunne response to these hundred’s of DNA DIFFERENT egg proteins being at a higher risk –

    It would seem a persons imunne response must play a role in soft plaque build-up –

  83. Maria  November 19, 2014

    Hi Peter,
    I am 48 years old and have hFH. I can’t tolerate statins, they make me depressed. 6 years ago I had a fast CT which revealed minimal plaque. I have been on a LCHF diet for about 11 years. From my understanding it appears that statins do not help in the case of FH since the cells are already depleted of cholesterol due to the lack of receptors. Statins would deplete the cells of vital cholesterol even further.
    My interpretation of the overwhelming litterature is thus. A diet low in carbohydrate (less than 70 g per day), strictly limiting fructose, and PUFA, while high in saturated fat from nutrient dense animal foods, along with vegies is my best bet. Is this correct? I recently started eating more butter and my HDL skyrocketed. For the first time my ratios of TC to HDL are in the normal range given this increase in saturated fat. I also read recently, that when carbs are eaten, the best time of day is in the evening, since insulin produces a blunted response at that time. Thanks and keep up the good fight.

    • Peter Attia  November 26, 2014

      Maria, statins (and other lipid lowering meds) do help in FH, but they need to be the right drugs. Also, not clear what best diet is to minimize cholesterol synthesis. Varies by person, genes, etc.

  84. kelly  February 20, 2015

    Hi Peter,
    Thanks so much for the education over the years. My families health is better for it and I don’t have to tell you what that’s worth.. I credit Taubes, you, Rosedale, Bernstein and a few others who can lay out this complex info in a way that makes sense to dopes like me so that we can apply the knowledge to improve our and our loved ones health.. Indeed, I’ve been able to “normalize” my boys T1D hbA1C – how awesome is that? 🙂 The state of medicine these days and the path that it’s got diabetics on (both t1 and t2) breaks my heart man.. But I digress…

    I wanted to bring to your attention a fascinating paper by Vladimir M Subbotin

    It corrects some common/persistent misperceptions of the coronary artery structure and offers an alternate hypothesis for the origin of atherosclerosis that answers a paradox or two that the current accepted model fails to explain.. It may have implications regarding this wonderful series you’ve written, maybe not.. I don’t think it’ll effect the focus I think you rightly put on particle count.. But it’s got important info in it, none the less.

    Regardless, I think I understand you well enough to bet money that you’ll enjoy it if you have time. It’s not a long read.
    Kind regards,
    Kelly T
    Ft. Collins CO

    • Peter Attia  February 20, 2015

      Look forward to checking it out.

    • kellyt  February 22, 2015

      Hey Peter,
      I’m still in the middle of corresponding with the author, Mr. Subbotin, but it sounds to me like the established “gatekeepers” of funding and publications have tried to marginalize him. Hmm a clear thinking, rational, scientific mind dared to point out inaccuracies of an accepted premise, upon which the most profitable phara intervention known to man has since been built… Made me think of the arrows that you and Taubes take when you dare to ask rational, thoughtful questions that challenge the accepted dogma in the world of metabolism and nutrition..

      When asked why he persists? “It is the meaning of my life.”
      His answer reminded me of the “What’s your legacy?” T your wife gave ya.

      Anyway. He sent me a link to a second paper he wrote on the subject.
      It’s a real gem. Enjoy 😉

    • Peter Attia  February 22, 2015

      I read his paper in detail–with highlighter!–and I think he makes some interesting arguments. I guess my question is this, even if he is correct, does it change the role for LDL-P minimization?
      It’s also possible that what occurs is a combo of both approaches (i.e., toward and from the lumen).

    • Bill  February 23, 2015

      Whether or not this most interesting gentleman turns out to be correct, that he even *might* be correct shows that despite their high confidence Dayspring et al. have not by any stretch truly demonstrated that LDL-P is causative in CVD. This has always seemed apparent to me. A seemingly plausible mechanism + weak evidence ? proof of causation.

      Even if LDL-P correlates better with CVD than LDL-C—and even if clinical trials show that pharmaceutically lowering LDL-P correlates better with improved outcomes than pharmaceutically lowering LDL-C—that in no way proves causation. Establishing basic biology takes an awful lot more than that. And without proven causation, and without clinical trials designed from the start to rigorously determine the risk/benefit of pharmaceutically lowering elevated LDL-P, how confident can any of us be that taking those drugs—which, to put it mildly, have non-trivial toxicity—is a wise move?

      Hate to say it, but I can’t help comparing this state of affairs to Zoe Harcombe’s devastating demonstration of how little, if any, real science existed to support the radical dietary guidelines of the 1970’s. I’m not saying Dayspring et al. are necessarily wrong, or that no one should take statins, but how much we really know about these things is a question worth some serious consideration, IMO.

    • Peter Attia  February 23, 2015

      Not so, Bill. Nothing this fellow says disputes the idea that lipoprotein particles trafficking sterols into the subendothelial space causes atherosclerosis. The only point he is disputing, is the path they take to get there: do they diffuse from the lumen or do they get there from the circulation via capillaries.
      In either case, fewer LDL-P is better, and this has been demonstrated by every study looking at CHD mortality vs. LDL-P.

    • Bill  February 23, 2015

      I don’t know, Peter. You write, “Nothing this fellow says disputes the idea that lipoprotein particles trafficking sterols into the subendothelial space causes atherosclerosis.” But in my reading that’s exactly what he claims: “. . . logically, it must be concluded that high LDL levels are not ‘a major cause’ of coronary atherosclerosis. One of the major “assumptions” he pillories is that “a high level of LDL initiates and is the main cause of atherosclerosis.” Perhaps I recall incorrectly, but doesn’t Dr. Dayspring claim exactly what Subbotin denies—that LDL-P infiltration is the initiating and fundamental cause of atherosclerosis?

      Subbotin does not deny that high LDL (I didn’t see him distinguishing between LDL-P and LDL-C) contributes to atherosclerosis, or that lowering LDL may modestly reduce the risk of getting CVD. But that’s not at all the same thing as accepting that LDL, in whatever form, is fundamentally causative of CVD.

      Perhaps this seems like only a semantic difference, but I think Subbotin is right that it’s not, just as Gary Taubes was right that the mainstream energy balance model of obesity fundamentally and disastrously misconstrues the true causality. I love Subbotin’s quote from Stebhens:

      “… differentiating between cause and non-causative factors is essential. Elimination of the latter only ameliorates or reduces the incidence whereas elimination of the former eradicates the disease. Swamps are not a cause of malaria. Draining swamps may reduce the incidence of malaria but it is eradication of the malarial parasites that eliminates the disease. Reduction in incidence rather than elimination of the disease precludes a causal relationship.”

      Subbotin, in the second paper linked above, states without reservation, “We do not have a hint about the causative mechanisms.” Once we do, he thinks, perhaps there will be some truly effective strategies for preventing and treating CVD. But if we think we already know the underlying causal mechanism of course there won’t be much looking beyond it.

      Other people, including Malcolm Kendrick and Carlos Monteiro, are also looking for alternate mechanisms of CVD in very serious ways. Jury still way out on the fundamental biology, to me at least.

      In the meantime, maybe reducing LDL-P is a good idea for some of us, even with toxic drugs, in search of that possible modest reduction of risk. I’m not convinced, though your support this idea certainly makes me think twice. I’d like to see independent clinical trials testing the outcomes of mass screening of healthy populations for LDL-P, and treatment of those thereby deemed at risk. We’ve discussed this topic of screening before here. Past examples are not encouraging. As Dr. Gilbert Welch among others has shown, almost always huge numbers of healthy people are identified to be at risk and are exposed to the harms of intervention in order to, perhaps, help a much smaller number. The wisdom of this tradeoff is, to Welch and me and lots of others, far from clear. Maybe LDL-P screening will be different . . . anyway, interesting discussion, and I love Subbotin’s courage in challenging the orthodoxies of the scientific elites—kinda like you and Gary :-).

    • Peter Attia  February 24, 2015

      Dayspring (and every other lipidologist) argue that LDL-P enter the S-E space from the lumen (i.e., the shortest path). This author argues they get there by another path–namely through neovascularization through the entire wall thickness.
      But they both agree that LDL particles end up the S-E space and that’s where the trouble takes place. What they disagree on is how they get there.
      I’m not sure which one is correct and will always have sympathy for a contrarian view. But I don’t see how this alternative view alters the treatment, even if it is correct.

  85. kelly  March 9, 2015

    Thank you for the thoughtful discussion, gentlemen.

    Two more papers that Mr. Subbotin has provided to me, both by William Stehbens. Do you have access to pubmed? I have these full pdf papers if not.. Anyone can ping me at my Kelly.trosper gmail account for the full papers.

    Coronary heart disease, hypercholesterolemia, and atherosclerosis. I. False premises.
    Coronary heart disease, hypercholesterolemia, and atherosclerosis. II. Misrepresented data.

    Peter – “But I don’t see how this alternative view alters the treatment, even if it is correct.”

    You’ve got a touching Tedx talk that demonstrates how important understanding the correct etiology of a condition/disease is when it comes to focusing on a target of treatment.. You went from a Dr. blaming the patient for being lazy and eating too much (calories-in/calories-out, exercise more – prevention/treatment for her diabesity), to understanding the etiology of obesity/diabetes (through your own personal journey) and eventually apologizing to her..

    That took great courage and revealed your value for the truth.

    You said you initially blamed her because you assumed the “pathological sequence of events was settled science.” And then, you went on to rattle off some very significant, important questions about diabetes and obesity that were only made possible by your efforts to step back and “question everything and challenge all assumptions…”

    This may have profound implications to the target of treatment and current hypotheses, it might not. But the fact is, as long as current hypotheses are built on a faulty intellectual foundation (incorrect arterial morphology/design, mechanisms/progression of disease), science and treatment will never even think to focus on these other possible areas of treatment. We’re essentially throwing darts, hoping that something sticks.. (and sometimes they do.. never look a gift horse in the mouth, right?)

    And you’re absolutely right. Particle count may be an important factor to control.. But if it is, it’s because we got lucky – not because we understand the true etiology of atherosclerosis…

    Bill – “Subbotin, in the second paper linked above, states without reservation, “We do not have a hint about the causative mechanisms.” Once we do, he thinks, perhaps there will be some truly effective strategies for preventing and treating CVD.”

    I see why he’s focused on educating the correct arterial morphology… That’s basically the lynch pin or the corner stone that current “pathological sequence of events and settled science” is built on.

    If the correct morphology is agreed upon, taught/understood, better questions would necessarily be asked. Current hypotheses would no longer make sense, better ones would come along to explain the paradigms that aren’t even visible to these Docs and scientists who are currently pushing research/treatment based on an incorrect model down the wrong road…

    Bill – ” I love Subbotin’s courage in challenging the orthodoxies of the scientific elites—kinda like you and Gary :-).”

    Exactly. That’s why I got goose bumps when I stumbled upon his first paper..

    I think of how Taubes’, in his book “Good Calories, Bad Calories”, documents the initial inertia built up by the (faulty and fraudulent) lipid hypothesis… How quickly it was backed by the entire weight of the established political, medical, nutritional and scientific communities..

    That inertia, as you know, continues to this day and at times seems unrelenting.. It’s has pulled and is continuing to pull most research, science and medicine down a fruitless, harmful path.. not to mention the damage it’s causing the growing population of metabolically deranged people in this world..

    Is it deja vu, all over again, with regard to Atherosclerosis?

    Peter, this guy is fascinating to speak to.. I think the implications here can’t be overstated..
    Would you consider emailing him and just having a conversation?? Wherever it might take you?
    I have his contact info.

    Quid enim iustificabit vitam tuam?

    • Peter Attia  March 13, 2015

      Of course, always happy to discuss.

    • Christopher  April 10, 2015

      Thanks for the studies you’ve listed!
      Currently fighting to apply a keto-adapted paleo autoimmune diet for a 7 year old nephew/godson, and am mounting evidence that fats are good (grew up on a farm in NH and ate plenty fat, eggs, cream, etc and at 46 my health is at it’s prime, because of the evolutionary oriented mindset I’ve always had).

      If you don’t mind, could you please email those study pdf’s to me? I will email you with “William E. Stehbens studies” in the subject line shortly.

      Thanks Peter for a great lead of thought and science here!

  86. Brendan  March 30, 2015

    Dear Peter,

    First, thank you for this simply outstanding series. I haven’t found such a detailed cause-effect explanation anywhere else.

    Like most other folks here, I have a question which I am currently unable to reconcile, but highly relevant to me, as my father died from a heart attack at 45, and his brother at 38; as I am 31, the clock is ticking.

    I have been following a roughly Paleo / bulletproof diet for approximately two years, and each blood test has revealed a pattern of “relatively” low LDL-P_NMR (the most recent test show 1,804 nmol/L), but still high ApoB (102 mg/dL). [For reference, Large HDL-P: 4,386 nmol/L, and ‘high’ and ‘low’ are based upon the ranges provided by WellnessFX]. I wasn’t easily able to find the information to do a conversion, but if the ratio of LDL partcles to ApoB is close to ~1, I wouldn’t have expected to find this discrepancy.

    You can find my full bloodwork here (though this link will expire after a few days):

    I found a recent article (http://www.lipidjournal.com/article/S1933-2874(14)00404-8/abstract?cc=y) suggesting that ApoB > LDL-P may indicate a higher-than-average prevalence of other non-LDL ApoB containing lipoproteins: however, my Lp(a) is low (21 mg/dL), sLDL (178), Medium LDL (393), TG (68), total Cholesterol 247, and phenotype A. I do not believe this makes up the discrepancy, though perhaps I am mistaken. The paper goes on to suggest to note that ApoB>LDL-P is most often associated with increased Lp(a) mass, but for me here that is not the case.

    The closest analgous situation I could find was located at http://www.quantifiedbob.com/2014/09/bulletproof-diet-intermittent-fasting-1-5-year-results/, where the increases in lipoprotein markers were caused by other issues, such as chronic infection and thyroid issues (as an aside, I have suspect I may have some thyroid issues for some time; though my TSH looks acceptable, I suffer from dry skin and for the past six months have been shedding hair from my head, with no history of genetic baldness). I am also carrier for alpha-1 anti-trypsan deficiency (SZ); I don’t know if that plays any role; recent work suggest that it may do something (http://www.ncbi.nlm.nih.gov/pubmed/6333180), but most work has only been done on those with the full-blown version, not just carriers.

    I’d love to get your thoughts on this. My PCP and cardiologist just want me on a low-dose statin. Would you recommend futher stool and/or saliva tests for investigation of thyroid and/or chronic infection? Is there someone in the Chicago area you would recommend seeing?

    Apologies for the long post. Even if you don’t have time to answer, thanks again for all the work you do.

    • Peter Attia  April 9, 2015

      Brendan you MUST see a bulge bracket lipidologist. Someone needs to figure out your Lp(a)-P (not just cholesterol content), apoE, etc.

    • Brendan  April 15, 2015

      Hi Peter,

      Sorry, what is a ‘bulge bracket lipidologist’? You mean someone who is well-known and respected? Can you give me names? The two folks I’m scheduling now are:
      http://www.feinberg.northwestern.edu/faculty-profiles/az/profile.html?xid=22239 (he’d like me on a low-dose statin)
      http://www.feinberg.northwestern.edu/faculty-profiles/az/profile.html?xid=17759 (haven’t spoken with him yet)


    • Maryann  April 16, 2015

      Renowned lipidologist Dr. Tara Dall does phone consults on advanced testing and interpretation. She can be contacted through her website taradall.com. Best wishes, maryann

    • Peter Attia  April 16, 2015

      Yes, Dr. D is great.

    • Brendan  May 5, 2015

      Thanks very much to you both – I will schedule a call ASAP.

  87. Ahmed A El-tahtawy  March 22, 2016

    Hi Peter, Love your blog and the heavy science!!
    I have been testing my lipids using NMR for years and my numbers are extremely high and not improving:
    ~2600 for LDL-p total, ~1800 LDL-P small. My wife (internal medicine) is fighting with me to take statins; as a clinical pharmacologist, I know the harm especially with no benefit. My TG is high (200-300), but not diabetic.

    I feel I am a healthy 60 y old, carotid artery are clean, thinking about coronary cat scan? waiting for APOe test; but still at loss what path to take or how to interpret the results.
    much appreciated…
    keep the good research.

  88. Nick  June 14, 2016

    Hello Peter,

    You have been a wealth of knowledge and I’ve read many of your blogs and watched you tube videos of your talks. I’ve looked for information regarding other markers in the Lipid Panel, such as Uric Acid and ALT and could find any associate blog posts. The reason I ask is because I just received my blood work back and both were flagged out of range high. I’ve read that Uric Acid has a tendency to go high, but after the adaptation it should go back down to normal levels, I’m at 9.7. I’m not sure about the ALT. Its a marker for liver damage as you know, but I haven’t been drinking and was only a social drinker before. My ALT was 48. I do carry extra weight. I’m about 30% BF right now. Working to bring that back down to 10% where I was just 4 years prior.

    I’ve been eating high fat/low carb for 3 weeks now. Just adjusted my carbs from 10% to 5%.

    Do you have any comments for people who may see abnormal Uric Acid and ALT numbers when beginning a ketogenic diet?

    In addition, my LDL went above high for the first time, 106. But I already plan to ask for the NMR when I go to see my doctor for my annual physical.

    Thanks for all you do!

  89. Tim  December 22, 2016

    Maybe I missed this somewhere thoughout this series but what is the mechanism of high sugar/carb intake that drives elevation of LDL-P? I understand as we become more insulin resistant this number goes up but how does high blood sugar do this?

  90. Matt  February 15, 2017

    Great Info…

    So it seems that if you are measured (by typical blood panel) to have low or normal LDL-C, you may still be at risk if your LDL-P is high. But, is the reverse scenario ever possible: where you are measured to have high LDL-C (by typical blood panel) but after an NMR the findings are that your LDL-P is low or within limits. Is this scenario even possible and would this mean you are, in fact, low risk for atherosclerosis?


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