May 17, 2012

Cardiovascular Disease

The straight dope on cholesterol – Part IV

In this post we’ll address the following concept: How does cholesterol actually cause problems?

Read Time 11 minutes

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?



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.

Intravascular ultrasound image of a coronary artery (left), with color coding on the right, delineating the lumen (yellow), external elastic membrane (blue) and the atherosclerotic plaque burden (green). The original uploader was Ksheka at English Wikipedia [CC BY-SA 2.5], via Wikimedia Commons

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  1. 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?

  2. 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?

    • 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. 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. 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.

    • 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. 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.

    • 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.

    • 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.

    • “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?

      • 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. 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!

    • 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.

    • 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. 🙂

      • 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.

    • 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.

  7. Peter,
    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.

    • 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?

    • 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 ( we can ship samples to the USA and our patients benefit from the most recent medical advances in diagnostic testing.

  8. 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! 😀

    • 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?

    • 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

    • 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., 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.

    • 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.

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

  9. 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? 🙂

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

    • 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.

  10. 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?

    • 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.

  11. 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?

    • 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.

    • 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!

  12. 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.

    • 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.

    • 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.

    • 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.

  13. 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?

    • 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?

    • 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.

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

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

  15. 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.

  16. 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.

  17. 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.

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