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. 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.

  2. 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?”

  3. 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…).

  4. 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. 😉

    • 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!

    • Word.

      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.

    • 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

  5. 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.

    • 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.

      • 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.

    • 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.


      • 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.

  6. Peter:

    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?


    • 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.

  7. 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!

    • Julie,

      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.

    • 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!

  8. Hello,

    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

  9. Hi Jared,

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

  10. 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?

  11. 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.

    • 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?

  12. 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. “

    • 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.”

    • 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 .

      “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.”

  13. 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.” .

    • 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.

  14. 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)?



    • 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.

  15. Hi,
    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!

    • 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.

  16. 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

  17. 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?


    • 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.

  18. Peter,

    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?

    • 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….

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