Marks Daily Apple
Serving up health and fitness insights (daily, of course) with a side of irreverence.
30 Aug

The Straight Dope on Cholesterol: 10 Things You Need to Know – Part 2

This is a guest post by Peter Attia and is a summary based on a 10-part series of the same name that you can find at The Eating Academy.

To read The Straight Dope on Cholesterol: 10 Things You Need to Know – Part 1 click here.

To start at the beginning of Peter’s 10-part series click here.

Now, Peter…

6. Inflammation makes it worse, but the inciting event is the LDL particle getting past the endothelium.

Because there is no experiment or clinical trial we can carry out to unambiguously resolve the exact role of inflammation in this process (and, by extension, the role of LDL particles), we rely on so-called “natural experiments.”

Such “natural experiments,” which help elucidate this role, are those 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. 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 - 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.

7. LDL particles (LDL-P), not LDL cholesterol content (LDL-C), is what drives sterols into artery walls – Don’t confuse the “boats” and the “cargo.”

There are several examples of long-term studies examining the predictive power of LDL-C versus LDL-P with respect to cardiovascular disease. This study followed a Framingham offspring cohort of about 2,500 patients over a median time period of almost 15 years in each of the four possible groups (i.e., high-high, high-low, low-high, and low-low) and tracked event-free survival. In this analysis the cut-off points for LDL-P and LDL-C were the median population values of 1,414 nmol/L and131 mg/dL, respectively. So, “high” implies above these values; “low” implies below these values. Kaplan-Meier survival curves are displayed over a 16 year period – the steeper the slope of the line the worse the outcome (survival).

The same patterns observed in the other studies are observed here:

  1. High LDL-P is the best predictor of adverse cardiac events.
  2. LDL-C is only a good predictor of adverse cardiac events when it is concordant with LDL-P; otherwise it is a poor predictor of risk.

Interestingly the persons with the worst survival had low (below median) LDL-C but high LDL-P. The patients most likely to have high LDL-P with unremarkable or low LDL-C are those with either small LDL particles, or TG-rich/cholesterol poor LDL particles, or both (e.g., insulin resistant patients, metabolic syndrome patients, T2DM patients). This explains why small LDL particles, while no more atherogenic on a per particle basis than large particles (see point #9), are often a marker for something sinister.

8. People with metabolic syndrome are at even greater risk of LDL-C/LDL-P discordance.

Concordance is a statistical term that refers to variables that predict the same thing. Conversely, discordance refers to variables that do not predict the same thing. When LDL-C (what most doctors measure in your blood test) and LDL-P (what most doctors do not measure in your blood test) predict the same risk, they are said to be concordant. When they do not, they are said to be discordant. In the latter case, LDL-P is the one to follow.

To illustrate the prevalence of discordance between LDL-C and LDL-P, consider the figure below.

This figure shows data from patients with LDL-C between 100 and 118 mg/dL (i.e., second quartile of risk: 25th to 50th percentile) without metabolic syndrome (top) and with metabolic syndrome (bottom). In the patients without metabolic syndrome, LDL-C under-predicts cardiac risk 22% of the time. However, when you look at the patients with metabolic syndrome, you can see that 63% of the time their risk of cardiac disease is under-predicted.

The data above were collected from nearly 2,000 patients with diabetes who presented with “perfect” standard cholesterol numbers: LDL-C < 70 mg/dL; HDL-C > 40 mg/dL; TG <150 mg/dL. However, only in 22% of cases were their LDL-P concordant with LDL-C. That is, in only 22% of cases did these patients have an LDL-P level below 700 nmol/L.

Remember, LDL-C < 70 mg/dL is considered VERY low risk – the 5th percentile. Yet, by LDL-P, the real marker of risk, 35% of these patients had more than 1,000 nmol/L and 7% were high risk. When you do this analysis with the same group of patients stratified by less stringent LDL-C criteria (e.g., <100 mg/dL), the number of patients in the high risk group is even higher.

As a general rule, the more “metabolically deranged” an individual is, the greater this discordance between LDL-C and LDL-P, as shown in the figure below. The axis of this figure is adjusted so that the red bars and the blue bars should be of the same height when LDL-C and LDL-P are concordant.

9. A smaller LDL particle is no more or less atherogenic than a large one – a particle is a particle.

Particle size is something many folks fixate on, and there is no doubt that smaller LDL particles are associated with greater risk.  But, on a particle-by-particle basis are they, in fact, more atherogenic? Let’s find out.

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

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

If you just looked at this figure, you might end up drawing the conclusion that both size and number are independently predictive of risk. Not an illogical conclusion…

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

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

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

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

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

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

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

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

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

10. The greatest way to reduce your risk of atherosclerosis is to make sure your boats are carrying the right cargo – that way you’ll need fewer of them.

LDL particles traffic not only cholesterol ester but also triglycerides. Each and every LDL particle has a variable number of cholesterol molecules which, because of constant particle remodeling, is constantly changing.  In other words, of the several quadrillion LDL particles floating in your plasma, no two are carrying the exact same number of cholesterol molecules. It takes many more cholesterol-depleted LDL particles than cholesterol-rich LDL particles to traffic a given cholesterol mass (i.e., number of cholesterol molecules) per volume of plasma (i.e., per dL). Core cholesterol mass is related to both LDL particle size (the volume of a sphere is a third power of the radius – it can take 40-70% more small particles than large LDL particles to traffic a given cholesterol mass) and the number of TG molecules per LDL particle.

TG molecules are larger than cholesterol ester molecules, so as the number of TG molecules per particle increases, the number of cholesterol molecules will be less – in a very non-linear manner. Regardless of size, it takes many more TG-rich LDL particles (which are necessarily cholesterol-depleted) to traffic a given cholesterol mass than TG-poor LDL particles.  The persons with the highest LDL particles typically (though not always) have small LDL particles that are TG-rich. These are incredibly cholesterol-depleted LDL particles.

Let’s start with what we know, then fill in the connections, with the goal of creating an eating strategy for those most interested in delaying the onset of cardiovascular disease.

There are several short-term studies that have carefully examined the impact of sugar, specifically, on cardiovascular risk markers. Let’s examine one of them closely. In 2011 Peter Havel and colleagues published a study titled Consumption of fructose and HFCS increases postprandial triglycerides, LDL-C, and apoB in young men and women. If you don’t have access to this journal, you can read the study here in pre-publication form. This was a randomized trial with 3 parallel arms (no cross-over). The 3 groups consumed an isocaloric diet (to individual baseline characteristics) consisting of 55% carbohydrate, 15% protein, and 30% fat. The difference between the 3 groups was in the form of their carbohydrates.

Group 1: received 25% of their total energy in the form of glucose

Group 2: received 25% of their total energy in the form of fructose

Group 3: received 25% of their total energy in the form of high fructose corn syrup (55% fructose, 45% glucose)

The intervention was relatively short, consisting of both an inpatient and outpatient period, and is described in the methodology section.

Keep in mind, 25% of total energy in the form of sugar is not as extreme as you might think. For a person consuming 2,400 kcal/day this amounts to about 120 pounds/year of sugar, which is slightly below the average annual sugar consumption in the United States. In that sense, the subjects in Group 3 can be viewed as the “control” for the U.S. population, and Group 1 can be viewed as an intervention group for what happens when you do nothing more in your diet than remove sugar, (which was the first dietary intervention I made in 2009).

Despite the short duration of this study and the relatively small number of subjects (16 per group), the differences brought on by the interventions were significant. The figure below shows the changes in serum triglycerides via 3 different ways of measuring them. Figure A shows the difference in 24-hour total levels (i.e., the area under the curve for serial measurements – hey, there’s our integral function again!). Figure B shows late evening (post-prandial) differences. Figure C shows the overall change in fasting triglyceride level from baseline (where sugar intake was limited for 2 weeks and carbohydrate consumption consisted only of complex carbohydrates).

The differences were striking. The group that had all fructose and HFCS removed from their diet, despite still ingesting 55% of their total intake in the form of non-sugar carbohydrates, experienced a decline in total TG (Figure A, which represents the daily integral of plasma TG levels, or AUC). However, that same group experienced the greatest increase in fasting TG levels (Figure C). Post-prandial TG levels were elevated in all groups, but significantly higher in the fructose and HFCS groups (Figure B). The question this begs, of course, is which of these measurements is most predictive of risk?

Historically, fasting levels of TG are used as the basis of risk profiling (Figure C), and according to this metric glucose consumption appears even worse than fructose or HFCS. However, recent evidence suggests that post-prandial levels of TG (Figure B) are a more accurate way to assess atherosclerotic risk, as seen herehere, and here.

The figure below summarizes the differences in LDL-C, non-HDL-C, apoB, and apoB/apoA-I (remember, apoB and apoA-I are good surrogates for LDL-P and HDL-P, respectively).

Again, the results were unmistakable with respect to the impact of fructose and HFCS on lipoproteins, and by extension the relative lack of harm brought on by glucose in isolation. [Removal of glucose and fructose/HFCS would have been a very interesting control group.]

In just a short period of time these dietary interventions had a profound impact on the markers of cardiovascular risk.

So, there you have it – everything you need to know about cholesterol in the length of time it takes to go to the grocery store, buy some high-cholesterol bacon and eggs, cook it, eat it, and savor it. Now it’s your turn to be the judge. Is the conventional wisdom about cholesterol being bad really true?

You want comments? We got comments:

Imagine you’re George Clooney. Take a moment to admire your grooming and wit. Okay, now imagine someone walks up to you and asks, “What’s your name?” You say, “I’m George Clooney.” Or maybe you say, “I’m the Clooninator!” You don’t say “I’m George of George Clooney Sells Movies Blog” and you certainly don’t say, “I’m Clooney Weight Loss Plan”. So while spam is technically meat, it ain’t anywhere near Primal. Please nickname yourself something your friends would call you.

  1. http://www.nejm.org/doi/full/10.1056/NEJM199103283241306

    Anyone who still thinks eggs will cause high cholesterol should read this.

    Anna wrote on August 30th, 2012
    • And not read this:
      http://cholesterol.about.com/od/dietitiansadvice/a/foodstoavoidlist.htm

      This article makes me sad and mad at the same time. THIS is why my family thinks its weird that I eat so many eggs and so much liver.

      Aaron wrote on August 31st, 2012
    • I don’t think the fact that a man who ate 25 eggs/day without any ill effects proves anything. By the same logic, would the discovery of a 90-year old man in perfect health who smoked three packs of cigarettes a day since he was 18 prove that cigarettes are healthy?

      Randy Burnett wrote on December 27th, 2013
      • I smell straw man.

        victor wrote on May 22nd, 2014
      • A 90 year old man that smoked 3 packs of cigs a day since he was 18 would NOT be in perfect health. My grandfather smoked a pack or more a day from 14 years old and he looked TERRIBLE until he died of lung cancer at 78.

        Addam wrote on September 18th, 2014
  2. The “boats” and “cargo” analogy is working great for me. Thank you, Dr. Attia!

    Joy Beer wrote on August 30th, 2012
    • This whole article including part 1 is way over my head. I’m not a doctor.

      Suzanne wrote on August 30th, 2012
      • Everything you need to know about cholesterol EXCEPT what to eat & do to prevent & reverse arterial plaque, coronary calcium & heart disease & heart attacks. He just didn’t use enough charts & graphs in these 2 articles to provide the answers.

        conrack wrote on August 30th, 2012
        • Conrack, Peter doesn’t have any explicit recommendations in this article. The data presented suggests, however, that in order to decrease the number of boats (ie. LDL-P), by way of reducing your triglycerides (TG), one strategy is to eliminate, or reduce, sugar from your diet. That’s it. No reading between the lines needed.

          However, there may be several strategies to reduce the number of boats (possibly by reducing omega-6 oils, increasing saturated fat intake, etc, who knows), but the last section only alludes to one strategy–sugar reduction or elimination (yeah, Yudkins). Maybe Peter will suggest other strategies at his site as his series continues there. I’d love to hear what else he has to say.

          Thanks Peter for all your work.

          Stipetic wrote on August 31st, 2012
        • Horrible pair of articles. It fails to explain it in a simple way for the laymen, and is incomplete and biased from a purely scientific stand. The comments gleefully insisting on eliminating all sugar from the diet are even more misdirected than mainstream nutritionism, with its cries to erase all cholesterol.
          Don’t you people see you are the same? I expect a PALEO diet adopter to realize that the ice age didn’t last millions of years and most of the time fruits and vegetables were available, as opposed to white sugar and HFCS. A hint: investigate the different digestive pathways of refined and natural sugars before writing the next fanatic nutritional recommendation.

          Verther wrote on September 5th, 2012
      • Neither am I. I didn’t even go to college…maybe it helps when you read these things all the time.

        It is a bit technical but I think I get most of it.

        I would rather not take a test on it though…please don’t make me teacher! :P

        Jonathan Swaringen wrote on September 1st, 2012
      • I like the boats and cargo analogy. However,I do agree that for most lay people, this article is over the top. We need it broken down into something like 7th grade English for the masses to understand.

        mark wrote on September 2nd, 2012
        • those reading at a 7th grade level, probably wouldn’t bother with an article like this anyways.

          It was a little thick, but a quicker second re-read kind of clears up any confusion.

          eric wrote on September 12th, 2012
      • I’m just glad I didn’t go to medical school!

        Michael wrote on September 5th, 2012
  3. So basically live Primal………

    Primal Toad wrote on August 30th, 2012
    • come one toad, thats too complicated.

      Max Ungar wrote on August 30th, 2012
    • Thanks for dumbing down for me…You should write blogs.

      What I wanted to ask is if I feel good, look good naked, and perform well, I shouldn’t have clogged arteries right? ;)

      JPizzay wrote on August 30th, 2012
  4. Maybe I missed it, and I went to the series (9 parts are up, waiting for Part X). How does one measure their LDL-P? The NMR blood lipid test?

    John D. Pilla wrote on August 30th, 2012
    • Correct, NMR is the only way to measure LDL-P, though measurement of apoB (which does not require NMR) is a very good proxy.

      Peter Attia wrote on August 30th, 2012
      • Does VAP not show that too? I thought both VAP and NMR showed that?

        Jonathan Swaringen wrote on September 1st, 2012
    • nmr ldl-p testing is not (it seems) available in Australia

      Clare wrote on September 6th, 2013
  5. “ingesting 55% of their total intake in the form of non-sugar carbohydrates”

    that was group 1, which ate 55% of calories as carbohydrates, and 25% of calories was glucose. that would make 30% of calories non-glucose, and presumably non-sugar, but that 25% as glucose is very much sugar.

    mARK wrote on August 30th, 2012
    • mARK,

      I believe he is referring to “sugar” as the generic, table sugar form and not the broad sense.

      I hate the confusion generated when referring to sugar so I always try to refer to its specific form (i.e. glucose, fructose, sucrose, HFCS).

      I think it would be more clear if it read, “ingesting 55% of their total intake in the form of non-sucrose (i.e. non-fructose) carbohydrates.”

      zach wrote on August 30th, 2012
      • they are all bad when over done – read Dr. A’s site – he tells you to quit it all

        lockard wrote on August 30th, 2012
      • I think it’s more confusing to refer to sugar by its specific form. I would rather sugar, of any form be called what it is – sugar. Sugar is sugar, Its all bad for you.

        eric wrote on September 12th, 2012
  6. Fascinating stuff, thanks Dr Attia for this great – and very readable – article.

    It poses a few interesting questions;

    What is the effect of eating short chain fatty acids, (e.g. coconut oil) that don;t get transported as triglycerides?

    What is the effect of fructose eaten as part of whole fruit, (or honey) instead of refined fructose/HFCS

    And, this would seem to suggest that eating (long chain) fats at the same time as fructose is a really bad idea! Most sweet fruits have very little fat, but most junk food, of course, is loaded with both!

    And, what is the effect of fructose eaten as part of whole fruit, (or honey) instead of refined fructose/HFCS?

    We and up at the same place as always – embrace the animal fats, eat whole foods, and easy on the sweet fruit – where have we heard that before?

    Paul N wrote on August 30th, 2012
  7. So I commented yesterday, after reading the first part of this post, about the possiblity that size of LDL made a difference. This post shows that this is not the truth. So, again, I learned something new and adjusted what I thought I did know.

    D. M. Mitchell wrote on August 30th, 2012
  8. I have a bit of difficulty following some of the science, but I think I understand the conclusion, which is really what matters most. At the end of the day, avoid processed food like the plague in part because it almost always contains added sugar or HFCS (or something similar) not to mention Omega 6 oils which also may be pretty harmful.

    Eat real food and odds are you are going to do a whole lot better than if you are eating something out of a package or can.

    Mario Vachon wrote on August 30th, 2012
  9. The sum of the square roots of any two sides of an isosceles triangle is equal to the square root of the remaining side… and that’s how Primal living works folks! Don’t make me repeat it because I can’t :)

    Groktimus Primal wrote on August 30th, 2012
    • That’s a RIGHT triangle you idiot!

      Homer wrote on August 30th, 2012
      • Haa ha.

        Ma Flintstone wrote on August 30th, 2012
    • It is the sum of the squares, NOT square roots. The sum of the squares of the sides of a right triangle equals the square of the hypotenuse. Pythagorus says so.

      artbuc wrote on August 30th, 2012
      • Ahhhh I’m out of school stop torturing me with that !!! I’m done not going back leave me be !!!!

        Jonathan Swaringen wrote on September 1st, 2012
  10. Thanks for providing all the science, but I couldn’t follow much of it really. Could you do another post where you summarize the information in layman’s terms and more importantly, clearly eclucidate what conclusions you think we should be drawing. Also, precisely what areas do you think CW is wrong? Thanks.

    Doug wrote on August 30th, 2012
    • I think a huge part of the reason for the two cholesterol posts in the first place is so that people can look at the science and the evidence and make up their own minds. Mark or Dr. Attia or the Wizard of Oz can “elucidate what conclusions you think we should be drawing” and “what areas do you think CW is wrong,” but what makes them any more convincing those people espousing the conventional approach? Mark is lean and muscular and Dr. Attia wears a lab coat and they both have a bunch of charts and diagrams, so they must be right. But so do plenty of the other guys.
      I think the only way for us to decide for ourselves, even if the science is over our heads, is to look at our lifestyles and see what doesn’t work for us. I’ve become used to a sedentary lifestyle with daily peaks and valleys of energy and lethargy, with at least one daily episode where I find it impossible to keep my eyes open in the middle of the day. Obviously what I had been doing wasn’t working, even if my diet was mostly what CW recommended. I tried jogging and other cardio, but it was hard on my body. So now I am trying the PB (about 6 weeks) and it’s had an immediate impact – my energy level is stable throughout the day, I don’t have cravings, and I enjoy daily walks with a little heavy lifting thrown in every couple of days. I’m not about to start worrying about whether my LDL particles are big or little, but I’ll have my bloodwork done in a month or two to see what kind of changes there are. I felt like I was getting dangerously close to metabolic syndrome and that I am now taking steps to avoid that. One person’s opinion about lifestyle seems to be winning out over another’s. The rest of the recommendations and conclusions to be drawn are available in the daily blogs and the books. But they’re still just opinion based on the same (or similar) evidence that’s available to us all. At the risk of insulting Mark Sisson, I don’t think he’s any smarter than the rest of us. He’s just educated himself about the reasons why certain lifestyle changes worked for him and he’s willing to share that.

      MarkA wrote on August 30th, 2012
  11. Whoa… too much information. I’m completely lost.

    Anyone want to have a go at a summary? What’s the take home message? Is it:

    – Standard cholesterol tests give you a figure for Total Cholesterol (TC), which includes HDL cholesterol and LDL cholesterol.
    – HDL is good.
    – But the total amount of LDL cholesterol doesn’t matter. What matters is how many particles it is carried in. (In other words, it’s not the total amount of cargo, it’s the number of boats that matters. The same total amount of cargo can be carried by more or less boats.)
    – Ideally, you want few boats, each carrying loads of cholesterol cargo.
    – However, if the cholesterol cargo is diluted by loads of triglycerides, then you will have more boats.
    – And that’s bad because it increases the chances of one of the boats breaking through the endothelium.
    – SO eat stuff that minimises triglycerides… like s/low-carb?

    Is that it? (I’m not quite sure where the different buoyant / VLDL / LDLa apoB particles come in…)

    If so, how do you measure the number of particles? In the absence of a proper clinical test, is it good enough to follow Chris Kresser’s advice:

    “the most important number on a conventional lipid panel is the relationship between triglycerides and HDL. (Divide triglyercids by HDL to get it.) If that number is less than 2, this suggests you have mostly large, buoyant LDL – which is not a risk factor for heart disease. If that number is higher than 3, it suggests you have mostly small, dense LDL – which most certainly is a risk factor for heart disease.”

    Scott UK wrote on August 30th, 2012
    • this was more helpful that the two part article.

      john wrote on August 30th, 2012
      • I believe Chris Kresser is modifying his stance on LDL particle density as being the strongest predictor for heart disease risk.

        In his new cholesterol program, Chris will talk about a ton of new things in relation to cholesterol, one of which is “Oxidized LDL particle number”.

        https://www.facebook.com/photo.php?fbid=435593603159575&set=a.346979575354312.107082.212758788776392&type=1&theater

        Chris’s perspective now represents that it is the numerous LDL particles that suggests the stronger predictor for heart disease risk.

        When those LDL particles become “oxidized” that’s when the immune system(s) goes on alert and things could (do) get sketchy.

        SeaSteve wrote on August 31st, 2012
    • That was my understanding, too, Scott. Nice job saying it in such a concise way.

      TokyoJay wrote on September 2nd, 2012
  12. Intuitively, it is hard to believe that when there are “several quadrillion LDL particles” (boats) in your blood supply that a section of blood vessel would be sensitive to a slightly higher number of “boats” (higher LDL-P). It seems to me that the nature of the boat has more to do with the ability to penetrate the epithelial lining than the sheer number of boats. So the argument is this: with more particles you are perhaps more likely to have more penetration-capable LDL particles; however, this is not necessarily true. In theory, you could have a very high LDL-P, with all the particles incapable of penetration.

    Ray wrote on August 30th, 2012
    • The theory seems plausible, and so was considered in evaluating the results, but the facts say otherwise.

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

      “Let me repeat this point: Once you account for LDL-P, the relationship of atherosclerosis to particle size is abolished”

      Nannsi wrote on August 30th, 2012
      • OK

        What about people with high LDL-P that do not manifest problems? The graph shows that of those followed, 80% with “high” LDL-P were “event free” for 16 years. Why does high LDL-P NOT affect the majority of the population? Something is missing in this model. Also, it is easy to trick yourself with “corrections” to the data.

        Ray wrote on August 30th, 2012
        • I am not a “real” scientist, I do not run any studies.

          I have no proof and I may be completely off base, but all I have is just my theory….

          …the body allows the boats to penetrate.

          1.) I theorize that every boat has the ability to penetrate, the body doesn’t allow it when it isn’t necessary.

          2.) If a person, generally has high LDL, it hints that there is something bad happening in the bad. The presence of high LDL is not a bad thing in of itself. The reason there is a high level of LDL IS THE BAD THING.

          3.) Inflammation and oxidative/free radical damage are those reasons.

          4.) Basically our immune system has 2 giant parts, a defense system and a healing system.

          5.) Defense system kills foreign invaders, and sometimes kills what it “thinks are foreign invaders”.

          6.) After the killing is over, there’s a lot of wreckage and collateral damage.

          7.) Healing system helps repair and clean up after the killing/battles are over.

          8.) High LDL presence in the blood stream is just a natural occurrence in the body…a natural response to unhealthiness.

          9.) When there is too much collateral damage to fix and clean up, the body tries to make cholesterol’s job easier and allows the LDL boats to penetrate the endothelium of the blood vessels.

          10.) Some of those LDL boats have been working too hard or have been out in the blood stream too long and gotten themselves “oxidized” or b) some of the LDL boats are still carrying “non-competely” dead free radicals.

          11.) When those LDL boats gain access and penetrate and dock themselves in the blood vessel walls…the immune system kicks up again and tries to complete its job. Then you are left with “scar tissue” or plaque build up.

          The reason I believe in this theory is because the human body, brain etc. are designed with purpose.

          I just do not believe that the LDL boats randomly dock themselves into our blood vessel walls. I believe that our body wants them to do it to complete a process.

          SeaSteve wrote on August 31st, 2012
  13. My brain hurts. Time to go back to some relaxing computer programming.

    Diane wrote on August 30th, 2012
    • Agree … back to work for me, will continue reading at home when the information overload fog dissipates a little :-)

      WildGrok wrote on August 30th, 2012
  14. So we get blood test done why? If the right things aren’t even being tested. And what is doesn’t give a whole picture. Then what is the point. Hence why any doctors career is called a “practice” A little scary if you ask me and also why I am my own health advocate and will remain to be. And our ancestors hold the answers.

    Tobie Johnson wrote on August 30th, 2012
    • Ditto what Tobie said.

      I’ve just got to say, I’m normally an information junkie, don’t mind taking as long as necessary to read a good, informative article, but this (these) post(s) lost me somewhere in the first paragraph. A shorter, more concise post, in layman’s terms, is definitely called for here. Can’t educate people if you aren’t speaking their language :)

      Wendy wrote on August 30th, 2012
      • I totally agree Wendy. This is very hard for me to grasp and I’ve read both posts many times. Would really appreciate an easy-to-understand executive summary.

        mars wrote on August 30th, 2012
      • The distinctions being made between LDL, cholesterol and other measures is being discussed because recent research makes it appear cholesterol doesn’t matter. And maybe some other considered-reliable measures weren’t accurate risk predictors either.

        What DOES seem to matter is [AN]OTHER factor which people were not previously emphasizing.

        It’s called LDL-P– and it IS associated with heart problems later to some degree; whereas older things we looked at are NOT important.

        If I understand correctly, that is the general gist of what all them SCIUNCE people are saying.

        Zoombie WOmby wrote on August 30th, 2012
        • So why take statin medication? if it does no good / does not assist in this who controversy?

          Clare wrote on September 6th, 2013
      • Go to www dot brianpeskin dotcom, under the banner hover the cursor on ‘Publications’ then ‘Original’ then click on ‘2011 Anti-Aging Therapeutics Volume XII (pdf) and read excerpted chapters 29 & 30 for a plain english, common sense explanation that CVD & arteial plaque are caused by the already OXIDIZED ADULTERATED industrially processed omega-6 polyunsaturated vegetable oils that all the experts have been pushing on people as being “healthier” than natural saturated fats.

        And remember you got the answers to ALL your questions from Brian Peskin, not Peter Attia.

        conrack wrote on September 1st, 2012
    • Agreed. Reading about this stuff is all well and fine, but don’t take it to heart, and don’t obsess over ideal blood test results. The stress will kill you long before your cholesterol does.

      Best to follow a healthy paleo diet, get some exercise, have some fun. Stay away from doctors as much as possible, because you’re right–they do “practice”, which is a lot different than getting it right every time. Enjoy life because it’s short, and there’s nothing we can do about that.

      Shary wrote on August 31st, 2012
    • Blood testing can show what you want to know. I think both VAP and NMR tests show ApoB ie LDL-P.

      Someone earlier said just NMR so I’m not sure if that is true.

      Also someone said dividing triglycerides by HDL gives you a good proxy so even a standard cholesterol test might be useful with that in mind.

      My first blood test ever showed a 2.11 ratio while my most recent showed a 3.0…somewhat weird as I thought my diet improved between those times…

      I don’t know. I’ll have another set of results within the next few weeks to look at.

      Jonathan Swaringen wrote on September 1st, 2012
      • Good points?I would word that as any pseorn who really doesn’t write on blogs much (in truth, this can be my first post), I don’t assume the time period lurker’ is very changing into to a non-posting reader. It’s no longer your fault in the slightest degree , but perhaps the blogosphere may get a hold of a greater, non-creepy title for the 90% people that enjoy reading the content .

        Ajmal wrote on December 22nd, 2012
  15. Gotta love the line, “metobolically deranged”. Me thinks if you eat Primal, your derangement will be rearanged!

    Nocona wrote on August 30th, 2012
    • With havin so much written ceontnt do you ever run into any issues of plagorism or copyright infringement? My site has a lot of unique ceontnt I’ve either written myself or outsourced but it seems a lot of it is popping it up all over the internet without my permission. Do you know any methods to help reduce ceontnt from being stolen? I’d really appreciate it.

      Misty wrote on December 22nd, 2012
  16. I still don’t know if one can get rid of plaque in the arteries. Once it is there, is it always there? Did I miss something? Even though I sorta get it, the science is obviously difficult for me to follow.

    Sharon wrote on August 30th, 2012
    • My understanding is that Vitamin K2 can reverse arterial plaque.

      It certainly does in rats, and there is anecdotal evidence that it does in people too.

      http://wholehealthsource.blogspot.ca/2008/11/can-vitamin-k2-reverse-arterial.html

      Paul N wrote on August 30th, 2012
    • yes, the body can remove plaque from the arteries.

      Ray wrote on August 30th, 2012
    • Fortunately, the arrival of atherosclerotic plaque is not a one-way street. Lifestyle modification (e.g., smoking cessation, removal of sugar and refined carbs) and medical intervention can actually reverse the build up of plaque.

      Peter Attia wrote on August 30th, 2012
      • Peter, thank you for stating this. I’ve been wondering if the body does “go in reverse” to correct the damage that’s been done by the CW-driven SAD, I just haven’t had a chance to do much reading on it yet!

        I love reading your work at the Eating Academy! Between your information and MDA, I’ve changed my diet, which has resulted in a 250+ point decrease in my TG number (TG=99 two weeks ago!). I’m telling anyone and everyone about it!

        Defrog wrote on August 31st, 2012
      • By “medical intervention” to reverse the buildup of plaque, are you referring to statin Drugs?

        Jack Cameron wrote on August 31st, 2012
        • In regards to arterial plaque, I tend to think of it this way….

          When you get a cut on your skin and you do all the necessary things to help heal it, most likely you end up with a scab or maybe a scar if the cut is fairly deep.

          Now, over time, does that scab just stay there….does it build up?

          Do the scars grow longer or do the scars tend to heal and try its best to look like your normal skin with maybe a little discoloration if your healing optimally?

          If you are healing well optimally, your arterial plaque should also….not continue to build up. The plaque, should, in fact, shed….just like the scab.

          Normally, the scabs just naturally “fall off” (unless you pick at it and scratch it off).

          The new cells that are forming underneath actually pushes the dead scab off.

          That’s what should happen in the arterial walls.

          And I believe, HDL has an important role in this natural process.

          SeaSteve wrote on August 31st, 2012
        • I believe Lipitor is the only statin with “anti-plaque” properties and it is only a very minor one.

          Lipitor would probably have no effect on advanced arterial plaque build up.

          SeaSteve wrote on August 31st, 2012
    • The answer is a yes. That is in essence the reversal of heart disease. HDL probably plays a roll in removing some of the damage.

      As well as things that lower the inflammation/immune response.

      Eating well ala Primal Blueprint and good exercise ala Body by Science should do well.

      Jonathan Swaringen wrote on September 1st, 2012
  17. As always a good science lesson and reasons to live Primal!

    Joanne - The Real Food Mama wrote on August 30th, 2012
  18. A high cholesterol diet it unhealthy for me due to my experience of eating different foods. I don’t eat meat because it makes me feel badly. The same goes for many of my friends, many of whom are good athletes. Therefore I can assume reasonably that primal eating is unhealthy for some people. Maybe it’s because of cholesterol or maybe its from something else…

    Michael wrote on August 30th, 2012
    • Shields up, Captain? :)

      Mark Cruden wrote on August 30th, 2012
    • What kind of meat have you tried eating…and do you just think this is unhealthy or have you tried it?

      Jonathan Swaringen wrote on September 1st, 2012
      • I ate exclusively local pastured meats from the farmers market. I know they are unhealthy for me because after I eliminated them from my diet and I becaume leaner, faster, more energized, and my acne finally went away. Anytime I started eating meat again bad things came back up. Thats the case for me, doesn’t mean it is for everyone, probably means that it is for at least some other people.

        Michael wrote on September 3rd, 2012
  19. Spot on once again.

    Dr. Matt Hanson wrote on August 30th, 2012
  20. I’d love to see a similarly brilliant analysis on the factors associated with hypertension!

    Ian Goldsmid wrote on August 30th, 2012
    • I have pretty much obliterated high blood pressure after ignoring it until it nearly killed me.
      So, get “The High Blood Pressure Hoax” by Dr. Sherry Rogers and change your life. A pre-owned far infrared sauna will be a part of the solution. Best of Luck.

      Dr. Fizzicks wrote on August 30th, 2012
  21. (Apologies, I’m repeating this to get responses emailed – pls ignore the last post, thank you :-) )

    I’d love to see a similarly brilliant analysis on the factors associated with hypertension!

    Ian Goldsmid wrote on August 30th, 2012
    • Me too, after a year of primal and some huge changes, I still have to take medication for hypertension. I really don’t understand the processes involved and how I can manage it.

      Heather wrote on August 30th, 2012
  22. Too much information. All we need is a summary. I’m not a pre-med student, but just trying to do the right things… :o)

    Jura wrote on August 30th, 2012
  23. I’m a fairly smart fellow as are the people commenting above, but unless I have completely misunderstood the general interest level of most of the people who probably read this site, this two part series, while informative, was far to clinical to actually walk away with any definitive information on WHAT TO DO. I think the information is brilliantly researched and articulated, but Dr…. know your audience. Were you presenting this for peer review?

    john wrote on August 30th, 2012
    • +1

      Mark Cruden wrote on August 30th, 2012
      • +10

        Joe wrote on August 30th, 2012
    • the article clearly states what to do: lay off fructose, sugar, and in general any foods that are high glycemic, i.e. high starch/carb e.g. wheat products, in fact grains; potatoes, low fat dairy etc ..

      Ian Goldsmid wrote on August 31st, 2012
    • Well, hopefully there will be a summary or conclusions, but personally, I LOVE that this article was a little more thorough.

      It’s so easy to find websites and people telling you what you should do and assuring you that the facts support it, but so much harder to actually find the evidence to tell if what people are suggesting is true or logical.

      TO wrote on August 31st, 2012
  24. Great post Dr. Attia.
    Your explanation is spot-on and will prove to be useful to my patients and my residents alike. For those who wish to have these values tested, I recommend an NMR Lipoprofile http://www.lipoprofile.com/. This test can be obtained via common commercial labs (Quest Diagnostics or LabCorp) and is covered by most insurance plans and medicare.

    Jeremy McConnell, MD wrote on August 30th, 2012
    • Any thoughts on VAP? I thought it also did these numbers. I guess I need to look up descriptions.

      I also thought there was something called electropheresis something…don’t remember what that may have been more specific than standard.

      Jonathan Swaringen wrote on September 1st, 2012
  25. When I went primal, my cholesterol shot through the roof. Pre-primal, I ate very little meat, a lot of beans, soy, low- fat. I also ate a lot of sugar, because I craved sugar all the time. I had borderline high cholesterol at that time, with high HDL & high LDL. Post-primal, I am eating whole foods, high protein, no sugars, a lot of veggies, little fruit. I no longer crave sugar, feel good, have energy. In other words, I would never go back to CW. However, during a routine physical required by my job, my cholesterol was very high….high HDL & High LDL. Obviously I have familial hypercholesteremia. Yet, my BP was 90/60; my heart rate is in the 50’s, and my CRP was extremely low, meaning there is no inflammation in the body. My blood sugar was normal, I’m normal weight. If I am going to flip out over some number because CW says that number is what is going to kill me, I’d be returning to CW so that I could feel awful again. No thank you. I’d rather live…..then drop dead :)

    Michelle wrote on August 30th, 2012
  26. Thanks for the analysis. The reason we can have “simple take-home messages” is because we have the detailed science like this to back it up.

    Tim wrote on August 30th, 2012
    • Take home message? Keep fructose to a minimum, especially HFCS. This syncs up nicely with Dr Robert Lustigs work on the unique harm done by consuming fructose in quantity.

      Gene wrote on August 30th, 2012
      • Only thing I don’t like about Lustig is hes a huge statist…I’m leaning anarcho-capitalist.

        His ideas of the government intervening bother me. I’d rather the government stay out its got its hands in too much already.

        Jonathan Swaringen wrote on September 1st, 2012
  27. Maybe you could title one of these “Cholesterol for Dummies” and include some simple cartoon drawings for those of us whose eyes glaze over at the sight of arcane chemical graphs.

    erik wrote on August 30th, 2012
  28. “Maybe you could title one of these “Cholesterol for Dummies” and include some simple cartoon drawings for those of us whose eyes glaze over at the sight of arcane chemical graphs”

    LOL! Someone DID: http://thefatnurse.files.wordpress.com/2012/06/cholesterolforallages5.pdf

    Janknitz wrote on August 30th, 2012
  29. I too consider myself to be pretty smart (degree in computer science and math; been working as a software engineer for 20 years, now a systems analyst) but I can’t get into this. My eyes start to glaze over after a few sentences. I like that Mark posted it especially for those that enjoy this level of depth. But I too would like a ‘for dummies’ version of the info. Thanks again for all you do, Mark!

    Ara wrote on August 30th, 2012
    • Its interesting how different people can be…I don’t have any degrees only finished High School and yet I find it interesting and didn’t have a problem finishing it.

      Interesting. Maybe a time preference thing and it takes time to get through an article like this so peoples eyes glaze over.

      Too bad learning to speed read isn’t easy :P Might help with that.

      Jonathan Swaringen wrote on September 1st, 2012
  30. Dummies version: Evidence says that Apo-b and TG are the major concerns in predicting risk, all others basically don’t matter anymore. To keep those two low, avoid fructose and corn syrup and you will prevent disease. Dietary fat literally has no effect on these markers. Only sugar does. This is why paleo, or any low GI diet is healthy and why white rice is okay too. Glucose had a very good response on these bad markers. Fructose I think in moderation needs to be tested this same way, but while still in whole food form, which greatly changes its effects metabolically.

    Dr Jason wrote on August 30th, 2012
    • To clarify, TG only rise to bad levels when there is excessive sugar. Too much glucose is bad too, it’s just a much better carb when eating as a whole food in moderation. Your liver turns fructose into TG directly, so it’s worse. high TG makes apoB rise (more boats clogging the river up) which makes hear diseases

      Dr Jason wrote on August 30th, 2012
      • I’m a biochemist and that’s an excellent summary Dr Jason.

        Elaine wrote on August 31st, 2012
    • Very good summary doctor.

      Regarding fat, you said: “Dietary fat literally has no effect on these markers. Only sugar does.” I was unable to find any reference to the effect of fat intake on TG levels in the two posts. Could you tell me where to find the reference?

      One aspect of fat intake that greatly increases CHD risk is excess dietary linoleic acid (LA) which elicits endothelial dysfunction which leads to atherosclerosis according to several recent articles about “lectin-like oxidized LDL receptor-1″ (LOX-1) which is an endothelial receptor for oxidized low-density lipoprotein (ox-LDL).

      In one recent study, endothelial cells incubated with LA had reduced glutathione levels, increased ox-LDL and inflammatory IL-6 levels and altered expression of endothelial nitric oxide synthase (ENOS). In effect, excessive dietary LA increases inflammation (by increasing Rho-a)which results in increased TG and reduced HDL-C.

      It was found that cholesterol “attenuates linoleic acid-induced endothelial cell activation”!

      Another study found that LOX-1 recognizes not only oxLDL but other pathogenic lipoproteins, platelets, leukocytes and CRP. As results, LOX-1 not only mediates endothelial dysfunction but contributes to to atherosclerotic plaque formation, thrombogenesis, leukocyte infiltration and myocardial infarction, which determine mortality and morbidity from atherosclerosis.”

      Intake of LA should be minimized to reduce CHD risk.

      Jack Cameron wrote on August 31st, 2012
  31. Great second part of a great article.

    primal_alex wrote on August 31st, 2012
  32. Thank you for posting this! This is something I could show to my doctor if the need arises.

    NIcole wrote on August 31st, 2012
  33. I’m a good unsweetened girl but my ApoB still shots through the roof. CRP at its lowest anyway but my doctors will keep on focefeed me statins. I guess you can’t have it all, is the only thing not working in my monthly testing.

    Luce wrote on August 31st, 2012
  34. For those of you looking for methods to prevent/combat atherosclerosis…

    Do yourselves a huge favor and google Linus Pauling, Matthias Rath and Vitamin C and Lysine. They were granted a US patent based on real scientific evidence showing these substances can reverse arterial plaques.

    Ascorbate Is Your Friend wrote on August 31st, 2012
  35. So it was concluded that LDL-C levels are directly proportional to the amount of complex carbohydrates consumed?
    Also, I am confused as to what exactly is the direct cause of cholesterol related diseases. Is it particle size, particle number, or overactive LDL-C and P receptors?

    PrimalSailor wrote on August 31st, 2012
  36. Not enough effort has been made here to make the 2 parts concise and understandable. I’m not a scientist and what I usually love about MDA is Mark’s ability to digest complex science into easily digestible chunks 8)

    Luke wrote on August 31st, 2012
  37. Something to consider is that dietary factors are not the only thing that leads to immune dysfunction, inflammation etc.

    Stress is also a big time “killer”, but the dying can be subtle.

    Diet is an important component, but sometimes we also gotta have fun!

    Mark Sisson does a great job promoting Play. We just not only hear him, but also listen.

    SeaSteve wrote on August 31st, 2012
  38. I am a devoted low-carber for a while, had in the past read tons about all omega3,6,9,cholestorol,ldl,apo,oxidization etc….

    This is an excellent summary. Everyone complaining its not for the layman – then maybe the layman should not read the “EVERYTHING you need to know version” :-)

    Andre wrote on January 10th, 2013
  39. hello there and thank you for your info – I have certainly picked up something new from right here. I did however expertise several technical points using this site, since I experienced to reload the web site many times previous to I could get it to load properly. I had been wondering if your web hosting is OK? Not that I am complaining, but sluggish loading instances times will sometimes affect your placement in google and can damage your high-quality score if ads and marketing with Adwords. Anyway I’m adding this RSS to my e-mail and can look out for a lot more of your respective exciting content. Ensure that you update this again soon.|

    Top Jumpers wrote on March 7th, 2013
  40. I am shocked at all the comments complaining that the articles were too hard to read. What are you, neanderthals? ( : …sorry, had to throw that one in!… Look, the articles were pretty clear, and really couldn’t have been any more concise without losing important information. I don’t have any academic background in these sciences, and I got them pretty easily. If you had trouble understanding them, re-read them again! That’s what people do who want to understand something complicated. The world is complicated. And what’s up with all the “don’t make me go back to school!” comments? Do you actually want to understand how things work or you just want to remain lazy and ignorant? Life is not just about using your body. It’s also about using your brains. Use your brains folks. It’s really not so hard. Thanks Peter, for the pretty clear and thorough explanation. I’m sorry so many people are too lazy to exercise their brains a little bit, but then still have the energy to whine about it being too hard.

    JORR wrote on May 19th, 2013

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