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. 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
  2. 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
  3. 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
  4. This was super interesting to read. But one thing is making me confused. The last four graphs seem to suggest that regular sugar (glucose) is far better then fructose (in terms of TG, apoB…)? Just seems utterly wrong to me. Is white sugar better than an apple al of a sudden? Am I misstaking the meaning of glucose here? Is it strach and not regular sugar? Google search calls glucose sugar…

    Chris-Alexander wrote on November 1st, 2013
  5. Extremely valuable info. I just embarked on a classic form Atkins diet (high saturated fat) and ended up here after searching for high fat diet & estrogen. The AMA brainwashing is so sadly complete that in most places people assume Atkins is high protein, even researchers. Johns Hopkins has recently begun to test a very high fat version of Atkins on epileptic adults after success with children. Dr. Kossoff has a vid on youtube about Modified Atkins Diet. Ya, worst acronym ever but at least it’s in use. Peace.

    Kenna wrote on November 2nd, 2013
  6. “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)”

    how come p=0.05 is insignificant?
    As I know 0.05 is usually considered significant (and even 0.1 can be sometimes though of as significant).

    Chen wrote on November 20th, 2014
  7. The surprising thing I got from this was that diet and lifestyle have an insignificant impact on cholesterol levels. I am not convinced that this is true as my levels swing wildly in direct correlation to dietary interventions. Meat and saturated fat = high LDL and veg and unsaturated fat = low LDL. Im about to repeat my vegan experiment after my perfect cholesterol levels on a vegan diet went through the roof on LCHF. Damn shame, I was loving all that meat and butter, now I got to go eat salad and falafel for 3 months or my docs gonna put me on statins

    Doug Gardiner wrote on August 18th, 2015
  8. Hi,

    I liked these articles, and in spite of me being pretty savvy, scientifically, and medically – whew, they were rough going!!

    I really LIKED the scientific, and medical detail in here, and the fact that the author tried to gloss over the many, many intricate details – that would have made it completely incomprehensible, ro anyone, except a spevialist in the same field – but even so, it’s prettyrough going, even for the highly educated average punter.

    On the other hand, dumbing it down, to make it into an “executive summary”, as someone has suggested – I feel, would have ruined it!!

    What it REALLY needs, is an “Executive Sumary” – what in medical literature, would probably be called, and “Extract” – at the beginning, to outline what you are talking about, in broad brushstrokes, and less technical terms, and give an outline, of where we start off, the journey, and what YOU are trying to show, and communicate to us – and the conclusions that you have drawn, and the deietary suggestions that you would suggest, because of that.
    And THEN get into the more technical aspects, and proof, and the process that you have used, and how you arrived at those conclusions.
    This way, WE get a chance to come up to speed, and have a clue, as to WHAT you are trying to say, and the overall lay of the land, and where we are going – before we get overwhelmed, with technical jargon (albeit necessary, for clarity – sometimes you just HAVE to call a ring-modulator, a ring-modulator…), and technical details.

    Even for those, that crave this level of technical detail, this is helpful – and for those that don’t, or can’t comprehend this level of language – it gives them enough information, to be beneficial.

    Call it an “Introduction” if you like – as YOU work with it everyday, obviously, YOU know, all the surrounding information, and background – and many of US, do not.

    To delve into this, “Cold Turkey” is pretty daunting, even for somone used to sophisticated technical explanations, as I am.

    Just a suggestion, that I think would help many!!

    Other than the missing “Introduction” section – excellent articles!!

    Thank You VERY MUCH!!

    MissionControl wrote on February 5th, 2016

Leave a Reply

If you'd like to add an avatar to all of your comments click here!

© 2016 Mark's Daily Apple

Subscribe to the Newsletter and Get a Free Copy
of Mark Sisson's Fitness eBook and more!