Can Cholesterol Get Any More Complicated?

I might have to put updates up as I continue to gather information (emails out to vetting sources) but I thought I'd put this up as a starter, maybe generate some conversation.

I've posted a lot about cholesterol and how and why I don't generally see it as a problem for most people on a good (paleo-like) diet. In other words, the diet is the problem causing the inflammation markers, small dense LDL, low HDL and high triglycerides (fat in the blood, caused by sugar, not dietary fat). So fix the diet. The problem, of course, is that the standard from-on-high dietary advice is precisely what's behind those aforementioned problems. A Paleo diet doesn't seem to work for everyone to get the sort of lipid numbers I enjoy, so that leaves the question open as to whether "bad" lipids are generally only a concern with a bad diet of processed foods, high sugar and omega-6 polly unsaturated fats. That's where I've placed my bet.

But what about familial hypercholesterolemia? Does that not substantiate if not prove the lipid hypothesis? After all, even children and infants afflicted with this genetic disorder get heart disease. But is it the high LDL itself, or what it's able to act upon? For an amazing education in all things cholesterol, take a listen to Jimmy Moore's recent interview of Chris Masterjohn who specifically addressed this disorder and argues that it's rather like having a ton more cars on the road (LDL) and the real problem is that because they're on the road so much longer that it makes them far more susceptible to oxidative stress; and combined with chronic inflammation caused by a nutritionally deficient, low fat, high sugar, high omega-6 diet, that's the real underlying cause of the plaque buildup. Give it a listen.

Added later: Think of the causal chain mixup like this when it's claimed that LDL is causal. It's like having a gunman shoot you through the heart and you die, and cause of death is that your heart can't stop bullets. So, when the underlying cause is inflammation and oxidized small-LDL, the "cause" is claimed to be that your heart can't withstand small-LDL, inflammation and oxidation.

Now comes the added complication. Via reader Dexter I got a link to an article about this very recent study today. Be warned: it's not a light read, at least not for me.

Strongest evidence yet that Lp(a) causes heart disease

Oxford, UK - New genetic research has identified two relatively rare single nucleotide polymorphisms (SNPs) that explain just over a third of the variance in lipoprotein(a) (Lp[a]) levels in individuals of European descent. The work confirms unequivocally that Lp(a) is a causal factor for coronary disease, say Dr Robert Clarke (University of Oxford, UK) and colleagues in their paper in the December 24, 2009 issue of the New England Journal of Medicine.

"This is the most convincing evidence so far that this protein [Lp(a)] is directly part of the pathway that causes heart disease rather than a bystander. If we can target it through treatment, we might expect to lower the risk of disease," coauthor Dr Hugh Watkins (University of Oxford) told heartwire.

Well I've known for sometime that high Lipoprotein(a) -- Lp(a) -- is a strong risk factor for CHD (mine is 4 mg/dl with "standard range" <30, so presumably low risk on that score), but that's based on association, not causation. But now they're saying it's unequivocally causal. OK, good, and I'll get to how you can naturally lower your Lp(a) in a bit. But first, here's what really struck out at me, making my head spin around and around a bit. From the article.

In a press release issued by the British Heart Foundation [3], which describes Lp(a) as a "third type of cholesterol," senior author of the new paper, Dr Martin Farrell (University of Oxford), tries to put the findings into perspective: "The increase in risk to people from high Lp(a) is significantly less than the risk from high LDL-cholesterol levels. So Lp(a) doesn't trump LDL, which has a larger impact. The hope now is that by targeting both we could get an even better risk reduction."

Say what? Here's what I'll state unequivocally: high LDL is only associated with CHD and even that's tenuous because I have many times (check the cholesterol links above) demonstrated that very low LDL is also associated with CHD (as well as increased all-cause mortality, particularly in the elderly and slam dunk in women). So let me get this straight: the risk from high Lp(a) that they are calling "unequivocally causal" is a significantly less risk than a mere association?

What say you, experts? I'm confused.

At any rate, and again not a light read by any means, but one blogger and good friend, Dr. BG really stands out in blogging about Lp(a) and other risk factors.

Cardio Controversies: Lp(a) Dangerous at ANY Value

Can Lp(a) create more damage than we previously thought?

Dr. Hecht has apparently showed it with his examination of lipoprotein, cardiac and metabolic parameter comparisons with the real measure of heart disease risk: EBCT-determined plaque burden. Lp(a) was 3rd after HDL and LDL particle diameter in being highly associated with coronary calcifications. See below. Free PDF HERE. Normally at TrackYourPlaque we consider Lp(a) greater than 20 mg/dl as a high contributor toward accelerated plaque burden. When I look at Dr. Hecht's graphs, what I notice is that indeed this may not be true.

It appears to my observations that at ANY Lp(a) value, plaque burden is quite high reaching even 97th, 98th or 99th calcium percentile for CAD risk (of population norms) at severely low Lp(a) levels of 5 mg/dl or 10 mg/dl.

OK...what the heck?

I can make the same observations for my CAD (heart), PVD (peripheral), or CVD (stroke) patients and individuals with extensive diabetic complications. At any Lp(a), the extent of disease can still be quite pronounced.

What other factors are correlated to vascular damage?

1. Low HDL2b

2. High small dense LDL.

These THREE factors determine almost entirely the extent of disease. Both visionaries Dr. Davis and Dr. Hecht focus on these predominantly to control and halt the progression of calcifications.

How are these 3 metabolic parameters created in the first place?
--low fat SAD AHA low cholesterol low saturated fat diet
--saturated fat deficiency
--excessive carbs (>10 g/d, >20 g/d, >50 g/d, >100 g/d -- depending on a person's insulin and insulin sensitivity and pancreas/adipose/hormone status)
--inflammation (excessive omega-6 oils)

But she has a lot of stuff on Lp(a), so here's a search link for those wanting to dig super deep. For those of us wanting to cut to the chase, how best to lower Lp(a) and keep it low? You know what I'm gonna say, dontcha? You guessed it: high saturated fat from natural sources, i.e., animals, butter, coconut oil. The Doctor again, from another post:

Lp(a) Reduced By Saturated Fatty Acids and Raised by Low-Sat-Fat Diets

Benefits of Krauss high-saturated fat diet cannot be overstated. Saturated fats control CETP and thus control the amount of Lp(a) individuals produce. In fact, when an experiment group was put on a low fat, high veggie diet, Lp(a) increased significantly by as much as 9% (Silaste ML et al Arterioscler Thromb Vasc Biol. 2004 Mar;24(3):498-503. Free Full Text)

Additionally, the low fat diet produced HIGHER oxidized LDL (OxLDL) by 27%. Recall the small dense LDL are less resistant to oxidation than buoyant large LDL and transform to OxLDL rapidly.

Not good.

For. Plaque. Burden.

OxLDL causes fatty/calcified organs: arteries (atherosclerosis); endothelium (hypertension); liver (NASH); pancreas (diabetes, MetSyn); thyroid (Hashimoto's), visceral fat (obesity); etc.

Saturated fat lowers and controls Lp(a) and coconut oil is one great example (Muller H et al . J Nutr. 2003 Nov;133(11):3422-7. Free PDF HERE). In this study by Muller et al women with elevated Lp(a) in the 30s mg/dl were provided a coconut oil-rich diet (22.7% sat fat; 3.9% PUFA) was compared with a high PUFA-diet (15.6% PUFA !!yikes). Lp(a) was reduced 5.1% compared to baseline habitual diets with the high saturated fat diet whereas in the high PUFA diet, Lp(a) increased a whooping 7.5%. The difference between Lp(a) on the high sat fat compared to the high PUFA diet was 13.3%.

Here are the conclusions from those two study links above, respectively.

The question remains as to why the Lp(a) levels increased in response to the dietary changes. The basal levels of Lp(a) are primarily genetically determined, but some data suggest that Lp(a) may act as an acute-phase reactant under some situations.40 In a previous study, a diet high in SAFA was found to produce approximately 10% lower plasma Lp(a) concentration than diets high in oleic acid or trans-fatty acids.41 This observation is consistent with our study in that both diets led to lower SAFA and consequently increased Lp(a).

In conclusion, we found that a diet traditionally considered to be anti-atherogenic (low in saturated fat and high in polyunsaturated fat and naturally occurring antioxidants) increased plasma levels of circulating oxidized LDL and Lp(a). The question of whether the changes observed in the present study are, in fact, pro-atherogenic or anti-atherogenic remains to be solved.

And...

The connection between Lp(a) and atherosclerosis is not entirely understood. Different studies have provided strong evidence that Lp(a) level is an independent risk factor for developing coronary artery disease in men (47,48), but the question of causality continues to be debated. Recent data suggest that Lp(a) might be atherogenic (49), in particular when combined with other risk factors. High levels of Lp(a) combined with other risk factors such as the ratio of plasma total/HDL cholesterol have been shown to increase the risk for coronary heart diseases (50). It has also been reported that when substantial LDL cholesterol reductions were obtained in men with coronary heart disease, persistent elevations of Lp(a) were no longer atherogenic or clinically threatening (51).

In conclusion, the present results show that the HSAFA- diet lowered postprandial t-PA antigen and thus potentially improved fibrinolysis compared with the HUFA-diet. Diets with either high or low levels of saturated fatty acids from coconut oil beneficially decrease Lp(a) compared with a HUFA-diet. The proportions of dietary saturated fatty acids more than the percentage of saturated fat energy may be of importance if the goal is to decrease Lp(a).

Alright, so for us KISS folks, it all just comes down once again to a natural, Paleo-like diet plenty high in delicious and healthful saturated fats.

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Comments

  1. The LDL theory is bust so they are looking for another “number” to treat with a new drug. They probably have a new patented wonderdrug in their arsenal and will introduce it when the statin cash cows isn’t giving anymore.

    A propos family hypercholestemia, there was an interesting discussion last year on Peter’s blog with good exchanges between him, Stephan and Chris. One point that I remember was that a good deal of the FH studies are more than worthless because of selection bias. You will find more heart disease in FH people if your inclusion criteria _is_ that they have high cholesterol and heart disease.

    • Yea, I should have quoted this from the end of the article:

      “Finally,” adds Kathiresan, “the genetic data suggest the hypothesis that lowering the plasma Lp(a) lipoprotein level by pharmacologic means will lower the risk of coronary disease.”

      The study by Clarke et al argues for a refocus on the plasma Lp(a) lipoprotein level as a potential therapeutic target.

      Watkins agrees: “There are drugs that lower Lp(a).” The only one currently available is niacin, say Kathiresan and Watkins, which was developed to raise HDL cholesterol but also significantly lowers Lp(a). However, it does have a major drawback in that it causes flushing.

      So, niacin works, but “unfortunately” raises HDL too. That’s “bad,” I guess.

      But Watkins says the ideal would be a compound “that solely lowers Lp(a). Then we could do a big trial, and that’s all we need to know.” Kathiresan agrees: “The study by Clarke et al argues for a refocus on the plasma Lp(a) lipoprotein level as a potential therapeutic target,” he concludes.

  2. Thanks for this wealth of evidence (and more reading).

  3. Alcinda Moore says:

    “confirms unequivocally” That right there makes me suspicious.

    Thanks for posting this.

    There are a lot of things about all of this that make my head spin. One article I read stated that the purpose of LDL was to repair blood vessels, then in a paragraph later stated that they didn’t know why LDL cholesterol was found in damaged arteries!

    What is the true cause of heart disease, vessel disease? In my opinion it’s the “healthy” eating principles along with poor blood sugar regulation and over reliance on drugs. If you eat “healthful” foods chances are good that you won’t need the drugs and your blood sugars will likely normalize!!

    I feel also that inflammation is a culprit….and again, inflammation is elevated with low SFA, high PUFA, and processed foods!

  4. Richard,

    You BEAT me to it babe!!! I think you’ve earned an honorary degree in Cardiology! You understand more than 99.9% of the ancel-keys-devil-worshipper, grant wh*re, lipidologists and cardiologists who embrace inflammation-generating diets and lifestyles… Paleo KING u rock!!

    Kenny Tourgeman MD sent this to me the other day (published Dec 24th from NEJM — I guess happy xmas EVE!!) … *haa* I’m still chewin on it…

    I love Lp(a) as it protects us from harm, diseases, microbes and bleeding internally when we have scurvy or other nutr’l deficiencies from living in harsh, hard-to-survive microclimates. Actually, I wish I had it but I don’t have significant amounts, and thus get sick more often than those who do.

    Well. What we know for sure is that statins don’t work for Lp(a) and in fact MAKE Lp(a) WORSE. This is a phenomena documented in the literature — and you linked up to the animal pharm posts already. At the TYP forum — it is observed countless cases of coronary calcification 10-54% progression year-after-sad-year on statins, tragically low HDL2b, mid range Lp(a) (eg 10-30 mg/dl the population median), and LOW low saturated fat diets by saturo-fat-phobes still consuming excessive carbs >20-50 grams/daily.

    Statins do not work and make Lp(a) and heart disease (and cancer) worse, apparently from the literature and case controls at the TYP membership. Why? Crestor raises insulin as well as eventually insulin resistance. It has a high rate of new onset diabetes, it is so POTENT and pathetic.

    What works to make Lp(a) anti-inflammatory, immunoprotective and potently GOOD STUFF?
    –egg yolks — lots of them *wink* esp if pastured, omega-3
    –dietary cholesterol — yolks dairy dairy dairy meat meat meat seafood
    –animal saturated fats
    –animal saturated fats
    –animal saturated fats esp if pastured, grassfed, getting plenty of sunshine
    –fruit saturated fats, eg unrefined coconut and palm oil (ok, olive oil if high quality which is 15% saturated, not Costco variety or canola/olive oil combo-garbage)
    –vitamin C + meat meat meat or seafood
    –omega-3
    –carb/fruit control
    –natural/bioidentical control of all sex and non-sex hormones (insulin, hGH, thyroid, testosterone, estrogen E3 E2, vitamin D, DHEA-S, etc)
    (I haven’t looked but I suspect omega-6 worsens Lp(a))

    -G

  5. David Marcon, DC says:

    Dear Paleo People,
    I come in peace. But I wonder if there is stress in your world? Things other than food can cause stress; like environmental, pharmacology, and eustress for all those who continue to work out to extreme tolerence.
    I enjoy the info but how about a little Hans Selye reference. Stress can drive up cholesterol too.

    • Hey David, Welcome.

      There’s a few of the paleo bloggers who talk more about stress than I do (my focus is dietary, primarily). But I have written about stress.

      Here was a pretty popular post:

      http://freetheanimal.com/2008/11/the-perverse-positive-feedback-of-stress.html

      Other than that, many on Paleo report that their sleep quality and duration makes a significant change for the better, and that’s certainly my experience. Even when I find myself wide awake at 4:00 am and where I used to get up and watch a DVD or read, I can now just relax in the knowledge that 99% of the time I’m going to drift off again for another 3 hours of bliss.

  6. This is a great post, and it got me to thinking about why the conventional medical establishment (and every CW person who thinks they’re an expert) thinks LDL is so bad. As you and many others have written about numerous times, the standard American diet (low fat, high carb) is a recipe for low HDL, high small, dense LDL, and high triglycerides. I think we can all agree that small, dense LDL are BAD, so maybe that’s why the conventional medical establishment has such a hard on for bringing down “high” cholesterol at all costs, usually with statins?

    And as for the correlation between high LDL and CHD, what are the diets of those in the “studies” showing the supposed link? If they’re eating SAD or something close to it (and I doubt it would be any different because of the obsession about getting the “minimum” 150-200 g of carbs the body “needs” per day), then I’d bet they show a correlation between high LDL and CHD–but, I’d also bet that it’s the small, dense stuff (and the study participants likely had low HDL, high triglycerides, and probably some of the nasty Lp(a) as well for good measure).

    Give me a big, bloody steak with butter and pile of veggies any day. I know my LDL are the large, fluffy kind, so I don’t stress too much over the number.

  7. Erik Cisler says:

    Something I’ve often pondered: does a preponderance of large LDL result in elevated LDL readings? That is, does the basic LDL reading measure particle number, or LDL “amount” or “volume”? Can two people with the same raw LDL number have different particle amounts depending on particle size?

    • From what I understand, Erik, standard LDL only measures serum cholesterol, not particle number and certainly not size. Thus, yes, people could have the same calculated LD yet vastly different profiles in terms of particle number and size.

    • I believe Richard stated the answer very well IMHO. Depending on antioxidant/hormone status and genetics (primarily apo E), the LDL ‘real’ could be low (apo E2) or average (apo E3) or extremely high (apo E4) based on a lot of work by Krauss and others. This is a generalization but holds true for many.

      B Lamarche et al has done wonderful research about the value, protection and benefits of a preponderance of large LDL, as you stated. Some cardiologists have in fact voiced concern about how large LDL are created. There is no nutritional or scientific basis for this fear and phobia. Saturated fats, low carbs, omega-3 and ketones all work mechanistically to generate nice large fluffy protective large LDL which Richard and O Primitivo has posted on, e.g. populations like Korea, Belgium, and France have wonderful disease protection and longevity where the LDL are high and predominantly large LDL.

      Crete is another population — they consume a high intake of fatty raw goat milk, goat/sheep cheese, grassfed beef/goat and pastured eggs.

      ACCUMULATION OF CHOLESTEROL IN LARGE LDL PARTICLES IS ASSOCIATED WITH A REDUCED RISK OF ISCHEMIC HEART DISEASE IN MEN
      AC St-Pierre, B Cantin, GR Dagenais, J-P Després, B Lamarche
      “CONCLUSIONS: These results suggest that a preferential accumulation of cholesterol in large LDL particles may be protective against the risk of IHD in men, even among those with elevated plasma LDL cholesterol concentrations.”
      http://www.pulsus.com/ccc2003/abs/a880.htm

      (Thanks Helen, commenter at Whole Health Source)

  8. Another home run, Richard.
    As for the association between studies/funding/publishing of dietary info I’m putting together a post showing major “health” association and their primary funding sources. Lots of goodies.
    Keep it up
    Ken

  9. “Masterjohn who specifically addressed this disorder and argues that it’s rather like having a ton more cars on the road (LDL) and the real problem is that because they’re on the road so much longer that it makes them far more susceptible to oxidative stress.”

    So is it beneficial to take old LDL off the road by donating blood every two months, thereby forcing the body to remake 12% of the blood components.

    • No idea if that would be effective, but for these people with the disorder, you pretty much have to lower cholesterol with statins, as I understand it. For normal people, lots of saturated fat should do it. Raising HDL increases the cycle time for LDL. HDL is what takes it back to the liver for recycling before it can oxidize.

      Of course, there’s also the issue of there being different LDL: small dense and big, and the former seems to be the most prone to oxidation. Saturated fat in the diet helps to shift the profile from atherogenic small dense to less harmful (or maybe beneficial) big.

      I’ve heard that donating blood is effective for combating iron buildup. particularly in men (menstruation does it for women).

  10. Great post as usual Richard.

    There is a lot of evidence that LDL is simply a marker of inflammation; and that inflammation is one of the main underlying mechanisms for CHD. The same is true for HDL, in terms of evidence out there, but to a lesser extent.

    I look forward to the time where we will also have discussion more on the role of VLDL, which is the precursor of LDL. We see a lot written about LDL and HDL, with an emphasis on LDL, but little about VLDL.

    There have been studies (see, e.g., link below) on how cholesterol particles evolved, and the grand-daddy of them all seems to be VLDL.

    http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TBP-4TYYNN1-1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=1150213867&_rerunOrigin=scholar.google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=92806536df06e7a2b2429f6bac3152c3

    Another thing that I think we do way too little of is to study centenarians, as well as folks who reach their 90s in good health. Most research looks at short term effects of this or that dietary/lifestyle intervention, but it is really the long term effects that eventually matter.

    When one looks at centenarians, one thing that you touched upon in your posting seems to rule – genetics. If you are a close relative of a centenarian, your chance of living beyond 100 years of age is many times higher than the average individual’s.

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