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Sep 20

Siobhan Debuts on 2 Keto Dudes

Our very own Siobhan Huggins was on 2 Keto Dudes for a really fantastic talk. They got into Full Geek with a lot of in-depth discussion on immune response, modified LDL, and the receptors that love them! This should be required listening for anyone interested in the process behind lipids and their role in the larger process of atherosclerosis.

Lipid Dysregulation with Siobhan Huggins

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  1. C

    Great interview! Check out this page: https://profgrant.com/2017/09/19/a-short-guide-to-reverse-cholesterol-transport/

    It has an interested video that animates some of this.

    Question – how does this all get calcified into hard plaques in the arteries? And are soft plaques dangerous (i.e. those that haven’t yet been calcified and don’t show up on a CAC scan)?

    1. Siobhan Huggins

      Yes I have seen! I agree it is worth sharing/viewing 🙂

      As for your question, the truth is I don’t quite know yet! I could make some guesses (a hard/stabilizing protective “bandage” to protect damaged areas where rupture has occurred for example) but it would be just that – a guess. It isn’t something I’ve reached in my studies yet, although I certainly would love to take a magnifying glass to it and figure out why it happens!
      It was mentioned in the podcast that Ivor Cummins does touch on plaque a bit, and lo and behold he does have a post on it you may find interesting:
      http://www.thefatemperor.com/blog/2017/3/31/atherosclerosis-and-calcification-important-paper-to-review-

      There is also this which discusses purpose, and relation to severity:
      https://www.ncbi.nlm.nih.gov/books/NBK2015/

      Basically that you can have severe burden in the arteries, without necessarily having severe calcification and that there are specific triggers for it (such as tissue injury/decay), and happens as a result of calcium deposits… specific pathways though I am unsure of for now.

      https://www.ncbi.nlm.nih.gov/pubmed/19520336/
      Plus this one which shows that calcium deposits very well predict heart events and low/no calcium deposits indicate very low risk.
      So it appears… complicated, but it seems like if you can have atherosclerosis without calcium deposition but it leaves you at a lower risk for having an actual clinical event, so “a burden on the system, but likely not enough to kill you”.
      I will need to go way more in depth to answer beyond that though, this is just first glances at the subject and a lot of speculation! Hopefully it will provide some hints though.
      I, of course, will do a deep dive into it to check out the mechanisms and speculate as to why it happens at a later date and I will make a mental (and physical!) note to follow up on in-depth later for a future post. 🙂

      Basically: Calcification seems to indicate severity (as in risk for an actual event) extremely well, but it is complicated and I will need to follow up later. “Soft plaques” appear to present a far lower risk – from what I see so far.

  2. C

    Hi Siobhan,
    I just found a reference to a recent study on hard vs soft plaques, which seems to confirm that we really only need to worry about the hard (calcified) plaques:

    https://www.medicalnewstoday.com/articles/316408.php and https://intermountainhealthcare.org/news/2017/03/major-study-of-atherosclerotic-plaque-deposits-shows-potential-breakthrough-in-determining-risk-for-heart-attacks/

    Unfortunately I could not find the referenced study on PubMed.

    If that is the case, then what is the specific mechanism that causes the calcification? I found this paper referenced on Peter Dobromylskyj’s blog (Hyperlipid…. been following it for a while now, http://high-fat-nutrition.blogspot.com/):

    https://www.ncbi.nlm.nih.gov/pubmed/17606264?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

    I think it provides some clues. And would confirm what Ivor said in his Ketofest talk (wish I could have been there) about all heart disease patients also being diabetic!

    Another question is how nutrients like vitamin K2 and its heart-protective role tie into all of this. Here is one interesting paper I stumbled across: https://www.ncbi.nlm.nih.gov/pubmed/28134400

    I think a lot more research needs to be done in this area. As Peter of Hyperlipid often points out, everyone has been off on a wild goose chase trying to pin this on lipoproteins! Remember, it is only the purple spotted small dense LDL that are the culprits! 😉

    1. xtronics

      There is great debate if calcified plaque is more dangerous that soft plaque. Some believe that statins do their little bit of good by promoting calcification.

      I think the amount of plaque is a good indication of the amount of disease – but doing things that reduce the calcification may or may not do net good.

      I take K2 – it is a hunch – I know I don’t know if it does net good.

      But if we look at CAD as 2 things – what causes it – how to prevent the cause. And what to do once we have significant damage – as separate issues – things make a little more sense. But as someone that has skin-in-the-game and has read huge piles of papers – one thing is clear – what the medical community thinks they know is full of false narratives – we actually know very little. There is no end of people pushing narratives for their egos, money, selling supplements ..

  3. C

    Here is a new study (August 2017) that further expands on the association between MGP, insulin and arterial calcification here: https://www.ncbi.nlm.nih.gov/pubmed/28654853

    Unfortunately, the actual paper is behind a paywall.

    They used HOMA-IR to estimate insulin resistance (I don’t know why they didn’t use the Kraft assay, which measures actual insulin resistance and is not dependent on a glucose variable). FYI, here is a convenient calculator for the simple HOMA-IR metric: http://www.thebloodcode.com/homa-ir-calculator/

    1. Siobhan Huggins

      Thanks for the link! I took a look through the study and to be honest it’s not altogether surprising (with what I know about insulin resistance and heart disease, and severity of atherosclerosis and calcification), but it does provide a hint as to where to begin with looking deeper into it.

      I agree about the kraft assay, as well. I wish people would use it more often (especially in studies like this), but I am betting it will catch on the more time goes on.

  4. xtronics

    Exactly why do you see the correlation of cholesterol with atherosclerosis seen as causation?

    How do we know that the arrow of causation isn’t the other-way-round? (CAD causes an immune reaction that causes LDL to go up? ) or many other possibilities.

    First, we need to know what we don’t know – anyway – correlations don’t show cause and effect. If we look at the long list of drugs that reduce LDL and yet don’t effect mortality – one has to assume that it isn’t causative. Only statins have an effect – a very small effect – (NNT 83 over 5 years) – but satins do more than lower LDL – they increase NO and might stabilize plaque by increasing calcification.

    I would suggest reading Malclm Kendricks writings before accepting the ungrounded narratives about LDL and CAD.

    1. Siobhan Huggins

      Hi, and thanks for the comment!
      Actually – I completely agree with you. I don’t think LDL (or modified LDL) is a root cause for atherosclerosis. I don’t even think native LDL contributes much (if at all) to the pathogenesis of the process, just based off of what I have learned so far.
      I merely have observed, based off of the evidence I’ve seen (e.g. studies, textbooks, etc), that modified LDL has a mechanistic role in the development of atherosclerosis.
      I realize that the title of the podcast of the episode may be rather misleading, but I do address in the episode, at the end, that I think the root causes are likely similar to the ones that Ivor Cummins outlines and if you want to get more specific – sources of chronic levels of oxidative stress. After all, you can’t have modified LDL without something to modify it 🙂

      Also, I think it is important to note that I am specifically referring to the development of lipid pools, plaque, etc, not heart disease as a whole – there is a bit of a difference there. I refer specifically to this small part of the process of the disease because that is what I heard about most often – and thus was most interested about.

      I also think it is an excellent point about all cause mortality. It does provide us quite a big hint when statins – which do effectively lower LDL – only reduce absolute risk of an event by 1%. I have also seen a trial involving lowering inflammation via drugs with almost the exact same result. That gives us a good hint that something else is going on and these methods are not addressing root causes. I think it very wise to check out all cause mortality when a study claims to lower risk of something – it is not much use if the mortality is the same just from a different cause, don’t you agree? 🙂

      Again, thank you for the comment! I am familiar with Dr. Kendrick, although I will admit I haven’t read the entirely of his beast of a series – haha! What I have read so far is quite insightful, however.

      1. xtronics

        As far as “modified LDL” – what ever that is – first LDL is not a single thing – it is a class of lipoproteins – an interesting subclass is oxLDL.

        If we consider oxLDL an important type of modification – we can then ask what changes the level of oxLDL? Turns out eating PUFA increases it – probably because they have double carbon bonds that are less stable than the single bonds found in Sat-fats. We also know that dietary polyphenols seem to lower oxLDL (but too much polyphenols isn’t good for us – no definitive studies for optimal dosages )

        So why does this matter? Turns out that macrophages have a receptor that responds to this oxidative bit – causing it to engulf oxLDL – as if it was a dead or dying bacteria. If this macrophage is in the wall of an artery – it can grow so full of oxLDL that we call it a foam cell – that can go on to crimp off the blood flow.

        I have looked an have not found any paper that shows LDL as a risk factor if oxLDL is held constant. But I still don’t think that even oxLDL is the initial cause of CAD. May be quite important in managing the disease once the damage is there.

        It also appears that a diet very high in PUFA causes inappropriate insulin sensitivity of adipose tissue – inducing weight gain. I think the promotion of veg oil may well be the smoking gun in the obesity pandemic. See health effects of different fatty acids
        ,.,.,

        There is another false meme implanted in the public brain – that HDL is good – first, it looks like there are about 100 types of HDL – some types seem to increase CAD. There was a drug under development that increased HDL – they stopped the study when the death rate got to high. My hunch is a general HDL level reflects the amount of sat-fat in the diet.

        So again – I warn people to ignore the false narratives – focus on experimental papers – ignore the observational – correlative papers – ( correlations can not show causation ) . Most of what people(and sadly MDs) think they know about heat-disease is based on ungrounded narratives.

        1. Siobhan Huggins

          You are correct in that the term “LDL” is a class – “modified LDL” refers to detrimental modification that can occur to this class (VLDL, LDL [phase], etc), this modification can mean a change in apoB (such as what occurs during glycation), a change in the fatty acids (such as PUFA oxidation as you mention), a change in the cargo (such as oxidation of the cholesterol e.g. production of oxysterol), and quite a few other things. Generally when modified LDL is mentioned it refers to oxLDL – but not always. Modified LDL, including but not limited to oxLDL, is recognized by scavenger receptors. Because it isn’t only oxLDL – but also glycated LDL, acetylated LDL, etc – that is recognized by scavenger receptors etc I found it appropriate to use the more generic term used in the literature.

          While I agree that it is important that oxLDL (et al) increases foam cell formation, but I would have to disagree that it “crimps off blood flow” once engorged with cholesterol the macrophages migrate deeper into the artery wall (within the endothelial layers), and if there is significant foam cell formation the artery will undergo reconstruction to ensure that the flow of the artery remains unimpeded. It is only much, much, much later that actual flow is disturbed by the process.

          Agreed, I have likewise not found any evidence that LDL – in itself – is a risk factor for heart disease.

          It has also been shown pretty well that too much PUFA does seem to contribute to oxidative stress, and it might indeed be a very big contributor. I think it’s also important to note that it isn’t the only contributor though. Glycation (e.g. from chronic levels of high blood glucose), smoking, and many other factors also likewise lead to an increase in oxLDL (or modified LDL). The root cause of heart disease would thus not be oxLDL, which is merely a byproduct of disruption, but rather the source of the oxidation (which Ivor Cummins often highlights). In my view anyway.

          You also make a good point that HDL isn’t necessarily good per se, and it does indeed have many functions. It is a very variable thing that changes often (functionally and physically, e.g. through swapping apolipoproteins, etc) and wears many hats. I agree that blindly labeling it as “good” is an over simplification, in order to understand its role in heart disease we must understand what it is doing exactly and what other roles it has.

          Lastly… I think observational studies do have their role – showing noncorrelation for example – and they can help us figure out where to look next. But as for drawing conclusions on anything I agree they aren’t much use as there are too many confounders that simply can’t be controlled very well.

          Thank you for the comment! You make many good points 🙂

          EDIT: Just curious, but have you read my post here on the blog? I cover a few points you mentioned in depth and you might find it interesting. A quick link to it: plaque.2keto.com

          1. xtronics

            Actually foam cells do swell the intima of artery walls – constricting flow – not a ‘good-thing’. These bumps are likely locations of clots forming – blocking the artery ( if you don’t like the word “crimping”)

            oxLDL is actually several things – and there is what they call doubly oxidized LDL – once oxidized it appears to be able to change more. Glycation complicates the picture further. Lp(a) – LDL with APO(a) added – can also be oxidized. Understanding that the recommended consumption of PUFA increases the level of these products should give us pause – and good reason to question the authorities that made these blanket pronouncements.

            My point about correlative vs experimental science stands – correlations give us good reasons to do careful experiments – but drawing conclusions and basing narratives on such things would make Karl Popper turn in his grave. Such papers are the inductive phase of science – and should not be misused to claim causation.

            Also – There really isn’t such a ‘thing’ as insulin resistance. Different tissue has different sensitivity for a wide range of reasons. What matters is not the sensitivity but the combination of sensitivity and insulin level.

            A couple of pedro’s factoids

            Liver becomes insulin resistant first, muscles second, adipocyres last.
            Insulin levels in the obese remain about 10 times those of a normal person even under complete starvation.

            ,.,
            One HAS to be a bit insulin resistant to lose weight!

            More of my messy notes on insulin here

            ,.,.
            One has to wonder why plaque only seems to form near the heart – where stresses from the reflected pressure wave meeting the primary pressure wave collide? Is it faulty elasticity of the collagen in the outer tunica? Related to the vit-C link? If LDL was causative – why only these arteries?

            My hunch – and I have a good feel on what is not known – is that it is only oxLDL that matters – after the initial damage. Is this initial damage the result of elevated insulin?
            http://onlinelibrary.wiley.com/doi/10.1002/hep.510290632/full
            A period in youth with low vit-C?

            What is clear is we don’t know – and it bothers me that so many know more than is possible. There are no end of bloggers willing to tell others how to prevent CAD based on some ungrounded narrative. This is not helpful.

            I come from a family of MDs – and medicine does a good job dealing with mechanical problems – they can sew up cuts – pin bones together – fix knees – open plugged up bits, but most of internal medicine is a lot of hand waving about ultra complex systems. Very few things I think we know with confidence – I think we know that elevated BG harms – we know replacing missing thyroid helps (but don’t really have definitive research on the optimal treatment – just T4 or T4+T3 – and thyroid is much more complex than what they teach in med school ) ..

            What we clearly don’t have clear answers to is why some people get CAD and others don’t. What is causative? What is merely complicating ( as I suspect oxLDL is ). What is the direction of the arrow of causation assumed from a correlation? To tell a patient an ungrounded narrative – in that calm voice – seems very wrong to me. It takes longer to tell them you don’t know – the patient wants their MD to know – might change MDs to find someone that will tell them sweet little lies.

            It is easier to keep the grant money flowing with cheap correlative studies that don’t challenge the prevailing narrative.. Experimental work can be expensive and politically dangerous.

    2. C

      I have also been following Dr. Kendrick’s blog…. his latest posts have been phenomenal! Great stuff…

  5. C

    Hi xtronics, love your fatty acids page.

    One question I have regards the peroxidation of linoleic acid stored in adipose tissue when a person loses weight. Studies have shown the linoleic acid content of “fat cells” skyrocket over the last 50 years (see http://advances.nutrition.org/content/6/6/660.full.pdf).

    When linoleic acid is oxidized, because of its double bonds it releases all sorts of nasty stuff, like aldehydes, 4-HNE, etc (see list here: http://www.cyberlipid.org/perox/oxid0009.htm).

    Some of these compounds are known to cause serious inflammation resulting in cancer, probably heart disease, etc.

    If an obese person decides to lose weight and burns their fat, do they increase their risk of these diseases through linoleic acid peroxidation and the release of these dangerous compounds?

    I believe that Peter of Hyperlipid may have hinted at this in one of his excellent blog posts, but I haven’t found anything in detail about this. If it is the case, it seems that those people are damned if they do, damned if they don’t!

    1. xtronics

      PUFA – and particularly LA gets concentrated in adipose tissue – and when someone loses weight – it comes out and can yes – I suspect it might do harm. On the other hand – being overweight long term appears harmful at some level. I don’t think we have a clear picture on how the risks balance.

      That these fatty acids effect insulin sensitivity – and are thought to have a 600-day half life is sobering..

      Yes – Pedro has hinted a bit – but there is a huge lack of definitive studies – he seems reluctant to speculate like most of the bloggers.

      It is a lot easier to get a grant for some cheap observational study rather than experimental science.

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