What causes heart disease – part 67 – The Blood Brain Barrier

10th November 2019

The Blood Brain Barrier

Here I am going backwards in time and space to try and explain, from a different angle, a fundamental problem with the LDL/cholesterol hypothesis. In doing so I hope to again make clear why I am certain the entire process of cardiovascular disease (CVD) requires a complete re-think.

In a medical school long, long ago, on a planet far, far, away, I was part of a small group teaching session on cardiology… Aberdeen 1980, actually. I have mentioned this event before, a critical moment in my life. The tutor was Dr Elspeth Smith, who was researching heart disease at the time. Research that, to my chagrin, I knew little about until several years later, when I began more detailed research into cardiovascular disease.

At one point in the tutorial, Dr Smith stated that LDL (low density lipoprotein) cannot get past, or through, the endothelium. At that time, I hadn’t much of a clue what LDL was, and very little idea about the endothelium. However, something about the intensity of her comment created an itch, one that I have spent very nearly forty years scratching.

I say this because, if LDL cannot get past the endothelium, then the widely accepted, and supposedly primary causal mechanism of heart disease, must be wrong!

Just to remind you that the central mechanism underpinning the ‘cholesterol hypothesis’ has always been that LDL leaks out of the blood past, or through, the endothelium, and into the arterial wall behind.

This then stimulates a whole series of downstream processes whereby you end up with thickenings in the artery wall narrowing the artery – known as atherosclerotic plaques. The higher the LDL level, the faster the leakage? I put a question mark there, because I don’t think I have ever seen this stated explicitly – I suppose it is implied as self-evident.

Clearly, however, if LDL cannot pass through the endothelium – the single layer of cells that lines all artery walls – then the ‘cholesterol hypothesis’ is a busted flush. Which is sort of interesting in a ‘hold the front page’ sort of fashion. ‘LDL hypothesis completely wrong – shock horror.’ Dr Elspeth Smith explains that LDL cannot get through the endothelium. Experts around the world, agree, and look for other explanations for heart disease.

This is a headline that I must have missed.

At this point you may be thinking, how do we get from LDL, and the endothelium, to the Blood Brain Barrier (BBB), which is the title of this blog. Well, are you sitting comfortably? Then I shall begin, at the end, with the blood brain barrier itself.

All doctors are taught there is a barrier between the bloodstream and the brain called the Blood Brain Barrier (BBB). Very few know what it actually consists of, other than that there is a barrier, of some kind, that prevents various things from entering the brain at will.

A barrier between the blood and the brain is critical because the brain is a highly delicate organ, which copes very badly with noxious substances, such as bacterial toxins. Which makes the BBB essential for life. However, it can become a problem if you have, for example, a brain tumour and the doctors want to give you chemotherapy. Because most anti-cancer drugs cannot get past the BBB. Some drugs can, most can’t.

However, a certain number of things must enter our brains, or we would almost instantly die. Glucose, for example. If our brain cannot get enough glucose, we go into a coma, then die. We also need amino acids (the building block of proteins), some fats and vitamins and suchlike.

Clearly, therefore, the BBB needs to be a selective barrier. It must block some things, but allow entry – and exit – of those substances that are required for brain function. Ethanol from malt whisky, for example, distilled from glucose. Well it is essential for my life anyway – in moderation obviously … obviously.

At this point you may be thinking, we are getting further and further away from LDL and heart disease, but please bear with me on this, because it does all come together at the end.

Next question, what is the BBB? The answer is that it is comprised of endothelial cells that are tightly bound to each other, and have a strong support structure underneath called the basement membrane. This membrane keeps the endothelial cells wrapped even more closely, further protecting them from any possible disruption.

This ‘tight’ binding of endothelial cells means that anything that wants to get into the brain must first pass through an endothelial cell. As you may imagine, this is an extraordinarily complicated and tightly controlled process. Substances in the blood cannot flow down a concentration gradient and straight through an endothelial cell.

LDL, for example, can only enter a cell, if there is an LDL receptor on the cell wall. The LDL links onto the receptor and then LDL and the receptor (the ‘LDL receptor complex’) is dragged inside the cell in a process known as ‘endocytosis.’

It does not matter what the concentration of LDL in the blood is – without a receptor, LDL is unable to gain entry to a cell. If it cannot get in, it cannot pass through. This is why the concentration of LDL becomes very high in Familial Hypercholesterolaemia (FH).

In this condition there is a lack of LDL receptors on all cells in the body, so LDL cannot easily enter cells, therefore the concentration in the blood rises very high.

Proof, if proof were needed, that LDL cannot ‘escape’ from the bloodstream and find refuge in the artery wall, or any other tissue. No matter what the concentration in the blood. Osmosis and/or diffusion of LDL through any cell is biologically impossible.

Therefore, getting back to the BBB, for substances to move through the BBB they first must be ‘endocytosed’ and then need to be shuttled through the cell via an active transportation system. This is known scientifically as ‘transcytosis.’ Literally, transport through the ‘cytoplasm’ where cytoplasm is the name for the jelly-like substance that fills up cells.

Once the substance has been transcytosed through the cell it must be ejected out through the cell membrane on the opposite side. Another complex process known as exocytosis.

Not everything needs a receptor to enter a cell. However, nothing gets in without the cell controlling the entry and exit. Even individual ions (charged atoms), tiny as they are, must pass through ‘gates’, or channels, to get into a cell. Calcium, sodium, potassium etc.

Their passage is carefully monitored and controlled. If this were not the case, you would instantly die. If a cell loses control of its internal environment it is either dying – or dead. See under, hyponatremic encephalopathy (for those with a scientific bent).

It has been argued that LDL molecules do not need to pass through endothelial cells, they can simply slip through the ‘cracks’ between endothelial cells. I have seen this argument used as to why ‘small dense LDL’ can cause CVD because, in this form, it is small enough to get through the cracks between the endothelial cells.

The problem with this hypothesis is that, first, small dense LDL is almost exactly the same size as normal LDL. Second, and most important, there are no cracks, or gaps, between the endothelial cells in our arteries – or the BBB. Endothelial cells in large arteries are bound together very tightly indeed. They are linked together by zips, buttons, and super-glue, then welded to create what is called a ‘tight junction’.

You can Google ‘tight junctions’ under ‘images’ to see how complex they are. There are over twenty protein bonds, sealing any gap shut. Tight junctions are so tight that they, too, can prevent the entry and exit of single ions. So, there is absolutely no way through for LDL here, either. For a quick size comparison, if a human were the size of an ion, an LDL molecule would proportionately be around the size of a super tanker.

In short, the idea that LDL can simply leak through the endothelium and into the artery wall behind requires that several key mechanisms – required for life – do not exist.

As I hope you can now see, Elspeth Smith was quite correct. LDL cannot pass through the endothelium. At least it cannot pass through a healthy endothelium, and nor can anything else either. Unless, unless the endothelium enables its passage.

Complication number one – yes, there is always a complication.

As blood vessels get smaller and smaller, like the branches on a tree, the endothelium changes dramatically. As arteries shrink down to became arterioles, then capillaries, the endothelium is no longer an impenetrable barrier.

In these very small blood vessels, the endothelium develops holes (fenestrations). Gaps also appear between individual endothelial cells, and the supporting basement membrane becomes loose. What you have is more like a sieve than a castle wall.

This ‘sieve like’ quality allows substances to move in and out of arterioles and capillaries, almost at will. Which, of course, makes perfect sense. There is little point in blood arriving at, say, the kidneys, where various waste products are removed, if it was all stuck behind an impenetrable endothelial barrier. The blood would flow into your kidneys, then flow out again, unchanged. This is not a good recipe for life.

So, yes, in the very small blood vessels, the endothelium allows the free passage of substances. But absolutely not in the larger blood vessels. If the blood simply leaked out as it passed through larger blood vessels, it would never reach the smaller blood vessels, nor get back to the heart again. It would be like having a garden hose that was full of holes along its entire length. Nothing would reach the sprinkler head.

Anyway, bringing some strands together here, the endothelium lining the large arteries has the same impenetrable structure as the endothelium lining the BBB, and therefore represents a barrier. Substances just cannot leak through this – and that includes LDL.

But can things be transcytosed through? More specifically, can LDL transcytose through it? Because, if it can, this would be a possible mechanism in support of the cholesterol hypothesis. Although, once again, you have to ask the question, why would the body have a system for actively transporting LDL through the endothelium and into the artery wall underneath. What would be the purpose of such a system? To cause atherosclerosis?

The mystery of this question is further deepened by the fact that the larger blood vessels in the body are supplied with nutrients via their own, small, blood vessels known as vasa vasorum. Literally, blood vessels of the blood vessels. These are arterioles, and capillaries, that penetrate/permeate the vessel wall.

These very small blood vessels, lying within the artery wall, have fenestrations (holes) and loose junctions that allow the free movement of LDL – in an out of artery walls. So, any LDL in the bloodstream can quite easily enter the artery – and exit the artery (and the veins) – without having to cross any barrier at all.

Which raises a further conundrum for the cholesterol hypothesis. Why would LDL that enters the artery wall, via the vasa vasorum, cause no problems. Whilst the LDL – that is claimed to enter the artery wall by forcing itself past the endothelium – creates atherosclerotic plaques. Same artery wall, same LDL.

Which then raises another question. Why do atherosclerotic plaques only form in artery walls? Why not everywhere else, within every other organ and tissue in the body. If LDL, once it leaves the bloodstream, is so destructive, acting as the focus for plaque development, why doesn’t it cause plaques within the liver, or the kidneys, or the muscles, or the gut. Only, it seems, in artery walls. [Please don’t say xanthelasma, until you have thought very carefully about it]


But to get back on track. I wanted to see if I could answer a final question. We know that LDL cannot simply flow through endothelial cells, nor can it squeeze between non-existent gaps. But can it be actively transported through? Because, if it cannot, then this is the final nail in the cholesterol hypothesis. There is, literally, no way past. Elspeth Smith was quite correct.

[Other than via the vasa vasorum, obviously. However, veins have more vasa vasorum than arteries, so this if this is the route for LDL to enter blood vessel walls, then veins should have more atherosclerosis than arteries, which they do not. In fact, veins never develop atherosclerosis – ever.]

So, deep breath.

I wanted to know if LDL could get past the BBB. If not, then it could not get past the endothelium in the larger arteries either, end game. This is the sort of question to which you would think there should be a straightforward, yes or no answer. It took me a long time to find a definitive answer.

I did know that the brain manufactures its own cholesterol, because cholesterol is absolutely vital for brain function. Neurones are wrapped in myelin/cholesterol sheaths. New synapses have a very high proportion of cholesterol in them, and animal work has shown that – without cholesterol – new synapses cannot be made.

‘Brain cholesterol accounts for a large proportion of the body’s total cholesterol, existing in two pools: the plasma membranes of neurons and glial cells and the myelin membranes  Cholesterol has been recently shown to be important for synaptic transmission, and a link between cholesterol metabolism defects and neurodegenerative disorders is now recognized.’ 1

This ‘brain’ cholesterol is synthesized in support cells, known as glial cells. These cells surround neurones and nourish neurones, and the cholesterol is transported about in its own lipoprotein called Apo E.

So, on initial analysis, it did seem unlikely that the brain would have developed its own, specific, cholesterol manufacturing capability if it could simply absorb it from the bloodstream. As it turns out, and as I eventually discovered, the brain cannot absorb LDL from the bloodstream.

‘… the blood brain barrier (BBB) prevents the uptake of lipoprotein-bound cholesterol from the circulation.’ 1

In quick summary here, the brain requires cholesterol, yet the BBB prevents it from entering the brain. Which means that an intact endothelium can completely block the passage of LDL Which means that LDL cannot get past, or through, the endothelium. Elspeth Smith was quite right.

But what did she think caused CVD, or atherosclerosis, or atherosclerotic plaques – or whatever term is currently in vogue? Well, this is one thing that she wrote about the matter:

‘After many years of neglect, the role of thrombosis in myocardial infarction is being reassessed. It is increasingly clear that all aspects of the haemostatic (blood clotting) system are involved: not only in the acute occlusive event, but also in all stages of atherosclerotic plaque development from the initiation of atherogenesis to the expansion and growth of large plaques.’ 2

She believed, as I have been trying to outline for a few years now, that to start atherosclerosis, you need to damage the endothelium, then a blood clots forms, then we are on the pathway to the final occlusive thrombosis (a blood clot that completely blocks an artery).

She believed, as I believe, that LDL has no part to play in this process. It does not, because it cannot. If you believe in the ‘thrombogenic’ hypothesis, you cannot believe in the LDL hypothesis, and vice-versa.

Which hypothesis is correct?  Well, it is certainly true that the LDL hypothesis is currently in the ascendancy. But science is not, thankfully, a popularity contest like Strictly Come Dancing. Science is built on facts. Well, it is eventually. The fact is that the LDL hypothesis requires a central fact to be true but which can be proven to be wrong.

Elspeth Smith proved it to be wrong over fifty years ago, but no-one was listening. She was a hero, and I intend to do all that I can to ensure that it is her name, not that of Ancel Keys, that will echo through the history of CVD research. Because she was a true scientist. Whereas he….

Next time, why LDL also cannot damage the endothelium.

1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837572/#:~:text=The%20CNS%20cholesterol%20is%20transported,%2C%2039%20kDa)%20and%20lipids.&text=Lipid%2Dpoor%20particles%20(for%20example,ApoE%20levels%20in%20the%20brain.

2: https://www.sciencedirect.com/sdfe/pdf/download/eid/1-s2.0-0049384894900493/first-page-pdf

117 thoughts on “What causes heart disease – part 67 – The Blood Brain Barrier

  1. Jean Humphreys

    Thanks. Before I have even read it, but it is to keep track of the comments, which are such an important part of this community that you have created.

  2. sue anspach

    Thank you. This is so interesting. Makes me question again why I didn’t follow a medical career. Sue Anspach

    On Sun, Nov 10, 2019, 9:53 AM Dr. Malcolm Kendrick wrote:

    > Dr. Malcolm Kendrick posted: “10th November 2019 The Blood Brain Barrier > Here I am going backwards in time and space to try and explain, from a > different angle, a fundamental problem with the LDL/cholesterol hypothesis. > In doing so I hope to again make clear why I am certain the” >

  3. Göran Sjöberg

    Thank you for this great knowledge indeed – now, as always, “popularly” revealed on this blog!

    Do we need to doubt the “corruption” behind the resistance from the medical establishment to endorse such obvious science?

  4. Chris Morriss

    Wow! What an interesting and well-researched article.

    Quick question.
    Can LDL get through the endothelium if it is damaged by early-stage scurvy. such as might be the case if the diet is deficient in vitamin C?

    1. Stephen Rhodes

      What is the mechanism by which haemorrhagic viruses cause bleeding through the epithelium, and can this mechanism occur in chronic disease without causing fairly immediate fatality as in Ebola/Black Death?

      Does the mechanism involving zonulin which the body uses to ‘flush’ the bowel of bacterial infections by loosening tight junctions there, have any relevance to the epithelial tight junctions?

      1. Dr. Malcolm Kendrick Post author

        Exotoxins can directly attack the endothelium and cause problems. For example, in meningococcal septicaemia, death is due to endothelial damage, widespread coagulation (disseminated intravascular coagulation) DIC. Many/most infectious agents target the endothelium.

    2. Paola

      @Malcolm , what about apoE4 genotype?
      APOE variant, is known to raise levels of circulating cholesterol, particularly low-density lipoprotein (LDL) and they say it raises the risk for Alzheimer and heart disease.
      How is it possibile, if Ldl can’t pass the endothelium?

      1. The New Neander

        There is no strong evidence that carriers of “ApoE”, ApoE isofrom e4/e4 and e3/e4, have higher LDL Cholesterol (LDL-c).
        “among the Framingham cohort study with a large number of participants, LDL Cholesterol is the same in ApoE isoforms e4/- carriers and in the isoform e3/e3 carriers.”
        “Elosua et al.(1), who investigated the association of APOE genotype with carotid atherosclerosis in men and women in the large Framingham Heart Study, concluded that “APOE4 genotype was significantly associated with a higher ICA IMT (carotid intima-media thickness) only in diabetic men” https://nneandersphysiologicalliteracy.wordpress.com/2019/05/16/debunking-rhonda-patrick-phd-on-apoe4-apoe-e4-and-ldl/

      2. Paola

        I agree with you .
        But I suspect that Apoe story is used to scare people and to justify the cholesterol theory and statin madness.

    3. JDPatten

      It’s understood that normal constituents of blood include LDL. Also, the cell wall of red corpuscles is largely made up of cholesterol. So, when a clot is formed at an injury site – such as arterial endothelium damaged by sickle cell disease, rampant high blood pressure, whatever – and when that clot is then covered by new endothelial cells by the endothelial progenitors always circulating with the other blood constituents, a certain amount of cholesterol will be found in that clot which is now situated within the arterial wall.
      It’s not that LDL gravitates to the site, it’s just that it’s a normal blood constituent that’s there when that blood clots.
      Those progenitor cells also differentiate into macrophages that begin busily cleaning up the clot detritus.
      I think I have this right.
      Dr Malcolm?

      1. robertL

        Excellent summary of what I have learnt from all 67 Heart Disease lectures by “our” Doctor

        And thank you Doctor K

  5. Mr Chris

    Great stuff
    Why if Elspeth Smith taught this 50 years ago, is it totally neglected now?
    Have their been any efforts made to demolish it as a theory?

    1. Tom Welsh

      Findings – even the most crystal-clear and indisuputable – are generally ignored if they don’t fit the prevailing paradigm.

      I think of scientists and doctors, in this respect, as being like birds building their nests. They pick up various bits and pieces of vegetation (and anything else), and fit them into the nest if there is an easy way to do so. Otherwise they discard them, and have immediately forgotten them.

      Cailtin Johnstone has brilliantly summed up this tendency, for instance here: https://caitlinjohnstone.com/2019/02/04/dissidents-must-understand-the-difference-between-fact-and-narrative/

      Roughly speaking, I think her view is that – psychologically speaking – narrative always beats fact.

  6. Lucie

    Thank you very much Dr Kendrick for this clear and evident explanation.
    Vladimir Subbotin has published in 2016 an interesting article you probably know about the way cholesterol enters the artery wall: URL=https://static1.squarespace.com/static/52faa95ee4b0b0a74811f732/t/576ed362b8a79bc10875b866/1466880934734/2016+Vladimir+Subbotin+Paper+-+ATHERO+.pdf

  7. Jennifer

    Many thanks again, Dr Kendrick. My brain followed your wonderful article by forming lovely coloured pictures of all the components in this fascinating explanation.
    As you are aware, over the years us mortals have been plagued by our blood profiles being (wrongly) interpreted by the labs, and ultimately pestered to take statins. I have mentioned that in this last year neither my endocrinologist or GP gave hinted at discussing lipid results deemed on the printouts as “outside normal limits”. Indeed my latest LDL measurement would have caused great consternation in years gone by, but not a mention this week. Interesting, eh?

  8. errett

    We humans seem to have a very strong penchant for thinking in analogies—a comparison between two things, typically for the purpose of explanation or clarification. Analogies often lead to insight, however they may obscure fine details. I enjoy your adventure in the sea of details.

    1. Dr. Malcolm Kendrick Post author

      Fatty streaks do not become atheroscelerotic plaques.

      The precursors of coronary atherosclerotic plaques in subjects up to 40 years old.
      Velican C, Velican D.
      The onset of coronary atherosclerotic plaques was investigated in 400 selected cases aged 1–40 years. During childhood the atherosclerotic plaques developed on their own, in preexisting branch pads or cushions. During adolescence the atherosclerotic plaques developed on their own, in both branch pads or cushions and thickened intimas. In young and mature adults the thickened intima became the main site for plaque histogenesis, whereas the role of branch pads or cushions decreased significantly. In mature adults incorporated microthrombi were accidentally involved in plaque development. In both branch pads or cushions and thickened intimas the atherosclerotic plaques developed through several stages including: histolysis, followed by nodular proliferation of smooth muscle cells (prevalent during childhood), insudation (prevalent during adolescence), accumulation of lipid-filled and foam cells (prevalent during early adulthood) and necrosis (prevalent in mature adults). Likewise the coronary fatty streaks developed on their own, through several stages, from early to advanced lesions. We were unable to reveal the conversion of fatty streaks into atherosclerotic plaques the two types of lesions occurring as unrelated pathological processes.

    2. Samir Barahj

      I remember having read somewhere that “fatty” streaks have the colour of fat but contains none. De Lorgeril maybe (another contrarian, I know ).

    3. Samir Barahj

      The book I read about the fatty streaks not being fat (gobsmacking, isn’t it ?) is de Lorgeril’s “How to prevent myocardial infarction and CVA”, chapter 4 how do arteries shrink, the case of atherosclerosis.
      This chapter presents the theories on atherosclerosis and plaque formation.

      Unfortunately for many there is no English translation of this French book.
      The googlish for the appropriate section (excerpt, I corrected the ugliest translation errors,) :

      “The very early lesion, first, that some call the fat streak. What is that ? When performing autopsies, including on young people, babies, and even fetuses, we can observe fatty streaks. These are white streaks visible almost to the naked eye on the inner side of the artery. These streaks are not fat; they are infiltrates of white cells, the leucocytes. Why do we say fat when there is no fat? I do not know ! What are these leucocytes doing here? Since the leucocytes in question are repairers, we can assume that they are there to repair the artery which, during development, or because of the traumatisms of the arterial dynamic (pressures up to 200 mm of mercury), has need to be repaired continuously. Researchers have studied arteries taken at random from hundreds of rather young people who died of non-cardiac causes in Japan and the United States. They found on both sides of the Pacific exactly the same frequency, the same distribution, and the same morphological aspects of fat streaks. These fat streaks are therefore not a causal factor of infarction since the Japanese have very little heart attack and the Americans a lot! On the other hand, experimental models can reproduce these fatty streaks in arteries. French researchers have shown that by treating animals with female hormones (estrogens), fatty streaks could be removed. Estrogen – prescribed to women who are deprived of them i, are known to increase the risk of heart attack. These fatty streaks are therefore not (or little) involved in the infarction.

    1. mikeezeem

      Rather, try to keep blood pressure down – stress busting meditation & plenty of rocket & beets for Nitric Oxide production
      Maybe a bit simplistic but i’m trying it

      1. Tom Welsh

        Until we have better detailed advice, I would suggest:

        1. Eat and drink healthily. Plain animal and vegetable foods, unprocessed and home cooked. No extra sweeteners, no vegetable fats or oils, and if possible no grains. Eat once or twice daily, and if possible fast for at least 18 hours in 24.

        2. Sleep well. At least 8 hours (of actual sleep) per night on average – more is good. If you can sleep, you should. If you have had enough sleep, you cannot go to sleep.

        3. Enough exercise of any kind you like, from gentle walking though games like tennis and football to running, gymnastics, or even weight lifting. Probably a minimum of 2-3 hours walking per day is ideal, but less helps. Walk 20-30 miles, and you’d be amazed how few problems you have left. (Finding something to sit down on is the most important).

        4. Avoid mental and emotional stress (as far as possible).

        5. Avoid pollution as far as possible. (This is easily the hardest recommendation).

        In short, the best route to relative health is to get back as close as possible to the way of life for which our ancestors evolved through several million years. We have moved very far away from it.

  9. Charles Penrose

    Thank you Dr Kendrick
    Another entertaining and informative explanation in support of your Hypothesis
    I found your recent discussion with Ivor Cummins so engaging that I had to listed to it a dozen or so times, however one area of the whole Atherosclerotic process that I haven’t been able to understand or get my head around is how the plaque becomes calcified, i.e. at what point does calcium feel it has to join the party and why? If you could point me to one of your many blogs that explains this that would complete the picture for me.

    1. Dr. Malcolm Kendrick Post author

      Most areas of damage in the body become calcified over time. Scars turn white (due to calcuim deposition). Quite why the body ‘calcifies’ areas of damage is not clear. In the most extreme form people have myositis ossificans, a condition whereby damaged muscle turns to bone. As you can imagine, this does not end well. There is a strong relationship to a lack of vitamin K. Warfarin, which is a vitamin K antogonist, and used to prevent blood clotting, greatly increases the rate of calcification of atherosclerotic plaques. Vitamin K supplementation can reduce/reverse calcification. Whether or not calcification is a good thing, or a bad thing, is not entirely clear.

      1. robertL

        Hi Doctor
        I assume for clarity that you are referring specifically to vitamin K2 (menaquinones) rather than K1 the warfarin antogonist. Correct?

      2. rhhanson

        Your comment above about whether or not calcification is a good thing or bad thing caught my attention. I know you can’t answer medical questions, but maybe you can point me in the right direction. I’m 72 years old and about as healthy as one could be. My resting heart rate is around 54, my BP averages 115/75, I weigh the same as I did in high school, I sleep well and eat well, there’s no history of heart problems in the family for many generations back, and so on. I still climb mountains here in Colorado and push my heart very hard for hours at a time with no ill effects. On my own, after my sister told me she had a calcium score of zero, I decided to get my calcium score. I came out with a score of 1848! Everything I’ve read thus far says I should be very concerned. It just doesn’t make sense to me. Could you point me anywhere that might ease my concern? Of course, my doctor wants me to take statins but I want no part of them. Thanks.

      3. Sasha

        I understand this is a question for Dr Kendrick and I apologize for interrupting. But you may be interested in looking into Dr Ames’ Triage Theory. He proposes that living organisms will triage problems to prevent acute issues from arising. Calcification of an artery may be a defense mechanism to prevent artery bursting.

      4. Sasha

        Sorry, yes, I misspoke. According to Dr Ames, it’s a mechanism to maintain the integrity of the blood vessel. And, possibly, to stabilize the plaque. But if I remember correctly, he spoke primarily of preventing bleeding.

      5. robertL

        I think the Doc you want to reference is Dr Gerber who also hails from Colorado (outside Denver I think)
        He was, if my memory serves me correct, the doctor who says he has lowered his calcium score to zero. The key factors were vitamin D, Magnesium, and vitamin K2 (mk 4 and 7). This combo moves calcium from soft tissues (=bad) to the bones and teeth (=good).

        Ivor Cummins has a number of talks (youtube); 1 of which is about calcification.

        Don’t panic just yet.
        Apparently, the rate of change in the score is more critical than the score itself.

      6. JDPatten

        I’m 75. I had my CAC done a few years ago, just to be sure. It was 1640.
        As with you, everything else that might have indicated CVD – but for some rhythm issues – was perfectly fine.
        I’ve learned to question the “solid predictability” of CAC scores and I don’t let it worry me any more.
        Calcification can come on from various causes such as a past infection that might have attacked your endothelial cells systemically. There are any number of diseases that will do this. Just figure to yourself that calcification is probably the last phase of healing.

  10. Sue Mulkerrin

    Interesting post as I have wondered for some time if there could be a link between the high level of prescription of statins and the increase in dementia / Alzheimer’s. I am not from a medical background (trained as a physicist) but I had read that the brain requires a high level of cholesterol. Could statins be interfering with how the brain manufactures cholesterol?

    1. Anne Croucher

      I was prescribed Atorvastatin with Metformin when diagnosed with type two diabetes. After a month I was sure I had dementia. I ‘lost’ all my songs, and have had to relearn them, and walked around in a daze, did all the Christmas shopping twice, lost the car in the car park – I contemplated suicide, but then threw away the tablets and have slowly recovered.

  11. piperclassique

    Fascinating stuff. The complexity of the human body never ceases to astound me, and you manage to make it seem not simple, but at least comprehensible. I wish there was an endocrinologist around with your gift for teaching. Or, come to that, a cardiologist who read your blog.

    1. Tom Welsh

      As a fascinated but highly amateur and unqualified reader, I agree very strongly with your remark about the astonishing complexity of the human body.

      To the extent that, some years ago, I reached the personal conclusion that it refutes any theory of intelligent design. It seems to me that the body is so complex that it could not have been designed; it could only have arisen through negative feedback, applied mercilessly over millions of years. In short, we are alive only because trillions of previous creatures lived (more or less briefly) and died, so that only the unbelievably complex systems that usually survive are left.

      1. Martin Back

        We are bad copies of our forefathers, but were lucky enough to find an ecological niche where we could survive and procreate.

    2. Frederica Huxley

      Thank you for yet another thought provoking article. Where does LPa fit in, or is it yet another red herring?

    3. Chris Morriss

      I would be very surprised if some cardiologists didn’t read this blog.
      Perhaps they keep quiet about it though!

  12. Martin Back

    If small dense LDL was able to penetrate cracks between endothelial cells, surely the artery walls would become uniformly infused with cholesterol. There is no mechanism to explain why cholesterol would congregate in plaques in some places and be absent in others.

    1. Jerome Savage

      Almost managed to read this without backtracking. (The effect of years of statin abuse slowly wearing off)
      One thing did raise my curiosity, yours; “I wanted to know if LDL could get past the BBB. If not, then it could not get past the endothelium in the larger arteries either”
      But the BBB is the stronger defence system is it not ?

      1. Jerome Savage

        Martin – this was intended for the learned Doctor. That’s not to say you don’t hav an answer !

      2. Dr. Malcolm Kendrick Post author

        I don’t think that it is. However, I can’t really prove it. I just know that if you have endothelial cells with tight junctions, supported by a sub endothelial layer, they should act the same way. I have never seen any evidence that the endothelial cells lining the BBB are different, in any way, from the endothelial cells lining the larger blood vessels.

    2. philalethes2368

      Somewhere recently I read or saw in a video that the weak spots where injury occurs, and thus cholesterol “patcing” sets in is at the branchings of the blood vessels. A turbulence is created in the plasma flow and this vibratory hammering weakens the tight junctions.
      Another post above asks the question about low level scurvy and Vitamin C. According to the Pauling Rath thesis vitamin C is necessary for collagen to make up the web of tight junctions, and when we are low (less than 3000 mg daily C; but Pauling says animals our size would make on average 10 grams daily! so all of us are very low) . The tight junctions are weakened and that is how the barrier goes down.
      I asked Dr. K. before to comment on the Pauling-Rath thesis; did I miss his answer? If Pauling is right, the solution is simple. PLEASE comment Dr. K.

  13. Martin Hunt

    I try to follow with personnel interest [Apoe 3/4 and high cholestrol] and understanding your posts but purely by coincindence have also just finished reading the following–https://peterattiamd.com/heart-disease-begin-tell-us-prevention/ Quite confusing but would like to hear your thoughts?

    1. andy

      Martin Hunt: according to Peter Attia-
      “To reiterate: atherosclerosis development begins with plaque accumulation in the vessel wall, which is accompanied by expansion of the outer vessel wall without a change in the size of the lumen. Only in advanced disease, and after significant plaque accumulation, does the lumen narrow.”

      The confusing part is that there are at least two ways to initiate lumen narrowing with both possibly operating at the same time.
      BAD CHOLESTEROL HYPOTHESIS: a slow steady progression over decades > oxLDL, foam cells, tunica intima thickening, angiogenesis via vasa-vasorum, necrotic cores, smooth muscle cell migration, rupture of capillaries leading to plaque formation
      ENDOTHELIAL DAMAGE HYPOTHESIS: the quicker route to plaque formation initiated by loss of glycocalyx > apoptosis/necrosis of endothelial cells, coagulation factors, Lp(a), tunica intima thickening, angiogenesis, multiple plaque layers
      CELL VIABILITY HYPOTHESIS: loss of cellular energy (ATP) > the corn oil route to plaque formation, accelerated apoptosis of endothelial cells. Many factors can upset mitochondrial ATP production.

      Bottom line: no need for LDL particles to pass through the endothelium.

  14. errett


    Endothelial microvesicles (EMVs) have emerged as markers of endothelial injury. However, little is known about their levels in the coronary circulation of acute coronary syndrome (ACS) and stable coronary artery disease (CAD). We hypothesized that ACS patients exhibit a more pronounced increase of EMVs both in the peripheral and coronary circulation when compared with CAD. We also investigated possible associations of EMVs with markers preclinical target organ damage.

  15. repsort

    Elspeth Smith = true scientist.
    And so are you, Dr. K.
    If you’re ever going to find the right answers, you’ve got to ask the right questions.
    I love your questions.

  16. oservodabloga

    Hi Dr. Malcolm,

    If my counting is correct, on paragraph 32, where it reads “and the supporting basement membrane *because *loose”, it should be “and the supporting basement membrane *becomes *loose”.

    Thank you very much for your enlightening posts. I’m a Portuguese citizen living in Portugal living with a couple of stents. Contrary to medical prescription, 4 years ago, after the procedure to remove the clot and place the stents, I don´t take statins (just took it in the first month after the procedure) and whenever I visit the cardiologist, like last month, she says the cholesterol levels are fine (like they always have been, prior or after the procedure to remove the clot and place the stents).

    Best regards, Victor.

    Dr. Malcolm Kendrick escreveu no dia domingo, 10/11/2019 à(s) 09:53:

    > Dr. Malcolm Kendrick posted: “10th November 2019 The Blood Brain Barrier > Here I am going backwards in time and space to try and explain, from a > different angle, a fundamental problem with the LDL/cholesterol hypothesis. > In doing so I hope to again make clear why I am certain the” >

  17. Bev

    I’ve never seen anything more completely and beautifully explained! Thank you. My GP commented after my latest blood tests that my cholesterol had gone up. I said, “that’s good” and referred him to your blog.

  18. Vincent McCann

    Thank you for this brilliant post about how Malt Whisky is complimentary to endothelial cells, a silver lining and important note moving forward.

    I read a hypothesis before that the arteries get damaged (rather than arterioles, capillaries)_because this is where blood pressure is at it highest, therefor its simply a case of mechanical stress. Also, the Q above regarding scurvy and Vitamin C, this never seems to even make it into the conversation with experts, it is a complete dead end?

    Thanks for this blog, so much info and so well written that even us layfolk can understand it.

  19. Iman van den Bout

    Hi Malcolm

    Good article. In case you haven’t seen it, there is a nice little review in nutrition last year regarding inflammation and cvd https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986484/

    Also, teaching first year medical students I noticed that while I taught the metabolism of lipids and the transport of cholesterol throughout the body, in the exam half of them started waffling about bad cholesterol and good cholesterol. If I find out which lecturer taught them that… well a heated exchange would definitely follow. Anyway, these are descriptions or definitions I feel no right thinking scientist or medical practitioner should ever use. Cholesterol is cholesterol. It made me think that much of the problem is that people, including the educated and educators, use such bad terminology that it makes them forget how the system actually operates. They forget that it these are lipoproteins, complexes of proteins on membranes surrounding triglycerides with cholesterol in it. And they forget why ldl is different from hdl, but the reason they are different has nothing to do with the cholesterol in it. These problems are clearly huge since even medical students get it completely wrong. May I suggest that at some point you write a short blog on the transport of lipids and cholesterols again just to inform many readers of your blog what exactly we are talking about?

    1. Dr. Malcolm Kendrick Post author

      I agree. It is why I wrote two books. They both explain what cholesterol is, what lipoproteins are etc. I even explain what Lp(a) is, and how chylomicrons transport TGs and cholesterol directly from the GI system, via the thoracic duct, straight into the bloodstream, without passing through the liver. I did do a blog explaining how fat could not raise LDL levels, whereas carbohydrates could.

      P.S. I am not an inflammation fan. I call inflammation ‘healing’ which, I realise is not quite true. But with CVD, raised CRP etc. is a sign that there is underlying damage going on, and the inflammation is the healing response in action.

    2. Göran Sjöberg

      Iman, I agree!

      It is a sad fact to note this even among people who should know better.

      As far as I remember it was, some thirty years ago, a way for the medical establishment to “get out of the trap” when it was then irrefutably shown that HDL-cholesterol was “good” relating to CVD as they minted this nonsensical terminology “good and bad cholesterol” while there is for sure only one chemical type of cholesterol molecule. As a natural science researcher I loose my respect for the “medical science” when I come across things like this in their proclaimed medical “science”.

  20. peterlepaysan

    Blood clearly gets through the brain. The barrier is clearly an inexplicable (again) medical anomaly..
    OBTW the brain does need glucose to function. It does very well on fats, ask anyone on a ketogenic diet.Espicially epiliptics.

    1. Dr. Malcolm Kendrick Post author

      I presume you mean that the brain does NOT need glucose to function. Sorry, but that is not correct. It can use ketones for a majority of energy requirement, but not entirely. Without glucose, your brain will stop functioning and you will die. This is simply, a fact.

      1. Lucie

        I am sorry to contradict you but some researchers such as Ben Bikman think that the human brain might not need glucose at all once keto-adapted. I understand that so far there has been no experimental data available proving either hypothesis.

      2. Dr. Malcolm Kendrick Post author

        Sorry, but I think this is not sensible. We know, beyond a shadow of doubt, that if the blood glucose level drops too low people enter a coma and die. You can be as keto-adapted as you like, but the blood glucose level will remain at a level sufficient to keep us alive – a level within ‘normal’ limits. When you break down triglcyerides for energy you will release a glycerol molecule. Glycerol is converted to glucose in the liver. So, even if you are feeding purely on fat, you will have glucose being released, sufficient to run those parts of the body that require glucose. I would suggest that no-one attempts to experiment on this area. Get a keto-adapted person, then drive their blood sugar down to zero. I suspect I know exactly what would happen. They would die. There is no experimental data available proving this hypothesis, because the proof would entail killing people. There is no experimental data proving that parachutes prevent death after jumping out of an aeroplane, for pretty much exactly the same reasons.

      3. chris c

        I understood that cells too small to contain mitochondria, such as the pointy ends of neurons, are the ones that depend on glucose. That’s why the body has several systems to increase blood glucose but only one to decrease it.

    2. Samir Barahj

      The brain uses glucose and ketones , he does need glucose, but evebn on a zero carbohydrate ketogenic diet, the body manufactures glucose (dextrose) : neoglucogenesis. Glucose blood levels are low but sufficient.

  21. Kate

    What a brilliant blog. Thank you. I love how you write, so rigorously academic and yet so light-hearted, assuredly simple despite the complexity of the topic and always with humour and a degree of the dour Scot, self-deprecation at its most charming. I love it. Thank you.


    Kate Berkeley registered Nutritional Therapist and Functional Medicine Practitioner DipION, AFMCP, mBANT, CNHC Kate Berkeley Nutrition Green Farm Edwards Lane White Ladies Aston Worcestershire WR7 4QF

    07971664106 http://www.kateberkeley.co.uk


  22. Martin Back

    Presumably arteries constantly suffer little nicks and scratches in the course of daily life. So there will always be a range of small plaques, some growing at new nicks, and some healing at older nicks which are healing successfully.

    Is this picture correct, i.e., if you autopsy a healthy individual, will you find these arterial plaques that cause no problems?

    1. Gary Ogden

      Martin Back: I don’t remember where, but I have read of reasonably healthy people dying of old age, rather than CVD, with one or more cardiac arteries completely blocked. They must have had well-developed collaterals.

  23. Jürgen Wildhardt

    “She believed, as I have been trying to outline for a few years now, that to start atherosclerosis, you need to damage the endothelium”.
    Seems very conclusive, since it is impermeable for LDL.

    So the really interesting question is:
    what damages the endothelium in the first place?
    Oxidative stress?
    Weak cell membranes because of certain highly oxidizable PUFAs in it?
    Maybe the combination of the three.
    What’s your opinion?

    1. Dr. Malcolm Kendrick Post author

      Please my previous 66 blogs. I have outlined a number of the factors that damage the endothelium. Lead, smoking, air pollution, raised blood glucose, rheumatoid arthritis, angiotensinogen, cocaine, Kawasakis disease, VEGF-inhibitors, bacterial exotoxins, PPIs, lack of vitamin C, hyperhomcystenaemia, etc. etc. etc. etc. As for oxidative stress, if someone can tell me what this is – exactly – I will be most grateful. All animal life requires oxidative stress to function. Unsurpisingly, all animal life has worked out a millon ways of dealing with the free radicals produced by oxygen. In fact, the molecule that is most protective for the endothelium, and overall cardiovascular health, is Nitric Oxide (NO). A highly reactive ‘oxygen’ free radical. As far as humans are concerned, oxidation is perfectly healthy. The entire oxidative stress hypothesis came about because plaques contain ‘oxidised’ LDL (actually oxidised Lp(a)). The reason for the oxidation is that macrophages fire a super-oxide burst at ‘alien’ materials to both kill them (if they are a virus or bactetria) and also to allow them to endocytose the alien material. Oxidised lipoprotein remnants are a sign that the body has been trying to clear up the area of damage.

      1. Gary Ogden

        Dr. Kendrick: Thank you very much for that explanation. We have hope if our macrophages can endocytose plaques. I suppose this can happen unless they get too big or calcified.

  24. Robert Bramel

    If the “leaking endothelials” hypothesis were correct then HDL particles must all leak out in the first few centimeters of blood vessels. The graph I’m viewing shows the biggest HDL is less than half the diameter of the the smallest LDL (100 A vs. >200 A). On the other hand, if even the smallest HDLs don’t leak out (60 A) it seems there’s no way for giant LDLs to “leak”.

  25. andy

    Dr. Kendrick: arteries, veins and LDL hypothesis
    Hydraulic conductivity and low-density lipoprotein transport of the venous graft wall in an arterial bypass
    “Autogenous vein (e.g., the greater saphenous vein) segments are widely used in vascular bypass surgery to relieve arterial occlusion. Nevertheless, when implanted into the arterial system as grafts, veins will develop a rapidly progressive and structurally diffusive form of atherosclerotic lesions which has been termed as “accelerated atherosclerosis” [1, 2, 3, 4], and this has become the major cause of venous graft late failure [5, 6].”

    Vein tight junctions are not very tight compared to arteries. Appears that high blood pressure canl force LDL particles into sub-endothelial space. Oxidized LDL then becomes driving factor for plaque initiation.

    1. Dr. Malcolm Kendrick Post author

      Sorry, but high blood pressure forces LDL particles into the sub-endothelial space? How does high blood pressure do this? [When I say that veins never develop atherosclerosis, perhaps I should have added, unless they are forced to act as replacement arteries]. As for vein ‘tight junctions’ not being very tight compared to arteries – do you have any support for this statement?

  26. chris c

    The blood brain barrier is obviously what keeps reality out and thoughts in. See Twitter for details.

    Seriously though this is a particularly awesome post.

    1. Gary Ogden

      chris c: Indeed so, an awesome post. I would add that our politicians, in both the U.S. and UK, have a BBB made of thick lead, allowing nothing at all in.

  27. Stuart

    If LDL is unable to cross the BBB and all that vital cholesterol has got to be synthesised in the brain itself then surely interfering with that synthesis with a statin is going to be bad for your brain cells. I have to wonder whether the epidemic of Alzheimer’s we are facing today and a whole host of demyelinating diseases like multiple sclerosis and ALS is a direct result of the widespread dosing of the population with statins. Plus the way statins block the production of a whole host of downstream hormones including estrogen, testosterone, Vitamin D and CoQ10, leading to muscle & bone loss and probably heart failure among other effects.

    IMO the medical profession and pharmaceutical industry have been recklessly carrying out a massive uncontrolled experiment on the population at large and we are now seeing the long-term consequences of that.

      1. Jean Humphreys

        Dear Dr Kendrick,
        I am glad to hear that you believe that statins cause neurological damage. I beg to go one better than you – I KNOW that they do from personal experience. I am still living with a certain amount of hangover. But what do I know? I am merely an uneducated person who has not been trained to respond like Pavlov’s dogs. When they train more curious and thoughtful people to be doctors, and desist from squashing their questions, we shall all be better served.

      2. Jerome Savage

        And if I can go another step, was speaking to a professional type who insisted on quitting statins some years ago, he fully believed that they contributed to depression. Alcohol certainly not a factor, active & sporting.
        I assume the statins were prescribed as a precaution.

  28. menlo

    I’m officially confused about LDL.

    This blog post from Peter Attia, MD suggests that those of us with high LDL-C are doomed to an early death: https://peterattiamd.com/191110/ (Interestingly, it ties together LDL-C and blood pressure.) I know from other posts and articles that Dr. Attia views high LDL-P as the primary contributor to cardiovascular disease (as I understand his writings; I have no science background).

    If anyone with a research or science background can comment on the Attia article, I would greatly appreciate it.

  29. Stuart

    It is well-known that diabetes causes damage to the artery walls as well as damage to the kidneys. Mike Eades writes about a RCT in Pakistan where they treated patients with diabetic nephropathy (kidney failure) with thiamine:

    One of the characteristics of kidney failure is high levels of protein in the urine. Diabetics are known to be low in thiamine. The researchers treated 20 patients with 300 mg/day of thiamine for 3 months, followed by a 2 month wash-out period. The results were spectacular – 7 of the patients had their urinary protein return to normal levels and ALL of the other 13 in the treatment group saw their levels improve, whereas only a few of the control group improved. Clearly the thiamine was enabling healing of the endothelial lining of the kidney tubules.

    Given that the endothelial lining in the kidneys is an extension of that of the blood vessels, might thiamine supplementation also help heal the lining of the veins and arteries?

  30. Jennifer

    Response to Chris C and Gary Ogden.
    My ancient A & P book (last published in 1987) states that erythrocytes do not contain mitochondria.


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